SECTION 2.7 CLINICAL SUMMARY Section 2.7.5 — Literature ...€¦ · antiretroviral therapy regimens is not observed more frequently: a cohort and case-control study. J Acquir Immune

SECTION 2.7 CLINICAL SUMMARY

Section 2.7.5 — Literature References

EMTRICITABINE/RILPIVIRINE/ TENOFOVIR DISOPROXIL FUMARATE

FIXED-DOSE COMBINATION

Gilead Sciences International Limited

18 August 2010

CONFIDENTIAL AND PROPRIETARY INFORMATION

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Section 2.7.5 Literature References Final

CONFIDENTIAL Page 2 18AUG2010

2.7. CLINICAL SUMMARY

2.7.5. Literature References

1469 Mulato AS, Cherrington JM. Anti-HIV activity of adefovir (PMEA) and PMPA incombination with antiretroviral compounds: in vitro analyses. Antiviral Res 1997Nov;36 (2):91-7.

1574 Robbins BL, Srinivas RV, Kim C, Bischofberger N, Fridland A. Anti-humanimmunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine(PMPA), Bis(isopropyloxymethylcarbonyl) PMPA. Antimicrob Agents Chemother 1998 Mar;42 (3):612-7.

2190 DeGruttola V, Dix L, D'Aquila R, Holder D, Phillips A, Mounir A-K, et al. Therelation between baseline HIV drug resistance and response to antiretroviraltherapy: re-analysis of retrospective and prospective studies using a standardizeddata analysis plan. Antivir Ther 2000;5 (1):41-8.

2226 Fischl MA, Richman DD, Hansen N, Collier AC, Carey JT, Pra MF, et al. The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildy symptomatic human immunodeficiency virus type 1 (HIV) infection. A double-blind, placebo-controlled trial. Ann Intern Med 1990;112 (10):727-37.

2520 Cihlar T, Ho ES, Lin DC, Mulato AS. Human renal organic anion transporter 1(hOAT1) and its role in the nephrotoxicity of antiviral nucleotide analogs.Nucleosides Nucleotides Nucleic Acids 2001;20 (4-7):641-8.

3019 Clarke SM, Mulcahy FM, Tjia J, Reynolds HE, Gibbons SE, Barry MG, et al. Thepharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz. Br J Clin Pharmacol 2001Mar;51 (3):213-7.

3854 Boelaert JR, Dom GM, Huitema ADR, Beijnen JH, Lange JMA. The boosting ofdidanosine by allopurinol permits a halving of the didanosine dosage. AIDS 2002Nov 8;16 (16):2221-3.

4249 Wilson JE, Martin JL, Borroto-Esoda K, Hopkins S, Painter G, Liotta DC, et al.The 5'-triphosphates of the (-) and (+) enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolane-5-yl]cytosine equally inhibit human immunodeficiency virus type 1 reverse transcriptase. Antimicrob AgentsChemother 1993 Aug;37 (8):1720-2.



4527 Paff MT, Averett DR, Prus KL, Miller WH, Nelson DJ. Intracellular metabolismof (-)- and (+)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine inHepG2 derivative 2.2.15 (subclone P5A) cells. Antimicrob Agents Chemother 1994 Jun;38 (6):1230-8.

4535 Furman PA, Davis M, Liotta DC, Paff M, Frick LW, Nelson DJ, et al. The anti-hepatitis B virus activities, cytotoxicities, and anabolic profiles of the (-) and (+) enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine.Antimicrob Agents Chemother 1992 Dec;36 (12):2686-92.

4620 Kaul S, Damle B, Bassi K, Xie J, Gale J, Ryan K, et al. Pharmacokinetic evaluation of reduced doses of didanosine enteric coated capsules (ddI-EC) in combination with tenofovir disoproxil fumarate (TDF) and food for a once-daily antiretroviral regimen [poster]. 4th International Workshop on ClinicalPharmacology of HIV Therapy; 2003 March 27-29; Cannes, France. Poster 8.1.

5024 Thio CL, Seaberg EC, Skolasky R, Jr, Phair J, Visscher B, Munoz A, et al. HIV-1,hepatitis B virus, and risk of liver-related mortality in the Multicenter CohortStudy (MACS). Lancet 2002 Dec 14;360 (9349):1921-6.

5040 Nasca MR, Micali G, Cheigh NH, West LE, West DP. Dermatologic andnondermatologic uses of thalidomide. Ann Pharmacother 2003 Sep;37 (9):1307-20.

5059 Food and Drug Administration/CDER Web site. Guidance for Industry: Antiretroviral Drugs Using Plasma HIV RNA Measurements - Clinical Considerations for Accelerated and Traditional Approval. October 2002.Available at: http://www.fda.gov/cder/guidance/3647fnl.doc. Accessed September29, 2003.

5467 Kaul S, Bassi K, Damle, Xie J, Gale J, Kearney B, et al. Pharmacokinetic (PK)evaluation of the combination of Atazanavir (ATV), enteric coated Didanosine(ddI-EC), and Tenofovir Disoproxil Fumarate (TDF) for a once-daily antiretroviralregimen [abstract A-1616]. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; 2003 September 14-17; Chicago, Ill.

5468 Robbins BL, Wilcox CK, Fridland A, Rodman JH. Metabolism of tenofovir anddidanosine in quiescent or stimulated human peripheral blood mononuclear cells.Pharmacotherapy 2003 Jun;23 (6):695-701.

5966 Roden MM, Nelson LD, Knudsen TA, Jarosinski PF, Starling JM, Shifflett SE, etal. Triad of acute infusion-related reactions associated with liposomal amphotericin B: analysis of clinical and epidemiological characteristics. ClinInfect Dis 2003 May 15;36 (10):1213-20.



5968 Moylett EH, Chinen J, Shearer WT. Trichosporon pullulans infection in 2 patientswith chronic granulomatous disease: an emerging pathogen and review of theliterature. J Allergy Clin Immunol 2003 Jun;111 (6):1370-4.

6042 Kaul S, Bassi K, Damle B, Smith R, Gale J, O'Mara E, et al. Lack of interactionbetween stavudine extended release formulation (d4T XR) and tenofovir disoproxilfumarate (TDF) [abstract]. 10th Conference on Retroviruses and OpportunisticInfections; 2003 February 10-14; Boston, Mass, USA. Abstract 534-W.

6043 Taburet AM, Piketty C, Gerard L, Vincent I, Chazallon C, Clavel F, et al.Pharmacokinetic parameters of atazanavir/ritonavir when combined to tenofovir inHIV infected patients with multiple treatment failures: a sub-study of Puzzle2-ANRS 107 Trial [poster]. 10th Conference on Retroviruses and OpportunisticInfections; 2003 February 10-14; Boston, Mass, USA. Poster 537.

6054 Ray A, Olson L, Fridland A. Role of purine nucleoside phosphorylase in drug interactions between 2',3'-dideoxyinosine and allopurinol, ganciclovir or tenofovir.Antimicrob Agents Chemother 2004 Apr;48 (4):1089-95.

6086 Gathe J, Podzamczer D, Johnson M, Schwartz R, Yeh V, Travers N, et al. Once-daily vs. twice-daily lopinavir/ritonavir in antiretroviral-naïve patients: 48-week results [poster]. 11th Conference on Retroviruses and Opportunistic Infections;2004 February 8-11; San Francisco, Calif, USA. Poster 570.

6113 The European Agency for the Evaluation of Medicinal Products. Committee forProprietary Medicinal Products (CPMP). Note for Guidance on the ClinicalDevelopment of Medicinal Products for the Treatment of HIV Infection. ReportNo. CPMP/EWP/633/02 draft. July 25, 2002.

6116 Kaul S, Bassi K, Damle B, Xie J, Gale J, O'Mara E, et al. Stavudine extendedrelease formulation (D4T XR) and tenofovir disoproxil fumarate (TDF): Lack of apharmacokinetic (PK) drug interaction [abstract]. 11th Conference on Retrovirusesand Opportunistic Infections; 2004 February 8-11; San Francisco, Calif, USA.

6180 Bica I, McGovern B, Dhar R, Stone D, McGowan K, Scheib R, et al. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis 2001 Feb 1;32 (3):492-7.

6181 Dore GJ, Cooper DA. The impact of HIV therapy on co-infection with hepatitis B and hepatitis C viruses. Curr Opin Infect Dis 2001 Dec;14 (6):749-55.

6266 Videx EC (SmPC). Bristol-Myers Squibb Pharmaceuticals. Hounslow. 06 January 2003.



6766 Gatell J, Lange J, Gartland J, The AVANTI study group. AVANTI 1: randomized,double-blind trial to evaluate the efficacy and safety of zidovudine plus lamivudineversus zidovudine plus lamivudine plus loviride in HIV-infected antiretroviral-naive patients. Antivir Ther 1999;4 (2):79-96.

6772 Jones R, Stebbing J, Nelson M, Moyle G, Bower M, Mandalia S, et al. Renaldysfunction with tenofovir DF containing HAART regimens is not observed morefrequently: a cohort and case control study [poster]. 10th Anniversary Conferenceof the British HIV Association (BHIVA); 2004 April 15-17; Cardiff, UnitedKingdom.

7034 Maggiolo F, Migliorino M, Maserati R, Rizzi L, Pan A, Rizzi A, et al. Once-a-day treatment for HIV infection: Final 48-week results. 8th Conference on Retrovirusesand Opportunistic Infections; 2001 February 4-8; Chicago, IL. Abstract 320.

7035 Felizarta F, Becker S, Bellos N, Jayaweera D, Sands M, Slater L, et al. Adherenceand efficacy with a once-daily efavirenz-based regimen: 48-week results from theDaily Antiretroviral Therapy II (DART II) Study [poster 5842]. XV InternationalAIDS Conference; 2004 July 11-16; Bangkok, Thailand.

7036 Arribas JR, Iribarren JA, Knobel H, Ribera E, Rubio R, Viciana P, et al.Adherence, treatment satisfaction and effectiveness of once-daily (QD) vs twice-daily (BID) antiretroviral therapy (AT), in a large prospective observational cohort(CUVA Study) [poster WePeB5780]. XV International AIDS Conference; 2004July 11-16; Bangkok, Thailand.

7374 Johnson M, De Jesus E, Grinsztein B. Comparison of Atazanavir (ATV) withRitonavir or Saquinavir vs Lopinavir/ritonavir in Patients with Multiple Virologic Failures: BMS AI424-045 96 Week Results. Long-term Efficacy and Durability ofAtazanavir With Ritonavir or Saquinavir vs Lopinavir/Ritonavir in HIV-InfectedPatients With Multiple Virologic Failures (Oral presentation PL14.4). 7thInternational Congress on Drug Therapy in HIV Infection; 2004 November 14-18;Glasgow, UK.

7380 Yeh V, Barros C, Easterbrook P, Lutz F, Naylor C, Luff K, et al. VirologicResponse to a Once-Daily Lopinavir/ritonavir (LPV/r) Based Regimen in ARV-Naïve Patients Is Not Associated with Trough Lopinavir Concentrations or Baseline HIV RNA and CD4 Count [Poster H-570]. 44th Interscience Conferenceon Antimicrobial Agents and Chemotherapy; 2004 October; Washington.

7625 Becker SL, Balu RB, Fusco JS, Fusco GP. Beyond serum creatinine: Identificationof renal insufficiency using GFR: Implications for clinical research and care [poster 819]. 12th Conference on Retroviruses and Opportunistic Infections; 2005February 22-25; Boston, Mass, USA.



7672 Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal functionassociated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis 2005;40 (8):1194-8.

7725 Harris M, Zalunardo N, Yip B, Werb R, Valyi M, Hogg R, et al. Nephrotoxicity oftenofovir DF in an expanded access program [oral presentation]. Presented at the12th Annual Canadian Conference on HIV/AIDS Research; 2003 April 10-13;Nova Scotia, Canada.

7871 Barrios A, Rendon A, Negredo E, Barreiro P, Garcia-Benayas T, Labarga P, et al.Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virussuppression taking tenofovir and didanosine. AIDS 2005;19 (6):569-75.

7987 Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function inpatients treated with Tenofovir DF (TDF) compared to nucleoside reverse transcriptase inhibitors (NRTIs) [abstract]. 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment; 2005 July 24-27; Rio de Janeiro,Brazil.

8056 Jones R, Stebbing J, Nelson M, Moyle G, Bower M, Mandalia S, et al. Renaldysfunction with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy regimens is not observed more frequently: a cohort and case-control study. J Acquir Immune Defic Syndr Hum Retrovirol 2004;37 (4):1489-95.

8057 Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accuratemethod to estimate glomerular filtration rate from serum creatinine: a newprediction equation. Modification of Diet in Renal Disease Study Group. AnnIntern Med 1999;130 (6):461-70.

8160 Negredo E, Bonjoch A, Paredes R, Puig J, Clotet B. Compromised immunologicrecovery in treatment-experienced patients with HIV infection receiving bothtenofovir disoproxil fumarate and didanosine in the TORO studies. Clin Infect Dis2005;41 (6):901-5.

8623 Karrer U, Ledergerber B, Furrer H, Elzi L, Battegay M, Cavassini M, et al. Dose-dependent influence of didanosine on immune recovery in HIV-infected patientstreated with tenofovir. AIDS 2005;19 (17):1987-94.

8715 Heffelfinger JD, Hanson DL, Voetsch AC, McNaghten AD, Sullivan PS. Renalimpairment associated with the use of tenofovir [poster 779]. 13th Conference onRetroviruses and Opportunistic Infections; 2006 February 5-9; Denver, Colo,USA.

9023 Winston A, Amin J, Mallon P, Marriott D, Carr A, Cooper DA, et al. Minor changes in calculated creatinine clearance and anion-gap are associated with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy. HIVMed 2006;7 (2):105-11.



9161 Moreno S, Domingo P, Palacios R, Santos J, Falco V, Murillas J, et al. RenalSafety of Tenofovir Disoproxil Fumarate in HIV-1 Treatment-experienced Patientswith Adverse Events Related to Prior NRTI Use: Data from a Prospective, Observational, Multicenter Study. J Acquir Immune Defic Syndr Hum Retrovirol2006;42 (3):385-7.

9334 Buchacz K, Brooks JT, Tong T, Moorman AC, Baker RK, Holmberg SD, et al.Evaluation of hypophosphataemia in tenofovir disoproxil fumarate (TDF)-exposedand TDF-unexposed HIV-infected out-patients receiving highly active antiretroviral therapy. HIV Med 2006;7 (7):451-6.

10394 Buchacz K, Young B, Baker RK, Moorman A, Chmiel JS, Wood KC, et al. RenalFunction in Patients Receiving Tenofovir With Ritonavir/Lopinavir or Ritonavir/Atazanavir in the HIV Outpatient Study (HOPS) Cohort. J AcquirImmune Defic Syndr 2006;43 (5):626-8.

10921 Nelson MR, Katlama C, Montaner JS, Cooper DA, Gazzard B, Clotet B, et al. Thesafety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults:the first 4 years. AIDS 2007;21 (10):1273-81.

11031 Yeh RF, Gaver VE, Patterson KB, Rezk NL, Baxter-Meheux F, Blake MJ, et al.Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymesCYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers. J Acquir Immune Defic Syndr 2006;42 (1):52-60.

11073 Feng J, Ly J, Myrick F, White K, Borroto-Esoda K, Miller M. Combination studiesof tenofovir, emtricitabine, and efavirenz as inhibitors of HIV-1 reversetranscriptase [poster]. HIV DART 2006: Frontiers in Drug Development forAntiretroviral Therapies; 2006 December 10-14, 2006; Cancun, Mexico.

11111 Nizoral (ketoconazole) Tablet. US Prescribing Information. Janssen PharmaceuticaProducts, L.P. Titusville, NJ. Revised: 08/2006.

12253 Ammassari A, Trotta MP, Murri R, Castelli F, Narciso P, Noto P, et al. Correlatesand predictors of adherence to highly active antiretroviral therapy: overview ofpublished literature. J Acquir Immune Defic Syndr 2002;31 Suppl 3:S123-7.

12520 Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Effects of the antifungalagents on oxidative drug metabolism: clinical relevance. Clin Pharmacokinet2000;38 (2):111-80.

12548 Epivir® Tablets (lamivudine tablets). Prescribing Information. GlaxoSmithKline.Research Triangle Park, NC. Revised February 2008.



12654 ZIAGEN® (abacavir sulfate) Tablets. ZIAGEN® (abacavir sulfate) Oral Solution.US Prescribing Information. GlaxoSmithKline. Research Triangle Park, NC. July 2008

12716 Hammer SM, Eron JJ, Jr., Reiss P, Schooley RT, Thompson MA, Walmsley S, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of theInternational AIDS Society-USA panel. JAMA 2008;300 (5):555-70.

13252 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28(7):412-9.

13882 Korhonen T, Turpeinen M, Tolonen A, Laine K, Pelkonen O. Identification of thehuman cytochrome P450 enzymes involved in the in vitro biotransformation oflynestrenol and norethindrone. The Journal of steroid biochemistry and molecularbiology 2008;110 (1-2):56-66.

13884 Zhang H, Cui D, Wang B, Han YH, Balimane P, Yang Z, et al. Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol: a new look at an old drug.Clin Pharmacokinet 2007;46 (2):133-57.

14065 Gazzard BG. British HIV Association Guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008. HIV Med 2008;9 (8):563-608.

15207 Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Departmentof Health and Human Services. December 1, 2009; 1-161. Available athttp://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.

15280 Kirk O, Mocroft A, Reiss P, De Wit S, Sedlacek D, Beniowski M, et al. ChronicKidney Disease and Exposure to ART in a Large Cohort with Long-term Follow-up: The EuroSIDA Study [Abstract 107LB]. 17th Conference on Retroviruses andOpportunistic Infections (CROI); 2010 February 16-19; San Francisco, CA.

15462 VIREAD® (tenofovir disoproxil fumarate) tablets. US Prescribing Information.Gilead Sciences, Inc. Foster City, CA. March 2010.

15541 Azijn H, Tirry I, Vingerhoets J, de Béthune M, Kraus G, Boven K, et al. TMC278,a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI),Active against Wild-Type and NNRTI-Resistant HIV-1. Antimicrob AgentsChemother 2010;54 (2):718-27.

15807 SUSTIVA® (efavirenz) capsules and tablets. US Prescribing Information. Bristol-Myers Squibb Company. Princeton, NJ. March 2010.



15845 Castillo R, Pedalino RP, El-Sherif N, Turitto G. Efavirenz-associated QTprolongation and Torsade de Pointes arrhythmia. Ann Pharmacother 2002;36(6):1006-8.

15846 Chinello P, Lisena FP, Angeletti C, Boumis E, Papetti F, Petrosillo N. Role of antiretroviral treatment in prolonging QTc interval in HIV-positive patients. J Infect 2007;54 (6):597-602.

15851 Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serumcreatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis2002;40 (2):221-6.

15852 Dickinson L, Khoo S, Back D. Differences in the pharmacokinetics of proteaseinhibitors between healthy volunteers and HIV-infected persons. Curr Opin HIVAIDS 2008;3 (3):296-305.

15853 Eap CB, Bourquin M, Martin J, Spagnoli J, Livoti S, Powell K, et al. Plasma concentrations of the enantiomers of methadone and therapeutic response in methadone maintenance treatment. Drug and alcohol dependence 2000;61 (1):47-54.

15857 AVANTI 2. Randomized, double-blind trial to evaluate the efficacy and safety ofzidovudine plus lamivudine versus zidovudine plus lamivudine plus indinavir inHIV-infected antiretroviral-naive patients. AIDS 2000;14 (4):267-374.

15858 Gartland M. AVANTI 3: a randomized, double-blind trial to compare the efficacy and safety of lamivudine plus zidovudine versus lamivudine plus zidovudine plusnelfinavir in HIV-1-infected antiretroviral-naive patients. Antivir Ther 2001;6(2):127-34.

15861 Hreiche R, Morissette P, Turgeon J. Drug-induced long QT syndrome in women:review of current evidence and remaining gaps. Gend Med 2008;5 (2):124-35.

15862 Jage J. [Methadone--pharmacokinetics and pharmacodynamics of an opiate]. DerAnaesthesist 1989;38 (4):159-66.

15865 Kharasch ED, Bedynek PS, Park S, Whittington D, Walker A, Hoffer C.Mechanism of ritonavir changes in methadone pharmacokinetics andpharmacodynamics: I. Evidence against CYP3A mediation of methadoneclearance. Clin Pharmacol Ther 2008;84 (4):497-505.

15867 Larsson A, Malm J, Grubb A, Hansson LO. Calculation of glomerular filtrationrate expressed in mL/min from plasma cystatin C values in mg/L. Scand J Clin LabInvest 2004;64 (1):25-30.



15870 Lucas D, Ferrara R, Gonzalez E, Bodenez P, Albores A, Manno M, et al.Chlorzoxazone, a selective probe for phenotyping CYP2E1 in humans.Pharmacogenetics 1999;9 (3):377-88.

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15885 Thummel KE, Wilkinson GR. In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol 1998;38:389-430.

15886 Van Den Bout-Van Den Beukel CJ, Fievez L, Michels M, Sweep FC, Hermus AR,Bosch ME, et al. Vitamin D deficiency among HIV type 1-infected individuals inthe Netherlands: effects of antiretroviral therapy. AIDS Res Hum Retroviruses2008;24 (11):1375-82.

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15890 Zhang X, Lalezari JP, Badley AD, Dorr A, Kolis SJ, Kinchelow T, et al.Assessment of drug-drug interaction potential of enfuvirtide in humanimmunodeficiency virus type 1-infected patients. Clin Pharmacol Ther 2004;75(6):558-68.

15969 Viramune® (nevirapine) tablets, 200 mg. US Prescribing Information. Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA. Revised January 2010.

15974 Videx EC (didanosine) Delayed-Release Capsules (125 mg, 200 mg, 250 mg, 400mg). Prescribing Information (United States). Bristol-Myers Squibb Company, January 2010.

15985 Kaletra (Lopinavir/Ritonavir) Liquid Filled Capsule (133.3 mg lopinavir/33.3 mg ritonavir); Solution (80 mg lopinavir/20 mg ritonavir). Prescribing Information(United States). Abbott Laboratories. April 2010.

15986 Prezista (Darunavir) Film Coated Tablets (75 mg, 150 mg, 300 mg, 400 mg, and600 mg). Prescribing Information (United States). Tibotec, April 2010.

15988 Mycobutin (Rifabutin) Capsule (150 mg). Prescribing Information (United States).Pfizer, October 2007.

15990 Viagra (Sildenafil Citrate) Film Coated Tablets (25 mg, 50 mg, 100 mg).Prescribing Information (United States). Pfizer, January 2010.

15991 Lipitor (Atorvastatin Sodium). Prescribing Information (United States) Tablets (10mg, 20 mg, 40 mg, and 80 mg). Pfizer, June 2009.



15992 Prilosec (Omeprazole). Delayed-Release Capsules (10 mg, 20 mg, and 40 mg);Delayed-Release Oral Suspension (2.5 mg, 10 mg). Prescribing Information(United States). Astra Zeneca, March 2008.

15993 PEPCID® (Famotidine) Tablets (20 mg, 40 mg). Prescribing Information (UnitedStates). Merck and Co., Inc., September 2009.

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SECTION 2.7 CLINICAL SUMMARY

SECTION 2.7.5—LITERATURE REFERENCES

EMTRICITABINE/RILPIVIRINE/TENOFOVIR DISOPROXIL FUMARATE SINGLE-TABLET REGIMEN

Gilead Sciences International Ltd

26 June 2013


Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate 2.7.5 Literature References Addendum FINAL

CONFIDENTIAL Page 2 26 June 2013

1. LITERATURE REFERENCES

24931 Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR Recomm Rep 2000;49 (RR-6):1-51.

24933 Norton BL, Holland DP. Current management options for latent tuberculosis: areview. Infection and drug resistance 2012;5:163-73.

24950 Mycobutin (Rifabutin) Capsule (150 mg) for oral administration. Summary of Product Characteristics (United Kingdom). Pfizer, March 2012.

24951 Walubo A. The role of cytochrome P450 in antiretroviral drug interactions. ExpertOpin Drug Metab Toxicol 2007;3 (4):583-98.

SECTION 5.2 TABULAR LISTING OF ALL CLINICAL STUDIES

EMTRICITABINE/RILPIVIRINE/ TENOFOVIR DISOPROXIL FUMARATE

FIXED-DOSE COMBINATION

Gilead Sciences International Limited

18 August 2010


Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Section 5.2 Tabular Listing of All Clinical Studies Final


5.2. TABULAR LISTING OF ALL CLINICAL STUDIES

Type of Study Study

Identifier

Location of Study Report

Objectives(s) of the Study

Study Design and Type of

Control

Test Product(s); Dosage Regimen;

Route of Administration

Number of Subjects

Healthy Subjects or Diagnosis of

Patients Duration of Treatment

Study Status; Type of Report

BA FTC-110

(Synopsis)

Module 5.3.1.1

To evaluate relative and absolute BA of FTC

OL, randomized, 3-way crossover, single 200-mg doses administered as IV solution, oral solution, or oral capsule

A: 1 × 200-mg FTC capsule, PO, fasted B: 20 mL of FTC 10 mg/mL solution, PO, fasted C: 20 mL of FTC 10 mg/mL solution, IV infused over 1 hour, fasted

12 subjects Healthy adult subjects

3 single doses

Complete; Final CSR

BA/BE FTC-109

(Synopsis)

Module 5.3.1.2

Pilot study to evaluate the BE/BA of FTC of the 100-mg and 200-mg capsules

OL, randomized, 2-way crossover, single 200-mg doses

A: 2 × 100-mg FTC capsules, PO, fasted B: 1 × 200-mg FTC capsule, PO, fasted


2 single doses

Complete; Final CSR

BA/BE FTC-111

(Synopsis) Module 5.3.1.2

To compare the BA of the 100-mg and 200-mg capsules and the effect of food on BA of FTC administered as a 200-mg capsule

OL, randomized, 3-way crossover, single 200-mg dose, food effect

A: 2 × 100-mg FTC capsules, PO, fasted B: 1 × 200-mg FTC capsule, PO, fasted C: 1 × 200-mg FTC capsule, PO, fed


3 single doses

Complete; Final CSR



Type of Study Study

Identifier




Control



Number of Subjects




BA/BE GS-00-914


To determine the PK profile of a single dose of the clinical formulation of TDF under fasted conditions, and the original commercial formulation under both fasted and under fed conditions. To determine the BE of the clinical and commercial formulations under fasted conditions

Single-center, 3-period, randomized, OL, BE and food effect

TDF (commercial formulation) 300-mg single dose (taken under fasting conditions and after a standardized high-fat breakfast). TDF (clinical formulation) 4 75-mg single dose (taken under fasting conditions)

40 subjects, 36 completed

Healthy subjects 3 single doses

Complete; Final CSR



Type of Study Study

Identifier




Control



Number of Subjects




BA/BE GS-US-104-0172

(Synopsis)

Module 5.3.1.2

To establish BE between the FTC/TDF tablet and concurrent administration of the TDF tablet and FTC capsule

OL, randomized, 4-treatment, single-center, 4-way crossover

A: 1 300-mg TDF tablet and 1 200-mg FTC capsule, PO, fasted B: 1 combination tablet (300-mg TDF/ 200-mg FTC), PO, fasted C: 1 combination tablet (300 mg TDF/ 200 mg FTC), PO with high-fat meal D: 1 combination tablet (300 mg TDF/ 200 mg FTC), PO with light meal

44 subjects (26 males; 18 females) 39 completed

Healthy subjects 4 single doses

Complete; Final CSR



Type of Study Study

Identifier




Control



Number of Subjects





(Synopsis)

Module 5.3.1.2

To evaluate the safety and BE of 2 FDC tablets (each containing FTC 200 mg, RPV 25 mg, and TDF 300 mg) compared with a 200-mg strength capsule of FTC, a 25-mg tablet of RPV, and a 300-mg tablet of TDF taken concurrently under fed conditions

Randomized, OL, single-center, single-dose, 3-way crossover study

A (reference): a 200-mg capsule of FTC, a 25-mg tablet of RPV, and a 300-mg tablet of TDF taken concurrently, PO, fed B and C (tests): 2 unique FDC tablets, each containing FTC 200 mg, RPV 25 mg, and TDF 300 mg, PO, fed

48 enrolled A: 45 B: 46 C: 46

Healthy adult subjects

3 single doses; 1 each of Treatment A, B, and C, on Days 1, 15, and 29

Complete; Final CSR



Type of Study Study

Identifier




Control



Number of Subjects





Module 5.3.1.2

To evaluate the safety and BE of 2 FDC tablets (each containing FTC 200 mg, RPV 25 mg, and TDF 300 mg) compared with a 200-mg strength capsule of FTC, a 25-mg tablet of RPV, and a 300-mg tablet of TDF taken concurrently under fed conditions

Randomized OL, single-center, single-dose, 3-way crossover Phase 1 study

A (reference): a 200-mg capsule of FTC, a 25-mg tablet of RPV, and a 300-mg tablet of TDF taken concurrently, PO, fed B and C (tests): 2 unique FDC tablets, each containing FTC 200 mg, RPV 25 mg, and TDF 300 mg, PO, fed

36 enrolled A: 35 B: 34 C: 35


3 single doses; 1 each of Treatment A, B, and C, on Days 1, 15, and 29

Complete; Final CSR



Type of Study Study

Identifier




Control



Number of Subjects




Healthy Subject PK and Initial Tolerability

FTC-106

(Synopsis)

Module 5.3.3.1

ADME of [14C]-FTC, mass balance by urinary and fecal recovery, PK of FTC-triphosphate in PBMCs

OL, single-dose and 8-day repeated doses of FTC (with a single [14C]FTC dose)

Day 1: 200-mg FTC single dose, PO, fasted Days 3 10: 200-mg once daily FTC capsules, PO, fed or fasted Day 11: 200 mg FTC solution containing 250- Ci [14C]FTC, PO, fasted

6 enrolled 5 completed

Healthy adult male subjects

10 days Complete; Final CSR

Patient PK and Initial Tolerability

Burroughs Wellcome 143-001

(Synopsis)

Module 5.3.3.2

Safety and PK food effect on PK for FTC

Randomized, single-blind, single-dose, placebo-controlled, escalating doses (100 to 1200 mg)

Single escalating oral doses of FTC administered as capsules: 100, 200, 400 ( food), 800, and 1200 mg, PO Placebo, PO

18 enrolled (12 active 6 placebo)

HIV-infected adult subjects

6 total doses, each given 1 week apart

Complete; Draft CSR


FTC-101

(Synopsis)

Module 5.3.3.2

Repeated-dose safety, tolerance, PK, antiviral activity

OL, dose-escalation, 5 cohort, 14 days of repeated doses of monotherapy

Multiple escalating oral doses of FTC administered as capsules for 14 days: 1: 25 mg BID 2: 100 mg BID 3: 200 mg BID 4: 100 mg QD 5: 200 mg QD

41 subjects: 1: N = 9 2: N = 8 3: N = 8 4: N = 8 5: N = 8

HIV-infected, therapy-naive adult subjects




Type of Study Study

Identifier




Control



Number of Subjects





FTC-102


Safety, antiviral activity, dose defining, comparison with 3TC

Randomized, OL, 3TC-controlled, 3 doses of FTC, 10-day repeated doses of monotherapy

A: FTC 25 mg QD B: FTC 100 mg QD C: FTC 200 mg QD D: 3TC 150 mg BID

81 subjects A: N = 19 B: N = 21 C: N = 19 D: N = 21

HIV-infected, therapy-naive adults


PK Intrinsic Factors

FTC-107

(Synopsis)

Module 5.3.3.3

Safety and PK profiles in subjects with various degrees of renal insufficiency (for potential dosage adjustment) and effect of hemodialysis on elimination of FTC in subjects with end-stage renal disease

OL, parallel group, single-dose of FTC in adult subjects with varying degrees of renal insufficiency without and with hemodialysis

1 single 200-mg FTC dose administered in capsule formulation to: --Group I (normal renal function, estimated CLCr

80 mL/min) --Group II (mild renal impairment, CLCr = 50 80 mL/min) --Group III (moderate renal impairment, not requiring dialysis, CLCr = 30 49 mL/min) --Group IV (severe renal impairment,

29 subjects enrolled and completed Group I: N = 6 Group II: N = 6 Group III: N = 6 Group IV: N = 5 Group V: N = 6

Adult subjects with varying degrees of renal function with and without hemodialysis

A single dose, except for subjects in Group V, who received a second dose

Complete; Final CSR Analysis & Simulations Report



Type of Study Study

Identifier




Control



Number of Subjects




CLCr 30 mL/min) --Group V (end-stage renal disease, requiring hemodialysis) For Group V subjects, a second 200-mg FTC dose was administered

1.5 h before the start of a 3-hour hemodialysis


GS-01-919


To evaluate the safety and PK of TFV following single-dose administration of TDF 300 mg in subjects with normal renal function and varying degrees of renal function impairment, including subjects undergoing hemodialysis. To develop

Multicenter, single-dose, OL, fixed-sequence study

TDF 300 mg 41 subjects enrolled; 40 subjects completed.

Healthy adult subjects and renally impaired adult subjects

Single dose Complete; Final CSR



Type of Study Study

Identifier




Control



Number of Subjects




dosing guidelines for renal function impairment


GS-01-931 A/B

(Synopsis)

Module 5.3.3.3

To evaluate the safety and PK of TFV following single-dose TDF 300 mg in subjects with normal hepatic function and varying degrees of hepatic impairment To develop dosing guidelines for renal function impairment

Multicenter, single-dose, OL, parallel-group study

TDF 300 mg tablet, PO, single dose

24 subjects enrolled; 24 subjects completed.

Healthy subjects and subjects with moderate and severe hepatic impairment (Child-Pugh-Turcotte Classification B and C, respectively)

Single dose Complete; Final CSR


GS-104-0235

(Synopsis)

Module 5.3.3.3

To evaluate safety and tolerability of TFV after administration of TDF 300 mg in combination with FTC 200 mg for

OL, multicenter, single-group study

TDF 300-mg tablet every 7 days, FTC 200-mg capsule every 96 hours, EFV 600-mg tablet QD, PO, or FTC/TDF 200 mg/300 mg (Truvada) tablet

8 enrolled 4 completed

HIV-1 infected subjects with stable renal impairment

48 weeks Complete; Abbreviated CSR



Type of Study Study

Identifier




Control



Number of Subjects




48 weeks in HIV-infected patients with various degrees of renal impairment Safety, tolerability of FTC; efficacy of TDF; PK of TFV and FTC

every 24, 48, or 72 hours, EFV 600 mg QD, depending on creatinine clearance, PO (only tx-naive subjects received EFV; tx-experienced subjects who switched to FTC + TDF could have remained on their NNRTI or PI)



Type of Study Study

Identifier




Control



Number of Subjects




PK Extrinsic Factors

FTC-103


Assess safety and potential PK interactions of FTC with other NRTIs (ZDV, d4T)

Randomized, OL, single-dose, 2-cohort, 3-way crossover

Cohort 1: 3 single crossover doses of: -- FTC 200 mg alone, PO --ZDV 300 mg alone, PO --FTC 200 mg + ZDV 300 mg, PO Cohort 2: 3 single crossover doses of: --FTC 200 mg alone, PO --d4T 40 mg alone, PO --FTC 200 mg + d4T 40 mg, PO

13 subjects enrolled, Cohort 1: N = 6 Cohort 2: N = 7 12 subjects completed


3 single doses

Complete; Final CSR



Type of Study Study

Identifier




Control



Number of Subjects





FTC-104


Assess safety and potential PK interactions of FTC with protease inhibitor (IDV) and NNRTI (MKC-442, EMV)

Randomized, OL, single-dose, 2-cohort, 3-way crossover study

Cohort 1: 3 single crossover PO doses of: --FTC 200 mg alone --IDV 800 mg alone --FTC 200 mg + IDV 800 mg Cohort 2: single crossover PO doses of: --FTC 200 mg alone --EMV 750 mg alone --FTC 200 mg + EMV 750 mg

24 subjects enrolled and completed Cohort 1: N = 12 Cohort 2: N = 12


3 single doses

Complete; Final CSR


FTC-108

(Synopsis)

Module 5.3.3.4

Assess safety and potential PK interactions of FTC with concomitant antiviral drug (ie, FCV) with extensive renal excretion

Randomized, OL, single-dose, 3-way crossover study in healthy adult subjects

3 single crossover doses of: --FTC 200 mg alone --FCV 500 mg alone --FTC 200 mg + FCV 500 mg


3 single doses

Complete; Final CSR



Type of Study Study

Identifier




Control



Number of Subjects





FTC-114


To determine safety and whether the PK parameters of TDF or FTC are affected following their coadministration

OL, single-center, randomized, 3-way crossover study of TDF and FTC

B: TDF 300 mg QD for 7 days A: FTC 200 mg QD for 7 days C: TDF 300 mg and FTC 200 mg coadministered QD for 7 days PO

19 subjects enrolled; 17 subjects completed


21 days Up to 14 days cumulative treatment with FTC QD, and up to 14 days cumulative with 300 mg TDF QD, with both drugs coadministered QD for 7 days

Complete; Final CSR


FTC-115

(Synopsis)

Module 5.3.3.4

Safety and tolerability of treatment; Effect of ZDV on FTC PK after concurrent multidose administration. Effect of FTC on ZDV PK after concurrent multidose administration

OL, randomized, 3-way crossover

A: FTC 200 mg QD, PO for 7 days B: ZDV 300 mg BID, PO for 7 days C: FTC 200 mg QD + ZDV 300 mg BID, PO for 7 days

30 subjects enrolled, 27 subjects completed





Type of Study Study

Identifier




Control



Number of Subjects





GS-01-932


To evaluate the potential for an interaction between TDF and enteric-coated ddI (ddI EC), and to determine if the administration of food in combination with the 2 had an effect on their PK

OL, fixed-sequence, drug-drug interaction and drug-drug-food interaction study of TDF and ddI EC

TDF 300 mg tablets, PO on Days 2 15 with a light meal ddI EC (Videx EC) 400 mg capsules, PO, on Days 1 and 8 (fasted) and on Day 9 with a light meal

28 subjects enrolled; 25 subjects completed.


14 days with TDF Single administra-tion of ddI EC on Days 1, 8, and 9.

Complete; Final CSR


GS-02-984

(Synopsis)

Module 5.3.3.4

To evaluate the PK of reduced-dose ddI (250 mg) and TDF with staggered administration and simultaneous administration (with/without food) relative to ddI 400 mg. To evaluate PK of abacavir and TDF after

OL, 1-sequence crossover, drug-drug interaction and drug-drug-food interaction study of TDF and ddI EC, and abacavir (exploratory)

TDF 300-mg tablets, PO, on Day 2 (Group 1, fed), on Days 3-9 (all, fed), on Day 10 (all, fasted), on Days 11-15 (Group 2, fed) ddI (Videx EC) 250-mg enteric-coated beadlet formulation capsule, PO, on Days 8 and 10 (all, fasted), on Day 9

28 subject enrolled; 28 subjects completed


Group 1: 9 days with TDF; single administra-tion of ddI EC on Days 1, 8, 9, and 10 Group 2: 13 days with TDF; single administra-tion of ddI EC on Days 1, 8, 9, and

Complete; Final CSR



Type of Study Study

Identifier




Control



Number of Subjects




coadministration with food

(all, fed), ddI (Videx EC) 400-mg enteric-coated beadlet formulation capsule, PO, on Day 1 (all, fasted) abacavir sulfate (Ziagen ) 300 mg tablet, PO, on Day 2 (Group 2, fed) and on Day 15 (Group 2, fed)

10; single administra-tion of abacavir sulfate on Days 2 and 15.


GS-01-943

(Synopsis)

Module 5.3.3.4

To determine whether the PK parameters of TDF or LPV/RTV are affected following coadministration with a meal

36-day, OL, randomized, multidose, crossover, 3-period, drug-drug interaction study of TDF and Kaletra (LPV/ RTV)

TDF 300-mg tablet once daily, PO, on Days 1-21 (Group I) or Days 1-7 and Days 22-35 (Group II). LPV/RTV 400/100 mg (3 133.3 mg/33.3-mg) capsules BID, PO, on Days 8-35 (all)


Healthy subjects 36 days Complete; Final CSR


GS-01-930 Module 5.3.3.4

To determine the effect of TDF on the PK of

OL, fixed-sequence drug-drug

TDF 300-mg tablets once daily, PO, on Days 23-29

24 subjects enrolled; 4 never

Normal, healthy females currently taking

Days 1–29 Ortho Tri-Cyclen

Complete; Final CSR



Type of Study Study

Identifier




Control



Number of Subjects




(Synopsis) norgestimate and ethinyl estradiol in female subjects

interaction study of TDF and norgestimate/ ethinyl estradiol (Ortho Tri-Cyclen )

Norgestimate/ ethinyl estradiol (Ortho Tri-Cyclen Dialpak ) tablets once daily, PO, on Days 1-29

received TDF Ortho Tri-Cyclen for at least 3 months prior to study entry

Days 23-29 TDF


GS-01-929

(Synopsis)

Module 5.3.3.4

To determine the effect of TDF on the steady-state PK of methadone, including the R- and S-enantiomers, in opiate-main-tained subjects

OL, fixed- sequence drug-drug interaction study of TDF and methadone hydrochloride

TDF 300-mg tablets once daily, PO, on Days 2-15 Methadone hydrochloride, 40 mg (minimum dose) to 110 mg (maximum dose) liquid formulation (10 mg/mL) once daily, PO


Methadone-maintained subjects



GS-01-940

(Synopsis)

Module 5.3.3.4

To evaluate whether the PK of TFV or ADV are affected by coadministration of multiple doses of TDF and single doses of ADV, and to examine safety

OL, fixed-sequence drug-drug interaction study

TDF 300-mg tablets once daily, PO, on Days 2-8 ADV 10 mg, PO, on Days 1 and 8


Healthy subjects 8 days TDF on Days 2-8 ADV on days 1 and 8

Complete; Final CSR



Type of Study Study

Identifier




Control



Number of Subjects




following co-administration of TFV and ADV


GS-02-1037

(Synopsis)

Module 5.3.3.4

Evaluate whether multiple doses of TDF had an effect on the PK profile of single dose of ribavirin, and to examine safety following coadministration of TFV and ribavirin

OL, fixed sequence, multidose TDF (Viread ) and single-dose ribavirin (Rebetol ), drug-drug interaction study

Ribavirin 600 mg (3 200-mg tablets), PO, on Days 1 and 22 TDF 300-mg tablets once daily, PO, on Days 17-24


Healthy subjects 24 days TDF on days 17–24 ribavirin on Days 1 and 22

Complete; Final CSR


GS-02-1038

(Synopsis)

Module 5.3.3.4

To study the effect of rifampicin on the PK of TDF To compare the PK of rifampicin + TDF versus historical controls To evaluate the safety of TDF when combined with rifampicin

OL, single-group, multidose, 2-period, single-center study

TDF (Viread ) 300-mg tablets once daily, PO, with breakfast, on Days 1 to 20 Rifampicin (Rifadin ) 600 mg (2 300-mg tablets), PO, with breakfast, on Days 11 to 20

25 subjects enrolled and 24 subjects received TDF and rifampicin 23 subjects completed


20 days Complete; Final Abbrevi-ated CSR



Type of Study Study

Identifier




Control



Number of Subjects





GS-US-104-0236

(Synopsis)

Module 5.3.3.4

To evaluate whether the PK parameters of TFV, SQV, or RTV are affected after coadministration of TDF and RTV-boosted SQV mesylate (SQV/r) under steady-state conditions

OL, single- and multiple-dose, drug-drug interaction study

TDF 300-mg tablet once daily, PO, on Days 2-24 SQV mesylate 1000 mg (5 200-mg hard capsules), PO, once daily on Days 1, 2, 9, 10, and 39 or BID on Days 11-38 RTV 100-mg soft gel, PO, once daily on Days 10 and 39 or BID on Days 11-38


Healthy subjects 39 days Complete; Final CSR


GS-US-104-0237

(Synopsis)

Module 5.3.3.4

To evaluate whether the PK parameters of TFV or NFV are affected following the coadministration of TDF and NFV mesylate compared with administration of each as a single agent

Randomized, OL, 3-treatment, crossover study

TDF 300 mg QD and NFV mesylate 1250 mg (5 250-mg tablets) BID, orally, in combination TDF 300 mg QD and NFV mesylate 1250 mg (5 250-mg tablets) BID, orally, administered separately

32 Healthy subjects 35 days Complete; Final CSR



Type of Study Study

Identifier




Control



Number of Subjects





GS-00-909


To evaluate the PK parameters of TDF, 3TC, ddI, IDV, ABT-378/r (LPV/r), and EFV when administered alone and in pairs containing TDF

2-center, 3-period, open- label, randomized, multiple-dose, crossover, drug interaction study

TDF alone, reference treatment alone, and TDF + reference treatment: TDF 300 mg/day 7 days 3TC 150 mg BID 7 days ddI 250 mg/day (weight 60 kg) or 400 mg/day (weight 60 kg) IDV 800 mg every 8 hours 7 days LPV/r 400 mg/100 mg BID 14 days EFV 600 mg/day 14 days

TDF, n = 103 TDF + 3TC, n = 18 TDF + ddI, n = 15 TDF + IDV, n = 15 TDF + LPV/r, n = 24 TDF + EFV, n = 31 90 subjects completed the study

Healthy subjects 43 to 99 days

Complete; Final CSR


GS-US-174-0105

(Synopsis)

Module 5.3.3.4

To evaluate the effect of coadministration of tacrolimus (TCL) on the steady-state PK of emtricitabine

OL, randomized, 3-way crossover, drug-drug interaction study

FTC/TDF 200/300 mg fixed-dose tablets once daily, PO, for 7 days TCL 0.1 mg/kg/day (as 0.5-mg or 1-mg

N=31 randomized N=21 evaluated for FTC/TDF PK N=22 evaluated for


Three 7-day treatment periods

Complete; Final CSR



Type of Study Study

Identifier




Control



Number of Subjects




and tenofovir (administered as the combination of emtricitabine and tenofovir disoproxil fumarate) and vice versa in healthy volunteers

capsules as appropriate), PO, for 7 days Both therapies taken together for 7 days

TCL PK

Human PD GS-96-701

(Synopsis)

Module 5.3.4

To evaluate the safety, PK, and anti-HIV activity of single and multiple doses of IV TFV in HIV infection

Multicenter, randomized, DB, placebo-controlled study

TFV 1 mg/kg IV over 1 hour on Day 1 and on Days 8-14 TFV 3 mg/kg IV over 1 hour on Day 1 and on Days 8-14 Placebo IV over 1 hour on Day 1 and on Days 8-14

TFV N = 16: TFV 1 mg/kg, n = 8 TFV 3 mg/kg, n = 8 Placebo, N = 4

HIV-1 infected subjects with CD4 cell counts

200 cells/mm3, plasma HIV RNA level

10,000 copies/mL

1 day of treatment followed by 7-day washout followed by 7 days day of treatment

Complete; Final CSR

Human PD GS-97-901

(Synopsis)

Module 5.3.4

To investigate the safety, tolerance, PK, and anti-HIV-1 activity of TDF as monotherapy

Multicenter Parts A & B: randomized, DB, placebo- controlled, dose escalation

Parts A & B, Day 1 and Days 8-35: TDF 75, 150, 300, or 600 mg as 75-mg tablets or placebo once daily,

TDF, N = 46: TDF 75 mg, n = 12 TDF 150 mg, n = 8 TDF 300 mg,

HIV-1 infected subjects with CD4 cell count

200 cells/mm3 and plasma HIV RNA levels

Blinded phase (Parts A & B): 35 days (single dose, then 7-day

Complete; Final CSR



Type of Study Study

Identifier




Control



Number of Subjects




or in combination with hydoxyurea in the treatment of HIV-1 infection

Part C: single- arm, OL Extended dosing: OL

PO (Cohorts 0-3) or TDF 75-mg tablet once daily or placebo + hydroxyurea 500-mg capsule BID, PO (Cohort 6) Part C, Cohort 6, up to 12 months of treatment: TDF 75-mg tablet once daily + hydroxyurea 500 mg BID, PO

n = 8 TDF 600 mg, n = 10 TDF + hydroxyurea, n = 8 Placebo, N = 13 Placebo + hydroxyurea, n = 2

10, 000 copies/mL

observation, then 28-day dose period)OL phase (Part C): 12 months Extended dosing: 12 months or until study termination or drug commerci-ally available

Controlled Efficacy and Safety

FTC-301A

(48-Week Synopsis)

Module 5.3.5.1

To compare safety and efficacy of FTC with that of d4T when used within a triple drug combination containing ddI and EFV

Randomized (1:1), DB, double-dummy, multicenter, active-controlled equivalence study in ART-naive subjects

d4T (40 mg BID if 60 kg; 30 mg

BID if 60 kg) capsule + ddI (400 mg once daily if 60 kg; 250 mg once daily if

60 kg) tablets + EFV 600 mg (3 200-mg capsules) once daily, PO,

N = 571 received treatment n = 286 for FTC group n = 285 for d4T group N = 513 completed 24 weeks N = 444

ART-naive subjects with HIV-1 RNA

5000 copies/mL

48 weeks or longer

Complete: 24-week interim CSR (no synopsis provided) (26 August 2002); 48-week final CSR (synopsis provided)



Type of Study Study

Identifier




Control



Number of Subjects




coadministered with either FTC 200-mg capsule or placebo capsule once daily, PO

completed 48 weeks

(18 December 2002)


FTC-302

(Synopsis)

Module 5.3.5.1

To compare safety and efficacy of FTC and 3TC within a triple drug combination containing d4T and NVP or EFV

Randomized (1:1), DB, double-dummy, multicenter

Arm 1: FTC 200 mg/day (2 100-mg capsules) PO + d4T (30 mg BID if 60 kg or 40 mg BID if

60 kg) capsules PO + NVP 200-mg tablet once daily for 14 days, then 200-mg tablet BID PO (n = 194) or EFV 600 mg (3 200-mg capsules) once daily PO (n = 40) Arm 2: 3TC 150-mg tablet BID PO + d4T (30 mg BID if 60 kg or 40 mg BID if 60 kg) capsules PO + NVP 200-mg tablet

Total subjects to receive treatment: N = 468 (234 in each arm) Total subjects to complete 48 weeks: N = 347 (167 in Arm 1 and 180 in Arm 2

HIV-1 infected, treatment-naive adults with HIV-1 RNA 5000 copies/mL and CD4+ cell counts 200 cells/mm3

48 weeks Complete; Final CSR



Type of Study Study

Identifier




Control



Number of Subjects




once daily for 14 days, then 200-mg tablet BID PO (n = 191) or EFV 600 mg (3 200-mg capsules) once daily PO (n = 43)


FTC-303

(CSR Synopsis)

Module 5.3.5.1

To compare FTC to 3TC in HIV-1 infected patients with HIV-1 RNA 400 copies/mL on a stable ( 12 weeks) ART regimen containing 3TC, d4T, or ZDV, and a PI or NNRTI

Randomized (2:1) OL, multicenter, equivalence study

Arm 1: patients switch from 3TC to FTC while continuing on current background therapy, or Arm 2: patients continuing on current 3TC-containing regimen; PO

Arm 1: N = 294 Arm 2: N = 146

HIV-1 infected adult subjects, 3TC-experienced, stable HIV-1 RNA

48 weeks Complete; Final CSR (10 June 2002) PK substudy report (10 June 2002) First Addendum (TLOVR) (27 August 2002)


GS-98-902(48-Week Synopsis) (Final CSR Synopsis)

Module 5.3.5.1

To evaluate safety and tolerability of 3 doses of TDF administered with other ARV agents for up to 48 weeks to

Phase 2, randomized, DB, placebo-controlled, multicenter study for 48 weeks, followed by an

Group 1: TDF 75 mg QD, PO Group 2: TDF 150 mg QD , PO Group 3: TDF 300 mg QD, PO Group 4: Placebo, PO

189 subjects enrolled in blinded phase: 54, 51, 56, and 28 enrolled into Groups 1, 2, 3, and 4,

HIV-1 infected subjects who had received a stable ARV regimen of 4 ARV agents for 8 weeks prior to enrollment and

48 weeks followed by OL phase for 80 to 100 weeks

Complete; 48-week CSR (20 April 2001) Final CSR (18 January 2002) Interim



Type of Study Study

Identifier




Control



Number of Subjects




treatment-experienced, HIV-1 infected subjects

optional OL, non-randomized, single-arm treatment phase of TDF

In OL phase, subjects received TDF 300 mg QD, PO

respectively. Of these, 135 (71%) subjects continued in OL phase

who had plasma HIV-1 RNA level

400 copies/mL and 100,000 copies/mL within 15 days prior to randomization

Extension Report (03 April 2001) 48-week Virology Report (26 January 2001) Final Extension Phase Virology Report (02 January 2002)


GS-99-907 (24-week synopsis) (Final CSR synopsis)

Module 5.3.5.1

To evaluate safety and efficacy of TDF 300 mg in treatment-experienced subjects on stable ARV therapy Evaluate PK in substudy

Randomized, DB, placebo- controlled, intensification study PK examined following single dose and during chronic treatment over 12 to 48 weeks

TDF 300 mg QD or placebo QD, PO

552 enrolled, 550 subjects received at least 1 dose of study drug; Single dose: n = 14 12-48 weeks: n = 7 to 14

HIV-1 infected subjects

400 and 100,000

copies/mL HIV-1 RNA levels No restriction on CD4

48 weeks (DB phase 24 weeks, OL to 48 weeks)

Complete; 24-week CSR (18 April 2001) Final 48-week CSR (18 March 2002) PK substudy report (18 March 2002)



Type of Study Study

Identifier




Control



Number of Subjects




48-week Virology Report (02 April 2002)


GS-99-903

(48-week synopsis) (144-week synopsis) (192-week synopsis)

Module 5.3.5.1

Evaluate efficacy and safety of TDF in a triple-combination regimen in HIV- infected ARV-naive subjects

Randomized, DB equivalence study

D4T + 3TC + EFV + TDF placebo, PO TDF + 3TC + EFV + d4T placebo, PO

600 subjects TDF: 299 d4T: 301

HIV infected, ARV-naive subjects Entry criteria: HIV-1 RNA 5000 copies/mL No restriction on CD4

144 weeks Ongoing; 48-week CSR (19 August 2002) 144-week CSR (19 April 2004) 192-week CSR (13 November 2008)


GS-01-934 (48-week synopsis) (144-week synopsis)

Module 5.3.5.1

To assess noninferiority of TDF and FTC in combination with EFV relative to Combivir in combination with EFV in the treatment of HIV-1 infected ARV-naive subjects, as

Randomized, OL, parallel, multicenter, active-controlled study

Group 1: To Week 96: TDF 300 mg QD + FTC 200 mg QD + EFV 600 mg QD, PO Weeks 96–144: EFV/TDF tablet (200/300 mg) QD + EFV 600 mg QD, PO Group 2: Combivir

TDF+FTC+EFV: n = 257 Combivir + EFV: n = 254

ARV-naive, HIV-1 infected subjects with plasma HIV-1 RNA > 10,000 copies/mL

144 weeks; amended to continue treatment up to 288 weeks

Completed; 48-week CSR (29 April 2005) 144-week CSR (02 May 2007)



Type of Study Study

Identifier




Control



Number of Subjects




determined by the achievement and maintenance of confirmed HIV-1 RNA < 400 copies/mL through Week 48 defined by the FDA TLOVR algorithm

(3TC/AZT) 150/300 mg BID + EFV 600 mg QD, PO


M02-418

(Final 96-week synopsis)

Module 5.3.5.1

To study safety, tolerability, PK, and antiviral activity of once-daily dosing of LPV/RTV in combination with TDF and FTC in the treatment of ARV-naive HIV-infected patients

Phase 3, OL, randomized, multicenter study

800 mg/200 mg LPV/RTV QD with TDF and FTC, PO 400 mg/100 mg LPV/RTV BID with TDF and FTC, PO

190 subjects randomized and treated

ARV-naive HIV-infected patients with HIV RNA

1000 copies/mL, no CD4 count restriction

96 weeks Complete; Interim 48-week CSR (no synopsis provided) (07 June 2004); Final 96-week CSR (07 July 2005)


GS-MC-164-0111 (synopsis)

Module 5.3.5.1

To investigate the effect of treatment with Truvada on hemoglobin and lipid profiles in

Phase 3, randomized, OL, multicenter, active-controlled

FTC/TDF (200 mg/300 mg) with EFV (600 mg) QD without regard to meals

250 subjects were randomized into the study; 234 subjects were treated,

Adults, with HIV-1 who had been maintained on stable ARV therapy of EFV given with ZDV




Type of Study Study

Identifier




Control



Number of Subjects




virologically suppressed subjects taking EFV who were switched from an NRTI backbone containing ZDV plus 3TC, and to determine whether the simplified regimen of FTC and TDF was associated with a reduced rate of AEs, as well as improved adherence and acceptability among other measures of quality of life.

study ZDV (250 mg in UK or 300 mg in Ireland) plus 3TC (150 mg) , PO; or Combivir (ZDV/ 3TC, 300 mg/150 mg) BID with EFV (600 mg) QD, PO

117 in each group

plus 3TC for at least 6 months and who had viral loads < 50 copies/mL on last 2 consecutive tests and < 400 copies/mL for > 3 months


GS-ES-164-0154 (RECOMB Study) (synopsis)

Module 5.3.5.1

To explore changes in limb fat by DEXA measurements, after substitution of the ZDV + lamivudine dual

Phase 4, multicenter, randomized, OL and controlled, study

Subjects continued on current NRTI-backbone regimen as the control group or switched to receive TVD (FTC 200 mg/TDF

80 subjects analyzed TVD group: n = 39 ZDV + lamivudine

HIV-1 infected subjects

72 weeks Complete; Final abbreviated CSR



Type of Study Study

Identifier




Control



Number of Subjects




NRTI-backbone by TVD, versus maintaining the original ZDV-containing regimen without any change, through 48 weeks

300 mg) , PO. All subjects continued to receive third agent of their HAART regimen, including a PI or NNRTI

group: n = 41

Uncontrolled Safety

GS-99-910 (synopsis)

Module 5.3.5.2

To observe the long-term safety effects of TDF, in combination with other ARVs, in patients who had completed prior TDF studies

OL, multicenter

TDF, 300 mg QD, orally, with food

575 enrolled; 573 received at least 1 dose of TDF

All active subjects participating in an ongoing trial of TDF (GS-97-901, GS-98-902, and GS-99-907) without treatment-limiting toxicity were eligible for enrollment

Until commercial availability or program termination by Gilead Sciences

Complete; Final CSR

Uncontrolled Efficacy and Safety

GS-US-164-0107 (synopsis)

Module 5.3.5.2

To characterize the risks, effectiveness, and benefits of switching from a Combivir (BID) /EFV (QD) regimen to an all once-daily

Prospective, single-arm, OL, switch study

FTC/TDF 200/300 mg/day, PO

402 treated HIV-1 infected, virologically suppressed subjects on a stable regimen of EFV taken with Combivir




Type of Study Study

Identifier




Control



Number of Subjects




regimen of Truvada/EFV.


GS-DE-164-0106 (synopsis)

Module 5.3.5.2

To assess efficacy and safety of treatment switch from a regimen with ZDV and 3TC plus a third partner to a once-daily regimen of FDC of TDF and FTC plus a third once-daily partner

Phase 3, prospective, non-randomized, single-group, OL, 48-week pilot study

FTC/TDF (200 mg/300 mg) QD with or without food, PO

52 subjects enrolled

Virologically suppressed (HIV-1 RNA concentration < 50 copies/ mL), HIV infected adults receiving ZDV- and 3TC-containing HAART (for > 3 months)



GS-US-164-0115 (synopsis)

Module 5.3.5.2

To assess the safety, tolerability, efficacy, PK and adherence of a once-daily regimen of fixed-dose FTC/ TDF (200 mg/ 300 mg) and ATV 300 mg (given as 2 150-mg capsules)

48-week, prospective, single-arm, OL pilot study

FTC/TDF (200 mg/300 mg) plus ATV 300 mg (given as 2 150-mg capsules) plus RTV 100 mg QD, PO

102 subjects were enrolled, 100 were treated

HIV-1 infected, ARV treatment-naive adults with plasma HIV-1 RNA levels > 1000 copies/mL and adequate renal function (CRCl >50 mL/min)

48 weeks Complete; Synoptic Report



Type of Study Study

Identifier




Control



Number of Subjects




boosted with RTV 100 mg

Other Studies PC-264-2005 (summary)

Module 5.3.5.4

To assess resistance for the Truvada (FTC/TDF) subset in 2 of Tibotec’s Phase III trials (TMC278-TiDP6-C209 and TMC278-TiDP6-C215)

Virology study at Week 48, comparing pooled data from 2 studies in RPV versus EFV group (both groups also received FTC/TDF)

C209/C215: RPV 25 mg + FTC/TDF or EFV 600 mg + FTC/TDF, PO All subjects in C209 received FTC/TDF. Only those subjects in C215 who received FTC/TDF were included.

Pooled RPV group: N=550; Pooled EFV control group: N=546

HIV-1 infected, ARV treatment-naive subjects with HIV-1 RNA levels

5000 copies/mL, susceptible to their background regimen, and no NNRTI mutations

48 weeks Complete; Virology Study Report

3TC, lamivudine; ABT-378, lopinavir; ADME, absorption, distribution, metabolism, excretion; ADV, adefovir dipivoxil; AE, adverse event; ART, antiretroviral therapy; AZT, azidothymidine (also known as zidovudine [ZDV]); BA, bioavailability; BE, bioequivalence; BID, twice daily; CHMP, Committee for Human Medicinal Products; CNS, central nervous system; CLCr, creatinine clearance; CSR, clinical study report; d4T, stavudine; ddI, didanosine; DB, double blind; DEXA, dual-energy x-ray absorptiometry; DF, disoproxil fumarate; EC, enteric-coated; EFV, efavirenz; EMV, emivirine; FCV, famciclovir; FDA, Food and Drug Administration; FDC, fixed-dose combination; FTC, emtricitabine; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; HIV-1, human immunodeficiency virus-1; IDV, indinavir; IU, international units; IV, intravenous; LPV, lopinavir; NFV, nelfinavir; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine; OL, open label; PBMC, peripheral blood mononuclear cell; PI, protease inhibitor; PK, pharmacokinetic; PO, oral; PSUR, periodic safety update report; QD, once daily; RNA, ribonucleic acid; RPV, rilpivirine; RTV, ritonavir; SQV, saquinavir; TDF, tenofovir disoproxil fumarate; TFV, tenofovir; TLOVR, time to loss of virologic response; TVD, Truvada; tx, treatment; UK, United Kingdom; ZDV, zidovudine

TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 1

Approved, Issued Date: 18-Jun-2010

Trial Naming Conventions

Throughout the development of TMC278 several different naming conventions were used for trials. The first part of the trial identifier was one of the following, depending on when the trial was conducted:

! R278474-CDE- (used for the earlier trials)

! R278474-

! TMC278-

! TMC278-TiDP6- (used for the most recent trials)

All trials were given a suffix of a unique 3-digit number preceded by the letter C (for ‘Clinical’), e.g., C201 or C209. The exception to this rule was the naming of trials R278474-CDE-101, R278474-CDE-102 and R278474-CDE-103, which did not include the letter C in the suffix. The Phase III and Phase I pooled analyses are also referred to by a suffix of a unique 3-digit number preceded by C, the first number always being 9 (i.e., the Phase III pooled analysis, TMC278-TiDP6-C904, is referred to as C904 and the Phase I pooled analysis, TMC278-TiDP6-C906, is referred to as C906).

Clinical Trials

During early development, TMC278 was referred to as R278474. This document will identify the compound only as TMC278. The International Nonproprietary Name and the United States Adopted Name is rilpivirine HCl.

In the early clinical trials, TMC278 was formulated as the free base in solution (R278474), but later the oral tablet formulation was developed in which TMC278 was present as an HCl salt (R314585). As a result, in later trials, TMC278 formulations were referred to as containing an amount of TMC278 as base equivalent (eq). In the Summary of Clinical Safety, for consistency, the following convention is used throughout: TMC278 X mg means either a dose of X mg when the base was used or X mg eq when the salt was used.



5.3.1 Reports of Biopharmaceutic Studies5.3.1.1 Bioavailability Study Reports

TrialPhase

Trial(Country)

DesignPrimary Trial Objectives

SubjectsN

Dosage RegimenRoute of AdministrationDuration of Treatment

StatusType of ReportTrial Report Location in CTD Modules

I R278474-C102

(Belgium)

Randomized, open label, 3-way crossover, food effect, single dose trial

Compare the oral bioavailability of the reference solution formulation of single dose TMC278 with 2 experimentalsolid formulations (tablets and capsules) of single dose TMC278, and assess the effect of food on the oralbioavailability of the 2 experimental solid formulations of single dose TMC278

Healthy volunteers

24

Treatment A: single dose of TMC278 100 mg in solution

Treatment B: single dose of TMC278 100 mg as capsule

Treatment C: single dose of TMC278 100 mg as tablet

Panel 1: Treatment A under fed conditions, Treatment B under fed conditions, and Treatment B under fasted conditions

Panel 2: Treatment A under fed conditions, Treatment C under fed conditions, and Treatment C under fasted conditions

Solution, tablets and capsules - oral

3 x 1 day, separated by 2 washout periods of 14 days each

Completed

Full Report

5.3.1.1

N: number of enrolled subjects.

Study Number Analytical Report TitleStudy Report Location in CTD Modules

R278474/017 LC-MS/MS Determination of R278474 in Human Heparin Plasma Originating from Clinical Trial R278474-C102 5.3.1.1

LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.



5.3.1 Reports of Biopharmaceutic Studies, Cont’d5.3.1.1 Bioavailability Study Reports

Trial Phase

Trial (Country)


SubjectsN



I TMC278-TiDP6-C137

(France)

Randomized, open label, 4-way crossover, single dose trial

Determine the effect of different types of meals on the oral bioavailability of TMC278 after a single dose, formulated as thePhase III tablet

Healthy volunteers

20

Treatment A: single dose of TMC278 75 mg under fed conditions (after a standard breakfast)

Treatment B: single dose of TMC278 75 mg under fasted conditions

Treatment C: single dose of TMC278 75 mg under fed conditions (after a high fat breakfast)

Treatment D: single dose of TMC278 75 mg under fed conditions (after a nutritional drink rich in proteins [Ensure® HP])

Tablets – oral


Completed

Full report

5.3.1.1



R278474/041 LC-MS/MS Determination of TMC278 in Human Heparin Plasma Samples Originating From Clinical Trial TMC278-TiDP6-C137

5.3.1.1




5.3.1 Reports of Biopharmaceutic Studies, Cont’d5.3.1.2 Comparative Bioavailability and Bioequivalence Study Reports

TrialPhase

Trial(Country)


SubjectsN



I TMC278-C117

(Belgium)


Compare the oral bioavailabilityof the 2 reference Phase IIb tablet formulations with the newly developed Phase III tablet formulation

Healthy volunteers

32

Treatment C: single dose of TMC278 100 mg Phase III tablet formulation

Treatment D: single dose of TMC278 100 mg Phase IIb tablet formulation

Treatment E: single dose of TMC278 150 mg Phase III tablet formulation

Treatment F: single dose of TMC278 150 mg Phase IIb tablet formulation

Panel 2: Treatment C under fed conditions, Treatment D under fed conditions

Panel 3: Treatment E under fed conditions, Treatment F under fed conditions

Tablets – oral

2 x 1 day, separated by a washout period of 13 days

Completed

Full Report

5.3.1.2


Note: Panel 1(including Treatments A and B, relating to a single dose of TMC278 25 mg [Phase III and Phase IIb tablet, respectively]) was removed from the trial design by protocol amendment 1 before the start of dosing.


R278474/037 LC-MS/MS Determination of TMC278 (R278474) in Human Heparin Plasma Originating from Clinical Trial TMC278-C117

5.3.1.2




5.3.1 Reports of Biopharmaceutic Studies, Cont’d5.3.1.2 Comparative Bioavailability and Bioequivalence Study Reports

Trial Phase

Trial (Country)


SubjectsN



I TMC278-TiDP38-C145

(The Netherlands)


Compare the oral bioavailability of 3 concept pediatric formulations of TMC278 (solution, suspension, granules) to that of the adult 25 mg Phase III tablet formulation, and to assess the food effect for eachconcept formulation

Healthy volunteers

36

Treatment A1: single dose of TMC278 25 mg in solution

Treatment B1: single dose of TMC278 25 mg in solution

Treatment A2: single dose of TMC278 25 mg in suspension

Treatment B2: single dose of TMC278 25 mg in suspension

Treatment A3: single dose of TMC278 25 mg in granule

Treatment B3: single dose of TMC278 25 mg in granule

Treatment C: single dose of TMC278 25 mg as tablet

Panel 1: Treatment A1 under fed conditions, Treatment B1 under fasted conditions



Panels 1, 2, and 3: Treatment C under fed conditions

Solution, suspension, granules, and tablets – oral


Completed

Full report

5.3.1.2



TMC278/049 LC-MS/MS Determination of TMC278 in Human Heparin Plasma Samples Originating From Clinical Trial TMC278-TiDP38-C145

5.3.1.2




5.3.1 Reports of Biopharmaceutic Studies, Cont’d5.3.1.3 In vitro- In vivo Correlation Study Reports

Trial Phase

Trial (Country)


SubjectsN



Not applicable



5.3.1 Reports of Biopharmaceutic Studies, Cont’d5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies


PRD BA28 Validation (Full) of an LC-MS/MS Method for the Determination of R278474 in Human Heparin Plasma 5.3.1.4

BA28 Validation of an LC-MS/MS method for the determination of R278474 in human heparin plasma (Amendment 1 to BA28)

5.3.1.4


5.3.1.4

BA218 Validation (Full) of an LC-MS/MS Method for the Determination of R278474 in Human Heparin Plasma, including Amendment 1

5.3.1.4


5.3.1.4


5.3.1.4

ABL6187 The Validation of the Determination of TMC278 in Human Plasma Using LC-MS/MS 5.3.1.4

PRD-BA1071 Validation (Full) of an LC-MS/MS Method for the Determination of TMC278 (JNJ-16150108) in Human Heparin Plasma

5.3.1.4

ABL2241 Validation of the determination of efavirenz in human plasma using LC-MS/MS 5.3.1.4

ABL3230 Validation of the determination of nevirapine in human plasma using LC-MS/MS 5.3.1.4

PBRL-RD-688 Validation of a method for the determination of tenofovir in human plasma samples 5.3.1.4

PBRL-RD-688 Validation of a method for the determination of tenofovir in human plasma samples (Amendment 1 to PBRL-RD-688) 5.3.1.4

ABL6037 Partial validation of the determination of tenofovir in human urine using HPLC with fluorescence detection 5.3.1.4

PPD LCMS B202 Quantitation of ketoconazole in human plasma via HPLC with MS/MS detection 5.3.1.4

PPD LCMS B202 Quantitation of ketoconazole in human plasma via HPLC with MS/MS detection (Addendum to LCMS B202) 5.3.1.4

ABL2184 Validation of the determination of lopinavir in human plasma using LC/MS-MS 5.3.1.4

ABL3021 Validation of the combined determination of TMC114 and ritonavir in human plasma using LC-MS/MS 5.3.1.4





ABL5150 The cross-validation of the determination of TMC114 and ritonavir in human plasma using an API-4000 LC-MS/MS system

5.3.1.4

ABL6044 The cross-validation of the determination of TMC114 and ritonavir in human heparin plasma by LC-MS/MS using D4-TMC114 and D6-ritonavir as internal standard

5.3.1.4

ABL4267 The validation of the determination of didanosine in human heparin plasma by LC-MS/MS 5.3.1.4

PBRL-RD-667 Validation of a method for the determination of rifampicin and 25-desacetyl rifampicin in human plasma samples 5.3.1.4

PBRL-RD-715 Validation of a method for the determination of paracetamol, paracetamol glucuronide and paracetamol sulphate in human plasma samples

5.3.1.4

PBRL-RD-715 Validation of a method for the determination of paracetamol, paracetamol glucuronide and paracetamol sulphate in human plasma samples (Amendment 1 to PBRL-RD-715)

5.3.1.4

R319064/R115891/BA502 Validation (full) of an LC-MS/MS method for the determination of R319064 (TMC114) and R115891 (ritonavir) in human heparin plasma

5.3.1.4

PPD P749 Determination of omeprazole, 5-hydroxyomeprazole, and omeprazole sulphone in human plasma by LC/MS/MS 5.3.1.4

PBRL-RD-722 Validation of a method for the determination of atorvastatin and five metabolites in human plasma samples 5.3.1.4

ABL2083 Validation of the determination of ethinyl estradiol (EE) using LC/MS/MS by LC/MS/MS 5.3.1.4

ABL2083 Validation of the determination of ethinyl estradiol (EE) using LC/MS/MS by LC/MS/MS (Amendment 1 to ABL2083) 5.3.1.4

ABL3200 The cross-validation of the determination of ethinyl estradiol (EE) in human plasma using an API-4000 LC-MS/MS system

5.3.1.4

ABL4125 The partial revalidation of the determination of ethinyl estradiol (EE) in human heparin plasma over the range of 3.00-600 pg/mL using LC-MS/MS

5.3.1.4

ABL6212 The validation of the determination of norethindrone in human plasma using GC-MS 5.3.1.4

PPD LCMS 323 Quantitation of methadone in human plasma via HPLC with MS/MS detection 5.3.1.4

PPD LCMSC 323.1 Quantitation of methadone enantiomers in human plasma via HPLC with MS/MS detection (February 2009) 5.3.1.4





PPD LCMSC 323.1 Quantitation of methadone enantiomers in human plasma via HPLC with MS/MS detection (May 2009) 5.3.1.4

LCMSC 323.1 Quantitation of methadone enantiomers in human plasma via HPLC with MS/MS detection (Addendum 1 to LCMSC 323.1)

5.3.1.4

LCMSC 323.1 Quantitation of methadone enantiomers in human plasma via HPLC with MS/MS detection (Addendum 2 to LCMSC 323.1)

5.3.1.4

PPD LCMS 231 Quantitation of sildenafil and desmethyl sildenafil in human plasma via HPLC with MS/MS detection (full validation, human plasma containing tripotassium EDTA)

5.3.1.4

PPD LCMS 231.1 Quantitation of sildenafil and desmethyl sildenafil in human plasma via HPLC with MS/MS detection (partial validation, human plasma containing sodium heparin)

5.3.1.4

PPD LCMS 231.1 Quantitation of sildenafil and desmethyl sildenafil in human plasma via HPLC with MS/MS detection (Addendum 1 to PPD LCMS 231.1)

5.3.1.4

PPD LCMS 231.1 Quantitation of sildenafil and desmethyl sildenafil in human plasma via HPLC with MS/MS detection (Addendum 2 to PPD LCMS 231.1)

5.3.1.4

ABL 2104 Validation of the combined determination of rifabutin and its metabolite 25-O-desacetylrifabutin in human plasma using LC-MS/MS

5.3.1.4

ABL 6237 The cross validation of the determination of rifabutin and 25-O-desacetylrifabutin in human plasma using API4000 LC-MS/MS

5.3.1.4

PBRL-RD-680 Validation of a method for the determination of moxifloxacin in human plasma samples 5.3.1.4

PPD LCMSC 255 Quantitation of norethindrone and ethinylestradiol in human plasma containing sodium heparin via HPLC with MS/MS detection

5.3.1.4

PPD LCMSC 255.5 Quantitation of norethindrone and ethinylestradiol in human plasma containing dipotassium EDTA via HPLC with MS/MS detection

5.3.1.4

PPD RHK2 Quantification of chlorzoxazone and 6-hydroxychlorzoxazone in human plasma via HPLC with MS/MS detection 5.3.1.4







ABL 7044 Validation of the determination of famotidine in human plasma using LC-MS/MS 5.3.1.4

PPD LCMSB 276 Quantitation of moxifloxacin in human plasma via HPLC with MS/MS detection 5.3.1.4

PPD LC346 Quantitation of efavirenz in human plasma via HPLC with UV detection (May 2002) 5.3.1.4

PPD LC346 Quantitation of efavirenz in human plasma via HPLC with UV detection (June 2002) 5.3.1.4

PPD LC346 Quantitation of efavirenz in human plasma via HPLC with UV detection (Addendum 1 to PPD LC346) 5.3.1.4



ABL 3101 The validation of zidovudine and zidovudine-glucuronide in human plasma samples, using LC-MS/MS 5.3.1.4

ABL 8096 Cross validation of the determination of zidovudine and zidovudine-glucuronide in human plasma samples, using LC-MS/MS

5.3.1.4

EDTA: ethylene diamine tetra acetate; EE: ethinyl estradiol; GC-MS: gas chromatography-mass spectrometry; HPLC: high performance liquid chromatography; LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry; MS/MS: mass spectrometry/mass spectrometry; UV: ultraviolet.



5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials5.3.2.1 Plasma Protein Binding Study Reports

Refer to Module 4.2.2.3/TMC278-NC112 (FK527)

5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials, Cont’d5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies

Refer to Module 4.2.2.4/TMC278-NC102Refer to Module 4.2.2.4/TMC278-TiDP6-NC157Refer to Module 4.2.2.4/TMC278-NC141Refer to Module 4.2.2.4/R278474-PRD-FK4123Refer to Module 4.2.2.4/TMC278-NC186Refer to Module 4.2.2.4/TMC278-NC283

Refer to Module 4.2.2.6/TMC278-NC194

5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials, Cont’d5.3.2.3 Reports of Studies Using Other Human Biomaterials

Refer to Module 4.2.2.2/TMC278-NC104



5.3.3 Reports of Human Pharmacokinetic Studies5.3.3.1 Healthy Subject Pharmacokinetics and Initial Tolerability Study Reports

TrialPhase

Trial(Country)


SubjectsN



I R278474-CDE-101

(Belgium)

Randomized, double-blind, placebo-controlled, ascending,single dose trial

Evaluate the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamics of singleascending doses of TMC278

Healthy male volunteers

27

Treatment A: single dose of TMC278 (12.5, 25, or 50 mg) orplacebo, under fed conditions

Solution – oral

1 day

Completed

Full report

5.3.3.1



R278474/004 LC-MS/MS Determination of R278474 in Human Heparin Plasma Originating from Clinical Trial R278474-CDE-101 5.3.3.1




5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d5.3.3.1 Healthy Subject Pharmacokinetics and Initial Tolerability Study Reports

Trial Phase

Trial (Country)


SubjectsN



I R278474-CDE-102

(The Netherlands)

Randomized, double-blind, placebo-controlled, ascending, multiple dose trial

Evaluate the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamics of multiple ascending doses of TMC278


27

Treatment A: once daily dose of TMC278 (25, 75, or 150 mg) or placebo, under fed conditions

Solution – oral

14 days

Completed

Full report

5.3.3.1








Trial Phase

Trial (Country)


SubjectsN



I R278474-CDE-103

(The Netherlands)

Randomized, double-blind, placebo-controlled, ascending, single dose trial

Evaluate the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamics of single ascending doses of TMC278


36

Treatment A: single dose of TMC278 (50, 100, or 200 mg) or placebo, under fed conditions

Solution – oral

1 day

Completed

Full report

5.3.3.1








Trial Phase

Trial (Country)


SubjectsN



I TMC278-C103

(Belgium)

Randomized, open label, parallel group, multiple dose ranging trial

Evaluate the safety, tolerability and pharmacokinetics of the solid formulation

Healthy volunteers

48

Treatment A: once daily dose of TMC278 25 mg, under fed conditions

Treatment B: once daily dose of TMC278 50 mg, under fed conditions

Treatment C: once daily dose of TMC278 100 mg, under fed conditions

Treatment D: once daily dose of TMC278 150 mg, under fed conditions

Tablets – oral

14 days

Completed

Full report

5.3.3.1


Study Number Analytical Report TitleStudy Report Location inCTD Modules

R278474/021 LC-MS/MS Determination of R278474 in Human Heparin Plasma Originating from Clinical Trial TMC278-C103 5.3.3.1





Trial Phase

Trial (Country)


SubjectsN



I TMC278-C119

(Belgium)

Open label, mass balance, single dose trial

Characterize absorption, distribution, excretion, and the overall metabolic profile of a single dose of 14C-labeled TMC278


6

Single dose of TMC278 150 mg 14C-labeled solution under fed conditions

Solution – oral

1 day

Completed

Full report

5.3.3.1



R278474/027 LC-MS/MS Determination of R278474 (TMC278) in Human Heparin Plasma Originating from Clinical Trial TMC278-C119

5.3.3.1





Trial Phase

Trial (Country)


SubjectsN



I TMC278-TiDP15-C146

(Belgium)

Randomized, double-blind, placebo-controlled, single dose trial

Evaluate the safety and tolerability of TMC278LA for single dose subcutaneous or intramuscular injections

Healthy volunteers

60

Panel 1: single 1 x 2 mL vehicle, or saline

Panel 2: single 2 x 2 mL or vehicle


Panel 4: single 2 x 1 mL vehicle, or saline



Panel 7: single 2 x 2 mL or saline

Panel 1-3: injectable suspension for TMC278LA and vehicle, solution for saline - subcutaneous

Panel 4-6: injectable suspension for TMC278LA and vehicle, solution for saline - intramuscular

Panel 7: injectable suspension for TMC278LA and solution for saline - intramuscular (deltoid)

1 day

Completed

Synopsis

2.7.6

LA: long acting.




Trial Phase

Trial (Country)


SubjectsN



I TMC278- TiDP15-C150

(Germany)

Randomized, double-blind, placebo-controlled, single dose and multiple dose trial

Evaluate the safety and tolerability of TMC278LA

Healthy volunteers

20

Panel 1: a single dose of TMC278LA 600 mg (2 mL in 1 IS) or vehicle or saline 3 successive doses (at 1-month intervals) of TMC278LA 300 mg (1 mL in 1 IS) or vehicle or saline

Panel 2: a single dose of TMC278LA 1200 mg (2 mL in each of 2 ISs) or vehicle or saline3 successive doses (at 1-month intervals) of 600 mg (2 mL in 1 IS) TMC278LA or vehicle or saline

Nanosuspension for TMC278LA and vehicle, solution for saline- intramuscular

4 doses with a 1-month interval between doses

Completed

Synopsis

2.7.6

IS: injection site: LA: long acting.



5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d5.3.3.2 Patient Pharmacokinetics and Initial Tolerability Study Reports

Trial Phase

Trial (Country)


SubjectsN



Not applicable



5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d5.3.3.3 Intrinsic Factor Study Reports

TrialPhase

Trial(Country)


SubjectsN



I TMC278-TiDP6-C130

(Belgium)

Open label, parallel group, controlled, sequential,multiple dose trial

Determine the single dose and steady-state (multiple dose) pharmacokinetics and short term safety and tolerability of TMC278 in subjects with mild or moderate hepatic impairment compared to matched healthy controlvolunteers

32

16 subjects with mild or

moderate hepatic

impairment16 healthy volunteers

Once daily dose of TMC278 25 mg, under fed conditions

Panel 1: 8 subjects with mild hepatic impairment and 8 healthy volunteers

Panel 2: 8 subjects with moderate hepatic impairment and 8 healthy volunteers

Tablets – oral

11 days

Completed

Full report

5.3.3.3




5.3.3.3




5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d5.3.3.4 Extrinsic Factor Study Reports

TrialPhase

Trial(Country)


SubjectsN



I R278474-C101

(United Kingdom)

Open label, parallel group, add-on single dose trial

Determine the single dose pharmacokinetics of TMC278 in HIV-1 infected subjects

HIV-1 infected male

subjects

15

Treatment A: single dose of TMC278 50 mg under fed conditions, as add on to an EFV (600 mg once daily) containing ARV regimen

Treatment B: single dose of TMC278 50 mg under fed conditions, as add on to a NVP (200 mg twice daily) containing ARV regimen

Solution (TMC278) – oral

1 day

Completed

Full report

5.3.3.4

ARV: antiretroviral; EFV: efavirenz; HIV: human immunodeficiency virus; N: number of enrolled subjects; NVP: nevirapine.


ABL4159 The Determination of Efavirenz in Human Plasma Samples, Derived From Tibotec Clinical Trial R278474-C101, Using LC-MS/MS

5.3.3.4

ABL4160 The Determination of Nevirapine in Human Plasma Samples, Derived From Tibotec Clinical Trial R278474-C101, Using LC-MS/MS

5.3.3.4

R278474/010 LC-MS/MS Determination of TMC278 in Human Heparin Plasma Samples Originating From Clinical Trial R278474-C101

5.3.3.4





Trial Phase

Trial (Country)


SubjectsN



I TMC278-C104

(The Netherlands)

Randomized, open label, 2-sequence, crossover, multiple dose, drug interaction trial

Determine the effect of steady-state (multiple dose) TMC278 concentrations on the steady-state pharmacokinetics and urinary excretion of tenofovir and the effect of steady-state tenofovir concentrations on the steady-state pharmacokinetics of TMC278

Healthy volunteers

16


Treatment B: once daily dose of TDF 300 mg plus once daily dose of TMC278 150 mg, under fed conditions

Panel 1: Treatment A, on Days 1-8, followed by Treatment B, on Days 1-16 (TDF plus TMC278 on Days 9-16)

Panel 2: Treatment A, on Days 1-8, followed by Treatment B,on Days 1-16 (TDF plus TMC278 on Days 1-8)

Tablets (TMC278 and TDF) – oral

8 days for Treatment A and 16 days for Treatment B, separated by a washout period of 14 days

Completed

Full report

5.3.3.4

TDF: tenofovir disoproxil fumarate; N: number of enrolled subjects.


ABL6034 The Determination of Tenofovir in Human Urine Samples, Derived From Tibotec Clinical Trial TMC278-C104, Using HPLC with Fluorescence Detection

5.3.3.4

BA429 LC-MS/MS Determination of Tenofovir in Human Plasma Samples Originating From Clinical Trial TMC278-C104 5.3.3.4


HPLC: high performance liquid chromatography; LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.




Trial Phase

Trial (Country)


SubjectsN



I TMC278-C105

(France)

Randomized, open label, 2-way crossover, multiple dose, drug interaction trial

Determine the effect of steady-state (multiple dose) TMC278 concentrations on the steady-state pharmacokinetics of lopinavir/ritonavir and the effect of steady-state lopinavir/ritonavir concentrations on the steady-state pharmacokinetics of TMC278

Healthy volunteers

16


Treatment B: twice daily dose of 400/100 mg lopinavir/ritonavir plus once daily dose of TMC278 150 mg, under fed conditions

Tablets (TMC278) and capsules (lopinavir/ritonavir) – oral

10 days for Treatment A and 20 days for Treatment B(Days 1-20 for lopinavir/ritonavir plus TMC278 on Days 11-20), separated by a washout period of 14 days

Completed

Full report

5.3.3.4



ABL6025 TMC278-C105-The Determination of Lopinavir in Human Plasma Samples, Derived From Tibotec Clinical Trial TMC278-C105, Using LC-MS/MS

5.3.3.4

ABL6026 TMC278-C105-The Determination of Ritonavir in Human Plasma Samples, Derived From Tibotec Clinical Trial TMC278-C105, Using LC-MS/MS

5.3.3.4






Trial Phase

Trial (Country)


SubjectsN



I TMC278-C106

(USA)

Randomized, open label, 2-sequence, multiple dose, drug interaction trial

Determine the effect of steady-state (multiple dose) TMC278 concentrations on the steady-state pharmacokinetics of ddI and the effect of steady-state ddI concentrations on the steady-state pharmacokinetics of TMC278

Healthy volunteers

26

Treatment A: once daily dose of TMC278 150 mg, under fed conditionsTreatment B: once daily dose of ddI 400 mg, under fasted conditions, plus once daily dose of TMC278 150 mg, under fed conditions

Panel 1: Treatment A, on Days 1-7, followed by Treatment B on Days 1-14 (ddI plus TMC278 on Days 8-14)

Panel 2: Treatment A, on Days 1-7, followed by Treatment Bon Days 1-14 (ddI plus TMC278 on Days 1-7)

A sub-study was performed, after all subjects had completed the main trial, in which 10 additional subjects were randomized to Treatment B in order to replace samples that were lost during shipment.

Tablets (TMC278) and capsules (ddI) – oral

7 days for Treatment A and 14 days for Treatment B, separated by a washout period of 14 days.

14 days for the repeat Treatment B (sub-study)

Completed

Full report

5.3.3.4

ddI: didanosine; N: number of enrolled subjects.

Continued





ABL5217 The Determination of ddI in Human Plasma Samples, Derived From Tibotec Clinical Trial TMC278-C106, Using LC-MS/MS

5.3.3.4

R278474/039 LC-MS/MS Determination of TMC278 in Human Heparin Plasma Samples Originating From Clinical Trial TMC278-C106

5.3.3.4

ddI: didanosine; LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.




Trial Phase

Trial (Country)


SubjectsN



I R278474-C108

(Belgium)


Determine the effect of steady-state (multiple dose) TMC278 concentrations on the steady-state pharmacokinetics of rifampin and its active metabolite 25-desacetylrifampin, and the effect of steady-state rifampin concentrations on the steady-state pharmacokinetics of TMC278

Healthy volunteers

16


Treatment B: once daily dose of rifampin 600 mg, under fed conditions

Treatment C: once daily doses of TMC278 150 mg plusrifampin 600 mg, under fed conditions

Solution (TMC278) and capsules (rifampin) – oral

3 x 7 days, separated by 2 washout periods of 14 days each

Completed

Full report

5.3.3.4



Rifampin/001 LC-UV Determination of Rifampicin and 25-Desacetyl Rifampicin in Human Plasma Samples Originating From Clinical Trial TMC278-C108

5.3.3.4


LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry; LC-UV: liquid chromatography-ultraviolet.




Trial Phase

Trial (Country)


SubjectsN



I TMC278-C109

(Belgium)


Determine the effect of steady-state (multiple dose) TMC278 concentrations on the pharmacokinetics of paracetamol and the effect of paracetamol on the steady-state pharmacokinetics of TMC278

Healthy volunteers

16

Treatment A: single dose of paracetamol 500 mg, under fed conditions

Treatment B: once daily dose of TMC278 150 mg plus a single dose of paracetamol 500 mg, under fed conditions

Tablets (TMC278 and paracetamol) – oral

1 day for Treatment A and 11 days for Treatment B(Days 1-11 for TMC278 plus paracetamol on Day 11), separated by a washout period of 14 days

Completed

Full report

5.3.3.4



Paracetamol/001 LC-UV Determination of Paracetamol, Paracetamol Glucuronide and Paracetamol Sulphate in Human Plasma Samples Originating From Clinical Trial TMC278-C109

5.3.3.4

R278474/028 LC-MS/MS Determination of R278474 (TMC278) in Human Heparin Plasma Originating from Clinical Trial TMC278-C109

5.3.3.4

LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry; LC-UV: liquid chromatography-ultraviolet.




Trial Phase

Trial (Country)


SubjectsN



I TMC278-C112

(Belgium)


Determine the effect of steady-state (multiple dose) TMC278 concentrations onthe pharmacokinetics of TMC114/ritonavir and the effect of steady-state TMC114/ritonavir concentrations on the steady-state pharmacokinetics of TMC278

Healthy volunteers

16


Treatment B: once daily dose of TMC114/ritonavir 800/100 mg plus once daily dose of TMC278 150 mg, under fed conditions

Tablets (TMC278 and TMC114) and capsules (ritonavir) –oral

11 days for Treatment A and 22 days for Treatment B(Days 1-22 for TMC114/ritonavir plus TMC278 onDays 12-22), separated by a washout period of 14 days

Completed

Full report

5.3.3.4



R278474/033 LC-MS/MS Determination of TMC278 (R278474) in Human Heparin Plasma Originating from Clinical Trial TMC278-C112

5.3.3.4

R319064/023 LC-MS/MS Determination of TMC114 and ritonavir in Human Heparin Plasma Samples Originating From Clinical Trial TMC278-C112 5.3.3.4





Trial Phase

Trial (Country)


SubjectsN



I TMC278-C114

(Belgium)


Determine the effect of single dose and steady-state (multiple dose) TMC278 concentrations on the steady-state pharmacokinetics ofomeprazole and its metabolites 5-hydroxyomeprazole and omeprazole sulfone, and the effect of steady-state omeprazole concentrations on the single dose and steady-state pharmacokinetics of TMC278

Healthy volunteers

16


Treatment B: once daily dose of omeprazole 20 mg plus once daily dose of TMC278 150 mg, under fed conditions

Tablets (TMC278 and omeprazole) – oral

11 days for Treatment A and 22 days for Treatment B(Days 1-22 for omeprazole plus TMC278 on Days 12-22),separated by a washout period of 14 days

Completed

Full report

5.3.3.4



ABL6191 The Determination of TMC278 in Human Plasma Samples, Using LC-MS/MS, Derived From Tibotec Clinical Trial TMC278-C114

5.3.3.4

Omeprazole/002 LC-MS/MS Determination of Omeprazole, 5-hydroxyomeprazole, and Omeprazole Sulphone in Human Sodium Heparin Plasma Originating from Clinical Trial TMC278-C114

5.3.3.4





Trial Phase

Trial (Country)


SubjectsN



I TMC278-C116

(Germany)


Determine the effect of steady-state (multiple dose) TMC278 concentrations on the steady-state pharmacokinetics of atorvastatin, atorvastatin lactone, and the active metabolites 2-hydroxyatorvastatin and 4-hydroxyatorvastatin, andthe effect of steady-state atorvastatin concentrations on the steady-state pharmacokinetics of TMC278

Healthy volunteers

16

Treatment A: once daily dose of atorvastatin 40 mg, under fed conditions

Treatment B: once daily dose of TMC278 150 mg plus once daily dose of atorvastatin 40 mg, under fed conditions

Tablets (TMC278 and atorvastatin) – oral

4 days for Treatment A and 15 days for Treatment B(Days 1-15 for TMC278 plus atorvastatin on Days 12-15), separated by a washout period of 14 days

Completed

Full report

5.3.3.4



Atorvastatin/001 LC-MS/MS Determination of Atorvastatin, 2- and 4-hydroxyatorvastatin and Atorvastatin Lactone in Human Plasma Samples Originating From Clinical Trial TMC278-C116

5.3.3.4


R278474/030-A-1 LC-MS/MS Determination of R278474 in Human Heparin Plasma (Amendment 1 to TMC278-C116-CPCD-BSS-PRD) 5.3.3.4





Trial Phase

Trial (Country)


SubjectsN



I TMC278-C120

(United Kingdom)

Open label, single-sequence, multiple dose, drug interaction trial

Determine the effect of steady-state (multiple dose) TMC278 concentrations on the steady-statepharmacokinetics of ethinylestradiol, and on the steady-state pharmacokinetics of norethindrone

Healthy female

volunteers

16

Treatment A: once daily doses of ethinylestradiol 35 ∀g and norethindrone 1.0 mg, under fed conditions

Treatment B: once daily doses of ethinylestradiol 35 ∀g and norethindrone 1.0 mg plus once daily dose of TMC278 150 mg, under fed conditions

Tablets (TMC278 and ethinylestradiol plus norethindrone) –oral

2 x 21 days: 21 days for Treatment A and 21 days for Treatment B (Days 1-21 for ethinylestradiol and norethindrone plus TMC278 on Days 1-15), separated by a 7-day pill-free period

Completed

Full report

5.3.3.4



ABL6146 The Determination of Ethinyl Estradiol in Human Plasma Samples, Derived From Tibotec Clinical Trial TMC278-C120, Using LC-MS/MS

5.3.3.4

ABL6147 The Determination of Norethindrone in Human Plasma Samples, Derived From Tibotec Clinical Trial TMC278-C120, Using GC-MS

5.3.3.4

ABL6190 The Determination of TMC278 in Human Plasma Samples, Using LC-MS/MS, Derived From Tibotec Clinical Trial TMC278-C120

5.3.3.4

GC-MS: gas chromatography-mass spectrometry; LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.




Trial Phase

Trial (Country)


SubjectsN



I TMC278-TiDP6-C121

(The Netherlands)

Open label, single-sequence,multiple dose, drug interaction trial

Determine the effect of steady-state (multiple dose) TMC278 concentrations on the steady-state pharmacokinetics of R- and S-methadone

Healthy volunteers

13

Once daily dose of TMC278 25 mg plus methadone individualized maintenance therapy (once daily dose of 60 to 150 mg), under fed conditions

Tablets (TMC278 and methadone) – oral

26 days: TMC278 on Days 1-11 in addition to methadone individualized maintenance therapy on Days -14 to 12

Completed

Full report

5.3.3.4



TMC278/051 LC-MS/MS Determination of TMC278 in Human Heparin Plasma Originating from Clinical Trial TMC278-TiDP6-C121

5.3.3.4

Methadone/001 LC-MS/MS Determination of (R)-methadone and (S)-methadone in Human EDTA Plasma Originating From Clinical Trial TMC278-TiDP6-C121 5.3.3.4

EDTA: ethylene diamine tetra acetate; LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.




Trial Phase

Trial (Country)


SubjectsN



I TMC278-TiDP6-C123

(USA)


Determine the effect of steady-state (multiple dose) TMC278 concentrations on the single dose pharmacokinetics of sildenafil and its active metabolite N-desmethyl sildenafil and the effect of single dose sildenafil concentrations on the steady-state pharmacokinetics of TMC278


16

Treatment A: single dose of sildenafil 50 mg, under fed conditions

Treatment B: once daily dose of TMC278 75 mg plus a single dose of sildenafil 50 mg, under fed conditions

Tablets (TMC278 and sildenafil) – oral

1 day for Treatment A and 12 days for Treatment B(Days 1-12 for TMC278 plus sildenafil on Day 12), separated by a washout period of 14 days

Completed

Full report

5.3.3.4



TMC278/043 LC-MS/MS Determination of TMC278 in Human Heparin Plasma Samples Originating From Clinical Trial TMC278-TiDP-C123

5.3.3.4

Sildenafil/BA1074 LC/MS/MS Determination of Sildenafil and Desmethylsildenafil in Human Sodium Heparin Plasma Originating From Clinical Trial TMC278-TiDP-C123

5.3.3.4





Trial Phase

Trial (Country)


SubjectsN



I TMC278-C125

(Belgium)


Determine the effect of steady-state (multiple dose) TMC278 concentrations on the steady-state pharmacokinetics of rifabutin and its active metabolite 25-O-desacetyl-rifabutin and the effect of steady-state rifabutin concentrations on the steady-state pharmacokinetics of TMC278

Healthy volunteers

18


Treatment B: once daily dose of rifabutin 300 mg, under fed conditions

Treatment C: once daily doses of TMC278 150 mg plusrifabutin 300 mg, under fed conditions

Tablets (TMC278) and capsules (rifabutin) – oral

3 x 11 days, separated by 2 washout periods of 14 days each

Completed

Full report

5.3.3.4



ABL6235 The Determination of Rifabutin and 25-O-desacetyl Rifabutin in Human Plasma Samples, Derived From Tibotec Clinical Trial TMC278-C125, Using LC-MS/MS

5.3.3.4

R278474/031 LC-MS/MS Determination of TMC278 (R278474) in Human Heparin Plasma Originating From Clinical Trial TMC278-C125

5.3.3.4





Trial Phase

Trial (Country)


SubjectsN



I TMC278-C127

(France)


Determine the effect of steady-state (multiple dose) TMC278 concentrations on the steady-state pharmacokinetics of ketoconazole and the effect of steady-state ketoconazole concentrations on the steady-state pharmacokinetics of TMC278

Healthy volunteers

16


Treatment B: once daily doses of ketoconazole 400 mg plus TMC278 150 mg, under fed conditions

Tablets (TMC278 and ketoconazole) – oral

11 days for Treatment A and 22 days for Treatment B(Days 1-22 for ketoconazole plus TMC278 on Days 12-22), separated by a washout period of 14 days

Completed

Full report

5.3.3.4



ABL6189 The Determination of TMC278 in Human Plasma Samples, Using LC-MS/MS Originating From Clinical Trial TMC278-C127

5.3.3.4

R41400/014 LC-MS/MS Determination of Ketoconazole in Human Sodium Heparin Plasma Originating From Clinical Trial TMC278-C127

5.3.3.4





Trial Phase

Trial (Country)


SubjectsN



I TMC278-TiDP6-C136

(United Kingdom)

Open label, single-sequence, multiple dose, drug interaction trial

Determine the effect of steady-state (multiple dose) TMC278 concentrations on the steady-state pharmacokinetics of ethinylestradiol and on the steady-state pharmacokinetics of norethindrone

Healthy female

volunteers

18

Treatment A: once daily doses of ethinylestradiol 35 ∀g and norethindrone 1.0 mg, under fed conditions

Treatment B: once daily doses of ethinylestradiol 35 ∀g and norethindrone 1.0 mg plus once daily dose of TMC278 25 mg, under fed conditions

Tablets (TMC278 and ethinylestradiol plus norethindrone) –oral

2 x 21 days: 21 days for Treatment A and 21 days for Treatment B (Days 29-49 for ethinylestradiol and norethindrone plus TMC278 on Days 29-43), separated by a 7-day pill-free period

Completed

Full report

5.3.3.4




5.3.3.4

Ethinylestradiol/001 LC-MS/MS Determination of Ethinyl Estradiol and Norethindrone in Human Dipotassium EDTA Plasma Originating From Clinical Trial TMC278-TiDP6-C136

5.3.3.4

EDTA: ethylene diamine tetra acetate; LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.




Trial Phase

Trial (Country)


SubjectsN



I TMC278-C139

(USA)

Open label, multiple dose, drug interaction trial

Determine the effect of single dose and steady-state (multiple dose) TMC278 concentrations on the pharmacokinetics of chlorzoxazone and 6-hydroxy-chlorzoxazone after a single dose of chlorzoxazone, and the effect of single dose chlorzoxazone concentrations on thesteady-state pharmacokinetics of TMC278

Healthy volunteers

25 (16 under the main

protocol and 9 under the sub-study protocol)

Main study: single dose of chlorzoxazone 500 mg on Days 1, 4 and 15 or 19 and once daily dose of TMC278 150 mg on Days 4-15 or 19 under fed conditions

Sub-study: single dose of chlorzoxazone 500 mg on Days 1, 4, and 19 and once daily dose of TMC278 150 mg on Days 4-19under fed conditions

Tablets (TMC278) and caplets (chlorzoxazone) – oral

13 or 17 days, excluding washout (2 days), (due to extreme weather conditions [hurricane] some subjects received 4 additional days of TMC278 dosing)

Completed

Full report

5.3.3.4



ABL6201 The Determination of TMC278 in Human Plasma Samples, Derived From Tibotec Clinical Trial TMC278-C139, Using LC-MS/MS

5.3.3.4

R278474/BA689 LC-MS/MS Determination of Chlorzoxazone and 6-hydroxychlorzoxazone in Human Sodium Heparin Plasma Originating From Clinical Trial TMC278-C139

5.3.3.4





Trial Phase

Trial (Country)


SubjectsN



I TMC278-C140

(France)

Randomized, open label, 4-way crossover, single dose, drug interaction trial

Determine the effect of single dose famotidine concentrations on the single dose pharmacokinetics of TMC278 in 3 different dosing regimens and investigate the relationship between intragastric pH and the pharmacokinetics of TMC278

Healthy volunteers

24

Treatment A: single dose of TMC278 150 mg under fed conditions

Treatment B: single dose of famotidine 40 mg, under fasted conditions, and a single dose of TMC278 150 mg 2 hours laterunder fed conditions

Treatment C: single dose of TMC278 150 mg and a single dose famotidine 40 mg 4 hours later, under fed conditions

Treatment D: single dose of famotidine 40 mg and a single dose of TMC278 150 mg 12 hours later, under fed conditions

Tablets (TMC278 and famotidine) – oral


Completed

Full report

5.3.3.4



R278474/036 LC-MS/MS Determination of TMC278 (R278474) in Human Heparin Plasma Originating From Clinical Trial TMC278-C140

5.3.3.4

ABL7045 The Determination of Famotidine in Human Plasma Samples, Derived From Tibotec Clinical Trial TMC278-C140, Using LC-MS/MS

5.3.3.4





Trial Phase

Trial (Country)


SubjectsN



I TMC278-TiDP6-C154

(Germany)


Determine the effect of steady-state (multiple dose) omeprazole concentrations on the pharmacokinetics of a single dose of TMC278, for 2 different dosing regimens; compare the TMC278 pharmacokinetics after a single dose in the presence of steady-state omeprazole to the TMC278 pharmacokinetics after a single dose of TMC278 alone; and explore the relationship between intragastric pH and the pharmacokinetics of TMC278

Healthy volunteers

16

Treatment A: single dose of TMC278 25 mg under fed conditions

Treatment B: single dose of omeprazole 20 mg, under fasted conditions, on Days 1-7 plus a single dose of TMC278 25 mg on Day 6, under fed conditions

Treatment C: single dose of omeprazole 20 mg, under fasted conditions, on Days 1-6 plus a single dose of TMC278 25 mg on Day 6, under fed conditions

Treatment D: single dose of omeprazole 20 mg, under fasted conditions, on Days 1-7 plus a single dose of TMC278 50 mg on Day 6, under fed conditions

Tablets (TMC278 and omeprazole) – oral

1 day for Treatment A, 7 days for Treatments B and D, and 6 days for Treatment C, separated by 3 washout periods of 14 days each. For Treatments B, C and D, the intake of omeprazole could start as early as the 10th day of the washout period for TMC278

Ongoing/Available 4Q2010

Full report

5.3.3.4

N: number of enrolled subjects




Trial Phase

Trial (Country)


SubjectsN



I TMC278-HIV1001

(United States)

Open label, single arm trial

Determine the pharmacokinetics of TMC278 following a 2-week period receiving EFV

Healthy volunteers

20

Treatment A: single dose of TMC278 25 mg on Days 1-14, under fed conditions

Treatment B: single dose of EFV 600 mg on Days 1-14, under fasted conditions

Treatment C: single dose of TMC278 25 mg on Days 1-28, under fed conditions

Tablets (TMC278 and EFV) – oral

14 days for Treatments A and B, separated by a washout period of 14 days, and 28 days for Treatment C (no washout period between Treatments B and C)


Full report

5.3.3.4

EFV: efavirenz; N: number of enrolled subjects.



5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d5.3.3.5 Population Pharmacokinetics Study Reports

Refer to 5.3.5.1/TMC278-C204: population PK reports (48 weeks and 96 weeks) of the Phase IIb trial TMC278-C204Refer to 5.3.5.3/0016435: population PK report (48 weeks) of the combined Phase III trials TMC278-TiDP6-C209/TMC278-TiDP6-C215PK: pharmacokinetic.



5.3.4 Reports of Human Pharmacodynamic Studies5.3.4.1 Healthy Subject Pharmacodynamics and Pharmacokinetic/Pharmacodynamics Study Reports

TrialPhase

Trial(Country)


SubjectsN



I TMC278-TiDP6-C131

(Belgium)

Randomized, double-blind, double-dummy, placebo- and active-controlled, 3-way crossover, multiple dose trial

Evaluate the effect of TMC278, compared to placebo, after a single dose and at steady-state on the QT/QTcF interval

Healthy volunteers

41

Treatment A: once daily doses of TMC278 75 mg and TMC278 placebo and a single dose of moxifloxacin placebo, under fed conditions

Treatment B: once daily dose of TMC278 300 mg and a single dose of moxifloxacin placebo, under fed conditions

Treatment C: once daily dose of TMC278 placebo and a single dose of moxifloxacin 400 mg, under fed conditions

Tablets (TMC278) and capsules (moxifloxacin) – oral

3 x 12 days: 12 days for Treatments A, B, and C (TMC278 or TMC278 placebo on Days 1-11 plus moxifloxacin or moxifloxacin placebo on Day 12), separated by 2 washout periods of 21 days each

Completed

Full report

5.3.4.1



Cortisol/002 LC-MS/MS Determination of Cortisol and 6β-hydroxycortisol in Human Urine Samples Originating From Clinical TrialTMC278-TiDP6-C131

5.3.4.1

Moxifloxacin/004 LC-MS/MS Determination of Moxifloxacin in Human Plasma Samples Originating From Clinical Trial TMC278-TiDP6-C131

5.3.4.1

R278474/040 LC-MS/MS Determination of TMC278 (R278474) in Human Heparin Plasma Samples Originating From Clinical Trial TMC278-TiDP6-C131

5.3.4.1




5.3.4 Reports of Human Pharmacodynamic Studies, Cont’d5.3.4.1 Healthy Subject Pharmacodynamics and Pharmacokinetic/Pharmacodynamics Study Reports

Trial Phase

Trial (Country)


SubjectsN



I TMC278-TiDP6-C151

(Belgium)

Randomized, double-blind, double-dummy, placebo- and active-controlled, parallelgroup, multiple dose trial

Evaluate the effect of TMC278 at steady-state, compared to baseline, on the QT/QTcF interval

Healthy volunteers

36

Treatment A: once daily dose of TMC278 25 mg and a single dose of moxifloxacin placebo, under fed conditions

Treatment B: once daily dose of TMC278 placebo and a single dose of moxifloxacin 400 mg, under fed conditions

Tablets (TMC278) and capsules (moxifloxacin) – oral

12 days (TMC278 or TMC278 placebo on Days 1-11 andmoxifloxacin or moxifloxacin placebo on Day 12)

Completed

Full report

5.3.4.1




5.3.4.1

Moxifloxacin/006 LC-MS/MS Determination of Moxifloxacin in Human Plasma Samples Originating From Clinical Trial TMC278-TiDP6-C151

5.3.4.1





TrialPhase

Trial(Country)


SubjectsN



I TMC278-TiDP6-C152

(USA)

Randomized, double-blind, double-dummy, placebo- and active-controlled, crossover, multiple dose trial

Evaluate the effect of TMC278 at steady-state and the effect of EFV at steady-state on the QT/QTcF interval, in 2 randomized panels

Healthy volunteers

120

Treatment A: once daily dose of TMC278 25 mg plus a single dose of moxifloxacin placebo, under fed conditions

Treatment B: once daily dose of TMC278 placebo plus a single dose of moxifloxacin placebo, under fed conditions

Treatment C: once daily dose of TMC278 placebo plus asingle dose of 400 mg moxifloxacin, under fed conditions

Treatment D: once daily dose of EFV 600 mg, under fastedconditions

Treatment E: once daily dose of EFV placebo, under fastedconditions

TMC278 panel: Treatments A, B, and C

EFV panel: Treatments D and E

Tablets (TMC278 and EFV) and capsules (moxifloxacin) –oral

For the TMC278 panel: 3 x 11 days (TMC278 or TMC278 placebo on Days 1-11 plus moxifloxacin or moxifloxacin placebo on Day 11), separated by 2 washout periods of 21 days each

For the EFV panel: 2 x 11 days (EFV or EFV placebo on Days 1-11), separated by a washout period of 53 days

Completed

Full report

5.3.4.1

I Refer to 5.3.5.3/0015283: PK/PD report pooled TQT Trials (TMC278-TiDP6-C131/C152)

EFV: efavirenz; N: number of enrolled subjects; PD: pharmacodynamic; PK: pharmacokinetic; TQT: thorough QT.

Continued






5.3.4.1

Moxifloxacin/008 LC-MS/MS Determination of Moxifloxacin in Human Sodium Heparin Plasma Samples Originating From Clinical Trial TMC278-TiDP6-C152

5.3.4.1

Efavirenz/001 HPLC Determination of Efavirenz in Human Sodium Heparin Plasma Samples Originating From Clinical Trial TMC278-TiDP6-C152

5.3.4.1

HPLC: high performance liquid chromatography; LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.

5.3.4 Reports of Human Pharmacodynamic Studies, Cont’d5.3.4.2 Patient Pharmacodynamics and Pharmacokinetic/Pharmacodynamics Study Reports

Refer to 5.3.5.3/0016436: PK/PD report of the combined Phase III trials (TMC278-TiDP6-C209/C215)

PD: pharmacodynamic; PK: pharmacokinetic.



5.3.5 Reports of Efficacy and Safety Studies, Cont’d 5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication

TrialPhase

Trial(Country)


SubjectsN



IIa R278474-C201

(United Kingdom, Germany, Russia)

Randomized, double-blind, placebo-controlled, dose-escalation, proof-of-principle, multiple dose trial

Evaluate the change from baseline in plasma viral load during treatment withmultiple dose (once daily)TMC278 as functional monotherapy

HIV-infected, treatment naïvemale subjects

(with documented absence of resistance)

47

Panel 1: once daily dose of TMC278 25 mg or matching placebo, under fed conditions




Solution – oral

7 days

Completed

Full report

5.3.5.1

HIV: human immunodeficiency virus; N: number of enrolled subjects.


R278474/016 LC-MS/MS Determination of R278474 in Human Heparin Plasma Originating From Clinical Trial R278474-C201 5.3.5.1





Trial Phase

Trial (Country)


SubjectsN



IIb TMC278-C204

(Argentina, Austria, Brazil, China, Germany, France, United Kingdom, Mexico, Puerto Rico, Russia, Thailand, Uganda, USA, SouthAfrica)

Randomized, partially blinded, active-controlled, dose finding, multiple dosetrial. All subjects could enter an optional open label trial extension up to 240 weeks. After 240 weeks, subjects on TMC278 will have the option to enter into another open label trial extension

Evaluate the dose-response relationship of antiviral efficacy (plasma viral load < 50 HIV-1 RNA copies/mL, according to TLOVR algorithm) at 48 weeks treatment with multiple dose TMC278

HIV-infected, treatment naïvesubjects

368

Once daily dose of TMC278 25, 75, or 150 mg, under fed conditions, or once daily dose of EFV 600 mg, under fastedconditions, for 96 weeks (each plus 2 investigator selected N[t]RTIs: AZT/3TC or TDF/FTC)

Once daily dose of TMC278 75 mg, under fed conditions, or once daily dose of EFV 600 mg, under fasted conditions, up to approximately Week 144 (each plus 2 investigator selected N[t]RTIs: AZT/3TC or TDF/FTC)

Once daily dose of TMC278 25 mg, under fed conditions,from approximately Week 144 onwards (plus 2 investigator selected N[t]RTIs: AZT/3TC or TDF/FTC)


240 weeks (+ optional extension)


Week 48 Report Body

5.3.5.1

Population Pharmacokinetic Week 48 Report

5.3.5.1

Week 96 Full Report

5.3.5.1

Population Pharmacokinetic Week 96 Report

5.3.5.1

Week 192 Statistical Analyses

5.3.5.1

Serious Adverse Event Week 192 Report

5.3.5.3

AZT: zidovudine; EFV: efavirenz; FTC: emtricitabine; HIV: human immunodeficiency virus; N: number of enrolled subjects; N[t]RTIs: nucleoside[tide] reverse transcriptase inhibitors; RNA: ribonucleic acid; 3TC: lamivudine; TDF: tenofovir disoproxil fumarate; TLOVR: time to loss of virologic response.

Continued





ABL8058 The Determination of Zidovudine and Zidovudine-glucuronide in Human Plasma Samples, Derived From Tibotec Clinical Trial TMC278-C204, Using LC-MS/MS

5.3.5.1

TMC278/032 LC-MS/MS Determination of TMC278 in Human Heparin Plasma Samples Originating From Clinical Trial TMC278-C204

5.3.5.1





Trial Phase

Trial (Country)


SubjectsN



III TMC278-TiDP6-C209

(Argentina, Australia, Austria, Brazil, Canada, Denmark, France, Italy, Mexico, Portugal, Puerto Rico, Romania, Russia, South Africa, Spain, Sweden, Taiwan, Thailand, The Netherlands, United Kingdom, USA)

Randomized, double-blind, double-dummy, active-controlled, multiple dose trial

Demonstrate non-inferiority of treatment with multiple dose TMC278 compared to control (EFV) in regard tothe proportion of virologic responders (plasma viral load < 50 HIV-1 RNA copies/mL, according to TLOVR algorithm) at 48 weeks, with a maximum allowable difference of 12%

HIV-infected, treatment naïve

subjects

694

Once daily dose of TMC278 25 mg, under fed conditions,and once daily dose of EFV placebo, under fastedconditions, (each plus TDF/FTC as background regimen),or Once daily dose of EFV 600 mg, under fasted conditions,and once daily dose of TMC278 placebo, under fed conditions, (each plus TDF/FTC as background regimen)


96 weeks


Week 48 Full Report

5.3.5.1

Reports of SAEs

5.3.5.3

A DEXA sub-study is currently ongoing, Week 96 results will be reported in a separate report.

EFV: efavirenz; FTC: emtricitabine; HIV: human immunodeficiency virus; N: number of enrolled subjects; RNA: ribonucleic acid; TDF: tenofovir disoproxil fumarate; TLOVR: time to loss of virologic response.


TMC278/054 (interim) LC-MS/MS Determination of TMC278 in Human Heparin Plasma Samples Originating From Clinical Trial TMC278-TiDP6-C209 5.3.5.1





Trial Phase

Trial (Country)


SubjectsN



III TMC278-TiDP6-C215

(Australia, Belgium, Brazil, Canada, Chile, China, Costa Rica, France, Germany, India, Italy, Mexico, Panama, Portugal, Puerto Rico, Russia, South Africa, Spain, Thailand, United Kingdom, USA)

Randomized, double-blind, double-dummy, active-controlled, multiple dose trial

Demonstrate non-inferiority of treatment with multiple dose TMC278 compared to control (EFV) in regard to the proportion of virologic responders (plasma viral load < 50 HIV-1 RNA copies/mL, according to TLOVR algorithm) at 48 weeks, with a maximum allowable difference of 12%

HIV-infected, treatment naïve

subjects

680

Once daily dose of TMC278 25 mg, under fed conditions,and once daily dose of EFV placebo, under fasted conditions, (each plus 2 investigator selected N[t]RTIs: ABC/3TC, AZT/3TC, or TDF/FTC),or Once daily dose of EFV 600 mg, under fasted conditions, and once daily dose of TMC278 placebo, under fed conditions, (each plus 2 investigator selected N[t]RTIs: ABC/3TC, AZT/3TC, or TDF/FTC)


96 weeks


Week 48 Full Report

5.3.5.1

Reports of SAEs

5.3.5.3

A DEXA sub-study is currently ongoing, Week 96 results will be reported in a separate report.

ABC: abacavir; AZT: zidovudine; EFV: efavirenz; FTC: emtricitabine; HIV: human immunodeficiency virus; N: number of enrolled subjects; N[t]RTIs: nucleoside[tide] reverse transcriptase inhibitors; RNA: ribonucleic acid; 3TC: lamivudine; TDF: tenofovir disoproxil fumarate; TLOVR: time to loss of virologic response.


TMC278/056 (interim) LC-MS/MS Determination of TMC278 in Human Heparin Plasma Samples Originating From Clinical Trial TMC278-TiDP6-C215 5.3.5.1




5.3.5 Reports of Efficacy and Safety Studies, Cont’d 5.3.5.2 Study Reports of Uncontrolled Clinical Studies

Trial Phase

Trial (Country)


SubjectsN



IIa R278474-C202

(Austria, France, Germany, United Kingdom, Italy, Russia)

Randomized, open label, proof-of-principle, multiple dose trial

Evaluate the change from baseline in plasma viral load during treatment withmultiple dose (once daily)TMC278 as functional monotherapy

HIV-1 infected subjects with

NNRTIexperience

and/or genotypic evidence of

NNRTI resistance associated mutations

36

Once daily dose of TMC278 25 mg, 50 mg, or 150 mg in combination with background regimen (N[t]RTIs, plus enfuvirtide, if applicable), under fed conditions

Solution (TMC278) – oral

7 days

Completed

Full report

5.3.5.2

HIV: human immunodeficiency virus; N: number of enrolled subjects; NNRTI: non-nucleoside reverse transcriptase inhibitor; N[t]RTIs: nucleoside[tide] reverse transcriptase inhibitors.


R278474/023 LC-MS/MS Determination of R278474 in Human Heparin Plasma Originating From Clinical Trial R278474-C202 5.3.5.2




5.3.5 Reports of Efficacy and Safety Studies, Cont’d 5.3.5.2 Study Reports of Uncontrolled Clinical Studies

Trial Phase Trial


SubjectsN



II TMC278-TiDP38-C213 Open label, single arm trial

Determine the effect of steady-state (multiple dose) pharmacokinetics and short-term safety and efficacy of TMC278 in adolescents

HIV-1 infected treatment naïve

adolescents (≥ 12 to

< 18 years)

35

Once daily dose of TMC278 25 mg, under fed conditions, plus 2 investigator selected N(t)RTIs: AZT/3TC or ABC/3TC

Tablets (TMC278) – oral

48 weeks

Planned/Available 2Q2013

Full report

5.3.5.2

II TMC278-TiDP38-C220a Trial will be conducted in children < 12 years

Design will depend on the conduct and outcome of the TMC278-TiDP38-C213 trial

HIV-1 infected treatment naïve

children (< 12 years)

Dosage regimen, route of administration, and duration of treatment will depend on the conduct and outcome of the TMC278-TiDP38-C213 trial

Oral

Planned/Available 2Q2017

Full report

5.3.5.2

a Protocol not available.

ABC: abacavir; AZT: zidovudine; HIV: human immunodeficiency virus; N: number of enrolled subjects; N(t)RTIs: nucleoside(tide) reverse transcriptase inhibitors;3TC: lamivudine.



5.3.5 Reports of Efficacy and Safety Studies, Cont’d5.3.5.3 Reports of Analyses of Data From More Than One Study

Trial Trial Title

Type of ReportTrial Report Location in CTD Modules

TMC278-C906 Statistical Analysis: Clinical Safety: Phase I Summary of Clinical Safety

2.7.4

Statistical Analyses

5.3.5.3

TMC278-C904 - Statistical Analysis: Clinical Safety: Phase III

- Statistical Analysis: Clinical Efficacy: Phase III

Summary of Clinical Safety

2.7.4

Summary of Clinical Efficacy

2.7.3

Statistical Analyses

5.3.5.3

TMC278-0015283 Pharmacokinetic/pharmacodynamic modeling and simulation of the effect of TMC278 on QTcF prolongation, based on pooled data from clinical trials TMC278-TiDP6-C131 and TMC278-TiDP6-C152 in healthy volunteers

Pharmacokinetic/ Pharmacodynamic Report

5.3.5.3

TMC278-0016435 TMC278 Phase III population pharmacokinetic modeling (48 weeks), empirical Bayesian feedback and covariate analysis

Population Pharmacokinetic Report

5.3.5.3

TMC278-0016436 Modeling (GAM) of the 48-week decrease in viral load and increase in CD4 count to explore the relationship with TMC278 exposure and other prognostic factors for the Phase III trials of TMC278

Population Pharmacokinetic/Pharmacodynamic Report

5.3.5.3

TMC278-Ongoing-Trials TMC278-TiDP6-C154, TMC278-C204, TMC278-TiDP6-C209, TMC278-TiDP6-C215, TMC278-HIV1001 Reports of SAEs

5.3.5.3



5.3.5 Reports of Efficacy and Safety Studies, Cont’d5.3.5.4 Other Study Reports

Trial Trial Title


TMC278-IV1-AVMR Mechanism of action and in-vitro antiviral activity of TMC278 against wild type and NNRTI-resistant HIV

Completed

Virology Report

Raw Data

5.3.5.4

TMC278-IV2-AVMR Mechanism of action and in-vitro antiviral activity of TMC278 against wild type and NNRTI-resistant HIV (Part 2)

Completed

Virology Report

Raw Data

5.3.5.4

TMC278-C204-W96-AVMR

Exploratory analysis of genotypic and phenotypic changes observed in the TMC278-C204 clinical trial virological failures (rebound and never suppressed) by Week 96 (primary endpoint)

Completed

Virology Report

5.3.5.4

TMC278-C204-W192-AVMR

Exploratory analysis of genotypic and phenotypic changes observed in the TMC278-C204 clinical trial virological failures (rebound and never suppressed) on or before Week 192

Completed

Virology Report

5.3.5.4

TMC278-C209-C215-C904-W48-AVMR

Exploratory analyses of genotypic and phenotypic changes observed in the TMC278-TiDP6-C209 and TMC278-TiDP6-C215 clinical trials virological failures (rebound and never suppressed) by Week 48

Completed

Virology Report

5.3.5.4

HIV: human immunodeficiency virus; NNRTI: non-nucleoside reverse transcriptase inhibitor.

Continued



5.3.5 Reports of Efficacy and Safety Studies, Cont’d5.3.5.4 Other Study Reports

Trial Trial Title


TMC278-C904-LLV-AVMR

Exploratory analyses of genotypic and phenotypic characteristics of HIV-1 recombinant clinical isolates obtained from a subset of subjects from the TMC278-TiDP6-C209 and TMC278-TiDP6-C215 clinical trials having persistent low level viremia or displaying viral load blips on or before Week 48, when viral load is determined using the Taqman assay

Completed

Virology Report

5.3.5.4

NPR-20060022-VRR-V5 List of Non-Nucleoside Reverse Transcriptase Inhibitor Resistance-Associated Mutations

Completed

Virology Report

5.3.5.4

NPR-20060022-VRR-V6 List of Non-Nucleoside Reverse Transcriptase Inhibitor Resistance-Associated Mutations

Completed

Virology Report

5.3.5.4

HIV: human immunodeficiency virus.



5.3.6 Reports of Post-marketing Experience

Trial Trial Title


Not applicable



5.3.7 Case Report Forms and Individual Patient Listings

Trial Trial Title


Individual CRFs on all subjects for whom narratives are provided will be included in the NDA, not in the MAA

NDA: New Drug Application; MAA: Marketing Authorization Application.

1.13 EU

1

EUAtripla Module 5

J

ED

I_D

EV

00 \

0900

fde9

8041

7d91

\ 1.

18 \

2013

-11-

13 2

0:55

1.13 EU

2

IV

TMC278IFD40051 5.3.3.1.1 TMC278 25 mg

TMC278

10 TMC27825 mg

8

1

I

TMC278-TiDP6-C1541

5.3.3.4.35 omeprazole 20 mg 1 1TMC278 25 mg

50 mgTMC278

4

A TMC278 25 mg

B omeprazole 20 mg 1 1 7 1

6 omeprazole1.5 TMC278 25 mg

C

omeprazole 20 mg 1 1 66 omeprazole

12 TMC278 25 mg

D omeprazole 20 mg 1 1 7 1

6 omeprazole1.5 TMC278 50 mg

TMC278

17

2

JEDI_DEV00 \ 0900fde980417d91 \ 1.18 \ 2013-11-13 20:55

1.13 EU

3

I

TMC278HIV10011 5.3.3.4.36 Efavirenz (EFV) 600 mg 2

TMC278 1 1

A

TMC278 25 mg 1 1 14

B EFV 600 mg 1 1 14

C

TMC278 1 1 28

A B 14 21

B C

20

3

IIb

TMC278-C2041 5.3.5.1.2-4 3 TMC278 48

-

96

96 144 TMC278 TMC278 75mg 1 1

EFV 600 mg 1 1

N(t)RTI 144 240 TMC278 TMC278 25 mg 1 1

N(t)RTI

TMC278: 279

: 89

HIV-1 240

4

JEDI_DEV00 \ 0900fde980417d91 \ 1.18 \ 2013-11-13 20:55

1.13 EU

4

IIb

TMC278-C2041 5.3.5.1.2-5 3 240

2240 TMC278

TMC278

TMC278

TMC278-TiDP6-C222

TMC278

240

240 TMC278 25 mg 1 1

N(t)RTI

166 HIV-1 240

III

TMC278-TiDP6-C2091

5.3.5.1.3-2 HIV-1

48

TMC278 25 mg 11 EFV 600 mg 1 112%

TMC278 TMC278 25 mg 1 1EFV 600 mg 1 1

TDF/FTC

TMC278: 346

: 344

HIV-1 96

5

III

TMC278-TiDP6-C2091

5.3.5.1.3-3 96 TMC278 96

96database lock

TMC278 TMC278 25 mg 1 1EFV 600 mg 1 1

TDF/FTC

TMC278: 268

: 270

HIV-1 96

JEDI_DEV00 \ 0900fde980417d91 \ 1.18 \ 2013-11-13 20:55

1.13 EU

5

III

TMC278-TiDP6-C2151

5.3.5.1.4-2 HIV-1

48

TMC278 25 mg 11 EFV 600 mg 1 112%

TMC278 TMC278 25 mg 1 1EFV 600 mg 1 1

N(t)RTI

TMC278: 340

: 338

HIV-1 96

6

III

TMC278-TiDP6-C2151

5.3.5.1.4-3 96 TMC278 96

96database lock

TMC278 TMC278 25 mg 1 1EFV 600 mg 1 1

N(t)RTI

TMC278: 274

: 263

HIV-1 96

III

GS-01-9342 5.3.5.1.11-3 144 240

EFV/TDF/FTC 240

CBV1 2 EFV1 1

EFV/TDF/FTC

144 EFV(600 mg)/ FTC (200 mg)/ TDF (300 mg) 1

1

286 HIV-1 168Clinical

Summary

JEDI_DEV00 \ 0900fde980417d91 \ 1.18 \ 2013-11-13 20:55

1.13 EU

6

III

GS-01-9342 5.3.5.1.11-4 144 240288

EFV/TDF/FTC 288

CBV1 2 EFV1 1

EFV/TDF/FTC

144 EFV(600 mg)/ FTC (200 mg)/ TDF (300 mg) 1

1

286 HIV-1 240 288

1 EU 2 Atripla

JEDI_DEV00 \ 0900fde980417d91 \ 1.18 \ 2013-11-13 20:55

R278474-C102 1

Clinical Research Report Version: 1.0 Date: 21-Jun-2005

SYNOPSIS Trial Identification and Protocol Summary

Company: Tibotec Pharmaceuticals Ltd. Trade Name: Indication: HIV-1 infection

Drug Substance: R278474 Trial no.: R278474-C102 Clinical Phase: I

Title: A Phase I, open-label, randomized, three-way cross-over trial in two panels of 12 subjects each to establish the relative oral bioavailability of two experimental solid formulations of R278474 versus the current oral solution formulation of R278474 and the effect of food on the bioavailability of these formulations. Investigator:

Belgium

Country: Belgium

Trial Period: Start: - -20 End: - -20

No. of Investigators: 1 No. of Subjects: 24

Objectives: The objectives of this Phase I trial were: to establish the relative oral bioavailability of R278474 administered as 2 experimental solid formulations relative to the oral solution under fed conditions; to evaluate the effect of food on the bioavailability of R278474 administered as 2 experimental solid formulations; to monitor the safety and tolerability of single doses of R278474 in healthy subjects.

Design: This was a Phase I, open-label, randomized, three-way crossover trial in 2 panels of 12 healthy subjects to investigate the bioavailability of 2 experimental solid formulations of R278474 (Treatments B and C), relative to a reference oral solution formulation (Treatment A). The effect of food on the bioavailability of Treatments B and C was also studied. Per panel, each subject received 3 single doses, each equivalent to 100 mg R278474 base. One panel of subjects took single doses of Treatment A after a standardized breakfast, Treatment B after a standardized breakfast, and Treatment B in the fasted state, in a randomized order, and the other panel of subjects received Treatment C instead of Treatment B. Safety and tolerability was assessed on an ongoing basis. There was at least a 2-week washout period between all doses. Blood samples were obtained for pharmacokinetic analysis predose and up to 216 hours after each dose. Subject Selection Inclusion Criteria

1. Aged between 18 and 55 years, extremes included. 2. Smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day (or non-smoking) for at least 3 months prior to selection. 3. Normal weight as defined by a Quetelet Index (Body Mass Index: weight in kg divided by the square of height in meters) of 18 to 30 kg/m2, extremes included. 4. Informed consent form signed voluntarily before first trial-related activity. 5. Cortisol of at least 550 nmol/L (19.9 g/dL) at any time at screening (i.e., morning cortisol, 30 or 60 minutes after 250 g adrenocorticotropic hormone [ACTH] stimulation). 6. Able to comply with protocol requirements. 7. Healthy on the basis of a pre-trial physical examination, medical history, electrocardiogram (ECG), vital signs, and the results of blood biochemistry and hematology tests and a urinalysis carried out within 2 weeks before the first dose.

Exclusion Criteria1. A positive HIV test at trial screening. 2. Female, except if postmenopausal for more than 2 years, or posthysterectomy or post tubal ligation (without reversal operation). 3. History or suspicion of alcohol, barbiturate, amphetamine, or narcotic drug use that in the investigator’s opinion could compromise the subject’s safety or ability to comply with trial procedures. 4. Hepatitis A infection (confirmed by Hepatitis A antibody IgM), or Hepatitis B infection (confirmed by Hepatitis B surface antigen), or Hepatitis C infection (confirmed by Hepatitis C virus antibody) at trial screening.

Synopsis

R278474-C102 2


Exclusion Criteria, continued

5. A positive urine drug test at trial screening. Urine was tested for the presence of amphetamines, benzodiazepines, cocaine, cannabinoids, and opioids. 6. Currently active or underlying gastrointestinal, cardiovascular, neurologic, psychiatric, metabolic, renal, hepatic, respiratory, inflammatory, or infectious disease. 7. Any current or previous adrenal illness. 8. Currently significant diarrhea, gastric stasis, or constipation that in the investigator’s opinion could influence drug absorption or bioavailability. 9. Any history of significant skin disease such as but not limited to drug rash or eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis, or urticaria. 10. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication. 11. Use of concomitant medication, including over the counter products and dietary supplements, except for ibuprofen up to 3 days before the first dose of trial medication. All other medication had to be discontinued at least 14 days before the first dose of trial medication. 12. Participation in an investigational drug trial within 30 days prior to the first intake of trial medication. 13. Donation of blood in the 60 days preceding the first intake of trial medication. 14. Subjects with the following laboratory abnormalities at screening as defined by the enhanced toxicity grading severity list: serum creatinine grade 1 or greater; pancreatic amylase or lipase grade 1 or greater; hemoglobin toxicity grade 1 or greater; platelet count grade 1 or greater; absolute neutrophil count grade 1 or greater; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) grade 1 or greater; total bilirubin grade 1 or greater; any other toxicity grade 2 or above, including proteinuria (spot urine) > 1+ and gross hematuria. 15. Having previously participated in a trial with R278474, TMC120, or TMC125.

Treatment Treatment A Treatment B Treatment C Concentration Dosage Form (TF No.) Usage

25 mg/mL R278474 in 100% PEG400 (100 mg base)

Solution (F002)

4 mL p.o.

50 mg R278474 per capsule with beads

(R278474:HPMC = 1:3) (50 mg base)

Capsules (F003)

2 capsules p.o.

100 mg R278474 equivalent (110 mg R314585; HCl salt

of R278474) per tablet 100 mg base equivalent

Tablets (F002)

1 tablet p.o.

Batch Number 04C15/F002 04C17/F003 04C22/F002 Dose Regimen A single dose, equivalent to 100 mg R278474 base, on Day 1 of each of the 3 sessions

with a washout period of at least 2 weeks between administrations. Treatment A after a standardized breakfast (n=24), Treatment B or Treatment C after a standardized breakfast (n=12), and Treatment B or Treatment C in the fasted state (n=12).

Duration of Treatment 3 x 1 day Duration of Trial 39 days (excluding screening and follow-up) Disallowed Medication During the entire trial, subjects were not allowed to use any medication other than the

trial medication. All medication, including herbal medication and dietary supplements, had to be discontinued at least 14 days before administration of trial medication, except for ibuprofen. Ibuprofen was allowed up to 3 days before administration of trial medication. After that, the clinical investigator could permit the use of ibuprofen (until 5 days after trial medication intake at no more than 1 x 400 mg per day). In case of cutaneous event/rash (grade 1) and/or an allergic reaction (grade 1 and 2), the use of cetirizine, topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In case of nausea (grade 1 and 2), the use of antiemetics was permitted. In case of diarrhea (grade 1 and 2), the use of loperamide was allowed.

Synopsis

R278474-C102 3


Assessments Screeninga Session I, II, and III Follow-upk

Day 1

14

days

Day

–1

Predose Postdose Day

2

Day

s 3-6

Day

7

Day

s 8-1

0

Day 31, 32, or 33

Drug screening X Alcohol breath test X X Pharmacokinetics Blood sample

Xd

Xe

Xf

Xg

Xh

Xi

Safety Adverse eventsb X X X X X X X X Concomitant meds X X X X X X X X Hemat & biochemc X Xd Xj X X X Urinalysis X Xd X X X Morning cortisol & ACTH stim test

X X

ECG & vital signs X Xd Xj X X X Skin exam X Physical exam X X X

meds = medication; Hemat & biochem = hematology & biochemistry; ACTH = adrenocorticotropic hormone; stim = stimulation; ECG = electrocardiogram; exam = examination. a At screening, subject’s demographics and characteristics, medical and surgical history, concomitant diseases, HIV, and Hepatitis A, B and C test; a serum pregnancy test was also performed if applicable. b Adverse events were monitored continuously from signing of the informed consent to final trial related visit. c Biochemistry samples were taken fasting for at least 10 hours with the exception of the 4-hour post-dose sample on Day 1. d Within 2 hours before R278474 intake and (if applicable) before breakfast. e Samples taken at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours postdose. f Samples taken at 24 and 32 hours postdose. g Samples taken at 48 hours (Day 3), 72 hours (Day 4), 96 hours (Day 5), and 120 hours (Day 6) postdose. h Sample taken at 144 hours postdose. i Samples taken at 168 hours (Day 8) and 216 hours (Day 10) postdose. j At 4 hours postdose. k In case of dropout, for other reasons than withdrawal of consent, additional blood and urine samples for safety were taken, additional ECG and vital signs were recorded, and a physical examination was performed at the time of dropout or the following morning, 7 days after dropout, and 30, 31, or 32 days after dropout. Additional blood samples for pharmacokinetics were also taken at the time of dropout or the following morning. In case of dropout, a morning cortisol and ACTH stimulation test was performed 7 days after dropout (in fasted subjects). Statistical Methods Descriptive statistics, frequency tabulations, graphical presentations, linear mixed effects

modeling, Wilcoxon matched-pairs signed-ranks test.

Synopsis

R278474-C102 4


Main Features of the Subject Sample and Summary of the Results

Baseline Characteristics - Subject Disposition

Panel 1 Treatments A and B

(F002 and F003)

Panel 2 Treatments B and C

(F003 and F002) Number of Subjects Entered (Male/Female) Age (yrs): median (range)

12/0 42.0 (25 - 55)

12/0 35.5 (25 - 53)

Dropouts 0 0

Pharmacokinetics Panel 1 Least Square Means Parameter N Treatment A-fed Treatment B-fed ratio % (B/A) 90% CI

Cmax (ng/mL) 12 386 399 103.2 93.7 – 113.7 AUClast (ng.h/mL) 12 14876 13294 89.4 81.9 – 97.5 AUC (ng.h/mL) 12 15489 13870 89.6 82.3 – 97.5 Panel 2 Least Square Means Parameter N Treatment A-fed Treatment C-fed ratio % (C/A) 90% CI

Cmax (ng/mL) 12 370 310 83.8 73.9 – 95.0 AUClast (ng.h/mL) 12 12188 10124 83.1 72.8 – 94.8 AUC (ng.h/mL) 12 12633 10526 83.3 73.0 – 95.1 Panel 1 Least Square Means Parameter N Treatment B-fed Treatment B-fasted ratio % (fed/fasted) 90% CI

Cmax (ng/mL) 12 399 248 160.7 112.6 – 229.2 AUClast (ng.h/mL) 12 13294 8771 151.6 117.6 – 195.3 AUC (ng.h/mL) 12 13870 9141 151.7 117.9 – 195.3 Panel 2 Least Square Means Parameter N Treatment C-fed Treatment C-fasted ratio % (fed/fasted) 90% CI

Cmax (ng/mL) 12 310 181 171.3 129.2 – 227.0

AUClast (ng.h/mL) 12 10124 6931 146.1 124.7 – 171.1 AUC (ng.h/mL) 12 10526 7286 144.5 124.1 – 168.2 N = number of subjects per treatment group; CI = confidence interval; Cmax = maximum plasma concentration; AUClast = area under the plasma concentration-time curve from time of administration until the last measurable or measured time point; AUC = area under the plasma concentration-time curve from time of administration until infinity.

Synopsis

R278474-C102 5


Panel 1 Panel 2 Safety, (n = number of subjects with data)

Trt A N = 12

WO N = 12

Trt B-fed N = 12

WO N = 12

Trt B-fasted N = 12

WO N = 12

Whole Triala

N = 12 Trt A

N = 12 WO

N = 12

Trt C-fed N = 12

WO N = 12

Trt C-fasted N = 12

WO N = 12

Whole Triala

N = 12 Adverse Events (AEs) Most frequently reported AEs (reported in > 1 subject), n (%)

Headache 1 (8.3) 1 (8.3) 3 (25.0) 0 2 (16.7) 2 (16.7) 5 (41.7) 0 0 0 0 1 (8.3) 1 (8.3) 3 (25.0) Hot flush 0 3 (25.0) 0 1 (8.3) 0 0 3 (25.0) 0 0 0 1 (8.3) 0 0 2 (16.7) Catheter site hemorrhage

0 0 0 0 0 0 1 (8.3) 0 2 (16.7) 0 1 (8.3) 0 0 3 (25.0)

Arthralgia 0 0 0 0 0 0 0 0 0 0 1 (8.3) 0 1 (8.3) 2 (16.7) Pharyngola-ryngeal pain

0 0 0 0 0 0 0 0 0 0 1 (8.3) 0 1 (8.3) 2 (16.7)

n (%) with 1 or more AEs

1 (8.3) 6 (50.0) 3 (25.0) 4 (33.3) 2 (16.7) 3 (25.0) 9 (75.0) 1 (8.3) 4 (33.3) 3 (25.0) 6 (50.0) 2 (16.7) 5 (41.7) 11 (91.7)

n (%) of deaths

0 0 0 0 0 0 0 0 0 0 0 0 0 0

n (%) with 1 or more other SAEs

0 0 0 0 0 0 0 0 0 0 0 0 0 0

n (%) of treatment stopped due to AEs

0 0 0 0 0 0 0 0 0 0 0 0 0 0

n (%) with 1 or more grade 3 or 4 AEs

0 0 0 0 0 0 0 0 0 0 0 0 0 0

a Includes events that occurred at Screening. Trt = Treatment; WO = Washout; N = number of subjects per treatment group; SAE = serious AE. Adverse events for each treatment include only those occurring on the day of trial medication intake.

Synopsis

R278474-C102 6


Panel 1 Panel 2

Safety, continued Trt A

N = 12 Trt B-fed

N = 12

Trt B-fasted N = 12

Trt A N = 12

Trt C-fed N = 12

Trt C-fasted N = 12

WO

N = 24 Clinical Laboratory Tests n (%) with 1 or more grade 3 or 4 treatment-emergent laboratory abnormalities

0 0 1 (8.3) 1 (8.3) 0 0 1 (8.3)a

a Panel 2, Day 7 of Session I (Treatment C-fed). Laboratory Tests There were no consistent or clinically relevant treatment-emergent changes over time

in median laboratory parameters. Three grade 4 abnormalities of hyperkalemia were reported, 1 subject in Panel 1 and 2 subjects in Panel 2. All grade 4 hyperkalemia were due to hemolysed samples. No grade 3 abnormalities were reported. Eight subjects had treatment-emergent grade 2 postdose laboratory abnormalities, 4 per panel. In general, the incidence of laboratory abnormalities was similar for the 6 treatment sequences and no trends or relationship to treatment were apparent. No subjects developed a laboratory abnormality that resulted in an AE. Urinalysis indicated occasional abnormalities. For 1 subject, polyuria (possibly related) was reported as a grade 1 AE on the day after R278474 intake in 2 of the 3 sessions (Treatment C-fed and fasted). No abnormalities in urinalysis were observed for this subject. One subject in Panel 2 had abnormal cortisol levels following treatment with R278474 (cortisol 0.55 mol/L). However, the abnormal values observed during Sessions I, II, and III actually constituted a better ‘response’ to ACTH stimulation than that observed at screening, even though the screening values were considered normal. All other subjects had normal adrenal function at all time points measured (screening and at Day 7 of each of the 3 treatment sessions).

Cardiovascular Safety

Minor median changes were reported for vital signs and ECG parameters and only a few were statistically significant. No trends or relationship to treatment were evident and no clinically significant changes in vital signs or ECG were reported.

Physical Examination

Three subjects reported a new abnormality at the follow-up visit (1 case of a swollen left ankle and 2 cases of retromandibular adenopathies bilateral). No skin abnormalities were reported at the follow-up visit.

Conclusions The results of the present trial demonstrate that the newly developed solid formulations of R278474 (capsule and tablet) both provide significant exposure to R278474 which is slightly lower compared to the reference oral solution of R278474. When administered as the tested experimental solid formulations, R278474 should be administered with food to improve the relative oral bioavailability. In these healthy subjects, the administration of R278474 as 3 single oral 100 mg doses, formulations F002 (Treatment A), F003 (Treatment B), and F002 (Treatment C), was considered to be generally safe and tolerable. No apparent differences in AE reporting were observed between the 3 R278474 formulations and no apparent differences in AE reporting were noticed between the administration of the solid formulations (Treatments B and C) under fed or fasted conditions. No clinical grade 3 or 4 AEs were observed and no AEs leading to discontinuation or SAEs were reported.

Synopsis

TMC278-TiDP6-C137 CONFIDENTIAL 3 Clinical Research Report


Company: Tibotec Pharmaceuticals Ltd.

Trade Name: -

Indication: HIV-1 infection

Drug Substance: TMC278

Trial no.: TMC278-TiDP6-C137

Clinical Phase: I

Title: The effect of food on the bioavailability of TMC278 after a single oral dose of 75 mg, formulated as the Phase III tablet, in healthy subjects

Investigator: France

Country: France

Trial Period: Start: - -20

End: - -20

No. of Investigators: 1

No. of Subjects: 20

Objectives: The primary objective of this study was to determine the effect of different types of meals on the bioavailability of TMC278 after a single oral dose of 75 mg, formulated as the Phase III tablet, in healthy subjects.

The secondary objective was to determine the short-term safety and tolerability of TMC278 after single dose administration under fasted and fed conditions in healthy subjects.

Design: This was a Phase I, open-label, randomized 4-way crossover trial in healthy subjects to investigate the effect of different types of meals on the bioavailability of TMC278 after a single oral dose of 75 mg, formulated as the Phase III tablet.

Twenty subjects received 4 different treatments in 4 sessions, separated by a washout period of at least 13 days.

Subjects received, in a randomized fashion, a single dose of 75 mg TMC278 after a standard breakfast (Treatment A), under fasting conditions (Treatment B), after a high-fat breakfast (Treatment C), and after a nutritional drink rich in proteins (Treatment D).

In each session, full pharmacokinetic profiles of TMC278 were obtained up to 168 hours post dose.

Safety and tolerability evaluations were recorded at regular intervals throughout the trial period.

Subject Selection

Inclusion Criteria

1. Aged between 18 and 55 years, extremes included.

2. Non-smoking or smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day for at least 3 months prior to selection.

3. Normal weight as defined by a Quetelet Index (Body Mass Index: weight in kg divided by the square of height in meters) of 18.0 to 30.0 kg/m2, extremes included.

4. Informed Consent Form (ICF) signed voluntarily before first trial-related activity.

5. Able to comply with protocol requirements.

6. Healthy on the basis of a medical evaluation that confirms the absence of any clinically relevant abnormality and includes a physical examination, medical history, electrocardiogram (ECG), vital signs, and the results of blood biochemistry and hematology tests and a urinalysis carried out at screening.

0296617, Final, 08-Dec-2008 14:08

Clinical Research Report Synopsis


Exclusion Criteria

1. A positive human immunodeficiency virus (HIV)-1 or HIV-2 test at trial screening.

2. Female, except if postmenopausal for more than 2 years, or post-hysterectomy, or post-tubal ligation (without reversal operation).

3. History or evidence of current use of alcohol, barbiturate, amphetamine, recreational, or narcotic drug(s), which in the investigator’s opinion would compromise subject’s safety and/or compliance with the trial procedures.

4. Hepatitis A, B, or C infection (confirmed by hepatitis A IgM antibody, hepatitis B surface antigen, or hepatitis C antibody, respectively) at screening.

5. A positive urine drug test at screening. Urine was tested to check the current use of methadone, barbiturates, amphetamines, benzodiazepines, cocaine, cannabinoids, and opioids.

6. Currently active or underlying gastrointestinal, cardiovascular, neurologic, psychiatric, metabolic, renal, hepatic, respiratory, inflammatory, or infectious disease.

7. Current or history of adrenal disorder.

8. Currently significant diarrhea, gastric stasis, or constipation that in the investigator’s opinion could influence drug absorption or bioavailability.

9. Any history of significant skin disease such as, but not limited to, drug rash or eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis, or urticaria.

10. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the medication administered in this trial (i.e., TMC278).

11. Use of concomitant medication, including over-the-counter products, herbal medications, and dietary supplements.

12. Having previously participated in more than 1 trial (single or multiple dose) with TMC125 and/or TMC120, or having developed a rash, erythema, or urticaria while participating in a trial with the aforementioned compounds.

13. Having participated in a trial with TMC278 (formerly known as R278474).

14. Participation in an interventional drug trial within 60 days prior to the first administration of trial medication.

15. Donation of blood or plasma within the 60 days preceding the first administration of trial medication.

16. Subjects with the following laboratory abnormalities at screening as defined by the Division of Acquired Immunodeficiency Syndrome (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (AEs) (“DAIDS grading table”) and in accordance with the normal ranges of the clinical laboratory: serum creatinine grade 1 or greater ( 1.1 x upper limit of laboratory normal range [ULN]); serum lipase grade 1 or greater ( 1.1 x ULN); hemoglobin toxicity grade 1 or greater ( 10.9 g/dL); platelet count grade 1 or greater ( 124.999/mm3); absolute neutrophil count grade 1 or greater ( 1300/mm3); aspartate aminotransferase or alanine aminotransferase grade 1 or greater ( 1.25 x ULN); total bilirubin grade 1 or greater ( 1.1 x ULN); any other toxicity grade 2 or above, including: proteinuria (spot urine) 2+ and microscopic hematuria > 10 red blood cells/high power field.

0296617, Final, 08-Dec-2008 14:08



Treatment Treatment A Treatment B Treatment C Treatment D

Dosage 75 mg TMC278 single dose

75 mg TMC278 single dose



Dosage Form (TF No.) 75 mg tablet (F008) 75 mg tablet (F008) 75 mg tablet (F008) 75 mg tablet (F008)

Usage 1 x 75 mg TMC278 tablet orally after a standard breakfast

on Day 1

1 x 75 mg TMC278 tablet orally under fasting conditions

on Day 1

1 x 75 mg TMC278 tablet orally after a high-fat breakfast

on Day 1

1 x 75 mg TMC278 tablet orally after a

nutritional drink rich in proteins on Day 1

Batch Number PD2115 PD2115 PD2115 PD2115

Dose Regimen Group 1: 75 mg TMC278 single dose in treatment sequence ADBC in 4 separate sessions.

Group 2: 75 mg TMC278 single dose in treatment sequence BACD in 4 separate sessions.

Group 3: 75 mg TMC278 single dose in treatment sequence CBDA in 4 separate sessions.

Group 4: 75 mg TMC278 single dose in treatment sequence DCAB in 4 separate sessions.

In all groups, a washout period of 13 days separated each session from the next.

Duration of Treatment 4 days (1 day per session, excluding washout).

Duration of Trial At least 43 days (excluding screening and follow-up).

Disallowed Medication All over-the-counter medication had to be discontinued at least 7 days before the first intake of trial medication and all prescribed medication had to be discontinued at least 14 days before the first intake of trial medication, except for ibuprofen and paracetamol (acetaminophen). Subjects were not to use any medication other than the trial medication up to 14 days after the last intake of trial medication, except for ibuprofen and paracetamol. Subjects were also not to use any herbal medications or dietary supplements including products containing Hypericum perforatum (e.g., St. John’s wort) from 14 days before the first intake of trial medication and up to 14 days after the last intake of trial medication. Ibuprofen or paracetamol could be used up to 3 days before the first intake of trial medication. After that, the clinical investigator could permit the use of ibuprofen (at no more than 400 mg per day) or paracetamol (at no more than 2 x 500 mg per day). In the event of cutaneous reaction/rash and/or an allergic reaction, the use of cetirizine (Zyrtec ), levocetirizine (Xyzal ), topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In case of nausea, the use of antiemetics was permitted. In case of diarrhea, the use of loperamide was allowed.

0296617, Final, 08-Dec-2008 14:08



Scre

enin

ga

Treatments A, B, C and Db

Follo

w-u

p Assessments

21

days

Day

1c

Day

2d

Day

3

Day

4

Day

6

Day

8

5, 6

or 7

&

30, 3

1, o

r 32

day

s af

ter l

ast

drug

inta

ke

Pharmacokinetics Blood samplee Xf Xg Xg Xg Xg Xg

Safety AEs + concomitant medicationh X X X X X X X X

Hematology & biochemistryi X Xj Xk Xk X Urinalysis X Xj Xk Xk X ECG X Xj X Vital Signsl X Xm X Skin examination X Xn Xn X Physical examination X Xn Xn X a At screening, subject’s demographics, medical and surgical history, smoking habits, and concomitant diseases

were recorded and an HIV-1 and HIV-2 test, hepatitis A, B, and C test and urine drug screening were performed; a serum pregnancy test was also performed for females.

b Treatments were separated by a washout period of at least 13 days. c Subjects were admitted to the unit in the afternoon before Day 1. d First day of washout period. e For determination of TMC278. f Taken immediately before the intake of TMC278 predose, and 0.5, 1, 2, 3, 4, 5, 6, 9, 12, and 16 hours post dose. g Taken 24 hours post dose (Day 2), 48 hours post dose (Day 3), 72 hours post dose (Day 4), 120 hours post dose

(Day 6), and 168 hours post dose (Day 8). h AEs and concomitant medications were monitored continuously from signing the ICF until the last trial-related

activity. i Biochemistry samples were taken fasted for at least 10 hours. j Taken predose within 2 hours before the intake of TMC278. k Performed 24 hours post dose (Day 2) and 168 hours post dose (Day 8). l Blood pressure and pulse. m Recorded predose within 2 hours before the intake of TMC278 and 4 hours post dose. n Performed at predose (Day 1) and 168 hours post dose (Day 8).

Statistical Methods Descriptive statistics, frequency tabulations, intent-to-treat analysis for safety analyses; descriptive statistics, linear mixed effects modeling, nonparametric test (Koch) (for time to maximum plasma concentration [tmax]) for pharmacokinetic analysis.

0296617, Final, 08-Dec-2008 14:08





Group 1 (ADBC)

N = 5

Group 2 (BACD)

N = 5

Group 3 (CBDA)

N = 5

Group 4 (DCAB)

N = 5

All Subjects

N = 20

Number of Subjects entered (M/F) 3/2 5/0 5/0 5/0 18/2

Age: median (range), yrs 38.0 (36-55) 31.0 (21-50) 31.0 (23-34) 35.0 (31-54) 34.5 (21-55)

Drop-Outs - withdrawal of consent

0 1 (20.0%) 1 (20.0%) 0 2 (40.0%)

Pharmacokinetics of TMC278

(mean SD, tmax:median [range])

Standard breakfast

(reference)Fasting conditions

(test 1) High-fat breakfast

(test 2)

Protein-richnutritional drink

(test 3)

n 19 19 19a 18

tmax, h 5.0 (2.0 - 9.0) 4.0 (2.0 - 24.0) 5.0 (3.0 - 9.0) 5.0 (4.0 - 9.0)

Cmax, ng/mL 296.4 ± 117.6 170.2 ± 65.61 279.8 ± 102.6 156.0 ± 59.66

AUClast, ng.h/mL 10340 ± 3894 6230 ± 2339 9717 ± 3535 5437 ± 2421

AUC , ng.h/mL 11450 ± 4431 7202 ± 3024 10670 ± 4331 6094 ± 3047

t1/2term, h 47.98 ± 22.08 54.84 ± 28.25 43.05 ± 17.28 47.29 ± 22.89

Least square mean ratio (90% CI), %

Test 1 vs reference Test 2 vs reference Test 3 vs reference

n - 19 vs 19 19a vs 19 18 vs 19

Cmax - 54.45 (42.92 - 69.07) 92.20 (80.97 - 105.0) 50.17 (39.66 - 63.46)

AUClast - 57.27 (45.72 - 71.75) 92.21 (79.81 - 106.5) 50.25 (41.36 - 61.05)

AUC - 59.02 (46.87 - 74.32) 90.94 (78.52 - 105.3) 50.55 (41.50 - 61.56) AUC = area under the plasma concentration-time curve CI = confidence interval Cmax = maximum plasma concentrationtmax = time to maximum plasma concentration t1/2term = terminal elimination half-lifea n=18 for AUClast, AUC and t1/2term

0296617, Final, 08-Dec-2008 14:08



Safety

(n = number of subjects with data)

Treatment A

N = 19

Treatment B

N = 19

Treatment C

N = 19

Treatment D

N = 18

All Subjects

N = 20

AEs

n (%) with 1 or more AEs 3 (15.8) 1 (5.3) 2 (10.5) 0 5 (25.0)

Diarrhea 0 1 (5.3) 0 0 1 (5.0)

Gastroenteritis 0 0 1 (5.3) 0 1 (5.0)

Puncture site pain 1 (5.3) 0 0 0 1 (5.0)

Rhinitis 1 (5.3) 0 0 0 1 (5.0)

Headache 0 0 1 (5.3) 0 1 (5.0)

Hot flush 1 (5.3) 0 0 0 1 (5.0)

n (%) deaths, serious adverse events, AEs leading to withdrawal, or grade 3 or 4 AEs 0 0 0 0 0

There was no predominance of AEs during each treatment and none of the reported AEs were experienced by > 1 subject. The only system organ class to contain > 1 subject experiencing an event was infections and infestations (gastroenteritis and rhinitis). No skin events of interest were experienced. The AE of hot flush experienced during Treatment A was considered possibly related to TMC278; all other AEs were considered doubtful or not related to TMC278. Most AEs were grade 1 in severity, with a small number of grade 2 events also experienced.

Clinical Laboratory Tests

All subjects experienced at least one treatment-emergent graded abnormality, most of which were grade 1 or 2. One grade 4 laboratory abnormality was experienced during the trial; hyponatremia by 1 subject (5.3%) during Treatment C. A total of 15 grade 3 treatment-emergent laboratory abnormalities were reported by 8 subjects (40.0%) during the trial. The majority of treatment-emergent, graded laboratory abnormalities were reported for phosphorous (grade 2 and 3 [6 subjects reported grade 3 abnormalities across on at least 1 occasion during the trial]), total cholesterol (grade 1 and 2), and direct low density lipoprotein (grade 1, 2, and one grade 3 abnormality). No differences in the frequency of laboratory abnormalities between the treatments were observed. Non-graded abnormalities were most frequently experienced for hematological parameters; however, the number of subjects affected was low (approximately 1 to 3 subjects per treatment for each parameter). There were no AEs reported for laboratory abnormalities.


Results for vital signs indicated minor variations over time that were not considered clinically relevant. Nine subjects (45.0%) experienced treatment-emergent abnormalities in vital signs; however, the number of subjects experiencing abnormalities for each vital signs parameter was low (4 subjects, 20.0% or fewer per parameter).

No subjects experienced any treatment-emergent abnormalities for QTcF or QRS. Three male subjects (15.0%) experienced increases in QTcB between 30 and 60 msec, 1 pre-dose, Treatment D (Session 3 for that subject), and 2 during follow-up; however, the resulting QTcB values were not abnormal (> 450 msec). Three subjects (15.0%) experienced treatment-emergent abnormalities for HR, and 1 subject for PR. There were no AEs reported for cardiovascular abnormalities.


There were no safety concerns revealed by physical examination and no AEs were reported as a result of the physical examinations.

0296617, Final, 08-Dec-2008 14:08



Conclusions

The results of this study demonstrate that the exposure (expressed as Cmax, AUClast and AUC to TMC278 was 40-50% lower when TMC278 was administered under fasting conditions or after a protein-rich nutritional drink, compared to TMC278 administered after a standard breakfast. Administration of TMC278 after a high-fat breakfast or after a standard breakfast resulted in similar exposures. TMC278 should therefore be administered with a meal to enhance the absorption and exposure. TMC278 was well-tolerated, and did not elicit any clinically relevant safety issues.

0296617, Final, 08-Dec-2008 14:08


FINAL CLINICAL STUDY REPORT

Study Title: Bioequivalence Study of Two, Fixed-dose, Combination Tablet Formulations Containing Emtricitabine, Rilpivirine, and Tenofovir Disoproxil Fumarate Compared to the Concurrent Administration of the Individual Components

Name of Test Drug: Emtricitabine (FTC), rilpivirine (RPV), and tenofovir disoproxil fumarate (TDF)

Dose and Formulation: Fixed-dose combination (FDC) tablet containing emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir disoproxil fumarate 300 mg (FTC/RPV/TDF)

200-mg strength capsule of emtricitabine, 25-mg strength tablet of rilpivirine, and 300-mg strength tablet of tenofovir disoproxil fumarate (FTC+RPV+TDF)

Indication: HIV-1 Infection

Sponsor: Gilead Sciences, Inc. 333 Lakeside Drive Foster City, CA 94404

Study No.: GS-US-264-0103

Phase of Development: Phase 1

IND No.: EudraCT No.:

106,252 Not applicable

Study Start Date: 20 (First Subject Screened) Study End Date: 20 (Last Subject Observation)

Principal or Coordinating Investigator:

USA

Gilead Responsible Medical Monitor:

Name: Telephone: Fax:

Report Date: 27 July 2010

CONFIDENTIAL AND PROPRIETARY INFORMATION This study was conducted in accordance with the guidelines of Good Clinical Practice,

including archiving of essential documents.

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Fixed-Dose Combination Study GS-US-264-0103 Final Clinical Study Report Final

CONFIDENTIAL Page 2 27JULY2010

STUDY SYNOPSIS Study GS-US-264-0103:

Gilead Sciences, Inc. 333 Lakeside Drive

Foster City, CA 94404 United States of America

Title of Study: Bioequivalence Study of Two, Fixed-dose, Combination Tablet Formulations Containing Emtricitabine, Rilpivirine, and Tenofovir Disoproxil Fumarate Compared to the Concurrent Administration of the Individual Components

Investigator:

Study Centers: Single Phase 1 center in the US ( )

Publications: None

Study Period: 20 (First subject screened) 20 (Last subject observation)


Objectives: The primary objective of this study was as follows:

To evaluate the bioequivalence of two fixed-dose combination (FDC) tablets, each containing emtricitabine (FTC) 200 mg, rilpivirine (RPV) 25 mg, and tenofovir disoproxil fumarate (TDF) 300 mg (FTC/RPV/TDF), compared to a 200-mg strength capsule of FTC, a 25-mg strength tablet of RPV, and a 300-mg strength tablet of TDF taken concurrently under fed conditions

The secondary objective of this study was as follows:

To evaluate the safety of FTC, RPV, and TDF when administered together, either as FDC tablets or individual dosage forms in healthy volunteers

Methodology: This was a Phase 1, randomized, open-label, single-center, single-dose, 3-way crossover study that evaluated the relative bioequivalence of two FDC tablets (FTC/RPV/TDF FDC test formulations 3 and 4, each containing FTC 200 mg, RPV 25 mg, and TDF 300 mg) compared to concurrent administration of the individual components under fed conditions. Eligible subjects were randomized to one of six treatment sequences and received 1 dose of study drug on the second day of three consecutive 14-day periods (i.e., study Days 1, 15, and 29). Periods 1 and 2 were followed by a 14-day washout. Following period 3 dosing, subjects returned to the study center 14 days after the last dose for a follow-up visit.



Number of Subjects (Planned and Analyzed): Planned: 36 to get 24 evaluable Analyzed: Safety Pharmacokinetics (PK) 35 Treatment A (FTC+RPV+TDF reference) 34 FTC 34 Treatment B (FTC/RPV/TDF FDC test formulation 3) 34 RPV 35 Treatment C (FTC/RPV/TDF FDC test formulation 4) 34 TDF

Diagnosis and Main Criteria for Inclusion: Eligible subjects were healthy males and nonpregnant, nonlactating females between 18 and 45 years of age (inclusive) with a body mass index (BMI) between 19 and 30 (inclusive), no significant medical history, normal renal function, and in good general health, as determined by the investigator at screening evaluation performed no more than 28 days prior to the scheduled first dose of study drug.

Duration of Treatment: Three single doses 14 days apart over 29 days

Test Product, Dose, Mode of Administration, and Lot No.: Treatment B (FTC/RPV/TDF FDC test formulation 3): A single dose of FDC tablet containing FTC 200 mg, RPV 25 mg (as 27.5 mg of the hydrochloride salt), and TDF 300 mg (Lot BY1001B1) administered orally in the morning and within 5 minutes of consuming a standardized meal.

Treatment C (FTC/RPV/TDF FDC test formulation 4): A single dose of FDC tablet containing FTC 200 mg, RPV 25 mg (as 27.5 mg of the hydrochloride salt), and TDF 300 mg (Lot BY1002B1) administered orally in the morning and within 5 minutes of consuming a standardized meal.

Reference Therapy, Dose, Mode of Administration, and Lot No.:

Treatment A (reference): A single dose of FTC 1 200-mg strength capsule (Lot 56766AF21), RPV 1 25-mg strength tablet (as 27.5 mg of the hydrochloride salt) (Lot 9CL1F), and TDF 1 300-mg strength tablet (Lot A117181A) administered together orally in the morning and within 5 minutes of consuming a standardized meal

Criteria for Evaluation: Efficacy: Not applicable; efficacy was not evaluated in this study.

Pharmacokinetics: The following plasma PK parameters of FTC, RPV, and tenofovir (TFV) were computed: Cmax, Tmax, Clast, Tlast, z, AUClast, AUCinf, %AUCexp, and T1/2.

Safety: Adverse events (AEs), routine clinical laboratory tests, complete and symptom-driven physical examinations, vital signs, electrocardiograms (ECGs), and concomitant medications were monitored throughout the study period.



Statistical Methods: Efficacy: Not applicable; efficacy was not evaluated in this study.

Pharmacokinetics: PK concentration data and parameters for FTC, RPV, and TFV are listed by subject and summarized by treatment using descriptive statistics. A parametric (normal theory) analysis of variance (ANOVA) using a mixed-effects model appropriate for the crossover design was fitted to the natural logarithmic transformation of FTC, RPV and TFV PK parameters AUCinf, AUClast, and Cmax for each treatment pair of interest. To evaluate the bioequivalence of FDC test formulation 3 and FDC test formulation 4 versus the reference treatment, 90% confidence intervals (CIs) were constructed for the ratio of geometric means (test/reference) of AUCinf, AUClast, and Cmax of FTC, RPV and TFV for each test/reference treatment pair. Bioequivalence was to be concluded if the 90% CI lay between the boundary of 80–125% for all primary parameters and for all components for each treatment pair of interest.

Safety: All safety data collected on or after the date of the first dose of the test product up to 30 days after the last dose of study drug were listed by subject and summarized by treatment group using descriptive statistics.

SUMMARY – RESULTS: Subject Disposition and Demographics: Thirty-six eligible subjects were enrolled and randomized, 6 subjects in each of the 6 treatment sequences. Thirty-four of the 36 randomized subjects completed the study; 1 subject discontinued because of angioedema of the face, and 1 subject was terminated from the study for a protocol violation. Of the 36 enrolled subjects, 15 (41.7%) were male, 27 (75.0%) were white, and 9 (25.0%) were black. The mean age was 33 years (range, 19 to 45 years), mean BMI was 25.4 kg/m2 (range, 19.6 to 29.0 kg/m2), and the mean creatinine clearance was 128.0 mL/minute (range, 91.4 to 157.4 mL/minute).

Efficacy Results: Not applicable; efficacy was not evaluated in this study.

Pharmacokinetic Results: Two FDC tablets were tested in this study. FTC, RPV, and TFV geometric least-squares (GLS) mean PK parameters and the statistical comparisons of GLS means ratios and associated 90% CIs, are presented in the summary table below.

GLS Mean GMR (%) FTC Test Formulation 3a Referencea Test/Reference 90% CI

AUCinf (ng h/mL) 9581.10 9594.63 99.86 97.67, 102.09

AUClast (ng h/mL) 9360.88 9366.29 99.94 97.77, 102.16

Cmax (ng/mL) 1714.21 1625.23 105.47 100.46, 110.74 Test Formulation 4a Referencea Test/Reference

AUCinf (ng h/mL) 9646.25 9594.63 100.54 98.34, 102.79

AUClast (ng h/mL) 9432.71 9366.29 100.71 98.52, 102.94

Cmax (ng/mL) 1753.57 1625.23 107.90 102.77, 113.28



GLS Mean GMR (%)

RPV Test Formulation 3a Referencea Test/Reference 90% CI

AUCinf (ng h/mL) 3166.87 2738.56 115.64 108.71, 123.01

AUClast (ng h/mL) 2854.58 2466.92 115.71 109.13, 122.69


AUCinf (ng h/mL) 3211.23 2738.56 117.26 110.24, 124.73

AUClast (ng h/mL) 2888.99 2466.92 117.11 110.45, 124.17

Cmax (ng/mL) 115.02 94.56 121.63 113.59, 130.23

GLS Mean GMR (%)

TFV Test Formulation 3a Referencea Test/Reference 90% CI

AUCinf (ng h/mL) 3264.17 3200.52 101.99 99.06, 105.00

AUClast (ng h/mL) 3053.10 2989.16 102.14 99.00, 105.38


AUCinf (ng h/mL) 3333.11 3200.52 104.14 101.15, 107.22

AUClast (ng h/mL) 3110.38 2989.16 104.06 100.86, 107.35

Cmax (ng/mL) 323.41 284.13 113.83 106.83, 121.28

GLS = geometric least squares; GMR = geometric means ratio; CI = confidence interval reference = FTC+RPV+TDF: single doses of FTC 200-mg strength capsule, RPV 25-mg strength tablet (as 27.5 mg of the hydrochloride salt), and TDF 300-mg strength tablet test formulation 3: FTC/RPV/TDF, a single dose of FDC tablet (FTC 200 mg, RPV 25 mg, and TDF 300 mg) test formulation 4: FTC/RPV/TDF, a single dose of FDC tablet (FTC 200 mg, RPV 25 mg, and TDF 300 mg) a N = 34

The FTC/RPV/TDF FDC test formulation 3 demonstrated bioequivalence to the reference treatment of concurrent administration of the individual components (FTC+RPV+TDF) under fed conditions. The 90% CIs for the GLS mean ratios (test treatment/reference treatment) were contained within the bioequivalence bounds of 80% to 125% for FTC, RPV, and TFV for all primary pharmacokinetic parameters (AUCinf, AUClast, and Cmax). The FTC/RPV/TDF FDC test formulation 4 is not bioequivalent to the reference products as not all three of the components, specifically RPV Cmax, of the FDC formulation met the bioequivalence criterion.



Safety Results: 34/36 enrolled subjects received all planned doses of study drugs and completed the study. One subject received only FTC/RPV/TDF FDC test formulation 4 and discontinued because of angioedema of the face, and 1 subject received only the reference treatment and was terminated from the study for a protocol violation. Overall, treatment-emergent AEs were reported in 3/35 subjects (8.6%) for the reference treatment, 4/34 subjects (11.8%) for FTC/RPV/TDF FDC test formulation 3, and 4/35 subjects (11.4%) for FTC/RPV/TDF FDC test formulation 4. Testicular pain (n = 2, both on reference treatment) was the only AE reported in 1 subject for a treatment. All AEs except one (Grade 2 allergic rhinitis, on FTC/RPV/TDF FDC test formulation 3) were Grade 1. Treatment-emergent AEs that were considered related to study drug included diarrhea, musculoskeletal pain, pain in extremity, headache, dysuria, testicular pain, angioedema, papular rash, and hot flash.

There was no death or other serious adverse event. One subject discontinued prematurely for Grade 1 angioedema of the right side of the face on study Day 1 following administration of the first dose of study treatment (FTC/RPV/TDF FDC test formulation 4). The investigator evaluated the AE as related to study drug.

Overall, treatment-emergent graded laboratory abnormalities were reported in 10/35 subjects (28.6%) for the reference treatment, 9/34 subjects (26.5%) for FTC/RPV/TDF FDC test formulation 3, and 5/35 subjects (14.3%) for FTC/RPV/TDF FDC test formulation 4. Grade 1 hemoglobinemia in 1 subject was the only graded hematology lab test reported. Fasting hypercholesterolemia was the most frequent treatment-emergent graded laboratory abnormality (all Grade 1): 6/34 subjects (17.6%) for the reference treatment, 1/34 subjects (2.9%) for FTC/RPV/TDF FDC test formulation 3, and 2/35 subjects (5.7%) for FTC/RPV/TDF FDC test formulation 4. No notable change in clinical laboratory test value treatment means, or vital signs or physical findings was observed during the study. No pregnancy occurred in this study.

CONCLUSIONS: Pharmacokinetics: The FTC/RPV/TDF FDC test formulation 3 is bioequivalent to concurrent administration of the individual components under fed conditions.

Safety: Single, oral doses of the reference treatment (FTC+RPV+TDF) and both FDC test formulations of FTC/RPV/TDF were well tolerated in this study.

TMC278-C117 1

Clinical Research Report Version: 1.0 Date: 10-May-2007



Trade Name: -



Trial no.: TMC278-C117

Clinical Phase: I

Title: A Phase I, open-label, randomized, 2-way, crossover trial to compare the oral bioavailability of the Phase III tablet formulation of TMC278 relative to that of the Phase IIb tablet formulations after single-dose intake with food in healthy subjects.

Investigator:

Belgium

Country: Belgium


End: - -20


No. of Subjects: 32

Objectives: The primary objective of this trial was to compare the rate and extent of absorption of TMC278 administered as the newly developed Phase III tablet formulation versus the Phase IIb tablet formulations when administered as a single oral dose in healthy subjects after a standardized breakfast.

The secondary objective was to determine the safety and tolerability of a single dose of a Phase III and different Phase IIb tablet formulations of TMC278.

Design: This was a Phase I, open-label, randomized, 2-way, crossover trial in 32 healthy subjects to assess the rate and extent of absorption of TMC278 following single-dose administration of different tablet formulations in the presence of food. The implementation of protocol amendment 1 before the start of dosing removed Treatments A and B (relating to a dose of 25 mg TMC278) and Panel 1 from the study design. Subjects were randomly assigned to 1 of 2 parallel panels. In Panel 2 (n=16), subjects were randomized to receive a single oral dose of 100 mg TMC278 as 4 separate 25 mg tablets of the Phase III tablet formulation (Treatment C) or a single oral dose of 100 mg TMC278 as the 100 mg Phase IIb tablet formulation (Treatment D). In Panel 3 (n=16), subjects were randomized to receive a single oral dose of 150 mg TMC278 as the 150 mg Phase III tablet formulation (Treatment E) or a single oral dose of 150 mg TMC278 as 3 separate 50 mg tablets of the Phase IIb tablet formulation (Treatment F). In both panels, subjects received the alternate treatment after a 13-day washout period. All drug intakes occurred after 10-hour overnight fasting and within 10 minutes after completion of a standardized breakfast. Plasma pharmacokinetics of TMC278 were assessed up to 168 hours following each treatment. Safety and tolerability evaluations were recorded at regular intervals throughout the trial period.

Subject Selection Inclusion Criteria1. Male or female, aged between 18 and 55 years, extremes included. 2. Smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day (or non-smoking) for at least 3 months

prior to selection. 3. Normal weight as defined by a Quetelet Index (body mass index: weight in kg divided by the square of

height in meters) of 18.0 to 30.0 kg/m2, extremes included. 4. Informed consent form (ICF) signed voluntarily before the first trial-related activity. 5. Able to comply with the protocol requirements. 6. Healthy on the basis of a medical evaluation that revealed the absence of any clinically relevant

abnormality and included a physical examination, medical history, electrocardiogram (ECG), vital signs, and the results of blood biochemistry and hematology tests and a urinalysis carried out at screening.

0128661, Final, 10-May-2007 09:04

Synopsis

TMC278-C117 2


Exclusion Criteria1. A positive human immunodeficiency virus (HIV)-1 or HIV-2 test at trial screening. 2. Female, except if postmenopausal since more than 2 years, or posthysterectomy or posttubal ligation

(without reversal operation). 3. History or evidence of current use of alcohol, barbiturate, amphetamine, recreational or narcotic drug use

which, in the investigator’s opinion, would compromise subject’s safety and/or compliance with the trial procedures.

4. Hepatitis A, B, or C infection (confirmed by hepatitis A antibody IgM, hepatitis B surface antigen, or hepatitis C virus antibody, respectively) at screening.

5. A positive urine drug test at trial screening. Urine was tested for the current use of amphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids, methadone, and opioids.


7. Current or history of adrenal disorder. 8. History of tuberculosis or ocular herpes. 9. History of renal insufficiency (estimated creatinine clearance below 60 mL/min). 10. Currently significant diarrhea, gastric stasis, or constipation that in the investigator’s opinion could

influence drug absorption or bioavailability. 11. Any history of significant skin disease such as, but not limited to, rash or eruptions, drug allergies, food

allergy, dermatitis, eczema, psoriasis, or urticaria. 12. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the

investigational medication administered in this trial (i.e., TMC278). 13. Use of concomitant medication, including over-the-counter products, herbal medications, and dietary

supplements. Over-the-counter medication had to be discontinued at least 7 days prior to the first intake of study medication and prescribed medication had to be discontinued at least 14 days prior to the first intake of study medication, except ibuprofen.

14. Having previously participated in more than 1 trial (single or multiple dose) with TMC125, TMC120, and/or TMC278 (formerly known as R278474) or developed a rash, erythema, or urticaria while participating in a trial with the aforementioned compounds.

15. Participation in an investigational drug trial within 60 days preceding the first intake of study medication. 16. Donation of blood or plasma within 60 days preceding the first intake of study medication. 17. Subjects with the following laboratory abnormalities at screening as defined by the Division of Acquired

Immunodeficiency Syndrome (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (AEs; “DAIDS grading table”) and in accordance with the normal ranges of the clinical laboratory: serum creatinine grade 1 or greater ( 1.1 x upper limit of normal range [ULN]); serum lipase grade 1 or greater ( 1.1 x ULN); hemoglobin grade 1 or greater ( 10.9 g/dL); platelet count grade 1 or greater ( 124.999/mm3); absolute neutrophil count grade 1 or greater ( 1.3 x 109/L); aspartate aminotransferase or alanine aminotransferase grade 1 or greater ( 1.25 x ULN); total bilirubin grade 1 or greater ( 1.1 x ULN); any other laboratory abnormality of grade 2 or above, including: proteinuria (spot urine)

2+ and microscopic hematuria (> 10 red blood cells/high power field). Treatment Treatment C Treatment D Treatment E Treatment F Dosage 100 mg TMC278 100 mg TMC278 150 mg TMC278 150 mg TMC278 Dosage Form [F No.] Phase III tablets

(25 mg [F006]) Phase IIb tablet (100 mg [F002])

Phase III tablet (150 mg [F007])

Phase IIb tablets (50 mg [F003])

Usage 4 x 25 mg tablets on Day 1, single

oral dose

1 x 100 mg tablet on Day 1, single

oral dose

1 x 150 mg tablet on Day 1, single

oral dose

3 x 50 mg tablets on Day 1, single

oral dose Batch Number PD1975 PD1268 PD2024 PD1273

Dose Regimen Panel 1: Treatments A and B – removed from the study design by protocol amendment 1 before the start of dosing. Panel 2: Treatment C or D in Session I, 13-day washout, alternate treatment in Session II. Panel 3: Treatment E or F in Session I, 13-day washout, alternate treatment in Session II.

0128661, Final, 10-May-2007 09:04

Synopsis

TMC278-C117 3


Duration of Treatment Treatment C, D, E, and F: 1 day each.

Duration of Trial Two treatment periods of 1 day with a washout period of at least 13 days in between (excluding screening and follow-up).

Disallowed Medication During the entire trial, subjects were not to use any medication other than study medication and ibuprofen, of which limited use was allowed. All over-the-counter medication, except for ibuprofen, had to be discontinued at least 7 days before the first intake of study medication and all prescribed medication had to be discontinued at least 14 days before first intake of study medication. Subjects were not to use any herbal medications or dietary supplements including products containing Hypericum perforatum (e.g., St. John’s wort) from 14 days before the first intake of study medication and up to 14 days after the last intake of study medication. Ibuprofen could be used up to 3 days before intake of study medication. After that, the investigator could permit the use of ibuprofen from 3 days before intake of study medication until Day 8 of each session (at no more than 400 mg per day). In the event of cutaneous reaction/rash and/or an allergic reaction, the use of cetirizine, levocetirizine, topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In case of nausea, the use of antiemetics was permitted. In case of diarrhea, the use of loperamide was allowed.

0128661, Final, 10-May-2007 09:04

Synopsis

TMC278-C117 4


Scre

enin

ga

Treatments C, D, E, and F (Session I or II)

Follo

w-u

p

Assessments

21

days

Day

1b

Day

2

Day

3

Day

4

Day

6

Day

8

Day

7

and

30,

31, o

r 32h

Pharmacokinetics Blood samplef X X X X X X Safety Adverse events + concomitant medsc

X X X X X X X X

Hemat & biochemd X Xe X X X Urinalysis X Xe X X X Cortisol and 17-OH-progesterone X Xg

T3, free-T4, and TSH X Xg

ECG & vital signs X Xi X X Physical examinationj X X X X meds = medication; Hemat & biochem = hematology & biochemistry; T3 = triidothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone; ECG = electrocardiogram. a At screening, subject’s demographics, medical and surgical history, smoking habits, and concomitant diseases were recorded and an HIV-1 and -2 test, hepatitis A, B, and C test and urine drug screening were performed; a serum pregnancy test was also performed for females. b Subjects were admitted to the unit the afternoon before Day 1. c Adverse events and concomitant medications were monitored continuously from signing the ICF until the last trial-related activity.d Biochemistry samples were taken fasting for at least 10 hours, before breakfast. e Within 2 hours before drug intake.f For determination of TMC278 plasma concentrations. Immediately before drug intake plus 0.5, 1, 2, 3, 4, 5, 6, 9, 12, and 16 hours postdose on Day 1, 24 hours postdose on Day 2, 48 hours postdose on Day 3, 72 hours postdose on Day 4, 120 hours postdose on Day 6, and 168 hours postdose on Day 8. g On Day 8, tests were only conducted at the end of the last session for each subject. h Days were in relation to the date of last drug intake. On Day 7 of follow-up, overlapping assessments were only performed and captured once. i Within 2 hours before drug intake and 4 hours postdose. j Included skin examination.

Statistical Methods Intent-to-treat analysis, descriptive statistics, frequency tabulations, linear mixed effects modeling, Wilcoxon matched pairs signed rank test.

0128661, Final, 10-May-2007 09:04

Synopsis

TMC278-C117 5


Main Features of the Subject Sample and Summary of the Results Baseline Characteristics - Subject Disposition Total

N = 32Number of Subjects Entered (M/F) Age: median (range), yrs

18/14 45.0 (19-55)

Race, n (%) Caucasian 32 (100)

Drop-Outs 0

Pharmacokinetics of TMC278 (mean SD, tmax: median [range])

Treatment C 100 mg TMC278 Phase III

(test)

Treatment D 100 mg TMC278 Phase IIb

(reference)n 16 16 tmax, h 4.5 (3.0 – 9.0) 4.0 (2.0 – 12.0) Cmax, ng/mL 339.2 ± 125.7 400.7 ± 149.6 AUClast, ng.h/mL 12270 ± 5123 12160 ± 3952 AUC , ng.h/mL 14070 ± 6678 14010 ± 5539 t1/2term, h 52.82 ± 17.62 56.46 ± 27.17

LSmean ratio (90% CI), % Test vs reference -

n 16 - Cmax 85.36 (71.62 – 101.7) - AUClast 99.07 (80.27 – 122.3) - AUC 98.21 (79.01 – 122.1) -


Treatment E 150 mg TMC278 Phase III

(test)

Treatment F 150 mg TMC278 Phase IIb

(reference)n 16a 16 tmax, h 4.0 (3.0 – 6.0) 4.0 (2.0 – 6.0) Cmax, ng/mL 597.6 ±116.9 630.4 ± 165.5 AUClast, ng.h/mL 19640 ± 6467 19400 ± 6414 AUC , ng.h/mL 20910 ± 8067 20740 ± 7389 t1/2term, h 40.02 ± 12.12 39.88 ± 11.80 LSmean ratio (90% CI), %

Test vs reference -n 16a - Cmax 96.29 (85.73 – 108.2) - AUClast 98.40 (87.90 – 110.2) - AUC 100.4 (89.75 – 112.4) -

a n=15 for AUClast

0128661, Final, 10-May-2007 09:04

Synopsis

TMC278-C117 6


Safety (n = number of subjects with data)

Treatment C 100 mg TMC278

Phase III N = 16

Treatment D 100 mg TMC278

Phase IIb N = 16

Treatment E 150 mg

TMC278 Phase III

N = 16

Treatment F 150 mg

TMC278 Phase IIb

N = 16 Totala

N = 32 Adverse Events (AEs) Most frequently reported AEs (reported in > 2 subjects in the whole trial), n (%)

Headache 6 (37.5) 3 (18.8) 5 (31.3) 3 (18.8) 14 (43.8) Nausea 1 (6.3) 2 (12.5) 3 (18.8) 1 (6.3) 6 (18.8) Erythema 1 (6.3) 0 1 (6.3) 1 (6.3) 3 (9.4) Nasopharyngitis 0 0 0 1 (6.3) 3 (9.4)b


10 (62.5) 7 (43.8) 10 (62.5) 9 (56.3) 28 (87.5)

n (%) of deaths 0 0 0 0 0

n (%) with 1 or more other serious AEs

0 0 0 0 0


0 0 0 0 0


0 0 0 0 0

a Includes screening and follow-up. b Also reported for 1 subject during screening and for 1 subject during follow-up. Overall, 28 subjects (87.5%) reported at least 1 AE. The most common AEs were headache (14 subjects, 43.8%) and nausea (6 subjects, 18.8%). There were no deaths or other serious adverse events. All AEs were considered grade 1 or 2 in severity. No subjects prematurely discontinued the trial due to an AE. Eight AEs considered to be skin events of interest were reported during the trial for 7 subjects. All skin events of interest were grade 1 in severity. Four events of erythema were reported for 3 subjects (1 event with Treatment C, 2 events with Treatment E, and 1 event with Treatment F). Both events of erythema reported with Treatment E (erythema of eyelid and erythema of cheeks and lips) were reported for the same subject and were considered to be possibly related to TMC278. Two events of eczema were reported for 2 subjects (1 event with Treatment C and 1 event with Treatment F). The event of eczema reported with Treatment F was considered to be possibly related to TMC278. Vasculitis and rash erythematous were each reported for 1 subject with Treatment C and Treatment E, respectively. The rash erythematous was considered to be possibly related to TMC278. All other skin events of interest were considered not or doubtfully related to TMC278.

0128661, Final, 10-May-2007 09:04

Synopsis

TMC278-C117 7


Clinical Laboratory Tests Treatment C

100 mg TMC278 Phase III

N = 16

Treatment D 100 mg

TMC278 Phase IIb

N = 16

Treatment E 150 mg

TMC278 Phase III

N = 16

Treatment F 150 mg

TMC278 Phase IIb

N = 16 Totala

N = 32 n (%) with 1 or more treatment-emergent graded laboratory abnormalities: grade 1 2 (12.5) 2 (12.5) 1 (6.3) 0 7 (21.9)b

grade 2 1 (6.3) 0 1 (6.3) 0 3 (9.4)c

grade 3 0 0 0 0 1 (3.1)d

grade 4 0 0 0 0 0a Includes follow-up but not screening.b Includes 3 subjects during follow-up and 1 subject with a grade 1 treatment-emergent laboratory abnormality during more than one treatment period. c Includes 1 subject during follow-up. d One subject during follow-up. There were no consistent or clinically relevant treatment-emergent changes over time in laboratory parameters. Except for 1 grade 3 treatment-emergent laboratory abnormality (increased lipase) during follow-up (Day 8 of Treatment D), all laboratory abnormalities in this trial were grade 1 or 2. Two subjects had a laboratory abnormality that was reported as an AE (increased lipase); one of these AEs was the grade 3 laboratory abnormality of increased lipase. Both laboratory-related AEs were grade 2 in severity and were considered to be possibly related to TMC278. No clinically relevant urinalysis results were observed. Cardiovascular Safety Minor changes were reported for vital sign values and ECG. None of the changes was considered to be clinically relevant. Physical and Skin Examinations Physical examination revealed a treatment-emergent abnormal finding for 1 subject during the trial (eczema), which was reported as an AE. ConclusionsIn conclusion, the results of this trial demonstrate that the oral bioavailability of TMC278 using the Phase III tablet is comparable to the bioavailability using the Phase IIb tablet for both the 100 mg (Treatments C and D) as well as the 150 mg (Treatments E and F) dose. In these healthy subjects, the administration of a single dose of either 100 mg or 150 mg TMC278, as either the Phase III or Phase IIb tablet formulation, was generally safe and well tolerated.

0128661, Final, 10-May-2007 09:04

Synopsis

TMC278-TiDP38-C145 CONFIDENTIAL 1Clinical Research Report Synopsis

SYNOPSISTrial Identification and Protocol Summary

Company: Tibotec Pharmaceuticals

Trade Name: -




Clinical Phase: I

Title: A Phase I, open-label, randomized, crossover trial in healthy adults to compare the oral bioavailability of 3 concept pediatric formulations of TMC278 (solution, suspension, granules) to that of the adult 25 mg Phase III tablet formulation, and to assess the food effect for each concept formulation.

Investigator: The

Netherlands.

Country: The Netherlands

Trial Period: Start: 13-Jan-2009

End: 02-May-2009


No. of Subjects: 36

Objectives: The primary objectives of this trial were: to compare the rate and extent of absorption of TMC278 when administered as a single 25 mg dose of the 3 concept pediatric formulations (solution [10 mg/mL], suspension [5 mg/mL], granules [2.5 mg/g]), under fed and fasted conditions, to that when administered as the 25 mg TMC278 Phase III tablet formulation, under fed conditions, in healthy adults; and to assess the effect of food on the bioavailability of TMC278 after a single 25 mg dose of the concept pediatric formulations in healthy adults.

The secondary objectives were: to evaluate short-term safety and tolerability of TMC278 following administration of 3 single oral doses of 25 mg, formulated as one of the concept pediatric formulations (under fed and fasted conditions) and as the Phase III tablet (under fed conditions), in healthy adults; and to evaluate the palatability of each concept pediatric formulation in healthy adults under fasted conditions.

Design: This was a Phase I, open-label, randomized, 3-way crossover trial to compare the oral bioavailability of TMC278 after administration as 1 of 3 concept pediatric formulations (a solution [10 mg/mL], a suspension [5 mg/mL], or granules [2.5 mg/g]) to that when administered as the adult 25 mg Phase III tablet formulation, and to assess the food effect for each concept formulation. The palatability of each concept formulation was assessed as well, under fasted conditions.

TMC278 is being investigated for the treatment of HIV-1 infected subjects.

The trial population consisted of 36 healthy adults, divided over 3 panels of 12 subjects each, 1 panel for each concept pediatric formulation.

In each of the 3 panels, subjects received 3 different TMC278 treatments in a randomized fashion, in 3 subsequent sessions, separated by a washout period of at least 14 days.

The different treatments were:

Panel 1: single 25 mg TMC278 dose (2.5 mL) of oral solution (10 mg base/mL) in fed (Treatment A1) and fasted (Treatment B1) condition;

Panel 2: single 25 mg TMC278 dose (5 mL) of oral suspension (5 mg base equivalents/mL) in fed (Treatment A2) and fasted (Treatment B2) condition;

Panel 3: single 25 mg TMC278 dose (10 g) of granules (2.5 mg base equivalents/g) in fed (Treatment A3) and fasted (Treatment B3) condition;

Panels 1, 2, and 3: single 25 mg TMC278 dose as a tablet (25 mg base equivalents/tablet) in fed condition



(Treatment C).

In each treatment session, full pharmacokinetic profiles of TMC278 were measured up to 168 hours after intake.

Safety and tolerability were monitored throughout the trial.

Subject Selection

Inclusion Criteria



3. A Body Mass Index (weight in kg divided by the square of height in meters) of 18.0 to 30.0 kg/m2, extremes included.

4. Informed Consent Form (ICF) signed voluntarily before the first trial-related activity.


6. Healthy on the basis of a medical evaluation that revealed the absence of any clinically relevant abnormality and included a physical examination, medical history, electrocardiogram (ECG), vital signs, and the results of blood biochemistry and hematology tests and a urinalysis carried out at screening.

Exclusion Criteria

1. A positive human immunodeficiency virus (HIV)-1 or HIV-2 test at screening.

2. Female, except if postmenopausal since more than 2 years, or posthysterectomy, or postsurgical sterilization (without reversal operation).

3. History or evidence of current use of alcohol, barbiturate, amphetamine, recreational, or narcotic drug use, which in the investigator’s opinion would compromise subject’s safety and/or compliance with the trial procedures.

4. Hepatitis A, B, or C infection (confirmed by hepatitis A antibody IgM, hepatitis B surface antigen, or hepatitis C virus antibody, respectively) at screening.

5. A positive urine drug test at screening. Urine was tested to check the current use of methadone, barbiturates, amphetamines, benzodiazepines, cocaine, cannabinoids, and opioids. Note: a positive test could be repeated once to exclude a technical error.

6. Currently active or underlying gastrointestinal, cardiovascular, neurologic, psychiatric, metabolic, endocrinologic, genitourinary, renal, hepatic, respiratory, inflammatory, or infectious disease.


8. Any history of significant skin disease such as, but not limited to, rash or eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis, or urticaria.

9. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication administered in this trial (i.e., TMC278).

10. Use of concomitant medication, including over-the-counter products, herbal medications, and dietary supplements. Over-the-counter medication had to be discontinued at least 7 days prior to the first administration of trial medication and prescribed medication had to be discontinued at least 14 days before the first intake of trial medication, except for ibuprofen and acetaminophen.

11. Participation in an investigational drug trial within 60 days prior to the first intake of trial medication.

12. Donation of blood or plasma or significant blood loss within the 60 days preceding the first intake of trial medication.



13. Subjects with the following laboratory abnormalities at screening, as defined by the Division of Acquired Immunodeficiency Syndrome Table for Grading the Severity of Adult and Pediatric Adverse Events and in accordance with the normal ranges of the clinical laboratory: serum lipase grade 1 or greater (≥ 1.1 x upper limit of laboratory range [ULN]); hemoglobin toxicity grade 1 or greater (≤ 10.9 g/dL); platelet count grade 1 or greater (≤ 124.999 x 109/L); absolute neutrophil count grade 1 or greater (≤ 1.3 x 109/L); aspartate aminotransferase or alanine aminotransferase grade 1 or greater (≥ 1.25 x ULN); total bilirubin grade 1 or greater (≥ 1.1 x ULN); any other laboratory abnormality of grade 2 or above, including proteinuria (spot urine) ≥ 2+, and microscopic hematuria (> 10 red blood cells/high power field), with the exception of grade 2 low density lipoprotein cholesterol or grade 2 total cholesterol values if < ULN of the local laboratory.

14. Having participated in more than 1 trial (single or multiple dose) with TMC125 (etravirine), TMC120 (dapivirine), and/or TMC278 (rilpivirine, formerly known as R278474), or having developed rash, erythema, or urticaria while participating in a trial with the aforementioned compounds.

15. History of clinically relevant heart rhythm disturbances or grade 2 or above electrolyte abnormalities (hypokalemia, hypocalcemia, hypomagnesemia) at screening.

16. Subjects with ageusia, hypogeusia, or dysgeusia.

17. Renal impairment: calculated creatinine clearance (CLCr) < 80 mL/min. Note: The site was to calculate CLCrusing the Cockroft-Gault formula.

Treatment Treatment A1, B1 Treatment A2, B2 Treatment A3, B3 Treatment C

Concentration TMC27810 mg/mL

TMC2785 mg base

equivalents/mL

TMC2782.5 mg base

equivalents/g

TMC27825 mg base

equivalents/tablet

Dosage 25 mg TMC278(base)

25 mg TMC278(HCl salt)



Dosage Form (TF No.) Solution(R278474-F008)

Suspension(R314585-F014)

Granules(R314585-F015)

Tablets(R314585-F006)

Usage Treatment A1: 25 mg on Day 1 of session (fed)

Treatment B1: 25 mg on Day 1

of session (fasted)

2.5 mL orallysingle dose

Treatment A2:25 mg on Day 1 of session (fed)

Treatment B2:25 mg on Day 1

of session (fasted)

5 mL orallysingle dose

Treatment A3:25 mg on Day 1 of session (fed)

Treatment B3:25 mg on Day 1

of session (fasted)

10 g orallysingle dose

25 mg on Day 1of session (fed)

1 tablet orallysingle dose

Batch Number 08K13 08K17 08K17 8BL2H



Dose Regimen Panel 1:

Group 1: treatment sequence A1/B1/C in 3 separate sessions.

Group 2: treatment sequence B1/C/A1 in 3 separate sessions.

Group 3: treatment sequence C/A1/B1 in 3 separate sessions.

Group 4: treatment sequence C/B1/A1 in 3 separate sessions.

Group 5: treatment sequence B1/A1/C in 3 separate sessions.

Group 6: treatment sequence A1/C/B1 in 3 separate sessions.

Panel 2:

Groups 1 – 6: Same treatment sequences in 3 separate sessions as Panel 1, but with suspension formulation.

Panel 3:

Groups 1 – 6: Same treatment sequences in 3 separate sessions as Panel 1, but with granules formulation.

Note: all sessions were separated by a 14-day washout period.

Duration of Treatment Treatments A1, A2, A3, B1, B2, B3, and C: 1 day (single dose) each.

Assessments were performed up to Day 8 (inclusive).

Duration of Trial For each panel, 3 treatment periods of 1 day (single dose) each, with a washout period of 14 days in between each period (excluding screening and follow-up).

Disallowed Medication All systemic over-the-counter medication had to be discontinued at least 7 days before the first administration of trial medication and all prescribed medication had to be discontinued at least 14 days before the first administration of trial medication, except for ibuprofen or acetaminophen. Subjects were not to use any medication other than the trial medication up to 14 days after the last intake of trial medication, except for ibuprofen or acetaminophen. Subjects were also not to use any systemic herbal medications or dietary supplements, including products containing Hypericum perforatum (e.g., St. John’s wort) from 14 days before the first trial medication intake up to 14 days after the last trial medication intake. Ibuprofen or acetaminophen could be used up to 3 days before the intake of trial medication in each treatment session. After that, the clinical investigator could permit the use of ibuprofen or acetaminophen from 3 days before the intake of trial medication until the last pharmacokinetic sample had been taken in each treatment session, at no more than 400 mg per day for ibuprofen, and at no more than 1000 mg per day for acetaminophen. Hormone replacement therapy was allowed in postmenopausal women. In case of cutaneous reaction/rash and/or an allergic reaction, the use of cetirizine (Zyrtec®), levocetirizine (Xyzal®), topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In case of nausea, the use of antiemetics was permitted. In case of diarrhea, the use of loperamide was permitted.



Assessments

Scre

enin

ga

Treatments

A1 (Panel 1), A2 (Panel 2), A3 (Panel 3), andC (Panels 1, 2, and 3): fed conditions

B1 (Panel 1), B2 (Panel 2), andB3 (Panel 3): fasted conditions

(Session I, II, or III)b

Follo

w-u

p

≤21

days

Day

-1c

Day

1d

Day

2e

Day

3

Day

4

Day

6

Day

8f

Day

8fan

d 30

, 31

, or 3

2

PharmacokineticsBlood sampleg Xh X X X X XSafetyAEs and concomitant medicationi X X X X X X X X XHematology & biochemistryj X Xk X X XUrinalysis X Xk X X XUrine drug screen X XSerum pregnancy test, females only X Xl

Urine pregnancy test, females only XECG X Xk

Vital signsm X Xk X X XSkin examination X X X XPhysical examination X X X XOtherTaste questionnaire Xn

AE = adverse event; ECG = electrocardiogram.a Informed consent, smoking habits, inclusion/exclusion criteria, concomitant diseases, height, weight, subject

characteristics and demographics, and medical and surgical history were recorded, and HIV-1 & -2 tests and hepatitis A, B, and C tests were performed before Day 1 of Session I.

b Treatments were separated by a washout period of at least 14 days.c Subjects were admitted to the unit in the evening before Day 1.d Start of water restriction began 2 hours before intake of trial medication and stopped 2 hours postdose.e Subjects were discharged from the unit on this day.f In Session III for each subject, Day 8 coincided with the first follow-up visit; therefore these investigations

were only performed once.g For determination of TMC278 plasma concentrations.h Pharmacokinetic samples were taken predose (within 2 hours before intake of trial medication), 0.5, 1, 2, 3, 4,

5, 6, 9, 12, and 16 hours postdose on Day 1. Further pharmacokinetic samples were taken at 24, 48, 72, 120, and 168 hours postdose.

i Adverse events and concomitant medication were monitored continuously from signing the ICF until the last trial related activity.

j Biochemistry samples were taken fasted for at least 10 hours, before breakfast.k Within 2 hours before intake of trial medication.l Performed on Day 30, 31, or 32.m Blood pressure and pulse rate: supine after 5 minutes, standing after 1 minute.n Taste questionnaire to be completed by the subject within 5 to 15 minutes after TMC278 intake in

Treatments B1, B2, and B3 only.



Statistical Methods Descriptive statistics, graphical presentations, frequency tabulations including 90% confidence limits, intent-to-treat analysis, linear mixed effects modeling, Mann-Whitney U-Test.




Baseline Characteristics - Subject Disposition Panel 1SolutionN = 12

Panel 2Suspension

N = 12

Panel 3Granules

N = 12Number of Subjects Entered (M/F)Age: median (range), yrs

8/443.5 (22-54)

10/239.5 (21-54)

11/139.5 (20-54)

Race, n (%)CaucasianAsianBlack

10 (83.3)1 (8.3)1 (8.3)

10 (83.3)1 (8.3)1 (8.3)

9 (75.0)1 (8.3)

2 (16.7)Drop-Outs – Reason

Any reasonAEsNon-compliance

1 (8.3)1 (8.3)

0

000

1 (8.3)0

1 (8.3)

Panel 1: oral solution, single dose of 25 mg TMC278Pharmacokinetics of TMC278 Tablet under

fed conditions (reference)

Oral solution under fed conditions

(test 1)

Oral solution under fasted conditions

(test 2)(mean ! SD, tmax: median [range])n 12 12 11Cmax, ng/mL 113.8 ± 30.00 137.9 ± 30.14 184.9 ± 28.82tmax, h 4.0 (4.0-5.0) 4.0 (3.0-6.0) 1.0 (1.0-2.0)AUClast, ng.h/mL 2910 ± 1150 3878 ± 890.9 3663 ± 561.4AUC∀, ng.h/mL 3338 ± 1332 4204 ± 1072 3964 ± 730.7t1/2term, h 46.59 ± 14.23 42.71 ± 12.87 44.46 ± 14.27

LS mean ratio (90% CI), %- Test 1 vs reference Test 2 vs reference

n - 12 vs 12 11 vs 12Cmax - 122.6 (102.8 - 146.3) 169.7 (153.3 - 187.8)AUClast - 138.7 (118.9 - 161.7) 129.5 (114.7 - 146.3)AUC∀ - 129.8 (111.5 - 151.1) 125.6 (110.9 - 142.1)

- - Test 2 vs test 1n - - 11 vs 12Cmax - - 131.6 (119.2 - 145.3)AUClast - - 92.94 (86.71 - 99.61)AUC∀ - - 92.72 (85.74 - 100.3)



Panel 2: oral suspension, single dose of 25 mg TMC278Pharmacokinetics of TMC278 Tablet under

fed conditions (reference)

Oral suspension under fed conditions

(test 1)

Oral suspension under fasted conditions

(test 2)(mean ! SD, tmax: median [range])n 12 12 12Cmax, ng/mL 108.7 ± 34.92 115.5 ± 26.12 130.4 ± 32.82tmax, h 4.5 (3.0-9.0) 4.0 (3.0-5.0) 2.0 (1.0-4.0)AUClast, ng.h/mL 3127 ± 1129 3390 ± 1161 3263 ± 1291AUC∀, ng.h/mL 3597 ± 1768 4005 ± 1897 3671 ± 1703t1/2term, h 47.81 ± 21.87 54.17 ± 29.73 47.77 ± 18.01



- - Test 2 vs test 1n - - 12 vs 12Cmax - - 112.1 (104.8 - 120.0)AUClast - - 95.40 (91.09 - 99.91)AUC∀ - - 91.92 (87.45 - 96.62)



Panel 3: oral granules, a single dose of 25 mg TMC278

Pharmacokinetics of TMC278 Tablet under fed conditions

(reference)

Granules under fed conditions (test 1)

Granules under fasted conditions (test 2)(mean ! SD, tmax: median

[range])n 11 11 11a

Cmax, ng/mL 102.9 ± 33.16 119.3 ± 26.81 85.95 ± 22.07tmax, h 5.0 (2.0-5.0) 4.0 (3.0-5.0) 4.0 (2.0-5.0)AUClast, ng.h/mL 2922 ± 1220 3665 ± 1273 2479 ± 1097AUC∀, ng.h/mL 3263 ± 1467 3990 ± 1425 2740 ± 1192t1/2term, h 43.34 ± 23.23 40.00 ± 16.89 45.90 ± 22.98



- - Test 2 vs test 1n - - 11 vs 11Cmax - - 70.05 (58.94 - 83.24)AUClast - - 71.08 (63.35 - 79.75)AUC∀ - - 72.04 (64.34 - 80.67)a n=12 for t1/2term

Panel 1: oral solution, single dose of 25 mg TMC278Safety(n = number of subjects with data)

TMC27825 mg solution

TMC27825 mg tablet

FedN=12

FastedN=11

FedN=12

Adverse Events (AEs)n (%) with 1 or more AEs 6 (50.0) 4 (36.4) 8 (66.7)n (%) of deaths 0 0 0n (%) with 1 or more other serious AEs 0 0 0n (%) of treatment stopped due to AEs 0 0 1 (8.3)n (%) with 1 or more grade 3 or 4 AEs 0 0 0

Most frequently reported treatment-emergent AEs (reported in ≥ 2 subjects with any treatment), n (%)Headache 2 (16.7) 2 (18.2) 4 (33.3)Myalgia 2 (16.7) 1 (9.1) 0Fatigue 2 (16.7) 0 2 (16.7)



Panel 2: oral suspension, single dose of 25 mg TMC278Safety(n = number of subjects with data)

TMC27825 mg suspension

TMC27825 mg tablet

FedN=12

FastedN=12

FedN=12

Adverse Events (AEs)n (%) with 1 or more AEs 6 (50.0) 5 (41.7) 6 (50.0)n (%) of deaths 0 0 0n (%) with 1 or more other serious AEs 0 0 0n (%) of treatment stopped due to AEs 0 0 0n (%) with 1 or more grade 3 or 4 AEs 0 0 0

Most frequently reported treatment-emergent AEs (reported in ≥ 2 subjects with any treatment), n (%)Headache 4 (33.3) 2 (16.7) 2 (16.7)Nasopharyngitis 1 (8.3) 2 (16.7) 2 (16.7)Oropharyngeal Pain 0 0 2 (16.7)

Panel 3: oral granules, a single dose of 25 mg TMC278Safety(n = number of subjects with data)

TMC27825 mg granules

TMC27825 mg tablet

FedN=11

FastedN=12

FedN=11

Adverse Events (AEs)n (%) with 1 or more AEs 7 (63.6) 5 (41.7) 3 (27.3)n (%) of deaths 0 0 0n (%) with 1 or more other serious AEs 0 0 0n (%) of treatment stopped due to AEs 0 0 0n (%) with 1 or more grade 3 or 4 AEs 0 0 0

Most frequently reported treatment-emergent AEs (reported in ≥ 2 subjects with any treatment), n (%)Headache 3 (27.3) 1 (8.3) 1 (9.1)Nasopharyngitis 0 0 2 (18.2)

There were no notable differences in the incidences of AEs across the panels. Within the solution, suspension, and granule treatment groups, a slightly higher incidence of AEs was observed under fed conditions, compared to fasted conditions. The most commonly reported AE during the trial was headache. One subject was reported with a grade 2 AE of rash maculo-papular during treatment with the TMC278 tablet (fed), which led to the withdrawal of the subject from the trial. No grade 3 (severe) or grade 4 (life-threatening) treatment-emergent AEs were reported. There were no deaths or SAEs reported in this trial.Skin events of interest were reported for 2 subjects during the trial: 1 (8.3%) subject during treatment with the TMC278 solution (fed) (rash papular) and 1 (8.3%) subject with a grade 2 AE of rash maculo-papular as mentioned above.Clinical Laboratory TestsNo clinically meaningful changes over time were observed in the hematology, biochemistry, and urinalysis parameters in any treatment group. The majority of treatment-emergent abnormalities were DAIDS grade 1. The most common treatment-emergent grade 2 abnormalities were decreased phosphorus, hyperglycemia, increased lipase, and increased total bilirubin; reported in no more than 2 subjects in any session. No grade 3 or 4 treatment-emergent laboratory abnormalities were observed during the trial. No subjects were observed with treatment-emergent AEs related to laboratory parameters or discontinued the trial for this reason.Vital SignsThere were no consistent or clinically relevant changes in vital signs parameters, and no clinically relevant individual abnormalities were observed.Physical ExaminationNo clinically relevant new physical examination findings were reported. No new physical examination abnormalities were reported as AEs.Taste Questionnaire



A higher proportion of subjects rated the overall palatability of the TMC278 suspension and granule formulation as “acceptable” or “good” (83.3% and 8.3% [suspension], and 66.7% and 16.7% [granules], respectively), compared to the solution (25.0% and 16.7%, respectively). The results of the visual analogue scale revealed that a higher proportion (58.3%) of subjects in the TMC278 solution group expressed a dislike (very much or a little) to the solution compared to the suspension or granule groups (16.7% each).

Conclusions

Pharmacokinetics

The results of the present trial demonstrate that all 3 concept pediatric formulations of TMC278 have an acceptableoral bioavailability when administered as a single dose of 25 mg.

Oral SolutionBoth in fed and fasted conditions, the TMC278 exposure (Cmax, AUC) for the oral solution was higher as compared to the tablet formulation in fed conditions, and this was especially apparent for Cmax of the solution in fastedconditions (70% higher). While the AUC for the solution was similar in fasted and fed conditions, the Cmax was 32% higher in the fasted as compared to the fed condition.

Oral SuspensionThe exposure for the oral suspension, both under fed and fasted conditions, was comparable to that of the tablet formulation under fed conditions, except for a higher Cmax (22%) when the oral suspension was administered under fasted conditions. There was no food effect for the suspension formulation.

Oral GranulesWhen administered in fed conditions, the exposure (Cmax, AUC) for the granules was about 20-30% higher as compared to the tablet formulation in fed conditions. Under fasted conditions, the exposure (AUC) for the granules was similar, with a lower Cmax as compared to the tablet formulation in fed conditions. There was a food effect for the granules, with a 28-30% lower exposure (Cmax, AUC) when administered under fasted as compared to fed conditions.

Safety

No new safety signals for AEs, laboratory parameters, vital signs, or ECG were observed.

Taste Questionnaire

The proportion of subjects in each panel that rated the concept formulation as “acceptable” or “good” was 41.7%, 91.7%, and 83.3% for the TMC278 solution, suspension, and granule formulations, respectively.


iv

v

vi

vii

viii

ix

x

1. STUDY SYNOPSIS

Gilead Sciences, Inc.333 Lakeside Drive

Foster City, CA 94404

Name of Sponsor:

Name of FinishedProduct:

Name of ActiveIngredient:

Individual Study TableReferring to Part _____of the Dossier

Volume:

Page

(For National Authority UseOnly)

Title of Study:

Investigator:

Study Centers:

Publications:

Study Period:

Objectives:

•

STUDY SYNOPSIS (CONTINUED)

Objectives(Continued):

•

•

•

•

Study Design:

Number ofPatients (Plannedand Analyzed):

Diagnosis andMain Criteria forInclusion:

Test Product, Dose,Mode ofAdministration, andBatch No.:


Reference Therapy,Dose, Mode ofAdministration, andBatch No.:

Criteria forEvaluation:Pharmacokinetics: ∞ λ

Safety:

Statistical Methods:Pharmacokinetics:

∞ λ

∞


Statistical Methods(continued):Safety:

Results:

PK:

Arithmetic Mean (SD) Tenofovir Pharmacokinetic Parameters(Treatments B and A)

Summary of the Pharmacokinetic Parameters of Serum and Urine Tenofovir for Treatments B and A

------------ Tenofovir ------------- Treatment B Treatment A ------------------------------------ Pharmacokinetic Arithmetic Arithmetic Parameters Mean SD Mean SD ---------------------------------------------------------------------------------- Cmax(ng/mL) 295.76 89.70 306.80 88.79 Tmax(hr) 0.993 0.384 1.01 0.595 AUC(0-24)(ng*hr/mL) 1541 405.6 1534 326.5 AUC(0-t)(ng*hr/mL) 1967 534.3 1958 442.5 AUC(0-inf)(ng*hr/mL) 2287 685.2 2266 549.5 t1/2λz (hr) 18.7 3.63 18.2 4.26 Kel(1/hr) 0.0382 0.00687 0.0399 0.00766 % dose recovered 16.7 4.8 16.9 4.6 CLr (mL/hr/kg) 167.3 43.8 172.5 67.0 CLCr (mL/hr/kg) 93.1 18.4 93.6 17.9 ---------------------------------------------------------------------------------- Treatment B = 1 x 300 mg TDF Tablet (Commercial Formulation), Fasted: test Treatment A = 4 x 75 mg TDF Tablets (Clinical Formulation), Fasted: reference


Arithmetic Mean (SD) Tenofovir Pharmacokinetic Parameters(Treatments C and B)

Summary of the Pharmacokinetic Parameters of Serum and Urine Tenofovir for Treatments C and B

----------- Tenofovir ---------- Treatment C Treatment B ------------------------------------ Pharmacokinetic Arithmetic Arithmetic Parameters Mean SD Mean SD ---------------------------------------------------------------------------------- Cmax(ng/mL) 334.87 80.22 295.76 89.70 Tmax(hr) 2.03 0.880 0.993 0.384 AUC(0-24)(ng*hr/mL) 2139 385.1 1541 405.6 AUC(0-t)(ng*hr/mL) 2710 499.5 1967 534.3 AUC(0-inf)(ng*hr/mL) 3100 597.8 2287 685.2 t1/2λz (hr) 17.4 3.47 18.7 3.63 Kel(1/hr) 0.0413 0.00789 0.0382 0.00687 % dose recovered 23.5 4.9 16.7 4.8 CLr (mL/hr/kg) 168.6 41.4 167.3 43.8 CLCr (mL/hr/kg) 92.3 14.6 93.1 18.4 ---------------------------------------------------------------------------------- Treatment C = 1 x 300 mg TDF Tablet (Commercial Formulation), Fed: test Treatment B = 1 x 300 mg TDF Tablet (Commercial Formulation), Fasted: reference

Statistical Comparisons of Serum Tenofovir Pharmacokinetic Parameters:Treatment B Versus Treatment A

Treatment Mean Confidence Intervals % Mean Parameter B A (90% Confidence) Ratio ---------------------------------------------------------------------------------- ln(Cmax) 5.649 5.687 87.8-105.6 96.3 ln[AUC(0-t)] 7.551 7.553 95.2-104.7 99.8 ln[AUC(0-inf)] 7.695 7.688 95.8-105.8 100.7 ---------------------------------------------------------------------------------- Treatment B = 1 x 300 mg TDF Tablet (Commercial Formulation), Fasted: test Treatment A = 4 x 75 mg TDF Tablets (Clinical Formulation), Fasted: reference

Values for Treatments B and A are the least - squares means (LSMEANS) from the ANOVA Parameters are ln-transformed parameters

Mean Ratio = 100*test/reference for untransformed parameters Mean Ratio = 100*exp(test-reference) for ln-transformed parameters

Statistical Comparisons of Serum Tenofovir Pharmacokinetic Parameters:Treatment C Versus Treatment B

Treatment Mean Confidence Intervals % Mean Parameter C B (90% Confidence) Ratio ---------------------------------------------------------------------------------- ln(Cmax) 5.784 5.649 104.4-125.4 114.4 ln[AUC(0-t)] 7.888 7.551 133.6-146.7 140.0 ln[AUC(0-inf)] 8.018 7.695 131.5-145.1 138.2 ---------------------------------------------------------------------------------- Treatment C = 1 x 300 mg TDF Tablet (Commercial Formulation), Fed: test Treatment B = 1 x 300 mg TDF Tablet (Commercial Formulation), Fasted: reference

Values for Treatments C and B are the least - squares means (LSMEANS) from the ANOVA Parameters are ln-transformed parameters

Mean Ratio = 100*test/reference for untransformed parameters Mean Ratio = 100*exp(test-reference) for ln-transformed parameters


Safety:

Conclusions:

∞

∞


Conclusions(continued):

•

•

•

Tenofovir Disoproxil Fumarate/Emtricitabine Fixed Dose Combination Product Protocol GS-US-104-0172 Clinical Study Report Final

CONFIDENTIAL Page 2 11FEB2004

2. STUDY SYNOPSIS


Foster City, CA 94404 USA

Name of Sponsor: Gilead Sciences, Inc. Name of Finished Product: Tenofovir disoproxil fumarate/emtricitabine fixed dose combination product Name of Active Ingredients: Tenofovir disoproxil fumarate, emtricitabine

Individual Study Table Referring to Part of the Dossier:

Volume:

Page:

(For National Authority Use Only)

Title of Study: A Phase 1 Pharmacokinetic Study in Healthy Volunteers to Evaluate the Bioequivalence of the Combined Formulated Tablet of Tenofovir Disoproxil Fumarate and Emtricitabine Compared to Tenofovir Disoproxil Fumarate and Emtricitabine Administered Concurrently and the Effect of Food on Pharmacokinetics

Investigators:

Study Centers:

Publications: None

Tenofovir Disoproxil Fumarate/Emtricitabine TabletFinal CSR GS-US-104-0172





Study Period: 20 (First study subject randomized) 20 (Last study subject observation)


Objectives: The primary objectives of this study were:

• To establish bioequivalence between the combination tablet (containing 300 mg tenofovir disoproxil fumarate/200 mg emtricitabine) and concurrent administration of the 300 mg tablet of tenofovir disoproxil fumarate and the 200 mg capsule of emtricitabine by evaluation of Cmax and AUC of tenofovir and emtricitabine.

• To investigate the effect of food (high-fat meal and light meal) on the pharmacokinetics (PK) of the combination tablet.

• To assess the safety of tenofovir disoproxil fumarate and emtricitabine when administered together either as a combination tablet or as separate formulations.

Methodology: Randomized, open-label, four-treatment, single center, four-way crossover study

Number of Subjects (Planned and Analyzed):

Planned: 36 evaluable subjects Enrolled: 44 Completed: 39

Diagnosis and Main Criteria for Inclusion:

Healthy male and healthy, nonpregnant, nonlactating female subjects between the ages of 18 and 60 years, inclusive

Duration of Treatment:

28 days

Test Product, Dose, Mode of Administration, and Lot No.:

Combination tablet of tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg, administered orally; Lot No. V301B2






Reference Therapy, Dose, Mode of Administration, and Lot No.:

Single tablet of tenofovir disoproxil fumarate 300 mg, administered orally; Lot No. J110B1

Single capsule of emtricitabine 200 mg, administered orally; Lot No. W303A1

Criteria for Evaluation:

Efficacy:

Efficacy was not evaluated in this study.

Pharmacokinetics: The following parameters were assessed for each analyte in plasma: Cmax, Tmax, AUC0 t, AUC0 ∞, % AUCexp, kel, T½λz, CL/F, and Vz/F.

Safety: Safety was evaluated by assessment of clinical laboratory tests at baseline and at various time points during the study, periodic physical examinations including vital signs, and documentation of adverse events.

Statistical Methods:

Pharmacokinetics: For each analyte (tenofovir or emtricitabine), a parametric (normal theory) general linear model appropriate for a 4-treatment crossover design was fit to the natural logarithmic transformation of the Cmax and AUC parameters. The analysis of variance (ANOVA) model included the following factors: sequence, subjects within sequence, period, and treatment.

For the assessment of formulation bioequivalence, a 90% confidence interval was obtained for the geometric mean ratio using treatment A (separate tenofovir DF tablet and emtricitabine capsule fasted) as the reference treatment and treatment B (tenofovir DF/emtricitabine combination tablet, fasted) as the test treatment. Ninety-percent confidence intervals were constructed about the ratio of geometric means of Cmax and AUC. The two treatments were considered bioequivalent if the 90% confidence intervals were encompassed within the bounds of 80% to 125% for Cmax and AUC.







Pharmacokinetics: (Continued)

From the same ANOVA, the assessment of food effect was performed by obtaining 90% confidence intervals for the geometric mean ratios using treatment B (tenofovir DF/ emtricitabine combination tablet, fasted) as the reference, and treatment C (tenofovir DF/emtricitabine combination tablet, standard high-fat meal) and treatment D (tenofovir DF/ emtricitabine combination tablet, standard light meal) as test treatments. No food effect on PK was concluded if the 90% confidence intervals were within the bounds of 80% to 125% for Cmax and AUC.

Safety: The frequency of treatment-emergent adverse events, treatment-related adverse events, treatment-emergent serious adverse events, and adverse events leading to study drug discontinuation were summarized using the Medical Dictionary for Regulatory Activities (MedDRA®, version 6.0). In addition, the change in value from pre-dose to post-dose in quantitative laboratory parameters (hematology, chemistry, and urinalysis) was summarized by parameter and treatment, as was the number of subjects with post-dosing laboratory toxicity by maximum toxicity grade.






SUMMARY – RESULTS:

Pharmacokinetics Results:

Bioequivalence: The mean (± SD) maximum concentrations (Cmax) of tenofovir after administration of the tenofovir DF tablet or the combination tablet were 267.59 ± 80.61 or 253.63 ± 83.46 ng/mL, respectively. Exposure (AUC0−∞) of tenofovir after administration of either tenofovir DF or the combination tablet was similar. The ratios for both the rate and extent (Cmax and AUC) of tenofovir bioavailability after its administration as tenofovir DF or as the combination tablet were contained within the bounds of 80% to 125%, demonstrating bioequivalence of tenofovir between the two treatments.

The mean emtricitabine Cmax values after administration of emtricitabine capsules or the combination tablet were 2.21 ± 0.59 and 2.13 ± 0.60 μg/mL, respectively. AUC0−∞ values were also similar between the two treatments (10.70 and 10.62 μg•hr/mL, respectively). The 90% confidence intervals for the geometric least squares means ratios of emtricitabine Cmax and AUC for treatment A (emtricitabine capsules) as reference and treatment B (combination tablet) as test were contained within the 80% to 125% interval, demonstrating bioequivalence for emtricitabine between the two study treatments.

Food Effect: Administration of the combination tablet with either a high-fat or light meal was associated with a delay in the time to maximum plasma tenofovir concentration (Tmax) relative to Tmax for the fasted state. The intake of a high-fat or light meal did increase the maximum plasma concentration (Cmax) of tenofovir by approximately 16% or 13.5%, respectively, compared with the fasted-state administration. Likewise, an increase of approximately 35% or 34% in tenofovir AUC0−∞ was observed after administration with a high-fat or light meal, respectively, compared with the fasted state.

Emtricitabine pharmacokinetic parameters after ingestion of food (high-fat or light meal) were essentially the same as those for the fasting state, indicating no food effect on the disposition of emtricitabine. The mean emtricitabine Cmax after fasting, high-fat meal, and light meal was 2.1, 2.0, and 2.0 μg/mL, and the mean total systemic exposure (AUC0−∞) was 10.6, 10.3, and 10.4 μg•hr/mL, respectively. These results indicate that food intake has no effect on emtricitabine pharmacokinetics.






Safety Results: Of the 44 subjects dosed with study drug, 8 subjects (18.2%) reported a total of 13 treatment-emergent adverse events. The only treatment-related adverse event reported in more than one subject of any treatment group was headache, which was reported in 2 (5%) of the 40 subjects receiving the combination tablet with a light meal. Twelve of the 13 adverse events were mild in severity (toxicity grade 1); 1 adverse event (hypertension, not related to study treatment) was considered to be of moderate severity (toxicity grade 2). The investigator considered 11 of the 13 adverse events to be related to the study treatment; the remaining (one grade 2 hypertension and one grade 1 headache) were considered to be unrelated to treatment. Two subjects were discontinued from the study because of adverse events, one because of moderate hypertension considered by the investigator to be not related to study treatment and the other because of mild rash considered to be related to study treatment. No serious adverse events were reported during this study.

CONCLUSION: The tenofovir DF/emtricitabine combination tablet is bioequivalent to coadministration of the tenofovir DF tablet and the emtricitabine capsule. Administration of the tenofovir DF/emtricitabine combination tablet with either a high-fat meal or a light meal increased the tenofovir exposure by approximately 30% compared with fasted-state administration. There is no effect of food on emtricitabine concentrations. Tenofovir DF and emtricitabine, either administered as the combination tablet (containing 300 mg tenofovir DF/200 mg emtricitabine) or coadministered as the 300 mg tablet of tenofovir DF and 200 mg capsule of emtricitabine, are well tolerated by the study subjects.



FINAL CLINICAL STUDY REPORT

Study Title: Bioequivalence Study of Two, Fixed-dose, Combination Tablet Formulations Containing Emtricitabine, Rilpivirine, and Tenofovir Disoproxil Fumarate Compared to the Concurrent Administration of the Individual Components

Name of Test Drug: Emtricitabine (FTC), rilpivirine (RPV), and tenofovir disoproxil fumarate (TDF)

Dose and Formulation: Fixed-dose combination (FDC) tablet containing emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir disoproxil fumarate 300 mg (FTC/RPV/TDF) 200-mg strength capsule of emtricitabine, 25-mg strength tablet of rilpivirine, and 300-mg strength tablet of tenofovir disoproxil fumarate

Indication: HIV-1 Infection Sponsor: Gilead Sciences, Inc.

333 Lakeside Drive Foster City, CA 94404

Study No.: GS-US-264-0101

Phase of Development: Phase 1 IND No.: EudraCT No.:

106,252Not applicable

Study Start Date: 20 (First Subject Screened)Study End Date: 20 (Last Subject Observation)Principal or Coordinating Investigator:

Name: Affiliation:

Gilead Responsible Medical Monitor:

Name: Telephone: Fax:

Report Date: 15 July 2010

CONFIDENTIAL AND PROPRIETARY INFORMATION This study was conducted in accordance with the guidelines of Good Clinical Practice,

including archiving of essential documents.

Emtricitabine/rilpivirine/tenofovir disoproxil fumarate Study GS-US-264-0101 Final Clinical Study Report Final


STUDY SYNOPSIS Study GS-US-264-0101:


Foster City, CA 94404 United States of America

Title of Study: Study GS-US-264-0101: Bioequivalence Study of Two, Fixed-dose, Combination Tablet Formulations Containing Emtricitabine, Rilpivirine, and Tenofovir Disoproxil Fumarate Compared to the Concurrent Administration of the Individual Components

Investigator:

Study Centers: Single Phase 1 center in the US ( )

Publications: None

Study Period: 20 (First subject screened) 20 (Last subject observation)



To evaluate the bioequivalence of two fixed-dose combination tablets (each containing emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir DF 300 mg) compared to a 200-mg capsule of emtricitabine, a 25-mg tablet of rilpivirine, and a 300-mg tablet of tenofovir DF taken concurrently under fed conditions

The secondary objective of this study was as follows:

To evaluate the safety of emtricitabine, rilpivirine, and tenofovir DF when administered together either as fixed-dose combination tablets or individual dosage forms in healthy volunteers



Methodology: This was a Phase 1, randomized, open-label, single-center, single-dose, 3-way crossover study that evaluated the relative bioequivalence of 2 fixed-dose combination (FDC) tablets (each containing emtricitabine [FTC] 200 mg, rilpivirine [RPV] 25 mg, and tenofovir disoproxil fumarate [TDF] 300 mg) compared with a 200-mg strength capsule of emtricitabine, a 25-mg strength tablet of rilpivirine, and a 300-mg strength tablet of tenofovir disoproxil fumarate taken concurrently under fed conditions. Rilpivirine in each of the FDC products was 25 mg as 27.5 mg of the hydrochloride salt. Eligible subjects were randomized to 1 of 6 treatment sequences and received 1 dose of study drug during each of 3 dosing periods. Periods 1 and 2 were followed by a 14-day washout period. Following Period 3 dosing, subjects returned to the study center 14 days after the last dose for a follow-up visit.

Number of Subjects (Planned and Analyzed):Planned: 48 subjects Analyzed: Safety analysis set: 48 subjects Pharmacokinetics (PK) analysis sets: FTC PK analysis set: 44 subjects; RPV PK analysis set: 44 subjects; TDF PK analysis set: 44 subjects

Diagnosis and Main Criteria for Inclusion:Eligible subjects were males and nonpregnant, nonlactating females, with a body mass index (BMI) between 19 and 30 (inclusive), no significant medical history, normal renal function, and in good general health, as determined by the investigator at the screening evaluation performed no more than 28 days prior to the scheduled first dose.

Duration of Treatment: Three single doses over 29 days

Test Product, Dose, Mode of Administration, and Batch No.:FTC/RPV/TDF FDC Formulation 1: A single dose of FDC tablet (emtricitabine 200 mg, rilpivirine 25 mg [as 27.5 mg of the hydrochloride salt], and tenofovir disoproxil fumarate 300 mg) administered orally in the morning and within 5 minutes of consuming a standardized meal. Formulation identifier: FP-11131, Lot Number BY0902B1

FTC/RPV/TDF FDC Formulation 2: A single dose of FDC tablet (emtricitabine 200 mg, rilpivirine 25 mg [as 27.5 mg of the hydrochloride salt], and tenofovir disoproxil fumarate 300 mg) administered orally in the morning and within 5 minutes of consuming a standardized meal. Formulation identifier: FP-11132, Lot Number BY0901B1

Reference Therapy, Dose, Mode of Administration, and Batch No.:

FTC+RPV+TDF (Reference): Single doses of emtricitabine 1 200-mg strength capsule, rilpivirine 1 25-mg strength tablet [as 27.5 mg of the hydrochloride salt], and tenofovir disoproxil fumarate 1 300-mg strength tablet administered together orally in the morning and within 5 minutes of consuming a standardized meal. FTC Lot Number: 67038AF21 RPV Lot Number: 9CL1F TDF Lot Number: J0604B1



Criteria for Evaluation: Efficacy: Not applicable.

Pharmacokinetics: The following plasma PK parameters were calculated: Cmax, Tmax, Clast,Tlast, z, AUClast, AUCinf, AUCexp, and T1/2.

Safety: Safety was evaluated by assessment of clinical laboratory tests, electrocardiograms (ECGs), periodic physical examinations, vital signs, and adverse events (AEs).

Statistical Methods: Efficacy: Not applicable.

Pharmacokinetics: PK parameters were estimated by application of a nonlinear model using standard noncompartmental methods (WinNonlin , Version 5.2) and summarized by analyte (emtricitabine, rilpivirine, and tenofovir [TFV]) using descriptive statistics. For each analyte, a parametric analysis of variance (ANOVA) model appropriate for this crossover design was fitted to the natural logarithmic transformation of PK parameters AUCinf, AUClast, and Cmaxfor evaluable subjects. The mixed-effects model included treatment, sequence, and period as fixed effects, and subject-within-sequence as a random effect. For the assessment of bioequivalence, the 90% confidence intervals (CIs) were constructed for the ratio of geometric least-squares (GLS) means (test treatment/reference treatment) of AUCinf, AUClast,and Cmax for each of the 3 analytes. Formulation bioequivalence was concluded if the 90% CIs for the ratio of the GLS means were within the range of 80% to 125% for each of the 3 PK parameters.

Safety: All safety data collected during the course of the study (after administration of the first dose of study drug until the date of the last dose of study drug plus 30 days) were listed by subject. Safety data were summarized by treatment group at baseline and at all post-dose visits. All AEs and clinical laboratory abnormalities in summaries were treatment emergent.

SUMMARY – RESULTS: Subject Disposition and Demographics: Forty-eight subjects were enrolled and received study drug, 8 in each of the 6 treatment sequences. Six subjects (12.5%) did not complete the study, 2 for protocol deviations and 4 withdrew consent. Five subjects (10.4%) did not complete all 3 study treatments. One subject completed all 3 treatments, but was withdrawn after the third treatment for protocol deviations. Of the 48 treated subjects, 45 (93.8%) received the reference treatment (FTC+RPV+TDF), 46 (95.8%) received FTC/RPV/TDF FDC Formulation 1, and 46 (95.8%) received FTC/RPV/TDF FDC Formulation 2. In the safety analysis set, 62.5% of the subjects were male, and the mean age was 28 years (range, 19 to 44 years). The majority of subjects (68.8%) were white, 22.9% were black, and 8.3% were American Indian or Alaska Native.

Efficacy Results: Not applicable



Pharmacokinetic Results: Bioequivalence testing results showed that while emtricitabine and tenofovir exposures met the bioequivalence criterion in each FDC test formulation versus the reference product, rilpivirine exposures did not. As shown in the table below, the 90% CIs for the geometric means ratio (GMR) of test:reference for the 3 primary PK parameters fell within the 80% to 125% range for emtricitabine and tenofovir, but not for rilpivirine.

GLS Mean GMR (%) FTC Test Formulation 1a Referenceb Test/Reference 90% CI

AUCinf (ng h/mL) 9659.28 9563.29 101.00 (99.27, 102.77) AUClast (ng h/mL) 9432.01 9337.61 101.01 (99.31, 102.75) Cmax (ng/mL) 1796.99 1656.68 108.47 (104.15, 112.97)

Test Formulation 2b Referenceb Test/Reference AUCinf (ng h/mL) 9577.65 9563.29 100.15 (98.45, 101.88) AUClast (ng h/mL) 9348.45 9337.61 100.12 (98.44, 101.82) Cmax (ng/mL) 1681.62 1656.68 101.51 (97.50, 105.68)

GLS Mean GMR (%) TFV Test Formulation 1a Referenceb Test/Reference 90% CI



GLS Mean GMR (%) RPV Test Formulation 1a Referenceb Test/Reference 90% CI



GLS = geometric least squares; GMR = geometric means ratio; CI = confidence interval Reference = FTC+RPV+TDF: single doses of FTC 200-mg strength capsule, RPV 25-mg strength tablet, and TDF 300-mg strength tablet Test Formulation 1: FTC/RPV/TDF, a single dose of FDC tablet (FTC 200 mg, RPV 25 mg, and TDF 300 mg) Test Formulation 2: FTC/RPV/TDF, a single dose of FDC tablet (FTC 200 mg, RPV 25 mg, and TDF 300 mg) a N = 43 b N = 44



Safety Results: Safety results demonstrate that the 3 treatments (FTC+RPV+TDF reference, FTC/RPV/TDF FDC Formulation 1, and FTC/RPV/TDF FDC Formulation 2) were well tolerated in this study. Higher percentages of subjects had AEs following FTC/RPV/TDF FDC Formulation 2 than the other 2 treatments. Treatment-emergent AEs were seen in 24.4% of those taking FTC+RPV+TDF reference, in 15.2% of those taking FTC/RPV/TDF FDC Formulation 1, and in 30.4% of those taking FTC/RPV/TDF FDC Formulation 2. Treatment-emergent AEs considered to be study drug related were reported in 8.9%, 6.5%, and 21.7% of subjects following administration of FTC+RPV+TDF reference, FTC/RPV/TDF FDC Formulation 1, and FTC/RPV/TDF FDC Formulation 2, respectively.

Nausea and headache were the most common AEs, and were seen in more subjects with FTC/RPV/TDF FDC Formulation 2. Nausea was reported in 2 subjects with FTC+RPV+TDF reference, 2 subjects with FTC/RPV/TDF FDC Formulation 1, and 6 subjects with FTC/RPV/TDF FDC Formulation 2. Headache was experienced by 1 subject with FTC+RPV+TDF reference, 1 subject with FTC/RPV/TDF FDC Formulation 1, and 6 subjects with FTC/RPV/TDF FDC Formulation 2.

All AEs were mild or moderate. Moderate AEs were reported in 6.7%, 4.3%, and 13.0% of subjects with FTC+RPV+TDF reference, FTC/RPV/TDF FDC Formulation 1, and FTC/RPV/TDF FDC Formulation 2, respectively.

There were no Grade 3 or 4 AEs or serious AEs reported in this study, nor were there any early study discontinuations because of AEs.

No Grade 4 treatment-emergent laboratory abnormalities were reported in this study, and no AEs related to graded laboratory abnormalities were reported. Two female subjects experienced Grade 3 hematuria on Day 14 following FTC/RPV/TDF FDC Formulation 1. No clinically relevant changes in vital signs, safety ECGs, or other observations related to safety occurred during the study.

CONCLUSIONS: While emtricitabine and tenofovir exposures met the bioequivalence criterion in each FDC test formulation (FTC/RPV/TDF FDC Formulation 1 and FTC/RPV/TDF FDC Formulation 2) versus the reference product, rilpivirine exposures did not. Since the bioequivalence criterion could not be achieved for all 3 components of the FDC formulations, the study concludes that FTC/RPV/TDF FDC Formulation 1 and FTC/RPV/TDF FDC Formulation 2 are not bioequivalent to the reference treatment (individual components FTC+RPV+TDF administered concurrently).

Safety results demonstrate that the 3 treatments (FTC+RPV+TDF reference, FTC/RPV/TDF FDC Formulation 1, and FTC/RPV/TDF FDC Formulation 2) were well tolerated in this study.

TMC278 (rilpivirine) Clinical Study Report TMC278IFD4005

7 Final, Date: 27 AUG 2013

SYNOPSIS Name of Sponsor/Company Janssen Pharmaceutical K.K. Name of Finished Product EDURANT tablets Name of Active Ingredient TMC278 (rilpivirine) Status: Final Date: 21 AUG 2013 Prepared by: Janssen Pharmaceutical K.K. Protocol No.: TMC278IFD4005

Title of Study: An Open-label, Single-dose Study to Investigate the Pharmacokinetics and Safety of TMC278 After Oral Administration of TMC278 25 mg Tablet Under Fed Condition in Healthy Japanese Adult Male Subjects

NCT No.: NCT01804244

Principal Investigator:

Study Center:

Publication (Reference): Not applicable

Study Period: 19 February 2013 (date of first subject enrolled [informed consent]) to 22 March 2013 (date of last observation for last subject); 20 (database lock)


Objectives:

Primary objective

To evaluate the pharmacokinetics (PK) of TMC278 after a single oral dose of TMC278 25 mg tablet (27.5 mg as the hydrochloride salt) under fed condition in healthy Japanese adult male subjects.

Secondary objective

To evaluate safety after a single oral dose of TMC278 25 mg tablet under fed condition in healthy Japanese adult male subjects.

Hypothesis:

No formal statistical hypothesis testing was planned for this study. This study was designed only to collect plasma TMC278 PK profiles in healthy Japanese adult male subjects, not to explore or generate any hypotheses.

Methodology:

This was a single center, open-label, single oral dose study in healthy Japanese adult male subjects. The study consisted of 3 phases: a screening phase up to 26 days (Day -28 to Day -3), an inpatient phase from Day -2 to Day 8, and a follow-up assessment phase on Day 15 (±2 days) or at the time of early withdrawal.

Subjects who met the selection criteria were admitted to the investigational institute 2 days before receiving the study drug (Day -2). All enrolled subjects received a single oral dose of one TMC278 25 mg



tablet on Day 1 within 10 minutes after completion of a standardized breakfast. Enrolled subjects remained in the investigational institute for the entire duration of the inpatient phase. Subjects were discharged on Day 8 after the completion of all required assessments. Serial blood samples for determination of plasma concentrations of TMC278 were collected over a period of 168 hours (7 days).

Standardized Breakfast

Japanese breakfast. Total energy was approximately 450 kcal, with percentages of energy from carbohydrates, protein, and fat of about 60%, 15%, and 25%, respectively.

Number of Subjects (planned and analyzed):

Eight subjects were enrolled to ensure that at least 6 subjects completed the planned collection of PK samples. All of the 8 subjects completed the study and were included in the safety and PK analysis population (Table 1).

Table 1: Subject Disposition and Number of Subjects Per Analysis Set; Safety Number of subjectsTotal number of subjects who were administered the study drug 8 Completed 8 Discontinued after administration 0 Evaluable subjects PK analysis set 8 Safety analysis set 8 Subjects excluded from analysis set PK analysis set 0 Safety analysis set 0 Cross-reference: Attachment TSIDISP

Diagnosis and Main Criteria for Inclusion:

Healthy Japanese men aged 20 to 40 years, inclusive; BMI between 18.5 and 25.0 kg/m2, inclusive; body weight of at least 50 kg.

Test Product, Dose and Mode of Administration, Batch No.:

TMC278 25 mg tablet containing 25 mg of TMC278 as the hydrochloride salt (27.5 mg). The batch number of the TMC278 25 mg tablet was 0002A.

The TMC278 25 mg tablet was taken between approximately 9:00 AM and 10:00 AM within 10 minutes after completion of a standardized breakfast as an oral dose with 150 mL of noncarbonated water and was swallowed whole, not chewed, divided, dissolved, or crushed.

Reference Therapy, Dose and Mode of Administration, Batch No.: Not applicable

Duration of Treatment:

The maximum study duration for each subject was 45 days, including the screening phase, inpatient period, and follow-up visit. If it was considered necessary, the study duration could be prolonged for additional follow-up.




Pharmacokinetics

Venous blood samples (4 mL each) were collected for the measurement of plasma TMC278 concentrations at the following time points:

Predose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 16, 24, 48, 72, 120, and 168 hours postdose.

The PK parameters determined for each subject included (but were not limited to) the following: maximum plasma concentration (Cmax), time to reach the maximum plasma concentration (tmax), area under the plasma concentration-time curve from time 0 to the last quantifiable time, calculated by linear trapezoidal summation (AUClast), area under the plasma concentration-time curve from time 0 to infinity (AUC ), elimination rate constant associated with the terminal phase ( z), elimination half-life (t1/2), apparent total body clearance of drug at the terminal phase after extravascular administration (CL/F), and apparent volume of distribution at the terminal phase after extravascular administration (Vdz/F), estimated by non-compartmental analysis using WinNonlin® (Version 6.2.1).

Safety

Safety was evaluated throughout the study by examining incidence, severity, type of adverse events (AEs), changes in clinical laboratory results (hematology, biochemistry, and urinalysis), vital signs, physical examinations, and 12-lead ECGs.


Sample Size Determination

Eight subjects were enrolled in the study to ensure that at least 6 subjects completed the study assessments up to Day 8. Based on a previous study (TMC278-TiDP38-C145), the intersubject coefficients of variation (CVs) for AUClast and Cmax of a single dose of TMC278 were estimated to be less than or equal to 42% in healthy non-Japanese adult subjects. Using an estimate of approximately 42% for intersubject CVs and a sample size of 6 subjects, the true mean AUClast and Cmax of TMC278 were estimated to be within 72% to 139% of the observed geometric means with 95% confidence.

Subject Information

For all subjects who had received at least one dose of study drug, descriptive statistics were provided.

All demographic (age, height, weight, and BMI) and other initial subject characteristics (eg, medical history, physical examination) were tabulated and analyzed descriptively.

Pharmacokinetics

For all subjects with at least one available plasma TMC278 concentration, plasma TMC278 concentration data were tabulated. Individual plasma TMC278 concentration-time profiles were visually presented.

All subjects who completed the treatment with sufficient TMC278 plasma concentration data for the estimation of the PK parameters were included in the PK analysis population. Descriptive statistics (eg, number of collected data, mean, standard deviation, median, minimum, maximum, CV) of plasma TMC278 concentration data at each time point were reported. Mean plasma TMC278 concentration-time profile data was visually presented on a linear scale.

PK parameters of plasma TMC278 were estimated using a non-compartmental analysis method with WinNonlin® (Version 6.2.1). Individual and descriptive statistics of plasma PK parameters of TMC278 were tabulated.



Safety

All subjects who received at least one dose of the study drug were included in the safety analysis.

Baseline laboratory evaluations, vital signs, and ECG measurements were defined as the last evaluation done before the study drug administration.

Safety data were summarized using descriptive statistics and frequency tables.

RESULTS:

Study Population:

Eight healthy Japanese male subjects aged 20 to 37 years, inclusive, were enrolled in the study. All of the 8 subjects received a single dose of the study drug, and all subjects completed the study.

Pharmacokinetic Results:

The estimated PK parameters are shown in Table 2.

Table 2: Summary of Plasma Pharmacokinetic Parameters After a Single Oral Dose of TMC278 25 mg Under Fed Condition (Number of Subjects=8)

Parameters (unit)

Cmax (ng/mL)

tmax (h)

AUClast (ng·h/mL)

AUC (ng·h/mL)

t1/2 (h)

z (1/h)

Vdz/F (L)

CL/F (L/h)

Mean 144.3 4.50 4,246 4,542 43.0 0.01695 397.4 6.389 SD 49.660 1.20 1,911.8 2,001.2 10.9 0.0038610 183.32 2.3964 Minimum 91.3 2.00 2,513 2,574 31.7 0.0109 178 3.27 Median 129.0 5.00 3,565 3,840 39.2 0.01770 361.6 6.559 Maximum 244 6.00 7,287 7,653 63.4 0.0219 665 9.71 %CV 34.4 45.0 44.1 25.4 22.8 46.1 37.5 Geo Mean 137.8 3,917 4,199 41.9 0.01654 360.1 5.954 h = hour(s), Geo Mean = geometric mean. Cross-reference: Attachment TPKPARAM

Safety Results:

No death, serious adverse event (SAE), or withdrawal from the study due to an AE occurred in this study (Table 3).

Table 3: Subjects With Adverse Events/Reactions TMC278 25 mg

(N=8)

N (%) One or more AEs 0 (0) One or more SAEs 0 (0) Deaths 0 (0) Treatment stopped due to AEs 0 (0) N = Number of subjects. Cross-reference: Attachment TSFAE01

No consistent changes in mean laboratory values over time were observed. All laboratory values outside the reference range were considered clinically insignificant by the investigator.

One subject experienced a change in QT corrected according to Bazett’s formula (QTcB) from baseline of >30 ms at 24 hours postdose. The finding was considered not clinically relevant. No other abnormal findings were reported in 12-lead ECGs, physical examination, and vital signs.



Study Limitations:

No notable study limitations were identified by the sponsor.

CONCLUSIONS:

Plasma TMC278 concentrations attained Cmax at 5.00 h postdose (median) and then declined with a mean t1/2 of 43.0 h after a single oral administration of TMC278 25 mg under fed condition in healthy Japanese adult male subjects.

TMC278 25 mg (single oral dose) was generally well tolerated in the Japanese subjects. There were no deaths or SAEs during this study, and no subject discontinued the study due to an AE.

No clinically significant findings were observed for laboratory results (hematology, biochemistry and urinalysis), vital signs, physical examination, and 12-lead ECGs.

SYNOPSIS

NAME OF SPONSOR/COMPANY:Johnson & Johnson Pharmaceutical Research & Development, Division of Janssen-Cilag Ltd.

INDIVIDUAL STUDY TABLE REFERRING TO PART OF THE DOSSIER

(FOR NATIONAL AUTHORITY USE ONLY)

NAME OF FINISHED PRODUCT:Not applicable

NAME OF ACTIVE INGREDIENT(S):R278474

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Protocol No.: R278474-CDE-101

Title of Study: Double-blind, randomized, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics and ex vivo pharmacodynamics of single oral doses of R278474 in healthy male subjects.

Principal Investigator: Belgium.


Study Period: 20 – 20 Phase of development: 1

Objectives: To evaluate the safety, tolerability, pharmacokinetics and ex vivo pharmacodynamics of single ascending oral doses of R278474 (NNRTI [Non-nucleoside Reverse Transcriptase Inhibitor]) in healthy male subjects. The pharmacokinetic profile of R278474 was to be compared with historical data for 3 other structurally related NNRTI compounds, R147681, R165335, and R152929.

Methodology: This was a randomized, double-blind, placebo-controlled study, with 6 planned groups each of 9 healthy male subjects. Planned doses were 12.5, 25, 50, 100, 200, and 400 mg R278474. In each study group, 6 subjects were to receive R278474 and 3 subjects were to receive placebo. Progression to the next dose level was dependent on a satisfactory review of the safety and plasma PK data.

Adrenal function was assessed during the screening phase (at Day –5) and postdose by measuring the diurnal changes in cortisol and adrenocorticotrophic hormone (ACTH) levels over a 24-hour period. Subjects were then stimulated with corticotrophin releasing hormone (CRH) and adrenal function measured for a further 2 hours.

Dosing was not escalated beyond 50 mg due to safety concerns raised by blunted responses to CRH in the 50-mg dosing group, therefore doses of 12.5 to 50 mg R278474 were studied.

Number of Subjects (planned and analyzed): 54 planned; 27 randomized and dosed; 27 analyzed.

Diagnosis and Main Criteria for Inclusion: Healthy caucasian males aged between 18 and 55 years (inclusive) with a body mass index range between 18.0 and 28.0 kg/m2. All subjects were to have a baseline morning cortisol (between 08:00 and 09:00 am) of at least 100 nmol/L and normal cortisol response to the CRH test at screening of a >20% increase in peak cortisol over baseline.

Test Product, Dose and Mode of Administration, Batch No.: 100% PEG 400 solution of R278474, 25 mg/mL. Subjects were given a single oral dose of 12.5, 25, and 50 mg as an oral solution. Batch no: 02130/F002

Reference Therapy, Dose and Mode of Administration, Batch No.: 100% PEG 400 solution, equal-volume dose, oral administration. Batch no: 02130/F001

Duration of Treatment: Single oral dose


Pharmacokinetics: Blood and urine samples were collected for pharmacokinetic analysis before and up to 144 hours and 72 hours, respectively, after administration of R278474 or placebo.

Pharmacodynamics (Ex Vivo Antiviral Activity): Serum and urine samples were collected for ex vivo antiviral activity assessment immediately before and up to 48 hours after administration of R278474 or placebo.

Safety: Adverse events, physical examination, clinical laboratory data, adrenal function testing, vital signs, and 12-lead ECG.

R278474: Clinical Study Report 278474-CDE-101

1Clinical Research Report Synopsis






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Pharmacokinetics: Descriptive statistics were conducted on plasma and urine drug concentration data and pharmacokinetic parameters. Comparisons of the PK profile of R278474 to historical data for 3 structurally related NNRTI compounds (R147681, R165335, and R152929), as well as dose normalized Cmax, AUC, tmax and t1/2term, were performed. No formal statistical analysis was carried out.

Pharmacodynamics: Descriptive statistics were conducted on ex vivo antiviral activity data.

Safety: Safety data were summarized and listed only; no formal statistical analysis was carried out. All subjects receiving treatment were included in the analysis.

SUMMARY – CONCLUSIONS PHARMACOKINETIC RESULTS:

R278474 Parameter 12.5 mg (N=6) 25 mg (N=6) 50 mg (N=6) aCmax (ng/mL) 73.1 14.1 149 32.3 267 27.4 btmax (h) 4 (4-4) 4 (2-6) 4 (4-4) aAUC0-144h (ng·h/mL) 2097 360 4496 1240 7879 973 aAUC (ng·h/mL) 2467 526 5210 2001 8872 1342 at1/2 (h) 50.5 21.6 47.7 18.6 44.7 8.7 aMean SD; bMedian (min-max)

Following a single oral dose of R278474, a gradual absorption phase was observed with the peak drug concentration attained at 4 hours postdose. Cmax and AUCt increased proportionally from 12.5 to 50 mg R278474 and the mean terminal elimination half-life was close to 48 hours at all doses. Less than 1% of the dose was excreted as unchanged drug in the urine. R278474 showed higher systemic exposure when compared with the historical data for 3 structurally related NNRTI compounds (R147681, R152929, and R165335).

R278474 was stable in plasma and blood. No Z-isomer was detected in these matrices. Small amounts of the Z-isomer were found in urine samples.

PHARMACODYNAMIC RESULTS: (Ex Vivo Antiviral Activity) R278474

Parameter 12.5 mg (N=6) 25 mg (N=6) 50 mg (N=6) tmax (h) a 3.6 0.9 3.3 1.0 3.7 0.8 Median (min-max) 4 (2-4) 4 (2-4) 4 (2-4)

Emax (ng/mL) a 26.6 6.0 103 80.0 205 (43.6) Median (min-max) 27.3 (18.9-33.2) 86.3 (29.2-234) 205 (160-261)

AUEC12h (ng h/mL) a 578 145 1745 1357 4279 1225 Median (min-max) 604 (377-730) 1567 (438-4028) 4328 (2120-5737) a Mean SD

The antiviral activity of serum samples from subjects dosed with R278474 appeared to increase in a concentration-dependent manner. No circulating active metabolites in the serum and urine were detected. Urine samples were not suitable for testing.


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SAFETY AND TOLERABILITY RESULTS:

Single oral doses of R278474 were well tolerated when administered at dose levels of 12.5 to 50 mg. There were no serious adverse events and no subjects were withdrawn due to adverse events. Adverse events were reported by all 9 subjects (100%) receiving placebo and by 14 (78%) of 18 subjects receiving R278474. There were no apparent dose-related trends in the incidence of adverse events. The majority of adverse events were mild in severity. One severe adverse event was reported during the study but was considered of doubtful relationship to the study drug. The most common adverse events were mild or moderate hot flushes and palpitations, which were noted in subjects receiving R278474 and placebo. These adverse events were associated with CRH stimulation and are documented in the product literature. There was no evidence of any drug-specific adverse events.

There were no clinically significant treatment-related changes in clinical laboratory analyses and no indication of any effect of treatment on vital signs and ECG parameters.

R278474 had no treatment effects on diurnal variation of plasma cortisol and ACTH. Blunted responses to CRH stimulation were seen after the 50-mg dose. The study was stopped to allow investigation of these changes. The lack of data for this test in healthy subjects made interpretation difficult. However, it appears that the effect on response to CRH stimulation at the 50-mg dose can be explained by the variability of the test and a high cortisol baseline in the placebo-treated subject group.

CONCLUSION:

Systemic exposure to R278474 increased in a dose-proportional manner at doses between 12.5 and 50 mg. AUC and Cmax values for R278474 were higher than for structurally related NNRTIs. The ex vivo antiviral activity of R278474 in serum increased in a dose-dependent manner.

R278474 single dose administration up to 50 mg/kg was safe and generally well tolerated. Given that the blunted reponses to CRH stimulation seen after the 50-mg dose can be explained by the variability of the test and high baseline cortisol levels, further investigation of higher doses was considered appropriate.

Date of the report: 15 September 2004



SYNOPSIS






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Title of Study: A double-blind, randomized, placebo-controlled study to evaluate the safety and tolerability, pharmacokinetics and ex vivo pharmacodynamics of multiple oral doses of R278474 in healthy male volunteers

Principal Investigator: The Netherlands.


Study Period (years): 20 - 20 Phase of development: 1

Objectives: To assess the safety and tolerability, pharmacokinetics, and ex vivo antiviral activity following multiple oral doses of R278474 (NNRTI [Non-nucleoside Reverse Transcriptase Inhibitor]) in healthy male subjects.

Methodology: This was a double-blind, randomized, placebo-controlled study. Twenty-seven subjects were randomized to 3 groups of 9, with 6 subjects receiving R278474 and 3 subjects receiving placebo in each group. Three doses (25, 75, and, 150 mg) of R278474 in PEG 400 solution were given once daily for 14 days in ascending order. Progression to the next dose level was dependent on a satisfactory review of the safety, tolerability and plasma PK data.

Adrenal function was assessed during the screening phase and postdose on Days 1, 7, and 14 by measuring the diurnal changes in cortisol and adrenocorticotrophic hormone (ACTH) levels over a 24-hour period. Subjects were then stimulated with low-dose ACTH and adrenal function measured for a further 2 hours.

Supine and standing renin and aldosterone levels, and precursors of cortisol were also measured.

Number of Subjects (planned and analyzed): 27 planned; 27 randomized and dosed; 27 analyzed.

Diagnosis and Main Criteria for Inclusion: Healthy, caucasian males, aged between 18 and 55 years with a body mass index range between 18.0 and 28.0 kg/m2. A baseline morning cortisol of at least 100 nmol/L and a normal 24 hour diurnal variation in cortisol and ACTH levels, and an increase of >20% from baseline in cortisol in response to low-dose ACTH stimulation.

Test Product, Dose and Mode of Administration: R278474 was supplied as a 25-mg/mL solution in 100% PEG 400. Subjects were given daily oral doses of 25, 75, and 150 mg R278474 as an oral solution.

Batch No.: 03E13/F002 (25 mg), 03E15/F002 (75 and 150 mg), 03E19/F002 (150 mg), 03E22/F002 (150 mg)

Reference Therapy, Dose and Mode of Administration: 100% PEG 400 solution (1.12 g/mL), equal-volume dose, oral administration. Batch No.: 03E26/F001

Duration of Treatment: Once daily doses for 14 days.


Pharmacokinetics: Plasma concentration-time profiles (0-24 hours) on Day 1 and Day 14 were determined. Peak and trough concentrations were measured from Day 2 to Day 13. Terminal elimination half-life of R278474 was estimated after the last dose.

A predose urine sample and complete urinary output during a 24-hour dosing interval were collected on Day 1 and Day 14 for the assessment of urinary clearance of unchanged R278474.

Pharmacodynamics (Ex Vivo Antiviral Activity): Blood samples were taken at predose and up to 24 hours postdose on Day 1 and Day 14, respectively, after administration of R278474 or placebo.









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Pharmacokinetics: Descriptive statistics were conducted for the plasma concentrations of R278474 at each sampling time and for the pharmacokinetic parameters. Mean (SD) Cmax and AUC on Day 1 and Day 14 were plotted as a function of dose in order to explore dose linearity. Statistical analysis of dose proportionality on log-transformed (dose normalized) Cmax and AUC on Day 1 and Day 14 was performed.

Pharmacodynamics: Descriptive statistics were conducted on ex vivo antiviral data.


SUMMARY – CONCLUSIONS

PHARMACOKINETIC RESULTS: Day 1 Day 14 Parameter 25 mg (N=6) 75 mg (N=6) 150 mg (N=6) 25 mg (N=6) 75 mg (N=6) 150 mg (N=6) aCmax (ng/mL) 100 ± 42 328 ± 76 463 ± 133 222 ± 21 664 ± 109 1069 ± 269 btmax (h) 4 (2-6) 4 (2-6) 4 (2-6) 4 (4-6) 4 (2-4) 4 (4-6) aCtrough (ng/mL) 44 ± 9 126 ± 28 155 ± 14 109 ± 14 375 ± 89 547 ± 95 aAUC (ng h/mL) 1345 ± 398 4397 ± 1058 5663 ± 981 3626 ± 368 11215 ± 2125 17703 ± 2908 at1/2 (h) N/A N/A N/A 48.9 ± 18.0 41.9 ± 9.9 41.0 ± 5.0 a Mean SD; b Median (min-max); N/A = Not available

R278474 was well absorbed when dosed orally as a PEG 400 solution. Following the first dose, the median tmax was attained at 4 hours postdose following all doses. The mean Cmax increased dose proportionally from 25 to 75 mg, but the increase in Cmax was less than dose proportional from 75 to 150 mg R278474. AUC ( = 24 hour) and Ctroughlevels showed similar dose proportional increases between 25 and 75 mg and a less than dose proportional increase between 75 and 150 mg R278474. Plasma concentrations of R278474 accumulated during once daily dosing and reached steady-state after 8 to 10 doses. The median accumulation index was 2.0 fold for Cmax, 2.6 fold for AUC , and 3.0 fold for Ctrough. The drug exposure increased with dose on both Day 1 and Day 14.

Very little R278474 was excreted unchanged in urine. The estimated mean renal clearance was low, ranging from 0.0020 to 0.0027 L/h. Renal clearance of R278474 appeared not to be a significant route of elimination.

Small amounts of the Z-isomer were found in the urine samples.

PHARMACODYNAMIC RESULTS: (Ex Vivo Antiviral Activity) Day 1 Day 14 Parameter 25 mg (N=6) 75 mg (N=6) 150 mg (N=6) 25 mg (N=6) 75 mg (N=6) 150 mg (N=6) aEmax (ng/mL) 43 ± 27 186 ± 38 288 ± 166 83 ± 32 502 ± 87 549 ± 51 btmax E (h) 5 (4-24) 5 (4-12) 4 (4-6) 6 (4-6) 5 (4-12) 4 (4-24) aAUEC (ng h/mL) 469 ± 195 2641 ± 727 3418 ± 1318 1268 ± 523 7555 ± 1188 9770 ± 3132 a Mean SD; b Median (min-max); Emax = maximum antiviral effect; tmax E = time to reach Emax

AUEC = area under the effect-time curve over a dosing interval The maximum antiviral activity assessed by the ex vivo assay was attained between 4 and 6 hours postdose (median times). Emax and AUEC increased by 2 to 3-fold over the 14-day dosing schedule. The magnitude of increase was similar to that of Cmax and AUC .








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Multiple oral doses of R278474 were well tolerated at dose levels of 25 to 150 mg. There were no serious adverse events. Adverse events were reported by all 9 subjects (100%) receiving placebo and by 16 (89%) of 18 subjects receiving R278474. The majority of adverse events were mild in severity and no adverse events were severe. The only safety concern was the higher incidence of headaches observed in subjects receiving R278474 compared with placebo, however all these adverse events were mild in severity, all resolved, and there were no apparent dose-related trends.

Subject 1004, who received 25 mg R278474 daily for 9 days, did not receive study drug from Day 10 onwards because of increased liver transaminases that were possibly related to the study drug. However, liver transaminase values returned to predose levels 19 days after receiving the last dose of R278474 on Day 9. There were no other clinically significant treatment-emergent changes in clinical laboratory analyses and no indication of any effect of treatment on vital signs and ECG parameters.

Adrenal function was assessed by measuring the 24-hour diurnal variation in cortisol and ACTH levels before and after dosing with R278474. The response to low-dose ACTH stimulation was also assessed for 2 hours at the end of the 24-hour period. Diurnal changes in cortisol and ACTH levels were normal for the 0 to 24 hour postdose period for all doses of R278474. Similarly, low-dose ACTH stimulation produced the expected response.

CONCLUSIONS:

The results in this study suggest that daily dosing with R278474 for 14 days is well tolerated in healthy male volunteers with no major adverse events. There were no adverse effects on adrenal function.

There was good drug exposure and pharmacokinetics were linear over time. The ex vivo antiviral activity showed a linear correlation with the plasma drug concentration.




SYNOPSIS






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Title of Study: Double-blind, randomized, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics and ex vivo pharmacodynamics of single oral doses of R278474 in healthy male subjects.

Principal Investigator: The Netherlands.


Study Period (years): 20 - 20 Phase of development: 1

Objectives: To assess the safety, tolerability, pharmacokinetics and ex vivo pharmacodynamics after single oral doses of 50 to maximally 300 mg of R278474 (NNRTI [Non-nucleoside Reverse Transcriptase Inhibitor]) in PEG 400 solution in healthy male subjects.

Methodology: This was a double-blind, randomized, placebo-controlled study in 4 groups of 9 healthy male subjects at doses of 50, 100, 200 and 300 mg R278474 in PEG 400 solution. In each group, 6 subjects were to receive R278474 and 3 subjects were to receive placebo. Progression to the next dose level was dependent on a satisfactory review of the safety and plasma PK data.

Adrenal function was assessed during the screening phase (at Day –5) and postdose by measuring the diurnal changes in cortisol and adrenocorticotrophic hormone (ACTH) levels over a 24-hour period. Subjects were then stimulated with low-dose ACTH and adrenal function measured for a further 2 hours.

Number of Subjects (planned and analyzed): 36 planned; 36 randomized and dosed; 36 analyzed. Diagnosis and Main Criteria for Inclusion: Healthy, caucasian, male subjects, aged between 18 and 55 years with a body mass index range between 18.0 and 28.0 kg/m2. A baseline morning cortisol of at least 100 nmol/L and a normal 24 hour diurnal variation in cortisol and ACTH levels, and an increase of >20% from baseline in cortisol in response to low-dose ACTH stimulation. Test Product, Dose and Mode of Administration: R278474 supplied as a 25 mg/mL solution in 100% PEG 400. Subjects were given a single oral dose of 50, 100, 200 and 300 mg R278474 as an oral solution. Batch No.: 03E06/F002.

Reference Therapy, Dose and Mode of Administration: 100% PEG 400 solution (1.12 g/mL), equal-volume dose, oral administration. Batch No.: 03C20/F001.

Duration of Treatment: Single oral dose


Pharmacokinetics: Blood and urine samples were collected from each subject before and up to 144 hours and 72 hours, respectively, after the administration of R278474 or placebo.

Pharmacodynamics (Ex Vivo Antiviral Activity): Blood samples were taken from each subject before and up to 12 hours postdose after the administration of R278474 or placebo.









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Pharmacokinetics: Descriptive statistics were conducted for plasma concentrations and pharmacokinetic parameters of R278474. Mixed effect ANOVA modeling, with dose as the primary predictor, was fitted to evaluate the dose proportionality on log-transformed (dose normalized), AUC , AUC0-144 and Cmax values. For the urine analysis, the total amount of unchanged R278474 excreted over each collection period and the cumulative amount were calculated. Urinary recovery was expressed as percentage of dose excreted as unchanged R278474 over 72 hours (Ae72h).

Pharmacodynamics: Descriptive statistics were conducted on ex vivo antiviral data.


SUMMARY – CONCLUSIONS

PHARMACOKINETIC RESULTS:R278474

Parameter 50 mg (N=6) 100 mg (N=6) 200 mg (N=6) 300 mg (N=6) a Cmax (ng/mL) 226 ± 15 482 ± 121 807 ± 207 944 ± 172 btmax (h) 4 (4.2-6) 4 (4-6) 4 (4-6) 4 (4-4) aAUC0-144h (ng·h/mL) 6,118 ± 1,558 13,013 ± 4,039 25,600 ± 5,621 27,910 ± 7,298 aAUC (ng·h/mL) 6,584 ± 1,881 15,820 ± 4,568 28,669 ± 6,876 32,794 ± 10,352 at1/2term (h) 34.2 ± 12.0 54.6 ± 17.9 43.1 ± 13.1 52.0 ± 17.2 a Mean SD; b Median (min-max)

Following a single oral dose of R278474, the drug was well absorbed and median tmax was achieved at 4 hours postdose in all dosing groups. After tmax, the drug concentration declined bi-exponentially with time, with slow elimination of the drug. The pharmacokinetics of R278474 were linear up to 200 mg, as Cmax, AUCt and AUCincreased proportionally with the dose. From 200 to 300 mg, the Cmax and AUCt increased less than proportionally.

The average urinary recovery of unchanged R278474 was 0.03% of the administered dose, suggesting that renal excretion was a minor route of drug elimination.

No Z-isomer was detected in the plasma samples. Small amounts of the Z-isomer were found in the urine samples.

PHARMACODYNAMIC RESULTS: (Ex Vivo Antiviral Activity): R278474

Parameter 50 mg (N=6) 100 mg (N=6) 200 mg (N=6) 300 mg (N=6) tmax (h) a 5 3 5 1 4 2 5 4 Median (min-max) 4 (4-12) 4 (4-6) 4 (2-6) 4 (2-12)

Emax (ng/mL) a 249 191 207 110 463 121 557 140 Median (min-max) 180 (92-613) 183 (91-417) 460 (268-589) 569 (326-697)

AUEC12h (ng h/mL) a 1,230 310 1,279 632 3,176 538 3918 1586 Median (min-max) 1,210 (772-1,733) 1,128 (678-2,514) 3,292 (2,224-3,665) 3,280 (2,142-6,253) a Mean SD

The ex vivo activity increased in a concentration-dependent manner. The median time for the maximum antiviral effect was observed at 4 hours postdose for all doses.








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Single oral doses of R278474 were well tolerated when administered at dose levels of 50 to 300 mg. There were no serious adverse events and no subjects were withdrawn due to adverse events. Adverse events were reported by 7 (58%) of 12 subjects receiving placebo and by 14 (58%) of 24 subjects receiving R278474. There were no apparent dose-related trends in the incidence of adverse events. The majority of adverse events were mild in severity. There was no evidence of any drug-specific adverse events.

There were no consistent clinically significant treatment-emergent changes in clinical laboratory analyses and no indication of any effect of treatment on vital signs and ECG parameters.

Adrenal function was assessed by measuring the 24-hour diurnal variation in cortisol and ACTH levels before and after dosing with R278474. The response to low-dose ACTH stimulation was also assessed for 2 hours at the end of the 24-hour period. There was no indication of any consistent treatment effects on diurnal changes in cortisol and ACTH levels and the response to low-dose ACTH stimulation.

CONCLUSIONS:

The results in this study suggest that R278474 is a well-tolerated NNRTI with no major adverse events in healthy male subjects. There were no adverse effects on adrenal function.

Good drug exposure, slow drug elimination and low inter-subject variability in PK parameters were observed. The ex vivo antiviral activity showed linear correlation with the plasma drug concentration.




TMC278-C103 1



Company: Tibotec Pharmaceuticals Ltd. Trade Name: Not applicable Indication: HIV-1 infection

Drug Substance: TMC278 Trial no.: TMC278-C103 Clinical Phase: I

Title: A Phase I, open label, randomized, multiple dose ranging trial in four parallel panels of 12 healthy subjects each, to determine the pharmacokinetics, safety and tolerability of once daily dosing of TMC278 formulated as a solid formulation

Investigator: Belgium

Country: Belgium



Objectives: The objectives of the trial were to determine single dose and steady-state pharmacokinetics and dose-proportionality of TMC278 after multiple once daily dosing of a solid oral formulation and to determine the short-term safety and tolerability of TMC278 after once daily dosing over a period of 14 days. Design: This was a Phase I, open label, multiple dose ranging trial in which 48 healthy subjects were randomized over 4 parallel panels of 12 subjects each. To each panel, TMC278 was administered orally as a once daily (q.d.) dose from Day 1 until 14. Panels 1, 2, 3, and 4 received 25 mg (Treatment A), 50 mg (Treatment B), 100 mg (Treatment C), and 150 mg (Treatment D) TMC278 q.d., respectively. Full pharmacokinetic profiles of TMC278 were determined on Day 1 up to 24 hours and on Day 14 up to 216 hours. Furthermore, tolerability and safety were assessed on an ongoing basis. The aim of this trial was to explore the single dose and steady-state pharmacokinetics and dose-proportionality of TMC278 after multiple oral q.d. dosing of this solid formulation. Subject Selection Inclusion Criteria

1. Aged between 18 and 55 years, extremes included. 2. Smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day (or non-smoking) for at least 3 months prior to selection. 3. Normal weight as defined by a Quetelet Index (Body Mass Index: weight in kg divided by square of height in meters) of 18.0 to 30.0 kg/m2, extremes included. 4. Informed Consent Form signed voluntarily before the first trial-related activity. 5. Cortisol of at least 550 nmol/L (19.9 g/dl) at any time point at screening (i.e., morning cortisol, 30 or 60 minutes after 250 g adrenocorticotropic hormone [ACTH] stimulation). 6. Able to comply with protocol requirements. 7. Healthy on the basis of a pre-trial physical examination, medical history, electrocardiogram, vital signs, and the results of blood biochemistry, hematology and coagulation tests, and a urinalysis at screening.

Exclusion Criteria1. A positive HIV-1 or HIV-2 test at study screening. 2. Female, except if postmenopausal for more than 2 years, or posthysterectomy or post tubal ligation (without reversal operation). 3. History or suspicion of alcohol, barbiturate, amphetamine, recreational, or narcotic drug use that, in the investigator’s opinion, could compromise the subject’s safety and/or ability to comply with trial procedures. 4. Hepatitis A infection (confirmed by Hepatitis A antibody IgM), or Hepatitis B infection (confirmed by Hepatitis B surface antigen), or Hepatitis C infection (confirmed by Hepatitis C virus antibody) at study screening. 5. A positive urine drug test at study screening. Urine was tested for the presence of amphetamines, benzodiazepines, cocaine, cannabinoids, and opioids. 6. Currently active or underlying gastrointestinal, cardiovascular, neurological, psychiatric, metabolic, renal, hepatic, respiratory, inflammatory, or infectious disease. 7. Any previous or current adrenal illness. 8. Currently significant diarrhea, gastric statis, or constipation that in the investigator’s opinion could influence drug absorption or bioavailability.

Synopsis

TMC278-C103 2


9. Any history of significant skin disease such as but not limited to drug rash or eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis, or urticaria. 10. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication administered in this trial. 11. Use of concomitant medication, including over the counter products and dietary supplements, except for ibuprofen up to 3 days before the first dose of trial medication. All other medication must have been discontinued at least 14 days before the first dose of trial medication. 12. Participation in an investigational drug trial within 30 days prior to the screening visit. 13. Donation of blood or plasma in the 60 days preceding the first intake of trial medication. 14. Having previously participated in a trial with TMC125, TMC120, or TMC278. 15. Subjects with the following laboratory abnormalities at screening as defined by the enhanced toxicity grading severity list: serum creatinine grade 1 or greater; pancreatic amylase or lipase grade 1 or greater; hemoglobin toxicity grade 1 or greater; platelet count grade 1 or greater; absolute neutrophil count grade 1 or greater; aspartate aminotransferase or alanine aminotransferase grade 1 or greater; total bilirubin grade 1 or greater; any other toxicity grade 2 or above, including: proteinuria (spot urine) > 1+ and gross hematuria.

Treatment Treatment A Treatment B Treatment C Treatment D Dose Dosage Form (TF No.) Usage

25 mg q.d. TMC278

Tablet (F001)

1 tablet p.o. Day 1-14

50 mg q.d. TMC278

Tablet (F001)

2 tablets p.o. Day 1-14

100 mg q.d. TMC278

Tablet (F002)

1 tablet p.o. Day 1-14

150 mg q.d TMC278

Tablet (F001) and (F002)

2 x 25 mg tablets p.o. and 1 x 100 mg tablet

p.o. Day 1-14

Batch Number PD1216 PD1216 PD1211 PD1216, PD1211 Dose Regimen Panel 1: Treatment A, Panel 2: Treatment B,

Panel 3: Treatment C, Panel 4: Treatment D Duration of Treatment 14 days Duration of Trial 24 days (excluding screening and follow-up) Disallowed Medication During the entire trial, subjects were not allowed to use any medication other than

the trial medication. All medication had to be discontinued at least 14 days before first drug administration, except for ibuprofen. Ibuprofen was allowed up to 3 days before drug administration. After that, the investigator could permit the use of ibuprofen (no more than 1 x 400 mg per day) until 9 days (216 hours) after the last trial medication intake. Subjects were not to use any herbal medications or dietary supplements including products containing Hypericum perforatum (e.g., St. John’s wort) from 14 days before the first drug administration up to 9 days after the last drug administration. In case of cutaneous event/rash and/or an allergic reaction, the use of cetirizine, topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In case of nausea, the use of antiemetics was permitted. In case of diarrhea the use of loperamide was allowed.

Synopsis

TMC278-C103 3


Assessments Screen-inga

Panels 1, 2, 3, and 4 Follow-upb

21

days

Day

–1

Day

1

Day

2

Day

3-6

, 8-9

+

11

Day

7

Day

10

Day

12

+ 13

Day

14

Day

15

Day

16-

21

Day

23

Day

30,

31,

32

, or,

33

Drug administration

X X X X X X X

Drug screening X Pregnancy test, if applicable

X

Pharmacokinetics Blood sample

Xc

Xd

Xd

Xd

Xd

Xe

Xf

Xg

Xg

Safety Adverse eventsh X X X X X X X X X X X X Concomitant meds X X X X X X X X X X X X Hemat & biochemi X Xk Xj X Xk X X X Urinalysis X Xj Xj Xj X X X ECG & vital signs X Xj, k Xj Xj, k X X X Morning cortisol X X ACTH stimulation test

X X

Skin exam X X X X Xl X X X Physical exam X X X Xm X meds = medication; Hemat & biochem = hematology & biochemistry; ACTH = adrenocorticotropic hormone; ECG = electrocardiogram; exam = examination. a At screening, subject’s demographics and characteristics, medical and surgical history, concomitant diseases, HIV-1 and -2 test, Hepatitis A, B, and C test, and smoking habits were recorded. b In case of dropout for reasons other than withdrawal of consent: additional blood and urine samples for safety were taken; additional ECG and vital signs were recorded; and a physical examination (including skin examination) was performed at the time of dropout or the following morning, 7, 8, or 9 days after dropout, and 30, 31, 32, or 33 days after last drug intake. A morning cortisol and ACTH stimulation test was performed 7, 8, or 9 days after dropout (preferably 7 days after dropout). Additional blood samples for pharmacokinetics were also taken at the time of dropout (or the following morning). A skin examination was performed 10 days after the first intake of TMC278 (only applicable in case of dropout for a non-cutaneous event/rash and if this time point had not yet been reached at the time of dropout). c Within 2 hours before TMC278 intake, before breakfast, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours postdose. d Within 15 minutes before TMC278 intake. e Within 15 minutes before TMC278 intake and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours postdose. f At 24 and 32 hours postdose. g Time window of 48 ± 1 hour on Day 16, 72 ± 1 hour on Day 17, 96 ± 1 hour on Day 18, 120 ± 1 hour on Day 19, 144 ± 1 hour on Day 20, 168 ± 1 hour on Day 21, and 216 ± 1 hour on Day 23. h Adverse events were monitored continuously from signing of the informed consent to final trial-related visit. i Biochemistry samples were taken fasting for at least 10 hours except at 4 hour postdose timepoint. j Within 2 hours before TMC278 intake and before breakfast. k Measured predose and at 4 hours postdose. l On Day 13 only. m Physical examination could be done on Day 21, in case Day 23 was a weekend. Statistical Methods Descriptive statistics, frequency tabulations, graphical presentations,

Intent-to-Treat analysis, Wilcoxon matched-pairs signed-ranks test, linear mixed effects modeling.

Synopsis

TMC278-C103 4


Main Features of the Subject Sample and Summary of the Results Baseline Characteristics - Subject Disposition

25 mg q.d. TMC278

50 mg q.d. TMC278

100 mg q.d. TMC278

150 mg q.d. TMC278 Total

Number of Subjects Entered (M/F) Age: median (range), yrs

11/1 39.0 (21-54)

10/2 39.0 (26-52)

10/2 43.0 (22-52)

11/1 38.0 (21-53)

42/6 39.5 (21-54)

Drop-Outs - Reason Adverse Event Subject Withdrew Consent

0 0 0

0 0 0

1 1 0

1 0 1

2 1 1

Pharmacokinetics of TMC278 (mean SD; tmax: median (range))

25 mg q.d. TMC278 50 mg q.d. TMC278 100 mg q.d. TMC278 150 mg q.d. TMC278

n 12 12 12a 12b Day 1 Cmax, ng/mL 90.08 ± 44.28 138.2 ± 63.10 397.6 ± 147.3 523.8 ± 136.9 tmax, h 4.0 ( 2.0 - 6.0 ) 4.0 ( 3.0 - 4.0 ) 4.0 ( 2.0 - 6.65 ) 4.0 ( 3.0 - 6.0 )

AUC24h, ng.h/mL 1072 ± 585.6 1551 ± 596.0 4464 ± 1520 5608 ± 1902 Day 7

C0h, ng/mL 79.13 ± 30.22 169.7 ± 61.44 353.6 ± 111.4 431.4 ± 133.7 Day 10

C0h, ng/mL 90.43 ± 39.36 161.8 ± 85.20 312.3 ± 105.3 482.4 ± 178.0 Day 12

C0h, ng/mL 91.72 ± 38.43 149.7 ± 52.83 336.5 ± 116.4 449.4 ± 198.0 Day 13

C0h, ng/mL 83.64 ± 38.23 168.6 ± 74.71 326.8 ± 129.3 459.5 ± 178.6 Day 14

C0h, ng/mL 89.85 ± 38.07 157.9 ± 52.23 347.8 ± 148.7 504.9 ± 174.6

Cmin, ng/mL 66.85 ± 29.53 115.7 ± 49.30 249.5 ± 90.51 362.0 ± 130.9 Cmax, ng/mL 203.8 ± 75.81 298.6 ± 98.05 685.5 ± 202.4 1019 ± 222.0 tmax, h 4.0 ( 2.0 - 4.0 ) 4.0 ( 2.0 - 6.0 ) 4.0 ( 2.0 - 6.0 ) 4.0 ( 3.0 - 6.0 )

AUC24h, ng.h/mL 2589 ± 868.8 4139 ± 1236 9278 ± 2846 13581 ± 3195

t1/2term, h 50.92 ± 19.56 48.75 ± 16.34 46.07 ± 15.44 44.83 ± 12.31

Css,av, ng/mL 107.8 ± 36.20 172.5 ± 51.48 386.6 ± 118.6 565.9 ± 133.1 FI, % 128.5 ± 41.71 107.8 ± 45.20 113.7 ± 35.59 121.7 ± 46.55 Acc. Ratio 3.020 ± 1.966 2.880 ± 0.7982 2.071 ± 0.7491 2.503 ± 0.7211 a for the parameters of Day 10 until Day 14: n=11 b for the parameters of Day 7 until Day 14: n=11

Synopsis

TMC278-C103 5


Safety (n = number of subjects with data during TMC278 treatment phase)

25 mg q.d. TMC278 (n=12)

50 mg q.d. TMC278 (n=12)

100 mg q.d. TMC278 (n=12)

150 mg q.d. TMC278 (n=12)

Adverse Events (AEs) Most frequently reported AEs (reported in > 1 subject), n (%)

Headache 2 (16.7%) 4 (33.3%) 2 (16.7%) 2 (16.7%) Hyperbilirubinaemia 2 (16.7%) 2 (16.7%) 2 (16.7%) 1 (8.3%) Lipase Increased 1 (8.3%) 1 (8.3%) 2 (16.7%) 1 (8.3%) Bowel Sounds Abnormal 2 (16.7%) 1 (8.3%) 1 (8.3%) 0 Dizziness 2 (16.7%) 1 (8.3%) 0 1 (8.3%)

n (%) with 1 or more AEs 8 (66.7%) 8 (66.7%) 7 (58.3%) 5 (41.7%) n (%) of deaths 0 0 0 0 n (%) with 1 or more other serious AEs 0 0 0 0 n (%) of treatment stopped due to AEs 0 0 1 (8.3%) 0 n (%) with 1 or more grade 3 or 4 AEs 0 0 2 (16.7%) 2 (16.7%)

Clinical Laboratory Tests n (%) with 1 or more grade 3 or 4 laboratory abnormalities

0 0 2 (16.7%) 1 (8.3%)

Laboratory Tests There were no consistent or clinically relevant treatment-emergent changes over time in laboratory parameters. No grade 4 events were reported. Four grade 3 abnormalites were reported during the trial: 2 during treatment with 100 mg q.d. TMC278 (elevated amylase and lipase) and 1 posttreatment (elevated lipase), and 1 during treatment with 150 mg q.d. TMC278 (elevated lipase). All grade 3 events had associated AEs reported. Urinalysis indicated occasional abnormalities in each panel however, no urinalysis results were considered to constitute an AE.

Adrenal Function Testing Normal adrenal function was recorded for all subjects at screening and on Day 15.

Synopsis

TMC278-C103 6


Cardiovascular Safety Minor changes were reported for vital signs, with statistically

significant changes mainly being decreases in diastolic blood pressure and mostly with the high doses (Panels 3 and 4). None of the statistically significant changes were considered to be clinically relevant. Minor changes were reported for ECG parameters, very few of which were statistically significant. No trends or relationship to treatment were apparent and no clinically relevant changes in ECG parameters were reported.

Physical Examination Physical examination revealed abnormal, new findings in each panel of subjects during the treatment phase. In the 25 mg q.d. TMC278 dose group, 1 subject had painful muscles (flu-like syndrome) on Day 15 and 2 subjects had red pharynx on Day 23. In the 50 mg q.d. TMC278 dose group, 1 subject had stuffed nose on Day 23. In the 100 mg q.d. TMC278 dose group, 1 subject had superficial phlebitis, left arm on Day 23. In the 150 mg q.d. TMC278 dose group, 1 subject had red pharynx (common cold) on Day 23 and 1 subject had pain lumbar region at follow-up. Skin examination also revealed abnormal, new findings during the treatment phase in the 50 mg q.d. TMC278 dose group (some scratch marks on left arm on Day 10, and dry skin disappeared on Day 13). No abnormal, new findings were reported in the 25, 100, or 150 mg q.d. TMC278 dose groups during the treatment phase.

Conclusions

The results of this study demonstrate that single dose and steady-state pharmacokinetic characteristics of TMC278 are independent of the dose within the investigated dose range of 25 mg to 150 mg once daily. Steady-state was reached before Day 7 for all dose levels. In these healthy subjects, the administration of TMC278 as multiple oral once daily doses (25, 50, 100, or 150 mg q.d.) for 14 days was generally well tolerated and safe. The safety and tolerability profile of TMC278 was similar for all dose groups.

Synopsis

TMC278-C119 1



Company: Tibotec Pharmaceuticals Ltd. Trade Name: - Indication: HIV-1 infection


Title: A Phase I, open label, single dose, mass-balance trial with 14C-labeled TMC278 Investigator:

Belgium

Country: Belgium



Objectives: The objective of this study was to characterize the excretion and the overall metabolic profile after a single dose of 14C-labeled TMC278 in humans. Design: This was a Phase I, open label, single dose, mass-balance trial in 6 healthy male subjects. TMC278 (14C-labeled and unlabeled) was administered at a dose of 150 mg as an oral solution. Plasma and urine samples were collected at least until Day 8 and thereafter until the respective discharge criteria had been met. After discharge, feces continued to be collected at home on a daily basis until Day 14. Unchanged TMC278 was determined in plasma. Total radioactivity was determined in whole blood, plasma, urine, and feces. Metabolic profiles were determined in selected plasma, urine, and feces samples, and structures of major metabolites were characterized, whenever possible. The mass-balance was calculated. Safety and tolerability after a single dose of TMC278 were assessed. There was a safety follow-up visit at least 30 days after TMC278 intake. Subject Selection Inclusion Criteria

1. Male. 2. Aged between 40 and 60 years, extremes included. 3. Smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day (or nonsmoking) for at least 3 months prior to selection. 4. Normal weight as defined by a Quetelet Index (Body Mass Index: weight in kg divided by length in meters squared) of 18.0 to 30.0 kg/m2, extremes included. 5. Informed Consent Form signed voluntarily before the first trial-related activity. 6. Cortisol of at least 550 nmol/L (19.9 g/dL) at any time point at screening (i.e., morning cortisol, 30 or 60 minutes after 250 g adrenocorticotropic hormone [ACTH] stimulation). 7. Able to comply with protocol requirements. 8. Healthy on the basis of a physical examination, medical history, electrocardiogram (ECG), vitals signs, and the results of blood biochemistry, and hematology tests, and a urinalysis at screening.

Exclusion Criteria1. A positive human immunodeficiency virus type 1 (HIV-1) or HIV-2 test at screening. 2. History or suspicion of alcohol, barbiturate, amphetamine, recreational, or narcotic drug use which in the investigator’s opinion would compromise subject’s safety and/or compliance with the trial procedures. 3. Hepatitis A, B, or C infection (confirmed by hepatitis A IgM antibody, hepatitis B surface antigen, or hepatitis C antibody, respectively) at screening. 4. A positive urine drug test at screening. Urine will be tested for the presence of amphetamines, benzodiazepines, cocaine, cannabinoids, and opioids. 5. Currently active or underlying gastrointestinal, cardiovascular, nervous system, psychiatric, metabolic, renal, hepatic, respiratory, inflammatory, or infectious disease. 6. Any previous or current adrenal illness. 7. Currently significant diarrhea, gastric statis, or constipation that in the investigator’s opinion could influence drug absorption or bioavailability. 8. Any history of significant skin disease such as, but not limited to, rash or eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis, or urticaria. 9. History of renal insufficiency (calculated creatinine clearance < 60 mL/min).

TMC278-C119 2


10. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication administered in this trial. 11. Use of concomitant medication, including over the counter products and dietary supplements, except for ibuprofen up to 3 days before the administration of study medication. All other medication must have been discontinued at least 14 days before the administration of study medication. 12. Participation in an investigational drug trial within 30 days preceding the administration of study medication. 13. Donation of blood or plasma in the 60 days preceding the administration of study medication. 14. Having received TMC125, TMC120, or TMC278 (formerly known as R278474) in a previous trial. 15. Exposure to noncosmic sources of radiation in the past year, such as X-ray photographs (except dental X-rays), intake of radionuclides for medical diagnostic purposes, and professional exposure to radionuclides). 16. Irregular defecation pattern (less than 1 defecation per 2 days). 17. Subjects with the following laboratory abnormalities at screening as defined by the enhanced toxicity grading severity list: serum creatinine grade 1 or greater (> 1.0 x upper limit of normal [ULN]); lipase grade 1 or greater (> 1.0 x ULN); hemoglobin grade 1 or greater (< 9.4 g/dL); platelet count grade 1 or greater (< 99000/mm3); aspartate aminotransferase or alanine aminotransferase grade 1 or greater (> 1.25 x ULN); total bilirubin grade 1 or greater (> 1.0 x ULN); any other toxicity grade 2 or above, including: proteinuria (spot urine) > 1+ and gross hematuria.

Treatment All Subjects Concentration Dosage Form (F no.) Usage

25 mg/mL 14C-labeled and unlabeled TMC278 in polyethylene glycol 400

Solution (F002) Single dose on Day 1

Batch Number FK5343 Dose Regimen All subjects received a single 150 mg (6 mL) oral dose of TMC278 Duration of Treatment 1 day Duration of Trial 14 days (excluding screening and follow-up) Disallowed Medication Until the last urine or feces collection, subjects were not to use any

medication other than the study medication and ibuprofen. All other mediation had to be discontinued at least 14 days before drug administration. Subjects were not to use any herbal medications or dietary supplements including products containing Hypericum perforatum (e.g., St. John’s wort) from at least 14 days before the start of the trial until the last urine or feces collection. Ibuprofen could be used up to 3 days before administration of study medication. From 3 days before the drug intake until the last urine or feces collection, the investigator could permit the use of ibuprofen at no more than 1 x 400 mg per day.

TMC278-C119 3



All subjects

21

days

Day

–1

Day

1

Day

2

Day

3

Day

4

Day

5

Day

6

Day

7

Day

8

Day

11

Leav

ing

site

p

Day

30-

35

Drug administration X Pharmacokinetics Blood sample

Xc,d

Xd,l

Xd

Xm

Xm

Xm

Xm

Xm

X

Safety Adverse eventsg X X X X X X X X X X X X X Concomitant meds X X X X X X X X X X X X X Hemat & biochemh X Xb Xe X X X X X Urinalysis X Xe,f Xi Xn X X ECG & vital signs X Xe X X X X Morning cortisol X X 17-OH-progesterone X X ACTH stimulation test X X T3, free T4, and TSH X X X

1-acid glycoprotein X X Feces collectionj X Xf X X X X X X Urine collectionk X X X X X X Skin exam X X X X X X Physical exam X X Xo X X meds = medication; Hemat & biochem = hematology & biochemistry; ACTH = adrenocorticotropic hormone; ECG = electrocardiogram; exam = examination; TSH = thyroid stimulating hormone, T3 = triiodothyronine, T4 = thyroxine. a At screening, subject’s demographics, medical and surgical history, concomitant diseases, HIV-1 and -2 test, hepatitis A, B, and C test, and smoking habits were recorded, and drug screening was performed. b Only for testing of coagulation parameters. c Within 2 hours before TMC278 intake, before breakfast, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours postdose. d At 1, 2, 4, 8, and 12 hours postdose on Day 1, 24 hours postdose on Day 2, and 48 hours postdose on Day 3, in addition to the regular blood sample, an additional amount of blood was collected for determination of radioactivity in whole blood and in plasma, as well as for metabolite quantification and structural characterization in plasma. e Within 2 hours before TMC278 intake and before breakfast. f For safety and pharmacokinetic assessments. Feces collection on Day 1 includes urine collection from 0-4, 4-8 and 8-24 hours. g Adverse events were monitored continuously from signing of the informed consent to final trial-related visit. h Biochemistry samples were taken fasting for at least 10 hours. On Day 1, water intake was allowed until 2 hours before drug intake. On all other days, water intake was allowed. Coagulation parameters were only determined on Days –1 and 7, and at the last trial-related visit. i 10 mL was taken from urine sample for safety analysis, remainder of urine sample was to be added to urine collection. j After discharge, feces continued to be collected at home on a daily basis until Day 14. k From 24-48 hours postdose on Day 2, 48-72 hours postdose on Day 3, 72-96 hours postdose on Day 4, 96-120 hours postdose on Day 5, 120-144 hours postdose on Day 6, and 144-168 hours postdose on Day 7. l Taken 24 and 32 hours postdose. m Time window of 1 h. n Only when leaving the site on Day 8. Subjects left the site on Day 8 if at least 7 stools had been delivered and if the radioactivity in the latest 2 urine collections (120-144 hours and 144-168 hours) accounted for 2% of the dose/24 hours. After discharge, feces continued to be collected at home on a daily basis until Day 14.

TMC278-C119 4


o Only if the discharge criteria on Day 8 were not met, collection of plasma continued with 24-h intervals until the radioactivity level fell 2% of the dose/24 hours in urine and at least 7 stools were delivered, but until Day 14 at the latest. Collection of urine continued with 24-h intervals until the radioactivity level fell 2% of the dose/24 h in urine and collection of feces continued per stool until at least 7 stools were available, but until Day 14 at the latest. p Only applicable for subjects who left the site on another day than Day 8. After Day 8, subjects left the site when the radioactivity level fell 2% of the dose/24 h in urine and at least 7 stools had been delivered, but on Day 14 at the latest. Stools were collected for 14 days. Statistical Methods Descriptive statistics, frequency tabulations, graphical presentations,

Wilcoxon matched-pairs signed-ranks test.


TMC278 (N = 6)


6/0 47.5 (45-51)

Drop-Outs 0


TMC278 (N = 6)

14C Total Radioactivity (N = 6)

tmax, h 3.5 (3.0-4.0) 4.0 (3.0-4.0) Cmax, ng(eq.)/mL 602.8 126.1 794.7 170.7 AUClast, ng(eq.)h/mL 16240 4186 33040 11160 AUC , ng(eq.)h/mL 18520 4709 56620a 14090a

z, l/h 0.01283 0.003019 0.006796a 0.001735a t1/2term, h 56.56 12.98 107.7a 27.45a a Accurate determination was not possible. Mass balance At 336 hours (14 days) after the administration of a single

oral dose of TMC278, on average 85.1% 4.0% of the administered radioactivity had been excreted via the feces. The average recovery in urine was 6.1% 2.1%. The total radioactivity recovered after 14 days was about 91.2 5.1% of the administered dose (range 82.5-96.3%). Unchanged drug was excreted in feces and accounted for 25.5% of the dose on average (range 12.1-33.4%).

Metabolite profiling and identification TMC278 was extensively metabolized and more than 15 metabolites were detected. The major fecal metabolites originated from oxidative pathways. The most abundant metabolite, metabolite 42, originated from oxidation at the 5-position of the pyrimidinyl moiety and accounted for 16.1% of the dose on average (10.2-20.5%). Three other metabolites each accounted for 2.2-3.0% of the dose on average. In urine, apart from one carboxylic acid metabolite (metabolite 30), all metabolites were phase-2 metabolites (glucuronides or glutathione-derived conjugates). Overall, glutathione-derived metabolites accounted for 1.2% of the dose on average. In plasma, unchanged drug accounted for the major part of the total radioactivity (76% based on Cmax and 51% based on AUClast). Blood/plasma ratios were time-independent and mean values ranged from 65-75%. These results indicate that TMC278 and its metabolites are not bound to blood cells to a significant extent.

TMC278-C119 5



TMC278 (N = 6)

Adverse Event (AE): Ear congestion 1 (16.7%) Diarrhea 1 (16.7%) Wound 1 (16.7%) Gastric pH decreased 1 (16.7%) Headache 1 (16.7%)

n (%) with 1 or more AEs 4 (66.7%) n (%) of deaths 0 n (%) with 1 or more other serious AEs 0 n (%) of treatment stopped due to AEs 0 n (%) with 1 or more grade 3 or 4 AEs 0 No AE was reported by more than 1 subject. No grade 3 or 4

AEs or serious adverse events (SAEs) occurred during the trial.

Clinical Laboratory Tests n (%) with 1 or more treatment-emergent grade 3 or 4 laboratory abnormalities

2 (33.3%)

There was no overall pattern of change in the clinical laboratory tests. No grade 4 abnormalities were reported. Grade 3 abnormalities were reported for 2 subjects: 1 subject reported increased alanine aminotransferase (ALT), which resolved by the follow-up visit, and 1 subject reported increased lipase, which reduced to grade 1 toxicity by the follow-up visit. No associated AEs were reported.

Adrenal Function Testing No effects of treatment were apparent on median values or median changes from reference (screening visit) for the adrenal function assessments of cortisol or 17-OH progesterone. All but one subject achieved a cortisol value

550 nmol/L at T60 post ACTH stimulation on Day 7. The cortisol value at T0 for this subject was within the normal laboratory ranges (82.77-689.75 nmol/L). In addition, the 17-OH progesterone value for this subject was not increased at T0 (within the normal laboratory ranges of 1.8-7.5 nmol/L), indicating that there was no accumulation of this precursor of cortisol. No AEs related to adrenal function test results were reported.

Cardiovascular Safety Minor changes were reported for vital signs. None of the changes was considered to be clinically significant. No trends or relationships to trial medication were apparent, and no clinically relevant changes in ECG parameters were reported.

Physical Examination Physical examination revealed 1 skin abnormality during the trial: 1 subject reported an AE (wound), which was not related to treatment with TMC278.

Conclusions The results of this study demonstrate that after a single dose of 150 mg TMC278 (14C-labeled and unlabeled), the radioactivity recovered from feces after 14 days was on average, 85.1% 4.0% of the administered dose and the radioactivity recovered from urine after 7 days was on average, 6.1% 2.1% of the administered dose. The total radioactivity recovered from feces and urine after 14 days was on average, 91.2% 5.1% of the administered dose.

TMC278-C119 6


A mean Cmax of unchanged TMC278 of 602.8 ng/mL was achieved at a median of 3.5 hours postdose. The mean ratio for Cmax of unchanged TMC278 versus total 14C-radioactivity was 76%. In the elimination phase, plasma concentrations for total radioactivity declined slower than those of unchanged TMC278. TMC278 was extensively metabolized and more than 15 metabolites were detected. The major fecal metabolites originated from oxidative pathways. The most abundant metabolite, metabolite 42, originated from oxidation at the 5-position of the pyrimidinyl moiety and accounted for 16.1% of the dose on average (10.2-20.5%). In urine, apart from the carboxylic acid metabolite (metabolite 30), all metabolites were phase-2 metabolites (glucuronides or glutathione-derived conjugates). In plasma, unchanged drug accounted for the major part of the total radioactivity in plasma. In these healthy subjects, the single dose administration of 150 mg TMC278 was generally safe and well tolerated.

4

5

iv

v

vi

vii

viii

ix

x

4

TMC278-TiDP6-C130 CONFIDENTIAL 1Clinical Research Report

Clinical Research Report Issued Date: 14-Apr-2010



Trade Name: -

Indication: Human immunodeficiency virus type 1 (HIV-1)



Clinical Phase: I

Title: Pharmacokinetics, safety and tolerability of TMC278 in subjects with mildly or moderately impaired hepatic function.

Coordinating Investigator:

Germany

Country: Germany

Trial Period: Start: 18-Jun-2008

End: 16-Nov-2009


No. of Subjects: 32

Objectives: The primary objective of this study was to assess the single-dose and steady-state pharmacokinetics of TMC278 in subjects with mild or moderate hepatic impairment compared to matched healthy control subjects.Secondary objective was to assess the short-term safety and tolerability of TMC278 in subjects with mild or moderate hepatic impairment compared to matched healthy control subjects.

Design: This was a Phase I, open-label, parallel, controlled, sequential study to investigate the single-dose and steady-state pharmacokinetics, and short-term safety and tolerability of TMC278 in subjects with mild or moderate hepatic impairment compared to subjects with normal hepatic function. The study population consisted of a total of 32 male and female subjects between 18 and 65 years. Panel A consisted of 8 subjects with mild hepatic impairment (Child-Pugh A, Panel A1) and 8 healthy subjects (Panel A2) matched for gender, age (± 5 yrs), and body mass index (BMI) (± 15%). Panel B consisted of 8 subjects with moderate hepatic impairment (Child-Pugh B, Panel B1) and 8 healthy subjects (Panel B2) matched for gender, age (± 5 yrs), and BMI (± 15%). Treatment in Panel A and Panel B was conducted sequentially. Subjects in Panel A received TMC278 25 mg once daily (q.d.) for a total of 11 days. Full pharmacokinetic profiles of TMC278 were determined on Day 1 up to 24 hours postdose, and on Day 11 up to 168 hours postdose. Safety and tolerability were assessed at regular intervals throughout the trial. The anticipated dose of TMC278 to be administered to subjects in Panel B was the same dose as for Panel A (25 mg q.d.).Subject Selection

Inclusion Criteria

1. Male or female, aged between 18 and 65 years, extremes included.


3. Body mass index (weight in kg divided by the square of height in meters) of 18.0 to 32.0 kg/m2, extremes included.



Only for subjects with hepatic impairment (Panels A1 and B1):6. History of hepatic disease, such as alcoholic liver disease, chronic infection with hepatitis B and C viruses,

primary biliary cirrhosis and primary sclerosing cholangitis or non-alcoholic steatohepatitis.7. Documented liver cirrhosis.

Synopsis



8. Mild or moderate liver function impairment defined by the Child-Pugh classification:- Mild (Panel A1): Child-Pugh score of 5 to 6.- Moderate (Panel B1): Child-Pugh score of 7 to 9.

9. General medical condition, in the Investigator’s opinion, did not interfere with the assessments and the completion of the trial.

Only for healthy control subjects (Panels A2 and B2):10. Healthy on the basis of a physical examination, medical history, electrocardiogram (ECG), vital signs and the

results of blood biochemistry and hematology tests and a urinalysis carried out at screening.11. Matched to a subject with hepatic impairment with regards to gender, age (! 5 yrs), and BMI (! 15%).

Exclusion Criteria1. A positive HIV-1 or HIV-2 test at trial screening.2. Female, except if post-menopausal for more than 2 years, or post-hysterectomy, or post-tubal ligation

(without reversal operation).3. Current barbiturate, amphetamine, recreational or narcotic drug use. 4. Current use of more than 1 unit of alcoholic beverages per day (1 unit of alcohol equals 1 pint [285 mL] of

beer, 1 glass [125 mL] of wine, 25 mL shot of 40% spirit).5. A positive urine drug test at trial screening. Urine was tested for the presence of amphetamines, barbiturates,

benzodiazepines, cannabinoids, cocaine, methadone, and opioids.6. Currently active gastrointestinal disease (with the exception of liver cirrhosis in the hepatically impaired

subjects), cardiovascular, neurologic, psychiatric, metabolic, renal, respiratory, inflammatory, or infectious disease.

7. Currently significant diarrhea, gastric stasis, or constipation that in the Investigator’s opinion could influence drug absorption or bioavailability.

8. History of any significant skin disease.9. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the

investigational medication administered in this trial (i.e. TMC278).10. Use of disallowed concomitant medication as specified in the protocol.11. Having previously participated in more than 1 trial (single or multiple dose) with TMC125, TMC120 and/or

TMC278 (formerly known as R278474) or having developed a rash, erythema or urticaria while participating in a trial with the aforementioned compounds.

12. Participation in an investigational drug trial within 60 days prior to the first administration of study medication.

13. Donation of blood or plasma or significant blood loss within the 60 days preceding the first administration of study medication.

14. Unlikely to comply with the protocol requirements, instructions and study-related restrictions; e.g.uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study.

15. Subject was the Investigator or any Sub-Investigator, Research Assistant, Pharmacist, Study Coordinator, other staff or relative thereof directly involved in the conduct of the study.

16. Vulnerable subjects (e.g. persons kept in detention).17. Subjects who were not able to read or write.

Only for subjects with hepatic impairment (Panels A1 and B1):18. Acute or active hepatitis (i.e. infection for less than 6 months).19. Evidence of hepatic decompensation.20. Grade 3 or 4 encephalopathy (Child-Pugh classification).21. Hepatic carcinoma.22. Hepatorenal syndrome.23. Severe liver insufficiency defined as class C according to Child–Pugh classification.

Synopsis



24. Active candidate for liver transplantation.25. Any grade 3 laboratory abnormalities with the exception of laboratory abnormalities related to hepatic

impairment.Only for healthy control subjects (Panels A2 and B2):

26. Hepatitis A infection (confirmed by hepatitis A antibody immunoglobulin M), or hepatitis B infection (confirmed by hepatitis B surface antigen), or hepatitis C infection (confirmed by hepatitis C virus antibody) at trial screening.

27. Any current hepatic disease.28. Subjects with the following laboratory abnormalities at screening as defined by the Division of AIDS Table

for Grading the Severity of Adult and Pediatric Adverse Events (“DAIDS grading table”) and in accordance with the normal ranges of the clinical laboratory:

- Serum creatinine grade 1 or greater (≥ 1.1 x upper limit of normal, ULN),- Serum lipase grade 1 or greater (≥ 1.1 x ULN),- Hemoglobin toxicity grade 1 or greater (≤ 10.9 g/dL),- Platelet count grade 1 or greater (≤ 124,999/mm3),- Absolute neutrophil count grade 1 or greater (≤ 1300/mm3),- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) grade 1 or greater (≥ 1.25 x

ULN),- Total bilirubin grade 1 or greater (∀ 1.1 x ULN),- Any other toxicity grade 2 or above, including on urinalysis.

Treatment

Dosage TMC278 25 mg for Panels A and B

Dosage Form (F No.) TMC278 25 mg tablet (F006)

Usage 1 tablet orally q.d. for 11 days

Batch Number 8BL2H

Dose Regimen TMC278 25 mg for 11 days

Duration of Treatment 11 days per panel

Duration of Trial 18 days per panel, excluding screening and follow-up

Synopsis



Disallowed Medication Only for subjects with hepatic impairment (Panels A1 and B1):The subjects with hepatic impairment were allowed to continue to use their regular medications for the management of their hepatic insufficiency e.g. albumin, diuretics, lactulose, beta-blockers and vitamins. Proton-pump inhibitors were prohibited. If necessary, proton-pump inhibitors could have been replaced by H2-antagonsist during treatment with TMC278 and were to be administered either 4 hours after or 12 hours before intake of TMC278. Any other medication the subject was using was to be discussed prior to inclusion with Tibotec Pharmaceuticals on a case-by-case basis, except for ibuprofen or paracetamol (acetaminophen).

Concomitant therapy that was allowed was not to be changed (started, stopped, or change in regimen) from screening until the last pharmacokinetic sample hadbeen obtained, except for ibuprofen or paracetamol. However, if there was a need to change (start, stop, or change in regimen) concomitant therapies during the trial, dosage and regimen had to be discussed in advance with Tibotec Pharmaceuticals.

Only for healthy control subjects (Panels A2 and B2):The matched healthy control subjects must have discontinued all over-the-counter medication at least 7 days before the first intake of study medication and all prescribed medication must have been discontinued at least 14 days before first intake of study medication, except for ibuprofen and paracetamol. Subjects were not permitted to use any medication other than the study medication up to 14 days after the last intake of study medication, except for ibuprofen or paracetamol and the comedication specified below for the treatment of specific adverse events (AEs).

For all subjects (Panels A1, A2, B1 and B2):

Subjects were not to use any herbal medications or dietary supplements (except vitamins) including products containing Hypericum perforatum (e.g. St. John’s wort) from 14 days before the first intake of study medication and up to 14 days after the last intake of study medication. Ibuprofen and paracetamol were permitted up to 3 days before the first intake of study medication. After that, the Investigator could permit the use of ibuprofen (at no more than 400 mg per day) or paracetamol (at no more than 1000 mg per day).

Other comedication was allowed in the following cases:

- In case of cutaneous reaction/rash and/or an allergic reaction, the use of cetirizine (Zyrtec#), levocetirizine (Xyzal#), topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted.

- In case of nausea, the use of antiemetics was permitted.

- In case of diarrhea, the use of loperamide was permitted.

In case any medication was used, the dose and dose regimen had to be recorded in the Concomitant Therapy section of the Case Report Form (CRF).

For any concomitant therapy given as a treatment for a new condition or a worsening of an existing condition, the condition had to be documented on the AE section of the CRF.

Synopsis



Assessments

Scre

enin

ga Panels A and B

Follo

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p

Day

≤ 21

days

-1b 1 2 3-4 5 6-8 9 10b 11 12-16

18c

7, a

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1 or

32

day

s afte

r la

st d

rug

inta

ked

Pharmacokinetics Blood samplee Xf Xg Xh Xg,h Xg,h Xf Xf Xf Xi

SafetyHematology & biochemistryj

X Xk Xk Xk X X

Urinalysis X X Xk Xk X XECG, pulse & BP

X Xk Xl Xl Xl Xk X X

Physical examination (including skinexamination)

X Xm Xm X X

AEs andconcomitant medicationsn

X X X X X X X X X X X X X

a Informed consent, smoking habits, inclusion/exclusion criteria, concomitant diseases, subject demographics, medical and surgical history, HIV-1 & -2 test, hepatitis A/B/C test, urine drug screening, serum pregnancy test (females only), plus Child-Pugh classification, documentation of clinical diagnosis of hepatic impairment and coagulation tests (only for subjects with hepatic impairment).

b Urine drug screening and also, on Day -1 only, urine pregnancy test (females only). c Day 18 corresponded to the first Follow-up visit (i.e. 7 days after last drug intake).d Coagulation test for subjects with hepatic impairment and serum pregnancy test (females only) 30, 31 or 32 days

after last drug intake. e For determination of TMC278.f Days 1 and 11: pre-dose (after breakfast, immediately before TMC278 intake), postdose at 0.5, 1, 2, 3, 4, 5, 6, 9,

12, 14 (Panel B only), 16, 18 (Panel B only), 20 (Panel B only) and 22 hours. The predose sample on Day 2 corresponds with the 24 hour postdose sample on Day 1. Samples on Days 12, 13, 14, 16 and 18 were taken at 24, 48, 72, 120 and 168 hours postdose, respectively.

g Predose sample, after breakfast, immediately before TMC278 intake. h Sample at 4 hours post dose for Panel B only.i 7 days after last drug intake only.j All biochemistry samples must be taken fasted for at least 10 hours.k Within 2 hours before TMC278 intake, and, on Days 1 and 11, ECG, pulse and blood pressure (BP) were

additionally assessed at 4 hours post dose. l Panel B only.m Within 2 hours before drug intake.n Adverse events and concomitant medication monitored continuously from signing of the ICF until the last

trial-related visit.

Synopsis



Statistical Methods Descriptive statistics and frequency tabulations were produced for safety parameters, and additional exploratory graphical analyses were done. Descriptive statistics, linear mixed effects modeling and a non-parametric statistical test were done for TMC278 plasma concentrations and pharmacokinetic parameters.

Synopsis





Panel A Panel B

HealthyN = 8

Mild Hepatic

ImpairmentN = 8

HealthyN = 8

Moderate Hepatic

ImpairmentN = 8

Number of Subjects Enrolled (male/female) 4/4 4/4 6/2 6/2Age: median (range), years 48.0 (36-61) 47.5 (41-57) 52.0 (45-65) 53.0 (47-64)Dropouts 0 0 0 0

Pharmacokinetics of TMC278Panel A Panel B

Healthy(reference)

Mild Hepatic Impairment (test)

Healthy(reference)

Moderate Hepatic Impairment (test)

(mean ! SD, tmax: median [range])n 8 8b 8 8d

Day 1Cmax, ng/mL 81.73 ± 20.01 90.29 ± 31.96 62.99 ± 22.31 44.43 ± 17.69tmax, h 4.0 (3.0 - 9.0) 4.5 (2.0 - 5.0) 5.0 (3.0 - 5.0) 5.0 (2.0 - 22.0)AUC24h, ng.h/mL 890.2 ± 169.0 1071 ± 266.3 726.9 ± 214.0 569.6 ± 227.5Day 9C0h, ng/mL 64.04 ± 18.79 126.8 ± 46.17 79.68 ± 24.35 98.31 ± 24.73Day 10C0h, ng/mL 69.08 ± 25.75 126.3 ± 49.95 86.26 ± 16.08 118.9 ± 53.73Day 11C0h, ng/mL 77.56 ± 22.12 137.8 ± 62.25 81.83 ± 17.81 122.2 ± 51.53Cmin, ng/mL 65.65 ± 18.58 84.13 ± 20.72 67.31 ± 14.88 76.55 ± 26.24C24h, ng/mL 82.09 ± 20.87 147.1 ± 50.20 88.75 ± 23.56 121.7 ± 62.22Cmax, ng/mL 144.3 ± 35.70 187.0 ± 66.31 146.8 ± 30.21 143.5 ± 49.69tmax, h 5.0 (3.0 - 12.0) 5.0 (2.0 - 24.0) 5.0 (3.0 - 5.0) 20.0 (2.0 - 24.0)AUC24h, ng.h/mL 2152 ± 538.1 3206 ± 1080 2318 ± 385.9 2525 ± 851.2t1/2term, h 60.59 ± 20.03 80.82c ± 33.17c 56.01 ± 21.31 90.56c ± 37.04c

Css,av, ng/mL 89.68 ± 22.42 133.6 ± 45.00 96.58 ± 16.08 105.2 ± 35.47FI, % 89.91 ± 29.74 74.40 ± 22.04 83.63 ± 30.34 65.26 ± 13.20AUC24h = area under the plasma concentration-time curve over 24 hours, C0h = predose plasma concentration, C24h = plasma concentration after 24 hours, Cmax = maximum plasma concentration, Cmin = minimum plasma concentration, Css,av = average steady-state plasma concentration over 24 hours, FI = fluctuation index, SD = standard deviation, tmax = time to maximum plasma concentration, t1/2term = terminal elimination half-life.a Ratio of mean pharmacokinetic parameter valuesb n = 7 for t1/2termc Accurate determination not possibled n = 6 for Day 1 and n = 5 for t1/2term

Synopsis




Panel A Panel BHealthy

(reference)Mild Hepatic

Impairment (test)Healthy

(reference)Moderate Hepatic Impairment (test)

Least squares mean ratio (90% confidence interval)- Test versus reference - Test versus reference

n - 8 versus 8 - 8a versus 8Day 1 - -Cmax - 1.060 ( 0.7834 - 1.435 ) - 0.7062 ( 0.4835 - 1.031 )AUC24h - 1.177 ( 0.9315 - 1.487 ) - 0.7635 ( 0.5426 - 1.074 )Day 11 - -Cmin - 1.307 (1.004 - 1.702) - 1.111 ( 0.8671 - 1.423 )C24h - 1.758 ( 1.343 - 2.301 ) - 1.276 ( 0.9079 - 1.792 )Cmax - 1.268 ( 0.9804 - 1.641 ) - 0.9496 ( 0.7514 - 1.200 )AUC24h - 1.467 ( 1.144 - 1.881 ) - 1.052 ( 0.8379 - 1.320 )a n = 6 for Day 1 of test

Synopsis



Safety(n = number of subjects with data)

Panel A Panel B

HealthyN = 8

Mild Hepatic Impairment

N = 8Healthy

N = 8

Moderate Hepatic

ImpairmentN = 8

n (%) with 1 or more AEs during treatment with TMC278

2 (25.0) 4 (50.0) 3 (37.5) 3 (37.5)

n (%) most frequently reported AEs in ≥ 2 subjects across all panels during treatment with TMC278

Dizziness 0 1 (12.5) 0 1 (12.5)Headache 0 1 (12.5) 1 (12.5) 0Back pain 0 1 (12.5) 0 1 (12.5)Conjunctivitis 0 0 1 (12.5) 1 (12.5)Nasopharyngitis 0 1 (12.5) 0 1 (12.5)Pruritus 0 0 1 (12.5) 1 (12.5)

n (%) deaths during the trial 0 0 0 0n (%) with 1 or more serious adverse event (SAE) during the trial 0 0 0 1 (12.5)n (%) treatment stopped due to AEduring the trial 0 0 0 0n (%) with 1 or more grade 3 or 4 AEs during the trial 0 0 0 2 (25.0)n (%) skin events of interest during the trial 0 0 0 0

There were no deaths, AEs leading to discontinuation, or skin events of interest reported during the trial. One SAE (grade 3, inguinal hernia leading to hospitalization, considered not related to TMC278) and 1 grade 4 AE (blood bilirubin increased, considered doubtfully related to TMC278) were reported during the trial, both during follow-up, in subjects with moderate hepatic impairment. Over the course of the trial, AEs were most frequently reported in subjects with hepatic impairment. The majority of AEs were grade 1 or 2 in severity and no AEs were considered probably or very likely related to TMC278. The only AE considered possibly related to TMC278 that was experienced by > 1 subject across all panels was headache. No single type of AE was reported by more than 1 subject in the same panel and no single type of AE was reported by > 2 subjects across all panels during treatment with TMC278. Nervous system disorders were the most frequently experienced AEs during treatment with TMC278, which were reported for a total of 5 subjects.

Synopsis




No consistent or clinically relevant changes in mean laboratory parameters were observed.

Graded treatment-emergent laboratory abnormalities were reported for more subjects with hepatic impairment (mild or moderate) than healthy subjects; most frequently in subjects with moderate hepatic impairment. The majority of graded laboratory abnormalities were grade 1 or 2 in severity. Two subjects experienced grade 4 laboratory abnormalities during the trial; both subjects had moderate hepatic impairment and experienced grade 4 increased total bilirubin during follow-up. One of these subjects also experienced a grade 4 decreased platelet count. A grade 4 AE corresponding to the grade 4 laboratory abnormality for total bilirubin was reported for 1 of the subjects. This subject also experienced grade 2 AEs for ALT and AST with corresponding grade 2 increased ALT and AST values at the same time as the grade 4 bilirubin AE. These were the only AEs relating to laboratory abnormalities reported during the trial.

No subjects had treatment-emergent abnormalities for urinalysis.


There were no notable variations in vital signs parameters over the course of the trial and no grade 3 abnormalities or AEs relating to vital signs parameters were reported.

There were no notable variations in ECG parameters over time and no AEs relating to ECGs were reported.Treatment-emergent abnormalities for QTcF and QTcB were reported more frequently in subjects with hepatic impairment than healthy subjects, and more frequently in subjects with mild hepatic impairment than moderate hepatic impairment. No subjects had increases > 60 ms or actual values > 500 ms for QTcB or QTcF intervals.


Two treatment-emergent abnormalities were reported for the physical examination. Both were abnormalities for the ears, nose and throat body system and were reported for 1 subject with moderate hepatic impairment and 1 healthy subject at follow up, 30 to 32 days after last study medication intake. The abnormality for the subject with moderate hepatic impairment was submandibular pain, which was linked to the subject’s AEs of nasopharyngeal pain and influenza. The abnormality for the healthy subject was mild rhinitis.

Conclusions

After a single dose, TMC278 Cmax and AUC24h were 6% and 18% higher, respectively, in subjects with mild hepatic impairment, compared to healthy subjects. At steady-state (Day 11) Cmax, AUC24h, Cmin and C24h were 27%, 47%, 31% and 76% higher, respectively. After a single dose in subjects with moderate hepatic impairment, Cmaxand AUC24h were 29% and 24% lower, respectively, compared to healthy subjects. At steady-state, Cmax was 5% lower and AUC24h was 5% higher. Mean Cmin and C24h were increased by 11% and 28%, respectively, in subjects with moderate hepatic impairment as compared to healthy subjects. The results of the trial also demonstrate that administration of TMC278 25 mg q.d. was generally safe and well tolerated and that no dose adjustment of TMC278 is needed in subjects with mild or moderate hepatic impairment.

Synopsis

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Tenofovir DF 300 mg Dosing Intervals for Patients with Renal Impairment

Creatinine Clearance (mL/min)a Hemodialysis Patients

30-49 10-29 < 10

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Tenofovir DFStudy GS-01-931Clinical Study Report Final


3. STUDY SYNOPSIS


Foster City, CA 94404

Name of Sponsor:Gilead Sciences, Inc.

Name of FinishedProduct:Viread

Name of ActiveIngredient:Tenofovir DF

Individual Study TableReferring to Partof the Dossier:

Volume:

Page:


Title of Study: A Phase 1, Open-Label, Parallel-Group, Single-Dose Study toEvaluate the Pharmacokinetics of Tenofovir DF in Subjects withNormal and Impaired Hepatic Function

Investigators:

Study Centers: France

France

USA

Publications: None

Study Period: 20 (First Subject Enrolled) 20 (Last Subject Observation)





Objectives: The primary objective of this study was:

To evaluate the pharmacokinetics of tenofovir followingadministration of a single dose of tenofovir DF 300 mg insubjects with normal hepatic function and varying degrees ofhepatic impairment.

The secondary objectives of this study were:

To develop dosing guidelines for tenofovir DF in subjects withimpaired hepatic function.

To evaluate the safety of tenofovir DF 300 mg followingadministration of a single dose in subjects with normal hepaticfunction and varying degrees of hepatic impairment.

Methodology: Phase 1, open-label, single-dose, parallel-group pharmacokinetic(PK) study of tenofovir DF 300 mg

Number of Subjects(Planned andAnalyzed):

24 evaluable subjects total; 3 groups with 8 subjects in each groupplanned; 24 analyzed for safety; 23 analyzed for PK

Diagnosis and MainCriteria for Inclusion:

There were three groups of eight subjects each. Subjects withhepatic impairment were stratified using the Child-Pugh-Turcotteclassification system. The groups studied were subjects withmoderate and severe hepatic impairment caused by viral-induced(non-hepatitis B) liver cirrhosis. The control group consisted ofhealthy volunteers with normal hepatic function.

Main criteria for inclusion were:

Healthy males and non-pregnant, non-lactating females Ages 18–70 (inclusive) Human immunodeficiency virus seronegative Hepatitis B virus surface antigen-negative

Duration of Treatment: Approximately 48 hours plus screening period





Tenofovir DF 300 mg tablet, single oral administration;

Lot Numbers J104B1 and J106B1


None


Safety: Safety was evaluated by physical examinations and collection oflaboratory samples (both serum and urine) at baseline and followingstudy drug administration, and by assessment of adverse eventsthroughout the study.

Pharmacokinetics: The following tenofovir PK parameters in serum were calculated:

Cmax, Tmax, Clast, Tlast, kel, T1/2 z, AUC0-t, AUC0-, % AUC0-, Vz/F,CL/F

Statistical Methods: Subject enrollment from studies 931A (France) and 931B (U.S.)was combined for a total enrollment of 24 evaluable subjects with8 subjects in each group (normal hepatic function, moderate hepaticimpairment, severe hepatic impairment).

Demographics and Disposition: Descriptive statistics werecalculated for continuous demographic variables. Dosing data werelisted for all subjects and study days.

Pharmacokinetics: PK parameters were summarized by groupusing descriptive statistics (geometric mean, arithmetic mean,standard deviation, coefficient of variation, median, minimum,maximum, Q1, Q3 and sample size). The relationship betweentenofovir pharmacokinetics and estimates of hepatic function wasexamined.




Statistical Methods(continued):

Safety: Adverse events were coded according to MedDRAdictionary version 5.0. Summary tables present the adverse eventprofile (number and percent of subjects with each treatmentemergent event). Continuous laboratory parameters (serumchemistry, hematology and urinalysis) were summarized bydescriptive statistics at each protocol-specified time point withineach group. The change from baseline to post-dose was alsopresented. All out-of-range and recheck values were listed bysubject for each laboratory parameter. Descriptive statistics forvital signs measurements at each time point (baseline and post-dose)and change from baseline to post-dose were provided for eachtreatment and group.


Safety Results:

Eight of the 24 subjects (33%) treated with tenofovir DF in this study experienced at leastone treatment-emergent adverse event, 2 subjects (25%) in the normal hepatic function group,1 subject (13%) in the moderate hepatic impairment group, and 5 subjects (63%) in the severeimpairment group. The only adverse events experienced by more than 1 subject were headache(2 subjects in the normal hepatic function group) and decreased urine volume (2 subjects in thesevere hepatic impairment group).

Five subjects experienced adverse events that were assessed as possibly or probably related tostudy drug. Two subjects (25%) in the normal hepatic function group reported headache; 1 ofthose subjects also reported nausea and vomiting (10 hours post-dosing). Decreased urinevolume was reported by 1 subject (13%) in the moderate hepatic impairment group and2 subjects (25%) in the severe impairment group. The decrease in urine volume was notassociated with any clinical or laboratory evidence of renal dysfunction.

The one death reported during the study (subject 0592-3015 in the severe hepatic impairmentgroup) was considered by the investigator to be unrelated to study drug. The subject had ahistory of decompensated cirrhosis, ascites, jaundice, chronic hepatic encephalopathy, infectiouspneumopathy, esophagitis, and recent hospitalizations for alcoholic cirrhosis and septic shock.The subject was hospitalized 10 days after a single dose of tenofovir DF when urine cultureresults were positive for Enterobacter cloacae infection. Despite treatment with numerousantibiotics, vasoactive agents, and mechanical ventilation, the subject expired. No other seriousadverse events were reported.




SUMMARY – RESULTS (continued):

Safety Results (continued):

Only grade 1 laboratory abnormalities were reported for subjects in the normal hepatic functiongroup. Four subjects in the moderate hepatic impairment group experienced a total of 5 grade 3laboratory abnormalities, and 5 subjects in the severe hepatic impairment group experienced atotal of 6 grade 3 abnormalities. No grade 4 laboratory abnormalities were reported. The onlylaboratory abnormality reported for more than 1 subject was elevated total bilirubin (1 subject inthe moderate impairment group and 4 subjects in the severe impairment group) which waspresent at screening, remained unchanged after study drug administration, and was reflective ofthe underlying hepatic impairment of the study population.

One subject was enrolled into the study with a medical history of renal failure. Screeninglaboratory results for this subject included grade 2 serum creatinine, grade 2 blood urea nitrogen,and grade 3 uric acid, which remained unchanged following study drug administration.

Pharmacokinetic Results:

Following administration of tenofovir DF 300 mg in the fasted state, the concentration-timeprofile of tenofovir in subjects with moderate or severe hepatic impairment was similar to thatobserved in subjects with normal hepatic function. Tenofovir Cmax was achieved within 2 hoursof dosing and was slightly higher in subjects with hepatic impairment relative to normal controls.Overall tenofovir exposures (AUC0-t and AUC0-8 ) were not substantially altered in the subjectswith hepatic impairment. These data indicate that despite profound hepatic impairment, onlysmall alterations in tenofovir pharmacokinetics are observed and no dose adjustments fortenofovir DF are required in these patients.

Pharmacokinetic results are summarized in the following table.

Tenofovir Pharmacokinetic Parameters by Hepatic Function Group

Hepatic ImpairmentNormal(N = 8)

Moderate(N = 7)

Severe(N = 8)

CPT1 Class: A B CCmax (ng/mL)2 223 77.7 289 133 305 75.6AUC0- (nghr/mL)2 2050 1040 2310 1000 2740 1210Tmax(hr)3 1.00 1.00 0.75

1 CPT = Child-Pugh-Turcotte classification 2 Mean SD 3 Median Source: Section 15, Table 3




CONCLUSION:

No substantial changes in tenofovir pharmacokinetics were observed in subjects with moderateand severe impairment, indicating that a dose of tenofovir DF 300 mg may be administeredwithout regard to hepatic function.

Tenofovir DF was reasonably well tolerated, with no clinically important adverse events or lababnormalities. The one death reported during the study (septic shock) was considered by theinvestigator to be unrelated to study drug. No other serious adverse events were reported.

Emtricitabine and Tenofovir Disoproxil Fumarate GS-104-0235 Final Clinical Study Report Final


STUDY SYNOPSIS


Foster City, CA 94404 USA

Title of Study: A Phase 4, Single-Arm Study To Evaluate the Safety, Antiretroviral Activity and Pharmacokinetics of Tenofovir Disoproxil Fumarate in Combination with Emtricitabine in HIV-1 Infected Patients Experiencing Various Degrees of Renal Impairment

Investigators: Multicenter

Study Centers: Four centers enrolled subjects, three in the United States, and one in France

Publications: None

Study Period: 25 October 2004 (First subject screened) 13 March 2006 (Last subject observation)



To evaluate the safety and tolerability of tenofovir following administration of tenofovir disoproxil fumarate (TDF, tenofovir DF) 300 mg for 48 weeks in human immunodeficiency virus (HIV) infected subjects experiencing various degrees of renal impairment

The secondary objectives of this study were as follows:

To evaluate the safety and tolerability of emtricitabine following administration of emtricitabine 200 mg for 48 weeks in HIV infected subjects experiencing various degrees of renal impairment

To evaluate the efficacy of tenofovir DF in combination with emtricitabine in renally-impaired HIV infected subjects

To evaluate the pharmacokinetics of tenofovir and emtricitabine in renally-impaired HIV infected subjects

Tenofovir DF Final CSR GS-104-0235





Methodology: This was an open-label, single-group study in treatment-naive or treatment-experienced HIV Type 1 (HIV-1) infected subjects with stable renal disease. Treatment-naive subjects received a fixed regimen of emtricitabine, tenofovir DF, and efavirenz for 48 weeks. Treatment-experienced subjects were switched from their existing stable regimen (defined as stable on their existing regimen for at least 3 months and a screening plasma HIV-1 ribonucleic acid [RNA] concentration of 50 copies/mL) to emtricitabine, tenofovir DF, and either to remain on their current non-nucleoside reverse transcriptase inhibitor or to remain on their current protease inhibitor for 48 weeks. Subjects with mild through severe renal impairment received emtricitabine 200 mg and tenofovir DF 300 mg in a fixed-dose combination tablet. The frequency of dosing differed for each renal impairment group, as summarized below.

Renal Impairment Group

Mild Moderate Severe ESRDa

Calculated Creatinine Clearance (mL/min)b

50 and 80 30 and 50 15 and 30 Requiring hemodialysis

Study Drugs

Tenofovir DF 300 mg Tablet Not applicable Not applicable Not applicable Every 7 daysc

Emtricitabine 200 mg Capsule Not applicable Not applicable Not applicable Every 96 hoursd

Emtricitabine 200 mg and tenofovir DF 300 mg Combined Tablet

Every 24 hours Every 48 hours Every 72 hours Not applicable

Efavirenz 600 mg Tablete Every 24 hours Every 24 hours Every 24 hours Every 24 hours

a End stage renal disease b Calculated creatinine clearance using the Cockcroft Gault equation and ideal body weight [IBW], unless total body

weight [TBW] was less than IBW in which case TBW was used c Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration each.

Tenofovir DF was administered following completion of dialysis. d If dosing on day of dialysis, emtricitabine was administered after dialysis. e Dosing regimen for efavirenz. Subjects remaining on a protease inhibitor or non nucleoside reverse transcriptase

inhibitor received them in accordance with dosing instructions in the package insert.

Number of Subjects (Planned and Analyzed):Planned: 32 to 40 evaluable HIV infected subjects with varying degrees of renal impairment, plus 12 subjects (HIV-1 infected not receiving tenofovir DF, preferred, or non-HIV-1 infected) with severe renal impairment or undergoing hemodialysis, matched for sex and age, as a control for bone density assessments Enrolled: 8 HIV infected subjects, zero control subjects Evaluable: Efficacy, 8 HIV infected subjects Pharmacokinetics, 8 HIV infected subjects Safety, 8 HIV infected subjects






Diagnosis and Main Criteria for Inclusion: Male and nonpregnant female HIV-1 infected subjects, aged 18 to 80, with stable renal impairment. Subjects were either: antiretroviral therapy-naive, requiring antiretroviral treatment, with HIV-1 RNA concentration

400 copies/mL; or antiretroviral therapy-experienced, on a stable antiretroviral regimen for at least 3 months, with HIV-1 RNA concentration 50 copies/mL at screening.

Duration of Treatment: 48 weeks

Test Product, Dose, Mode of Administration, and Batch No.:Tenofovir DF 300 mg tablet administered orally: Lots J208D1 and J408B1.

Emtricitabine 200 mg capsule administered orally: Lots W304A1 and W306A1.

Emtricitabine 200 mg and tenofovir DF 300 mg combined tablet: Lots V301B2, V402B1, and V402B1-1.

Reference Therapy, Dose, Mode of Administration, and Batch No.: Not applicable

Criteria for Evaluation: Efficacy: Plasma HIV-1 RNA concentrations, CD4 cell counts, and HIV-1 genotyping.

Pharmacokinetics: The following pharmacokinetic parameters were determined for emtricitabine and tenofovir in plasma: Cmax, Cmin, Tmax, AUCtau, Avg Daily AUC, T½, z, and CL/F.

Safety: Adverse events (AEs), clinical laboratory tests (including renal function assessments), vital signs, physical examinations, and bone density assessments.

Statistical Methods: Statistical analyses in this study were based on available data rather than the protocol-specified analyses, since only eight HIV infected subjects were enrolled.

Efficacy: Efficacy analyses were conducted on all subjects in the intent-to-treat (ITT) analysis set. The proportion of subjects with HIV RNA concentrations 50 copies/mL was summarized by renal impairment group and overall. Changes from baseline in CD4 cell count and percentage were summarized using descriptive statistics by renal impairment group and overall.






Statistical Methods (continued): Pharmacokinetics: Steady-state pharmacokinetic parameters were computed for all subjects in the pharmacokinetic analysis set. Pharmacokinetic parameters were estimated for individual subjects using standard noncompartmental methods (WinNonlin®, Version 5.0.1). Plasma concentrations and pharmacokinetic parameters of tenofovir and emtricitabine were presented for each subject and descriptive statistics (sample size, arithmetic mean, standard deviation, coefficient of variation [% CV], median, minimum, maximum, geometric mean and 95% confidence intervals, mean and standard deviation of log) were calculated and tabulated per sampling time by dosage regimen. Additional summary statistics were calculated excluding data when the dosage regimen administered was not appropriate for the subject’s renal function (i.e., calculated creatinine clearance) on the day of pharmacokinetic evaluation. Mean and median concentration-time profiles of tenofovir and emtricitabine were plotted by dosage regimen.

Safety: Safety characteristics were summarized using descriptive statistics, with changes from baseline for laboratory parameters. Clinical and laboratory AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 9.1. All safety data were listed.

SUMMARY – RESULTS: Of the eight subjects enrolled, four subjects completed the 48-week study period. Two subjects experienced decreases in calculated CLcr of 20% from baseline and were discontinued from the study due to AEs. Two further subjects discontinued due to investigator and/or subject request: both of these subjects experienced increased serum creatinine.

Efficacy Results: Plasma HIV-1 RNA concentrations remained 50 copies/mL after switching NRTIs to emtricitabine and tenofovir DF in all treatment-experienced subjects, except for one subject who had a plasma HIV-1 RNA concentration of 252 copies/mL at Week 48. Plasma HIV-1 RNA concentrations declined from 32,200 copies/mL at baseline to

50 copies/mL at Week 4 and at every subsequent study visit in the only antiretroviral-naive subject enrolled.






Pharmacokinetic Results: For four subjects with mild renal impairment on the day of pharmacokinetic evaluation, median tenofovir Cmax, Cmin, and AUCtau were in good agreement with predicted values based on the single-dose data used to develop the current dosage adjustment regimens for renal impairment. The highest Cmax, Cmin, and AUCtauobserved were approximately 2-fold higher than the maximum predicted values; this was not unexpected given that the subject for whom these values were reported had a CLcr of 51 mL/min, just above the upper cutoff for the moderate renal impairment group. For two subjects with moderate renal impairment on the day of pharmacokinetic evaluation, median Cmax, Cmin, and AUCtau were about 2-fold higher than predicted median values, and the highest Cmax, Cmin, and AUCtau were slightly higher than the maximum predicted values. For one subject with severe renal impairment on the day of pharmacokinetic evaluation, Cmax,Cmin, and AUCtau were within the predicted range.

Emtricitabine Cmax, Cmin, and AUCtau in subjects with mild, moderate, or severe renal impairment on the day of pharmacokinetic evaluation were in reasonable agreement with predicted values based on the single-dose data used to develop the current dosage adjustment regimens for renal impairment.






Safety Results: Tenofovir DF and emtricitabine were generally well tolerated in this study. There were no deaths during the study. One SAE of urinary retention was reported; however, this event began before study treatment so was not considered treatment emergent. Four subjects completed 48 weeks of treatment and four discontinued; all four subjects who discontinued experienced decreased renal function (increased serum creatinine or 20% decrease in calculated creatinine clearance [CLcr] from baseline) of varying etiology, as follows. Two subjects discontinued study drug due to AEs; renal impairment and glomerular filtration rate decreased, both considered related to study drug by the investigator. These subjects had confirmed reductions in calculated creatinine clearance and the study drugs were stopped in accordance with protocol requirements. Two other subjects had study drugs interrupted due to increases in serum creatinine concentrations.

All eight subjects in the ITT analysis set had at least one treatment-emergent AE reported during the study. The most frequently reported treatment-emergent AEs were rhinitis (three subjects), upper respiratory tract infection (two subjects), and blood creatinine increased (two subjects). AEs considered possibly/probably related to study drug were diarrhoea, blood creatinine increased, glomerular filtration rate decreased, dizziness, depression, renal impairment, and dry skin; no event considered related to study drug was reported for more than one subject. Blood creatinine increased in one subject was the only Grade 3 or 4 treatment-emergent AE reported during the study.

Treatment-emergent Grade 3 and 4 abnormalities in clinical chemistry analytes were seen only in subjects initially assigned to the moderate renal impairment group; no Grade 3 or 4 abnormalities in hematology or urinalysis analytes were seen. Treatment-emergent Grade 4 abnormalities were reported for serum bicarbonate and serum glucose (both for the same subject). Treatment-emergent Grade 3 abnormalities were reported for creatinine (two subjects), and amylase, glucose, and triglycerides (each in one subject); all Grade 3 abnormalities were classed as marked laboratory abnormalities.

Five subjects had on-treatment serum creatinine abnormalities reported: Grade 1 for two subjects, Grade 2 for one subject, and Grade 3 for two subjects. Two subjects had confirmed changes from baseline in calculated Clcr of 20% and were discontinued from the study in accordance with the protocol; in addition, one subject had a 20% decrease in CLcr from baseline at the early study withdrawal visit (21 mL/min to 13 mL/min) and was discontinued by the investigator due to increased serum creatinine believed to be related to study drug. No graded serum phosphorus abnormalities were reported during the study.

There were no clinically relevant findings reported during the study for bone mineral density or hormonal profiles, or for changes in vital signs, body weight, and physical examinations.






CONCLUSIONS: Tenofovir DF and emtricitabine were generally well tolerated during this study; safety findings were generally consistent with those anticipated in this small population of renally-impaired subjects.

For this limited dataset, median tenofovir and emtricitabine pharmacokinetics in subjects with varying degrees of renal impairment were in reasonable agreement with predicted values based on the single-dose data used to develop the current dosage adjustment regimens. While the majority of subjects fell within the range of predicted exposures, there were exposures outside predicted ranges in subjects with calculated CLcr in the borderline range between impairment groups.

From the limited data available from this study, it is not possible to make conclusions regarding the planned efficacy objectives.



R278474-C101 1

Clinical Research Report Version: 2.0 Date: 24-Sep-2004



Drug Substance: R278474 Trial No.: R278474-C101 Clinical Phase: I

Title: A Phase I, open label, parallel group, add-on trial to explore the pharmacokinetics, safety, and tolerability of a single oral dose of 50 mg R278474 in HIV-1 infected male subjects taking at least 2 NRTIs/NtRTIs and efavirenz or nevirapine

Investigator:

United Kingdom

Country: United Kingdom



Objectives: The primary objective of this study was to determine the single dose pharmacokinetics of R278474 in human immunodeficiency virus (HIV)-1 infected subjects taking at least 2 NRTIs/NtRTIs and efavirenz or nevirapine. Secondary objectives were to determine the short-term safety and tolerability of R278474 in HIV-1 infected subjects taking at least 2 NRTIs/NtRTIs and efavirenz or nevirapine. Design: This was a Phase I, open label, parallel group, add-on trial to explore the pharmacokinetics of a single oral dose of R278474 in HIV-1 infected male subjects taking at least 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs)) and efavirenz or nevirapine. Two groups of subjects each received a single oral dose of 50 mg R278474, on top of their current antiretroviral therapy (ART), which consisted of efavirenz (Group 1 [7 subjects]) or nevirapine (Group 2 [8 subjects]) and at least 2 NRTIs/NtRTIs. A 144-hour pharmacokinetic profile of R278474 was determined after administration of the investigational drug. Tolerability and safety were also assessed. Subject Selection: Inclusion Criteria:1. Male, aged between 18 and 55 years, extremes included. 2. Smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day (or non-smoking) for at least 3 months

prior to selection. 3. Informed consent form signed voluntarily. 4. Able to comply with protocol requirements. 5. Documented HIV-1 infection. 6. Undetectable plasma viral load (< 50 HIV RNA copies/mL, assayed by Amplicor ) at screening and for at

least 8 weeks prior to screening. 7. Current use of efavirenz (600 mg once daily [q.d.]) or nevirapine (200 mg twice daily [b.i.d.]) and at least

2 NRTIs (tenofovir is considered as a NRTI) for at least 8 weeks prior to screening. T-20 was optional. 8. Agreement not to change the current ART from screening until 6 days after the intake of study medication

(unless medically indicated as decided by investigator). Changes in NRTIs for reasons of toxicity were allowed.

9. Normal morning cortisol and normal cortisol response to low-dose adrenocorticotropin hormone (ACTH) stimulation test (Short Synacthen Test).

Exclusion Criteria:1. History or suspicion of alcohol, barbiturate, amphetamine, or narcotic drug abuse. 2. Acute hepatitis A infection (confirmed by hepatitis A antibody IgM), or acute hepatitis B infection (confirmed

by hepatitis B surface antigen), or acute hepatitis C infection (confirmed by hepatitis C virus (HCV) antibody, or HCV RNA if CD4+ count is less than 100).

3. A positive urine drug test at 2 consecutive screenings (a positive drug test at study screening was repeated at baseline). Urine was tested for the presence of amphetamines, cocaine, and opioids.

4. Any active clinically significant disease (e.g., tuberculosis, cardiac dysfunction), or findings during screening of medical history or physical examination that in the investigator’s opinion, would have compromised the outcome of the study.

5. Any current or previous adrenal illness.

Synopsis

R278474-C101 2


6. Currently significant diarrhea, gastric stasis, or constipation that in the investigator’s opinion could have influenced drug absorption or bioavailability.

7. Currently active acquired immune deficiency syndrome (AIDS)-defining illness (Category C conditions according to the Centers for Disease Control [CDC] Classification System for HIV Infection 1993) with the following exception, which was to be discussed with the sponsor prior to enrollment:

Stable cutaneous Kaposi’s Sarcoma (i.e., no pulmonary or gastrointestinal involvement other than oral lesions) that was unlikely to require any form of systemic therapy during the trial period.

8. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication.

9. Use of disallowed concomitant therapy from 14 days before the intake of study medication until 6 days after intake of the study medication.

10. Participation in an investigational drug trial within 90 days prior to the first intake of study medication. 11. Having previously participated in a trial with R278474. 12. The electrocardiogram (ECG) at screening must have been within normal limits or considered by the

investigator as not clinically significant. 13. Renal impairment: serum creatinine > 2 times the upper limit of normal (ULN). 14. Lipase > 1.5 times the ULN. 15. Hemoglobin < 5.7 mmol/L (9.1 g/dL). 16. Platelet count < 75 x 109 cells/L. 17. Absolute neutrophil count < 1.0 x 109 cells/L. 18. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times the ULN. Any grade 3 or 4 toxicity according to the enhanced AIDS Clinical Trial Group (ACTG) grading severity list, except for grade 3 or 4 asymptomatic triglyceride/cholesterol elevations.Treatment Concentration Usage

25 mg/mL of R278474 in 100% polyethylene glycol 400 (PEG400) Oral

Batch Number 03G07/F002 Dose Regimen 1 oral dose of 50 mg of R278474, together with the subject’s current NNRTIs,

within 10 minutes of completing a standardized meal on Day 1 Duration of Treatment 1 intake of study medication on 1 day Duration of Trial 7 days (excluding screening and a follow-up visit on Day 31, 32, or 33 of the

trial) Disallowed Medication All investigational drugs were disallowed from 90 days before the start of the trial

until 6 days after intake of study medication. The following medications were disallowed from 14 days before the start of the trial until 6 days after intake of study medication:

protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), with the exception of efavirenz and nevirapine; all vaccines, including HIV vaccines; cytochrome P450 3A4 (CYP3A4) inhibitors and inhibitors of transporting proteins:

- azoles: ketoconazole, itraconazole, voriconazole, and fluconazole. Local application was allowed;

- macrolide antibiotics: erythromycin, clarithromycin, and troleandomycin;

CYP3A4 inducers: - rifamycins: rifabutin, rifampicin; - anticonvulsants: phenobarbital, phenytoin, carbamazepine; - all products containing Hypericum perforatum (St John’s Wort);

CYP3A4 substrates with a small therapeutic index: terfenadine, astemizole, cisapride, amiodarone, quinidine, triazolam, midazolam, ergot derivatives, simvastatin, sildenafil; cytochrome P450 2D6 substrates with a small therapeutic index: tricyclic antidepressants;

Synopsis

R278474-C101 3


immunomodulators: systemic corticosteroids, interleukins and interferons; drugs depending on glutathione conjugation for metabolism: paracetamol (acetaminophen).

Assessments Pharmacokinetics On Day 1 prior to dosing with R278474, blood samples were collected for

determination of efavirenz or nevirapine concentration. On Days 1 through 7, blood samples were collected for determination of R278474 concentrations. The following pharmacokinetic parameters for R278474 were derived from plasma concentration-time data:

area under the plasma concentration-time curve (AUC) from time of administration until infinity (AUC ); AUC from time of administration until last measurable time point (AUClast); maximum plasma concentration (Cmax); elimination rate constant ( z); terminal elimination half-life (t1/2term); time to Cmax (tmax);

The following pharmacokinetic parameters for efavirenz and nevirapine were derived from plasma concentration-time data:

predose plasma concentration (C0h); plasma concentration at 12 hours (C12h);

Safety Adverse Events Adverse events (AEs), serious adverse events (SAEs), and AEs leading to

discontinuation of the trial were recorded at each visit and were reported from screening through the last trial-related activity. The severity and relationship to R278474, efavirenz, or nevirapine were determined by the investigator. Dermatological events, allergic reactions, HIV-related events, AST and ALT elevations, and clinical hepatitis were monitored.

Clinical Laboratory Blood samples were collected for hematology, biochemistry, and urinalysis testing during the course of the trial. Additional clinical laboratory tests included adrenal function testing by ACTH stimulation tests, resistance testing using peripheral blood mononuclear cells (PBMCs), plasma viral load assessments, and CD4+ cell counts (absolute and percentage).

Other Safety Observations Other safety observations included measurements of cardiovascular safety such as ECG assessments, blood pressure (BP), and pulse rate (PR); and physical examinations.

Statistical Methods Descriptive statistics, frequency tabulations, graphical presentations, Wilcoxon’s matched pairs signed rank test

Synopsis

R278474-C101 4


Main Features of the Subject Sample and Summary of the Results Baseline Characteristics - Subject Disposition Efavirenz Nevirapine All Subjects Number of Subjects Entered Age: median (range), yrs

7 44.0 (33-53)

8 46.0 (30-61)

15 45.0 (30-61)

Dropouts - Reason Adverse event

1

0

1

Pharmacokinetics of R278474 (mean ± SD, tmax: median [range])

R278474 and Efavirenz (n=7)

R278474 and Nevirapine (n=8)

tmax, h 4.0 (4.0 - 4.0) 4.0 (4.0 - 8.0) Cmax, ng/mL 176 ± 36.5 222 ± 40.9 AUClast, ng·h/mL 2179 ±734 6402 ± 1343 AUC , ng·h/mL 2246 ± 765 7144 ± 1696 t1/2term, h 19.4 ± 8.23 40.1 ± 15.9 Pharmacokinetics of NNRTI (mean ± SD)

Efavirenz (n=7)

Nevirapine (n=8)

n 2 8 C0h, ng/mL 1003 4531 ± 1023 n 5 - C12h, ng/mL 3466 ± 2148 -

Safety Efavirenz/

50 mg R278474 (n = 7)

Nevirapine/ 50 mg R278474

(n = 8)

Total 50 mg R278474

(n = 15)

Adverse events, n (%)

50 mg R278474 50 mg R278474 50 mg R278474 AE during the treatment period Any AEs 2 (28.6) 1 (12.5) 3 (20.0)

Headache 2 (28.6) 0 2 (13.3) Nausea 0 1 (12.5) 1 (6.7) Respiratory tract infection 1 (14.3) 0 1 (6.7)

n (%) of deaths 0 0 0 n (%) with 1 or more other serious AEs

0 0 0


1 (14.3) 0 0


0 0 0

n (%) with 1 or more skin events of interest

0 0 0

AEs during follow-up period Any AEs 1 (14.3) 1 (12.5) 2 (13.3)

Periorbital edema 1 (14.3) 0 1 (6.7) Tonsillitis 0 1 (12.5) 1 (6.7)


0 0 0

Synopsis

R278474-C101 5


Efavirenz/ 50 mg R278474

(n = 7)

Nevirapine/ 50 mg R278474

(n = 8)

Total 50 mg R278474

(n = 15)

Clinical Laboratory Tests (Treatment-emergent results)

50 mg R278474 50 mg R278474 50 mg R278474 n (%) with any treatment-emergent grade 3 or 4 laboratory abnormalities during the treatment period

0 0 0

Treatment-emergent, grade 2 laboratory abnormalities were observed in 1 subject in the efavirenz group (increased cholesterol) and in 2 subjects in the nevirapine group (increased cholesterol and amylase) during the treatment period. During the follow-up period, treatment-emergent, grade 2 laboratory values were reported in 1 subject in the efavirenz group (increased GGT) and in 1 subject in the nevirapine group (increased amylase [this subject also had grade 2 amylase during the treatment period]). One subject in the efavirenz group experienced a treatment-emergent, grade 3 laboratory abnormality (increased triglyceride) during the follow-up period. None of the changes over time in laboratory parameters were considered clinically significant. No subjects had a laboratory abnormality that resulted in an AE or in discontinuation from the trial.

Cardiovascular Safety Minor median changes were reported for all vital sign and ECG parameters. Only a few of these changes were statistically significant. None of these changes were considered clinically significant, and no trends or relationships were evident.

Other Safety Observations One subject in the efavirenz treatment group experienced an HIV-related event (grade 2 respiratory tract infection). No physical examination abnormalities were reported.

Conclusions The results of this trial demonstrate that after the administration of a single dose of 50 mg R278474, systemic exposure to R278474 (expressed as AUC ) was approximately 70% lower when added to chronic ART with efavirenz and at least 2 NRTIs when compared to historical controls. Systemic exposure to R278474 (expressed as AUC ) was unchanged when added to chronic ART with nevirapine and at least 2 NRTIs when compared to historical controls. The administration of a single dose of 50 mg R278474 was considered safe and well tolerated.

Synopsis

TMC278-C104 1

Clinical Research Report Version: 1.0 Date: 03-Oct-2005 Clinical Research Report Amendment 1 Version: 1.0 Date: 28-Apr-2006




Title: A Phase I open-label trial to investigate the pharmacokinetic interaction between tenofovir (administered as tenofovir disoproxil fumarate) and TMC278 at steady-state in healthy subjects.

Investigator: The Netherlands



No. of Investigators: 1 No. of Subjects:16

Objectives: The primary objective of this study was to determine the effect of steady-state concentrations of TMC278 on the steady-state pharmacokinetics and urinary excretion of tenofovir and to determine the effect of steady-state concentrations of tenofovir on the steady-state pharmacokinetics of TMC278 in healthy subjects. Secondary objective was to determine the short-term safety and tolerability of the coadministration of tenofovir DF and TMC278 in healthy subjects. Design: This was an open-label, two-sequence, randomized crossover trial in 16 healthy subjects to investigate the pharmacokinetic interaction between TMC278 and tenofovir disoproxil fumarate (tenofovir DF, prodrug of tenofovir) at steady-state. During Session I, 150 mg q.d. of TMC278 was administered from Day 1 to Day 8. After a washout period of at least 14 days, Session II consisted of a repeated-dose regimen of 300 mg q.d. of tenofovir DF from Day 1 to Day 16. In session II, 150 mg q.d. of TMC278 was coadministered from Day 9 to Day 16 (inclusive) in 8 subjects randomized to Group 1 and from Day 1 to Day 8 (inclusive) in 8 subjects randomized to Group 2. All treatments were taken under fed conditions. Plasma concentrations of both TMC278 and tenofovir were determined. Urinary excretion of tenofovir was assessed. Short term safety and tolerability were assessed as well. Subject Selection Inclusion Criteria

1. Aged between 18 and 55 years, extremes included. 2. Smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day (or non-smoking) for at least 3 months

prior to selection. 3. Normal weight as defined by a Quetelet Index (Body Mass Index) of 18.0 to 30.0 kg/m2, extremes included. 4. Informed consent form (ICF) signed voluntarily before first trial-related activity. 5. Cortisol of at least 550 nmol/l (19.9 g/dL) at any timepoint at screening (i.e. morning (prestimulation)

cortisol, 30 or 60 minutes after 250 g ACTH stimulation). 6. Able to comply with protocol requirements. 7. Healthy on the basis of a pretrial physical examination, medical history, electrocardiogram, vital signs and

the results of blood biochemistry, hematology tests and a urinalysis at screening. Exclusion Criteria

1. A positive HIV-1 or HIV-2 test at study screening. 2. Female, except if postmenopausal since more than 2 years, or post-hysterectomy or post-tubal ligation

(without reversal operation). 3. History or suspicion of alcohol, barbiturate, amphetamine, recreational or narcotic drug use which in the

investigator’s opinion would compromise subject’s safety and/or compliance with study procedures. 4. Hepatitis A infection (confirmed by hepatitis A antibody IgM), or hepatitis B infection (confirmed by

hepatitis B surface antigen), or hepatitis C infection (confirmed by hepatitis C virus antibody) at study screening.

5. A positive urine drug test at study screening. Urine was tested for the presence of amphetamines, benzodiazepines, cocaine, cannabinoids and opioids.

6. Currently active gastrointestinal, cardiovascular, nervous system, psychiatric, metabolic, renal, hepatic, respiratory, inflammatory or infectious disease.

7. History of renal insufficiency (creatinine clearance of < 60 mL/min) or an estimated creatinine clearance of < 60 mL/min.


TMC278-C104 2


8. Any current or previous adrenal illness. 9. Currently significant diarrhea, gastric stasis or constipation that in the investigator’s opinion could influence

drug absorption or bioavailability. 10. Any history of significant skin disease such as but not limited to drug rash or eruptions, drug allergies, food

allergy, dermatitis, eczema, psoriasis or urticaria. 11. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the

investigational medication administered in this trial or to tenofovir disoproxil fumarate or to any of the excipients of Viread®.

12. Use of concomitant medication, including over-the-counter products and dietary supplements, except for ibuprofen up to 3 days before the first dose of trial medication. All other medication had to be discontinued at least 14 days before the first dose of study medication.

13. Participation in an investigational drug trial within 60 days prior to the first intake of study medication. 14. Donation of blood or plasma within the 60 days preceding the first intake of study medication. 15. Subjects with the following laboratory abnormalities as defined by the enhanced toxicity grading severity

list: serum creatinine grade 1 or greater (>1.0 x upper limit of normal (ULN)); pancreatic amylase or lipase grade 1 or greater (>1.0 x ULN); hemoglobin toxicity grade 1 or greater (<9.4 g/dL); platelet count grade 1 or greater (<99.000/mm3); absolute neutrophil count grade 1 or greater (<1500/mm3); aspartate aminotransferase (AST) or alanine aminotransferase (ALT) grade 1 or greater (>1.25 x ULN); total bilirubin grade 1 or greater (>1.0 x ULN); any other toxicity grade 2 or above, including: proteinuria (spot urine) >1+ and gross hematuria.

16. Having previously participated in a trial with TMC125, TMC120 or TMC278. Treatment TMC278 Tenofovir DF

Dosage Dosage Form (TF No.) Usage

25 mg or 100 mg Tablet (F001 or F002)

Oral

300 mg Tablet Oral

Batch Number Expiration date

25 mg tablet: PD1216 10/2004

100 mg tablet: PD1211 10/2004

SBK181D

11/2005 Session I Group 1 and Group 2 (n = 16): 150 mg TMC278 (1 tablet F002 and 2

tablets F001) q.d. from Day 1 to Day 8 Dose Regimen

Session II Group 1 (n = 8): 300 mg tenofovir DF (1 tablet) q.d. from Day 1 to Day 16, 150 mg TMC278 (1 tablet F002 and 2 tablets F001) q.d. from Day 9 to Day 16 Group 2 (n = 8): 300 mg tenofovir DF (1 tablet) q.d. from Day 1 to Day 16, 150 mg TMC278 (1 tablet F002 and 2 tablets F001) q.d. from Day 1 to Day 8

Session I 8 days Duration of Treatment Session II 16 days

Duration of Trial 6 weeks (exclusive screening and follow-up period) Disallowed Medication - All medication other than the study medication (except ibuprofen)

- The use of ibuprofen was allowed up to 3 days before administration of the study medication. From 3 days before drug intake until end of each session, the clinical investigator could permit the use of ibuprofen at a maximum daily dose of 1 x 400 mg.

- Concomitant medication was allowed for rash/allergic reaction (cetirizine, topical corticosteroids, antipruritic agents); nausea (antiemetics); diarrhea (loperamide).


TMC278-C104 3


Assessments Pharmacokinetics Blood samples were taken:

- Days 1, 3, 5, 7 and Day 8 (predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16 hours after dosing) and Day 9 of Session I

- Days 1, 3, 5, 7, 9, 11, 13, 15, 17, and Days 8 and 16 (predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 hours after dosing) of Session II

- At time of dropout (other than withdrawal of consent) Urine samples were taken: - Days 8 and 16 of Session II (24-hour collection).

Safety Adverse Events (AEs) Adverse events were checked at every visit and reported from signing the ICF

onwards until the last trial-related activity. Clinical Laboratory (biochemistry and hematology)

- At screening. - Days 1, 3, 5 and Day 8 (predose and 4 hours after dosing) and Day 9 of Session I. - Days 3 and 6 of washout period. - Days 1, 3, 5, 9, 11, 13 and Days 8 and 16 (predose and 4 hours after dosing), Days 17, 19 (only Group 1) and 22 (only Group 1) of Session II.

- 7 days and 30, 31 or 32 days after last drug intake at follow-up period. - In case of dropout (other than withdrawal of consent): at time of dropout, 7 days after dropout and 30, 31 or 32 days after last drug intake.

Urinalysis - At screening - Days 1 and 8 , Day 9 of Session I. - Day 6 of the washout period. - Days 1, 8 and 16 and Day 22 (only Group 1) of Session II - 7 days and 30, 31 or 32 days after last drug intake at follow-up period. - In case of dropout (other than withdrawal of consent): at time of dropout, 7 days after dropout and 30, 31 or 32 days after last drug intake.

Adrenal Function Testing - At screening. - Day 17 of Session II (Group 1). - Day 9 of Session II (Group 2). - In case of dropout (other than withdrawal of consent): 7 days after dropout.

Cardiovascular Safety - At screening. - Day 1, Day 8 (predose and 2, 4 hours after dosing) and Day 9 of Session I. - Day 1, Day 8 (predose and 2, 4 hours after dosing), Day 9 (only for Group 1), Day 16 (predose and 2, 4 hours after dosing) and Day 17 (only for Group 1) of Session II.

- 7 days and 30, 31 or 32 days after last drug intake at follow-up period - In case of dropout (other than withdrawal of consent): at time of dropout, 7 days after dropout and 30, 31 or 32 days after last drug intake.

Physical examination (inclusive skin examination)

- At screening - Days –1 and 8 of Session I. - Days 3 and 6 of washout period (only skin examination) - Days –1, 9, 16, 19 (only skin examination) and 22 (only skin examination) of Session II, group 1 - Days –1, 8, 11 (only skin examination), 13 (only skin examination) and 16 of Session II; group 2 - 7 days and 30, 31 or 32 days after last drug intake at follow-up period - In case of dropout (other than withdrawal of consent): at time of dropout, 7 days after dropout, 10 days after first intake of TMC278 (only skin examination) and 30, 31 or 32 days after last drug intake.

Alcohol breath test Day –1 of both sessions. Statistical Methods Descriptive statistics, frequency tabulations, Wilcoxon matched-pairs signed-ranks

test, linear mixed effect model, Least Square means ratio and 90% Confidence Intervals.


TMC278-C104 4


Main Features of the Subject Sample and Summary of the Results Baseline Characteristics - Subject Disposition Group 1 Group 2 All subjects Number of Subjects Entered (M/F) Age: median (range), yrs

8/0 34.0 (21-47)

8/0 41.0 (20-51)

16/0 38.5 (20-51)

Dropouts - Reason AE

1

0

1

Pharmacokinetics TMC278 Least squares means

Treatment ratio

Parameter Test, (T)

TMC278 + TDF Reference, (R)

TMC278 T/R 90% CIn 15 16 - - C0h (ng/mL) 447 462 0.97 0.84 - 1.12 Cmin (ng/mL) 373 379 0.99 0.83 - 1.16 Cmax (ng/mL) 902 940 0.96 0.81 - 1.13 AUC24h (ng.h/mL) 14031 13832 1.01 0.87 - 1.18

TENOFOVIR, (TDF)

Least squares means

Treatment ratio

Parameter Test, (T)

TMC278 + TDF Reference, (R)

TDF T/R 90% CIn 15 16 - - C0h (ng/mL) 68 55 1.24 1.09 - 1.40 Cmin (ng/mL) 65 53 1.24 1.10 - 1.38 Cmax (ng/mL) 352 295 1.19 1.06 - 1.34 AUC24h (ng.h/mL) 3563 2885 1.23 1.16 - 1.31 Durine,total (%) 40.4 36.2 1.12 1.00 - 1.24

Pharmacokinetics of TMC278 Test Reference(mean SD, tmax: median [range]) TMC278 + TDF TMC278

n 15 16 C0h (ng/mL) 467 ± 164 500 ± 179 Cmax (ng/mL) 921 ± 230 1005 ± 315 Cmin (ng/mL) 391 ± 139 409 ± 141 AUC24h (ng.h/mL) 14404 ± 3925 14805 ± 4609 tmax (h) 4.0 [3.0-24.0] 4.0 [2.0-6.0]


TMC278-C104 5


Pharmacokinetics of Tenofovir Test Reference(mean SD, tmax: median [range]) TMC278 + TDF TDF

n 15 16 C0h (ng/mL) 70 ± 22 59 ± 20 Cmax (ng/mL) 353 ± 64 305 ± 80 Cmin (ng/mL) 67 ± 19 56 ± 20 AUC24h (ng.h/mL) 3593 ± 800 2991 ± 877 tmax (h) 2.5 [1.0-4.0] 2.0 [0.5-4.0] Durine,total (%) 40.8 ± 9.8 36.2 ± 7.8


TMC278-C104 6



TMC278

(n=16)

Tenofovir DF

(n=16)

TMC278/tenofovir DF

(n=16) Adverse Events (AEs)

Most frequently reported AEs (reported in 2 subjects in any treatment with TMC278), n (%)

Headache 9 (56.3) 4 (25.0) 6 (37.5) Nausea 3 (18.8) 2 (12.5) 3 (18.8) Abdominal pain 2 (12.5) 1 (6.3) 1 (6.3) Dizziness 1 (6.3) 0 2 (12.5) Loose stools 2 (12.5) 0 0

n (%) with 1 or more AEs 12 (75.0) 5 (31.3) 13 (81.3) n (%) of deaths 0 0 0 n (%) with 1 or more other serious AEs 0 0 0 n (%) of treatment stopped due to AEs 0 0 1 (6.3) n (%) with 1 or more grade 3 or 4 AEs 0 0 1 (6.3)

Clinical Laboratory Tests There were no consistent or clinically relevant changes over time in median laboratory parameters. The only treatment-emergent grade 4 laboratory result during treatments including TMC278 was a grade 4 lipase during treatment with TMC278. This grade 4 lab result was not reported as AE. Grade 3 treatment-emergent laboratory results during treatments including TMC278 were all observed in 1 subject and include a grade 3 lipase and a grade 3 ALT during treatment with TMC278/tenofovir DF. For this subject, increased lipase and amylase were reported as AE during combined treatment and increased ALT and AST during combined treatment and follow-up. This subject discontinued treatment after 15 days of tenofovir DF intake and 7 days after combined treatment start, due to increased ALT. All these AEs were considered not to be related to study medication. No other laboratory abnormalities were reported as AE. The results of adrenal function tests will be discussed in an amendment to the CRR.

Urinalysis Occasional abnormal results in urinalysis were observed. No abnormalities in urinalysis were reported as AE.

Adrenal Function Testing No consistent or clinically relevant changes from reference (screening visit) were noted during the trial. All but 1 subject (6.7%) achieved a cortisol value 550 nmol/L during the ACTH stimulation test on Day 9 of Session II (i.e., 24 hours after last TMC278 intake). The pre-stimulation cortisol values were within the laboratory normal range for all subjects. No AEs related to adrenal function were reported. These results suggest that there is no observed adverse effect of TMC278 on adrenal function in this trial.

Cardiovascular Safety No clinically relevant median changes in vital signs or electrocardiogram (ECG) parameters were noted during the trial. No abnormalities in vital signs or ECG parameters were reported as AE.

Physical and Skin Examination One new finding compared to screening was found for one subject (arthropod bite), but not reported as an AE.


TMC278-C104 7


Conclusions The results of this study in healthy subjects at steady-state conditions show that the exposure to TMC278 is unaffected when coadministered with tenofovir DF and that the exposure to tenofovir measured as AUC24h is increased by 23% when coadministered with TMC278. This increase is not considered to be clinically relevant, and therefore no dosage adjustments are needed when TMC278 and tenofovir DF are combined. The results of the present trial demonstrate that TMC278 treatment, alone or in combination with tenofovir, appeared generally safe and was well tolerated in healthy subjects.


TMC278-C105 1

Clinical Research Report Version: 1.0 Date: 13-Apr-2006




Title: A Phase I, open label, randomized, 2-way crossover trial in 16 healthy subjects to investigate the potential pharmacokinetic interaction between TMC278 and lopinavir/ritonavir at steady-state.


Country: France



Objectives: The objectives of this Phase I trial were: to determine the potential effect at steady-state of lopinavir/ritonavir on the steady-state pharmacokinetics of TMC278 and the potential effect at steady-state of TMC278 on the steady-state pharmacokinetics of lopinavir/ritonavir; to determine the short-term safety and tolerability of coadministration of TMC278 and lopinavir/ritonavir.

Design: This was a Phase I, open label, randomized, 2-way crossover trial to investigate the potential pharmacokinetic interaction between TMC278 and lopinavir/ritonavir at steady-state. In 2 sessions, 16 healthy subjects were randomized to receive TMC278 alone (Treatment A) and lopinavir/ritonavir alone followed by the combination of TMC278 and lopinavir/ritonavir (Treatment B). There was a washout period of at least 14 days between sessions. Randomization was performed in such a way that in each session 8 out of 16 subjects received the same treatment and that each subject received a different treatment in each session. Treatment A consisted of TMC278 150 mg once daily (q.d.) for 10 days. Treatment B consisted of lopinavir/ritonavir 400/100 mg twice daily (b.i.d.) for 20 days with coadministration of TMC278 150 mg q.d. from Days 11 to 20. Full pharmacokinetic profiles of TMC278 up to 24 hours postdose were determined on Day 10 of Treatment A and Day 20 of Treatment B. Full pharmacokinetic profiles of lopinavir and ritonavir up to 12 hours postdose were determined on Days 10 and 20 of Treatment B. Tolerability and safety were assessed on an ongoing basis. Subject Selection Inclusion Criteria

1. Aged between 18 and 55 years, extremes included. 2. Smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day (or nonsmoking) for at least 3 months prior to selection. 3. Normal weight as defined by a Quetelet Index (Body Mass Index: weight in kg divided by length in square meters) of 18.0 to 30.0 kg/m2, extremes included. 4. Informed Consent Form signed voluntarily before the first trial-related activity. 5. Cortisol of at least 550 nmol/L (19.9 g/dL) at any time at screening (i.e., morning cortisol, 30 or 60 minutes after 250 g adrenocorticotropic hormone [ACTH] stimulation). 6. Able to comply with protocol requirements. 7. Healthy on the basis of a physical examination, medical history, electrocardiogram (ECG), vital signs, and the results of blood biochemistry and hematology tests and a urinalysis carried out at screening.

Exclusion Criteria

1. A positive human immunodeficiency virus (HIV)-1 or HIV-2 test at screening. 2. Female, except if postmenopausal for more than 2 years, or posthysterectomy, or post-tubal ligation (without reversal operation). 3. History or suspicion of alcohol, barbiturate, amphetamine, recreational, or narcotic drug use, which in the investigator’s opinion would compromise the subject’s safety and/or compliance with the trial procedures. 4. Hepatitis A, B, or C infection (confirmed by Hepatitis A antibody IgM, Hepatitis B surface antigen, or Hepatitis C virus antibody, respectively) at screening. 5. A positive urine drug test at screening. Urine was tested for the presence of amphetamines, benzodiazepines, cocaine, cannabinoids, and opioids.

Synopsis

TMC278-C105 2


Exclusion Criteria, continued 6. Currently active or underlying gastrointestinal, cardiovascular, nervous system, psychiatric, metabolic, renal, hepatic, respiratory, inflammatory, or infectious disease. 7. Any previous or current adrenal illness. 8. History of pancreatitis. 9. Currently significant diarrhea, gastric stasis, or constipation that in the investigator’s opinion could influence drug absorption or bioavailability. 10. Any history of significant skin disease such as, but not limited to, rash or eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis, or urticaria. 11. Previous experience of clinically significant hypersensitivity to lopinavir or ritonavir. 12. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication administered during the trial. 13. Use of concomitant medication, including over the counter products and dietary supplements, except for ibuprofen up to 3 days before the first dose of trial medication. All other medication must have been discontinued at least 14 days before the first dose of trial medication. 14. Participation in an investigational drug trial within 30 days prior to the first intake of trial medication. 15. Donation of blood or plasma in the 60 days preceding the first intake of trial medication. 16. Having received TMC125, TMC120, or TMC278 (formerly known as R278474) in a previous trial. 17. Subjects with the following laboratory abnormalities at screening as defined by the enhanced toxicity grading severity list: serum creatinine grade 1 or greater (> 1.0 x upper limit of normal [ULN]); pancreatic lipase grade 1 or greater (> 1.0 x ULN); hemoglobin toxicity grade 1 or greater (< 9.4 g/dL); platelet count grade 1 or greater (< 99000/mm3); absolute neutrophil count grade 1 or greater (< 1500/mm3); aspartate aminotransferase or alanine aminotransferase grade 1 or greater (> 1.25 x ULN); total bilirubin grade 1 or greater (> 1.0 x ULN); any other toxicity grade 2 or above, including: proteinuria (spot urine) > 1+ and gross hematuria.

Treatment Treatment A Treatment BDosage TMC278 150 mg q.d. Lopinavir/ritonavir 400/100 mg b.i.d. and

TMC278 150 mg q.d. Dosage Form (F No.)

25 mg tablets (F001) and 100 mg tablets (F002)

Lopinavir/ritonavir capsules (Kaletra ) containing 133.3 mg of lopinavir and

33.3 mg of ritonavir and TMC278 tablets (F001 and F002)

Usage 2 x 25 mg and 1 x 100 mg tablets for oral usage on Days 1 - 10

3 capsules on Days 1 – 20 + 1 x 100 mg and 2 x 25 mg tablets oral usage on Days 11 – 20

Batch Numbers 25 mg TMC278 tablet: PD1216 100 mg TMC278 tablet: PD1211

Kaletra capsule: 23293VA 25 mg TMC278 tablet: PD1216

100 mg TMC278 tablet: PD1211 Dose Regimen Group 1: Treatment A during Session I, Treatment B during Session II, with a washout

period of at least 14 days between sessions. Group 2: Treatment B during Session I, Treatment A during Session II, with a washout period of at least 14 days between sessions.

Duration of Treatment

30 days (excluding washout)

Duration of Trial 48 days (excluding screening and follow-up) Disallowed Medication

During the entire trial, subjects were not allowed to use any medication other than trial medication. All medication, including herbal medications and dietary supplements, had to be discontinued at least 14 days before administration of trial medication, except for ibuprofen. Ibuprofen was allowed up to 3 days before administration of trial medication. After that, the clinical investigator could permit the use of ibuprofen (until the end of each session at no more than 1 x 400 mg per day). In case of cutaneous event/rash and/or allergic reaction, the use of cetirizine, levocetirizine, topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In the case of nausea, the use of antiemetics was permitted. In case of diarrhea, the use of loperamide was allowed.

Synopsis

TMC278-C105 3


Assessments

Scre

en-in

ga

Session I or II/Treatment A or Treatment Bb

Session I or II/Treatment B

Follo

w-u

p

21

days

Day

1

Day

4

Day

8

Day

9

Day

10

D

ay

11

Day

14

Day

18

Day

19

D

ay

20

Day

21

D

ays 7

an

d 30

, 31

, or 3

2

Drug screening X Pharmacokinetics Blood sample

Xe,f

Xg,h

Xg,h

Xg,h,i

Xh,l

Xg,j

Xg,j

Xg,i

Xj

Safety Adverse events X X X X X X X X X X X X Concomitant medsc X X X X X X X X X X X X Hemat & biochemd X Xe Xe Xe Xe Xe Xe X X Urinalysis X Xe Xe X X Morning cortisol & ACTH stim test; 17-OH- progesteronem

X X X

Apo A1, Apo B, insulin, and 1-acid glycoproteinm

X X X

T3, T4, and TSHn X X X X ECG & vital signs X Xe Xe,k Xe Xe,k X X Skin examination X Xo X X X X Physical examination

X X X X

meds = medication; Hemat & biochem = hematology & biochemistry; ACTH = adrenocorticotropic hormone; stim = stimulation; Apo = apolipoprotein; T3 = triidothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone; ECG = electrocardiogram. a At screening, subject’s demographics and characteristics, smoking habits, medical and surgical history, family history related to skin disease, concomitant diseases, concomitant medication, HIV-1 and -2 test, and Hepatitis A, B, and C test; a serum pregnancy test was also performed if applicable. b Subjects were admitted to the unit the night before Day 1 and a skin examination and physical examination were performed. c Adverse events and concomitant medications were monitored continuously from signing the informed consent form until the last trial-related activity. d Biochemistry samples were taken fasting for at least 10 hours. e Within 2 hours before drug intake and before breakfast (Treatments A and B), with the exception of the Day 11 safety sample, urine sample, and ECG and vital signs assessment for Treatment A. f For determination of TMC278, lopinavir, and ritonavir (Treatment A) and for determination of TMC278 only (Treatment B). g Within 15 minutes before drug intake. h For determination of TMC278 only (Treatment A; Days 8, 9, 10, and 11) and for determination of lopinavir and ritonavir only (Treatment B; Days 8, 9, and 10). i At 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose for determination of TMC278 only (Treatment A; Day 10), lopinavir/ritonavir only (Treatment B; Day 10), and TMC278, lopinavir, and ritonavir (Treatment B; Day 20). j For determination of TMC278, lopinavir, and ritonavir on Days 18 and 19 and TMC278 only on Day 21 (Treatment B). k ECG and vital signs also measured at 4 hours postdose. l 24-hour postdose sample on Day 11 (for determination of TMC278 [Treatment A]). m At Day 11 only for Treatment A (Sessions I or II). n At Day 1 only for Treatment A (Sessions I or II). o Treatment A only (Sessions I or II).

Synopsis

TMC278-C105 4


Statistical Methods Descriptive statistics, frequency tabulations, intent-to-treat analysis, Wilcoxon matched-pairs signed-rank test, linear mixed effects modeling, least squares means ratio and 90% confidence intervals.


Group 1 TMC278

LPV/r/TMC278 N = 8

Group 2 LPV/r/TMC278

TMC278 N = 8

Total N = 16


8/0 33.0 (21 – 47)

8/0 26.0 (19 – 48)

16/0 29.0 (19 – 48)

Drop-Outs - Reason Withdrew Consent

1 subject (12.5%)

withdrew consent during treatment with LPV/r

alone in Session II

1 subject (12.5%)

withdrew consent before starting the washout phase

after treatment with LPV/r/TMC278 in

Session I

2 (12.5%)


(mean ± SD, tmax: median [range]) Treatment A (Day 10): TMC278 150 mg q.d.a

Treatment B (Day 20): LPV/r 400/100 mg b.i.d. +

TMC278 150 mg q.d.a

n 15 15 C0h, ng/mL 507.3 ± 256.5 971.6 ± 485.4

C24h, ng/mL 649.3 ± 337.4 1281 ± 647.2 Cmin, ng/mL 478.8 ± 248.7 809.4 ± 370.0 tmax, h 5.0 (3.0 – 12.0) 4.0 (3.0 – 24.0) Cmax, ng/mL 1265 ± 420.7 1619 ± 603.0

AUC24h, ng.h/mL 19770 ± 8436 29990 ± 12900

Css,av, ng/ml 823.9 ± 351.5 1250 ± 537.3 FI, % 104.5 ± 37.94 68.02 ± 20.75 LSmean ratio (90% CI), %

Treatment B vs Treatment A Cmin 174.2 (146 – 208)b Cmax 128.6 (118 – 140)b AUC24h 152.1 (136 – 170)b

a Data from Groups 1 and 2 were combined. b p-value < 0.05

Synopsis

TMC278-C105 5


Pharmacokinetics of Lopinavir

(mean SD, tmax: median [range]) Treatment B (Day 10): LPV/r 400/100 mg b.i.da

Treatment B (Day 20): LPV/r 400/100 mg b.i.d +

TMC278 150 mg q.d.a

n 15 15 C0h, ng/mL 7482 ± 2386 7375 ± 2868

C12h, ng/mL 6285 ± 2127 6297 ± 2681

Cmin, ng/mL 5982 ± 1977 5555 ± 2490 tmax, h 4.0 (3.0 – 5.0) 4.0 (1.0 – 5.0) Cmax, ng/mL 13850 ± 2964 13300 ± 3118

AUC12h, ng.h/mL 112900 ± 22170 113700 ± 32450

Css,av, ng/mL 9411 ± 1847 9479 ± 2704 FI, % 85.00 ± 22.47 86.00 ± 26.89 LSmean ratio (90% CI), %

Day 20 vs Day 10 Cmin 88.80 (73.2 – 108) Cmax 96.01 (87.5 – 105) AUC12h 99.11 (89.1 – 110) a Data from Groups 1 and 2 were combined.

Pharmacokinetics of Ritonavir

(mean SD, tmax: median [range]) Treatment B (Day 10): LPV/r 400/100 mg b.i.da

Treatment B (Day 20): LPV/r 400/100 mg b.i.d +

TMC278 150 mg q.d.a

n 15 15

C0h, ng/mL 273.1 ± 192.9 275.5 ± 156.2

C12h, ng/mL 192.9 ± 103.4 198.7 ± 102.0

Cmin, ng/mL 168.5 ± 96.33 177.9 ± 100.5

tmax, h 4.0 (2.0 – 5.0) 4.0 (3.0 – 5.0) Cmax, ng/mL 1256 ± 648.4 1070 ± 417.7

AUC12h, ng.h/mL 6331 ± 2731 6035 ± 2444

Css,av, ng/mL 527.6 ± 227.6 502.9 ± 203.6 FI, % 206.1 ± 41.58 183.8 ± 43.97 LSmean ratio (90% CI), %

Day 20 vs Day 10 Cmin 106.6 (89.1 – 128) Cmax 88.81 (72.8 – 108) AUC12h 96.38 (84.0 – 111) a Data from Groups 1 and 2 were combined.

Synopsis

TMC278-C105 6


Trial Phase


TMC278a

N = 15 LPV/ra

N = 16

LPV/r/ TMC278a

N = 15 Follow-upa

N = 14 Totala

N = 16 Adverse Events (AEs) Most frequently reported AEs (reported in > 1 subject in the whole trial), n (%)

Pain 1 (6.7%) 1 (6.3%) 0 0 2 (12.5%) n (%) with 1 or more AEs 3 (20.0%) 6 (37.5%) 1 (6.7%) 1 (7.1%) 8 (50.0%) n (%) of deaths 0 0 0 0 0 n (%) with 1 or more other serious AEs 0 0 0 0 0 n (%) of treatment stopped due to AEs 0 0 0 0 0 n (%) with 1 or more grade 3 or 4 AEs 0 0 0 0 0 a Data from Groups 1 and 2 were combined. No AEs were reported during screening or during the washout phases.

Safety


Total

N = 16


n (%) with 1 or more grade 3 laboratory abnormalities

3 (18.8%)

There were no consistent or clinically relevant treatment-emergent changes over time in laboratory parameters. No grade 4 abnormalities were reported during the trial. Grade 3 treatment-emergent abnormalities were reported for 3 subjects during treatment with lopinavir/ritonavir/TMC278: decreased phosphorus for 2 subjects and elevated low density lipoprotein cholesterol for 1 subject. No associated AEs were reported. No effects of treatment were apparent on median values or median changes from reference (screening visit) for the adrenal function assessments of cortisol or 17-OH-progesterone. Five subjects (33.3%) did not achieve a cortisol value 550 nmol/L following ACTH stimulation at the end of treatment with TMC278 alone but had no coinciding increase in 17-OH-progesterone at T0 (17-OH progesterone was within the laboratory normal ranges 1.51-7.56 nmol/L). All subjects achieved a cortisol value

550 nmol/L at the end of the coadministration of TMC278 and lopinavir/ritonavir. No AEs related to adrenal function test results were reported.


Minor changes were reported for vital signs. None of the changes was considered to be clinically relevant. No trends or relationship to trial medication were apparent and no clinically relevant changes in ECG parameters were reported.

Physical Examination With the exception of an event of grade 1 rash maculo-papular in 1 subject, physical examination revealed no abnormal new findings for any subject during the trial.

Synopsis

TMC278-C105 7


Conclusions

The results of this trial demonstrate that coadministration of lopinavir/ritonavir increased the plasma concentrations (expressed as AUC24h) of TMC278 by an average of 52%. Cmin increased more than Cmax (74% and 29%, respectively). TMC278 did not affect the pharmacokinetics of lopinavir or ritonavir. Dosage recommendations for this combination will follow after selection of the therapeutic dose for TMC278. In these healthy subjects, the administration of TMC278 150 mg q.d. for 10 days, and lopinavir/ritonavir 400/100 mg b.i.d. for 20 days with coadministration of TMC278 150 mg q.d. from Days 11 to 20, was generally well tolerated.

Synopsis

TMC278-C106 1

Clinical Research Report Version: 1.0 Date: 27-Mar-2007



Drug Substance: TMC278Trial no.: TMC278-C106Clinical Phase: I

Title: A Phase I, open-label trial to investigate the pharmacokinetic interaction between didanosine (ddI) and TMC278 at steady-state in healthy individuals

Investigator:

USA

Country: USA



Objectives: The primary objective of this trial was to determine the effect of steady-state concentrations of TMC278 on the steady-state pharmacokinetics of ddI and to determine the effect of steady-state concentrations of ddI on the steady-state pharmacokinetics of TMC278. The secondary objective was to determine the short-term safety and tolerability of co-administration of ddI and TMC278. Design: This was a Phase I, open-label, randomized trial in healthy subjects to investigate the pharmacokinetic interaction between ddI and TMC278 at steady-state. During Session I, all subjects received 150 mg q.d. TMC278 from Day 1 to Day 7. In Session II, after a washout period of at least 2 weeks, subjects in Group 1 received 400 mg ddI q.d. for 14 days with additional 150 mg q.d. TMC278 dosing from Day 8 to Day 14. Subjects in Group 2 received 400 mg ddI q.d. for 14 days with additional 150 mg q.d. TMC278 dosing from Day 1 to Day 7. Plasma concentrations of TMC278 and ddI were determined. Safety and tolerability were assessed. A substudy was performed in which 10 additional subjects were randomized in order to repeat Session II of the study. Repeat Session II was performed in accordance with the dosing regimen outlined above in order to replace samples that were lost during shipment.Subject Selection Inclusion Criteria

1. Aged between 18 and 55 years, extremes included. 2. Weight 60 kg and a Quetelet Index (Body Mass Index: weight in kg divided by length in square meters) of 18.0 to 30.0 kg/m2, extremes included. 3. Informed Consent Form signed voluntarily before first trial-related activity. 4. Cortisol of at least 550 nmol/L (19.9 mg/dL) at any time point at screening (i.e., morning cortisol, 30 or 60 minutes after 250 μg adrenocorticotropic hormone stimulation). 5. Able to comply with protocol requirements. 6. Healthy on the basis of a pretrial physical examination, medical history, electrocardiogram, vital signs, and the results of blood biochemistry, hematology tests, and a urinalysis at screening.

0137268, Final, 02-May-2007 12:14

Synopsis

TMC278-C106 2


Exclusion Criteria1. A positive human immunodeficiency virus (HIV)-1 or HIV-2 test at study screening. 2. Female, except if postmenopausal since more than 2 years, or post-hysterectomy or post-tubal ligation (without reverse operation). 3. Smoking of cigarettes, cigars, or pipes, or having smoked or chewed tobacco within the past 6 months before selection. 4. History or suspicion of alcohol, barbiturate, amphetamine, recreational, or narcotic drug use, which, in the investigator’s opinion, could compromise subject’s safety and/or compliance with trial procedures. 5. Hepatitis A infection (confirmed by hepatitis A antibody IgM), or hepatitis B infection (confirmed by hepatitis B surface antigen), or hepatitis C infection (confirmed by hepatitis C virus antibody) at study screening. 6. A positive urine drug test at study screening. Urine was tested for the presence of amphetamines, benzodiazepines, cocaine, cannabinoids, and opioids. 7. Currently active or underlying gastrointestinal-, cardiovascular-, nervous system-, psychiatric-, metabolic-, renal-, hepatic-, respiratory-, inflammatory-, or infectious disease. 8. Any current or previous adrenal illness. 9. History of pancreatitis or peripheral neuropathy. 10. History of renal insufficiency (creatinine clearance < 60 mL/min) or an estimated creatinine clearance of < 60 mL/min. 11. Currently significant diarrhea, gastric stasis, or constipation that in the investigator’s opinion could influence drug absorption or bioavailability. 12. Any history of significant skin disease such as but not limited to drug rash or eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis, or urticaria. 13. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication administered in this trial. 14. Use of concomitant medication, including over-the-counter products and dietary supplements, except for ibuprofen for up to 3 days before the first dose of study medication. All other medication must have been discontinued at least 14 days before the first dose of study medication. 15. Participation in an investigational drug trial within 30 days prior to the first intake of study medication. 16. Donation of blood or plasma within the 60 days preceding the first intake of study medication. 17. Subjects with the following laboratory abnormalities at screening as defined by the enhanced toxicity grading severity list: serum creatinine grade 1 or greater, pancreatic amylase or lipase grade 1 or greater, hemoglobin toxicity grade 1 or greater, platelet count grade 1 or greater, absolute neutrophil count grade 1 or greater, aspartate aminotransferase or alanine aminotransferase grade 1 or greater, total bilirubin grade 2 or greater, and any other toxicity grade 2 or above, including: proteinuria (spot urine) >1+ and gross hematuria. 18. Having previously participated in a trial with TMC278 (formerly known as R278474), TMC120, or TMC125.

Treatment TMC278 ddI Dosage

Dosage Form (F No.)

Usage

150 mg q.d.

25 mg tablets (F001) 100 mg tablets (F002)

2 x 25 mg tablets per os (p.o.) and 1 x 100 mg tablet p.o.

400 mg q.d.

400 mg capsule

1 capsule p.o.

Batch Number Main study: PD1320 (F001), PD1268 (F002)

Substudy: PD1320 (F001), PD1411 (F002)

Main study: MFD12 Substudy: 5F3054A

Dose Regimen Session I, Groups 1 and 2: 150 mg TMC278 q.d. from Day 1 to Day 7 Session II, Group 1: 400 mg ddI q.d. from Day 1 to Day 14 and 150 mg TMC278 q.d. from Day 8 to Day 14 Session II, Group 2: 400 mg ddI q.d. from Day 1 to Day 14 and 150 mg TMC278 q.d. from Day 1 to Day 7 Subjects randomized to Repeat Session II (substudy) received study medication as outlined above for Session II.

Duration of Treatment Session I: 7 days. Session II: 14 days

0137268, Final, 02-May-2007 12:14

Synopsis

TMC278-C106 3


Duration of Trial 35 days (excluding screening and follow-up) plus 14 days (excluding screening and follow-up) for the Repeat Session II (substudy).

Disallowed Medication During the entire trial, subjects were not allowed to use any medication other than study medication and ibuprofen. All other medication had to be discontinued at least 14 days before first drug administration. Subjects were also not allowed to use any herbal medications or dietary supplements including products containing Hypericum perforatum (e.g., St. John’s Wort) from 14 days before the start of the trial and throughout the duration of the trial. Ibuprofen was allowed up to 3 days before drug administration in each session. After that, the investigator could permit the use of ibuprofen at no more than 1 x 400 mg per day. Hormone replacement therapy was allowed in postmenopausal women. In case of cutaneous event/rash and/or an allergic reaction, the use of cetirizine, topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In case of nausea, the use of antiemetics was permitted. In case of diarrhea, the use of loperamide was allowed.

Assessments Screeninga Sessions I (Days 1-8 only), II and Repeat Session II Follow-up

14

days

Day

-1

Day

1

Day

3 +

5

Day

6

Day

7

Day

8n

Day

10

+ 12

Day

13

Day

14

Day

15

Day 7 & 30, 31, or 32

Pharmacokinetics Blood sample Xd Xd Xd Xh Xj Xd Xd Xd,l Xj

Safety Adverse eventsb X Xf X X X X X X Xf X X Concomitant medsb X Xf X X X X X X Xf X X Hemat & biochemc X Xe Xe Xe Xe Xe Xe Xe X X Urinalysis X Xf Xf Xf Xf X X ACTH stimulation test with determination of cortisolk

X X X

Apo A1, Apo B, & insulin, T3, T4, and TSH

X Xg Xg X

ECG & vital signs X Xf Xf,i Xf Xf,i X X Skin examinationm X X X X X X X X Physical examination

X X Xo X X X

meds = medication; Hemat & biochem = hematology & biochemistry; ACTH = adrenocorticotropic hormone; Apo = apolipoprotein; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone; ECG = electrocardiogram; exam = examination. a At screening, subject’s demographics and characteristics, medical and surgical history, and concomitant diseases

were recorded, and drug screening, HIV-1 and -2 tests, and hepatitis A, B, and C tests were performed. A serum pregnancy test was also performed if applicable.

b Adverse events and concomitant medications were monitored continuously from signing the informed consent form until the last trial-related activity.

c Biochemistry samples were taken fasted for at least 10 hours (except those taken at 4 hours post drug intake). d Blood sample immediately before TMC278 or ddI intake. e Day -1 sample in Session I and Repeat Session II only. Day 1 sample in Session II only. Day 7 sample also taken at

4 hours post drug intake in Session I, and Day 7 and 14 samples taken 6 hours post ddI intake in Session II and Repeat Session II.

f Within 2 hours before TMC278 or ddI intake. g Apo A1, Apo B, and insulin only at Day -1 for Session I and Repeat Session II, and on Day 1 of Session II.

0137268, Final, 02-May-2007 12:14

Synopsis

TMC278-C106 4


h Day 7 blood sample predose and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours post TMC278 intake (Session I) and 2, 2.5, 3, 4, 5, 6, 8, 10, 14 and 18 hours post TMC278 intake (Session II and Repeat Session II, Group 2 only) for determination of TMC278 and predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, and 12 hours post ddI intake for determination of ddI (Session II and Repeat Session II).

i ECG and vital signs also measured at 2 and 4 hours postdose (Day 7, Session I) and 2 and 6 hours postdose (Days 7 and 14, Session II and Repeat Session II).

j 24-hour post TMC278 intake on Day 8 for determination of TMC278 (Session I), and both ddI and TMC278 (Session II), and on Day 15 for determination of ddI (Session II). 24-hour post TMC278 intake on Day 15 for determination of TMC278 (Session II only). 26-hours post TMC278 intake on Day 8 for determination of TMC278 (Session II, Group 2). 26-hours post TMC278 intake on Day 15 for determination of TMC278 (Session II, Group 1 and Repeat Session II only).

k Day 8 test in Session I and Session II and Repeat Session II, Group 2 only. Day 15 test only in Session II and Repeat Session II, Group 1.

l Day 14 blood sample predose and at 2, 2.5, 3, 4, 5, 6, 8, 10, 14, and 18 hours post TMC278 intake (Session II and Repeat Session II, Group 1 only) for determination of TMC278, and predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, and 12 hours post ddI intake for determination of ddI (Session II and Repeat Session II).

m Skin examination performed as part of physical examination, plus at Day 14 for Session II and Repeat Session II, and Days 7, 10, and 12 for Session II and Repeat Session II, Group 2 only.

n Day 8 of Session I was Day 1 of the washout period. Blood safety sample, AE and concomitant medications check and skin examination performed on Days 3 and 6 of washout and urine sample on Day 6.

o Day 7 physical exam only in Session I. Statistical Methods Descriptive statistics, frequency tabulations, intent-to-treat analysis, linear

mixed effects modeling, Mann-Whitney-U test.

0137268, Final, 02-May-2007 12:14

Synopsis

TMC278-C106 5


Main Features of the Subject Sample and Summary of the Results Original and Substudy Combined

Baseline Characteristics - Subject Disposition Group 1 N = 13

Group 2 N = 13


10/3 28.0 (18-54)

11/2 24.0 (19-52)

Discontinuations - Reason Withdrew consent Adverse event (AE) Lost to follow-up

201a

1

431b

0a Subject 1060097 discontinued due to an AE of grade 1 blood triglycerides increased. b Subject 1060059 discontinued due to AEs of grade 4 blood lipase increased and grade 3 pancreatic amylase increased.


TMC278 + ddI

(Test)

TMC278 Alone

(Reference)

LSmean ratio (90% CI),%

(Test/Reference) n 21 14 21 vs 14 tmax, h 4.0 [3.0-4.0] 4.0 [2.0-6.0]a - C0h, ng/mL 644 ± 218 542 ± 138 108 (99 –118) Cmin, ng/ml 527 ± 163 491 ± 107 100 (92 – 109) Cmax, ng/mL 1379 ± 463 1366 ± 384a 100 (91 – 110) AUC24h, ng.h/mL 18429 ± 5085 18286 ± 4130 100 (95 – 106) Css, av, ng/mL 768 ± 212 762 ± 172 - FI, % 110.5 ± 30.3 115.3 ± 18.8 -

a For Cmax and Tmax n =15

Pharmacokinetics of ddI (mean SD, tmax: median [range])

TMC278 + ddI

(Test)

ddI Alone

(Reference)

LSmean ratio (90% CI),%

(Test/Reference) n 13 13 13 vs 13 tmax, h 2.0 [1.0-3.0] 2.0 [1.0-3.0] - C0h, ng/mL NQ NQ - Cmin, ng/mL NQ NQ - Cmax, ng/mL 1270 ± 426 1398 ± 538 96 (80 – 114) AUC24h, ng.h/mL 4140 ± 1181 3648 ± 944 112 (99 – 127 ) Css, av, ng/mL 173 ± 49 152 ± 39 - FI, % 747 ± 215 924 ± 313 -

NQ: Not Quantifiable

0137268, Final, 02-May-2007 12:14

Synopsis

TMC278-C106 6



TMC278 N = 16

ddIN = 22

ddI + TMC278

N = 21 Follow-up

N = 22 Total

N = 26 AEsMost frequently reported AEs (reported in >1 subject in any group), n (%)

Headache 4 (25.0%) 1 (4.5%) 1 (4.8%) 0 6 (23.1%) Nausea 2 (12.5%) 0 2 (9.5%) 0 4 (15.4%) Abdominal pain 2 (12.5%) 0 0 0 2 (7.7%) Pollakiuria 2 (12.5%) 0 0 0 2 (7.7%) n (%) with 1 or more AEs 6 (37.5%) 3 (13.6%) 6 (28.6%) 2 (9.1%) 13 (50.0%) n (%) of deaths 0 0 0 0 0 n (%) with 1 or more other serious AEs 0 0 0 0 0 n (%) of treatment stopped due to AEs 1 (6.3%) 1 (4.5%) 0 0 2 (7.7%) n (%) with 1 or more grade 3 or 4 AEs 1 (6.3%) 0 0 0 1 (3.8%)

Overall, 13 subjects (50.0%) experienced at least 1 AE during the trial (original study and substudy combined). The most frequently reported AE was headache, affecting 6 subjects (23.1%) in total. One grade 3 and 1 grade 4 AE was experienced during the trial. Both events were experienced by the same subject during treatment with TMC278 alone; a grade 3 event of pancreatic amylase increased and a grade 4 event of blood lipase increased. Both events led to the subject permanently stopping study medication. Study medication was also permanently stopped for 1 other subject due to grade 1 blood triglycerides increased during treatment with ddI alone. No subjects experienced a SAE and no subjects died. A total of 9 subjects (34.6%) experienced AEs that were considered to be possibly or probably related to TMC278 and 7 subjects (26.9%) experienced AEs that were considered to be possibly or probably related to ddI. No AEs were experienced that were considered to be very likely related to study medication. There were no skin events of interest. Clinical Laboratory Tests

TMC278 N = 16

ddIN = 22

ddI + TMC278

N = 21 Follow-up

N = 22 Total

N = 26 n (%) with 1 or more grade 1 treatment-emergent laboratory abnormalities

7 (43.8%) 8 (36.4%) 7 (33.3%) 7 (31.8%) 17 (65.4%)

n (%) with 1 or more grade 2 treatment-emergent laboratory abnormalities

4 (25.0%) 3 (13.6%) 2 (9.5%) 2 (9.1%) 10 (38.5%)


1 (6.3%) 1 (4.5%) 0 1 (4.5%) 3 (11.5%)


1 (6.3%) 0 0 0 1 (3.8%)

n (%) with 1 or more grade 3 or 4 treatment-emergent laboratory abnormalities

1 (6.3%) 1 (4.5%) 0 1 (4.5%) 3 (11.5%)

No notable patterns in laboratory data were apparent. Three subjects experienced grade 3 treatment-emergent abnormalities (increased pancreatic amylase during treatment with TMC278 alone, increased cholesterol during treatment with ddI alone, and increased low density lipoprotein cholesterol during follow-up [last study medication received by the subject was ddI]). The grade 3 increased pancreatic amylase was recorded as an AE that led to the subject withdrawing from the study and the subject also experienced a grade 4 treatment-emergent abnormality (increased lipase during treatment with TMC278 alone). The subject who experienced grade 3 increased cholesterol withdrew from the study due to an AE of grade 1 blood triglycerides increased. There was no notable difference in abnormalities between different treatments. No subjects experienced clinically significant abnormalities in urinalysis parameters. Adrenal Function Testing At all assessments time points for which data were available, the median cortisol level increased at T30 and T60 relative to T0 after ACTH stimulation. There was a median decrease in T0 cortisol during treatment compared to Screening (-125.40 nmol/L during TMC278 treatment and –141.54 nmol/L during ddI + TMC278 treatment). All subjects in both the original study and substudy had a T0 cortisol level 55 nmol/L. After stimulation, all subjects achieved a cortisol level of 550 nmol/L.

0137268, Final, 02-May-2007 12:14

Synopsis

TMC278-C106 7


Cardiovascular Safety Minor changes in vital signs and ECG measurements were observed. None of the changes was considered clinically relevant. Physical Examination Physical examination identified one abnormality of the skin and mucous membranes: apthous ulcer on the buccal mucosa.

Conclusions

For TMC278, the primary pharmacokinetic parameters (i.e. C0h, Cmin, Cmax, and AUC24h) were not influenced by coadministration of ddI. The 90% CI for the treatment ratios of all pharmacokinetic parameters were within the no-effect boundaries (80-125%). No clinically relevant changes in the exposure to ddI (expressed as AUC24h) or the Cmax were observed when ddI was coadministered with TMC278. The LSmeans ratio for Cmax was 96% (90% CI: 80 – 114%) and for the AUC24h it was 112% (90% CI: 99-127%). For Cmax, the 90% CI of the LSmeans ratio was contained within the pre-defined no-effect boundaries of 80-125%. For the AUC24h the upper limit of the 90% CI was 127%.The results of this study demonstrated that TMC278 and ddI can be coadministered without dosage modifications, and that the combination is generally safe and well tolerated.

0137268, Final, 02-May-2007 12:14

Synopsis

R278474-C108 1

Clinical Research Report Version: 1.0 Date: 3-Oct-2005


Company: Tibotec Pharmaceuticals Ltd. Trade Name:Not applicable Indication: HIV-1 infection

Drug Substance: TMC278 Trial no.: R278474-C108 Clinical Phase: I

Title: A Phase I, open-label, randomized, three-way crossover trial in 16 healthy subjects to establish the two-way pharmacokinetic interaction between TMC278 and rifampin at steady-state.

Investigator:

Country: Belgium



Objectives: The primary objective of this study was to investigate the effect of steady-state rifampin on the steady-state pharmacokinetics of TMC278, and to investigate the effect of steady-state TMC278 on the steady-state pharmacokinetics of rifampin and its active metabolite 25-desacetylrifampin in healthy volunteers. Secondary objectives were to determine the tolerability and safety of TMC278 alone and in combination with rifampin when administered for 7 days in healthy volunteers. Design: This was a randomized, open-label, three-way crossover trial to study the pharmacokinetic interaction between TMC278 and rifampin at steady-state in 16 healthy subjects. The trial was divided into 3 sessions in which TMC278 only (Treatment A), rifampin only (Treatment B), and a combination of TMC278 and rifampin (Treatment C) were administered. Each subject received these 3 treatments in a randomized sequence in such a way that each subject received a different treatment in each session. Treatment A consisted of 150 mg q.d. TMC278 for 7 days. Treatment B consisted of 600 mg rifampin q.d. for 7 days. Treatment C was the combination of TMC278 150 mg q.d. and rifampin 600 mg q.d. for 7 days. Between Sessions I, II and III there was a washout period of at least 14 days. A full pharmacokinetic profile of rifampin and its active metabolite 25-desacetylrifampin was determined on Day 7 of Treatments B and C. A full pharmacokinetic profile of TMC278 was determined on Day 7 of Treatments A and C. Tolerability and safety were also assessed throughout the trial. Subject Selection Inclusion Criteria

1. Male or female of non-childbearing potential, aged between 18 and 55 years, extremes included. 2. Smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day (or non-smoking) for at least 3 months

prior to selection. 3. Normal weight as defined by a Quetelet Index (Body Mass Index: weight in kg divided by the square of

height meters) of 18.0 to 30.0 kg/m2, extremes included1. 4. Informed Consent Form (ICF) signed voluntarily before first trial-related activity. 5. Cortisol of at least 550 nmol/L (19.9 μg/dL) at screening (i.e., at any time point of morning cortisol, 30 or

60 minutes after 250 g ACTH stimulation). 6. Able to comply with protocol requirements. 7. Healthy on the basis of a pretrial physical examination, medical history, electrocardiogram (ECG), vital

signs and the results of blood biochemistry, hematology tests and a urinalysis carried out within 21 days before the first intake of trial medication. If the results of the biochemistry or hematology tests and urinalysis testing were not within the laboratory’s reference ranges (including exclusion criterion 16) and/or ECG readings were not within normal limits, but these findings were not considered clinically significant by the investigator, inclusion of the subject was only considered following documented discussion between the investigator and the sponsor. Final written approval had to be given by the sponsor. This had to be clearly recorded in the Case Report Form (CRF).

Exclusion Criteria1. A positive HIV-1 or HIV-2 test at study screening. 2. Female, except if postmenopausal for more than 2 years, or post-hysterectomy or post-tubal ligation

(without reversal operation).

Exclusion Criteria, cont’d

Synopsis

R278474-C108 2


3. History or suspicion of alcohol, barbiturate, amphetamine or narcotic drug use that in the investigator’s opinion could compromise subject’s safety and/or compliance with study procedures.

4. Hepatitis A infection (confirmed by hepatitis A antibody IgM), or hepatitis B infection (confirmed by hepatitis B surface antigen), or hepatitis C infection (confirmed by hepatitis C virus antibody) at study screening.

5. A positive urine drug test at study screening. Urine was tested for the presence of amphetamines, benzodiazepines, cocaine, cannabinoids and opioids.

6. Currently active or underlying gastrointestinal, cardiovascular, nervous system, psychiatric, metabolic, renal, hepatic, respiratory, inflammatory or infectious disease.

7. Any current or previous adrenal illness. 8. Currently significant diarrhea, gastric stasis or constipation that in the investigator’s opinion could

influence drug absorption or bioavailability. 9. Any history of significant skin disease such as, but not limited to, drug rash or eruptions, drug allergies,

food allergy, dermatitis, eczema, psoriasis or urticaria. 10. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the

investigational medication administered in this trial. 11. History of uveitis. 12. Use of concomitant medication, including over-the-counter products and dietary supplements, except for

ibuprofen up to 3 days before the first dose of trial medication. All other medication had to have been discontinued at least 14 days before the first dose of trial medication.

13. Participation in an investigational drug trial within 30 days prior to the first intake of trial medication. 14. Donation of blood or plasma within the 60 days preceding the first intake of trial medication. 15. Having previously participated in a trial with TMC278, TMC120 or TMC125. 16. Subjects with the following laboratory abnormalities at screening as defined by the enhanced toxicity

grading severity list: Serum creatinine grade 1 or greater; Pancreatic amylase or lipase grade 1 or greater; Hemoglobin toxicity grade 1 or greater; Platelet count grade 1 or greater; Absolute neutrophil count grade 1 or greater; Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) grade 1 or greater; Total bilirubin grade 1 or greater; Any other toxicity grade 2 or above, including: proteinuria (spot urine) >1+ and gross hematuria.

Treatment TMC278 RifampinConcentration Dosage Form (F No.) Usage

25 mg/mL solution (F002)

6 mL, oral

300 mg capsule

2 capsules, oral Batch Number 04D01/04C29 03K24 Dose Regimen Treatment A: 150 mg TMC278 q.d. for 7 days.

Treatment B: 600 mg rifampin q.d. for 7 days. Treatment C: 150 mg TMC278 q.d. and 600 mg rifampin q.d. for 7 days. There was a washout period of at least 14 days between subsequent treatments.

Duration of Treatment 3 sessions of 7 days Duration of Trial At least 47 days including 2 washouts of at least 14 days

(exclusive screening of 21 days and follow-up of 32 days)

Synopsis

R278474-C108 3


Disallowed Medication During the entire trial, subjects were not allowed to use any medication other

than the trial medication. All medication had to be discontinued at least 14 days before the first drug administration, except for ibuprofen. Subjects were also not allowed to use any herbal medications or dietary supplements including products containing Hypericum perforatum (e.g., St. John’s wort) from at least 14 days before the start of the trial and throughout the duration of the trial. Ibuprofen could be used up to 3 days before administration of trial medication. After that, the clinical investigator could permit the use of ibuprofen (from 3 days before drug intake until the 5th day [96 hours] after drug intake at no more than 1 x 400 mg per day).

Assessments

SCR1 Session I,II and III Washout2 FU3 Drop-out4

Day 1 3 5 7 8 3 7 Pharmacokinetics X7 X7 X7 X9 X X12 Safety

Adverse Events5 X8 X8 X8 X8 X X X X X12 Blood Sample6 X X8 X8 X8 X10 X11 X X X X12 Urine Sample X X8 X8 X X X12 ECG & Vital Signs X X8 X10 X X12 Physical examination X X X X X12 Skin examination X X Morning cortisol & ACTH stimulation testing

X X X13

SCR: screening, FU: follow-up 1 Informed consent, subject characteristics & demographics, smoking habits, inclusion/exclusion criteria,

medical and surgical history & concomitant diseases, HIV & hepatitis A, B and C test, urine drug screening, concomitant medication and serum pregnancy test if applicable.

2 Washout period of at least 14 days, after each session. 3 Follow-up visit was scheduled 30, 31 or 32 days after last drug intake. 4 Visits after dropout for other reasons than withdrawal of consent were scheduled at time of dropout (or the

following morning), 7 days after dropout and 30, 31 or 32 days after last drug intake. 5 Adverse events were monitored continuously between signing of the informed consent and the last trial visit. 6 All biochemistry samples were taken fasted for at least 10 hours, except for the safety sample 4h postdose at

Day 7 in Session I, II and III and the safety sample at time of dropout. 7 Immediately before intake of study medication. 8 Within 2 hours before drug intake and before breakfast if applicable. 9 Predose (immediately before intake of study medication), 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours after intake of

study medication. 10 Within 2 hours before drug intake and before breakfast if applicable and 4 hours after intake of study

medication. 11 Before breakfast. 12 At time of dropout or the following morning. 13 Morning cortisol is only performed 7 days after dropout. Statistical Methods Descriptive statistics, frequency tabulations, Intent-to-Treat analysis, Wilcoxon

matched-pairs signed-ranks test, linear mixed effect model, least square means ratio and 90% confidence intervals.

Synopsis

R278474-C108 4


Main Features of the Subject Sample and Summary of the Results Baseline Characteristics - Subject Disposition All subjects

Number of Subjects Entered (M/F) Age: median, yrs

16 (10/6) 42.0

Dropouts - Reason AE

1

Pharmacokinetics

TMC278 (mean SD, tmax: median (range))

TMC278 + rifampin Test (C)

TMC278 alone Reference (A)

LS mean ratio Test/Reference,%

(90% CI) N 16 15 16 tmax, h 4.0 [1.0-6.0] 4.0 [3.0-6.0] - C0h, ng/mL 56.7 ± 21.7 544.7 ± 207.6 - Cmin, ng/mL 53.0 ± 17.4 478.4 ± 161.4 10 (9-12) Cmax, ng/mL 356 ± 96 1123 ± 261 31 (27-36) AUC24h, ng.h/mL 3218 ± 865 16051 ± 4764 20 (18-23)

rifampin (mean SD, tmax: median (range))


rifampin alone Reference (B)


(90% CI) N 16 15 16 tmax, h 3.0 [2.0-6.0] 3.0 [2.0-4.0] - Cmax, μg/mL 9.31 ± 3.31 9.58 ± 3.98 102 (93-112) AUC24h, μg.h/mL 44.20 ± 18.37 47.14 ± 23.74 99 (92-107)

25-desacetylrifampin (mean SD, tmax: median (range))


rifampin alone Reference (B)


(90% CI) N 16 15 16 tmax, h 3.5 [2.0-6.0] 3.0 [3.0-6.0] - Cmax, μg/mL 0.808 ± 0.402 0.913 ± 0.581 100 (87-115) AUC24h, μg.h/mL 4.294 ± 2.423 5.006 ± 3.621 91 (77-107)

Synopsis

R278474-C108 5


Safety (N = number of subjects with data)

TMC278

(N=15)

Rifampin

(N=16)

TMC278 + rifampin (N=16)

Adverse Events (AEs) Most frequently reported AEs (reported in 2 subject during any treatment including TMC278), n (%)

Lipase increased 1 (7) 3 (19) 3 (19) Liver function test abnormal 0 0 2 (13) Hypercholesterolemia 2 (13) 1 (6) 2 (13) Headache 5 (33) 0 2 (13) Chromaturia 0 16 (100) 16 (100) Pruritus 1 (7) 0 3 (19)

n (%) with 1 or more AEs 10 (67) 16 (100) 16 (100) n (%) of deaths 0 0 0 n (%) with 1 or more other serious AEs 0 0 0 n (%) of treatment stopped due to AEs

0 1 (6) 0


0 1 (6) 0

All subjects reported at least 1 AE during the treatment period. Except for one case of increased lipase (grade 3) reported during treatment with rifampin, all AEs were grade 1 or 2 in severity. This subject discontinued treatment. There were no deaths or other SAEs reported in this trial.

Clinical Laboratory Tests There were no consistent or clinically relevant changes over time in median laboratory parameters. No grade 4 or grade 3 abnormalities were reported during treatments including TMC278. The most commonly reported laboratory related AE was increased lipase, during treatment with rifampin and during combined treatment. No urinalysis related abnormalities during treatments including TMC278 were reported as AE. Adrenal function was normal for all subjects.

Cardiovascular Safety No clinically relevant median changes in vital signs or ECG parameters were noted during the trial. No abnormalities in vital signs or ECG parameters were reported as AE.

Physical and Skin Examination Skin examination revealed a new abnormality (not present at screening) for 4 subjects. These findings were all reported as grade 1 AEs. Maculopapular rash was observed in one subject during follow-up. One subject experienced pruritus during combined treatment with TMC278 and rifampin (Session III) and skin discoloration secondary to scratching during follow-up. One subject experienced a hematoma during treatment with TMC278 (Session III). One subject experienced aphtous stomatitis during treatment with TMC278 and rifampin (Session III).

Synopsis

R278474-C108 6


Conclusions

The results of this study demonstrate that the steady-state plasma concentrations of TMC278 show a large decrease of around 80% after combined treatment of TMC278 and rifampin for 7 days compared to TMC278 given alone for 7 days. The steady-state plasma concentrations of rifampin and 25-desacetylrifampin were similar after combined treatment of TMC278 and rifampin for 7 days compared to rifampin given alone for 7 days. TMC278 treatment, alone or combined with rifampin appeared generally safe and well tolerated. Based upon the pharmacokinetic interaction, TMC278 and rifampin cannot be coadministered.

Synopsis

TMC278-C109 1





Title: A Phase I, open-label, randomized, 2-way crossover trial in 16 healthy subjects to establish the 2-way pharmacokinetic interaction between steady-state TMC278 and paracetamol


Country: Belgium



Objectives: The primary objective of this trial was to determine the effect of paracetamol on the steady-state pharmacokinetics of TMC278 in healthy volunteers and to establish the effect of steady-state TMC278 on the pharmacokinetics of paracetamol. Secondary objectives were to monitor the short-term tolerability and safety of TMC278 when concurrently administered with paracetamol to healthy subjects. Design: This was an open-label, randomized, 2-way crossover trial in 2 panels of 8 healthy subjects each, to determine the pharmacokinetic interaction between steady-state TMC278 and a single dose of paracetamol. For each panel, the trial consisted of 2 sessions. During Session I, Panel 1 received Treatment A consisting of a single dose of paracetamol 500 mg followed by a 24-hour pharmacokinetic profile of paracetamol, paracetamol glucuronide, and paracetamol sulphate. Panel 2 received Treatment B consisting of TMC278 150 mg once daily (q.d.) for 11 days and a single dose of paracetamol 500 mg on Day 11. During Treatment B, pharmacokinetic profiles of TMC278 were assessed over 24 hours on Day 10 (before paracetamol) and Day 11 (concomitantly with paracetamol); the pharmacokinetic profile of paracetamol, paracetamol glucuronide, and paracetamol sulphate was assessed on Day 11. For each panel, Session II consisted of the alternative treatment from Session I, i.e., Panel 1 received Treatment B and Panel 2 received Treatment A. The washout between sessions was at least 14 days. Safety and tolerability were assessed throughout the trial. Subject Selection Inclusion Criteria1. Aged between 18 and 55 years, extremes included. 2. Smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day (or nonsmoking) for at least 3 months prior

to selection. 3. Normal weight as defined by a Quetelet Index (Body Mass Index: weight in kg divided by the square of height

in meters) of 18.0 to 30.0 kg/m2, extremes included. 4. Informed consent form (ICF) signed voluntarily before first trial-related activity. 5. Cortisol of at least 550 nmol/L (19.9 μg/dL) at least at 1 of the 3 time points (i.e., morning cortisol, 30 or

60 minutes after 250 μg adrenocorticotropic hormone [ACTH] stimulation) on the screening assessment. 6. Able to comply with protocol requirements. 7. Healthy on the basis of a pretrial physical examination, medical history, electrocardiogram (ECG), vital signs,

and the results of blood biochemistry, hematology tests, and a urinalysis carried out at screening. Exclusion Criteria1. A positive human immunodeficiency virus (HIV)-1 or HIV-2 test at trial screening. 2. Female, except if postmenopausal since more than 2 years, or posthysterectomy or post-tubal ligation (without

reversal operation). 3. History or suspicion of alcohol, barbiturate, amphetamine, recreational, or narcotic drug use which, in the

investigator’s opinion, would compromise the subject’s safety and/or compliance with the trial procedures. 4. Hepatitis A infection (confirmed by hepatitis A antibody IgM), or hepatitis B infection (confirmed by

hepatitis B surface antigen), or hepatitis C infection (confirmed by hepatitis C virus antibody) at screening. 5. A positive urine drug test at screening. Urine was tested for the presence of amphetamines, benzodiazepines,

cocaine, cannabinoids, and opioids. 6. Currently active gastrointestinal, cardiovascular, nervous system, psychiatric, metabolic, renal, hepatic,

respiratory, inflammatory, or infectious disease. 7. Chronic renal failure. 8. Any current or previous adrenal illness.

Synopsis

TMC278-C109 2


Exclusion Criteria, continued 9. Currently significant diarrhea, gastric stasis, or constipation that, in the investigator’s opinion, could influence

drug absorption or bioavailability. 10. Any history of significant skin disease such as, but not limited to, rash or eruptions, drug allergies, food


investigational medication administered in this trial, or to paracetamol or any of its excipients. 12. Use of concomitant medication, including over-the-counter products and dietary supplements, except for

ibuprofen, up to 3 days before the first dose of study medication. All other medication must have been discontinued at least 14 days before the first dose of study medication.

13. Participation in an investigational drug trial within 60 days prior to the first intake of study medication. 14. Donation of blood or plasma within the 60 days preceding the first intake of study medication. 15. Having previously participated in a trial with TMC120, TMC125, or TMC278. 16. Subjects with the following laboratory abnormalities at screening as defined by the enhanced toxicity grading

severity list: serum creatinine grade 1 or greater; lipase grade 1 or greater (> 1.0 x upper limit of normal [ULN]); hemoglobin toxicity grade 1 or greater (< 9.4 g/dL); platelet count grade 1 or greater (< 99,000/mm3); absolute neutrophil count grade 1 or greater (< 1500/mm3); aspartate aminotransferase or alanine aminotransferase (ALT) grade 1 or greater (> 1.25 x ULN); total bilirubin grade 2 or greater (> 1.5 x ULN); any other toxicity grade 2 or above, including: proteinuria (spot urine) > 1+ and gross hematuria.

17. Since the effects of TMC278 on conception are unknown, male subjects were advised to use a condom with spermicide when having heterosexual intercourse from screening onwards until 1 month after the last trial drug administration, i.e., until the 30-day follow-up visit or 1 month after discontinuation of the study medication in case of premature discontinuation.

Treatment Paracetamol (Treatment A) TMC278/Paracetamol (Treatment B) Dosage Paracetamol 500 mg (single dose) TMC278 150 mg q.d. on Days 1-11 and

paracetamol 500 mg (single dose) on Day 11

Dosage Form (F No.) Paracetamol 500 mg tablet TMC278 25 mg and 100 mg tablets (F001 and F002) and paracetamol 500 mg

tablet Usage (oral intake) 1 x 500 mg tablet on Day 1 2 x 25 mg and 1 x 100 mg TMC278

tablets on Days 1-11; 1 x 500 mg paracetamol tablet on Day 11

Batch Numbers 04BS01D F001: PD1216 F002: PD1211

Dose Regimen Panel 1: Treatment A during Session I, Treatment B during Session II, with a washout period of at least 14 days between sessions Panel 2: Treatment B during Session I, Treatment A during Session II, with a washout period of at least 14 days between sessions

Duration of Treatment 12 days (excluding washout) Duration of Trial 27 days (excluding screening and follow-up) Disallowed Medication All medication had to be discontinued at least 14 days before drug administration

except for ibuprofen and hormone replacement therapy. Subjects were not to use any herbal medications or dietary supplements including Hypericum perforatum (e.g., St. John’s wort) for 14 days before the start of the trial and throughout the duration of the trial. Use of paracetamol, except when indicated as per protocol, was explicitly not allowed. Ibuprofen could be used up to 3 days before administration of study medication. After that, the clinical investigator could permit the use of ibuprofen (from 3 days before drug intake until the end of each session at no more than 1 x 400 mg per day). Hormone replacement therapy was allowed in postmenopausal women. In the event of cutaneous event/rash and/or allergic reaction, the use of cetirizine, levocetirizine, topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In the case of nausea, the use of antiemetics was permitted. In case of diarrhea, the use of loperamide was allowed.

Synopsis

TMC278-C109 3


Assessments

Scre

enin

ga Session I, Panel 1;

Session II, Panel 2 W

asho

ut Session II, Panel 1; Session I, Panel 2 Follow-up

14

days

Day

s 1 &

2

14

days

Day

s 1 &

5

Day

3

Day

6

Day

7

Day

10

Day

11

Day

12

Day

s 7, &

30,

31

, or 3

2 af

ter

last

dru

g in

take

Drug screening X Pharmacokinetics Blood sample Xd Xj Xj Xj Xj,m Xj,o Xp Safety Adverse Eventsb X X Xh X X X X X X X X Concomitant meds X X Xh X X X X X X X X Hemat & biochemc X Xe Xh Xk Xk Xk Xk X X Urinalysis X Xe Xh Xk Xk X X ECG & vital signs X Xf Xk Xn Xn X ACTH stim test with determinations of cortisol & 17-OH-progesterone

X X

AAG, HDL, LDL, & total cholesterol, triglycerides, T3, free T4, TSH, insulin

X Xl X

Skin examination X Xg Xh,i Xl X X X X Physical examination X Xg Xl X X ACTH = adrenocorticotropic hormone; ECG = electrocardiogram; Hemat & biochem = hematology and biochemistry; meds = medications; stim = stimulation; OH = hydroxy; T3 = triidothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; AAG = alpha-1-acid glycoprotein; HDL = high density lipoprotein; LDL = low density lipoprotein. a At screening, subjects’ demographics, medical and surgical history, family history related to skin disease, concomitant diseases, and smoking habits were recorded; a HIV-1 and -2 test, hepatitis A, B, and C test, and a pregnancy test, if applicable, were also performed. b Adverse events were monitored continuously from signing the ICF onwards until the last trial-related visit. c Biochemistry sample had to be taken fasted for at least 10 hours. d Immediately before intake of study medication and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose on Day 1 and 24 hours postdose on Day 2. e On Day 1, within 2 hours before drug intake and before breakfast. On Day 2, only hematology and biochemistry samples had to be taken (before breakfast). f On Day 1, within 2 hours before drug intake and before breakfast, 1 hour postdose and 4 hours postdose. g On Day 1 (predose) only. h On Day 7 of washout (Day 1 of washout = Day 2 for Panel 1 and Day 12 for Panel 2). i For those subjects who received Treatment B (TMC278) only. j Immediately before intake of study medication. The predose sample on Day 11 counted as the 24-hour sample of Day 10. k Within 2 hours before drug intake and before breakfast. l Day 1 only. m Immediately before intake of study medication and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours postdose. n Predose and at 1 and 4 hours postdose. o Predose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours postdose, samples were drawn for TMC278 and paracetamol in separate tubes. At 0.25, 0.75, and 1.5 hours, samples were drawn for paracetamol only. p Samples were drawn for TMC278 and paracetamol in separate tubes. This was the 24-hour sample. Statistical Methods Descriptive statistics, Intent-to-Treat analysis, linear mixed effect modeling,

Mann-Whitney U-Test, and Wilcoxon’s matched pairs signed rank test.

Synopsis

TMC278-C109 4



Panel 1 Paracetamol

TMC278/Paracetamol N = 8

Panel 2 TMC278/Paracetamol

Paracetamol N = 8

Total N = 16


5/3 46.5 (19 - 54)

4/4 41.0 (18 - 49)

9/7 43.5 (18 - 54)

Drop-Outs 0 0 0

Pharmacokinetics Pharmacokinetics of TMC278 (mean SD, tmax: median [range])

TMC278/ ParacetamolTest

TMC278 Alone Reference

LSmean Ratio (90% CI),%Test/Reference

n 16 16 - tmax, h 3.0 [2.0 - 6.0] 4.0 [2.0 - 6.0] - C0h, ng/mL 461 ± 144 390 ± 162 119 (108 - 132)* Cmin, ng/mL 403 ± 111 323 ± 111 126 (116 - 138)* Cmax, ng/mL 1015 ± 189 937 ± 237 109 (101 - 118) AUC24h, ng.h/mL 14679 ± 3015 12799 ± 3290 116 (110 - 122)* Css, av, ng/mL 612 ± 126 533 ± 137 - FI, % 101.9 ± 22.5 117.7 ± 27.9 - Level of significance: * p 0.01 Both panels were combined in the pharmacokinetic analysis.

Pharmacokinetics of Paracetamol (mean SD, tmax: median [range])

TMC278/ParacetamolTest

Paracetamol Alone Reference


n 16 16 - tmax, h 1.0 [0.3 - 2.0] 1.5 [0.3 - 2.0] - Cmax, μg/mL 5.81 ± 2.08 5.93 ± 2.04 97 (86 - 110) AUClast, μg.h/mL 18.42 ± 4.35 19.98 ± 4.57 92 (85 - 99) AUC , μg.h/mL 20.72 ± 4.63 22.63 ± 4.89 91 (86 - 97)* t1/2term, h 2.05 ± 0.32 2.42 ± 0.37 - Level of significance: * p 0.05 Both panels were combined in the pharmacokinetic analysis.

Pharmacokinetics of Paracetamol Glucuronide (mean SD, tmax: median [range])




n 16 16 - tmax, h 3.0 [2.0 - 4.0] 3.0 [2.0 - 4.0] - Cmax, μg/mL 8.38 ± 1.70 8.79 ± 2.05 96 (90 - 103) AUClast, μg.h/mL 54.82 ± 11.89 54.71 ± 12.59 101 (95 - 107) AUC , μg.h/mL 61.33 ± 12.76 62.59 ± 14.23 98 (94 - 103) t1/2term, h 3.29 ± 0.62 3.46 ± 0.37 -

Both panels were combined in the pharmacokinetic analysis.

Synopsis

TMC278-C109 5


Pharmacokinetics of Paracetamol Sulphate (mean SD, tmax: median [range])




n 16 16 - tmax, h 2.0 [1.0 - 3.0] 2.0 [0.8 - 3.0] - Cmax, μg/mL 3.30 ± 0.73 3.28 ± 0.69 100 (94 - 107) AUClast, μg.h/mL 15.63 ± 4.33 16.47 ± 4.76 95 (88 - 102) AUC , μg.h/mL 19.00 ± 4.46 19.72 ± 4.93 97 (91 - 103) t1/2term, h 2.69 ± 0.38 2.93 ± 0.39 -

Both panels were combined in the pharmacokinetic analysis.

Synopsis

TMC278-C109 6


Trial Phase


Paracetamol AloneN = 16

TMC278 AloneN = 16

TMC278/ Paracetamol

N = 16 Whole Trial

N = 16 Adverse Events (AEs) Most frequently reported AEs (reported in > 1 subject in the whole trial), n (%)

Alanine aminotransferase increased 0 0 0 2 (12.5) Neutrophil count decreased 0 2 (12.5) 0 2 (12.5) Headache 2 (12.5) 6 (37.5) 4 (25.0) 8 (50.0) Dry skin 0 2 (12.5) 0 2 (12.5) Pruritus 0 3 (18.8) 1 (6.3) 4 (25.0) Phlebitis 0 1 (6.3) 1 (6.3) 2 (12.5)

n (%) with 1 or more AEs 2 (12.5) 11 (68.8) 7 (43.8) 13 (81.3) n (%) of deaths 0 0 0 0 n (%) with 1 or more other serious AEs 0 0 0 0 n (%) of treatment stopped due to AEs 0 0 0 0 n (%) with 1 or more grade 3 or 4 AEs 0 0 0 0 Overall, 13 (81.3%) subjects reported at least 1 AE. The overall incidence of AEs was higher during treatment with TMC278 alone and during treatment with TMC278 in combination with paracetamol than during treatment with paracetamol alone. The most common AE was headache (8 subjects, 50.0%). There were no deaths or other serious adverse events. All AEs were considered grade 1or 2 in severity. No subjects prematurely discontinued the trial due to an AE. Two AEs that were considered skin events of interest were reported during the trial: erythema in 1 subject on Day 11 during treatment with TMC278 alone (event started before coadministration of paracetamol on Day 11 and resolved after 8 days) in Session I and rash papular in 1 subject on Day 7 during washout following treatment with paracetamol alone (follow-up) in Session II (TMC278 alone and TMC278/paracetamol were administered in Session I). Both events were grade 1 in severity. The event of erythema was considered to be possibly related to both TMC278 and paracetamol (although the event started before coadministration of paracetamol) and the event of rash papular was considered to be possibly related to TMC278 and not related to paracetamol. Clinical Laboratory Tests

Trial Phase

Paracetamol AloneN = 16

TMC278 AloneN = 16

TMC278/ Paracetamol

N = 16 Whole Trial

N = 16 n (%) with 1 or more grade 1 treatment-emergent laboratory abnormalities

0 5 (31.3) 5 (31.3) 10 (62.5)

n (%) with 1 or more grade 2, 3, or 4 treatment-emergent laboratory abnormalities

0 0 0 0

There were no consistent or clinically relevant treatment-emergent changes over time in laboratory parameters. No grade 4, grade 3, or grade 2 treatment-emergent abnormalities were reported during the trial. Grade 1 treatment-emergent abnormalities were reported for 10 subjects (62.5%) during the trial. Six subjects had clinically relevant laboratory abnormalities that were reported as AEs: ALT increased and neutrophil count decreased were each reported for 2 subjects, and blood amylase increased, blood triglycerides increased, and lipase increased were each reported for 1 subject. No consistent effects of treatment were apparent on median values or median changes from reference (screening visit) for the adrenal assessments of cortisol or 17-OH-progesterone. All but 2 subjects (12.5%) achieved a cortisol value 550 nmol/L following ACTH stimulation at the end of treatment with TMC278/paracetamol. No corresponding relevant increase in 17-OH-progesterone was noted for these 2 subjects. No AEs related to adrenal function test results were reported.

Synopsis

TMC278-C109 7


Cardiovascular Safety Minor changes were reported for median vital signs values. None of the changes was considered to be clinically relevant. No trends or relationship to study medication were apparent and no clinically relevant changes in ECG parameters were reported. Physical and Skin Examinations Physical and skin examination revealed abnormal new findings for 4 subjects during the trial: dry skin and pruritus during treatment with TMC278 alone (1 subject), dry skin during treatment with TMC278 alone and phlebitis during treatment with TMC278/paracetamol (1 subject), erythema during treatment with TMC278 (1 subject), and rash papular during follow-up (1 subject).

Conclusions

The results of this trial indicate that the exposure to TMC278 (measured as the AUC24h) was increased by 16% after coadministration of a single dose of paracetamol on Day 11. This is not considered to be clinically relevant. A small but statistically significant reduction was observed for the paracetamol AUC which was reduced by 9% after the combined treatment. TMC278 did not significantly influence the pharmacokinetics of the glucuronide or sulphate conjugates of paracetamol.

A final recommendation for the combined use of TMC278 and paracetamol will follow upon completion of study TMC278-C139, which investigates the interaction between TMC278 and chlorzoxazone in healthy subjects and the effect of TMC278 on CYP2E1 in vivo.

In healthy subjects in this trial, TMC278 150 mg q.d. administered alone or in combination with a single dose of paracetamol 500 mg was generally safe and well tolerated.

Synopsis

TMC278-C112 1

Clinical Research Report Version: 1.0 Date: 18-Jan-2007



Trade Name: -




Clinical Phase: I

Title: A phase I, open-label, randomized 2-way crossover trial in 16 healthy subjects to investigate the steady-state pharmacokinetic interaction between TMC278 and TMC114/ritonavir (rtv)


Country: Belgium


End: - -20


No. of Subjects: 16

Objectives: The primary objectives of this study were to determine the effect of steady-state concentrations of TMC114/rtv on the steady-state pharmacokinetics of TMC278 and to determine the effect of steady-state concentrations of TMC278 on the steady-state pharmacokinetics of TMC114 and ritonavir. The secondary objective was to determine the short-term safety and tolerability of the co-administration of TMC278 and TMC114/rtv.

Design: This was a phase I, open-label, randomized, 2-way crossover trial to investigate the pharmacokinetic interaction between TMC278 and TMC114/rtv at steady-state. The trial comprised 2 sessions, each subject received a different treatment in each session. Treatment A consisted of TMC278 150 mg once daily (q.d.) for 11 days. Treatment B consisted of TMC114/rtv 800/100 mg q.d. for 22 days with co-administration of TMC278 150 mg q.d. from Day 12 to 22. Randomization was done in such a way that 8 subjects received treatment in sequence AB and 8 subjects received treatment in sequence BA. There was a washout period of at least 14 days between Sessions 1 and 2. Full pharmacokinetic profiles of TMC278 up to 24 hours postdose were determined on Day 11 of Treatment A and Day 22 of Treatment B. Full pharmacokinetic profiles of TMC114 and ritonavir up to 24 hours postdose were determined on Days 11 and 22 of Treatment B. Tolerability and safety were assessed throughout the study period.

Subject Selection

Inclusion Criteria1. Male or female, aged between 18 and 55 years, extremes included. 2. Smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day (or non-smoking) for at least 3 months prior

to selection. 3. Normal weight as defined by a Quetelet Index (Body Mass Index, weight in kg divided by height in meters

squared) of 18.0 to 30.0 kg/m2, extremes included. 4. Informed consent form (ICF) signed voluntarily before first trial-related activity. 5. Cortisol of at least 550 mmol/L (19.9 μg/dL) at least at one of the 3 time points (i.e., prestimulation cortisol, 30

or 60 minutes after 250 μg adrenocorticotropic hormone [ACTH] stimulation) at the screening assessment. 6. Able to comply with protocol requirements. 7. Healthy on the basis of a physical examination, medical history, electrocardiogram, vital signs, and the results of

blood biochemistry, hematology tests, and a urinalysis carried out at screening.

Synopsis

TMC278-C112 2


Exclusion Criteria1. A positive human immunodeficiency virus (HIV)-1 or HIV-2 test at screening. 2. Female, except if postmenopausal since more than 2 years, or posthysterectomy or posttubal ligation

(without reversal operation). 3. History or suspicion of alcohol, barbiturate, amphetamine, recreational, or narcotic drug use which in the

investigator’s opinion would compromise subject’s safety and/or compliance with the trial procedures. 4. Hepatitis A, B, or C infection (confirmed by hepatitis A antibody IgM, hepatitis B surface antigen, or

hepatitis C virus antibody, respectively) at screening. 5. A positive urine drug test at screening. Urine was tested for the presence of amphetamines, barbiturates,

benzodiazepines, cocaine, cannabinoids, methadone, and opioids. 6. Currently active or underlying gastrointestinal, cardiovascular, neurological, psychiatric, metabolic, renal,

hepatic, respiratory, inflammatory, or infectious disease. 7. Any previous or current adrenal illness. 8. Any history of tuberculosis or ocular herpes. 9. Currently significant diarrhea, gastric stasis, or constipation that in the investigator’s opinion could


food allergy, dermatitis, eczema, psoriasis, or urticaria. 11. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the

investigational medication administered in this trial (i.e., TMC278, TMC114, ritonavir, and tetracosactide). 12. History of allergy to drugs such as, but not limited to, sulphonamides and penicillins. TMC114 is a

sulphonamide. The potential for cross-sensitivity between drugs in the sulphonamide class and TMC114 is unknown in healthy volunteers. Therefore healthy subjects with a known sulphonamide allergy were excluded from this trial.

13. Use of concomitant medication, including over-the-counter products and dietary supplements. Over-the-counter medication had to have been discontinued at least 7 days prior to the first administration of study medication and prescribed medication must have been discontinued at least 14 days before the first administration of study medication, except ibuprofen.

14. Participation in an investigational drug trial within 60 days prior to the first intake of study medication. 15. Donation of blood or plasma within the 60 days preceding the first intake of study medication. 16. Subjects with the following laboratory abnormalities at screening as defined by the Division of Acquired

Immunodeficiency Syndrome (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (“DAIDS grading table”) and in accordance with the normal ranges of the trial clinical laboratory: serum creatinine grade 1 or greater ( 1.1 x upper limit of normal range [ULN]); serum lipase grade 1 or greater ( 1.1 x ULN); hemoglobin toxicity grade 1 or greater ( 10.9 g/dL); platelet count grade 1 or greater ( 124.999 x 109/L); absolute neutrophil count grade 1 or greater ( 1.3 x 109/L); aspartate aminotransferase or alanine aminotransferase grade 1 or greater ( 1.25 x ULN); total bilirubin grade 1 or greater ( 1.1 x ULN); any other toxicity grade 2 or above, including: proteinuria (spot urine) 2+ and microscopic hematuria (>10 red blood cells/high power field).

17. Having previously participated in more than 1 trial (single or multiple dose) with TMC114, TMC125, TMC278, and/or TMC120 or having developed a rash, erythema, or urticaria while participating in a trial with the above mentioned compounds.

Treatment TMC278 TMC114/rtv

Dosage TMC278 150 mg q.d. TMC114 800 mg q.d. and ritonavir 100 mg q.d.

Dosage Form (F No.) Tablets (50 mg [F003] and 100 mg [F002])

TMC114 tablets (400 mg [F021]) and ritonavir capsules (100 mg [Norvir ])

Usage 1x 100 mg and 1x 50 mg tablet, oral use Treatment A: Days 1 to 11 Treatment B: Days 12 to 22

2x 400 mg TMC114 tablets, oral use and 1x 100 mg ritonavir capsule, oral use

Treatment B: Days 1 to 22

Synopsis

TMC278-C112 3


Batch Number PD1273 and PD1268 (R314585) TMC114: PD1647 (R319064) and ritonavir: 17614VA

Dose Regimen Group 1: Treatment A in Session I, Treatment B in Session II. Group 2: Treatment B in Session I, Treatment A in Session II.

Duration of Treatment Treatment A: 11 days, Treatment B: 22 days.

Duration of Trial 35 days (excluding screening and follow-up) plus at least a 2-week washout period.

Disallowed Medication During the entire trial, subjects were not to use any medication other than study medication, although a restricted dose of ibuprofen was allowed. All over-the-counter medication had to be discontinued at least 7 days before the first intake of study medication and all prescribed medication had to be discontinued at least 14 days before first intake of study medication, except for ibuprofen. Subjects were not to use any herbal medications or dietary supplements including products containing Hypericum perforatum (i.e., St. John’s wort) from 14 days before the first intake of study medication and up to 14 days after the last intake of study medication. Ibuprofen could be used up to 3 days before administration of study medication. After that, the clinical investigator could permit the use of ibuprofen (from 3 days before drug intake until the end of each session at no more than 1 x 400 mg per day). In the event of cutaneous event/rash and/or allergic reaction, the use of cetirizine, levocetirizine, topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In case of nausea, the use of antiemetics was permitted. In case of diarrhea, the use of loperamide was allowed.

Synopsis

TMC278-C112 4


Assessments

Scre

enin

ga Session I or 2/Treatment A or Treatment B

Session I or 2/Treatment B

Follo

w-u

p

21

days

Day

1b

Day

9

Day

10

Day

11

Day

12k

Day

20

Day

21

Day

22

Day

23k

Day

7

and

30,

31, o

r 32

Pharmacokinetics Blood sample Xe, f Xe,f Xe,f Xe,f Xe,f Xe,f Xe,f Xe,f Xe,f

Safety Adverse events + concomitant medicationsc

X X X X X X X X X X X

Hematology & biochemistryd X Xg X X Xg X X X X Urinalysis X Xh Xh Xl X X ACTH stimulation test with determinations of cortisol and 17-OH progesterone

X Xl X

Apo A1, Apo B, insulin, and 1-acid glycoprotein

X Xi Xi Xl Xi X

T3, free-T4, and TSH X Xl X Coagulation test X X X Xl X X ECG & vital signs X Xg Xh,j Xm Xh,j X X Skin examination X X X X X X X Physical examination X X X X X ACTH = adrenocorticotropic hormone; Apo = apolipoprotein; T3 = triidothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone; ECG = electrocardiogram. a At screening, subject’s demographics, medical and surgical history, smoking habits and concomitant diseases were recorded. An HIV-1 and -2 test, a hepatitis A, B, and C test and a drug screening were performed and a serum pregnancy test was also performed for females. b Subjects were admitted to the unit the night before Day 1. c Adverse events and concomitant medications were monitored continuously from signing the ICF until the last trial-related activity.d Biochemistry samples were taken fasted for at least 10 hours, before breakfast. e For determination of TMC114 and ritonavir concentrations on Day 1 (predose only) of Treatment A and Day 1 (predose and 4 hours postdose), Day 9 (predose), Day 10 (predose), Day 11 (predose, 30 mins postdose, and 1, 2, 3, 4, 5, 6, 9, 12, and 16 hours postdose), Day 12 (predose and 4 hours postdose), Day 20 (predose), Day 21 (predose), Day 22 (predose, 30 mins postdose, and 1, 2, 3, 4, 5, 6, 9, 12, and 16 hours postdose), and Day 23 of Treatment B. f For determination of TMC278 concentrations on Day 1 (predose and 4 hours postdose), Day 9 (predose), Day 10 (predose), Day 11 (predose, 30 mins postdose, and 1, 2, 3, 4, 5, 6, 9, 12, and 16 hours postdose), and Day 12 of Treatment A and Day 1 (predose), Day 12 (predose and 4 hours postdose), Day 20 (predose), Day 21 (predose), Day 22 (predose, 30 mins postdose, and 1, 2, 3, 4, 5, 6, 9, 12, and 16 hours postdose), and Day 23 of Treatment B. g Predose and 4 hours postdose on D1 of both Treatments and on D12 of Treatment B only. h Within 2 hours before drug intake and 4 hours post drug intake. i

1-acid glycoprotein not assessed at this time point. j Vital signs only at 4 hours postdose. k Day 1 of washout period (if applicable). l Treatment A only (Sessions 1 or 2). m Within 2 hours before drug intake and 4 hours postdose during Treatment B.

Synopsis

TMC278-C112 5


Statistical Methods Intent-to-treat analysis, descriptive statistics, frequency tabulations, Wilcoxon matched-pairs signed-ranks test, linear mixed effects modeling, nonparametric test (Koch).

Synopsis

TMC278-C112 6




Treatment A B

N = 8

Treatment B A

N = 8

Total

N = 16

Number of Subjects Entered (M/F)

Age: median (range), yrs

8/0

32.5 (24-53)

5/3

47.5 (37-51)

13/3

38.0 (24-53)

Drop-Outs - Reason 1

Adverse event of maculo-papular

rash during Treatment B

2

Adverse events of diarrhea and

abdominal pain during Treatment A and enteritis during

Treatment B

3

Adverse events

Pharmacokinetics of TMC278 (mean ± SD, Tmax:median [range])

Treatment A TMC278 alone

(Reference)

Treatment B TMC278 + TMC114/rtv

(Test)

N 14 14

tmax, h 4.0 [1.0 – 5.0] 4.0 [4.0-24.0]

C0h, ng/mL 415.9 ± 103.7 1233 ± 474.0

C24h, ng/mL 407.3 ± 109.3 1190 ± 528.2

Cmin, ng/mL 359.9 ± 91.55 1013 ± 407.9

Cmax, ng.h/mL 991.3 ± 208.4 1860 ± 673.0

AUC24h, ng.h/mL 12740 ± 2008 30630 ± 11230

Css, av, ng/mL 530.9 ± 86.68 1276 ± 468.0

FI, % 121.9 ± 47.89 68.26 ± 23.38

LSmean ratio (90% CI), % Test versus Reference

N 14 vs 14

Cmin 278.3 (239.3 – 323.6)

Cmax 178.7 (155.5 – 205.5)

AUC24h 229.9 (197.9 – 267.2) Data from subjects who received either treatment sequence AB or BA were combined in these tables SD = standard deviation tmax = time to reach maximum plasma concentration C0h = predose plasma concentration C24h = plasma concentration after 24 hours Cmin = minimum plasma concentration Cmax = maximum plasma concentration h = hour AUC24h = area under the plasma concentration-time curve from time of administration up to 24 hours post dosing Css, av = average steady-state plasma concentration FI = fluctuation index LS = least square CI = confidence interval

Synopsis

TMC278-C112 7


Pharmacokinetics of TMC114 (mean ± SD, Tmax:median [range])


(Reference)


(Test)

N 15 14

tmax, h 2.0 [1.0 – 5.0] 3.0 [1.0 – 4.0]

C0h, ng/mL 1887 ± 1010 1890 ± 1330

C24h, ng/mL 2140 ± 831.4 1592 ± 764.0

Cmin, ng/mL 1714 ± 916.2 1388 ± 614.6

Cmax, ng.h/mL 7586 ± 1988 6676 ± 1374

AUC24h, ng.h/mL 82780 ± 24980 71930 ± 21350

Css, av, ng/mL 3449 ± 1041 2997 ± 889.7

FI, % 176.5 ± 39.47 184.8 ± 35.06


N 15 vs 14

Cmin 88.88 (67.98 – 116.2)

Cmax 90.06 (80.95 – 100.2)

AUC24h 89.45 (80.87 – 98.94)

Pharmacokinetics of ritonavir (mean ± SD, Tmax:median [range])


(Reference)


(Test)

N 15 14

tmax, h 4.0 [1.0 – 6.0] 4.5 [2.0 – 6.0]

C0h, ng/mL 43.30 ± 15.99 37.64 ± 25.78

C24h, ng/mL 45.23 ± 24.53 31.06 ± 13.42

Cmin, ng/mL 35.74 ± 15.08 27.67 ± 14.26

Cmax, ng.h/mL 690.3 ± 293.1 558.3 ± 277.3

AUC24h, ng.h/mL 5201 ± 2381 4060 ± 1537

Css, av, ng/mL 216.7 ± 99.20 169.2 ± 64.03

FI, % 312.7 ± 75.32 314.6 ± 85.40


N 15 vs 14

Cmin 78.49 (68.25 – 90.26)

Cmax 82.95 (72.32 – 95.14)

AUC24h 84.55 (78.21 – 91.41)

Synopsis

TMC278-C112 8


Safety TMC278

N = 15

TMC114/ rtv

N = 16

TMC114/rtv + TMC278

N = 15

Follow-up

N = 16

Total

N = 16

Adverse Events (AEs)

Most frequently reported AEs (reported in 3 subjects throughout the whole trial), n (%) Hypercholesterolemia 2 (13.3) 2 (12.5) 2 (13.3) 0 6 (37.5) Headache 2 (13.3) 2 (12.5) 5 (33.3) 0 6 (37.5) Lipids increased 0 1 (6.3) 4 (26.7) 2 (12.5) 5 (31.3) Pruritus 0 4 (25.0) 1 (6.7) 0 5 (31.3) Lipase increased 0 2 (12.5) 2 (13.3) 0 4 (25.0) Blood creatinine increased 1 (6.7) 0 1 (6.7) 1 (6.3) 3 (18.8) Hyperbilirubinemia 2 (13.3) 0 1 (6.7) 2 (12.5) 3 (18.8) Aphthous stomatitis 0 0 2 (13.3) 1 (6.3) 3 (18.8) Diarrhea 1 (6.7) 2 (12.5) 0 0 3 (18.8) Nausea 1 (6.7) 1 (6.3) 1 (6.7) 0 3 (18.8)

n (%) with 1 or more AEs 13 (86.7) 11 (68.8) 11 (73.3) 6 (37.5) 16 (100)

n (%) of deaths 0 0 0 0 0


0 0 0 0 0


1 (6.7) 2 (12.5)* 0 0 3 (18.8)


0 1 (6.3) 2 (13.3) 1 (6.3) 3 (18.8)

* Subject 1121738 (B A) discontinued the study during treatment with TMC114/rtv plus TMC278 due to an AE that occurred in phase TMC114/rtv.

Overall, 16 subjects (100%) experienced at least 1 AE. No subjects experienced an SAE and no subjects died. There were no AEs that were considered to have a probable or very likely relationship to either TMC278 or TMC114/rtv. A total of 13 subjects (81.3%) experienced AEs that were considered to have a possible relationship to TMC278 and 14 subjects (87.5%) experienced AEs that were considered to have possible relationship to TMC114/rtv. Three subjects had study medication permanently stopped due to AEs. During treatment with TMC278, 1 subject experienced grade 2 AEs of diarrhea and abdominal pain and during treatment with TMC114/rtv, 1 subject had a grade 2 AE of enteritis and 1 subject had a grade 2 AE of maculo-papular rash. No grade 4 AEs were reported during the trial. A total of 5 grade 3 AEs was experienced by 3 subjects (18.8%) during the study. The grade 3 AEs were 4 events of increased lipids, experienced by 2 subjects, 1 event during treatment with TMC114/rtv and 3 events during treatment with TMC114/rtv plus TMC278. In addition, during follow-up 1 subject experienced grade 3 gastric pain. Skin events of interest were experienced by 3 subjects. One subject had a grade 2 maculo-papular rash during treatment with TMC114/rtv alone. One subject had a grade 1 erythema and 1 subject had a grade 1 maculo-papular rash, both during treatment with TMC114/rtv alone. All three skin events of interest were considered to have a possible relationship to TMC114/rtv.

Synopsis

TMC278-C112 9


Clinical Laboratory TestsTMC278

N = 15

TMC114/ rtv

N = 16

TMC114/rtv + TMC278

N = 15

Follow-up

N = 16

Total

N = 16

n (%) with 1 or more treatment-emergent grade 3 laboratory abnormalities

0 1 (6.3%) 2 (13.3%) 1 (6.3%) 2 (12.5%)

n (%) with 1 or more treatment-emergent grade 4 laboratory abnormalities

0 0 0 0 0

No notable patterns in laboratory or urinalysis data were apparent. There were no subjects with grade 4 treatment-emergent laboratory abnormalities. Two subjects experienced a grade 3 treatment-emergent laboratory abnormality, these were elevated LDL cholesterol and elevated prothrombin time. Adrenal Function TestingMedian cortisol at T0 was highest during screening (510.0 nmol/L) and lowest during the TMC114/rtv plus TMC278 phase (372.0 nmol/L). During treatment with TMC278 alone, there was a median increase from reference in cortisol at T0 (56.0 nmol/L) and during treatment with coadministration of TMC114/rtv plus TMC278 there was a median decrease from reference in cortisol at T0 (-110.0 nmol/L). Median 17-OH progesterone was highest during treatment with TMC278 alone (6.65 nmol/L) and lowest during screening (5.50 nmol/L). Median changes from reference during TMC278 alone and TMC114/rtv plus TMC278 were 0.75 nmol/L and 0.55 nmol/L, respectively. At T0, all 16 subjects had a cortisol value 55 nmol/L. During stimulation with ACTH, all subjects had a cortisol value of 550nmol/L. There were no clinically relevant results for any of the adrenal function tests during the study. No adverse events were reported related to adrenal function. Cardiovascular SafetyMinor changes in vital signs and ECG parameters were observed; none of the observed changes were considered to be clinically relevant. Physical Examination Three subjects who received treatment sequence AB, had physical abnormalities reported as AEs, including 1 subject who discontinued the study due to a maculo-papular rash reported as a grade 2 AE. Three subjects who received treatment sequence BA, had physical abnormalities reported as AEs. One subject had a swollen jaw during follow-up reported as a grade 2 AE of toothache and 1 subject had a grade 1 AE of maculo-papular rash. One subject had abdominal muscular tenderness reported as a grade 2 AE. None of the other physical abnormalities were reported as AEs.

Conclusions

In conclusion, the results of this study demonstrate that after the addition of TMC278 to treatment with TMC114/rtv, the Cmin, Cmax, and AUC24h of TMC278 were increased by, respectively, 178%, 79%, and 130%. For TMC114, Cmin, Cmax, and AUC24h were decreased by, respectively, 11%, 10% and 11% in the presence of TMC278 compared to TMC114/rtv administered alone and for ritonavir Cmin, Cmax, and AUC24h were decreased by, respectively, 22%, 17%, and 15%. Dose recommendations for the combination of TMC278 and TMC114/rtv will follow after the optimal dose has been selected for TMC278.

In these healthy subjects, the administration of 150 mg TMC278 alone and in combination with 800/100 mg TMC114/rtv was safe and generally well tolerated.

Synopsis

TMC278-C114 1




Trade Name: -




Clinical Phase: I

Title: A Phase I, open-label trial to investigate the two-way, pharmacokinetic drug-drug interaction between single-dose and steady-state TMC278 and steady-state omeprazole in healthy volunteers


Country: Belgium


End: - -20


No. of Subjects: 16

Objectives: The primary objectives of this study were to investigate the effect of steady-state omeprazole on the single-dose and steady-state pharmacokinetics of TMC278 and to investigate the effect of single-dose and steady-state TMC278 on the steady-state pharmacokinetics of omeprazole and its metabolites 5-hydroxyomeprazole and omeprazole sulfone. Secondary objectives were to determine the effect of cytochrome P450 2C19 (CYP2C19) polymorphism on the extent of the drug-drug interaction between TMC278 and omeprazole, to determine the effect of H.pylori status on the extent of drug-drug interaction between TMC278 and omeprazole, and to determine the short-term safety and tolerability of coadministration of TMC278 and omeprazole.

Design: This was a Phase I, open-label, randomized, 2-way crossover trial to investigate the pharmacokinetic interaction between TMC278 and omeprazole. In 2 sessions, 16 healthy subjects received, in a randomized order, TMC278 alone (Treatment A) or the combination of TMC278 and omeprazole (Treatment B). There was a washout period of at least 14 days between sessions. Randomization was done in such a way that in each session, 8 out of 16 subjects received the same treatment and that each subject received a different treatment in each of the 2 sessions. Treatment A consisted of TMC278 150 mg once daily (q.d.) for 11 days. Treatment B consisted of omeprazole 20 mg q.d for 22 days with coadministration of TMC278 150 mg q.d. from Day 12 to 22. Full pharmacokinetic profiles of TMC278 up to 24 hours postdose were determined on Days 1 and 11 of Treatment A and Days 12 and 22 of Treatment B. Full pharmacokinetic profiles of omeprazole, and its metabolites 5-hydroxyomeprazole and omeprazole sulfone, up to 24 hours postdose were determined on Days 11, 12, and 22 of Treatment B. Safety and tolerability were assessed throughout the trial.

Subject Selection Inclusion Criteria

1. Male or female, aged between 18 and 45 years, extremes included. 2. Smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day (or non-smoking) for at least

3 months prior to selection. 3. Normal weight as defined by a Quetelet Index (Body Mass Index, weight in kg divided by the square of

height in meters) of 18.0 to 30.0 kg/m2, extremes included. 4. Informed consent form (ICF) signed voluntarily before first trial-related activity. 5. Cortisol of at least 550 mmol/L (19.9 μg/dL) at least at one of the 3 time points (i.e., prestimulation

cortisol, 30 or 60 minutes after 250 μg adrenocorticotropic hormone [ACTH] stimulation) at the screening assessment.

6. Able to comply with protocol requirements. 7. Healthy on the basis of a physical examination, medical history, electrocardiogram, vital signs, and the

results of blood biochemistry, hematology tests, and a urinalysis carried out at screening.

Synopsis

TMC278-C114 2


Exclusion Criteria1. A positive human immunodeficiency virus (HIV)-1 or HIV-2 test at screening. 2. Female, except if postmenopausal since more than 2 years, or posthysterectomy or posttubal ligation

(without reversal operation). 3. History or suspicion of alcohol, barbiturate, amphetamine, recreational, or narcotic drug use which in

the investigator’s opinion would compromise subject’s safety and/or compliance with the trial procedures.

4. Hepatitis A, B, or C infection (confirmed by Hepatitis A antibody IgM, Hepatitis B surface antigen, or Hepatitis C virus antibody, respectively) at screening.

5. A positive urine drug test at screening. Urine was tested for the presence of amphetamines, benzodiazepines, cocaine, cannabinoids, opioids, barbiturates, and methadone.


7. Any current or previous adrenal illness. 8. Currently significant diarrhea, gastric stasis, or constipation that in the investigator’s opinion could


food allergy, dermatitis, eczema, psoriasis, or urticaria. 10. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the

investigational medication administered in this trial (i.e., TMC278 as well as omeprazole). 11. Use of concomitant medication, including over-the-counter products, herbal supplements, and dietary

supplements. Over-the-counter medication had to have been discontinued at least 7 days prior to the first administration of study medication and prescribed medication must have been discontinued at least 14 days before the first administration of study medication, except ibuprofen.

12. Participation in an investigational drug trial within 60 days prior to the first intake of study medication. 13. Donation of blood or plasma within the 60 days preceding the first intake of study medication. 14. Subjects with the following laboratory abnormalities at screening as defined by the Division of

Acquired Immunodeficiency Syndrome (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (“DAIDS grading table”): serum creatinine grade 1 or greater ( 1.1 x upper limit of normal range [ULN]); pancreatic lipase grade 1 or greater ( 1.1 x ULN); hemoglobin grade 1 or greater ( 10.9 g/dL); platelet count grade 1 or greater ( 124.999 x 109/L); absolute neutrophil count grade 1 or greater ( 1.3 x 109/L); aspartate aminotransferase or alanine aminotransferase grade 1 or greater ( 1.25 x ULN); total bilirubin grade 1 or greater ( 1.1 x ULN); any other grade 2 or above, including: proteinuria (spot urine) 2+ and microscopic hematuria (> 10 red blood cells/high power field).

15. Having previously participated in more than 1 trial (single or multiple dose) with TMC125, TMC120, and/or TMC278 or having developed a rash, erythema, or urticaria while participating in a trial with TMC125, TMC120, and/or TMC278.

Treatment Treatment A Treatment B

Dosage TMC278 150 mg q.d. Omeprazole 20 mg q.d. and TMC278 150 mg q.d.

Dosage Form (F No.) Tablets (50 mg [F003] and 100 mg [F002])

Omeprazole tablet and TMC278 tablets (50 mg [F003] and 100 mg [F002])

Usage 1 x 100 mg and 1 x 50 mg tablet on Days 1 to 11

1 x 20 mg omeprazole on Days 1 to 22 and 1 x 100 mg and 1 x 50 mg TMC278

tablets on Days 12 to 22

Batch Number F002 batch number: PD1268 F003 batch number: PD1273

Omeprazole batch number: EF8339 TMC278 (F002) batch number: PD1268 TMC278 (F003) batch number: PD1273

Dose Regimen Panel 1: Treatment A in Session 1, Treatment B in Session 2. Panel 2: Treatment B in Session 1, Treatment A in Session 2.

Duration of Treatment Treatment A: 11 days, Treatment B: 22 days.

Duration of Trial 47 days (excluding screening and follow-up)

Synopsis

TMC278-C114 3


Disallowed Medication During the entire trial, subjects were not to use any medication other than study

medication and restricted doses of ibuprofen. All over-the-counter medication had to be discontinued at least 7 days before the first intake of study medication and all prescribed medication had to be discontinued at least 14 days before first intake of study medication, except for ibuprofen. Subjects were not to use any herbal medications or dietary supplements including products containing Hypericum perforatum (e.g., St. John’s wort) from 14 days before the first intake of study medication and up to 14 days after the last intake of study medication. Ibuprofen could be used up to 3 days before administration of study medication. After that, the clinical investigator could permit the use of ibuprofen (from 3 days before drug intake until the end of each session at no more than 1 x 400 mg per day). In the event of cutaneous event/rash and/or allergic reaction, the use of cetirizine, levocetirizine, topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In the case of nausea, the use of antiemetics was permitted. In case of diarrhea, the use of loperamide was allowed.

Synopsis

TMC278-C114 4


Assessments

Scre

enin

ga

Session 1 or 2/Treatment A or Treatment B

Session 1 or 2/Treatment B

Follo

w-u

p

2

1 da

ys

Day

–1b

Day

1

Day

2j

Day

9

Day

10

Day

11

Day

12

Day

13

Day

20

Day

21

Day

22

Day

23

Day

7

and

30,

31, o

r 32

Drug screening X Pharmacokinetics Blood sample Xf,g Xf,g Xf,g Xf,g Xf,g Xf,g Xf,g Xf,g Xf,g Xf,g Xf,g Safety Adverse events + concomitant medsc

X X X X X X X X X X X X X X

Hemat & biochemd X Xi X Xi Xi X Xi X X Urinalysis X Xh Xh X X ACTH stimulation test with determinations of cortisol and 17-OH-progesterone

X Xk X


X Xk X

T3, free-T4, and TSH X Xk X H.pylori testing, blood sample for CYP2C19 genotyping

Xl

ECG & vital signs X Xe Xh,i Xh,i Xh,i Xh,i X X Skin examination X X Xj Xk X X X Physical examination X X Xk X X meds = medication; Hemat & biochem = hematology & biochemistry; ACTH = adrenocorticotropic hormone; Apo = apolipoprotein; T3 = triidothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone; ECG = electrocardiogram. a At screening, subject’s demographics, medical and surgical history, smoking habits, and concomitant diseases were recorded and an HIV-1 and -2 test and Hepatitis A, B, and C test were performed; a serum pregnancy test was also performed for females. b Subjects were admitted to the unit the night before Day 1. c Adverse events and concomitant medications were monitored continuously from signing the ICF until the last trial-related activity. d Predose biochemistry samples were taken fasting for at least 10 hours, before breakfast. e Vital signs only. f For Treatment A, immediately before drug intake plus 0.5, 1, 2, 3, 4, 5, 6, 9, 12, and 16 hours postdose on Days 1 and 11, and immediately before drug intake on Days 2, 9, and 10. For Treatment B, immediately before drug intake plus 4 hours postdose on Day 1, immediately before drug intake plus 0.5, 1, 2, 3, 4, 5, 6, 9, 12, and 16 hours postdose on Days 11, 12, and 22, and immediately before drug intake on Days 9, 10, 13, 20, and 21. (Predose samples of Days 2, 12, 13, and 23 count as 24-hour samples of Days 1, 11, 12, and 22, respectively). g For Treatment A, for determination of TMC278 concentrations. For Treatment B, for determination of omeprazole, 5-hydroxyomeprazole, and omeprazole sulfone concentrations predose and 4 hours postdose on Day 1, predose on Days 9 and 10, and predose and 4 hours postdose on Day 11; for determination of TMC278 and omeprazole, 5-hydroxyomeprazole, and omeprazole sulfone concentrations on Days 12, 13, 20, 21, 22 and 23. (For Treatments A and B, for determination of TMC278 and omeprazole, 5-hydroxyomeprazole, and omeprazole sulfone concentrations predose on Day 1). Predose samples of Days 2, 12, 13, and 23 count as 24-hour samples of Days 1, 11, 12, and 22, respectively. (Footnotes continued on next page)

Synopsis

TMC278-C114 5


(Continued from previous page) h Within 2 hours before drug intake. On Day 12, within 2 hours before drug intake for Treatment B only. i Predose and 4 hours postdose. On Day 12 of Treatment A assessments were not performed 4 hours postdose. j Treatment A only (Sessions 1 or 2). k Treatment A only. l Only if this is the first treatment period.

Statistical Methods Descriptive statistics, frequency tabulations, Intent-to-Treat analysis, Wilcoxon matched-pairs signed-ranks test, linear mixed effects modeling, nonparametric test (Koch).



Panel 1 TMC278

Omeprazole/TMC278

Panel 2 Omeprazole/TMC278

TMC278



Ethnic Origin, n (%) Caucasian/White Black

Type of Smoker, n (%) No (non-smoker) Yes (light)

H.pylori Test Negative Positive

7/1

32.0 (24 - 45)

8 (100.0)

0

7 (87.5) 1 (12.5)

8 (100.0)

0

6/2

36.0 (20 - 43)

7 (87.5) 1 (12.5)

6 (75.0) 2 (25.0)

5 (62.5) 3 (37.5)

Drop-Outs - Reason

Withdrew consent

1 (12.5%)

0

All subjects were identified as extensive metabolizers with regard to CYP2C19 metabolism. Twelve out of 16 subjects had a genotype WT/WT, 3 subjects had genotype HET/WT and 1 subject had genotype NEG/WT.

Synopsis

TMC278-C114 6


Pharmacokinetics


(mean standard deviation, tmax: median [range])

Treatment A: TMC278 Alone

Treatment B: Omeprazole + TMC278

n 16 15 Day 1 (Treatment A)/Day 12 (Treatment B) (single dose)

Cmax, ng/mL 682.6 ± 264.8 308.9 ± 179.4 tmax, h 3.5 (2.0 - 6.0) 5.0 (2.0 - 6.0) AUC24h, ng.h/mL 7711 ± 3770 3502 ± 2092 Day 9 (Treatment A)/Day 20 (Treatment B) (multiple dose)

C0h, ng/mL 539.4 ± 243.5 435.0 ± 325.6 Day 10 (Treatment A)/Day 21 (Treatment B) (multiple dose)

C0h, ng/mL 541.9 ± 248.9 427.6 ± 266.2 Day 11 (Treatment A)/Day 22 (Treatment B) (steady-state)

C0h, ng/mL 620.5 ± 314.5 431.4 ± 240.5 Cmin, ng/mL 507.1 ± 241.0 347.0 ± 196.2 Cmax, ng/mL 1205 ± 311.3 779.4 ± 408.7 tmax, h 4.0 (0.0 - 6.0) 4.0 (2.0 - 9.0) AUC24h, ng.h/mL 18730 ± 6307 11920 ± 6573 Css,av, ng/mL 780.5 ± 262.8 496.6 ± 273.9 FI, % 94.98 ± 31.05 87.85 ± 25.34 LSmean ratio (90% CI), %

Effect of omeprazole on single dose TMC278 -B vs A

Day 12 vs Day 1 n - 15 vs 16 Cmax - 41.84 (32.35 - 54.12)a AUC24h - 44.24 (35.31 - 55.42)a

Effect of omeprazole on multiple dose TMC278 -

B vs A Day 22 vs Day 11

n - 15 vs 16 C0h - 70.25 (59.94 - 82.35)a Cmin - 67.36 (58.02 - 78.20)a Cmax - 59.53 (48.39 - 73.23)a AUC24h - 60.02 (51.05 - 70.57)a

a p-value < 0.05 Note: Both groups were combined in this table.

Synopsis

TMC278-C114 7


Pharmacokinetics of Omeprazole (mean standard deviation, tmax: median [range])

Day 11: Omeprazole Alone

Day 12: Omeprazole + TMC278 (SD)

Day 22: Omeprazole + TMC278 (MD)

n 15a 15a 15b C0h, ng/mL NQc NQc NQc Cmin, ng/mL NQc NQc NQc Cmax, ng/mL 415.5 ± 215.3 409.8 ± 257.8 385.1 ± 238.6 tmax, h 4.0 (1.0 - 5.0 ) 4.0 (1.0 - 6.0 ) 4.0 (2.0 - 6.0) AUC24h, ng.h/mL 1251 ± 919.7 1271 ± 1081 1136 ± 1054 t1/2, h 1.166 ± 0.3684 1.217 ± 0.3099 1.145 ± 0.3191 Css,av, ng/mL 52.12 ± 38.32 52.98 ± 45.02 47.33 ± 43.93 FI, % 987.5 ± 383.8 925.3 ± 337.0 978.2 ± 374.9 LSmean ratio (90% CI), %

- Day 12 vs Day 11 Day 22 vs Day 11 n - 15 vs 15 15 vs 15 Cmax - 94.21 (74.95 - 118.4) 85.64 (67.57 - 108.6) AUC24h - 99.43 (89.19 - 110.8) 85.77 (75.68 - 97.21)d

a n = 10 for t1/2 b n = 12 for t1/2 c NQ = not quantifiable (< 1.00 ng/mL) d p-value < 0.05 SD = single dose; MD = multiple dose. Note: Both groups were combined in this table.

Pharmacokinetics of 5-hydroxyomeprazole (mean standard deviation, tmax: median [range])


Day 12: Omeprazole and

TMC278 (SD)

Day 22: Omeprazole and TMC278 (MD)

n 15 15a 15 C0h, ng/mL NQb NQb NQb Cmin, ng/mL NQb NQb NQb Cmax, ng/mL 176.6 ± 56.34 187.9 ± 73.36 192.3 ± 76.48 tmax, h 4.0 (1.0 - 5.0) 5.0 (1.0 - 6.0) 4.0 (2.0 - 6.0) AUC24h, ng.h/mL 594.5 ± 139.6 631.4 ± 175.5 652.5 ± 181.4 t1/2, h 1.521 ± 0.5309 1.485 ± 0.3346 1.448 ± 0.3456 Css,av, ng/mL 24.77 ± 5.816 26.31 ± 7.314 27.19 ± 7.557 FI, % 739.3 ± 252.0 708.8 ± 190.6 716.2 ± 228.1 Ratio AUC24h, 5-hydroxyomeprazole/omeprazole (%) 72.36 ± 42.44 78.29 ± 49.43 92.28 ± 55.46 LSmean ratio (90% CI), %

- Day 12 vs Day 11 Day 22 vs Day 11 n - 15 vs 15 15 vs 15 Cmax - 103.4 (87.44 - 122.2) 106.5 (91.04 - 124.7) AUC24h - 105.5 (99.10 - 112.4) 108.6 (101.7 - 115.9)c Ratio AUC24h, 5-hydroxyomeprazole/omeprazole - 106.1 (99.59 - 113.1) 126.6 (117.7 -136.2)c

a n = 14 for t1/2 b NQ = not quantifiable (< 1.00 ng/mL) c p-value < 0.05 SD = single dose; MD = multiple dose. Note: Both groups were combined in this table.

Synopsis

TMC278-C114 8


Pharmacokinetics of Omeprazole Sulfone

(mean standard deviation, tmax: median [range])


Day 12: Omeprazole + TMC278 (SD)

Day 22: Omeprazole + TMC278 (MD)

n 15a 15 15a C0h, ng/mL 7.211 ± 12.32 6.239 ± 9.853 5.058 ± 8.825 Cmin, ng/mL 5.773 ± 9.776 4.989 ± 8.409 NQb Cmax, ng/mL 98.63 ± 50.35 91.67 ± 53.93 91.31 ± 64.18 tmax, h 5.0 (2.0 - 9.0) 5.0 (2.0 - 9.0) 5.0 (3.0 - 6.0) AUC24h, ng.h/mL 845.8 ± 690.1 851.5 ± 846.8 742.9 ± 825.3 t1/2, h 3.571 ± 1.594 3.417 ± 1.574 3.060 ± 1.555 Css,av, ng/mL 35.24 ± 28.76 35.48 ± 35.28 30.96 ± 34.39 FI, % 381.3 ± 197.3 355.9 ± 168.8 425.8 ± 212.2 Ratio AUC24h, omeprazole sulfone/omeprazole (%) 66.96 ± 27.72 61.08 ± 14.44 57.70 ± 16.23 LSmean ratio (90% CI), %

- Day 12 vs Day 11 Day 22 vs Day 11 n - 15c vs 15c 15c vs 15c

C0h - 95.81 (81.73 - 112.3) 66.19 (57.25 - 76.53)d

Cmin - 93.92 (77.79 - 113.4) -

Cmax - 89.75 (75.20 - 107.1) 84.52 (69.21 - 103.2)

AUC24h - 94.05 (83.12 - 106.4) 75.87 (65.15 - 88.36)d

Ratio AUC24h, omeprazole sulfone/omeprazole - 94.59 (84.26 - 106.2) 88.46 (77.66 - 100.8)

a n = 14 for t1/2 b NQ = not quantifiable (< 1.00 ng/mL) c n = 8 for C0h and Cmin d p-value < 0.05 SD = single dose; MD = multiple dose. Note: Both groups were combined in this table.

Synopsis

TMC278-C114 9


Safety

(n = number of subjects with data) TMC278 (N = 16)

Omeprazole (N = 16)

Omeprazole + TMC278

(N = 15)

Follow-up

(N = 16) Adverse Events (AEs)

n (%) with 1 or more AEs 10 (62.5%) 14 (87.5%) 11 (73.3%) 5 (31.3%) Most common preferred terms, n (%) Headache 8 (50.0%) 6 (37.5%) 4 (26.7%) 0 Fatigue 3 (18.8%) 1 (6.3%) 2 (13.3%) 0 Hyperbilirubinaemia 2 (12.5%) 2 (12.5%) 1 (6.7%) 2 (12.5%) Blood creatinine increased 0 0 0 4 (25.0%) Hyperuricaemia 1 (6.3%) 1 (6.3%) 2 (13.3%) 1 (6.3%) n (%) of deaths 0 0 0 0 n (%) with 1 or more other serious AEs 0 0 0 0 n (%) of treatment stopped due to AEs 0 0 0 0 n (%) with 1 or more grade 3 or 4 AEs 0 0 0 0

Of the 16 subjects enrolled in the trial, 15 (93.8%) subjects were reported with an AE during the trial. The most commonly reported AEs during the trial were headache (62.5%) and fatigue and hyperbilirubinemia (both 31.3%). No grade 3 or 4 AEs were reported; 14 subjects (87.5%) were reported with grade 1 (mild) AEs and 9 subjects (56.3%) were reported with grade 2 (moderate) AEs. No subjects had an AE that was considered to be probably related to study medication. One (6.3%) subject had an AE that was considered to be very likely related to TMC278: a grade 1 event of rash macular reported during treatment with TMC278 alone. There were no deaths or other SAEs reported in this trial. No subjects discontinued the trial due to an AE. Three AEs considered to be skin events of interest were reported during the trial: 2 events of rash maculo-papular and 1 event of rash macular. The events of rash maculo-papular were considered to be possibly related to TMC278 and the event of rash macular was considered to be very likely related to TMC278. Clinical Laboratory Tests

n (%) with 1 or more post-dose grade 3 or 4 laboratory abnormalities

0 0 0 0

There were no consistent or clinically relevant treatment-emergent changes over time in laboratory parameters. No grade 3 or 4 treatment-emergent abnormalities were reported during the trial. Two subjects had at least 1 treatment-emergent grade 2 abnormality in this trial (1 subject was reported with elevated total bilirubin and elevated LDL cholesterol and 1 subject was reported with elevated cholesterol). Twelve subjects had at least 1 grade 1 treatment-emergent abnormality. Adrenal Function Results At all time points, the median cortisol values increased from T0 to T30 and T60. The median cortisol value at T0 at the 3 assessment time points was 461.58 nmol/L at screening visit, 484.62 nmol/L on Day 12 of the TMC278 alone phase, and 512.07 nmol/L on Day 23 of the omeprazole + TMC278 phase. The median change in T0 cortisol after TMC278 administration compared to reference (screening) was -9.79 nmol/L on Day 12 of the TMC278 alone phase and 1.10 nmol/L on Day 23 of the omeprazole + TMC278 phase. In response to ACTH stimulation 87.5% and 100% of subjects in the TMC278 alone and omeprazole + TMC278 groups, respectively, achieved a cortisol value 550 nmol/L; 2 subjects did not achieve a cortisol value 550 nmol/L after ACTH stimulation when TMC278 was administered alone in Session 2. At all time points, the median 17-OH-progesterone value increased post-ACTH stimulation (T30 and T60) compared to T0. The median value at T0 was higher after TMC278 administration (4.993 nmol/L at screening visit, 7.868 nmol/L on Day 12 of the TMC278 alone phase, and 8.473 nmol/L on Day 23 of the omeprazole + TMC278 phase). Cardiovascular Safety Minor changes were reported for vital signs. None of the observed changes were considered to be clinically relevant. Minor changes were reported for ECG parameters, with observed changes mainly being decreases in PQ, QT, and RR intervals. No trends or relationship to study medication were apparent and no clinically relevant changes were reported. Physical and Skin Examinations

Two subjects had rash-related findings on scheduled physical examination, and in total 3 were reported with AEs considered to be skin events of interest: 2 events of rash maculo-papular (1 grade 2 event and 1 grade 1 event) and 1 grade 1 event of rash macular. Additionally on scheduled physical examination, 1 subject each had the findings of discrete thrombophlebitis, swollen ankle (posttraumatic), and scar right knee (secondary to dog bite).

Synopsis

TMC278-C114 10


Conclusions

The results of this study demonstrated that coadministration of omeprazole (20 mg q.d.) resulted in a decrease in the AUC24h of TMC278 of 56% for a single 150 mg TMC278 dose and a decrease of 40% at steady-state after 150 mg q.d. doses of TMC278 compared to administration of TMC278 alone. A single dose of 150 mg TMC278 did not influence the pharmacokinetics of omeprazole or its metabolites 5-hydroxyomeprazole and omeprazole sulfone. TMC278, dosed at 150 mg q.d. for 11 days, caused decreases in omeprazole and omeprazole sulfone AUC24h of 14% and 24%, respectively, and an increase in 5-hydroxyomeprazole of 9% compared to administration of omeprazole alone. The ratio of the AUC24h of omeprazole sulfone to omeprazole was not significantly affected by TMC278, which suggests that TMC278 did not significantly influence the CYP3A4-mediated metabolism of omeprazole. The ratio of the AUC24h of 5-hydroxyomeprazole to omeprazole increased by 27%, which suggests a modest induction of CYP2C19-mediated metabolism after repeated administration of TMC278 150 mg q.d. Given the marked reduction in the exposure to TMC278 when omeprazole is coadministered, the combined use of these drugs should be avoided.

In these healthy subjects, the administration of 150 mg q.d. TMC278 with or without 20 mg q.d. omeprazole was generally well tolerated.

Synopsis

TMC278-C116 1




Trade Name: -




Clinical Phase: I

Title: A Phase I, open-label, randomized, two-way crossover trial in 16 healthy subjects to investigate the potential pharmacokinetic interaction between steady-state TMC278 and steady-state atorvastatin

Investigator: Germany

Country: Germany


End: - -20


No. of Subjects: 16

Objectives: The primary objectives of this trial were: to investigate the effect of steady-state atorvastatin on the steady-state pharmacokinetics of TMC278; and to investigate the effect of steady-state TMC278 on the steady-state pharmacokinetics of atorvastatin, atorvastatin lactone, and the active metabolites 2-hydroxy (2-OH)-atorvastatin and 4-OH-atorvastatin. The secondary objective was to determine the short-term safety and tolerability of coadministration of TMC278 and atorvastatin.

Design: This was a Phase I, open-label, randomized, two-way crossover trial to investigate the pharmacokinetic interaction between TMC278 and atorvastatin at steady-state. In 2 periods, 16 healthy subjects received, in a randomized order, atorvastatin alone (Treatment A) or the combination of TMC278 and atorvastatin (Treatment B). There was a washout period of at least 14 days between the 2 treatment periods. Randomization was done in such a way that in each period, 8 out of 16 subjects received the same treatment, and that each subject received a different treatment in each period. Treatment A consisted of atorvastatin 40 mg once daily (q.d.) for 4 days. Treatment B consisted of TMC278 150 mg q.d. for 15 days with coadministration of atorvastatin 40 mg q.d. from Days 12 to 15. Full pharmacokinetic profiles of atorvastatin, atorvastatin lactone, 2-hydroxy (2-OH)-atorvastatin and 4-OH-atorvastatin up to 72 hours postdose were determined on Day 4 of Treatment A and Day 15 of Treatment B. Full pharmacokinetic profiles of TMC278 up to 24 hours postdose were determined on Days 11 and 15 of Treatment B. Tolerability and safety were assessed throughout the trial period.

Subject Selection Inclusion Criteria

1. Male or female, aged between 18 and 45 years, extremes included. 2. Smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day (or non smoking) for at least 3 months prior to selection. 3. Normal weight as defined by a Quetelet Index (Body Mass Index, weight in kg divided by height in meters squared) of 18.0 to 30.0 kg/m2, extremes included. 4. Informed Consent Form (ICF) signed voluntarily before the first trial-related activity. 5. Cortisol of at least 550 nmol/L (19.9 g/dL) at least at 1 of the measured time points at screening (i.e., prestimulation cortisol, 30 or 60 minutes after 250 g adrenocorticotropic hormone [ACTH] stimulation). 6. Able to comply with protocol requirements. 7. Healthy on the basis of a pre-trial physical examination, medical history, electrocardiogram (ECG), vital signs, and the results of blood biochemistry, hematology and urinalysis tests carried out at screening.

0105325, Final, 06-Nov-2007 17:38

Synopsis

TMC278-C116 2


Exclusion Criteria1. A positive human immunodeficiency virus (HIV)-1 or HIV-2 test at screening. 2. Female, except if postmenopausal for more than 2 years, or posthysterectomy, or post-tubal ligation (without reversal operation). 3. History or suspicion of alcohol, barbiturate, amphetamine, recreational, or narcotic drug use, which, in the investigator’s opinion, could compromise subject safety or compliance with the trial procedures. 4. Hepatitis A, B, or C infection (confirmed by Hepatitis A antibody IgM, Hepatitis B surface antigen, or Hepatitis C antibody, respectively) at screening. 5. A positive urine drug test at screening. Urine was tested for the presence of amphetamines, benzodiazepines, cocaine, cannabinoids, opioids, barbiturates, and methadone. 6. Currently active or underlying gastrointestinal, cardiovascular, neurologic, psychiatric, metabolic, renal, hepatic, respiratory, inflammatory, or infectious disease. 7. Currently significant diarrhea, gastric stasis, or constipation that in the investigator’s opinion could influence drug absorption or bioavailability. 8. Any current or previous adrenal illness. 9. Any history of tuberculosis or ocular herpes. 10. Any history of significant skin disease such as, but not limited to, drug rash or eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis, or urticaria. 11. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication administered in this trial (i.e., TMC278, atorvastatin, and tetracosactide). 12. Use of concomitant medication, including over-the-counter products, dietary supplements, and herbal medications. Over-the-counter medication must have been discontinued at least 7 days prior to the first administration of study medication and prescribed medication must have been discontinued at least 14 days before the first administration of study medication, except ibuprofen. 13. Participation in an investigational drug trial within 60 days prior to the first intake of study medication. 14. Donation of blood or plasma within 60 days preceding the first intake of study medication. 15. Subjects with the following laboratory abnormalities at screening as defined by the Division of Acquired Immunodeficiency Syndrome Table for Grading the Severity of Adult and Pediatric Adverse Events (AEs) and in accordance with the normal ranges of the trial clinical laboratory: serum creatinine grade 1 or greater ( 1.1 x upper limit of laboratory normal range [ULN]); serum lipase grade 1 or greater ( 1.1 x ULN); hemoglobin grade 1 or greater ( 10.9 g/dL); platelet count grade 1 or greater ( 124.999 x 109/L); absolute neutrophil count grade 1 or greater ( 1.3 x 109/L); aspartate aminotransferase or alanine aminotransferase grade 1 or greater ( 1.25 x ULN); total bilirubin grade 1 or greater ( 1.1 x ULN); any other grade 2 or above, including proteinuria (spot urine) 2+, and microscopic hematuria (>10 red blood cells/high power field). 16. Having previously participated in more than 1 trial (single or multiple dose) with TMC125, TMC120, and/or TMC278 or having developed rash, erythema, or urticaria while participating in a trial with TMC125, TMC120, and/or TMC278.


Dosage

Dosage Form (F No.)

Usage

40 mg q.d. atorvastatin

40 mg tablets

1 x 40 mg tablet orally on Days 1-4

150 mg q.d. TMC278 and 40 mg q.d. atorvastatin

100 mg tablets (F002) and 50 mg tablets (F003) and 40 mg atorvastatin tablets

1 x 50 mg tablet and 1 x 100 mg tablet orally on Days 1-15 and 1 x 40 mg tablet orally on Days 12-15

Batch Number 0444104D PD1268, PD1273 (TMC278) 0444104D (atorvastatin)

Dose Regimen Sequence 1: Treatment A during Period 1 and Treatment B during Period 2, with a washout period of at least 14 days between periods.

Sequence 2: Treatment B during Period 1 and Treatment A during Period 2, with a washout period of at least 14 days between periods.

0105325, Final, 06-Nov-2007 17:38

Synopsis

TMC278-C116 3



19 days (excluding washout)

Duration of Trial

39 days (excluding screening and follow-up)

Disallowed Medication

During the entire trial, subjects were not to use any medication other than study medication and ibuprofen. All over-the-counter medication must have been discontinued at least 7 days before the first intake of study medication and all prescribed medication must have been discontinued at least 14 days before first intake of study medication, except for ibuprofen. Subjects were not to use any herbal medications or dietary supplements including products containing Hypericum perforatum (e.g., St. John’s wort) from 14 days before the first intake of study medication up to 14 days after the last intake of study medication. Ibuprofen could be used up to 3 days before the intake of study medication. From 3 days before intake of study medication until the end of each period, the investigator could permit the use of ibuprofen at no more than 1 x 400 mg per day. In case of cutaneous reaction/rash and/or an allergic reaction, the use of cetirizine (Zyrtec ),levocetirizine (Xyzal ), topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In case of nausea, the use of antiemetics was permitted. In case of diarrhea, the use of loperamide was permitted.

0105325, Final, 06-Nov-2007 17:38

Synopsis

TMC278-C116 4


Assessments

Scre

enin

ga

Period 1 or 2/Treatment A or Treatment B

Period 1 or 2/Treatment B

Follo

w-u

p

21

days

Day

1

Day

2, 3

j

Day

4j

Day

5i,j

Day

6, 7

j

Day

8

Day

9, 1

0

Day

11,

15

Day

12

Day

13,

14

Day

16m

Day

17,

18

Day

7 &

30,

31

, or 3

2

Drug screening

X

Pharmaco-kinetics Blood sample

Xd,e,f Xd,e Xd,e Xe Xe Xd,f Xd,f Xd,e,f Xd,e,f Xd,e,f Xe,f Xe

Safety AEs + concomitant medsb

X X X X X X X X X X X X X X

Hemat & biochemc

X Xh Xh X X Xh Xh X X

Urinalysis X Xg Xg Xg X X ACTH stimulation test with determination of cortisol and 17-OH-progesterone

X X X X

Apo A1, Apo B, insulin, and

1-acid glycoprotein

X X X

T3, free-T4,and TSH

X X X

ECG & vital signs

X Xg,h Xg,h Xg,h Xl X X

Skin examination

X X X Xk X X X

Physical examination

X X X X X X

meds = medication; Hemat & biochem = hematology & biochemistry; stim = stimulation; Apo = apolipoprotein; T3 = triidothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone; a At screening, subject’s demographics, medical and surgical history, smoking habits, concomitant diseases, HIV-1

and -2 test, and Hepatitis A, B, and C test; a serum pregnancy test was also performed if applicable. b AEs and concomitant medications were monitored continuously from signing the ICF until the last trial-related

activity.c Biochemistry samples were taken fasting for at least 10 hours, before breakfast.d For Treatment A, immediately before study medication intake on Days 1-4. For Treatment B, immediately before

study medication intake on Days 1, 8, 9, 10, 11, 12, 13, 14, and 15.

0105325, Final, 06-Nov-2007 17:38

Synopsis

TMC278-C116 5


e For Treatment A, for determination of atorvastatin, atorvastatin lactone, 2-OH-atorvastatin, and 4-OH-atorvastatin concentrations predose on Days 1, 2, 3, and 4 plus 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 16, 24, 36, 48, and 72 hours postdose on Day 4. For Treatment B, for determination of atorvastatin, atorvastatin lactone, 2-OH-atorvastatin, and 4-OH-atorvastatin concentrations predose on Days 1, 12, 13, 14, and 15 plus 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 16, 24, 36, 48, and 72 hours postdose on Day 15.

f For Treatment A, for determination of TMC278 concentrations predose on Day 1. For Treatment B, for determination of TMC278 concentrations predose and 4 hours postdose on Day 1, predose on Days 8, 9, 10, 11, 12, 13, 14, and 15 plus 0.5, 1, 2, 3, 4, 5, 6, 9, 12, and 16 hours postdose on Day 11 and 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours postdose on Day 15.

g Within 2 hours before study medication intake; on Days 1 and 4 of Treatment A, and Days 1, 11 and 15 (ECG only) for Treatment B.

h For Treatment A, predose on Day 1 and predose and 4 hours postdose on Day 4. For Treatment B, predose and 4 hours postdose on Days 1, 11, 12 (ECG 4 hours postdose only), and 15.

i Day 5 is Day 1 of washout period (if applicable). j Treatment A only. k Day 10 only. l 4 hours postdose only. m Day 16 is Day 1 of washout period (if applicable).

Statistical Methods Descriptive statistics, frequency and summary tabulations, cross-tabulations Intent-to-Treat analysis, two-sided Wilcoxon matched-pairs signed-ranks test, linear mixed effects modeling, Mann-Whitney U test (Koch).

0105325, Final, 06-Nov-2007 17:38

Synopsis

TMC278-C116 6



Baseline Characteristics - Subject Disposition Atorvastatin TMC278 +

Atorvastatin

N = 8

TMC278 + Atorvastatin

Atorvastatin

N = 8

Total

N = 16 Number of Subjects Entered (M/F) Age: median (range), yrs

8/0 32.0 (21-39)

8/0 29.5 (19-40)

16/0 32.0 (19-40)

Drop-Outs 0 0 0


TMC278 Alone (Reference) TMC278 + Atorvastatin (Test)

n 16 16C0h, ng/mL 451.8 ± 173.4 429.8 ± 163.7 Cmin, ng/mL 382.4 ± 141.5 345.9 ± 126.3 Cmax, ng/mL 886.5 ± 255.3 843.7 ± 302.7 tmax, h 4.0 [2.0 - 5.0] 5.0 [2.0 - 24.0] AUC24h, ng.h/mL 14130 ± 4202 13110 ± 4908 Css, av, ng/mL 588.8 ± 175.1 546.3 ± 204.5 FI, % 88.12 ± 26.23 90.75 ± 22.54

LS mean Ratio (90% CI), % Test vs Reference

n - 16 vs 16 C0h - 94.13 (84.86 - 104.4) Cmin - 90.02 (84.44 - 95.96)* Cmax - 91.36 (78.99 - 105.7) AUC24h - 89.50 (80.66 - 99.30)

SD = standard deviation tmax = time to reach maximum plasma concentration C0h = predose plasma concentration Cmin = minimum plasma concentration Cmax = maximum plasma concentration h = hour AUC24h = area under the plasma concentration-time curve from time of administration up to 24 hours post dosing Css, av = average steady-state plasma concentration FI = fluctuation index LS = least square CI = confidence interval Statistical significance at p <0.05 is indicated by * Note: data from both groups are combined.

0105325, Final, 06-Nov-2007 17:38

Synopsis

TMC278-C116 7


Pharmacokinetics of Atorvastatin

(mean SD, tmax: median [range])

Atorvastatin Alone (Reference)

Atorvastatin + TMC278 (Test)

n 16 16C0h, ng/mL 1.161 ± 0.5782 1.017 ± 0.6764 Cmin, ng/mL 1.104 ± 0.5528 1.001 ± 0.6771 Cmax, ng/mL 14.45 ± 10.77 17.77 ± 9.201 tmax, h 4.0 [0.5 - 5.0] 3.0 [0.5 - 5.0] AUC24h, ng.h/mL 98.88 ± 52.68 104.9 ± 63.14 t1/2term, h 11.26 ± 3.031 10.26 ± 3.397 Css, av, ng/mL 4.120 ± 2.195 4.370 ± 2.631 FI, % 318.8 ± 198.2 432.2 ± 265.1 LS mean Ratio (90% CI), %

Test vs Reference n - 16 vs 16 C0h - 81.98 (67.25 - 99.94) Cmin - 84.57 (69.44 - 103.0) Cmax - 134.9 (108.3 - 168.1)* AUC24h - 104.0 (96.55 - 112.1)

t1/2term = terminal elimination half-life Statistical significance at p <0.05 is indicated by * Note: data from both groups are combined.

Pharmacokinetics of Atorvastatin Lactone




n 16 16C0h, ng/mL 1.199 ± 0.5662 0.9475 ± 0.6053 Cmin, ng/mL 1.115 ± 0.4936 0.8903 ± 0.5500 Cmax, ng/mL 8.479 ± 5.445 7.882 ± 5.126 tmax, h 5.0 [1.0 - 6.0] 5.0 [1.0 - 5.0] AUC24h, ng.h/mL 91.70 ± 52.71 76.35 ± 46.32 t1/2term, h 11.67 ± 1.879 10.17 ± 1.903 Css, av, ng/mL 3.821 ± 2.196 3.181 ± 1.930 FI, % 185.6 ± 41.59 218.2 ± 41.92


n - 16 vs 16 C0h - 73.28 (62.57 - 85.81)* Cmin - 73.95 (63.46 - 86.18)* Cmax - 93.19 (84.33 - 103.0) AUC24h - 82.08 (76.73 - 87.80)*

Statistical significance at p <0.05 is indicated by * Note: data from both groups are combined.

0105325, Final, 06-Nov-2007 17:38

Synopsis

TMC278-C116 8


Pharmacokinetics of 2-OH-Atorvastatin




n 16 16C0h, ng/mL 1.125 ± 0.5078 1.548 ± 0.8653 Cmin, ng/mL 0.9946 ± 0.3970 1.348 ± 0.6084 Cmax, ng/mL 8.634 ± 6.056 12.52 ± 5.426 tmax, h 5.0 (0.5 - 12.0) 5.0 (0.5 - 6.0) AUC24h, ng.h/mL 80.80 ± 34.86 113.6 ± 53.21 t1/2term, h 15.01 ± 7.897 10.82 ± 2.439 Css, av, ng/mL 3.367 ± 1.453 4.733 ± 2.217 FI, % 217.3 ± 105.3 248.4 ± 94.49 Ratio AUC24h, 2-OH-atorvastatatin/atorvastatin, % 85.73 ± 17.93 115.2 ± 26.17


n - 16 vs 16 C0h - 131.0 (107.8 - 159.2)* Cmin - 131.5 (109.5 - 158.1)* Cmax - 157.6 (132.6 - 187.2)* AUC24h - 139.1 (128.9 - 150.1)* Ratio AUC24h, 2-OH-atorvastatatin/atorvastatin - 133.7 (128.5 -139.2)*

Statistical significance at p<0.05 is indicated by * Note: data from both groups are combined.

0105325, Final, 06-Nov-2007 17:38

Synopsis

TMC278-C116 9


Pharmacokinetics of 4-OH-Atorvastatin (mean SD, tmax: median [range])



n 16a 16b

C0h, ng/mL 0.2928 ± 0.2335 0.3603 ± 0.2232 Cmin, ng/mL NQ 0.2626 ± 0.2017 Cmax, ng/mL 0.7561 ± 0.3489 0.9896 ± 0.5375 tmax, h 5.0 [1.0 - 16.0] 5.0 [0.5 - 16.0] AUC24h, ng.h/mL 11.23 ± 5.887 13.92 ± 6.849 t1/2term, hc 28.73 ± 12.41 23.57 ± 5.825Css, av, ng/mL 0.4680 ± 0.2454 0.5802 ± 0.2854 FI, % 175.5 ± 175.8 175.9 ± 184.1 LS mean Ratio (90% CI), %

Test vs Reference nd - 16 vs 16 C0h - 124.7 (104.3 - 149.1)* Cmax - 128.2 (114.7 -143.4)* AUC24h - 122.9 (113.4 – 133.1)*

NQ = Not Quantifiable (<0.250 ng/mL) a n = 7 for t1/2term b n = 8 for t1/2term c Accurate determination not possible d n = 13 vs 13 for C0h Statistical significance at p <0.05 is indicated by * Note: data from both groups are combined.

0105325, Final, 06-Nov-2007 17:38

Synopsis

TMC278-C116 10


Safety Atorvastatin

(n = 16)

TMC278

(n = 16)


(n = 16)

Follow-up

(n = 16)

Total

(n = 16)

AEs Most frequently reported AEs (reported in >1 subject), n (%)

Headache 0 2 (12.5%) 0 0 2 (12.5%) n (%) with 1 or more AEs 1 (6.3%) 8 (50.0%) 3 (18.8%) 1 (6.3%) 9 (56.3%) n (%) of deaths 0 0 0 0 0n (%) with 1 or more serious AEs (SAEs)

0 0 0 0 0


0 0 0 0 0


0 0 0 0 0

Overall, 9 subjects (56.3%) experienced at least 1 AE during the trial. Headache was reported by 2 subjects (12.5%) during treatment with TMC278 alone; all other AEs were reported by no more than 1 subject. The most severe grade of any event was grade 2, affecting 1 subject (6.3%) during TMC278 treatment (pharyngitis) and TMC278 plus atorvastatin treatment (conjunctivitis). No grade 3 or 4 AEs were reported and no subjects withdrew from the trial due to an AE. No subjects experienced SAEs, and no subjects died. No AEs were considered probably or very likely to be related to study medication. Clinical Laboratory Tests

Atorvastatin

(n = 16)

TMC278

(n = 16)


(n = 16)

Follow-up

(n = 16)

Total

(n = 16)


0 0 0 1 (6.3%) 1 (6.3%)

No notable patterns in laboratory data were apparent. No subjects experienced a grade 4 treatment-emergent abnormality in laboratory results, and 1 subject experienced a grade 3 abnormality (abnormally high creatine kinase) during the follow-up period. There was no notable difference in the frequency of abnormalities between different treatment periods. The majority of the abnormal laboratory results occurred during the follow-up period. No associated AEs were reported. Adrenal Function Testing

No effects of treatment were apparent on median values and median changes from reference for cortisol levels. Median 17-OH progesterone levels were similar at screening and during atorvastatin treatment, and were higher during TMC278 and TMC278 plus atorvastatin treatment. Prior to adrenal gland stimulation, all 16 subjects had a T0 cortisol value of 55 nmol/L. After adrenal gland stimulation, 1 subject (Subject 1160012) did not achieve a cortisol level 550 nmol/L in the TMC278 plus atorvastatin phase. Levels of 17-OH progesterone were above normal range at T0 at each assessment. The MC of 17-OH progesterone at each time point that the cortisol level did not reach >550 nmol/L was within normal limits, indicating no significant inhibition of 21-hydroxylase. Cardiovascular Safety

Minor changes in vital signs parameters were observed, with statistically significant changes occurring predominantly for supine diastolic blood pressure (BP) and standing diastolic BP. There was no predominance of statistically significant changes during any one treatment period. None of the changes were considered clinically relevant.

Minor changes from reference were observed in most ECG measurements, and some changes reached statistical significance, predominantly for QT interval and QT corrected for heart rate using Fridericia’s formula. None of the statistically significant changes were considered clinically relevant.

0105325, Final, 06-Nov-2007 17:38

Synopsis

TMC278-C116 11



Physical examinations revealed 1 skin abnormality during the trial: 1 subject had erythema, which was not related to trial treatment.

Conclusions

The results of this trial demonstrate that after the combined intake of TMC278 and atorvastatin, the Cmin of TMC278 was statistically significantly decreased by 10%, which was not considered to be clinically relevant. No statistically significant changes were observed in C0h, Cmax, and AUC24h of TMC278. In the presence of TMC278, the Cmax of atorvastatin was statistically significantly increased by 35%. No statistically significant changes were observed in C0h, Cmin, and AUC24h of atorvastatin. The C0h, Cmax, and AUC24h of 2-OH-atorvastatin and 4-OH-atorvastatin were statistically significantly increased by 23-58%. The ratio AUC24h of 2-OH-atorvastatin versus atorvastatin was statistically significantly increased by 34%. For total hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase activity, calculated as the sum of atorvastatin and the active metabolites 2-OH-atorvastatin and 4-OH-atorvastatin, the Cmax and AUC24h were statistically significantly increased by 39% and 20%, respectively, when combined with TMC278. No statistically significant changes were observed in C0h and Cmin for the total HMG-CoA reductase activity. For the inactive atorvastatin lactone, C0h, Cmin, and AUC24h were statistically significantly decreased by 27%, 26%, and 18%, respectively. No statistically significant change was observed in Cmax. The changes in total HMG-CoA reductase activity during combination of atorvastatin and TMC278 were not considered to be clinically relevant. No dosage adjustments are required when these drugs are coadministered. The 34% increased ratio of 2-OH atorvastatin to atorvastatin during combination with steady-state TMC278 may be explained by modest induction of systemic cytochrome P450 3A4-mediated metabolism of atorvastatin.

In these healthy subjects, the administration of 150 mg TMC278, both alone and in combination with 40 mg atorvastatin, was generally safe and well tolerated.

0105325, Final, 06-Nov-2007 17:38

Synopsis

TMC278-C120 1




Trade Name: -




Clinical Phase: I

Title: A Phase I, open-label trial to investigate the effect of steady-state TMC278 on the pharmacokinetic characteristics of ethinylestradiol and norethindrone at steady-state in healthy women.

Investigator:

United Kingdom




Objectives: The primary objectives of this trial were to determine the effect of steady-state concentrations of TMC278 on the steady-state pharmacokinetics of ethinylestradiol, and on the steady-state pharmacokinetics of norethindrone. Secondary objectives were to determine the short-term safety and tolerability of coadministration of TMC278, ethinylestradiol, and norethindrone and to assess the effect of daily dosing of ethinylestradiol and norethindrone on the steady-state pharmacokinetics of TMC278, based on historical data.

Design: This was a Phase I, open-label trial in healthy women to investigate the pharmacokinetic interaction between the combination of ethinylestradiol and norethindrone, and TMC278. The trial population consisted of 16 healthy women who were willing to continue or initiate oral contraceptives (OC), specifically ethinylestradiol 35 g once daily (q.d.) and norethindrone 1.0 mg q.d. (the components of Ortho-Novum1/35), and were stable on it (i.e., received Ortho-Novum 1/35 for at least 1 OC cycle prior to the start of Treatment A). The treatment period consisted of 2 OC cycles (Treatments A and B). During Treatment A, subjects received OC alone for 21 days. During Treatment B, subjects received OC for 21 days with TMC278 150 mg q.d. coadministered for the first 15 days. There was no OC treatment on Days 22-28 (Treatment A) or on Days 50-56 (Treatment B). The full pharmacokinetic profile of TMC278 was determined on Day 15 of Treatment B (i.e. Day 43). Full pharmacokinetic profiles of ethinylestradiol and norethindrone were determined on Day 15 of both OC cycles (Treatment A, Day 15 and Treatment B, Day 43). Pharmacodynamic assessments of oral contraceptive effectiveness, i.e., levels of serum progesterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were determined before dosing and after 14 days of Treatments A and B (Days 1, 14, 29, and 42). Safety and tolerability were also assessed.

Subject Selection

Inclusion Criteria

1. Female, aged between 18 and 45 years, extremes included.

2. Willing to continue or initiate OC therapy, specifically, ethinylestradiol 35 μg and norethindrone 1.0 mg (the components of Ortho-Novum® 1/35) for at least 1 complete OC cycle before Treatment A, and until the end of the OC cycle following the last dose of TMC278.

3. Subjects consented to use a double barrier method of birth control from the first intake of TMC278 until at least 1 month after the last study medication intake (i.e., a condom with spermicide or condom without spermicide combined with either an intra uterine device, diaphragm, cervical cap, or female condom) or to practice abstinence.


Synopsis

TMC278-C120 2


Inclusion Criteria, continued


6. Cortisol of at least 550 nmol/L (19.9 μg/dL) at least at 1 of the measured time points (i.e., prestimulation cortisol, 30 or 60 minutes after 250 μg adrenocorticotropic hormone [ACTH] stimulation) at the screening assessment.


8. Healthy on the basis of a physical examination (including gynecologic), medical history, electrocardiogram (ECG), vital signs, and the results of blood biochemistry and hematology tests and a urinalysis carried out at screening.

Exclusion Criteria

1. A positive human immunodeficiency virus (HIV)-1 or -2 test at screening.

2. History or suspicion of alcohol or barbiturate, amphetamine, recreational, or narcotic drug use which, in the investigator’s opinion, would compromise subject safety or compliance with trial procedures.

3. Hepatitis A infection (confirmed by hepatitis A antibody IgM), or hepatitis B infection (confirmed by hepatitis B surface antigen), or hepatitis C infection (confirmed by hepatitis C virus antibody) at screening.

4. A positive urine drug test at screening. Urine was tested for the presence of amphetamines, benzodiazepines, cocaine, cannabinoids, opioids, methadone, and barbiturates.

5. Currently active gastrointestinal, cardiovascular, neurological, psychiatric, metabolic, renal, hepatic, respiratory, inflammatory, or infectious disease.


7. History of tuberculosis or ocular herpes.

8. Currently significant diarrhea, gastric stasis, or constipation that, in the investigator’s opinion, could influence drug absorption or bioavailability.


10. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the study medication administered in this trial (i.e., TMC278 as well as Ortho-Novum® 1/35), and to ACTH.

11. A clinically significant abnormal finding in the gynecological examination including Papanicolaou’s smear III or IV in the cervical smear carried out at screening.

12. Currently active gynecological disorders including, but not limited to, vaginal bleeding without an obvious reason and hyperprolactinemia with or without galactorrhea.

13. Any major medical condition that would preclude the safe administration of OC therapy such as, but not limited to, high blood pressure, diabetes, clinically significant abnormal lipid profile, had or had had a heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice, malignant or benign liver tumors, clotting disorders, thrombophlebitis or thromboembolic disorders, and headache with focal neurological symptoms.

14. Use of concomitant medication, including over-the-counter products and dietary supplements. Over-the-counter medication must have been discontinued at least 7 days prior to the start of the second OC cycle (Day 1) and prescribed medication must have been discontinued at least 14 days before the start of the second OC cycle, except for ibuprofen.

15. Participation in an investigational drug trial within 30 days prior to the start of the first OC cycle before Treatment A.

Synopsis

TMC278-C120 3


Exclusion Criteria, continued

16. Donation of blood or plasma within the 60 days preceding the start of the first OC cycle before Treatment A.

17. Had previously participated in more than 1 trial (single or multiple dose) with TMC125, TMC120, and/or TMC278 (formerly known as R278474) or had developed a rash, erythema, or urticaria while participating in a trial with the before mentioned compounds.

18. Subjects with the following laboratory abnormalities at screening as defined by the Division of Acquired Immunodeficiency Syndrome Table for Grading the Severity of Adult and Pediatric Adverse Events: serum creatinine grade 1 or greater ( 1.1 x upper limit of normal range [ULN]), lipase grade 1 or greater ( 1.1 x ULN), hemoglobin toxicity grade 1 or greater ( 10.9 g/dL), platelet count grade 1 or greater ( 124.999/mm³), absolute neutrophil count grade 1 or greater ( 1300/mm³), aspartate aminotransferase or alanine aminotransferase grade 1 or greater ( 1.25 x ULN), total bilirubin grade 1 or greater ( 1.1 x ULN), any other abnormality grade 2 or above, including: proteinuria (spot urine) 2+ and microscopic hematuria > 10 red blood cells/high power field, unless menstruating.

19. Pregnant or breastfeeding.

20. Smoked cigarettes, cigars, or pipes, or had smoked within the past 6 months before selection.


Dosage Ortho-Novum 1/35 q.d. Ortho-Novum 1/35 q.d. and TMC278 150 mg q.d.

Dosage Form (TF No.) Ortho-Novum 1/35 tablets containing ethinylestradiol 35 g and norethindrone

1.0 mg

Ortho-Novum 1/35 tablets and TMC278 50 mg tablets (F003) and

100 mg tablets (F002)

Usage 1 Ortho-Novum tablet on Days 1-21, oral intake

1 Ortho-Novum tablet on Days 1-21 + 1 x 50 mg and 1 x 100 mg TMC278

tablets on Days 1-15, oral intake

Batch Number Ortho-Novum : 04LS078 Ortho-Novum : 04LS078 TMC278 50 mg: PD1273TMC278 100 mg: PD1268

Dose Regimen All subjects must have received Ortho-Novum 1/35 for at least 1 OC cycle prior to the start of Treatment A. All subjects received Treatment A during the second OC cycle and Treatment B during the third OC cycle.

Duration of Treatment 42 days

Duration of Trial 56 trial days, of which 15 days treatment with TMC278 (excluding screening and follow-up)

Synopsis

TMC278-C120 4


Disallowed Medication All over-the-counter medication had to be discontinued at least 7 days before Day 1 and all prescribed medication had to be discontinued at least 14 days before Day 1, except for ibuprofen and Ortho-Novum 1/35. Subjects were not to use any medication other than the study medication up to 14 days after the last intake of TMC278 on Day 43, except for ibuprofen. Subjects were not to use any herbal medications or dietary supplements including products containing Hypericum perforatum (e.g., St John’s wort) from 14 days before Day 1 up to 7 days after the last intake of TMC278 on Day 43. Ibuprofen was permitted up to 3 days before Day 1. After that, the clinical investigator could permit the use of ibuprofen (at no more than 400 mg per day). In case of cutaneous reaction/rash and/or an allergic reaction, the use of cetirizine, levocetirizine, topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In case of nausea, the use of antiemetics was permitted. In case of diarrhea, the use of loperamide was permitted.

Synopsis

TMC278-C120 5


Assessments

Scre

enin

ga

Firs

t OC

C

ycle

Treatment A (Second OC Cycle)

Treatment B (Third OC Cycle)

Follo

w-u

p

Day –7 Day 1b

Day 13 Day 14 Day 15 Day 16 Day 28 Day 29

b

Day 35 Day 41 Day 42 Day 43 Day 44

Day

s 7,

30-3

5

Drug screening X X Pharmaco-kinetics Blood sample

Xe,f Xe,f Xe,f Xe,f,g Xf Xe,f,h Xe,f,i Xe,f,i Xe,j Xf,i

Safety AEs & concomitant medsc

X X X X X X X X X X X X X X X

Hemat & biochemd

X X X X X X X X X X

Urinalysis X X Xk Xk Xk X X ACTH stim test with determinations of cortisol and 17-OH-progesterone

X X

Apo A1, Apo B, insulin, and

1-acid glycoprotein

X X X

T3, free-T4, and TSH

X X X

ECG & vital signs

X X Xk Xl Xk,l Xl X

Prolactin X X X Progesterone, LH, FSH

X X X X

Pregnancy testm X X X X X Coagulation test

X X X Xn

Physical exam, including skin exam

X X X X X X X X

Synopsis

TMC278-C120 6


AEs = adverse events; meds = medication; Hemat & biochem = hematology & biochemistry; ACTH = adrenocorticotropic hormone; stim = stimulation; Apo = apolipoprotein; T3 = triidothyronine; free-T4 = free-thyroxine; TSH = thyroid stimulating hormone; ECG = electrocardiogram; LH = luteinizing hormone; FSH = follicle stimulating hormone; exam = examination. a At screening, within 28 days before Day -28 (start of first OC cycle), subject’s demographics and characteristics, smoking habits, medical and surgical history, and concomitant diseases were recorded; HIV-1 and -2 test, hepatitis A, B, and C test, a gynecological exam, smear, and serum pregnancy test were performed. b Subjects were to start OC intake on these days in the second (Treatment A) and third (Treatment B) OC cycles. c Adverse events and concomitant medications were monitored continuously from signing the ICF until the last trial-related visit. d Biochemistry samples were taken fasting for at least 10 hours, before breakfast where applicable. e Within 30 minutes before drug intake. f For determination of ethinylestradiol and norethindrone concentrations. g Predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 9, and 12 hours postdose. h Predose for determination of ethinylestradiol and norethindrone concentrations; 4 hours postdose for TMC278 concentrations. i For determination of TMC278 concentrations. j Predose and at 0.5, 1, 2, 3, 4, 6, 9, and 12 hours postdose for determination of ethinylestradiol, norethindrone, and TMC278 concentrations and at 1.5 hours postdose for determination of ethinylestradiol and norethindrone only and at 5 and 16 hours postdose for determination of TMC278 only. k Within 2 hours before drug intake. l Predose and 4 hours postdose. m Urine pregnancy test on Days 1, 14, 28, and 42. A urine pregnancy test was also performed on Day 56. A serum pregnancy test was performed at follow-up (30-35 days after last TMC278 intake). n At 7 days after last TMC278 intake only.

Statistical Methods Intent-to-treat (ITT) analysis, descriptive statistics, frequency tabulations, Wilcoxon matched-pairs signed-ranks test, linear mixed effects modeling, nonparametric test (Koch).

Synopsis

TMC278-C120 7



Baseline Characteristics - Subject Disposition All subjects entering treatment period (OC cycle 2 in Treatment A)

(N = 16)

Number of Subjects Entered (Female)


16

25.0 (21 - 43)

Dropouts - Reason

Withdrew consent 1 (6.3%) subject withdrew consent during Treatment A (OC alone)

Pharmacokinetics


(mean SD, tmax: median [range]) Treatment B: OC + TMC278

n 15

C0h, ng/mL 600.9 ± 208.9

C24h, ng/mL 662.0 ± 257.6

Cmin, ng/mL 419.5 ± 135.2

Cmax, ng/mL 899.3 ± 193.3

tmax, h 4.0 (2.0 - 24.0)

AUC24h, ng.h/mL 14450 ± 3848

Css,av, ng/mL 602.2 ± 160.3

FI, % 83.83 ± 30.27

Synopsis

TMC278-C120 8


Pharmacokinetics of Ethinylestradiol

(mean SD, tmax: median [range]) Treatment A: OC Alone Treatment B: OC + TMC278

n 15 15

C0h, pg/mL 28.94 ± 9.456 24.12 ± 8.669

C24h, pg/mL 30.94 ± 11.20 27.96 ± 9.386

Cmin, pg/mL 28.45 ± 9.495 24.05 ± 8.722

Cmax, pg/mL 84.93 ± 19.94 97.76 ± 32.74

tmax, h 4.0 (1.5 - 6.0) 4.0 (1.0 - 6.0)

AUC24h, pg.h/mL 1225 ± 313.9 1226 ± 337.5

Css,av, pg/mL 51.12 ± 13.15 51.10 ± 14.06

FI, % 112.9 ± 26.21 144.6 ± 37.33

LSmean ratio (90% CI), %

- B vs A

n - 15 vs 15

Cmin - 83.05 (75.49 - 91.37)a

Cmax - 112.0 (101.3 - 123.9)

AUC24h - 99.33 (93.01 - 106.1) a p-value < 0.05

Synopsis

TMC278-C120 9


Pharmacokinetics of Norethindrone

(mean SD, tmax: median [range]) Treatment A: OC Alone Treatment B: OC + TMC278

n 15 15

C0h, ng/mL 3.185 ± 1.193 1.725 ± 0.7169

C24h, ng/mL 3.473 ± 1.359 1.928 ± 0.7567

Cmin, ng/mL 3.137 ± 1.206 1.722 ± 0.7180

Cmax, ng/mL 14.54 ± 3.922 9.827 ± 3.194

tmax, h 2.0 (1.5 - 6.0) 2.0 (1.0 - 4.0)

AUC24h, ng.h/mL 178.0 ± 52.90 104.4 ± 29.82

Css,av, ng/mL 7.429 ± 2.206 4.349 ± 1.242

FI, % 159.1 ± 45.35 189.6 ± 46.06

LSmean ratio (90% CI), %

- B vs A

n - 15 vs 15

Cmin - 53.63 (49.14 - 58.53)a

Cmax - 66.60 (60.14 - 73.75)a

AUC24h - 58.74 (56.45 - 61.11)a

a p-value < 0.05

Synopsis

TMC278-C120 10


Trial Phase All subjects entering treatment period

(OC cycle 2 in Treatment A)

Safety


Treatment A (OC Alone)

(N = 16)

Treatment B (OC + TMC278)

(N = 15)

Whole Trial (Including

Screening and Follow-up)

(N = 16)


Most frequently reported AEs (reported in > 2 subjects), n (%)

Headache 3 (18.8) 7 (46.7) 12 (75.0)

Metrorrhagia 1 (6.3) 4 (26.7) 5 (31.3)

Nasopharyngitis 2 (12.5) 3 (20.0) 5 (31.3)

Nausea 0 3 (20.0) 4 (25.0)

Fatigue 0 3 (20.0) 3 (18.8)

n (%) with 1 or more AEs 9 (56.3) 14 (93.3) 16 (100.0)

n (%) of deaths 0 0 0

n (%) with 1 or more other serious AEs 0 0 0

n (%) with treatment stopped due to AEs 0 0 0

n (%) with 1 or more grade 3 or 4 AEs 0 0 0Of the 16 subjects starting the treatment phase, all 16 (100.0%) subjects were reported with an AE during the trial. The most commonly reported AEs during the trial were headache (75.0%) and metrorrhagia and nasopharyngitis (both 31.3%). No grade 3 or 4 AEs were reported; 16 (100.0%) subjects were reported with grade 1 (mild) AEs and 2 (12.5%) subjects were reported with grade 2 (moderate) AEs. No subjects had an AE that was considered to be probably or very likely to be related to study medication (either TMC278 or Ortho-Novum ).There were no deaths or other SAEs reported in this trial. No subjects discontinued the trial due to an AE. No AEs considered to be skin events of interest were reported during the trial.

Synopsis

TMC278-C120 11



Trial Phase All subjects entering treatment period

(OC cycle 2 in Treatment A)

Treatment A (OC Alone)

(N = 16)

Treatment B (OC + TMC278)

(N = 15)

Whole Trial (Including

Screening and Follow-up)

(N = 16)


5 (31.3) 7 (46.7) 11 (68.8)


2 (12.5) 0 4 (25.0)


0 0 0

There were no consistent or clinically relevant treatment-emergent changes over time in laboratory parameters. No grade 4 or grade 3 treatment-emergent laboratory abnormalities were reported during the trial. No subjects had clinically relevant laboratory abnormalities that were reported as AEs.

Adrenal Function

Prior to ACTH stimulation at the end of Treatment B (T0), there was an increase from reference (screening) in median cortisol values and a decrease from refererence in median 17-OH-progesterone values: both were regarded to be not clinically relevant. All 15 subjects achieved a cortisol value 550 nmol/L following ACTH stimulation at the end of treatment with OC + TMC278. No AEs related to adrenal function were reported.

Cardiovascular Safety Minor changes were reported for vital sign values. None of the changes was considered to be clinically relevant. No trends or relationship to study medication were apparent and no clinically relevant changes in ECG parameters were reported. Physical Examinations Physical examination revealed abnormal new findings for 3 subjects during the trial: scratch marks around neck (erythematous) during Treatment B (1 subject), insect bites on back during Treatment A (1 subject), and erythematous pharynx, rhinitis, and cervical lymphadenopathy during Treatment B (1 subject).

Conclusions

The results of this trial show that when TMC278 150 mg q.d. was coadministered with a regimen of ethinylestradiol 35 μg q.d. and norethindrone 1.0 mg q.d. (Ortho-Novum 1/35), both in steady-state, the Cmin,Cmax, and AUC24h of norethindrone were statistically significantly decreased by 46%, 33%, and 41%, respectively. Additionally, the Cmin of ethinylestradiol was statistically significantly decreased by 17%. The pharmacokinetic parameters C0h, Cmin, tmax, AUC24h, and Css,av for TMC278 in Treatment B in this trial were within the expected range, suggesting that coadministration of ethinylestradiol/norethindrone did not influence the steady-state pharmacokinetics of TMC278. Although there were no marked effects of coadministration of TMC278 and ethinylestradiol/norethindrone on the LH, FSH, and progesterone levels at Day 14 in Treatment B compared to Treatment A, the efficacy of oral contraceptives may be compromised when combined with TMC278, given the marked reduction in the exposure to norethindrone. In healthy subjects in this trial, TMC278 150 mg q.d. administered in combination with Ortho-Novum 1/35 q.d. was generally safe and well tolerated.

Synopsis




Trade Name: -

Indication: HIV-1



Clinical Phase: I

Title: A Phase I, open-label, single-sequence drug-drug interaction trial in subjects on stable methadone maintenance therapy, to investigate the potential interaction between TMC278 25 mg q.d. and methadone, at steady-state.

Investigator:

The Netherlands


Trial Period: Start: 31-Oct-2008

End: 15-Jun-2009


No. of Subjects: 13

Objectives: The primary objective of this trial was to evaluate the effect of steady-state TMC278 25 mg once daily (q.d.) on the steady-state pharmacokinetics of R- and S-methadone.

Secondary objectives were to:

! Evaluate the potential effect of TMC278 on the pharmacodynamic effects of methadone therapy.

! Evaluate the steady-state pharmacokinetics of TMC278 25 mg q.d. in subjects on stable methadone maintenance therapy.

! Evaluate the short-term safety and tolerability of coadministration of TMC278 and methadone in subjects on stable methadone maintenance therapy.

Design: This was a Phase I, open-label, single-sequence drug-drug interaction trial in subjects on stable methadone maintenance therapy to investigate the potential interaction between TMC278 25 mg q.d. and methadone at steady-state. TMC278 is under development for the treatment of HIV-1 infected patients.

The trial population consisted of 13 HIV-negative subjects on stable methadone maintenance therapy. Subjects received TMC278 25 mg q.d. for 11 days, added to their current methadone therapy. The current methadone dosage for each subject was not changed from screening until Day 11 inclusive, unless an immediate adjustment of the methadone dosage was warranted. Methadone dose was individualized for each subject and could be between 60 and 150 mg daily.

Full 24 hour pharmacokinetic profiles of R- and S-methadone were determined on Day –1 (methadone alone) and on Day 11 (methadone + TMC278). A full 24 hour pharmacokinetic profile of TMC278 was determined on Day 11 (methadone + TMC278).

Pharmacodynamic assessments of the symptoms of methadone withdrawal (Short Opiate Withdrawal Scale [SOWS], Desires for Drugs Questionnaire [DDQ], pupillometry) were performed on Day -7 and daily from Day -3 until Day 11, within 2 hours before the intake of methadone. Safety and tolerability were evaluated throughout the trial.

Clinical Research Report Synopsis 1 of 12


Subject Selection

Inclusion Criteria

1. Male or female subjects, aged between 18 and 55 years, extremes included.

2. Body mass index (BMI: weight in kg divided by the square of height in meters) of 18.0 to 35.0 kg/m2, extremes included.

3. Informed Consent Form signed voluntarily before the first trial-related activity.

4. Receiving oral methadone maintenance therapy at a stable individualized dose of 60 to 150 mg q.d.

5. The subject agreed:! Not to change the current methadone dose from screening until Day 11 inclusive.! To have a daily observed and documented methadone intake from Day –14 until Day 12, and a daily

observed and documented TMC278 intake from Day 1 until Day 11.


7. The subject had obtained approval from his/her addiction physician for participation in this trial. Furthermore, the addiction physician agreed to provide medical care for the subject after discharge from the testing facility.

8. General medical condition, in the investigator’s opinion, did not interfere with the assessments and the completion of the trial.

9. Otherwise healthy on the basis of a physical examination, medical history (except drug abuse), electrocardiogram (ECG), vital signs and the results of blood biochemistry and hematology tests and a urinalysis carried out at screening.

Exclusion Criteria

1. A positive HIV-1 or HIV-2 test at trial screening.

2. Female, except if postmenopausal for more than 2 years, or posthysterectomy, or postsurgical sterilization (without reversal operation).

3. Evidence of current use of barbiturate, amphetamine, recreational drugs or opioids, with the exception of methadone. The urine drug screening involved analysis for amphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids, and opioids. Drug screening results had to be negative from Day –1 onwards.

Note: Positive drug screening tests for the following did not result in exclusion of a subject:! Cannabinoids.! Temazepam, oxazepam, lorazepam, chlordiazepoxide, and codeine, when used in a prescribed dose.

4. Current use of alcohol, which in the investigator’s opinion, would have compromised subject’s safety and/or compliance with the trial procedures. Alcohol breath tests had to be negative from Day –1 onwards.

5. Hepatitis A infection (confirmed by hepatitis A antibody IgM) or hepatitis B infection (confirmed by hepatitis B surface antigen) at screening.

6. Decompensated liver function defined as clinical or laboratory evidence of significantly decreased hepatic function or decompensation, irrespective of liver enzyme levels (international normalized ratio > 1.5 or albumin < 30 g/L or total bilirubin ≥ 2.5 x ULN [upper limit of laboratory normal range]).

Note: Clinically stable chronic hepatitis C was allowed if aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN (no increase in the enhanced Division of AIDS [DAIDS] grade for these parameters over the 3 months prior to screening) and if platelets were within laboratory normal range.

7. Currently active or underlying gastrointestinal, cardiovascular, neurologic, psychiatric (other than drug dependency), metabolic, renal, hepatic, respiratory, inflammatory, or infectious disease.



8. Presence of one or more of the following risk factors for QTc prolongation:! a confirmed prolongation of QT/QTc interval, e.g.repeated demonstration of QTcF (Fridericia

correction) interval > 450 ms on the screening ECG (i.e. retesting to reassess eligibility was allowed once using an unscheduled visit during the screening period);

! pathological Q-waves (defined as Q-wave > 40 ms or depth > 0.4-0.5 mV);! evidence of ventricular pre-excitation;! electrocardiographic evidence of complete left bundle branch block or right bundle branch block;! evidence of second or third degree heart block;! intraventricular conduction delay with QRS duration > 120 ms;! bradycardia as defined by sinus rate < 50 beats per minute;! personal or family history of long QT syndrome;! personal history of cardiac disease, symptomatic or asymptomatic arrhythmias, with the exception of

sinus arrhythmia;! syncopal episodes;! risk factors for torsade de pointes (e.g.heart failure, hypokalemia, hypomagesemia).

9. Current or history of adrenal disorder.

10. Currently significant diarrhea, gastric stasis, or constipation (other than the pharmacodynamic effects ofmethadone) that in the investigator’s opinion could have influenced drug absorption or bioavailability.


12. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication administered in this trial (i.e. TMC278).

13. Previous experience of clinically significant hypersensitivity to methadone hydrochloride.

14. Use of disallowed concomitant therapy during the 14 days prior to the first dose of TMC278. Concomitant therapy that was not disallowed was not to be changed between Days -14 and 11, except for ibuprofen and paracetamol.

15. Having previously participated in more than 1 trial (single or multiple dose) with TMC125, TMC120 and/or TMC278 (formerly known as R278474) or having developed a rash, erythema or urticaria while participating in a trial with the aforementioned compounds.

16. Lack of good/reasonable venous access.

17. Participation in an investigational drug trial within 60 days prior to Day -14.

18. Donation of blood or plasma or significant blood loss within 60 days prior to Day -14.

19. Any of the following laboratory abnormalities at screening as defined by the DAIDS toxicity grading severity list and in accordance with the normal ranges of the clinical laboratory:

! serum creatinine grade 1 or greater (≥ 1.1 x ULN);! serum lipase grade 1 or greater (≥ 1.1 x ULN);! hemoglobin toxicity grade 1 or greater (≤ 10.9 g/dL);! platelet count grade 1 or greater (≤ 124.999 x 109/L);! absolute neutrophil count grade 1 or greater (≤ 1.3 x 109/L);! AST or ALT grade 1 or greater (≥ 1.25 x ULN), except for subjects with chronic hepatitis C (see

exclusion criterion 6);! total bilirubin grade 1 or greater (≥ 1.1 x ULN), except for subjects with decompensated liver

function as defined in exclusion criterion 6;! any other laboratory abnormality of grade 2 or above, including proteinuria (spot urine) > 2+, and

microscopic hematuria (> 10 red blood cells [RBCs]/high power field).



Treatment Methadone Treatment TMC278 Treatment

Dosage

Dosage Form (F No.)

Usage

60 to 150 mg

Tablet (Symoron®)

Orally, q.d. Days -14 to -4: before noon. Day –3 to Day 11: between

7:30 a.m. and 10:00 a.m., within 10 minutes after completion of breakfast,immediately after TMC278 intake if

applicable.

25 mg

Tablet (F006)

1 tablet orally q.d. within 10 minutes after completion of breakfast

Batch Number Not applicable as provided by the testing facility.

8BL2H

Dose Regimen Methadone individualized maintenance therapy, 60 to 150 mg q.d. from Days -14 to 12.

TMC278 25 mg q.d. from Day 1 to 11.

Duration of Treatment 25 days of methadone intake with 11 days coadministration of TMC278.

Duration of Trial 25 days excluding screening and follow-up.



Disallowed Medication All investigational drugs (except TMC278) were disallowed from 60 days prior to the first supervised methadone intake (Day -14) until the end of the trial. The following medications were not allowed from Day -14 until Day 12: ! Cytochrome P450 inducers: rifamycins: rifabutin, rifampin; rifapentin,

anticonvulsants: phenobarbital, phenytoin, carbamazepine, oxcarbazepine systemic dexamethasone and other systemic glucocorticoids, all products containing Hypericum perforatum (St. John’s Wort), modafinil, pioglitazone, troglitazone.

! Cytochrome P450 inhibitors and inhibitors of transporting proteins: systemic azole antifungals: ketoconazole, itraconazole and voriconazole, fluconazole (except if not exceeding 200 mg/day), macrolide antibiotics: erythromycin, clarithromycin, troleandomycin, roxithromycin, telithromycin.

! Cytochrome P450 substrates: cisapride, terfenadine, and astemizole, aprepitant, felodipine, nifedipine, nicardipine, amlodipine, verapamil, diltiazem, pimozide.

! The antiarrhythmics bepiridil, flecainide, propafenone, systemic lidocaine, mexilitine, disopyramide, amiodarone, and quinidine.

! The antimigraines ergotamine, dihydroergotamine, ergonovine, methylergonovine, ergometrine, methylergonovine, and other ergot derivatives.

! Megestrol acetate.! Nefazodone.! Proton pump inhibitors.! H2 blockers (except if taken at least 12 hours before or 4 hours after intake

of trial medication) and antacids (except if taken at least 2 hours before or 4 hours after intake of TMC278).

! The immunomodulators cyclosporin, tacrolimus, sirolimus, rapamycin, and thalidomide.

! The anticoagulants warfarin, phenoprocoumon, and acenocoumarol.

Ibuprofen and paracetamol (acetaminophen) could be used up to 3 days before the first intake of TMC278. After that, the investigator could permit the use of ibuprofen (at no more than 400 mg per day) or paracetamol (at no more than 1000 mg per day). In case of cutaneous reaction/rash and/or an allergic reaction, the use of cetirizine (Zyrtec®), levocetirizine (Xyzal®), topical corticosteroids, or antipruritic agents in the recommended dosing scheme were permitted. In case of nausea, the use of antiemetics was permitted. In case of diarrhea, the use of loperamide was permitted. Hormone replacement therapy was allowed in postmenopausal women.



Assessments

Scre

enin

ga Treatment Period

Follo

w-u

pvi

sits

≤ 21

day

s bef

ore

Day

-14

Day

-14

Day

-7

Day

-4b

Day

-3

Day

-2

Day

-1c

Day

1

Day

2

Day

3

Day

4

Day

5-6

Day

7

Day

8-1

0

Day

11

Day

12c

7 &

30, 3

1, o

r 32

days

af

ter l

ast T

MC

278

PharmacokineticsBlood Sample Xd,e Xd,e Xd,e Xd,e Xd,e Xf,e Xf,e Xf,e Xf,e Xf,e Xe,g Xe,g Xg

PharmacodynamicsSOWS, DDQ, and pupillometryh

X X X X X X X X X X X X

SafetyAdverse Events and concomitant medicationsi

X X X X X X X X X X X X X X X X X

Hematology and biochemistryj

X X X X X X X X X

Urinalysisk X X X X X X X X X X X X XECGl X X X X X X X XVital Signsm X X X X X X X XPhysical Examinationn

X X X X

Pregnancy testo X XAlcohol Breath Test

X X X X X X X X X X X X X

AE = adverse event, DDQ = desires for drugs questionnaire, ECG = electrocardiogram, PR = pulse rate, SOWS = short opiate withdrawal scale.

a Informed consent, inclusion/exclusion criteria, concomitant diseases, subject characteristics and demographics, height, weight, smoking habits, medical and surgical history, family history related to allergic skin disease, international normalized ratio determination, HIV-1 and -2 test, hepatitis A/B/C test, urine drug screening, serum pregnancy test (females only).

b Admission to test facility in the evening. During admission, methadone was taken within 10 minutes after completion of breakfast, immediately after TMC278 intake, if applicable.

c Discharged from unit. d For determination of R- and S-methadone plasma concentrations. e Sample taken immediately before the intake of TMC278 and/or methadone, as applicable. On Days -1 and 11,

sample taken at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, and 16 hours postdose. f Upon the discretion of the investigator, a predose pharmacokinetic sample (corresponding to the 24 hour

postdose samples on Days -1 and 11) could be taken if the subject demonstrated clinical withdrawal symptoms, for the determination of R- and S-methadone plasma concentrations.

g For determination of TMC278, R- and S-methadone plasma concentrations. h Short Opiate Withdrawal Scale, DDQ, and pupillometry were performed within 2 hours before methadone

intake. i Adverse events and intake of concomitant medication were monitored throughout the trial from the signing of

the informed consent form to the last trial related activity. j Biochemistry sample was taken fasted for at least 10 hours before breakfast, if applicable.k Taken within 2 hours before medication intake. In addition to urinalysis, a urine drug screen was performed at

screening and on Days -7, -4 to -1, 1, 11, and 12. l Triplicate 10 second recording collected at 60 second intervals apart from screening and follow-up, when



triplicate measurements were not required. Electrocardiogram was performed in supine position. Postdose ECG was performed within 10 minutes before pharmacokinetic sampling at the corresponding timepoint on Day -1 and Day 11. The predose ECGs were taken within 10 minutes before breakfast. Additional triplicate postdose ECGs were performed on Days -1 and 11 at 2, 3, 4 and 5 hours after medication intake.

m Blood pressure and pulse: supine after 5 minutes, standing after 1 minute. Taken within 2 hours before medication intake.

n Including skin examination. o Urine pregnancy test on Day -3, serum pregnancy test on Days 30, 31, or 32 at follow-up.Note: In case the urine drug screen was positive, the pharmacokinetic profiling of Day -1 was to be postponed and the screening period extended until the urine drug screen was negative, for a maximum of 3 days. Each day of the extended screening period was to be a repeat of Day-1, with the exception of the pharmacokinetic profiling from the 0.5 hour sample onwards, which was only to be performed if the urine drug screen for that day was negative.

Statistical Methods

Descriptive statistics, graphical presentations and exploratory graphical analysis, and linear mixed effects modeling were carried out for pharmacokinetic parameters. Descriptive statistics were used for pharmacodynamic parameters, and descriptive statistics and frequency tabulations were produced for safety parameters.




Baseline Characteristics - Subject Disposition All Subjects (N = 13)

Number of Subjects Entered (all male)

Age: median (range), years

13

41.0 (31-54)

Dropouts - Reason

Socially unacceptable behavior 1 (7.7%)

Pharmacokinetics of R-methadone

Individualized methadone therapy (reference)

Individualized methadone therapy + 25 mg TMC278 q.d.

on Days 1-11 (test)(mean ∀∀ SD, tmax: median [range])n 13 12Day -4/Day 8C0h, ng/mL 253.0 ± 107.1a 178.2 ± 80.61Day -3/Day 9C0h, ng/mL 230.1 ± 118.8 176.1 ± 79.77Day -2/Day 10C0h, ng/mL 229.7 ± 115.3a 176.8 ± 79.97Day -1/Day 11C0h, ng/mL 216.3 ± 101.9 177.3 ± 83.15Cmin, ng/mL 195.9 ± 86.66 159.4 ± 81.25Cmax, ng/mL 315.8 ± 122.8 279.3 ± 109.2tmax, h 2.5 (1.5 - 4.0) 2.5 (1.15 - 6.0)AUC24h, ng.h/mL 5578 ± 2343 4811 ± 2106Ratio AUC24h, S-/R-methadone, % 101.5 ± 17.17 99.84 ± 11.67Css,av, ng/mL 232.4 ± 97.61 200.5 ± 87.74FI, % 54.63 ± 15.19 63.86 ± 22.61LSmean ratio (90% CI), %b

test versus referenceCmin, ng/mL - 78.05 (66.86 - 91.10)Cmax, ng/mL - 85.86 (77.53 - 95.08)AUC24h, ng.h/mL - 83.82 (73.93 - 95.03)Ratio AUC24h, S-/R-methadone, % - 100.6 (96.49 - 104.8)AUC24h = area under the plasma concentration time curve over 24 hours, C0h = predose plasma concentration, Cmax = maximum plasma concentration, Cmin = minimum plasma concentration, Css,av = average steady-state plasma concentration, FI = fluctuation index, LS = least squares, SD = standard deviation, tmax = time to maximum plasma concentration.a n = 12b n = 13 for reference and n = 12 for test



Pharmacokinetics of S-methadone

Individualized methadone therapy (reference)

Individualized methadone therapy + 25 mg TMC278 q.d.

on Days 1-11 (test)(mean ± SD, tmax: median [range])n 13 12Day -4/Day 8C0h, ng/mL 244.7 ± 114.4a 160.2 ± 91.22Day -3/Day 9C0h, ng/mL 226.3 ± 124.5 159.9 ± 88.81Day -2/Day 10C0h, ng/mL 221.6 ± 118.8a 159.6 ± 84.03Day -1/Day 11C0h, ng/mL 200.4 ± 99.49 157.5 ± 84.86Cmin, ng/mL 179.9 ± 90.59 146.1 ± 85.02Cmax, ng/mL 358.1 ± 145.2 316.1 ± 123.2tmax, h 2.5 (1.5 - 4.0) 2.5 (1.2 - 6.0)AUC24h, ng.h/mL 5610 ± 2515 4815 ± 2275Css,av, ng/mL 233.7 ± 104.8 200.7 ± 94.77FI, % 81.25 ± 22.61 92.78 ± 32.29LSmean ratio (90% CI), %b

test versus referenceCmin, ng/mL - 78.57 (67.45 - 91.52)Cmax, ng/mL - 86.91 (77.64 - 97.28)AUC24h, ng.h/mL - 84.30 (74.16 - 95.84)AUC24h = area under the plasma concentration time curve over 24 hours, C0h = predose plasma concentration, Cmax= maximum plasma concentration, Cmin = minimum plasma concentration, Css,av = average steady-state plasma concentration, FI = fluctuation index, LS = least squares, SD = standard deviation, tmax = time to maximum plasma concentration.a n = 12b n = 13 for reference and n = 12 for test




25 mg TMC278 q.d. on Days 1-11 +

individualized methadone therapy

(TMC278-TiDP6-C121, healthy volunteers)

25 mg TMC278 q.d. on Days 1-11

(TMC278-TiDP6-C152, healthy volunteers)

25 mg TMC278 q.d. on Days 1-11

(TMC278-TiDP6-C130, healthy volunteers)(mean ± SD, tmax:

median [range])

n 12 57 16Day 8C0h, ng/mL 66.62 ± 24.00 - -Day 9C0h, ng/mL 72.57 ± 29.94a 114.6 ± 36.42 71.86 ± 22.51Day 10C0h, ng/mL 83.48 ± 31.67 113.0 ± 33.55 77.67 ± 22.56Day 11C0h, ng/mL 81.98 ± 35.09 132.3 ± 40.60 79.69 ± 19.53Cmin, ng/mL 67.63 ± 25.08 95.23 ± 29.07 66.48 ± 16.29Cmax, ng/mL 156.3 ± 65.20 246.8 ± 74.36b 145.5 ± 31.97tmax, h 4.0 (2.5 - 24.0) 5.0 (4.0 - 24.0)b 5.0 (5.0 – 12.0)AUC24h, ng.h/mL 2174 ± 759.2a 3324 ± 884.0b 2235 ± 460.4Css,av, ng/mL 90.63 ± 31.68a 138.5 ± 36.83b 93.13 ± 19.18FI, % 89.48 ± 27.33a 111.1 ± 32.47b 86.77 ± 29.20AUC24h = area under the plasma concentration time curve over 24 hours, C0h = predose plasma concentration, Cmax= maximum plasma concentration, Cmin = minimum plasma concentration, Css,av = average steady-state plasma concentration, FI = fluctuation index, SD = standard deviation, tmax = time to maximum plasma concentration.a n = 11 b n = 56

Pharmacodynamics

The DDQ scores were categorized into the following sub-scores: control, desire, and negative reinforcement. For the control and negative reinforcement sub-scores, there were no clinically relevant changes over time. For the desire sub-score, for the subgroup of subjects who had a > 30% decrease from reference (Day -1) in R-methadone exposure, there was an increase, i.e. a worsening of the desire sub-score, which suggested an increased desire for drugs. Given the small number of subjects in this subgroup (3 subjects), this result should be interpreted with caution. Analysis of the SOWS results indicated that there were no clinically relevant changes over time. Minor variations in mean pupil diameter (mostly decreases in diameter) as measured by pupillometry were seen over the course of the trial with no trend for change in mean pupil diameter over time.



Safety


Run-ina

(N = 13)TMC278 25 mg q.d.

(N = 13)

n (%) with 1 or more AEs 9 (69.2) 12 (92.3)n (%) of deaths, serious AEs, AEs leading to withdrawal, grade 3 and 4 AEs, skin events of interest

0 0

Most frequently reported AEs (reported in ≥ 2 subjectson TMC278), n (%)

Hyperhidrosis 1 (7.7) 3 (23.1)Nausea 0 3 (23.1)Headache 6 (46.2) 2 (15.4)Constipationb 3 (23.1) 2 (15.4)Diarrhea 0 2 (15.4)Drug withdrawal syndrome 0 2 (15.4)Fatigue 0 2 (15.4)Pain in extremity 0 2 (15.4)Dizziness 0 2 (15.4)Dysgeusia 0 2 (15.4)Pruritus 0 2 (15.4)

AE = adverse eventa Run-in = Day -14 to Day 1, 1 minute before TMC278 administration.b Subject 121-0008 experienced an AE of constipation during the TMC278 25 mg q.d. phase that was not captured

in the trial database because the investigational site did not send the information about the occurrence of the AE for inclusion in the trial database . The AE was considered probably related to TMC278 and doubtfully related to methadone.

A total of 12 subjects (92.3%) experienced an AE during the trial; with all of these subjects experiencing AEs during the TMC278 25 mg q.d. phase. The majority of subjects experienced events that were considered to be grade 1 in severity (12 subjects in total, 92.3%) although grade 2 AEs were reported by 3 subjects (23.1%) in total during the trial. No deaths, serious AEs, AEs leading to discontinuation, grade 3 or 4 events, or skin events of interest were reported during the trial. A total of 9 subjects (69.2%) experienced AEs that were considered possibly or probably related to TMC278, and 4 subjects (30.8%) experienced AEs that were considered possibly related to methadone. Overall, AEs were more frequently reported during the TMC278 25 mg q.d. phase; however, the difference in the number of subjects reporting each type of AE between the TMC278 25 mg q.d. phase and the other phases of the trial was mostly only a difference of ≤ 2 subjects, except for nausea (3 subjects on TMC278 and no subjects during the run-in phase).




No consistent or clinically relevant changes in mean laboratory parameters were observed. Treatment-emergent abnormalities were recorded in 12 subjects (92.3%) during treatment with TMC278 25 mg q.d. and 11 subjects (91.7%) during the follow-up phase. No grade 4 treatment-emergent laboratory abnormalities were reported. One subject (7.7%) reported a grade 3 treatment-emergent abnormality during the trial, which was for LDL cholesterol. Otherwise, ≤ 4 subjects for any 1 laboratory parameter experienced grade 1 or 2 treatment-emergent laboratory abnormalities. The laboratory parameters for which graded abnormalities of ≤ grade 2 were reported during treatment with TMC278 were, ALT (4 subjects), AST (2 subjects), lipase (1 subject), phosphorus (1 subject), total cholesterol (6 subjects) and LDL cholesterol (3 subjects). One AE relating to laboratory parameters was reported during the trial: an AE of grade 2 ALT increased in the TMC278 25 mg q.d. treatment phase.


There were no notable variations in vital signs over the course of the trial and no grade 2, 3 or 4 abnormalities or AEs relating to vital signs parameters were reported.

There were no notable variations in ECG parameters over time and no AEs relating to ECGs were reported. At TMC278 steady-state on Day 11, only mean decreases from reference (Day -1) in QTcF were observed. No subjects had increases > 60 ms or actual values > 500 ms for QTcB or QTcF intervals.


Physical examination revealed 3 subjects with treatment-emergent abnormal findings at the body system level. However, for 2 of these subjects, it was noted by the investigator that the findings were related to their medical history. For the third subject, abnormalities of the skin and mucous membranes were noted during the TMC278 phase and follow-up; however, the precise abnormalities were not specified. Otherwise, the physical examination results were unremarkable.

Conclusions

The results of this trial demonstrate that when TMC278 25 mg q.d. was added to a stable individualized methadone maintenance therapy (ranging from 60 mg to 100 mg methadone daily), the Cmin, Cmax, and AUC24h values of R-methadone were decreased by 22%, 14%, and 16%, respectively, compared to treatment with methadone alone. For S-methadone, the Cmin, Cmax, and AUC24h values were decreased by 21%, 13%, and 16%, respectively, after the addition of TMC278 25 mg q.d. to the methadone treatment. Ratio AUC24h S-methadone/R-methadone values were comparable between both treatments, indicating the absence of a stereo-specific effect. The exposure to TMC278 when administered in the presence of methadone was within the range observed in previous trials with TMC278 25 mg q.d. in healthy volunteers. The results of this trial also demonstrate that coadministration of TMC278 25 mg q.d. and methadone was generally safe and well tolerated and it did not have a clinically relevanteffect on pharmacodynamic parameters as judged by the DDQ, SOWS and pupillometry, nor did it have an effect on the QTcF interval.





Trade Name: -




Clinical Phase: I

Title: A Phase I, open-label, randomized 2-way crossover trial in 16 healthy subjects to investigate the potential pharmacokinetic interaction between TMC278 and sildenafil.

Investigators:

USA.

Country: USA


End: - -20

No. of Investigators: 1 (plus 1 sub-investigator)

No. of Subjects: 16

Objectives: The primary objectives of this trial were to investigate the effect of steady-state TMC278 on the single-dose pharmacokinetics of sildenafil and its active metabolite N-desmethyl sildenafil and to investigate the effect of single-dose sildenafil on the steady-state pharmacokinetics of TMC278 in healthy subjects.

The secondary objective was to investigate the short-term safety and tolerability of coadministration of TMC278 and sildenafil in healthy subjects.

Design: This was a Phase I, open-label, randomized, 2-way crossover trial to investigate the pharmacokinetic interaction between TMC278 (which is being developed for use in the treatment of human immunodeficiency virus [HIV]-1 infection) and sildenafil. A total of 16 healthy male subjects received each treatment in a randomized order, sildenafil alone (Treatment A) or the combination of TMC278 and sildenafil (Treatment B). Both treatments were given under fed conditions. There was a washout period of at least 14 days between the treatment periods. Each subject had 2 treatment sessions and received a different treatment in each of the sessions.

In Treatment A, a single dose of 50 mg sildenafil was administered on Day 1. In Treatment B, subjects received TMC278 75 mg once daily (q.d.) on Days 1 to 12, with coadministration of a single dose of 50 mg sildenafil on Day 12.

Full pharmacokinetic profiles of sildenafil and its active metabolite N-desmethyl sildenafil were determined up to 24 hours after sildenafil intake on Day 1 of Treatment A and on Day 12 of Treatment B. Full 24 hour pharmacokinetic profiles of TMC278 were determined on Days 11 and 12 of Treatment B.

Safety and tolerability evaluations were recorded at regular intervals throughout the trial period.


Subject Selection

Inclusion Criteria

1. Male, aged between 19 and 55 years, extremes included.2. Normal weight as defined by a Quetelet Index (Body Mass Index: weight in kg divided by the square of height

in meters) of 18.0 to 30.0 kg/m2, extremes included.3. Informed Consent Form (ICF) signed voluntarily before the first trial-related activity.4. Able to comply with protocol requirements.5. Healthy on the basis of a medical evaluation that revealed the absence of any clinically relevant abnormality

and included a physical examination (including skin examination and genital examination), medical history, electrocardiogram (ECG), vital signs, and the results of blood biochemistry, blood coagulation, and hematology tests, and a urinalysis carried out at screening.


Exclusion Criteria1. A positive HIV-1 or HIV-2 test at screening.2. History or evidence of current use of alcohol, barbiturate, amphetamine, recreational, or narcotic drug use,

which in the investigator’s opinion would compromise the subject’s safety and/or compliance with the trial procedures.

3. Current or recent use of amyl nitrate or -nitrite (“poppers”).4. Hepatitis A, B, or C infection (confirmed by hepatitis A antibody IgM, hepatitis B surface antigen, or hepatitis

C virus antibody, respectively) at screening.5. A positive urine alcohol or drug test at screening. The urine drug test was performed to check the current use

of methadone, barbiturates, amphetamines, benzodiazepines, cocaine, cannabinoids, and opioids. 6. Currently active or underlying gastrointestinal, cardiovascular, neurologic, psychiatric, metabolic, renal,

hepatic, respiratory, inflammatory, or infectious disease.7. History of or current hypertension or hypotension.8. History of or current retinitis pigmentosa.9. Anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease) or

predisposition to priapism.10. History of renal insufficiency (estimated creatinine clearance below 60 mL/min).11. Currently significant diarrhea, gastric stasis, or constipation that in the investigator’s opinion could influence

drug absorption or bioavailability.12. Current or history of adrenal disorder. 13. Any history of significant skin disease such as, but not limited to, rash or eruptions, drug allergies, food

allergy, dermatitis, eczema, psoriasis, or urticaria, as determined by the investigator.14. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the

investigational medication administered in this trial (i.e., TMC278 and sildenafil).15. Use of concomitant medication, including over-the-counter products, herbal medications, and dietary

supplements.16. Having previously participated in more than 1 trial (single or multiple dose) with TMC125, TMC120, and/or

TMC278 (formerly known as R278474) or having developed rash, erythema, or urticaria while participating in a trial with the aforementioned compounds.

17. Participation in an investigational drug trial within 60 days prior to the first intake of trial medication.18. Donation of blood or plasma or significant blood loss within 60 days preceding the first intake of trial

medication.19. Subjects with the following laboratory abnormalities at screening as defined by the Division of Acquired

Immunodeficiency Syndrome (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS grading table) and in accordance with the normal ranges of the clinical laboratory: serum creatininegrade 1 or greater (≥ 1.1 x upper limit of laboratory normal range [ULN]); lipase grade 1 or greater (≥ 1.1 x ULN); hemoglobin (≤ 12 g/dL); platelet count grade 1 or greater (≤ 124.999 x 109/L); absolute neutrophil count grade 1 or greater (≤ 1.3 x 109/L); aspartate aminotransferase or alanine aminotransferase grade 1 or greater (≥ 1.25 x ULN); direct bilirubin ≥ 1.1 x ULN; any other laboratory abnormality of grade 2 or above, including proteinuria (spot urine) > 2+, and microscopic hematuria (> 10 red blood cells/high power field).

20. Use of nicotine products or smoking cigarettes, cigars, or pipes or having used nicotine products or have smoked cigarettes, cigars, or pipes within the past 6 months.



Dosage 50 mg sildenafil single dose 75 mg TMC278 q.d. + 50 mg sildenafil single dose

Dosage Form (TF No.) 50 mg tablet 75 mg tablet (F008) + 50 mg tablet

Usage 1 x 50 mg sildenafil tablet orallyon Day 1

1 x 75 mg TMC278 tablet orally q.d. on Days 1-12

+1 x 50 mg sildenafil tablet orally

on Day 12

Batch Number 6084303 (sildenafil) PD2115 (TMC278)

6084303 (sildenafil)

Dose Regimen Group 1: treatment sequence AB in 2 separate sessions each separated by a 14-day washout.

Group 2: treatment sequence BA in 2 separate sessions each separated by a 14-day washout.

Duration of Treatment Treatment A: 1 day.

Treatment B: 12 days.

(The above duration excludes screening, washout and follow-up visits).

Duration of Trial One treatment period of 1 day plus 1 treatment period of 12 days with a washout period of 14 days in between (excluding screening and follow-up).

Disallowed Medication All over-the-counter medication was to have been discontinued at least 7 days before the first intake of trial medication and all prescribed medication was to have been discontinued at least 14 days before first intake of trial medication, except for ibuprofen or paracetamol. Subjects were not to use any medication other than the trial medication up to 14 days after the last intake of trial medication, except for ibuprofen or paracetamol. Subjects were also not to use any herbal medications or dietary supplements including products containing Hypericum perforatum (e.g., St. John’s wort) from 14 days before the first intake of trial medication and up to 14 days after the last intake of trial medication. Ibuprofen or paracetamol could be used up to 3 days before the first intake of trial medication. After that, the clinical investigator could permit the use of ibuprofen (at no more than 400 mg per day) or paracetamol (at no more than 1000 mg per day). In case of cutaneous reaction/rash and/or an allergic reaction, the use of cetirizine (Zyrtec!), levocetirizine (Xyzal!), topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In case of nausea, the use of antiemetics was permitted. In case of diarrhea, the use of loperamide was permitted.


Assessments

Scre

enin

ga Treatment Ab Treatment Bb

Follo

w-u

p

≤21

days

Day

-1c

Day

1

Day

2

Day

-1c

Day

1

Day

8+9

Day

10

Day

11

Day

12

Day

13

Day

s 7 a

nd

30, 3

1,or

32

PharmacokineticsBlood sample Xd,e,f Xd Xd,f,g Xf,g Xf,g Xh Xe,h Xd,f

SafetyAEs and concomitant medicationi X X X X X X X X X X X X

Hematology & biochemistryj X Xk,l Xl Xk,l Xk Xk,l X X

Urinalysis X X Xk X X Xk X Xk Xk X XUrine drug and alcohol screen X X X X

ECG X Xk,m X Xk Xk,m Xk,m X XVital signs (PR, BP) X Xk,m X Xk Xk,m Xk,m X X

Skin examination X X X X X X X XPhysical examination X X X X X X XAE = adverse event; BP = blood pressure; ECG = electrocardiogram; PR = pulse rate.a Informed consent, genital examination (as part of physical exam), smoking habits, inclusion/exclusion criteria,

concomitant diseases, height, weight, subject demographics, medical and surgical history, family history related to skin disease, HIV-1 & -2 tests, hepatitis A/B/C test, coagulation testing.

b Treatments were separated by a washout period of at least 14 days.c Subjects were admitted to the unit in the evening before Day 1.d For determination of sildenafil and N-desmethyl sildenafil concentrations.e Taken immediately before drug intake and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, and 16 hours postdose for

determination of sildenafil and N-desmethyl sildenafil concentrations.f For determination of TMC278 concentrations.g Taken immediately before drug intake.h Taken immediately before drug intake and 0.5, 1, 2, 3, 4, 5, 6, 9, 12, and 16 hours postdose for determination

of TMC278 concentrations.i AEs and concomitant medication were monitored continuously from signing the ICF until the last trial related

activity.j Biochemistry samples were taken fasted for at least 10 hours, before breakfast.k Taken predose within 2 hours before drug intake.l Included coagulation testing.m Recorded 4 hours postdose.

Statistical Methods

Descriptive statistics, graphical presentations, frequency tabulations including 90% confidence limits, Intent-to-Treat analysis, linear mixed effects modeling, 2-sided Wilcoxon signed-ranks test.




50 mg sildenafil → 75 mg

TMC278 q.d. + 50 mg sildenafil

(Group 1)

75 mg TMC278 q.d. + 50 mg

sildenafil →50 mg sildenafil (Group 2)

All SubjectsN =16

Number of Subjects Entered (all male)


8

38.0 (22-45)

8

42.0 (23-55)

16

38.5 (22-55)

Drop-Outs – ineligible to continue 0 1 (12.5%) 1 (6.3%)

Pharmacokinetics of TMC278 (mean ± SD, tmax: median [range])

75 mg TMC278 q.d. (reference)

75 mg TMC278 q.d. + 50 mg sildenafil (test)

ntmax, hC0h, ng/mLCmin, ng/mLCmax, ng/mLAUC24h, ng.h/mLCss,av, ng/mLFI, %

165.0 (2.0 - 5.0)201.7 ± 63.08176.9 ± 58.32459.8 ± 120.76517 ± 1778

271.6 ± 74.00106.5 ± 32.91

164.0 (1.0 - 9.0)210.2 ± 76.30187.3 ± 70.80427.5 ± 137.86504 ± 2035270.8 ± 84.5892.51 ± 32.48

Least square means ratio (90% CI), %

nCmin, ng/mLCmax, ng/mLAUC24h, ng.h/mL

----

Test vs reference16 vs 16

103.5 (98.11 - 109.1)91.65 (84.89 - 98.94)98.11 (92.11 - 104.5)

AUC24h = area under the plasma concentration-time curve from time of administration up to 24 hours post dosing;C0h = predose plasma concentration; CI = confidence interval; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; Css,av = average steady-state plasma concentration; FI = fluctuation index;tmax = time to maximum plasma concentration.


Pharmacokinetics of sildenafil (mean ± SD, tmax: median [range])

50 mg sildenafil (reference)


ntmax, hCmax, ng/mLAUClast, ng.h/mLAUC∞, ng.h/mLλz, 1/ht1/2term, h

151.5 (0.5 - 5.0)143.8 ± 43.91560.6 ± 208.4572.4 ± 212.7

0.2087 ± 0.10673.813 ± 1.163

16a

2.0 (0.5 - 3.0)131.5 ± 41.08530.9 ± 159.6553.4 ± 160.6

0.2015 ± 0.067583.770 ± 1.109

Least square means ratio (90% CI), %

nCmax, ng/mLAUClast, ng.h/mLAUC∞, ng.h/mL

----

Test vs reference16b vs 15

92.74 (80.03 – 107.5)96.96 (87.34 – 107.6)96.81 (86.62 – 108.2)

AUClast = AUC from time of administration up to the last time point with a measurable concentration post dosing; AUC∞ = AUC extrapolated to infinity; ∀z = terminal elimination rate constant; t½ term = terminal elimination half-life.a n=15 for AUC∞, ∀z, and t1/2 term.b n=15 for test AUC∞.

Pharmacokinetics of N-desmethyl sildenafil (mean ± SD, tmax: median [range])

50 mg sildenafil (reference)


ntmax, hCmax, ng/mLAUClast, ng.h/mLAUC∞, ng.h/mL b

λz, 1/h b

t1/2term, h b

151.5 (0.5 - 4.0)98.77 ± 39.53365.1 ± 151.2380.3 ± 158.2

0.1359 ± 0.058845.934 ± 2.236

16 a

2.0 (0.5 - 3.0)87.49 ± 43.76326.8 ± 156.1355.3 ± 168.5

0.1342 ± 0.064806.146 ± 2.318

Least square means ratio (90% CI), %c

nCmax, ng/mLAUClast, ng.h/mL

---

Test vs reference16 vs 15

90.26 (79.75 – 102.1)91.68 (85.13 – 98.74)

a n=15 for AUC∞, λz, and t1/2term.b Accurate determination not possible for > 50% of subjects because parameter could not be calculated.c Statistical analysis was not performed for AUC∞.


Safety


50 mg sildenafil alone (Treatment A)

N = 15

75 mg TMC278 q.d. (Treatment B,

Days 1-11)N=16

75 mg TMC278 q.d. + 50 mg

sildenafil (Treatment B,

Day 12)N=16

Follow-up

(N=16)

AEs

n (%) with 1 or more AEs 1 (6.7) 4 (25.0) 2 (12.5) 1 (6.3)

Vision Blurred 0 1 (6.3) 0 0

Flatulence 0 1 (6.3) 0 0

Nausea 0 1 (6.3) 0 0

Vomiting 0 1 (6.3) 0 0

Body Tinea 0 1 (6.3) 0 0

Excoriation 0 0 0 1 (6.3)

Skin Laceration 1 (6.7) 0 0 0

Headache 0 0 1 (6.3) 0

Somnolence 0 1 (6.3) 0 0

Nasal Congestion 1 (6.7) 0 0 0

Pruritus 0 1 (6.3) 1 (6.3) 0

Skin Ulcer 0 0 1 (6.3) 0n (%) of deaths, serious AEs, AEs leading to withdrawal, or grade 3 or 4 AEs

0 0 0 0

Seven subjects (43.8%) experienced AEs during the trial. No single type of AE was experienced by more than 1 subject, with the exception of grade 1 pruritus which was experienced by 2 subjects and was considered doubtfully and not related to either TMC278 or sildenafil. A grade 1 skin event of interest (skin ulcer, not related to TMC278 or sildenafil) was reported in 1 subject (6.3%).


Changes in mean laboratory parameters over time were considered not clinically relevant. The majority of treatment-emergent laboratory abnormalities were DAIDS grade 1, although 7 subjects (43.8%) experienced grade 2 laboratory abnormalities and 1 subject (6.3%) experienced a grade 3 laboratory abnormality (increased lipase). No grade 4 laboratory abnormalities were reported. The majority of treatment-emergent, graded laboratory abnormalities were reported for lipase, total cholesterol, and low density lipoprotein. There were no consistent trends in laboratory abnormalities or in urinalysis abnormalities between treatments. No AEs relating to laboratory abnormalities or urinalysis abnormalities were reported.



Results showed minor variations in vital signs over time, but these were not considered clinically relevant. There were no notable differences in the results of the ECG measurements over time between treatments. No trend or pattern was observed between treatments for abnormalities in any vital signs parameter or in any ECG parameter. No AEs relating to ECG abnormalities were reported.


A number of observations during physical examination were recorded as AEs: 3 subjects were each reported with 1 new finding observed during treatment (skin ulcer, skin laceration) or during follow-up (excoriation). One further subject was reported with a new physical abnormality of a skin lesion, which was not reported as an AE.

Conclusions

The results of this trial demonstrate that steady-state concentrations after administration of 75 mg TMC278 q.d. did not affect the exposure to sildenafil and its active metabolite, N-desmethyl sildenafil, after a single dose of 50 mg sildenafil. Furthermore, the N-desmethyl sildenafil/sildenafil ratios for Cmax, AUClast and AUC∞ were similar after administration of sildenafil alone or in the presence of TMC278. The results of this trial thus indicate that there is no effect of TMC278 at a dose of 75 mg q.d. on cytochrome P450 3A4 activity in vivo. Also, the steady-state concentrations of 75 mg TMC278 q.d. were not affected by a single dose of 50 mg sildenafil. There were no safety or tolerability issues after coadministration of TMC278 and sildenafil. The results of this trial suggest that coadministration of sildenafil and TMC278 in HIV-1 infected subjects does not require a dose adjustment for either drug.

TMC278-C125 1




Drug Substance: TMC278Trial no.: TMC278-C125Clinical Phase: I

Title: A Phase I, open label, randomized, three-way crossover trial in 18 healthy subjects to investigate the pharmacokinetic interaction between steady-state TMC278 and steady-state rifabutin.


Country: Belgium



Objectives: The primary objectives of this study were: - to determine the effect of steady-state TMC278 on the steady-state pharmacokinetics of rifabutin and its active

metabolite 25-O-desacetyl-rifabutin; - to determine the effect of steady-state rifabutin on the steady-state pharmacokinetics of TMC278. The secondary objective was to determine the short-term safety and tolerability of coadministration of TMC278 and rifabutin for 11 days in healthy volunteers. Design: This was a Phase I, open label, randomized, 3-way crossover trial to investigate the steady-state pharmacokinetic interaction between TMC278 and rifabutin. Eighteen healthy subjects were to receive 3 different treatments in 3 separate sessions in a randomized fashion. There was a washout period of at least 2 weeks between the sessions. Treatment A consisted of TMC278 150 mg once daily (q.d.) for 11 days, Treatment B consisted of rifabutin 300 mg q.d. for 11 days, and Treatment C consisted of TMC278 150 mg q.d. in combination with rifabutin 300 mg q.d. for 11 days. Randomization was done in such a way that in each session 6 subjects received the same treatment, and each subject received a different treatment in each session. Full pharmacokinetic profiles of TMC278, rifabutin, and 25-O-desacetyl-rifabutin up to 24 hours postdose were determined on the last day of each session (Day 11). Tolerability and safety were assessed throughout the trial.Subject Selection Inclusion Criteria

1. Male or female, aged between 18 and 55 years, extremes included. 2. Normal weight as defined by a Quetelet Index (Body Mass Index, weight in kg divided by the square of

height in meters) of 18.0 to 30.0 kg/m2, extremes included. 3. Informed Consent Form (ICF) signed voluntarily before the first trial-related activity. 4. Cortisol of at least 550 nmol/L (19.9 μg/dL) at least at 1 of the measured time points (i.e., morning cortisol,

30 or 60 minutes after 250 g adrenocorticotropic hormone [ACTH] stimulation) at the screening assessment.

5. Able to comply with protocol requirements. 6. Healthy on the basis of a physical examination, medical history, electrocardiogram (ECG), vital signs, and

the results of blood biochemistry, and hematology tests and a urinalysis carried out at screening.

Exclusion Criteria1. A human immunodeficiency virus (HIV)-1 or HIV-2 test at screening. 2. Smoking of cigarettes, cigars, or pipes, or having smoked within the last 3 months prior to selection. 3. Female, except if postmenopausal for more than 2 years, or posthysterectomy, or post-tubal ligation

(without reversal operation). 4. History or suspicion of alcohol, barbiturate, amphetamine, recreational, or narcotic drug use which, in the

investigator’s opinion, would compromise subject’s safety and/or compliance with the trial procedures. 5. Hepatitis A, B, or C infection (confirmed by Hepatitis A antibody IgM, Hepatitis B surface antigen, or

Hepatitis C virus antibody, respectively) at screening. 6. A positive urine drug test at screening. Urine was tested for the presence of amphetamines, barbiturates,

benzodiazepines, cocaine, cannabinoids, methadone, and opioids. 7. Currently active or underlying gastrointestinal, cardiovascular, neurologic, psychiatric, metabolic, renal,

hepatic, respiratory, inflammatory, or infectious disease.

0137287, Final, 02-May-2007 12:29

Synopsis

TMC278-C125 2


Exclusion Criteria, continued 8. Current or history of adrenal disorder. 9. Any history of tuberculosis, ocular herpes, or uveitis. 10. Creatinine clearance of 60 mL/min. 11. Currently significant diarrhea, gastric stasis, or constipation that, in the investigator’s opinion, could

influence drug absorption or bioavailability. 12. Any history of significant skin disease such as, but not limited to, rash or eruptions, drug allergies, food


study medication administered in this trial (i.e.,TMC278 and Mycobutin or any other rifamycin), or to tetracosactide (used for the ACTH stimulation test).

14. Use of concomitant medication, including over-the-counter products, herbal medications, and dietary supplements. All medication must have been discontinued at least 14 days prior to the first intake of trial medication, except ibuprofen.

15. Having participated in more than 1 trial (single or multiple dose) with TMC125/TMC278/TMC120 or having developed rash, erythema, or urticaria while participating in a trial with TMC125/TMC278/TMC120.

16. Participation in an investigational drug trial within 60 days prior to the first intake of study medication. 17. Donation of blood or plasma within 60 days preceding the first intake of study medication. 18. Subjects with the following laboratory abnormalities at screening as defined by the Division of Acquired

Immunodeficiency Syndrome Table for Grading the Severity of Adult and Pediatric Adverse Events: serum creatinine grade 1 or greater ( 1.1 x upper limit of normal [ULN]); serum lipase grade 1 or greater ( 1.1 x ULN); hemoglobin grade 1 or greater ( 10.9 g/dL); platelet count grade 1 or greater ( 124.999 x 109/L); absolute neutrophil count grade 1 or greater ( 1.3 x 109/L); aspartate aminotransferase or alanine aminotransferase grade 1 or greater ( 1.25 x ULN); total bilirubin grade 1 or greater ( 1.1 x ULN); any other grade 2 or above, including proteinuria (spot urine) > 1+, and microscopic hematuria (> 10 red blood cells/high power field).

Treatment Treatment A Treatment B Treatment C Dosage TMC278 150 mg q.d. Rifabutin 300 mg q.d. TMC278 150 mg q.d. and

rifabutin 300 mg q.d. Dosage Form (TF No.)

50 mg tablets (F003) and 100 mg tablets (F002)

Rifabutin capsules (Mycobutin ) containing

150 mg rifabutin

TMC278 tablets (F003 and F002) and rifabutin

capsules (Mycobutin )Usage 1 x 50 mg and 1 x 100 mg

tablets on Days 1 – 11 (oral intake)

2 capsules on Days 1 – 11 (oral intake)

1 x 50 mg and 1 x 100 mg tablets of TMC278 and

2 capsules of rifabutin on Days 1 – 11 (oral intake)

Batch Numbers 50 mg TMC278 tablet: PD1273

100 mg TMC278 tablet: PD1268

Mycobutin capsule: 04F01 Mycobutin capsule: 04F01



Dose Regimen Each subject received Treatments A, B, and C over the course of Sessions I to III, with a washout period of at least 2 weeks between sessions.


3 sessions of 11 days each (excluding washout)


0137287, Final, 02-May-2007 12:29

Synopsis

TMC278-C125 3


Disallowed Medication

All concomitant medication, except ibuprofen must have been discontinued and subjects were not to use any herbal medications or dietary supplements including Hypericum perforatum(St. John’s wort) for at least 14 days prior to the first intake of study medication until the last trial-related visit or after dropout. Ibuprofen was allowed up to 3 days before the intake of study medication. After that, the investigator could permit the use of ibuprofen (at no more than 1 x 400 mg per day). In case of cutaneous reaction/rash and/or an allergic reaction, the use of cetirizine (Zyrtec ),levocetirizine (Xyzal ), topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In case of nausea, the use of antiemetics was permitted. In case of diarrhea, the use of loperamide was permitted.

Scre

enin

ga

Treatment A Treatment B or Treatment C

Follo

w-u

p

Assessments

21

days

Day

1

Day

9

Day

10

Day

11

Day

12b

Day

1

Day

5

Day

9

Day

10

Day

11

Day

12b

Day

s 7 a

nd

30, 3

1, o

r 32

Pharmacokinetics Blood sample Xc,f Xe Xe Xe,d Xe Xc,f Xe Xe Xe Xd,e Xe

Safety Adverse eventsg X X X X X X X X X X X X X Concomitant medsg X X X X X X X X X X X X X Hemat & biochemh X Xi X Xi Xi X X Xi X Urinalysis X Xj Xj Xj Xj Xj X ACTH stimulation test with determinations of cortisol and 17-OH-progesterone

X X Xk

Apo A1, Apo B, insulin, and 1-acid glycoprotein testing

X X Xk

T3, free-T4, and TSH X X Xk

ECG & vital signs X Xi,j Xi,j Xi,j Xl Xi,j X Skin examination X X X X X X X X X X X Physical examination X X X X X X X X X X

0137287, Final, 02-May-2007 12:29

Synopsis

TMC278-C125 4


meds = medication; Hemat & biochem = hematology & biochemistry; ACTH = adrenocorticotropic hormone; stim = stimulation; Apo = apolipoprotein; T3 = triidothyronine; free-T4 = free-thyroxine; TSH = thyroid stimulating hormone; ECG = electrocardiogram, 17-OH = 17-hydroxyprogesterone. a At screening, subject’s demographics and characteristics, smoking habits, medical and surgical history, family history related to skin disease, and concomitant diseases were recorded. An HIV-1 and -2 test, Hepatitis A, B, and C test, and drug screening, as well as a pregnancy test for females were performed. b Day 1 of washout period, if applicable. c Immediately before drug intake for determination of TMC278, rifabutin, and 25-O-desacetyl-rifabutin concentrations. d At 0.5, 1, 2, 3, 4, 5, 6, 9, 12, and 16 hours postdose for determination of TMC278 concentrations (Treatment A), for determination of rifabutin and 25-O-desacetyl-rifabutin concentrations (Treatment B), and for determination of TMC278, rifabutin, and 25-O-desacetyl-rifabutin concentrations (Treatment C). e For determination of TMC278 concentrations (Treatment A), rifabutin and 25-O-desacetyl-rifabutin concentrations (Treatment B), and TMC278, rifabutin, and 25-O-desacetyl-rifabutin concentrations (Treatment C). f Also at 4 hours postdose for determination of TMC278 concentrations (Treatment A), rifabutin, and 25-O-desacetyl-rifabutin concentrations (Treatment B) and TMC278, rifabutin, and 25-O-desacetyl-rifabutin concentrations (Treatment C). g Adverse events and concomitant medications were monitored continuously from signing the ICF until the last trial-related activity. h Predose biochemistry samples were taken fasted for at least 10 hours. i Also at 4 hours postdose. j Within 2 hours before drug intake. k Treatment C only. l Vital signs only.

Statistical Methods

Intent-to-treat analysis, descriptive statistics, frequency tabulations, linear mixed effects model, Mann-Whitney U-test, and Wilcoxon matched pairs signed ranks test.


Baseline Characteristics - Subject Disposition Total N = 18


16/2 42.5 (22-52)

Ethnic Origin, n (%) Caucasian 18 (100)

Drop-outs - Reason Any reason

Adverse event Withdrew consent

4 (22.2%) 2 (11.1%) 2 (11.1%)

0137287, Final, 02-May-2007 12:29

Synopsis

TMC278-C125 5




Treatment A, TMC278 alone

(reference)

Treatment C, TMC278 + rifabutin

(test) n 14 16 tmax, h 5.0 [4.0 - 9.0] 5.0 [2.0 - 9.0] C0h, ng/mL 433.9 ± 112.1 229.3 ± 76.66 Cmin, ng/mL 363.8 ± 80.28 187.0 ± 57.03 Cmax, ng/mL 991.6 ± 240.6 682.5 ± 227.0 AUC24h, ng.h/mL 15184 ± 3254 8692 ± 2564 Css, av, ng/mL 632.7 ± 135.6 362.1 ± 106.8 FI, % 97.85 ± 21.28 134.3 ± 32.56 LSmeans ratio (90% CI), %

Test vs Reference n 16 vs 14 C0h - 52.60 (47.46-58.30) Cmin - 50.99 (48.04-54.13)Cmax - 65.31 (57.84-73.74) AUC24h - 53.97 (50.04-58.22)

Pharmacokinetics of rifabutin


Treatment B, Rifabutin alone

(reference)


(test) n 17 16 tmax, h 3.0 [2.0 - 6.0] 4.5 [2.0 - 6.0] C0h, ng/mL 66.83 ± 19.38 71.45 ± 27.11 Cmin, ng/mL 62.16 ± 17.58 64.33 ± 25.24 Cmax, ng/mL 415.6 ± 136.9 420.7 ± 111.6 AUC24h, ng.h/mL 3943 ± 982.1 4109 ± 1083 Css, av, ng/mL 164.3 ± 40.92 171.2 ± 45.14 FI, % 212.2 ± 40.34 209.9 ± 32.95 LSmeans ratio (90% CI), %

Test vs Reference n 16 vs 17 C0h - 105.1 (94.58-116.8) Cmin - 101.4 (94.03-109.4) Cmax - 103.0 (93.47-113.6)AUC24h - 102.7 (96.56-109.1)

0137287, Final, 02-May-2007 12:29

Synopsis

TMC278-C125 6


Pharmacokinetics of 25-O-desacetyl-rifabutin


Treatment B, Rifabutin alone

(reference)


(test)

n 17 16tmax, h 4.0 [2.0 - 5.0] 5.0 [3.0 - 5.0] C0h, ng/mL 3.939 ± 1.444 4.734 ± 2.393 Cmin, ng/mL 3.427 ± 1.491 3.956 ± 1.862 Cmax, ng/mL 27.66 ± 7.368 32.41 ± 13.91 AUC24h, ng.h/mL 259.9 ± 77.78 315.3 ± 172.6 Css, av, ng/mL 10.83 ± 3.241 13.14 ± 7.191 FI, % 227.7 ± 32.81 223.8 ± 35.03 LSmeans ratio (90% CI), %

Test vs Referencen 16/15 vs 17/16a

C0h - 113.1 (97.06-131.9) Cmin - 111.9 (102.7-121.9) Cmax - 107.1 (97.82-117.2) AUC24h - 106.5 (101.8-111.4)

a For C0h, Cmax, and AUC24h: n=16 for Treatment C (test) and n=17 for Treatment B (reference); for Cmin: n=15 for Treatment C (test) and n=16 for Treatment B (reference).


Treatment A, TMC278

alone N = 14

Treatment B, Rifabutin

alone N = 17


N = 17

Total

N = 18 Adverse Events (AEs) Most frequently reported treatment-emergent AEs (reported in 2 subjects), n (%)

Chromaturia 0 7 (41.2) 6 (35.3) 10 (55.6) Headache 5 (35.7) 4 (23.5) 2 (11.8) 6 (33.3) Back pain 0 1 (5.9) 4 (23.5) 5 (27.8) Diarrhoea 1 (7.1) 0 3 (17.6) 4 (22.2) Fatigue 1 (7.1) 2 (11.8) 2 (11.8) 4 (22.2) Lipase increased 1 (7.1) 0 2 (11.8) 4 (22.2)a

Nausea 1 (7.1) 0 2 (11.8) 3 (16.7) Pyrexia 0 1 (5.9) 2 (11.8) 3 (16.7) Influenza like illness 0 0 2 (11.8) 2 (11.1) Pharyngolaryngeal pain 0 0 2 (11.8) 2 (11.1) Rash 2 (14.3) 0 0 2 (11.1) n (%) with 1 or more AEs 10 (71.4) 12 (70.6) 14 (82.4) 17 (94.4) n (%) of deaths 0 0 0 0n (%) with 1 or more other serious AEs

0 0 0 0

n (%) with treatment stopped due to AEs

0 0 2 (11.8) 2 (11.1)

n (%) with 1 or more grade 3 or 4 AEs 0 0 1 (5.9) 2 (11.1)b

a including 1 subject with lipase increased during the follow-up period. b including 1 subject with grade 3 blood triglycerides increased during the screening period.

0137287, Final, 02-May-2007 12:29

Synopsis

TMC278-C125 7


Seventeen subjects (94.4%) reported at least 1 AE during the trial. The most commonly reported AEs during the trial were chromaturia (55.6%), which was only reported in subjects treated with rifabutin alone or in combination with TMC278, and headache (33.3%). The majority of the AEs were grade 1 or 2. One (5.6%) subject was reported with a grade 3 (severe) AE of lipase increased during Treatment C and 1 (5.6%) subject was reported with an ungraded elevated triglyceride level at screening which worsened in severity to a grade 3 (severe) AE of blood triglycerides increased during Treatments B and C. Ten and 14 subjects, respectively, had an AE considered to be at least probably related to TMC278 and rifabutin. There were no deaths or other SAEs reported in this trial. Two subjects discontinued the trial due to an AE (lipase increased [1 subject] and blood triglycerides increased [1 subject]). During the trial, three subjects were reported with AEs considered to be skin events of interest (2 events of rash and 1 event of erythema), all of which were grade 1 in severity.

Clinical Laboratory Tests Safety(n = number of subjects with data)

Treatment A, TMC278

alone N = 14

Treatment B, Rifabutin

alone N = 17


N = 17

Total

N = 18 n (%) with 1 or more treatment-emergent graded laboratory abnormalities

grade 1 1 (7.1) 5 (29.4) 10 (58.8) 11 (61.1) grade 2 2 (14.3) 5 (29.4) 4 (23.5) 9 (50.0) grade 3 0 1 (5.9) 1 (5.9) 2 (11.1) grade 4 0 1 (5.9) 2 (11.8) 3 (16.7)

There were no consistent or clinically relevant treatment-emergent changes over time in laboratory parameters. Grade 4 abnormalities were reported as the worst grade for triglycerides (1 subject) during Treatment B and for neutrophils (1 subject) and lymphocytes (1 subject) during Treatment C. Grade 3 abnormalities were observed as the worst grade for lymphocytes (1 subject) during Treatment B and for lipase (1 subject) during Treatment C. Nine subjects had 1 or more treatment-emergent grade 2 abnormalities. The most common treatment-emergent grade 2 abnormalities were for decreased neutrophil levels (4 subjects) and hyperglycemia (3 subjects). All other treatment-emergent laboratory abnormalities were of grade 1 severity. Abnormalities reported as AEs were blood triglycerides increased (1 subject) and lipase increased (4 subjects). Adrenal Function At all assessment time points, the median cortisol value increased after ACTH stimulation (T30 and T60) relative to T0. The median cortisol values at T0 were 310.39 nmol/L at the screening visit, 346.25 nmol/L on Day 12 of Treatment A, and 322.80 nmol/L on Day 12 of Treatment C. The median change in T0 cortisol compared to reference was 91.87 nmol/L on Day 12 of Treatment A and 49.66 nmol/L on Day 12 of Treatment C. These median changes from reference were not considered to be clinically relevant. At all assessment time points, the median 17-OH-progesterone value increased post ACTH stimulation (T30 and T60) compared to T0. The median values at T0 were 3.270 nmol/L at the screening visit, 5.385 nmol/L on Day 12 of Treatment A, and 3.870 nmol/L on Day 12 of Treatment C. One subject did not achieve a normal cortisol response ( 550 nmol/L) after ACTH stimulation. On Day 12 of Treatment C, this subject had a maximum cortisol level of 549.0 nmol/L, however 17-OH-progesterone did not increase abnormally during this test. No AEs related to adrenal function were reported.

0137287, Final, 02-May-2007 12:29

Synopsis

TMC278-C125 8


Cardiovascular Safety Minor changes were reported for vital sign values. None of the changes was considered to be clinically relevant. No trends or relationship to study medication were apparent and no clinically relevant changes in ECG parameters were reported. Physical Examination and Skin Examination The following abnormal, new findings were reported during the trial; rash from band aid and rash on scalp during Treatment A, erythema at location of band aid during Treatment B, burn wound wrist during Treatment B, and herpes labialis during Treatment A. All events were reported as AEs.

ConclusionsThe results of the present trial demonstrate that after the combined intake of TMC278 and rifabutin, the C0h, Cmin,Cmax, and AUC24h of TMC278 were decreased by 47%, 49%, 35%, and 46%, respectively, in comparison to intake of TMC278 alone. No changes were observed in C0h, Cmin, Cmax, and AUC24h of rifabutin during combination with TMC278, in comparison to intake of rifabutin alone. The C0h of 25-O-desacetyl-rifabutin was increased by 13% when combined with TMC278. There were no changes for the other pharmacokinetic parameters of the metabolite when combined with TMC278. Dosage recommendations for the combination of TMC278 and rifabutin will follow after dose selection for further development of TMC278. In healthy subjects in this trial, 150 mg TMC278 q.d. administered alone or in combination with 300 mg rifabutin q.d. was generally safe and well tolerated.

0137287, Final, 02-May-2007 12:29

Synopsis

TMC278-C127 1

Clinical Research Report Version: 1.0 Date: 04-Aug-2006



Trade Name: -




Clinical Phase: I

Title: A Phase I, open-label, randomized, two-way crossover trial in 16 healthy subjects to investigate the potential pharmacokinetic interaction between steady-state TMC278 and steady-state ketoconazole


Country: France



Objectives: The objectives of this trial were: - to investigate the effect of steady-state ketoconazole on the steady-state pharmacokinetics of TMC278; - to investigate the effect of steady-state TMC278 on the steady-state pharmacokinetics of ketoconazole; - to determine the short-term safety and tolerability of coadministration of TMC278 and ketoconazole.

Design: This was a Phase I, open-label, randomized, two-way crossover trial to investigate the pharmacokinetic interaction between TMC278 and ketoconazole at steady-state. In two sessions, 16 healthy subjects received, in a randomized order, TMC278 alone (Treatment A) or ketoconazole alone followed by the combination of TMC278 and ketoconazole (Treatment B). There was a washout period of at least 14 days between the two sessions. Randomization was done in such a way that, in each session, 8 out of 16 subjects received the same treatment and that each subject received a different treatment in each session. Treatment A consisted of TMC278 150 mg once daily (q.d.) for 11 days. Treatment B consisted of ketoconazole 400 mg q.d. for 22 days with coadministration of TMC278 150 mg q.d. from Days 12 to 22. Full pharmacokinetic profiles of TMC278 up to 24 hours postdose were determined on Day 11 of Treatment A and Day 22 of Treatment B. Full pharmacokinetic profiles of ketoconazole up to 24 hours postdose were determined on Days 11 and 22 of Treatment B. Tolerability and safety were assessed throughout the trial period.

Subject Selection

Inclusion Criteria

1. Male or female, aged between 18 and 45 years, extremes included.

2. Smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day (or non-smoking) for at least 3 months prior to selection.


4. Informed Consent Form (ICF) signed voluntarily before first trial-related activity.

5. Cortisol of at least 550 nmol/L (19.9 μg/dL) at least at one of the time points (i.e., prestimulation cortisol, 30 or 60 minutes after 250 μg adrenocorticotropic hormone [ACTH] stimulation) at the screening assessment.


7. Healthy on the basis of a physical examination, medical history, electrocardiogram (ECG), vital signs, and the results of blood biochemistry and hematology tests and a urinalysis carried out at screening.

Synopsis

TMC278-C127 2


Exclusion Criteria

1. A positive human immunodeficiency virus (HIV)-1 or -2 test at screening.

2. Female, except if postmenopausal for more than 2 years, or post-hysterectomy, or post-tubal ligation (without reversal operation).

3. History or suspicion of alcohol, barbiturate, amphetamine, recreational, or narcotic drug use which in the investigator’s opinion would compromise subject safety or compliance with trial procedures.

4. Hepatitis A, B, or C infection (confirmed by Hepatitis A antibody IgM, Hepatitis B surface antigen, or Hepatitis C virus antibody, respectively) at screening.

5. A positive urine drug test at screening. Urine was tested for the presence of amphetamines, benzodiazepines, cocaine, cannabinoids, and opioids.

6. Currently active gastrointestinal, cardiovascular, neurological, psychiatric, metabolic, renal, hepatic, respiratory, inflammatory, or infectious disease.




10. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication administered in this trial (i.e., TMC278 as well as ketoconazole), or any imidazole antifungal.

11. History of recurrent fungal infection that required the use of a triazole (fluconazole, itraconazole, voriconazole).

12. Use of concomitant medication, including over-the-counter products, herbal medications, and dietary supplements. Over-the-counter medication must have been discontinued at least 7 days prior to the first administration of trial medication and prescribed medication, herbal medications, and dietary supplements must have been discontinued at least 14 days before the first administration of trial medication, except for ibuprofen.

13. Participation in an investigational drug trial within 30 days prior to the first administration of trial medication.

14. Donation of blood or plasma within the 60 days preceding the first administration of trial medication.

15. Having previously participated in more than 1 trial (single or multiple dose) with TMC125, TMC120, and/or TMC278 (formerly known as R278474) or having developed a rash, erythema, or urticaria while participating in a trial with the before mentioned compounds.

16. Subjects with the following laboratory abnormalities at screening as defined by the Division of Acquired Immunodeficiency Syndrome (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events: serum creatinine grade 1 or greater ( 1.1 x upper limit of normal [ULN]); lipase grade 1 or greater ( 1.1 x ULN); hemoglobin toxicity grade 1 or greater ( 10.9 g/dL); platelet count grade 1 or greater ( 124.999/mm3); absolute neutrophil count grade 1 or greater ( 1300/mm3); aspartate aminotransferase or alanine aminotransferase grade 1 or greater ( 1.25 x ULN); total bilirubin grade 1 or greater ( 1.1 x ULN); any other toxicity grade 2 or above, including: proteinuria (spot urine) 2+ and microscopic hematuria > 10 red blood cells/high power field.

Synopsis

TMC278-C127 3



Dosage 150 mg q.d. TMC278 for 11 days

400 mg q.d. ketoconazole on Days 1-22 and 150 mg q.d. TMC278 on Days 12-22

Dosage Form (F No.) 50 mg tablets (F003) and 100 mg tablets (F002)

200 mg ketoconazole tablets and 50 and 100 mg TMC278 tablets (F003 and F002)

Usage 1 x 50 mg and 1 x 100 mg tablets for oral usage on

Days 1-11

2 x 200 mg ketoconazole tablets on Days 1-22 + 1 x 50 mg and 1 x 100 mg TMC278 tablets for oral usage

on Days 12-22

Batch Number 50 mg TMC278 tablets: PD1273

100 mg TMC278 tablets: PD1268

200 mg ketoconazole tablets: 02GB749/A 50 mg TMC278 tablets: PD1273

100 mg TMC278 tablets: PD1268

Dose Regimen Group 1: Treatment A during Session I, Treatment B during Session II, with a washout period of at least 14 days between sessions.

Group 2: Treatment B during Session I, Treatment A during Session II, with a washout period of at least 14 days between sessions.

Duration of Treatment 33 days (excluding washout)


Disallowed Medication All over-the-counter medication must have been discontinued at least 7 days and all prescribed medication must have been discontinued at least 14 days before the first intake of trial medication, except for ibuprofen. Subjects were not to use any medication other than the trial medication up to 7 days after the last intake of trial medication, except for ibuprofen. Subjects were also not to use any herbal medications or dietary supplements including products containing Hypericum perforatum (e.g., St. John’s wort) from 14 days before the first intake of trial medication and up to 7 days after the last intake of trial medication. Ibuprofen could be used up to 3 days before the first intake of trial medication. After that, the clinical investigator could permit the use of ibuprofen (at no more than 1 x 400 mg per day). In case of cutaneous reaction/rash and/or an allergic reaction, the use of cetirizine (Zyrtec ), levocetirizine (Xyzal ), topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In case of nausea, the use of antiemetics was permitted. In case of diarrhea, the use of loperamide was permitted.

Synopsis

TMC278-C127 4


Assessments

Scre

enin

ga

Session I or II/Treatment A or Treatment B

Sess

ion

I /II

Tr

eatm

ent A

Session I or II/Treatment B

Follo

w-u

p

21

days

Day

–1b

Day

1

Day

9

Day

10

Day

11

Day

12e

Day

12

Day

20

Day

21

Day

22

Day

23e

Day

7,

and

30,

31, o

r 32

Pharmacokinetics Blood sample

Xg,h

Xg,h

Xg,h

Xg,h

Xg,h

Xg,h

Xg,h

Xg,h

Xg,h

Xg,h

Safety Adverse events + concomitant medsc


Hemat & biochemd X Xi Xi Xi,j X Xi Xi Xi,j X X Urinalysis X Xi X Xi X X ACTH stim test with determinations of cortisol and 17-OH progesterone

X X X X


X X X

T3, free T4, and TSH X X X ECG & vital signs X Xf Xi,j Xi,j X Xi,j Xi,j X X Skin examination X X Xk X X X X X Physical examination X X X X X X meds = medication; Hemat & biochem = hematology & biochemistry; ACTH = adrenocorticotropic hormone; stim = stimulation; Apo = apolipoprotein; T3 = triidothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone; ECG = electrocardiogram. a At screening, information on subject’s demographics and characteristics, medical and surgical history, smoking habits, concomitant diseases, and concomitant medication was collected, and HIV-1 and -2 test, Hepatitis A, B, and C tests, and drug screening tests were performed; a serum pregnancy test was also performed if applicable. b Subjects were admitted to the unit the night before Day 1. c Adverse events and concomitant medications were monitored continuously from signing the ICF until the last trial-related activity. d Biochemistry samples were taken fasting for at least 10 hours, before breakfast. e Day 12 is Day 1 of washout after Treatment A (if applicable); Day 23 is Day 1 of washout after Treatment B (if applicable). f Vital signs only. g For Treatments A and B: immediately before drug intake plus 4 hours postdose on Day 1; predose on Days 9, 10, and 12; predose and 0.5, 1, 2, 3, 4, 5, 6, 9, 12, and 16 hours postdose on Day 11. Treatment B: predose and 0.5, 1, 2, 3, 4, 5, 6, 9, 12, and 16 hours postdose on Day 22; predose on Days 20, 21, and 23; 4 hours postdose on Day 12. h For determination of both TMC278 and ketoconazole concentrations predose on Day 1 (Treatments A and B), 4 hours postdose on Day 1 (Treatment B), predose and 4 hours postdose on Day 12 (Treatment B), and on Days 20-23 (Treatment B); TMC278 concentrations alone 4 hours postdose on Day 1 (Treatment A) and on Days 9-12 (Treatment A); ketoconazole concentrations alone on Days 9-11 (Treatment B). i Within 2 hours before drug intake. j And 4 hours postdose. k Treatment A only (Sessions I or II).

Statistical Methods Descriptive statistics, frequency tabulations, intent-to-treat analysis, Wilcoxon matched-pairs signed ranks test, and linear mixed effects modeling.

Synopsis

TMC278-C127 5




Group 1 TMC278

Ketoconazole + TMC278 (N = 8)

Group 2 Ketoconazole +

TMC278 TMC278 (N = 8)

All Subjects (N = 16)



8/0

25.5 (18 – 31)

8/0

26.0 (20 – 37)

16/0

25.5 (18 – 37)

Ethnic Origin, n (%)

Caucasian/White Black

4 (50.0) 4 (50.0)

4 (50.0) 4 (50.0)

8 (50.0) 8 (50.0)

Drop-Outs - Reason

Withdrew consent

2 (25.0%)

0

2 (12.5%)


(mean SD, tmax: median [range]) Treatment A, Day 11:

TMC278 Alone Treatment B, Day 22:

Ketoconazole + TMC278 n 15 14 tmax, h 5.0 (3.0 – 12.0) 7.0 (3.0 – 12.0) C0h, ng/mL 462.2 ± 142.8 843.7 ± 304.2 Cmin, ng/mL 378.5 ± 115.1 674.1 ± 255.9 Cmax, ng/mL 1015 ± 215.8 1385 ± 523.8 AUC24h, ng.h/mL 14960 ± 3248 23590 ± 8779 Css, av, ng/mL 623.3 ± 135.3 983.1 ± 365.8 FI, % 103.9 ± 24.94 71.64 ± 17.15 LSmean ratio (90% CI), %

Treatment B vs Treatment A n - 14 vs 15 C0h - 180.3 (161.3 – 201.6)a Cmin - 175.7 (156.9 – 196.7)a Cmax - 129.5 (113.2 – 148.2)a AUC24h - 149.4 (130.9 – 170.4)a

a p-value < 0.05 Data from both groups were pooled for the analysis.

Synopsis

TMC278-C127 6


Pharmacokinetics of ketoconazole

(mean SD, tmax: median [range]) Treatment B, Day 11: Ketoconazole Alone

Treatment B, Day 22: Ketoconazole + TMC278

n 14 14 tmax, h 4.0 (2.0 - 5.0) 4.0 (3.0 - 12.0) C0h, μg/mL 0.4625 ± 0.3246 0.1426 ± 0.08989 Cmin, μg/mL 0.4327 ± 0.2964 0.1373 ± 0.09035 Cmax, μg/mL 8.936 ± 1.475 7.602 ± 1.234 AUC24h, μg.h/mL 83.33 ± 14.79 63.57 ± 12.46 Css, av, μg/mL 3.472 ± 0.6163 2.649 ± 0.5190 FI, % 249.1 ± 47.51 287.6 ± 53.71 LSmean ratio (90% CI), %

Ketoconazole + TMC278 vs Ketoconazole Alone

n - 14 vs 14 C0h - 33.66 (24.74 - 45.78)a Cmin - 33.90 (24.94 - 46.06)a Cmax - 85.06 (80.06 - 90.37)a AUC24h - 75.98 (70.40 - 82.01)a

a p-value < 0.05 Data from both groups were pooled for the analysis.

Safety

(n = number of subjects with data) TMC278 Alone

(N = 16)

KetoconazoleAlone

(N = 15)


Adverse Events (AEs) n (%) with 1 or more AEs 1 (6.3%) 1 (6.7%) 0 Headache 0 1 (6.7%) 0 Pyrexia 1 (6.3%) 0 0 n (%) of deaths 0 0 0 n (%) with 1 or more other serious AEs 0 0 0 n (%) of treatment stopped due to AEs 0 0 0 n (%) with 1 or more grade 3 or 4 AEs 0 0 0

One subject was reported with a grade 2 AE of pyrexia on Day 9 of treatment with TMC278 alone. The event was judged to have a doubtful relationship with TMC278 and resolved after 2 days. One subject was reported with a grade 2 AE of headache on Day 2 of treatment with ketoconazole alone. The event was not judged to be related to either TMC278 or ketoconazole and resolved after 2 days.

Synopsis

TMC278-C127 7


TMC278 Alone (N = 16)

KetoconazoleAlone

(N = 15)


Clinical Laboratory Tests n (%) with 1 or more postdose treatment-emergent grade 1 laboratory abnormalities

5 (31.3%) 9 (60.0%) 6 (42.9%)

n (%) with 1 or more postdose treatment-emergent grade 2 laboratory abnormalities

2 (12.5%) 3 (20.0%) 2 (14.3%)


1 (6.3%) 0 1 (7.1%)


0 0 0

There were no consistent or clinically relevant treatment-emergent changes over time in laboratory parameters. No grade 4 treatment-emergent abnormalities were reported. Three subjects had a treatment-emergent grade 3 abnormality during this trial: decreased phosphorus (2 subjects) and elevated lipase (1 subject). Five subjects had 1 or more treatment-emergent grade 2 abnormalities. The most common treatment-emergent grade 2 abnormalities were decreased phosphorus and elevated lipase (2 subjects each). No laboratory abnormalities were reported as AEs. Adrenal Function Results At all time points, the median cortisol values increased from T0 to T30 and T60. The median cortisol values at T0 were 389.05 nmol/L at the screening visit, 298.00 nmol/L on Day 12 of Treatment A (TMC278 alone), 328.30 nmol/L on Day 12 of Treatment B (ketoconazole alone), and 372.45 nmol/L on Day 23 of Treatment B (coadministration of ketoconazole + TMC278). The median change in T0 cortisol compared to reference was -49.70 nmol/L on Day 12 of Treatment A (TMC278 alone), -53.80 nmol/L on Day 12 of Treatment B (ketoconazole alone), and 22.05 nmol/L on Day 23 of Treatment B (coadministration of ketoconazole + TMC278). These median changes from reference were not considered to be clinically relevant. In response to ACTH stimulation 66.7% and 92.9% of subjects during treatment with Treatment A and Treatment B, respectively, achieved a cortisol value

550 nmol/L; 5 subjects did not achieve a cortisol value 550 nmol/L during treatment with Treatment A and 1 subject did not achieve a cortisol value 550 nmol/L during treatment with Treatment B. At all assessment time points, the median 17-OH-progesterone value increased post ACTH stimulation (T30 and T60) compared to T0. The median values at T0 were 3.180 nmol/L at the screening visit, 4.240 nmol/L on Day 12 of Treatment A (TMC278 alone), 7.865 nmol/L on Day 12 of Treatment B (ketoconazole alone), and 6.350 nmol/L on Day 23 of Treatment B (coadministration of ketoconazole + TMC278). There was no clinically significant change in the median T0 17-OH-progesterone value after TMC278 administration alone compared to reference (0.910 nmol/L on Day 12 of Treatment A), but a small increase after ketoconazole alone (4.685 nmol/L on Day 12 of Treatment B) and after coadministration of ketoconazole + TMC278 (3.020 nmol/L on Day 23 of Treatment B). Cardiovascular Safety Minor changes were reported for vital signs, with statistically significant changes evenly distributed across treatments. None of the statistically significant changes was considered to be clinically relevant. Minor changes were reported for ECG parameters, with statistically significant changes mainly being decreases in PR and PQ intervals and increases in QTcF interval. No trends or relationship to study medication were apparent and no clinically relevant changes were reported. Physical and Skin Examinations. Physical and skin examination revealed no abnormal new findings during the trial.

Synopsis

TMC278-C127 8


Conclusions

The results of the present trial show that there was a statistically significant increase in exposure to TMC278 (measured as AUC24h) of 49% when 150 mg TMC278 q.d. was coadministered with 400 mg ketoconazole q.d. The exposure to ketoconazole (measured as AUC24h) was statistically significantly decreased (by 24%) when TMC278 was coadministered. Dosage recommendations for the combined administration of TMC278 and ketoconazole will follow after dose selection for TMC278. In these healthy subjects, the administration of 150 mg q.d. TMC278 with or without 400 mg q.d. ketoconazole was generally well tolerated.

Synopsis




Trade Name: Not applicable




Clinical Phase: I

Title: A Phase I, open-label drug-drug interaction trial to investigate the effect of TMC278 25 mg q.d. on the steady-state pharmacokinetics of ethinylestradiol and norethindrone, in healthy women.

Investigator:

United Kingdom


Trial Period: Start: 28-Jul-2008

End: 02-Dec-2008


No. of Subjects: 18 Objectives: The primary objectives of this trial were to:

determine the effect of steady-state concentrations of TMC278 25 mg once daily (q.d.) on the steady-state pharmacokinetics of ethinylestradiol 35 μg q.d., determine the effect of steady-state concentrations of TMC278 25 mg q.d. on the steady-state pharmacokinetics of norethindrone 1 mg q.d.

Secondary objectives were to: evaluate the short-term safety and tolerability of coadministration of TMC278 25 mg q.d., ethinylestradiol and norethindrone, in healthy women, evaluate the effect of the combination of norethindrone and ethinylestradiol on the steady-state pharmacokinetics of TMC278, compared to historical data for TMC278.

Design: This was a Phase I, open-label trial in healthy women to investigate the pharmacokinetic interaction between the combination of ethinylestradiol and norethindrone and TMC278 25 mg once daily (q.d.). TMC278 is being investigated for the treatment of HIV-1 infected subjects. The trial population consisted of 18 healthy women who were stable on oral contraceptives (OC), specifically ethinylestradiol 35 μg and norethindrone 1.0 mg (the components of Ovysmen®), or who, if they were not currently using this OC, were willing to start or switch to this OC for the duration of the trial.

Subjects received OC q.d. for 21 days for at least 1 OC cycle prior to Day 1 (stabilizing OC cycle from Day -28 to Day -1). During the second OC cycle (from Day 1 to Day 28), subjects received OC alone q.d. for 21 days (Treatment A). During the third OC cycle (from Day 29 to Day 56), subjects received OC for 21 days and in addition TMC278 25 mg q.d. in the morning for 15 days, starting on the first day of OC intake (Day 29 [Treatment B]). During the 3 OC cycles, OCs were administered q.d. at approximately the same time each morning. Oral contraceptive treatment consisted of OC tablets (fixed-dose combination of ethinylestradiol 35 μg and norethindrone 1.0 mg) during Days 1 to 21 of each OC cycle, followed by a pill-free period during Days 22 to 28 of each OC cycle.

Twenty-four hour pharmacokinetic profiles of ethinylestradiol and norethindrone were determined after the first 2 weeks of the second OC cycle (Treatment A: OC alone; Day 15) and after the first 2 weeks of the third OC cycle (Treatment B: OC plus TMC278; Day 43). On these days, blood samples to determine plasma concentrations of ethinylestradiol and norethindrone were drawn just before drug intake (predose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12 and 24 hours postdose. A 24-hour pharmacokinetic profile of TMC278 was determined on Day 43. Blood samples to determine plasma concentrations of TMC278 were drawn just before drug intake (predose) and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 16 and 24 hours postdose. On pharmacokinetic sampling days, all treatments were administered within 10 minutes after a standardized breakfast.

Pharmacodynamic assessments of serum levels of progesterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were done on Days 1 and 14 (Treatment A, OC alone), and on Days 29 and 42 (Treatment B, OC plus TMC278). Safety and tolerability were evaluated throughout the trial.

0313942, Final, 23-Jul-2009 14:50



Subject Selection

Inclusion Criteria

1. Female, willing to start or continue OC therapy, specifically, ethinylestradiol 35 μg and norethindrone 1.0 mg (the components of Ovysmen®) for at least 1 complete OC cycle (stabilizing treatment) before Treatment A, and willing to continue until the end of the third OC cycle during which TMC278 25 mg q.d. was received.

2. Subjects that consented to a method of birth control in addition to the OC trial medication from the first intake of TMC278 until 1 month after last TMC278 intake, e.g.:

male or female condom with spermicide;

diaphragm or cervical cap;

were non-heterosexually active, practiced sexual abstinence or had a vasectomized partner.


4. Non-smoking or smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day for at least 3 months prior to screening.

5. Body mass index (weight in kg divided by the square of height in meters) of 18.0 to 30.0 kg/m2, extremes included.

6. Informed Consent Form signed voluntarily before first trial-related activity.


8. Healthy on the basis of a physical examination, medical history, electrocardiogram (ECG), vital signs and the results of blood biochemistry and hematology tests and a urinalysis carried out at screening.

Exclusion Criteria

1. Women who were pregnant or breastfeeding.

2. Women who were postmenopausal.

3. A positive HIV-1 or -2 test at trial screening.

4. History or suspicion of alcohol or barbiturate, amphetamine, recreational or narcotic drug use which in the investigator’s opinion would have compromised subject safety or compliance with trial procedures.

5. Hepatitis A infection (confirmed by hepatitis A antibody IgM), or hepatitis B infection (confirmed by hepatitis B surface antigen), or hepatitis C infection (confirmed by hepatitis C virus antibody) at trial screening.

6. A confirmed positive urine drug test at trial screening. Urine was tested for the presence of amphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids, methadone, and opioids.

7. Currently active gastrointestinal, cardiovascular, neurologic, psychiatric, metabolic, renal, hepatic, respiratory, inflammatory or infectious disease.


9. Currently significant diarrhea, gastric stasis or constipation that in the investigator’s opinion could have influenced drug absorption or bioavailability.

10. Any history of significant skin disease such as but not limited to drug rash or eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis or urticaria.

11. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the medication administered in this trial (i.e. TMC278, Ovysmen®).

12. A clinically significant abnormal finding in the gynecological examination including PAP III or IV in cervical smear carried out at screening.

0313942, Final, 23-Jul-2009 14:50



13. Currently active gynecological disorders including but not limited to vaginal bleeding without an obvious reason and hyperprolactinemia with or without galactorrhea.

14. Any major medical condition that would have precluded the safe administration of OC therapy such as, but not limited to, high blood pressure, diabetes, clinically significant abnormal lipid profile, had or had had heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice, malignant or benign liver tumors, clotting disorders, thrombophlebitis or thromboembolic disorders and headache with focal neurological symptoms.

15. Use of concomitant medication, including over-the-counter products, herbal medications and dietary supplements. Over-the-counter medication had to be discontinued at least 7 days prior to the start of the second OC cycle (Day 1) and prescribed medication had to be discontinued at least 14 days before the start of the second OC cycle (Day 1), except for ibuprofen and Ovysmen®.

16. Previous participation in more than 1 trial (single or multiple dose) with TMC125 (etravirine), TMC120 (dapivirine) and/or TMC278 (rilpivirine, formerly known as R278474) or having developed a rash, erythema or urticaria while participating in a trial with the aforementioned compounds.

17. Participation in an investigational drug trial within 60 days prior to the start of the first OC cycle prior to Treatment A.

18. Donation of blood or plasma or significant blood loss within the 60 days preceding the start of Treatment A.

19. Subjects with the following laboratory abnormalities at screening as defined by the Division of AIDS (DAIDS) grade and in accordance with the normal ranges of the trial clinical laboratory:

Serum creatinine grade 1 or greater ( 1.1 x upper limit of normal [ULN]);

Serum lipase grade 1 or greater ( 1.1 x ULN);

Hemoglobin toxicity grade 1 or greater ( 10.9 g/dL);

Platelet count grade 1 or greater ( 124.999 x 109/L);

Absolute neutrophil count grade 1 or greater ( 1.3 x 109/L);

Aspartate aminotransferase or alanine aminotransferase grade 1 or greater ( 1.25 x ULN);

Direct bilirubin grade 1 or greater ( 1.1 x ULN);

Any other toxicity of grade 2 or above, including proteinuria (spot urine) > 2+, and microscopic hematuria (> 10 red blood cells [RBC]/high power field). Subjects that had their menstrual period at screening could repeat the urine test after the end of menses.

0313942, Final, 23-Jul-2009 14:50



Treatment Stabilizing Treatment First OC cycle

Treatment A Second OC cycle

Treatment B Third OC cycle

Dosage

Dosage Form (F No.)

Usage

1 mg norethindrone/ 35 μg ethinylestradiol

Ovysmen®

1 tablet orally q.d. on Days -28 to -8

1 mg norethindrone/ 35 μg ethinylestradiol

Ovysmen®

1 tablet orally q.d. on Days 1 to 21

1 mg norethindrone/ 35 μg ethinylestradiol,

25 mg TMC278

Ovysmen®,TMC278 25 mg tablet

(F006)

1 tablet Ovysmen® orally q.d. on Days 29 to 49.

1 tablet TMC278 orally q.d. Days 29 to 43

Batch Numbers 7KS3M01 7KS3M01 7KS3M01 (Ovysmen®)8BL2H (TMC278)

Dose Regimen Stabilizing treatment (First OC cycle): 1 tablet Ovysmen® q.d. orally on Days -28 to -8, followed by 7 day pill-free period. Treatment A (Second OC cycle): 1 tablet Ovysmen® q.d. orally on Days 1 to 21, followed by 7 day pill-free period. Treatment B (Third OC cycle): 1 tablet Ovysmen® orally q.d. on Days 29 to 49 followed by 7 day pill-free period. One tablet TMC278 orally q.d. under fed conditions on Days 29 to 43.

Duration of Treatment All cycles: 28 days each

Duration of Trial 12 weeks: 3 OC cycles, excluding screening and follow-up.

Disallowed Medication All over-the-counter medication had to be discontinued at least 7 days before the start of the second OC cycle (i.e., Day 1) and all prescribed medication had to be discontinued at least 14 days before the start of the second OC cycle, except for ibuprofen and Ovysmen®. Subjects could not use any medication other than the trial medication up to 14 days after the last intake of TMC278 on Day 43, except for ibuprofen. Subjects could not use any herbal medications or dietary supplements, including products containing Hypericum perforatum (e.g., St. John’s wort) from 14 days before the start of the second OC cycle and up to 14 days after the last intake of TMC278 on Day 43. Ibuprofen could be used up to 3 days before the start of the second OC cycle (Day 1). After that, only the investigator could permit the use of ibuprofen (at no more than 400 mg per day). In case of cutaneous reaction/rash and/or an allergic reaction, the use of cetirizine (Zyrtec®),levocetirizine (Xyzal®), topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In case of nausea, the use of antiemetics was permitted. In case of diarrhea, the use of loperamide was permitted.

0313942, Final, 23-Jul-2009 14:50



Scre

enin

ga Treatments A and Bb

Follo

w-u

p Assessments

21

days

bef

ore

Day

-28

Day

1 (s

tart

2nd

OC

cyc

le)

Day

13

Day

14c

Day

15

Day

16d

Day

29

(sta

rt 3rd

OC

cyc

le)

Day

41

Day

42c

Day

43

Day

44d

7 an

d 30

to 3

2 da

ys a

fter l

ast

TMC

278

inta

kee

Pharmacokinetics

Blood sample Xf,g Xf,g Xf,h Xf,g Xi,g Xi,g Xh,i Xi

Pharmacodynamics

Blood samplej,k X X X X

Safety

Adverse Events and concomitant medicationsl


Hematology and biochemistrym

X Xj Xj Xj Xj Xj Xj X

Urinalysis X Xj,n Xj Xj,n Xj X

ECG X Xj Xj Xj Xj X

Vital signso X Xj Xj Xj Xj Xj Xj X

Physical examinationp X X X X X X X a. At screening, informed consent was obtained, inclusion/exclusion criteria were checked, concomitant diseases,

subject characteristics and demographics, height, weight, medical and surgical history were recorded, a HIV-1 and -2 test, hepatitis A/B/C test, urine drug screening, serum pregnancy test, physical examination including gynecological examination, and smear were performed, and prolactin was assessed.

b. No assessments were performed during the first stabilizing OC cycle. c. Admission in the evening for overnight stay in unit. d. Discharge from unit. e. Serum pregnancy test repeated at last follow-up. f. For the determination of norethindrone and ethinylestradiol plasma concentrations. g. Immediately before trial medication intake. For days 15 and 43, this is the 24 hour pharmacokinetic sample. h. Sample taken at 0 hours, immediately before trial medication intake, and at 0.5, 1, 1.5, 2, 3, 4, 6, 9 and 12 hours

after trial mediation intake. Sample also taken at 5 and 16 hours on Day 43. i. For the determination of TMC278, norethindrone and ethinylestradiol plasma concentrations. Samples taken at

5 and 16 hours on Day 43 for the determination of TMC278 only. j. Taken within 2 hours before drug intake. k. For the determination of progesterone, luteinizing hormone and follicle stimulating hormone serum

concentrations. l. Adverse events and intake of concomitant medications were monitored throughout the trial from the signing of

the informed consent form onwards until the last trial related activity. m. Biochemistry sample was taken fasted for at least 8 hours and taken before breakfast at all timepoints. n. Included urine pregnancy test. o. Blood pressure and pulse: supine after 5 minutes, standing after 1 minute. p. Included skin examination.

0313942, Final, 23-Jul-2009 14:50



Statistical Analysis Descriptive statistics and linear mixed effects modeling were carried out for pharmacokinetic parameters. Descriptive statistics were used for pharmacodynamic parameters, and descriptive statistics and frequency tabulations were produced for safety parameters.


Baseline Characteristics - Subject Disposition All subjects

Number of Subjects Entered (all female)


18

26.0 (20-38)

Drop-Outs - Reason

Withdrawn consent

Lost to follow-up

5 (27.8%)

3 (16.7%)

2 (11.1%)

Pharmacokinetics of norethindrone(mean SD, tmax: median [range])

1 mg norethindrone / 35 μg ethinylestradiol q.d.

(reference)


+ 25 mg TMC278 q.d. (test)

Day 13/ Day 41 n 16 14 C0h, pg/mL 2382 ± 1269 2791 ± 2388 Day 14/ Day 42 n 16 15 C0h, pg/mL 2520 ± 1276 2499 ± 1453 Day 15/ Day 43 n 17a 15b

C0h, pg/mL 2268 ± 1226 2066 ± 1093 Cmin, pg/mL 2268 ± 1226 2055 ± 1084 Cmax, pg/mL 14520 ± 5120 13150 ± 4042 tmax, h 1.0 (0.5-6.0) 1.5 (1.0-4.0) C24h, pg/mL 3040 ± 1592 2377 ± 1253AUC24h, pg.h/mL 152800 ± 52350 128700 ± 40240 Css,av, pg/mL 6369 ± 2181 5365 ± 1676 FI, % 209.8 ± 54.35 217.7 ± 71.55 LS mean ratio (90% CI), %

- test vs reference n - 15b vs 17a

Cmin - 98.72 (90.04 – 108.2) Cmax - 94.10 (83.37 - 106.2) AUC24h - 88.92 (83.77 - 94.38) AUC24h = area under the plasma concentration time curve over 24 hours, C0h = predose plasma concentration, C24h = plasma concentration 24 hours after dosing, Cmax = maximum plasma concentration, Cmin = minimum plasma concentration, Css,av = average steady-state plasma concentration over 24 hours, FI = fluctuation index, SD = standard deviation, tmax = time to maximum plasma concentrationa n=15 for AUC24h, Css,av and FI b n=14 for C24h, AUC24h, Css,av and FI

0313942, Final, 23-Jul-2009 14:50



Pharmacokinetics of ethinylestradiol(mean SD, tmax: median [range])


(reference)


+ 25 mg TMC278 q.d. (test)

Day 13/ Day 41 n 16 14 C0h, pg/mL 23.88 ± 6.144 28.86 ± 18.47 Day 14/ Day 42 n 16 15 C0h, pg/mL 24.29 ± 6.343 27.85 ± 10.38 Day 15/ Day 43 n 17a 15b

C0h, pg/mL 23.56 ± 10.06 23.83 ± 7.279 Cmin, pg/mL 23.56 ± 10.06 23.77 ± 7.340 Cmax, pg/mL 82.22 ± 26.74 94.65 ± 28.36 tmax, h 1.5 (1.0-6.0) 1.5 (1.0-4.0) C24h, pg/mL 27.38 ± 10.60 27.24 ± 8.396AUC24h, pg.h/mL 1015 ± 292.5 1093 ± 271.7 Css,av, pg/mL 42.28 ± 12.19 45.53 ± 11.32 FI, % 153.9 ± 39.05 149.6 ± 49.47 LSmean ratio (90% CI), %

- test vs. reference n - 15b vs. 17a

Cmin - 109.2 (102.9 -115.8) Cmax - 117.2 (106.1 - 129.5) AUC24h - 114.2 (109.8 - 118.8) AUC24h = area under the plasma concentration-time curve over 24 hours, C0h = predose plasma concentration, C24h = plasma concentration 24 hours after dosing, Cmax = maximum plasma concentration, Cmin = minimum plasma concentration, Css,av = average steady-state plasma concentration over 24 hours, FI = fluctuation index, SD = standard deviation, tmax = time to maximum plasma concentrationa n=15 for AUC24h, Css,av and FI b n=14 for C24h, AUC24h, Css,av and FI

0313942, Final, 23-Jul-2009 14:50





+ 25 mg TMC278 q.d.

n 15

Day 41 C0h, ng/mL a 113.6 ± 55.08 Day 42 C0h, ng/mL 121.2 ± 45.65 Day 43 C0h, ng/mL 121.2 ± 51.70 Cmin, ng/mL 89.49 ± 38.04 Cmax, ng/mL 172.1 ± 37.91 tmax, h 4.0 (2.0-24.0) C24h, ng/mL 126.2 ± 52.95AUC24h, ng.h/mL 3028 ± 941.4 Css,av, ng/mL 126.2 ± 39.22 FI, % 71.24 ± 23.65 AUC24h = area under the plasma concentration-time curve over 24 hours, C0h = predose plasma concentration, C24h = plasma concentration 24 hours after dosing, Cmax = maximum plasma concentration, Cmin = minimum plasma concentration, Css,av = average steady-state plasma concentration over 24 hours, FI = fluctuation index, SD = standard deviation, tmax = time to maximum plasma concentrationa n=14

0313942, Final, 23-Jul-2009 14:50



Pharmacodynamics: Actual Values and Changes from Predose Values (median, range)Treatment Period

Time Point Follicle Stimulating

Hormone (IU/L) Luteinizing

Hormone (IU/L) Progesterone

(nmol/L) n 15 15 15 Day 1 6.50 (4.6, 15.0) 4.30 (0.4, 9.7) 1.50 (0.4, 4.1) n 18 18 18 Day 14 2.00 (0.3, 5.9) 1.35 (0.0, 9.2) 1.70 (0.5, 4.1) n 15 15 15

Treatment A: OC q.d. alone

Day 14 change from reference

-5.20 (-13.9, -1.1) -2.90 (-6.8, 0.5) 0.10 (-0.3, 0.4)

n 16 16 16 Day 29 6.65 (1.3, 12.5) 3.00 (1.4, 14.1) 1.70 (0.4, 3.1) n 15 15 15 Day 42 1.60 (0.5, 6.4) 1.40 (0.0, 8.1) 1.80 (0.4, 3.9) n 15 15 15

Treatment B: OC q.d. + TMC278 25 mg q.d.

Day 42 change from reference

-4.50 (-11.7, -0.3) -1.90 (-6.6, 4.3) 0.00 (-0.9, 1.4)

Note: For the OC alone treatment period, the reference time point was the Day 1 2-hour predose measurement. For the OC plus TMC278 treatment period, the reference time point was the Day 29 2-hour predose measurement.

Pharmacodynamics: Intrasubject Changes Across Treatments: Predose Values, Mid-Cycle Values and Changes From Predose Values (median, range) Parameter Follicle Stimulating

Hormone (IU/L) Luteinizing Hormone

(IU/L) Progesterone (nmol/L) n 14 14 14 Difference in predose values between OC q.d. + TMC278 25 mg q.d. (Day 29) and OC q.d. alone (Day 1) treatment periods

0.10 (-8.6, 2.0) -0.85 (-8.3, 3.4) 0.00 (-1.3, 0.7)

n 15 15 15 Difference in mid-cycle values between OC q.d. + TMC278 25 mg q.d. (Day 42) and OC q.d. alone (Day 14) treatment periods

-0.10 (-2.0, 3.0) 0.00 (-5.9, 7.2) -0.10 (-0.8, 1.8)

n 13 13 13 Difference in change from predose values between OC q.d. + TMC278 25 mg q.d. (Day 42 – Day 29) and OC q.d. alone (Day 29 – Day 1) treatment periods

-0.10 (-1.8, 6.6) 0.90 (-1.5, 3.8) 0.00 (-1.0, 1.1)

Note: For the OC alone treatment period, the reference time point was the Day 1 2-hour predose measurement. For the OC plus TMC278 treatment period, the reference time point was the Day 29 2-hour predose measurement.

0313942, Final, 23-Jul-2009 14:50




Treatment A: OC q.d. alone

(N=18)

Treatment B: OC q.d. +

TMC278 25 mg q.d.

(N=16) Follow-up

(N=15)


Most frequently reported AEs (reported in > 1 subject), n (%) 14 (77.8) 12 (75.0) 3 (20.0)

Diarrhea 0 3 (18.8) 0

Nausea 1 (5.6) 2 (12.5) 0

Vomiting 0 3 (18.8) 0

Fatigue 0 2 (12.5) 0

Nasopharyngitis 5 (27.8) 2 (12.5) 1 (6.7)

Dizziness 2 (11.1) 0 0

Headache 4 (22.2) 6 (37.5) 0

Paresthesia 0 2 (12.5) 0

n (%) with 1 or more AEs 14 (77.8) 12 (75.0) 3 (20.0)

n (%) of deaths, serious AEs, AEs leading to withdrawal, grade 3 and 4 AEs, skin events of interest

0 0 0

Treatment-emergent AEs were reported in 14 subjects (77.8%) during treatment with OC alone and 12 subjects (75.0%) during treatment with OC plus TMC278 25 mg q.d. The majority of subjects experienced events that were considered to be grade 1 in severity (83.3%) although 6 subjects (33.3%) experienced AEs that were considered to be at least grade 2 in severity. No deaths, serious AEs, AEs leading to discontinuation, grade 3 or 4 events, or skin events of interest were reported during the trial. Over half of the events were considered at least possibly related to treatment with OC or TMC278. More AEs in the gastrointestinal and nervous system disorders system organ classes were observed during treatment with OC plus TMC278 25 mg q.d. than during treatment with OC alone: 7 subjects (43.8%) and 1 subject (5.6%), respectively in the gastrointestinal system organ class, and 7 subjects (43.8%) and 6 subjects (33.3%), respectively in the nervous system disorders system organ class.


There were no clinically relevant changes in mean laboratory parameters over time. Treatment-emergent laboratory abnormalities were recorded in 15 subjects [83.3%] during treatment with OC alone and 12 subjects [75.0%] during treatment with OC plus TMC278 25 mg q.d. The majority of graded abnormalities were DAIDS grade 1, although 2 subjects experienced grade 2 abnormalities (one for lipase increased and one for blood glucose increased [hyperglycemia]). No subjects experienced grade 3 or 4 laboratory abnormalities. The majority of treatment-emergent graded laboratory abnormalities were reported for decreased phosphorus, most of which were reported during the follow-up period. Treatment-emergent abnormalities were observed in urine RBC and WBC count, most of which were reported during treatment with OC alone and the follow-up period, but were not considered to be clinically relevant. There were no consistent trends in urinalysis abnormalities between treatments. No AEs relating to laboratory parameters or urinalysis abnormalities were reported.


Small numbers of subjects experienced treatment-emergent abnormalities in vital signs and ECG parameters. No subjects experienced abnormalities in QTcF. All ECG abnormalities were reported during treatment with OC alone.

0313942, Final, 23-Jul-2009 14:50




Physical examination revealed 2 subjects with treatment-emergent lymph node abnormalities and 1 subject with a mucous membrane abnormality (slight redness and erosion areas on cuticle), none of which were reported as AEs. Otherwise, the physical examination results were unremarkable.

Conclusions

In conclusion, norethindrone pharmacokinetics were unaffected by coadministration of TMC278. Ethinylestradiol Cmin and AUC24h were unaffected by coadministration of TMC278. The Cmax of ethinylestradiol was increased by 17% in the presence of TMC278. This is not expected to result in a clinically relevant effect on the pharmacodynamic effects of ethinylestradiol. The pharmacokinetic parameters of TMC278 were within the expected range, suggesting that coadministration of ethinylestradiol/norethindrone did not affect TMC278 steady-state exposure. The results of the present trial also demonstrate that the coadministration of TMC278 25 mg q.d. and Ovysmen® has no marked effect on the concentrations of FSH, LH and progesterone. Coadministration was generally safe and well tolerated. Therefore, TMC278 25 mg q.d. can be coadministered with ethinylestradiol/norethindrone-based contraceptives without dose modifications.

0313942, Final, 23-Jul-2009 14:50


TMC278-C139 1





Title: A Phase I, open label trial in 16 healthy subjects to investigate the effect of single-dose and steady-state TMC278 on the pharmacokinetics of chlorzoxazone

Investigator:

US

Country: US


No. of Investigators: 1 No. of Subjects: 25 (16 subjects under the main protocol and 9 subjects under the substudy protocol)

Objectives: The primary objectives of this trial were to investigate the effect of single dose and steady-state TMC278 on the pharmacokinetics of chlorzoxazone and 6-hydroxy-chlorzoxazone after a single dose of chlorzoxazone, and to investigate the effect of single dose chlorzoxazone on the steady-state pharmacokinetics of TMC278. The secondary objective was to determine the short-term safety and tolerability of coadministration of TMC278 and chlorzoxazone. Design: This was a Phase I, open label trial to investigate the pharmacokinetic interaction between TMC278 and chlorzoxazone, a well established probe substrate to assess CYP2E1 activity. Under the main protocol, 16 healthy subjects were planned to receive a single 500 mg dose of chlorzoxazone on Day 1 (baseline assessment), followed by a 2-day washout period. On Day 4 all subjects were planned to start TMC278 at 150 mg once daily (q.d.) for a total of 12 days. Single 500 mg doses of chlorzoxazone were planned to be coadministered with TMC278 on Day 4 (single dose TMC278) and on Day 15 (steady-state TMC278). Under the main protocol, full pharmacokinetic profiles of TMC278 up to 24 hours postdose were planned to be determined on Days 4, 14, and 15. Pharmacokinetic profiles of chlorzoxazone and 6-hydroxy-chlorzoxazone up to 14 hours postdose were planned to be determined on Days 1, 4, and 15. Because of extreme weather conditions (hurricane) there was a high dropout rate and subjects remaining in the study had to receive 4 additional days of TMC278 dosing and the pharmacokinetics of the combination of steady-state TMC278 with chlorzoxazone were actually assessed on Day 19. To ensure 16 evaluable subjects, a substudy was performed following a high number of discontinuations under the main protocol due to environmental circumstances caused by extreme weather conditions (hurricane). In the substudy, the trial was repeated for 9 additional healthy subjects, the dosing of TMC278 was equally extended by 4 days, and the pharmacokinetics of the combination of steady-state TMC278 and single-dose chlorzoxazone were assessed on Day 19 to keep in line with the way the main study was actually performed. For the substudy, full pharmacokinetic profiles of TMC278 up to 24 hours postdose were thus determined on Days 4, 18, and 19. Pharmacokinetic profiles of chlorzoxazone and 6-hydroxy-chlorzoxazone up to 14 hours postdose were determined on Days 1, 4, and 19. Tolerability and safety were assessed throughout the study period. Subject Selection Inclusion Criteria

1. Males and females, aged between 18 and 55 years, extremes included. 2. Normal weight as defined by a Quetelet Index (Body Mass Index: weight in kg divided by square of height in meters) of 18.0 to 30.0 kg/m2, extremes included. 3. Informed Consent Form (ICF) signed voluntarily before the first trial-related activity. 4. Cortisol of at least 550 nmol/L (19.9 g/dL) at any time point at screening (i.e., prestimulation cortisol, 30 or 60 minutes after 250 g adrenocorticotropic hormone [ACTH] stimulation). 5. Able to comply with protocol requirements.

0136917, Final, 02-May-2007 09:40

Synopsis

TMC278-C139 2


6. Healthy on the basis of a physical examination, medical history, electrocardiogram (ECG), vital signs, and the results of blood biochemistry and hematology tests and a urinalysis carried out at screening.

Exclusion Criteria1. A positive human immunodeficiency virus (HIV)-1 or -2 test at trial screening. 2. Smoking cigarettes, cigars, or pipes, or having smoked within the last 3 months prior to selection. 3. Female, except if postmenopausal for more than 2 years, or posthysterectomy or post-tubal ligation (without reversal operation). 4. History or suspicion of alcohol, barbiturate, amphetamine, recreational, or narcotic drug use that, in the investigator’s opinion, could compromise subject safety and/or compliance with trial procedures. 5. Hepatitis A infection (confirmed by Hepatitis A antibody IgM), or Hepatitis B infection (confirmed by Hepatitis B surface antigen), or Hepatitis C infection (confirmed by Hepatitis C virus antibody) at trial screening. 6. A positive urine drug test at trial screening. Urine was tested for the presence of amphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids, methadone, and opioids. 7. Currently active gastrointestinal, cardiovascular, neurological, psychiatric, metabolic, renal, hepatic, respiratory, inflammatory, or infectious disease. 8. Any current or previous adrenal illness. 9. A history of tuberculosis or ocular herpes. 10. Currently significant diarrhea, gastric statis, or constipation that in the investigator’s opinion could influence drug absorption or bioavailability. 11. Any history of significant skin disease such as but not limited to drug rash or eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis, or urticaria. 12. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the study medication administered in this trial (i.e. TMC278 and chlorzoxazone), or to tetracosactide (ACTH stimulation test). 13. Use of concomitant medication, including over the counter products, herbal medications, and dietary supplements. 14. Having previously participated in more than 1 trial (single or multiple dose) with TMC114, TMC125, TMC120, and/or TMC278 (formerly known as R278474) or having developed a rash, erythema, or urticaria while participating in a trial with the before mentioned compounds. 15. Participation in an investigational drug trial within 30 days prior to the first administration of study medication. 16. Donation of blood or plasma within the 60 days preceding the first administration of study medication. 17. Subjects with the following laboratory abnormalities at screening as defined by the Division of Acquired Immunodeficiency Syndrome Table for Grading the Severity of Adult and Pediatric Adverse Events and in accordance with the normal ranges of the trial clinical laboratory: serum creatinine grade 1 or greater ( 1.1 x upper limit of normal [ULN]); serum lipase grade 1 or greater ( 1.1 x ULN); hemoglobin toxicity grade 1 or greater ( 10.9 g/dL); platelet count grade 1 or greater ( 124.999/mm3); absolute neutrophil count grade 1 or greater ( 1300/mm3); aspartate aminotransferase or alanine aminotransferase grade 1 or greater ( 1.25 x ULN); total bilirubin grade 1 or greater ( 1.1 x ULN); any other toxicity grade 2 or above, including: proteinuria (spot urine) 2+ and microscopic hematuria > 10 red blood cells/high power field.

Treatment TMC278 ChlorzoxazoneDosage 150 mg q.d. TMC278 500 mg single dose chlorzoxazone Dosage (F No.) 50 mg tablets (F003) and 100 mg tablets

(F002) Chlorzoxazone caplets (Parafon

Forte®) containing 500 mg chlorzoxazone

Usage 1 x 50 mg tablet and 1 x 100 mg tablet orally (p.o.) on Days 4-15 or on

Days 4-19

1 caplet p.o. on Days 1, 4, and 15 or on Days 1, 4, and 19

Batch Number F003: PD1273 F002: PD1268

5JG252

0136917, Final, 02-May-2007 09:40

Synopsis

TMC278-C139 3


Dose Regimen All subjects under the main protocol were planned to receive a single 500 mg dose of chlorzoxazone on Days 1, 4, and 15 and TMC278 150 mg q.d. on Days 4-15. All subjects under the substudy protocol were planned to receive a single 500 mg dose of chlorzoxazone on Days 1, 4, and 19 and TMC278 150 mg q.d. on Days 4-19.

Duration of Treatment 13 or 17 days, excluding washout (due to extreme weather conditions [hurricane] some subjects received 4 additional days of TMC278 dosing)

Duration of Trial 17 or 21 days, excluding screening and follow-up (due to extreme weather conditions [hurricane] some subjects received 4 additional days of TMC278 dosing)

Disallowed Medication During the entire trial, subjects were not allowed to use any medication other than the study medication and restricted use of ibuprofen. All over the counter medication had to be discontinued at least 7 days before the first intake of study medication and all prescribed medication had to be discontinued at least 14 days before first intake of study medication, except for ibuprofen. Subjects were not to use any medication other than the study medication up to 14 days after the last intake of study medication, except for ibuprofen. Ibuprofen was allowed up to 3 days before drug administration. After that, the investigator could permit the use of ibuprofen until the end of each period at no more than 1 x 400 mg per day. Subjects were not to use any herbal medications or dietary supplements including products containing Hypericum perforatum (e.g., St. John’s wort) from 14 days before the first intake of study medication and up to 14 days after the last intake of study medication. In case of cutaneous reaction/rash and/or an allergic reaction, the use of cetirizine (Zyrtec®), levocetirizine (Xyzal®), topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In case of nausea, the use of antiemetics was permitted. In case of diarrhea, the use of loperamide was allowed.

0136917, Final, 02-May-2007 09:40

Synopsis

TMC278-C139 4



Treatment Period Follow-up

21

days

Day

1b

Day

s 4 +

15

or 1

9 (s

ubst

udy)

b

Day

s 5 +

13

or 1

7 (s

ubst

udy)

b

Day

12

or 1

6 (s

ubst

udy)

b

Day

14

or 1

8 (s

ubst

udy)

b

Day

16

or 2

0 (s

ubst

udy)

b

Day

7, a

nd

30, 3

1, o

r 32

Pharmacokinetics Blood sample Xe,f Xe,f,g Xe,g Xe,g Xe,g Xg

Safety Adverse eventsc X X X X X X X X Concomitant medsc X X X X X X X X Hemat & biochemd X Xh Xh Xi Xi X X Urinalysis X Xi Xi Xi X X ECG & vital signs X Xh Xh Xh X T3, free-T4, and TSH testing

X X

1-acid glycoprotein, Apo A1, Apo B, and insulin testing

X X

ACTH stimulation test with determination of cortisol and 17-OH-progesterone

X X

Coagulation parameters (PT, PTT, and INR)j

X X X Xl

Skin examination X X Xk X X X X Physical examination X X Xk X X X

0136917, Final, 02-May-2007 09:40

Synopsis

TMC278-C139 5


ACTH = adrenocorticotropic hormone; Apo = apolipoprotein; ECG = electrocardiogram; Hemat & biochem = hematology & biochemistry; INR = international normalized ratio; meds = medication; PT = prothrombin time; PTT = partial thromboplastin time; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone. Note: There were deviations from this assessment schedule under the main protocol due to extreme weather conditions (hurricane); some subjects also had assessments performed on Day 19 instead of Day 15. a At screening, subject’s demographics and characteristics, medical and surgical history, concomitant diseases, and smoking habits were recorded, and a HIV-1 and -2 test, Hepatitis A, B, and C test, and drug screening for all subjects, and pregnancy test for females were performed. b Scheduled times were relative to the first drug intake on pharmacokinetic sampling days (e.g., sample at 2 hours on Day 4 was 2 hours postdose for TMC278 but predose for chlorzoxazone, etc). c Adverse events and concomitant medications were monitored continuously from signing of the ICF until the last trial related activity. d Biochemistry samples were taken fasted for at least 10 hours, before breakfast. e Immediately before drug intake. f For determination of chlorzoxazone and 6-hydroxychlorzoxazone concentrations predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 14 hours postdose on Day 1 (main study and substudy); and 2 (immediately before chlorzoxazone intake), 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 14, and 16 hours postdose on Days 4 (main study and substudy) and 15 (main study) or 19 (substudy). g For determination of TMC278 concentrations predose and 0.5, 1, 2, 3, 4, 5, 6, 9, 12, and 16 hours postdose on Days 4 (main study and substudy), 14 and 15 (main study) or 18 and 19 (substudy), predose on Days 5 (main study and substudy), 12 and 13 (main study) or 16 and 17 (substudy), and on Day 16 (main study) or 20 (substudy). h Within 2 hours before drug intake plus 2 hours postdose on Day 1 (main study and substudy), 4 hours postdose on Days 4 (main study and substudy), and Days 14 and 15 (main study) or 18 and 19 (substudy).i Within 2 hours before drug intake. j Coagulation parameters were only assessed in patients under the substudy protocol on Day 4.k Performed on Day 4 only. l Day 7 only.

Statistical Methods Intent-to-Treat analysis, descriptive statistics, frequency tabulations, Wilcoxon matched-pairs signed-ranks test, linear mixed effects modeling.

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Synopsis

TMC278-C139 6



Baseline Characteristics - Subject Disposition Main Protocol

N = 16 Substudy Protocol

N = 9

All Subjects (Main Protocol + Substudy Protocol Combined)

N = 25 Number of Subjects Entered (M/F) Age: median (range), yrs

8/8 43.0 (23 - 53)

5/4 49.0 (31 - 55)

13/12 45.0 (23 - 55)

Race, n (%) Black Caucasian Hispanic

2 (12.5) 1 (6.3)

13 (81.3)

00

9 (100.0)

2 (8.0) 1 (4.0)

22 (88.0) Dropouts - Reason

Withdrew consenta

Non-compliant

6 (37.5%) 5 (31.3%) 1 (6.3%)

000

6 (24.0%) 5 (20.0%) 1 (4.0%)

a High number of subjects withdrawing consent occurred during the period of extreme weather (hurricane) at the investigational site.


(mean ± SD, tmax: median [range])

TMC278 (Single Dose) +

Chlorzoxazone) (Day 4)

TMC278 (Multiple Dose)

alone (Reference) (Day 18)

TMC278 (Multiple Dose) +

Chlorzoxazone (Test) (Day 19)

n 16 16 16

C0h, ng/mL - 403.1 ± 154.1 505.6 ± 188.4 Cmin, ng/mL - 349.8 ± 138.0 401.5 ± 121.2 Cmax, ng/mL 579.6 ± 219.6 946.4 ± 325.0 1107 ± 329.9 tmax, h 4.0 [3.0 - 9.0] 4.0 [3.0 – 5.0] 4.5 [4.0 - 5.0]

AUC24h, ng.h/mL 6026 ± 2409 13010 ± 4757 15950 ± 4303

Css,av, ng/mL - 542.0 ± 198.0 664.7 ± 179.3

FI, % - 112.2 ± 24.42 104.7 ± 19.75 LSmeans ratio (90% CI), %

Test vs Reference n 16 vs 16 C0h 125.0 (115.4 - 135.4) Cmin 118.0 (108.5 - 128.3) Cmax 117.2 (107.8 - 127.4) AUC24h 125.2 (116.4 - 134.7)

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Synopsis

TMC278-C139 7


Pharmacokinetics of Chlorzoxazone


Chlorzoxazone alone

(Reference)(Day 1)

Chlorzoxazone + TMC278 (Single Dose)

(Test 1) (Day 4)

Chlorzoxazone + TMC278 (Multiple

Dose) (Test 2) (Day 19)

n 16 16 16

Cmax, μg/mL 15.19 ± 3.683 14.89 ± 4.789 14.70 ± 2.775

tmax, h 1.5 [0.5 - 3.0] 1.5 [1.0 – 3.0] 1.5 [0.5 - 3.0]

AUClast, μg.h/mL 36.29 ± 9.404 35.19 ± 9.372 36.87 ± 6.381

AUC , μg.h/mL 36.31 ± 9.410 35.21 ± 9.369 36.89 ± 6.390

t1/2term, h 1.099 ± 0.1525 1.135 ± 0.2192 1.120 ± 0.1980 LSmeans ratio (90% CI), %

Test 1 vs Reference Test 2 vs Reference n - 16 vs 16 16 vs 16 Cmax - 95.69 (82.01 - 111.7) 97.81 (84.67 - 113.0)

AUClast - 96.53 (87.49 - 106.5) 103.2 (94.59 - 112.7)

AUC - 96.55 (87.51 - 106.5) 103.3 (94.59 - 112.7)

Pharmacokinetics of 6-hydroxy-chlorzoxazone


Chlorzoxazone alone

(Reference)(Day 1)

Chlorzoxazone + TMC278 (Single Dose)

(Test 1) (Day 4)

Chlorzoxazone + TMC278 (Multiple

Dose) (Test 2) (Day 19)

n 16 16 16

Cmax, μg/mL 0.3025 ± 0.09440 0.2998 ± 0.09370 0.2934 ± 0.08432

tmax, h 2.0 [1.0 - 3.0] 2.0 [1.0 – 3.0] 1.75 [0.5 - 3.0]

AUClast, μg.h/mL 1.101 ± 0.3604 1.040 ± 0.3646 1.062 ± 0.3279

AUC , μg.h/mL 1.119 ± 0.3613 1.060 ± 0.3639 1.081 ± 0.3308

t1/2term, h 1.504 ± 0.1975 1.602 ± 0.3966 1.679 ± 0.3466

Ratio AUClast, 6-OH-CLX/CLX, (%) 3.124 ± 1.321 3.127 ± 1.267 2.931 ± 0.8889 LSmeans ratio (90% CI), %

Test 1 vs Reference Test 2 vs Reference n - 16 vs 16 16 vs 16 Cmax - 98.97 (94.35 - 103.8) 97.38 (90.19 - 105.1) AUClast - 93.50 (89.11 - 98.11) 96.70 (87.21 - 107.2) AUC - 93.89 (89.76 - 98.21) 96.81 (87.44 - 107.2) Ratio AUClast, 6-OH-CLX/CLX - 96.86 (87.10 - 107.7) 93.66 (81.03 - 108.3)

6-OH-CLX/CLX = 6-hydroxy-chlorzoxazone / chlorzoxazone.

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Synopsis

TMC278-C139 8


Trial Phase


Chlorzoxazone AloneN = 25

Chlorzoxazone + TMC278

(Single Dose) N = 25

TMC278 AloneN = 25


(Steady-state) N = 19

Whole Trial

N = 25 Adverse Events (AEs) Most frequently reported AEs (reported in > 2 subjects in the whole trial), n (%)

Headache 3 (12.0) 4 (16.0) 5 (20.0) 4 (21.1) 8 (32.0) Dizziness 3 (12.0) 2 (8.0) 2 (8.0) 1 (5.3) 5 (20.0) Pruritus 1 (4.0) 1 (4.0) 4 (16.0) 0 5 (20.0) Skin lesion 1 (4.0) 0 4 (16.0) 0 4 (16.0) Abdominal pain upper

0 1 (4.0) 2 (8.0) 0 3 (12.0)

Diarrhea 1 (4.0) 0 2 (8.0) 0 3 (12.0) Vomiting 2 (8.0) 0 1 (4.0) 0 3 (12.0)


9 (36.0) 7 (28.0) 15 (60.0) 8 (42.1) 19 (76.0)

n (%) of deaths 0 0 0 0 0


0 0 0 0 0


0 0 0 0 0


0 0 0 0 0

Overall, 19 (76.0%) subjects reported at least 1 AE. The overall incidence of AEs was higher during treatment with TMC278 alone. This may have been due to the TMC278 phase being longer than the other treatment phases. The most common AE was headache (8 subjects, 32.0%). There were no deaths or other serious adverse events. All AEs were considered grade 1 or 2 in severity. No subjects prematurely discontinued the trial due to an AE. Six AEs considered to be skin events of interest were reported during the trial for 4 subjects: 2 events of skin lesion were reported for 1 subject (1 event during treatment with chlorzoxazone alone and 1 event during treatment with TMC278 alone), and skin lesion was reported for an additional 3 subjects, one of whom also had 2 events, during treatment with TMC278 alone. The event of skin lesion reported during treatment with chlorzoxazone alone was considered to be not related to TMC278 and to have a doubtful relationship to chlorzoxazone and the event reported for the same subject during treatment with TMC278 alone was considered to be very likely to be related to both TMC278 and chlorzoxazone. The events of skin lesion during treatment with TMC278 alone were considered to have a doubtful relationship to TMC278 and to be not related to chlorzoxazone for 1 subject (2 events), to be possibly related to TMC278 and to be not related to chlorzoxazone for 1 subject, and to have a doubtful relationship to TMC278 and to be not related to chlorzoxazone for 1 subject. Each event was grade 1 in severity.

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Synopsis

TMC278-C139 9


Clinical Laboratory Tests Trial Phase

Chlorzoxazone Alone N = 25

Chlorzoxazone + TMC278 (Single

Dose)N = 25

TMC278 Alone N = 25


(Steady-state) N = 19

Whole Trial N = 25

n (%) with 1 or more treatment-emergent graded laboratory abnormalities: grade 1a 5 (20.0) 2 (8.0) 9 (36.0) 8 (42.1) 21 (84.0) grade 2b 2 (8.0) 1 (4.0) 3 (12.0) 1 (5.3) 9 (36.0) grade 3 0 0 2 (8.0) 0 2 (8.0) grade 4 0 0 0 0 0 a 15 (60.0%) subjects during follow-up. b 7 (28.0%) subjects during follow-up.

There were no consistent or clinically relevant treatment-emergent changes over time in laboratory parameters. No subjects had a grade 4 treatment-emergent laboratory abnormality during the trial. Two subjects (8.0%) had a grade 3 treatment-emergent laboratory abnormality during treatment with TMC278 alone: decreased lymphocytes (1 subject) and decreased phosphate (1 subject). Nine subjects (36.0%) had at least 1 treatment-emergent grade 2 laboratory abnormality during the trial and 21 subjects (84.0%) had at least 1 treatment-emergent grade 1 laboratory abnormality during the trial. Five subjects had clinically relevant laboratory abnormalities that were reported as AEs after the first intake of study medication: AST abnormal, blood triglycerides abnormal, lipase abnormal, and lipase increased were each reported for 1 subject, and 1 subject was reported with AEs of hematocrit abnormal, hemoglobin abnormal, and serum ferritin abnormal. The majority of these AEs were grade 1 in severity and were considered to have a doubtful relationship to study medication. No clinically relevant urinalysis results were observed. Adrenal Function Results The median cortisol at T0 was 386.26 nmol/L at the screening visit and 347.63 nmol/L during the chlorzoxazone and TMC278 (steady-state) phase. The median change in T0 cortisol after TMC278 administration compared to reference was -49.66 nmol/L during the chlorzoxazone and TMC278 (steady-state) phase. This change was not considered to be clinically relevant. There was no consistent change in cortisol values as 19 subjects had a decrease in T0 cortisol values from screening after TMC278 administration and 6 subjects had an increase in T0 cortisol values. The median value of 17-OH-progesterone at T0 at the screening visit and during the chlorzoxazone and TMC278 (steady-state) phase was the same (2.602 nmol/L). The median change in T0 17-OH-progesterone value after TMC278 administration compared to reference was +0.514 nmol/L during the chlorzoxazone and TMC278 (steady-state) phase. This change was not considered to be clinically relevant. All subjects achieved a normal cortisol response (cortisol value 550 nmol/L) during the ACTH stimulation test after administration of TMC278. No AEs related to adrenal function were reported.

Cardiovascular Safety Minor changes were reported for median vital signs values. None of the changes was considered to be clinically relevant. No trends or relationship to study medication were apparent and no clinically relevant changes in ECG parameters were reported.Physical and Skin Examinations Physical and skin examination revealed treatment-emergent abnormal new findings for 8 subjects during the trial, all of which were reported as AEs (herpes zoster, skin lesion [3 subjects], acne, contusion, and influenza like illness [2 subjects]).

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Synopsis

TMC278-C139 10


ConclusionsThe results of the present trial demonstrate that when multiple doses of TMC278 150 mg q.d. were coadministered with a single dose of 500 mg chlorzoxazone, C0h, Cmin, Cmax, and AUC24h of TMC278 were increased with, respectively, 25%, 18%, 17%, and 25%, based on the ratios of the LSmeans. Coadministration of a single dose of chlorzoxazone and a single dose of TMC278 did not change the plasma concentrations of chlorzoxazone, in comparison to administration of chlorzoxazone alone, while the AUClast and AUC of the metabolite 6-hydroxy-chlorzoxazone were decreased with 6%. The Cmax of 6-hydroxy-chlorzoxazone was unchanged. Coadministration of a single dose of chlorzoxazone and multiple doses of TMC278 did not change the plasma concentrations of chlorzoxazone and 6-hydroxy-chlorzoxazone. For the Ratio AUClast,6-OH-CLX/CLX, the LSmeans ratio was 97% (90% CI 87.10-107.7%) when a single dose of chlorzoxazone was coadministered with a single dose of TMC278 and 94% (90% CI 81.03-108.3%) when a single dose of chlorzoxazone was coadministered with multiple doses of TMC278 in comparison to administration of chlorzoxazone alone. Based on the results of this study, no inhibitory or induction effects of TMC278 on CYP2E1 were observed in vivo. In healthy subjects in this trial, TMC278 150 mg q.d. administered alone or in combination with a single dose of chlorzoxazone 500 mg was generally safe and well tolerated.

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Synopsis

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