Trial synopsis 1220 DS DR - Boehringer Ingelheim€¦ · [q.d.] and 240 mg q.d.) of 8 patients each. Within each dose group 6 patients received BI 201335 NA and 2 received placebo

abcd Clinical Study Synopsis for Public Disclosure This clinical study synopsis is provided in line with Boehringer Ingelheim’s Policy on Transparency and Publication of Clinical Study Data. The synopsis ‐ which is part of the clinical study report ‐ had been prepared in accordance with best practice and applicable legal and regulatory requirements at the time of study completion. The synopsis may include approved and non‐approved uses, doses, formulations, treatment regimens and/or age groups; it has not necessarily been submitted to regulatory authorities. A synopsis is not intended to provide a comprehensive analysis of all data currently available regarding a particular drug. More current information regarding a drug is available in the approved labeling information which may vary from country to country.. Additional information on this study and the drug concerned may be provided upon request based on Boehringer Ingelheim’s Policy on Transparency and Publication of Clinical Study Data. The synopsis is supplied for informational purposes only in the interests of scientific disclosure. It must not be used for any commercial purposes and must not be distributed, published, modified, reused, posted in any way, or used for any other purpose without the express written permission of Boehringer Ingelheim.

Name of company: Boehringer Ingelheim

Tabulated Trial Report ABCD

Synopsis No.:

Name of finished product:

Not applicable

Name of active ingredient:

BI 201335 NA

Page:

1 of 9

Module: Volume:

{hyperlink }

Report date: 05 JUN 2012

Trial No. / U No.:1220.14 / U10- 2102-01

Date of trial: 28 JUL 2009 – 10 AUG 2011

Date of revision: Not applicable

Proprietary confidential information © 2012 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.

This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.

Title of trial: Safety, pharmacokinetics and antiviral effect of BI 201335 NA in HCV-1 infected patients treated for 28 days for treatment naïve and experienced patients treated in combination with Peg Interferon α-2a and ribavirin

Principal/Coordinating Investigator:

Trial sites: Multicentre trial,

Publication (reference): Data of this trial have not been published.

Clinical phase: II

Objectives: The objective of this trial was to investigate the safety, pharmacokinetics, and antiviral activity of BI 201335 NA in combination with pegylated interferon (PegIFN) alfa-2a and ribavirin (RBV) for 4 weeks in treatment-naïve patients and treatment-experienced patients both with genotype 1 hepatitis C virus (HCV) infection.

Methodology: This multicentre trial consisted of 2 parts.

Part 1: randomised, double-blind, placebo-controlled within a dose group, multiple rising dose trial. A total of 16 treatment-naïve patients with genotype 1 HCV infection participated in the trial: 2 sequential groups (120 mg once daily [q.d.] and 240 mg q.d.) of 8 patients each. Within each dose group 6 patients received BI 201335 NA and 2 received placebo. One dose was tested within each group.

Part 2: open-labelled, multiple dose trial. A total of 6 treatment-experienced patients with genotype 1 HCV infection participated in the trial: 1 group (240 mg q.d.) of 6 patients.

In both parts, BI 201335 NA was administered in combination with the standard of care (SOC) of PegIFN alfa-2a and RBV for 28 days (4 weeks) followed by 44-week administration of PegIFN alfa-2a and RBV. On the first day of treatment with BI 201335 NA, all patients received a loading dose of BI 201335 NA (e.g., 240 mg for the 120 mg dose group and the 480 mg for the 240 mg dosegroup).

c03302860



Synopsis No.:


Not applicable


BI 201335 NA

Page:

2 of 9

Module: Volume:

{hyperlink }


Trial No. / U No.:1220.14/ U10- 2102-01




This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

No. of subjects: Part 1 Part 2

planned: To be entered: 16 6

BI 201335 NA 12 6

Placebo 4 none

actual: enrolled: 19 treatment-naïve patients for Part 1 and 7 treatment-experienced patients for Part 2

Part 1

BI 201335 NA 120 mg q.d. dose group: entered: 8, treated: 8, analysed (for primary endpoint): 8


Part 2


Diagnosis and main Main inclusion criteria: criteria for inclusion: - Chronic genotype 1 HCV infection, diagnosed by positive HCV serology

test (HCV antibody positive) or detectable HCV ribonucleic acid (RNA)

- HCV viral load ≥100000 IU/mL at screening

- Exclusion of liver cirrhosis by liver biopsy within 24 months before drug administration

- Age 20 to 70 years

- Agree to abstain from intercourse from the date of screening until 6 months after the last dose of RBV

Part 1

- Treatment-naïve to interferon (IFN) (including any experimental or investigational IFN products as monotherapy or in combination with any other agents), PegIFN alfa-2a, or RBV for acute or chronic HCV infection

Part 2

- Patients who have experienced virological failure during or after combination treatment with PegIFN alfa-2a and RBV

c03302860



Synopsis No.:


Not applicable


BI 201335 NA

Page:

3 of 9

Module: Volume:

{hyperlink }


Trial No. / U No.:1220.14/ U10- 2102-01





Test product: BI 201335 NA soft gelatine capsule

dose: 120 mg q.d. (for treatment-naïve patients), 240 mg q.d. (for treatment-naïve patients), and 240 mg q.d. (for treatment-experienced patients)

240 mg q.d. or 480 mg q.d. for a loading dose on the first day of administration

mode of admin.: Oral

batch no.: B083000978

Combination therapy: PegIFN alfa-2a (Pegasys®) solution for injection and RBV (Copegus®) tablet for 48 weeks

dose: PegIFN alfa-2a (Pegasys®): 180 µg, once weekly

RBV (Copegus®): 600 mg/day divided into 2 doses for body weight ≤60 kg; 800 mg/day for >60 kg and ≤80 kg; 1000 mg/day for >80 kg

mode of admin.: PegIFN alfa-2a (Pegasys®): subcutaneous injection

RBV (Copegus®): oral

batch no.: PegIFN alfa-2a (Pegasys®): B081005158

RBV (Copegus®): B091000850

Reference therapy: Placebo

dose: Not applicable

mode of admin.: Oral

batch no.: B083001306

Duration of treatment: 4-week combination therapy with BI 201335 NA, PegIFN alfa-2a, and RBV followed by 44-week SOC with PegIFN alfa-2a and RBV

c03302860



Synopsis No.:


Not applicable


BI 201335 NA

Page:

4 of 9

Module: Volume:

{hyperlink }


Trial No. / U No.:1220.14/ U10- 2102-01





Criteria for evaluation: Efficacy:

Efficacy / clinical No primary efficacy endpoint was set in this trial. pharmacology:

Secondary endpoints

- Week 2 virological response (W2VR): plasma HCV RNA level below the limit of quantification (BLQ) at Week 2

- Week 4 virological response (W4VR): plasma HCV RNA level BLQ at Week 4

- Rapid virological response (RVR): plasma HCV RNA level below the limit of detection (BLD) at Week 4

- Change from baseline in HCV RNA level at Week 4

- Day 28 virological response (D28VR): ≥2 log10 reduction in plasma HCV RNA level from baseline at Week 4

- Early virological response (EVR): ≥2 log10 reduction in plasma HCV RNA level from baseline at Week 12

- Complete early virological response (cEVR): plasma HCV RNA level BLDat Week 12

- End-of-treatment response (ETR): plasma HCV RNA level BLD at Week 48

- Sustained virological response (SVR): plasma HCV RNA level BLD 24 weeks after treatment completion at Week 72

c03302860



Synopsis No.:


Not applicable


BI 201335 NA

Page:

5 of 9

Module: Volume:

{hyperlink }


Trial No. / U No.:1220.14/ U10- 2102-01





Efficacy / clinical Pharmacokinetics: pharmacology:

Secondary endpoints (continued)

- Plasma concentration time profiles of BI 201335 ZW

- Pharmacokinetic parameters after the first dose: Cmax, tmax, AUCτ,1

(BI 201335 ZW and RBV)

- Trough concentration (BI 201335 ZW, RBV, and PegIFN alfa-2a)

- Pharmacokinetic parameters at steady state after the 4-week triple combination therapy:

Cmax,ss, tmax,ss, Cmin,ss, AUCτ,ss, CL/F,ss, Cavg (BI 201335 ZW and RBV)

λz,ss, t1/2,ss, MRTpo,ss, Vz/F,ss (only for BI 201335 ZW if possible)

C72,ss (only for PegIFN alfa-2a)

Safety: Primary endpoints

Safety for the triple combination therapy with BI 201335 NA, PegIFN alfa-2a, and RBV:

- Adverse events (AEs)

- Laboratory test abnormalities

- Laboratory test value changes over time

- Tolerability

Secondary endpoints

Safety for the SOC with PegIFN alfa-2a and RBV:

- AEs

- Laboratory test abnormalities

- Laboratory test value changes over time

- Tolerability

c03302860



Synopsis No.:


Not applicable


BI 201335 NA

Page:

6 of 9

Module: Volume:

{hyperlink }


Trial No. / U No.:1220.14/ U10- 2102-01





Statistical methods: Efficacy and safety

Descriptive statistics for efficacy and safety endpoints were calculated.

Pharmacokinetics

Descriptive statistics for pharmacokinetic endpoints were calculated.

For the attainment of steady state, the trough concentrations of BI 201335 ZW, RBV, and PegIFN alfa-2a were analysed by a linear mixed model on the log scale with ‘subject’ as a random effect and ‘time’ as a repeated effect. Subsequently, pair-wise comparisons of the differences between all subsequent time points were performed by using t tests. For the evaluation of pharmacokinetic drug-drug interaction, the pharmacokinetic parameters related to PegIFN alfa-2a and RBV at steady state after the 4-week triple combination therapy were descriptively compared between the BI 201335 NA/PegIFN alfa- 2a/RBV group and the PegIFN alfa-2a/RBV group.

SUMMARY – CONCLUSIONS:

As for treatment-naïve patients participating in Part 1, 19 patients were enrolled and 16 of them were entered and completed the trial. Of the 16 patients, 7 (43.8%) were male and the mean age was 52.4 years old. As for treatment- experienced patients participating in Part 2, 7 patients were enrolled and 6 of them were entered and 4 of them completed the trial. All the 6 patients were male with the mean age of 58.0 years: 4 (66.7%) were null-responders to PegIFN/RBVtherapy and 2 (33.3%) were relapsers.

Efficacy / clinical Efficacy pharmacology results:

BI 201335 NA produced a rapid decrease in HCV viral load for treatment-naïve patients compared with placebo: RVR was observed in 5 (83.3%) of the 6 patients with BI 201335 NA 120 mg q.d.; all of the 6 patients with BI 201335 NA 240 mg q.d.; and none of the 4 patients with placebo. For treatment-experienced patients, RVR was observed in 4 (66.7%) of the 6 patientswith BI 201335 NA 240 mg q.d.

c03302860



Synopsis No.:


Not applicable


BI 201335 NA

Page:

7 of 9

Module: Volume:

{hyperlink }


Trial No. / U No.:1220.14/ U10- 2102-01





Efficacy / clinical SVR was achieved in 4 (66.7%) of the 6 patients with BI 201335 NA 120 mg pharmacology results: q.d.; 5 (83.3%) of the 6 patients with BI 201335 NA 240 mg q.d.; and 2 (50.0%)

(continued) of the 4 patients with placebo. For treatment-experienced patients, SVR was achieved in 3 (50.0%) of the 6 patients with BI 201335 NA 240 mg q.d.

Pharmacokinetics

BI 201335 ZW

The plasma concentrations of BI 201335 ZW after the first administration of BI 201335 NA 240 mg or 480 mg (loading dose) with PegIFN alfa-2a/RBV reached the maximum at 5 to 8 hours after drug administration and thereafter declined slowly. The plasma concentrations of BI 201335 ZW after 4-week multiple administrations of BI 201335 NA 120 mg q.d. and BI 201335 NA 240 mg q.d. (maintenance dose) with PegIFN alfa-2a/RBV reached the maximum at 3 to 4 hours after drug administration and thereafter declined with a half-life of 21 to 29 hours. The exposure to BI 201335 ZW increased more than proportionally to the dose. BI 201335 ZW plasma concentrations reached the steady state within 7 days after the start of multiple administrations.

The exposure to BI 201335 ZW in treatment-experienced patients was slightly higher than that in treatment-naïve patients after both first and multiple administrations. However, no apparent difference was observed between treatment-naïve patients and treatment-experienced patients in the elimination half-life.

Ribavirin (RBV)

The plasma concentrations of RBV after the first administration of BI 201335 NA 240 mg or 480 mg (loading dose) with PegIFN alfa-2a/RBV reached the maximum at 4 to 5 hours after drug administration and then declined slowly. The plasma concentrations of RBV after 4-week multiple administrations of BI 201335 NA 120 mg q.d. and BI 201335 NA 240 mg q.d. with PegIFN alfa-2a/RBV reached the maximum at 3 to 4 hours after drug administration and then declined slowly. The plasma concentrations of RBV in both treatment-naïve patients and treatment-experienced patients reached an almost steady state after 4 weeks of treatment.

c03302860



Synopsis No.:


Not applicable


BI 201335 NA

Page:

8 of 9

Module: Volume:

{hyperlink }


Trial No. / U No.:1220.14/ U10- 2102-01





Efficacy / clinical No apparent difference was observed between treatment-naïve patients and pharmacology results: treatment-experienced patients in the plasma concentrations of RBV after

(continued) multiple administrations of BI 201335 NA 240 mg q.d. with PegIFN alfa- 2a/RBV. However, plasma concentrations of RBV in the BI 201335 NA 240 mgq.d. group were slightly lower than those in the placebo group.

Pegylated interferon alfa-2a (PegIFN alfa-2a)

PegIFN alfa-2a reached an almost steady state after 4 weeks of treatment. No apparent difference was observed between treatment-naïve patients and treatment-experienced patients. No apparent difference was observed between the placebo group and active dose groups of BI 201335 NA.

Pharmacokinetics and pharmacodynamics

No statistically significant correlation was observed between viral load reduction(on Days 4 and 8) and the natural logarithm of pharmacokinetic parameters of BI 201335 ZW for either treatment-naïve patients or treatment-experienced patients.

Statistically significant correlation were observed between increase of total bilirubin levels on Day 29 from baseline and pharmacokinetic parameters of BI 201335 ZW at steady state (Cmax,ss and AUCτ,ss) in both treatment-naïve patients and treatment-experienced patients.

Safety results: BI 201335 NA was well tolerated.

Rash AEs (rash and generalised rash in Medical Dictionary for Regulatory Activities [MedDRA] preferred term) were more frequently reported for treatment-naïve patients with BI 201335 NA than those with placebo: 3 (50.0%) of the 6 patients with BI 201335 NA 120 mg q.d. and 3 (50.0%) of the 6 patients with BI 201335 NA 240 mg q.d. experienced rash or generalised rash, whereas 1 (25.0%) of the 4 patients with placebo experienced rash. For treatment- experienced patients, rash was reported only for 1 (16.7%) of the 6 patients.

In total, nausea and vomiting were more frequently reported for treatment-naïvepatients with BI 201335 NA 240 mg q.d. than those with BI 201335 NA 120 mgq.d. or placebo. For treatment-experienced patients, those AEs were not reported.

c03302860



Synopsis No.:


Not applicable


BI 201335 NA

Page:

9 of 9

Module: Volume:

{hyperlink }


Trial No. / U No.:1220.14/ U10- 2102-01





Safety results Overall, increase of total bilirubin as well as indirect bilirubin was dose-

(continued) dependent. All increases in total bilirubin were predominantly indirect. Ocular icterus was reported for 1 (16.7%) of the 6 treatment-naïve patients with BI 201335 NA 120 mg q.d. and jaundice for 1 (16.7%) of the 6 treatment-naïve patients with BI 201335 NA 240 mg q.d.

All other AEs were known to be associated with SOC and the frequency of AEs was not dose-dependent.

Conclusions: No marked concerns were found for the safety in respect of adverse events and laboratory parameters. BI 201335 NA was well tolerated under the treatment with pegylated interferon alfa-2a and ribavirin. Rapid antiviral effect was observed both for treatment-naïve patients and treatment-experienced patients. No viral rebound was seen during the 4-week treatment with BI 201335 NA. The assessment of sustained virological response in efficacy was limited because the duration of the triple combination therapy of BI 201335 NA, pegylated interferon alfa-2a, and ribavirin was only 4 weeks.

BI 201335 ZW plasma concentrations reached the steady state within 7 days after multiple administrations. The exposure to BI 201335 ZW increased more than proportionally to the dose. The exposures to ribavirin at steady state were decreased slightly (<30%) by co-administration of BI 201335 NA. No apparent effect of BI 201335 NA on the exposure to PegIFN alfa-2a was observed. No statistically significant correlation between early viral load reduction and natural logarithm of pharmacokinetic parameters of BI 201335 ZW was observed.

Given the number of participating patients was limited and the treatment period was short in this trial, further evaluation is required for the safety and efficacy of BI 201335 NA in Japanese patients in a long-term phase III trial.

c03302860

Boehringer Ingelheim BI trial number 1220.14 Trial Synopsis - Appendix

Trial Synopsis – Appendix

The appended tables on the following pages supplement the trial results presented in the trial

synopsis. They complement results for patient disposition, and the primary and secondary

endpoints for the study.

Results for presented in

Patient Disposition

Treatment Naïve Patients

Treatment Experienced Patients

Table 15.1.1: 1

Table 15.1.1: 2

AE Summary, Baseline Through 4 Weeks, (Primary EP)

Treatment Naïve Patients

Treatment Experienced Patients

Table 15.3.2.1.1: 1

Table 15.3.2.1.2: 1

Week 2 Virologic Response (Secondary EP)

Treatment Naïve BI 201335 NA 120 & 240 mg

Treatment Experienced BI 201335 NA 240 mg

Table 15.2.2.1: 1

Table 15.2.2.2: 1

Week 4 Virologic Response (Secondary EP)



Table 15.2.2.1: 2

Table 15.2.2.2: 2

Change from Baseline in HCV RNA level at Week 4 (Secondary EP)



Table 15.2.2.1: 4

Table 15.2.2.2: 4

Day 28 Virologic Response (Secondary EP)



Table 15.2.2.1: 5

Table 15.2.2.2: 5

Early Virologic Response (at Week 12) (Secondary EP)



Table 15.2.2.1: 6

Table 15.2.2.2: 6

Complete Early Virologic Response (at Week 12)

(Secondary EP)



Table 15.2.2.1: 7

Table 15.2.2.2: 7

c03302860

Boehringer Ingelheim BI trial number 1220.14 Trial Synopsis - Appendix

End of Treatment Response (at Week 48)

(Secondary EP)



Table 15.2.2.1: 8

Table 15.2.2.2: 8

Pharmacokinetic Summary for BI 201335 ZW (Secondary EP)

Treatment Naïve BI 201335 NA 120 mg



Table 15.6.2.1: 1

Table 15.6.2.1: 2

Table 15.6.2.1: 3

Pharmacokinetic Summary for Ribavirin (Secondary EP)




Table 15.6.2.1: 5

Table 15.6.2.1: 6

Table 15.6.2.1: 7

Pharmacokinetic Summary for PegIFN alfa-2a (Secondary EP)




Table 15.6.2.1: 9

Table 15.6.2.1: 10

Table 15.6.2.1: 11

c03302860

Table 15.1.1: 1 Disposition of TN patients

Dose group=All

____________________________________________________________________________________________________________________ Placebo 120 mg q.d. 240 mg q.d. Total

Enrolled 19 Not entered/randomised 3 Entered/randomised 4 6 6 16 Not treated 0 0 0 0 Treated 4(100.00) 6(100.00) 6(100.00) 16(100.00) End of Treatment − triple combination 4 6 6 16 Not prematurely discontinued from trial medication 4(100.00) 5( 83.33) 6(100.00) 15( 93.75) Prematurely discontinued from trial medication 0( 0.00) 1( 16.67) 0( 0.00) 1( 6.25) Adverse event 0( 0.00) 1( 16.67) 0( 0.00) 1( 6.25) Worsening of disease under study 0( 0.00) 0( 0.00) 0( 0.00) 0( 0.00) Worsening of other pre−existing disease 0( 0.00) 0( 0.00) 0( 0.00) 0( 0.00) Other adverse event 0( 0.00) 1( 16.67) 0( 0.00) 1( 6.25) Lack of efficacy 0( 0.00) 0( 0.00) 0( 0.00) 0( 0.00) Non compliant with protocol 0( 0.00) 0( 0.00) 0( 0.00) 0( 0.00) Lost to follow−up 0( 0.00) 0( 0.00) 0( 0.00) 0( 0.00) Refused to continue taking trial medication 0( 0.00) 0( 0.00) 0( 0.00) 0( 0.00) Other 0( 0.00) 0( 0.00) 0( 0.00) 0( 0.00) End of Treatment − standard of care 4 5 6 15 Not prematurely discontinued from trial medication 4(100.00) 5( 83.33) 4( 66.67) 13( 81.25) Prematurely discontinued from trial medication 0( 0.00) 0( 0.00) 2( 33.33) 2( 12.50) Adverse event 0( 0.00) 0( 0.00) 0( 0.00) 0( 0.00) Worsening of disease under study 0( 0.00) 0( 0.00) 0( 0.00) 0( 0.00) Worsening of other pre−existing disease 0( 0.00) 0( 0.00) 0( 0.00) 0( 0.00) Other adverse event 0( 0.00) 0( 0.00) 0( 0.00) 0( 0.00) Lack of efficacy 0( 0.00) 0( 0.00) 1( 16.67) 1( 6.25) Non compliant with protocol 0( 0.00) 0( 0.00) 0( 0.00) 0( 0.00) Lost to follow−up 0( 0.00) 0( 0.00) 0( 0.00) 0( 0.00) Refused to continue taking trial medication 0( 0.00) 0( 0.00) 1( 16.67) 1( 6.25) Other 0( 0.00) 0( 0.00) 0( 0.00) 0( 0.00) _____________________________________________________________________________________________________________________

Source data: Appendix 16.2.1, Listing 1, 3 sa\term1_sa.sas 04NOV2011

Page BI Trial No.:

Boehringer Ingelheim 1951220.14 U10-2102-01

1. - 15. CTR Main Part

c03302860

Table 15.1.1: 2 Disposition of TE patients

__________________________________________________________________________ 240 mg q.d.

Enrolled 7 Not entered/randomised 1 Entered/randomised 6 Not treated 0 Treated 6(100.00) End of Treatment − triple combination 6 Not prematurely discontinued from trial medication 6(100.00) Prematurely discontinued from trial medication 0( 0.00) Adverse event 0( 0.00) Worsening of disease under study 0( 0.00) Worsening of other pre−existing disease 0( 0.00) Other adverse event 0( 0.00) Lack of efficacy 0( 0.00) Non compliant with protocol 0( 0.00) Lost to follow−up 0( 0.00) Refused to continue taking trial medication 0( 0.00) Other 0( 0.00) End of Treatment − standard of care 6 Not prematurely discontinued from trial medication 4( 66.67) Prematurely discontinued from trial medication 2( 33.33) Adverse event 0( 0.00) Worsening of disease under study 0( 0.00) Worsening of other pre−existing disease 0( 0.00) Other adverse event 0( 0.00) Lack of efficacy 1( 16.67) Non compliant with protocol 0( 0.00) Lost to follow−up 0( 0.00) Refused to continue taking trial medication 0( 0.00) Other 1( 16.67) __________________________________________________________________________

Source data: Appendix 16.2.1, Listing 1, 3 sa\term2_sa.sas 04NOV2011

Page BI Trial No.:



c03302860

Table 15.3.2.1.1: 1 Adverse event overall summary − treated set

For treatment naive patients Treatment analysis: Triple combination therapy

___________________________________________________________________________________________________________ Placebo 120 mg q.d. 240 mg q.d. Total N (%) N (%) N (%) N (%)___________________________________________________________________________________________________________

Number of patients 4 (100.0) 6 (100.0) 6 (100.0) 16 (100.0)

Patients with any AE 3 ( 75.0) 6 (100.0) 6 (100.0) 15 ( 93.8)

Patients with severe AEs 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)

Patients with investigator defined drug−related 3 ( 75.0) 6 (100.0) 6 (100.0) 15 ( 93.8)AEs

Patients with other significant AEs (according to 0 ( 0.0) 1 ( 16.7) 0 ( 0.0) 1 ( 6.3)ICH E3)

Patients with AEs leading to discontinuation of 0 ( 0.0) 1 ( 16.7) 0 ( 0.0) 1 ( 6.3)trial drug

Patients with significant AEs (pre−specified 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)events)

Patients with serious AEs 0 ( 0.0) 1 ( 16.7) 0 ( 0.0) 1 ( 6.3) Fatal 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Imm life−threatening 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Disability/incap. 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Req.hospitalisation 0 ( 0.0) 1 ( 16.7) 0 ( 0.0) 1 ( 6.3) Prol.hospitalisation 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Congenital anomaly 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Other 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)___________________________________________________________________________________________________________

A patient may be counted in more than one seriousness criterion.Percentages are calculated using total number of patients per treatment as the denominator.MedDRA version used for reporting: 14.0

Source data: Appendix 16.2.7, Listing 3 sa\ae1_sa.sas 04NOV2011

Page BI Trial No.:



c03302860

Table 15.3.2.1.2: 1 Adverse event overall summary − treated set

For treatment experienced patients Treatment analysis: Triple combination therapy

_________________________________________________________________ 240 mg q.d. N (%)_________________________________________________________________

Number of patients 6 (100.0)

Patients with any AE 6 (100.0)

Patients with severe AEs 0 ( 0.0)

Patients with investigator defined drug−related 5 ( 83.3)AEs

Patients with other significant AEs (according to 0 ( 0.0)ICH E3)

Patients with AEs leading to discontinuation of 0 ( 0.0)trial drug

Patients with significant AEs (pre−specified 0 ( 0.0)events)

Patients with serious AEs 0 ( 0.0) Fatal 0 ( 0.0) Imm life−threatening 0 ( 0.0) Disability/incap. 0 ( 0.0) Req.hospitalisation 0 ( 0.0) Prol.hospitalisation 0 ( 0.0) Congenital anomaly 0 ( 0.0) Other 0 ( 0.0)_________________________________________________________________

A patient may be counted in more than one seriousness criterion.Percentages are calculated using total number of patients per treatment as the denominator.MedDRA version used for reporting: 14.0

Source data: Appendix 16.2.7, Listing 3 sa\ae1_sa.sas 04NOV2011

Page BI Trial No.:



c03302860

Table 15.2.2.1: 1 Summary of W2VR for TN patients full analysis set

_______________________________________________________________________________________________________________ W2VR(<25 IU/mL) at week 2 Placebo 120 mg q.d. 240 mg q.d.

Number of patients [N (%)] 4 (100.0) 6 (100.0) 6 (100.0)

Number (%) satisfying W2VR 0 ( 0.0) 5 ( 83.3) 6 (100.0) 95% Confidence interval [%]* (0.0 , 60.2) (35.9 , 99.6) (54.1 , 100.0) ______________________ ___________________________________________________________________________________ * 95% CI based on the F distribution

Source data: Appendix 16.2.6, Listing 1 sa\hcv2_sa.sas 04NOV2011

Page BI Trial No.:



c03302860

Table 15.2.2.2: 1 Summary of W2VR for TE patients full analysis set

___________________________________________________________________ W2VR(<25 IU/mL) at week 2 240 mg q.d.

Number of patients [N (%)] 6 (100.0)

Number (%) satisfying W2VR 3 ( 50.0) 95% Confidence interval [%]* (11.8 , 88.2) ______________________ _______________________________________ * 95% CI based on the F distribution


Page BI Trial No.:



c03302860

Table 15.2.2.1: 2 Summary of W4VR for TN patients full analysis set

_______________________________________________________________________________________________________________ W4VR(<25 IU/mL) at week 4 Placebo 120 mg q.d. 240 mg q.d.


Number (%) satisfying W4VR 0 ( 0.0) 6 (100.0) 6 (100.0) 95% Confidence interval [%]* (0.0 , 60.2) (54.1 , 100.0) (54.1 , 100.0) ______________________ ___________________________________________________________________________________ * 95% CI based on the F distribution


Page BI Trial No.:



c03302860

Table 15.2.2.2: 2 Summary of W4VR for TE patients full analysis set

___________________________________________________________________ W4VR(<25 IU/mL) at week 4 240 mg q.d.


Number (%) satisfying W4VR 5 ( 83.3) 95% Confidence interval [%]* (35.9 , 99.6) ______________________ _______________________________________ * 95% CI based on the F distribution


Page BI Trial No.:



c03302860

Table 15.2.2.1: 4 Summary of change form baseline in HCV viral load (log10) after 4 weeks for TN patients full analysis set

_______________________________________________________________________________________________________________ Placebo 120 mg q.d. 240 mg q.d.

Number of patients 4 6 6

Change from baseline in HCV viral load (log10) after 4 weeks Mean (SE) −3.30 (0.74) −5.88 (0.17) −5.95 (0.21) 95% Confidence interval −5.65 , −0.95 −6.32 , −5.43 −6.51 , −5.40 __________________________________________________________________________________________________________


Page BI Trial No.:



c03302860

Table 15.2.2.2: 4 Summary of change form baseline in HCV viral load (log10) after 4 weeks for TE patients full analysis set

___________________________________________________________________ 240 mg q.d.

Number of patients 6

Change from baseline in HCV viral load (log10) after 4 weeks Mean (SE) −5.53 (0.29) 95% Confidence interval −6.28 , −4.78 ______________________________________________________________


Page BI Trial No.:



c03302860

Table 15.2.2.1: 5 Summary of HCV viral loard reduction >= 2 log10 from baseline after 28 days for TN patients full analysis set

_______________________________________________________________________________________________________________ HCV viral load reduction >= 2 log10 from baseline after 28 days Placebo 120 mg q.d. 240 mg q.d.


Number (%) satisfying the endpoint 3 ( 75.0) 6 (100.0) 6 (100.0) 95% Confidence interval [%]* (19.4 , 99.4) (54.1 , 100.0) (54.1 , 100.0) ______________________ ___________________________________________________________________________________ * 95% CI based on the F distribution


Page BI Trial No.:



c03302860

Table 15.2.2.2: 5 Summary of HCV viral loard reduction >= 2 log10 from baseline after 28 days for TE patients full analysis set

___________________________________________________________________ HCV viral load reduction >= 2 log10 from baseline after 28 days 240 mg q.d.


Number (%) satisfying the endpoint 6 (100.0) 95% Confidence interval [%]* (54.1 , 100.0) ______________________ _______________________________________ * 95% CI based on the F distribution


Page BI Trial No.:



c03302860

Table 15.2.2.1: 6 Summary of EVR for TN patients full analysis set

_______________________________________________________________________________________________________________ EVR (VL reduction >= 2 log10) at week 12 Placebo 120 mg q.d. 240 mg q.d.


Number (%) satisfying the endpoint 4 (100.0) 5 ( 83.3) 6 (100.0) 95% Confidence interval [%]* (39.8 , 100.0) (35.9 , 99.6) (54.1 , 100.0) ______________________ ___________________________________________________________________________________ * 95% CI based on the F distribution


Page BI Trial No.:



c03302860

Table 15.2.2.2: 6 Summary of EVR for TE patients full analysis set

___________________________________________________________________ EVR (VL reduction >= 2 log10) at week 12 240 mg q.d.




Page BI Trial No.:



c03302860

Table 15.2.2.1: 7 Summary of cEVR for TN patients full analysis set

_______________________________________________________________________________________________________________ cEVR (<10 IU/mL) at week 12 Placebo 120 mg q.d. 240 mg q.d.


Number (%) satisfying the endpoint 3 ( 75.0) 5 ( 83.3) 5 ( 83.3) 95% Confidence interval [%]* (19.4 , 99.4) (35.9 , 99.6) (35.9 , 99.6) ______________________ ___________________________________________________________________________________ * 95% CI based on the F distribution


Page BI Trial No.:



c03302860

Table 15.2.2.2: 7 Summary of cEVR for TE patients full analysis set

___________________________________________________________________ cEVR (<10 IU/mL) at week 12 240 mg q.d.




Page BI Trial No.:



c03302860

Table 15.2.2.1: 8 Summary of ETR for TN patients full analysis set

_______________________________________________________________________________________________________________ ETR (<10 IU/mL) at week 48 Placebo 120 mg q.d. 240 mg q.d.


Number (%) satisfying the endpoint 3 ( 75.0) 5 ( 83.3) 4 ( 66.7) 95% Confidence interval [%]* (19.4 , 99.4) (35.9 , 99.6) (22.3 , 95.7) ______________________ ___________________________________________________________________________________ * 95% CI based on the F distribution


Page BI Trial No.:



c03302860

Table 15.2.2.2: 8 Summary of ETR for TE patients full analysis set

___________________________________________________________________ ETR (<10 IU/mL) at week 48 240 mg q.d.


Number (%) satisfying the endpoint 4 ( 66.7) 95% Confidence interval [%]* (22.3 , 95.7) ______________________ _______________________________________ * 95% CI based on the F distribution


Page BI Trial No.:



c03302860

Boehringer Ingelheim BI Trial No.: 1220.14

Page 1413U10-2102-01


Table 15.6.2.1: 1 Indiv. noncomp. PK parameters of BI 201335 ZW after multiple oral admin. of 120 mg q.d. BI 201335 NA (240 mg at the first dose) with RBV and Peg−IFN alpha 2a in TN patients with descriptive statistics

lambda_z: slope for extrapolation to calculate AUCtau,1

Source data: Section 15, Table 6.1.1: 2, 6.1.1: 14 pk\pkparam.sas 26DEC2011

BI 201335 NA 120 mg q.d. (loading dose 240 mg) with RBV and Peg−IFN alpha 2a Noncompartmental parameters of BI 201335 ZW

AUCτ,1 [ng*h/mL]

AUCτ,1,norm [ng*h/mL/mg]

AUC0−tz [ng*h/mL]

No,λZ λZ [1/h]

tλZ,start [h]

tλZ,end [h]

Cmax [ng/mL]

Cmax,norm [ng/mL/mg]

tmax [h]

N 6 6 6 6 6 6 6 6 6 6gMean 68900 287 68500 3.00 0.0468 9.93 23.8 5500 22.9 5.58gCV [%] 25.3 25.3 25.2 0 54.3 0.541 0.210 24.4 24.4 39.0Mean 70700 294 70300 3.00 0.0511 9.93 23.8 5640 23.5 5.94CV [%] 23.8 23.8 23.8 0 37.5 0.542 0.210 24.6 24.6 40.5SD 16800 70.1 16700 0 0.0192 0.0538 0.0499 1390 5.79 2.41Min 48400 202 48300 3.00 0.0177 9.88 23.7 4220 17.6 3.92Median 71500 298 70900 3.00 0.0552 9.92 23.8 5250 21.9 4.98Max 90100 376 89800 3.00 0.0738 10.0 23.8 7640 31.8 9.88

Individual patient information removed from table

c03302860


Page 1414U10-2102-01






AUCτ,ss [ng*h/mL]

AUCτ,ss,norm [ng*h/mL/mg]

AUC0−tz,ss[ng*h/mL]

Cmax,ss [ng/mL]

Cmax,ss,norm [ng/mL/mg]

tmax,ss[h]

Cmin,ss [ng/mL]

tmin,ss[h]

Cavg [ng/mL]

t½,ss [h]

N 5 5 5 5 5 5 5 5 5 5gMean 70800 590 70600 5880 49.0 3.53 1550 6.80 2950 29.3gCV [%] 86.5 86.5 86.4 61.5 61.5 43.6 138 423 86.5 7.70Mean 88700 739 88400 6720 56.0 3.76 2340 14.7 3690 29.3CV [%] 73.9 73.9 73.9 59.3 59.3 36.2 95.7 84.8 73.9 7.44SD 65500 546 65300 3980 33.2 1.36 2240 12.5 2730 2.18Min 34700 289 34600 3310 27.6 1.85 553 1.00 1440 25.8Median 55000 458 54800 4550 37.9 3.83 1130 23.8 2290 29.4Max 181000 1510 181000 12700 106 5.07 5620 23.8 7550 31.5


c03302860


Page 1417U10-2102-01






AUCτ,1 [ng*h/mL]


AUC0−tz [ng*h/mL]

No,λZ λZ [1/h]

tλZ,start [h]

tλZ,end [h]

Cmax [ng/mL]


tmax [h]

N 4 4 4 4 4 4 4 4 4 4gMean 171000 356 170000 3.00 0.0471 9.94 23.9 12600 26.3 5.57gCV [%] 21.2 21.2 21.2 0 6.62 0.719 0.218 29.0 29.0 29.3Mean 174000 362 173000 3.00 0.0471 9.94 23.9 13000 27.1 5.74CV [%] 22.0 22.0 21.9 0 6.76 0.717 0.218 28.4 28.4 29.0SD 38200 79.5 38000 0 0.00319 0.0712 0.0519 3700 7.70 1.67Min 142000 296 142000 3.00 0.0448 9.83 23.8 9610 20.0 4.03Median 163000 340 163000 3.00 0.0460 9.97 23.9 12500 26.0 5.50Max 227000 472 226000 3.00 0.0516 9.98 23.9 17400 36.3 7.93


c03302860




Page 1418U10-2102-01




AUCτ,ss [ng*h/mL]



Cmax,ss [ng/mL]


tmax,ss[h]

Cmin,ss [ng/mL]

tmin,ss[h]

Cavg [ng/mL]

t½,ss [h]

N 6 6 6 6 6 6 6 6 6 6gMean 361000 1500 359000 24500 102 2.99 10200 8.14 15000 21.2gCV [%] 68.0 68.0 67.7 52.2 52.2 1.64 85.0 387 68.0 9.00Mean 427000 1780 424000 27200 113 2.99 12800 16.2 17800 21.2CV [%] 67.6 67.6 67.3 53.2 53.2 1.63 76.4 72.9 67.6 9.16SD 288000 1200 285000 14500 60.2 0.0488 9820 11.8 12000 1.94Min 193000 806 193000 14300 59.6 2.90 4440 0.933 8060 19.4Median 339000 1410 338000 23100 96.3 2.99 10400 23.8 14100 20.5Max 953000 3970 945000 52900 220 3.05 30700 23.9 39700 24.0


c03302860


Page 1421U10-2102-01


Table 15.6.2.1: 3 Indiv. noncomp. PK parameters of BI 201335 ZW after multiple oral admin. of 240 mg q.d. BI 201335 NA (480 mg at the first dose) with RBV and Peg−IFN alpha 2a in TE patients with descriptive statistics




AUCτ,1 [ng*h/mL]


AUC0−tz [ng*h/mL]

No,λZ λZ [1/h]

tλZ,start [h]

tλZ,end [h]

Cmax [ng/mL]


tmax [h]

N 6 6 6 6 6 6 6 6 6 6gMean 233000 485 231000 3.00 0.0342 9.94 23.8 15000 31.2 6.98gCV [%] 38.5 38.5 38.6 0 32.6 0.773 0.330 40.4 40.4 46.4Mean 246000 512 244000 3.00 0.0356 9.94 23.8 15800 32.9 7.45CV [%] 34.4 34.4 34.5 0 28.8 0.776 0.330 29.3 29.3 31.8SD 84600 176 84000 0 0.0102 0.0771 0.0785 4630 9.64 2.37Min 126000 263 125000 3.00 0.0198 9.87 23.7 6930 14.4 2.88Median 238000 495 236000 3.00 0.0352 9.93 23.8 16600 34.5 7.97Max 370000 771 367000 3.00 0.0490 10.1 23.9 19900 41.5 9.92


c03302860


Page 1422U10-2102-01


Table 15.6.2.1: 3 Indiv. noncomp. PK parameters of BI 201335 ZW after multiple oral admin. of 240 mg q.d. BI 201335 NA (480 mg at the first dose) with RBV and Peg−IFN alpha 2a in TE patients with descriptive statistics




AUCτ,ss [ng*h/mL]



Cmax,ss [ng/mL]


tmax,ss[h]

Cmin,ss [ng/mL]

tmin,ss[h]

Cavg [ng/mL]

t½,ss [h]

N 6 6 6 6 6 6 6 6 6 6 gMean 499000 2080 496000 29100 121 3.44 16000 8.01 20800 23.0gCV [%] 41.3 41.3 41.4 35.3 35.3 16.7 54.1 405 41.3 19.8Mean 539000 2250 536000 30800 128 3.48 18100 16.2 22500 23.4CV [%] 49.9 49.9 50.2 40.8 40.8 16.4 64.7 73.1 49.9 20.4SD 269000 1120 269000 12600 52.3 0.573 11700 11.8 11200 4.77Min 340000 1420 338000 20700 86.3 2.92 9460 0.833 14200 19.0Median 459000 1910 455000 28200 118 3.49 14000 23.7 19100 21.4Max 1080000 4500 1080000 55500 231 4.03 41500 23.9 45000 30.3


c03302860


Page 1428U10-2102-01


Table 15.6.2.1: 5 Indiv. noncomp. PK parameters of RBV after multiple oral admin. of 120 mg q.d. BI 201335 NA (240 mg at the first dose) with RBV and Peg−IFN alpha 2a in TN patients with descriptive statistics

lambda_z and lambda_z_ss: slopes for extrapolation to calculate AUCtau,1 and AUCtau,ss respectively


BI 201335 NA 120 mg q.d. (loading dose 240 mg) with RBV and Peg−IFN alpha 2a Noncompartmental parameters of RBV

AUCτ,1 [ng*h/mL]


AUC0−tz [ng*h/mL]

No,λZ λZ [1/h]

tλZ,start [h]

tλZ,end [h]

Cmax [ng/mL]


tmax [h]

N 6 6 6 6 6 6 6 6 6 6 gMean 4660 16.5 4600 3.00 0.0533 7.93 11.8 761 2.69 3.50gCV [%] 35.8 21.3 35.5 0 67.1 0.719 0.449 29.7 16.5 32.4Mean 4910 16.8 4840 3.00 0.0602 7.93 11.8 789 2.72 3.64CV [%] 36.1 21.0 35.8 0 43.7 0.720 0.449 29.8 14.9 27.5SD 1770 3.53 1730 0 0.0263 0.0571 0.0529 235 0.404 1.00Min 3130 12.3 3090 3.00 0.0171 7.87 11.7 580 1.97 2.00Median 4650 16.2 4590 3.00 0.0687 7.92 11.8 709 2.83 3.98Max 7920 21.9 7780 3.00 0.0918 8.00 11.8 1100 3.14 4.88


c03302860


Page 1429U10-2102-01





AUCτ,ss AUC0−tz,ss Cmax,ss tmax,ss Cmin,ss tmin,ss Cavg No,λZ,ss λZ,ss tλZ,start,ss g*h/mL] [ng*h/mL] [ng/mL] [h] [ng/mL

][h] [ng/mL] [1/h] [h]

N

5 5 5 5 5 5

5 5 5 5

gMean 25200 25000 2710 2.66 1730 6.97 2100 3.00 0.0246 8.02gCV [%] 42.4 42.0 47.3 33.4 44.0 151 42.4 0 48.0 0.863Mean 26900 26600 2930 2.78 1850 9.29 2240 3.00 0.0267 8.02CV [%] 38.5 38.2 43.5 32.5 39.6 50.8 38.5 0 44.1 0.860SD 10400 10100 1270 0.903 735 4.71 863 0 0.0118 0.0690Min 14800 14600 1570 1.85 1010 1.00 1230 3.00 0.0135 7.92Median 24800 24500 2530 2.92 1750 11.8 2070 3.00 0.0225 8.03Max 38200 37700 4390 4.08 2610 11.9 3180 3.00 0.0426 8.08



c03302860


Page 1431U10-2102-01






AUCτ,1 [ng*h/mL]


AUC0−tz [ng*h/mL]

No,λZ λZ [1/h]

tλZ,start [h]

tλZ,end [h]

Cmax [ng/mL]


tmax [h]

N 4 4 4 4 4 4 4 4 4 4gMean 4620 11.5 4570 3.00 0.0748 7.97 11.8 724 1.81 3.70gCV [%] 22.9 22.9 22.9 0 43.5 0.950 0.686 33.7 33.7 46.4Mean 4710 11.8 4660 3.00 0.0800 7.97 11.8 754 1.89 3.96CV [%] 22.9 22.9 22.8 0 44.1 0.954 0.687 33.9 33.9 40.4SD 1080 2.69 1060 0 0.0353 0.0760 0.0811 256 0.639 1.60Min 3670 9.16 3630 3.00 0.0474 7.92 11.7 553 1.38 2.05Median 4550 11.4 4510 3.00 0.0712 7.94 11.8 687 1.72 3.92Max 6070 15.2 5980 3.00 0.130 8.08 11.9 1090 2.73 5.97


c03302860




Page 1432U10-2102-01




AUCτ,ss [ng*h/mL]


Cmax,ss [ng/mL]

tmax,ss[h]

Cmin,ss [ng/mL]

tmin,ss [h]

Cavg [ng/mL]

No,λZ,ss λZ,ss [1/h]

tλZ,start,ss [h]

N 5 5 5 5 5 5 5 5 5 5 gMean 22400 22100 2280 2.88 1590 7.96 1860 3.00 0.0175 7.97gCV [%] 38.5 39.0 43.2 47.2 36.4 92.4 38.5 0 151 0.995Mean 23600 23300 2440 3.14 1660 9.46 1960 3.00 0.0239 7.97CV [%] 34.0 34.4 40.3 51.3 32.1 45.1 34.0 0 61.3 0.994SD 8020 8000 985 1.61 533 4.27 669 0 0.0147 0.0792Min 13700 13500 1400 1.93 1000 1.97 1140 3.00 0.00269 7.85Median 26300 26100 2610 2.90 1930 11.7 2190 3.00 0.0231 7.97Max 32500 32200 3850 5.88 2170 11.9 2710 3.00 0.0380 8.07


c03302860


Page 1434U10-2102-01


Table 15.6.2.1: 7 Indiv. noncomp. PK parameters of RBV after multiple oral admin. of 240 mg q.d. BI 201335 NA (480 mg at the first dose) with RBV and Peg−IFN alpha 2a in TE patients with descriptive statistics




AUCτ,1 [ng*h/mL]


AUC0−tz [ng*h/mL]

No,λZ λZ [1/h]

tλZ,start [h]

tλZ,end [h]

Cmax [ng/mL]


tmax[h]

N 6 6 6 6 6 6 6 6 6 6 gMean 3500 12.4 3460 3.00 0.0980 7.98 11.8 509 1.80 4.35gCV [%] 41.2 23.5 41.0 0 69.8 0.979 0.518 51.0 32.5 45.8Mean 3730 12.6 3680 3.00 0.115 7.98 11.8 556 1.88 4.66CV [%] 38.8 22.1 38.5 0 60.8 0.977 0.518 42.1 33.2 35.2SD 1450 2.80 1420 0 0.0697 0.0780 0.0610 234 0.623 1.64Min 2000 8.82 1970 3.00 0.0358 7.87 11.7 238 1.19 1.97Median 3400 13.1 3370 3.00 0.104 8.01 11.8 591 1.72 4.98Max 5790 16.3 5700 3.00 0.241 8.08 11.9 895 2.94 6.02


c03302860


Page 1435U10-2102-01


Table 15.6.2.1: 7 Indiv. noncomp. PK parameters of RBV after multiple oral admin. of 240 mg q.d. BI 201335 NA (480 mg at the first dose) with RBV and Peg−IFN alpha 2a in TE patients with descriptive statistics




AUCτ,ss [ng*h/mL]


Cmax,ss [ng/mL]

tmax,ss[h]

Cmin,ss [ng/mL]

tmin,ss [h]

Cavg [ng/mL]

No,λZ,ss λZ,ss [1/h]

tλZ,start,ss [h]

N 6 6 6 6 6 6 6 6 6 6 gMean 20000 19700 2130 3.49 1400 11.0 1670 3.15 0.0316 7.58gCV [%] 18.7 19.0 18.0 33.2 18.5 16.5 18.7 11.8 58.2 12.5Mean 20300 20000 2160 3.63 1420 11.1 1690 3.17 0.0349 7.62CV [%] 19.4 19.7 18.2 28.7 18.6 14.3 19.4 12.9 40.7 11.3SD 3950 3960 392 1.04 263 1.59 329 0.408 0.0142 0.858Min 15900 15600 1730 2.00 1090 7.90 1320 3.00 0.0121 5.88Median 19700 19400 2120 3.92 1440 11.8 1650 3.00 0.0412 7.94Max 27300 27000 2770 5.03 1850 11.8 2280 4.00 0.0466 8.08


c03302860


Page 1438U10-2102-01


Table 15.6.2.1: 9 Indiv. noncomp. PK parameters of Peg−IFN alpha 2a after multiple oral admin. of 120 mg q.d. BI 201335 NA(240 mg at the first dose) with RBV and Peg−IFN alpha 2a in TN patients with descriptive statistics

Source data: Section 15, Table 6.1.1: 10 6.1.1: 22 pk\pkparam.sas 26DEC2011

BI 201335 NA 120 mg q.d. (loading dose 240 mg) with RBV and Peg−IFN alpha 2a Noncompartmental parameters of Peg−IFN alpha 2a

Cpre,2 [pg/mL]

Cpre,3 [pg/mL]

Cpre,4 [pg/mL]

Cpre,ss [pg/mL]

C72,ss [pg/mL]

N 6 4 6 4 4gMean 10400 18400 20300 20400 25700gCV [%] 73.0 40.0 57.6 49.9 53.9Mean 12200 19600 22500 22300 28200CV [%] 57.3 44.3 43.6 50.4 49.0SD 6970 8680 9830 11300 13800Min 3300 13900 8100 14100 14400Median 10500 16000 23000 18600 26300Max 24500 32500 34000 38000 45900

Individual patient data removed from table

c03302860


Page 1439U10-2102-01


Table 15.6.2.1: 10 Indiv. noncomp. PK parameters of Peg−IFN alpha 2a after multiple oral admin. of 240 mg q.d. BI 201335 NA(480 mg at the first dose) with RBV and Peg−IFN alpha 2a in TN patients with descriptive statistics



Cpre,2 [pg/mL]

Cpre,3 [pg/mL]

Cpre,4 [pg/mL]

Cpre,ss [pg/mL]

C72,ss [pg/mL]

N 5 4 4 −−− −−− gMean 6400 12900 16700 −−− −−−gCV [%] 73.6 20.4 24.6 −−− −−−Mean 7580 13100 17100 −−− −−−CV [%] 63.8 20.3 24.4 −−− −−−SD 4830 2650 4170 −−− −−−Min 3080 10500 12700 −−− −−−Median 6060 12800 16600 −−− −−−Max 14500 16200 22500 −−− −−−

Individual patient data removed from table −−− no descriptive statistics calculated

c03302860


Page 1440U10-2102-01


Table 15.6.2.1: 11 Indiv. noncomp. PK parameters of Peg−IFN alpha 2a after multiple oral admin. of 240 mg q.d. BI 201335 NA(480 mg at the first dose) with RBV and Peg−IFN alpha 2a in TE patients with descriptive statistics



Cpre,2 [pg/mL]

Cpre,3 [pg/mL]

Cpre,4 [pg/mL]

Cpre,ss [pg/mL]

C72,ss [pg/mL]

N 6 6 6 6 6gMean 12100 15800 18500 19400 26900gCV [%] 40.3 43.5 38.1 66.2 69.5Mean 12900 17000 19600 22300 30800CV [%] 38.3 41.9 35.3 53.9 49.3SD 4940 7130 6910 12000 15200Min 6990 9660 12400 8590 8660Median 11700 15700 19900 21000 27000Max 20300 28200 26700 37600 49400

Individual patient data removed from table

c03302860

Documents

Trial synopsis 1220 DS DR - Boehringer Ingelheim€¦ · [q.d.] and 240 mg q.d.) of 8 patients each. Within each dose group 6 patients received BI 201335 NA and 2 received placebo