Bloom RB. Comprehensive study report, Pravafen, Sciele (now Shionogi Sciele)

Clinical Study Report: Sc-PRAVA-06-02

1 TITLE PAGE

Study Title: A Multi-Center, Prospective, Longitudinal, Randomized, Double-Blind, Phase III Study to Evaluate the Efficacy and Safety of Daily Administration of Pravastatin 40 mg or Fenofibrate 160 mg or Pravafen (combination of Pravastatin and Fenofibrate 40/160 mg) for 12 Weeks, Followed by a 52-Week Open-Label Safety Phase of Pravafen Alone, in the Treatment of Combined Hyperlipidemia.

Protocol Number: Sc-PRAVA-06-02

Study Phase: Phase III

Name of Test Drug/ Investigational Product:

Pravafen

Formulation: Combination of Pravastatin and Fenofibrate 40/160 mg

Indication Studied: Combined hyperlipidemia

Study Design, Comparison, Duration, Dose, and Patient Population:

A Multi-Center, Prospective, Longitudinal, Randomized, Double-Blind, Phase III Study to Evaluate the Efficacy and Safety of Daily Administration of Pravastatin 40 mg or Fenofibrate 160 mg or Pravafen (the combination of Pravastatin and Fenofibrate 40/160 mg) for 12 Weeks, Followed by a 52-Week Open-Label Safety Phase of Pravafen Alone, in the Treatment of Combined Hyperlipidemia.

Patients were 18-75 years of age, inclusive at the time of dosing with a history of a combined hyperlipidemia. (LDL cholesterol 100 mg/dl and/or TG 150 mg/dl and 400 mg/dl at Week-1 / Visit 2 after taking Pravastatin 40 mg/day from Visit 1.)

Study Initiation Date (first patient randomized):

<DD

Study Completion Date (last patient completed):

<DD

Principal or Coordinating Investigator(s):

Multicenter (see Appendix 16.1.4)

Sponsor: Scīele™ Pharma, IncFive Concourse Parkway Suite 1800

Atlanta, Georgia 30328

678-992-1021

Sponsor’s Responsible Medical Officer:

{responsible

Name of Sponsor Signatory: Larry Dillaha, MD

Statement of GCP Compliance:

Date of Report: {final

Confidentiality Statement

The information contained in this document is the property of Scīele™ Pharma, Inc., and is confidential. The document contains trade secrets and commercial information that are privileged or confidential and may not be disclosed unless such disclosure is required by applicable laws and regulations. Persons to whom the information is disclosed must be informed that the information is privileged and confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally to all future information supplied to you, which is identified as privileged or confidential.

2 SYNOPSIS

Name of Sponsor:

Scīele™ Pharma, Inc

Individual Study TableReferring to Partof the Dossier

(For National AuthorityUse only)

Name of Finished Product:Pravafen

Volume:

Name of Active Ingredient:Pravafen (combination of Pravastatin and Fenofibrate 40/160 mg)

Page:

Study Title:A Multi-Center, Prospective, Longitudinal, Randomized, Double-Blind, Phase III Study to Evaluate the Efficacy and Safety of Daily Administration of Pravastatin 40 mg or Fenofibrate 160 mg or Pravafen (combination of Pravastatin and Fenofibrate 40/160 mg) for 12 Weeks, Followed by a 52-Week Open-Label Safety Phase of the Pravafen Alone, in the Treatment of Combined Hyperlipidemia.

Investigators and Study Centers: Multicenter (see Appendix 16.1.4)

Publication (reference): see Appendix 16.1.11

Confidential Page 2 of 151

Studied Period:

<DD (date of first enrollment) <DD (date of last completed)

Phase of Development: Phase III

Objectives: To evaluate the efficacy of administering either Pravastatin 40 mg or Fenofibrate 160 mg or Pravafen (the combination of Pravastatin and Fenofibrate 40/160 mg) daily for 12 weeks, followed by a Pravafen open-label 52-week safety follow-up, in the treatment of combined hyperlipidemia.

Methodology: Double blind, prospective, longitudinal, randomized, 12-week study to evaluate the safety and efficacy of daily administration of Pravastatin 40 mg or Fenofibrate 160 mg or Pravafen (the combination of both Pravastatin and Fenofibrate 40/160 mg) in the treatment of combined hyperlipidemia with a 52-week open-label safety follow-up during which all patients will receive Pravafen (the combination of Pravastatin and Fenofibrate 40/160 mg). Study duration is 72 weeks, divided into an initial 8-week Selection Phase followed by a 12-week Efficacy Phase and ending with a 52-week Safety Phase.

Number of Patients (Planned and Analyzed):400 patients were planned; 475 patients were analyzed for safety; 410 patients were analyzed for efficacy.

Diagnosis and Main Criteria for Inclusion: Selected male or female patients from 18-75 years of age inclusive at the time of dosing, with a history of combined hyperlipidemia: LDL cholesterol 100 mg/dL and/or TG 150 mg/dL and 400 mg/dL at Week-1/Visit 2 after taking Pravastatin 40 mg/day from Visit 1.

Reference Therapy, Dose and Mode of Administration, Batch Number:

Efficacy Phase:

Either Pravastatin 40 mg and Prevafen placebo or Fenofibrate 160 mg and Prevefen placebo or Prevafen (combination of Pravastin/Fenofibrate 40/160 mg) capsules; PO administration (with evening meals)

Safety Phase:

Pravafen (combination of Pravastatin/Fenofibrate 40/160 mg) capsules; P.O. administration (with evening meals)

Duration of Treatment: Following the 8-week Selection Phase, a 12-week Efficacy Phase and a 52-week Safety Phase

Criteria for Evaluation:

Efficacy:The primary efficacy measure is the mean percent change from baseline in plasma non-HDL cholesterol levels at the end of the efficacy period. Secondary efficacy measures include:

Percentage of patients who achieve the therapeutic goals concerning the non-HDL and LDL levels, as defined in the NCEP ATP III


Change from baseline in LDL levels

Change from baseline in: HDL, TG, TC

Change from baseline in ApoA1, ApoB levels

Differences in estimated cardiovascular risk for myocardial infarction (PROCAM risk calculator).

Safety:Safety variables assessed include:

Adverse events, physical examination and laboratory evaluation assessed in all patients included in the study

Events of myopathy and/or rhabdomyolysis

Increase in transaminase levels ( threefold the upper normal limit)

Increase in CPK ( fivefold the upper normal limit)

Increase in creatinine

Withdrawals or drop out rate.

Study Procedures:

Following an open-label, 8-week, Selection Phase prior to randomization in which all patients were stabilized on Pravastatin 40 mg/day, patients who met all inclusion/exclusion criteria were randomized to a three-arm, double blind, 12-week Efficacy Phase during which patients received either Pravastatin 40 mg or Fenofibrate 160 mg alone or Pravafen, a combination of Pravastatin and Fenofibrate 40/160 mg. This 12-week Efficacy Phase was followed by an open-label, 52-week Safety Phase, in which all patients who had completed the Efficacy Phase received Pravafen.

Prior to treatment with any lipid-lowering medication, fasting (8 hours) blood samples were collected from each patient to determine total cholesterol (TC), triglycerides (TG), Low-density Lipoprotein Cholesterol (LDL-C), High-density Lipoprotein Cholesterol (HDL-C), TC/HDL-C, non HDL-C (TC - HDL-C), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine phosphokinase (CK), and thyroid stimulating hormone (TSH). Complete physical examinations were performed at screening, prior to first dosing, at Visit 8 (Week 24), Visit 9 (Week 36), and at the end of the study. Six standard ECGs were performed during the study: at screening, prior to first dosing, at Visit 8 (Week 24) and Visit 9 (Week 36), and at the end of the study.

Each patient was seen at 3-week intervals during the Efficacy Phase of the study and every 12 weeks (16 weeks for last visit) thereafter through the end of the study with the last visit at Week 64. At Visits 3, 5, 7, 8, 9, 10 and 11, blood samples were obtained and patients were carefully questioned concerning adverse effects. Blood sample testing included measurements of liver function, lipids, and lipoproteins [TC, TG, LDL-C, HDL-C (absolute and percentage change), non HDL-C (TC - HDL-C)], AST, ALT, CK, Apolipoprotein A1 and Apolipoprotein B. In addition, blood chemistry, hematology, and urinalysis were done at Visits 1, 7, 8, 9, 10 and Exit Visit (Visit 11). Blood chemistry was done at Visit 5 (Week 6). CRP was done at Visits 3, 7, 8, 9, and Exit Visit (Visit 11). Urine pregnancy test was done at Visits 3, 7, 8, and 9 and at the Exit Visit (Visit 11).


After completing the 12-week Efficacy Phase, all patients (except those with an AE that precluded them from further participation) were rolled into the 52-week Safety Phase, during which the overall safety of patients receiving Pravafen was assessed.

Statistical Methods: Primary efficacy analysis compared the percent changes in non-HDL cholesterol levels at 12 weeks among the three treatment groups using analysis of covariance (ANCOVA). Site, treatment group, and relationship between site and treatment group were analyzed, with baseline non-HDL cholesterol the covariate term. Treatment groups were compared (Pravastatin/Fenofibrate versus Pravastatin alone and Pravastatin/Fenofibrate versus Fenofibrate alone) using one-sided tests that were considered statistically significant when the p-value was less than 0.025--the Bonferroni adjusted level of significance. (If the distribution of this data was non-Gaussian, a transformation was performed to obtain normalized data or, if necessary, the appropriate non-parametric test was used.)

Secondary efficacy analysis compared all other lipidemic parameters at 12 weeks of the three treatment groups by analysis of covariance, using the same statistical model as for the primary efficacy analysis. Secondary parameters were compared using one-sided tests at a 0.05 significance level. (If the distribution of this data was non-Gaussian, a transformation was performed to obtain normalized data or, if necessary, a non-parametric test was used.) Repeat analysis was performed at 12 weeks for 10-year CHD risk.

The percentages of the three treatment groups who achieved therapeutic goals at the end of the efficacy period (non-HDL cholesterol < 130 mg/dL, LDL < 100 mg/dL as defined in the NCEP ATP III) were analyzed by chi-square test. (Chi-square test was replaced by Fisher’s exact test if the expected frequency in any of the cells of the contingency table was less than 5.)

Efficacy:The primary efficacy endpoint was defined as the mean percent change from baseline in non-HDL cholesterol level for patients receiving Pravafen (combination of Pravastatin/Fenofibrate) 40/160 mg versus patients receiving either Pravastatin 40 mg or Fenofibrate 160 mg alone at the end of the 12-week efficacy period.

Secondary efficacy endpoints are:

Mean percent changes of the LDL cholesterol levels at the end of the efficacy period compared to baseline

Percentage of patients who achieved therapeutic goals for levels of non-HDL and LDL at the end of the efficacy period as defined in the NCEP ATP III

Mean percent changes of the following other lipidemic parameter levels at the end of the efficacy period compared to baseline: HDL, triglycerides (TG), total cholesterol (CT), ApoA1, ApoB

Absolute changes in estimated 10-year Cardiovascular Heart Disease (CHD) risk (PROCAM risk calculator) at the end of the efficacy period compared to baseline.

Safety:


Safety parameters were evaluated during two different phases:

The safety profiles of the three treatment groups were compared during the 12-week Efficacy Phase

The safety profile of the group taking the combination alone was described during the 52-week Safety Phase.

The safety parameters analyzed were:

Adverse events (AEs), laboratory evaluation, vital signs, and physical examination were assessed in all patients who received at least one dose of active study medication (Pravastatin, Fenofibrate and/or Pravafen)

Increase of transaminase levels (>3 times of the upper normal limit) during the treatment period (SGOT/ASAT and SGPT/ALAT)

Appearance of myopathy and/or rhabdomyolysis during the treatment period

Increase of creatine phosphokinase (CPK) levels ( fivefold the upper normal limit) during the treatment period

Decrease of GFR levels (< 60 mL/min) during the treatment period

Presence of signs/symptoms of gallbladder disease (i.e., abdominal fullness, abdominal pain that is severe, located on the right upper quadrant or over the epigastrium, occurring mostly after meals, worsening during deep intake of breath, radiating to back or below the right shoulder blade, worse after eating fatty foods; fever, nausea, vomiting, heartburn, chest pain under the breastbone, etc.)

Decrease in the GFR ≤ 60 mL/min/1.73 m2

Drop out rate due to adverse events.

Efficacy Results:

During the Efficacy Phase of the study, the Pravafen group showed greater decreases in non-HDL cholesterol from baseline (-7.6%) than either the Pravastatin alone or Fenofibrate alone groups (p<0.001).

Total cholesterol (TC) was also reduced more effectively by the Pravafen combination therapy (-5.6%) than by Pravastatin or Fenofibrate alone (p<0.001).

While Fenofibrate raised HDL cholesterol more effectively than the other two regimens (+2.4%)(p=0.032),

The combination Pravafen therapy reduced triglycerides (TG) more dramatically that either of the monotherapies (-19.5% vs. -13.8% and +12.9%; p<0.001).

Higher percentages of patients achieved their therapeutic goals of lowering non-HDL (37.9%)(p<0.001) and LDL cholesterol (19.8%)(p=0.025) while taking the combination Pravafen therapy than while taking either Pravastatin alone (18.7% and 14.0%) or Fenofibrate alone (12.1% and 4.3%). Nearly twice the percentage of patients


achieved both therapeutic goals on Pravafen (19.4%) as on Pravastatin alone (10.3%) or Fenofibrate alone (4.3%)(P=0.002).

Fenofibrate caused LDL cholesterol to increase an average of 17.6% during the Efficacy Phase (p<0.001), while no statistically significant changes in LDL cholesterol were observed in either the Pravafen or Pravastatin groups.

Similarly, Apolipoprotein A1 (ApoA1) was seen to rise significantly in the Fenofibrate group (+6.4%)(P<0.001) despite the absence of significant changes in ApoA1 in either of the other groups. On the other hand, Apolipoprotein B declined an average of 11.5% in the group on Pravafen, compared to smaller declines in the Pravastatin (-4.0%) and Fenofibrate (-0.6%) groups (P<0.001).

No statistically significant declines in 10-year CHD risk were observed in the Pravafen and Pravastatin groups; a small but significant increase in 10-year risk was observed in the group taking Fenofibrate alone (p=0.017).

Safety Phase:

Safety Results:

Efficacy Phase:

Forty-one patients (8.6% of 475 patients monitored for safety) suffered adverse AE, significant but for the most part not serious, that nevertheless led to their withdrawal from participation in the study. A summary of these events and the circumstances surrounding them is presented in Appendix 16.2.7.3.

Muscle-related disorders--myalgias, muscle spasms, and extremity pain--make up the largest category (24.4%) of patients experiencing discontinuation-causing AE during the study. The study drug was thought to have caused the extremity pain of all 4 patients with this symptom, and all but one recovered after being withdrawn from the study. Myalgias were also attributed to the study drug; two of the three patients suffering from study-related muscle pain recovered after being withdrawn from participation and the circumstances of the third are unknown. Finally, the muscle spasms of 2 of the 3 patients suffering these AE were attributed to the study medication, and discontinuation of that medication resolved these symptoms. The third’s symptoms were thought to have resolved after discontinuation of the study drug.

With a likely etiological relation to these muscle complaints were increases in creatine kinase levels in 4 patients (9.8%). In 3 of these 4, the study drug was thought to be the cause of the symptom. Two of these patients recovered after their study medication was discontinued, another’s high CK levels persist, and a fourth’s circumstances are presently unknown.

Eight (19.5%) of these patients experienced slowing of their glomerular filtration


rate early in the course of their treatment with the study medication. All but one of these patients suffered this condition during their first few days of treatment with the study drug and withdrew from the study. The other delayed his symptoms until the 32nd day of treatment and similarly withdrew from study participation. The study drug was thought to be of doubtful or no relation to the symptom in 5 of the 8 cases and to have either possibly or definitely caused the symptom in the other 3. Two patients for whom it was thought the study drug probably did not cause the adverse event have recovered; in the other 6 the AE persists.

Six patients (14.6%) suffered gastrointestinal side effects during the study--nausea, vomiting, and/or dyspepsia--and withdrew from participation. The symptoms of four were thought to be the result of administration of the study drug, and those of the other two probably unrelated. All but the lone dyspepsia patient recovered.

The remaining AE study patients (36.5%) suffered from an assortment of ailments, including 2 with arthralgias, 2 with increases in glomerular filtration rate, and 1 each with fatigue, dizziness, night sweats, decreased libido, sinusitus, bradycardia, biliary dyskinesia, influenza, Eustacian tube dysfunction, asthenia, increases in alanine and aspartate aminotransferases, abnormal glucose tolerance test, hypokalemia, hyponatremia, and diarrhea. Most of these were thought caused by the study medication and resolved following its discontinuation. The cases of increases in glomerular filtration rate, bradycardia, and hepatic dyskinesia persist as of last report.

Safety Phase:

CONCLUSIONS

Efficacy Conclusions:

Statins and certain fibrates, such as Fenofibrate, act on different metabolic pathways and therefore work synergistically. Statins reduce serum levels of total and low-density lipoprotein cholesterol, while fibrates reduce triglycerides, raise low levels of high-density lipoprotein cholesterol, and reduce overall risk of cardiovascular morbidity and mortality. In particuclar, Pravastatin (PRAVACHOL, Bristol-Meyers Squibb) and Fenofibrate have been shown to be effective against hyperlipidemia without interacting with each other to increase risk of adverse effects. Patients are far more likely to meet with success in attaining dual therapeutic goals of reducing low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol on combination Pravastatin-Fenofibrate therapy than while taking either Pravastatin or Fenofibrate alone. Therapeutic use of Pravafen (combination Pravastatin/Fenofibrate 40/160mg) in the treatment of mixed hyperlipidemia is therefore recommended.

Safety Conclusions:

Caution should prevail when combination statin-fibrate therapy is administered concomitantly with other medications and when predisposing conditions, such as diabetes mellitus, renal insufficiency, and hypothyroidism are present or suspected. Dosages should


be adjusted to reflect these conditions. Other lipid-lowering medications must be discontinued when statin-fibrate combinations are administered.

Nevertheless, this particular combination of Pravastatin and Fenofibrate, present in Pravafen (combination Pravastatin/Fenofibrate 40/160mg), offers so many therapeutic advantages, with only slight chances for usually reversible adverse side effects, that it must be considered the preferred therapeutic alternative for hyperlipidemia in the majority of clinical circumstances.

Final Report Date: 1 August 2008

Prepared in: Microsoft Word version Office 2000


3 TABLE OF CONTENTS FOR THE INDIVIDUAL CLINICAL STUDY REPORT

1 TITLE PAGE.................................................................................................................1

2 SYNOPSIS.....................................................................................................................2

3 TABLE OF CONTENTS FOR THE INDIVIDUAL CLINICAL STUDY REPORT. .8

LIST OF IN-TEXT TABLES............................................................................................12

LIST OF IN-TEXT FIGURES..........................................................................................12

LIST OF APPENDICES....................................................................................................12

4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..............................13

5 ETHICS........................................................................................................................16

5.1 Independent Ethics Committee (IEC) or Institutional Review Board (IRB)......16

5.2 Ethical Conduct of the Study..............................................................................16

5.3 Patient Information and Consent........................................................................17

6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE..................18

6.1 Coordinating Investigators..................................................................................18

6.2 Sponsor...............................................................................................................18

6.3 Contract Research Organization (CRO).............................................................18

6.4 Central Laboratories............................................................................................18

7 INTRODUCTION.......................................................................................................19

8 STUDY OBJECTIVES................................................................................................23

8.1 Primary Objective(s)...........................................................................................23

8.2 Secondary Objective(s).......................................................................................23

9 INVESTIGATIONAL PLAN......................................................................................24

9.1 Overall Study Design and Plan: Description......................................................24

9.2 Discussion of Study Design Including the Choice of Control Groups...............27

9.3 Selection of Study Population.............................................................................27

9.3.1 Inclusion Criteria.......................................................................................28

9.3.2 Exclusion Criteria......................................................................................28

9.3.3 Removal of Patients from Therapy or Study Treatment Discontinuation. 30

9.4 Treatments...........................................................................................................30

9.4.1 Treatments Administered...........................................................................30

9.4.2 Identity of Investigational Product(s)........................................................30

9.4.2.1 Selection Phase.................................................................................31

9.4.2.2 Efficacy Phase...................................................................................31

9.4.2.3 Safety Phase......................................................................................31

9.4.2.4 Available study treatments at the study centersError! Bookmark not defined.

9.4.3 Method of Assigning Patients to Treatment Groups..................................31


9.4.4 Selection of Doses in the Study.................................................................31

9.4.5 Selection and Timing of Dose for Each Patient.........................................32

9.4.6 Blinding Procedures...................................................................................32

9.4.7 Prior and Concomitant Therapy.................................................................32

9.4.7.1 Inhibited concomitant therapy..........................................................32

9.4.7.2 Permitted concomitant therapy under certain conditions..................33

9.4.8 Treatment Compliance...............................................................................33

9.5 Efficacy and Safety Variables.............................................................................33

9.5.1 Definition and Timing of Efficacy and Safety Assessments.....................33

9.5.1.1 Efficacy Measurements.....................................................................34

9.5.1.2 Safety Measurements........................................................................34

9.5.1.3 Schedule of Events............................................................................37

9.5.2 Appropriateness of Measurements.............................................................41

9.5.3 Efficacy Variable(s)...................................................................................41

9.5.3.1 Primary Efficacy Variable(s)............................................................41

9.5.4 Drug Concentration Measurements............Error! Bookmark not defined.

9.6 Data Quality Assurance......................................................................................41

9.6.1 Study Administration and Conduct............................................................41

9.6.2 Data Generation and Analysis...................................................................41

9.7 Statistical Methods Planned in the Protocol and Determination of Sample Size42

9.7.1 Statistical and Analytical Plans..................................................................42

9.7.1.1 General Methodology.......................................................................42

9.7.1.2 Description of the populations analyzed...........................................43

9.7.1.3 Statistical Analysis Methods.............................................................44

9.7.2 Determination of Sample Size...................................................................45

9.8 Changes in the Conduct of the Study or Planned Analyses................................46

9.8.1 Changes in the Conduct of the Study.........................................................46

9.8.2 Changes in the Planned Analyses..............................................................46

9.8.3 Changes to the Analyses, Made After the Database Lock.........................46

10 STUDY PATIENTS..................................................................................................47

10.1 Disposition of Patients......................................................................................47

10.1.1 Description of the Populations Analyses during the Efficacy Phase.......49

10.1.1.1 Safety Population (Efficacy Phase)................................................49

10.1.1.2 Intent-to-Treat Population (ITT) (Efficacy Phase).........................49

10.1.1.3 Per Protocol Population (PP) Efficacy Phase)................................49

10.1.2 Description of the Populations Analyses during the Safety Phase..........49

10.1.2.1 Intent-to-Treat Population (ITT) (Efficacy Phase).............................

10.1.2.2 Per Protocol Population (PP) Efficacy Phase)....................................


10.1.3 Withdrawals from Study during the Efficacy Phase................................49

10.1.4 Withdrawals from Study during the Safety Phase...................................49

10.2 Protocol Deviations...........................................................................................49

10.2.1 Protocol Violations met at Inclusion and during the Efficacy Phase.......49

10.2.2 Protocol Violations met during the Safety Phase....................................53

11 EFFICACY EVALUATION.....................................................................................53

11.1 Data Sets Analyzed...........................................................................................53

11.2 Demographic and Other Baseline Characteristics............................................54

11.2.1 Demographics..........................................................................................54

11.2.2 Contraception Data (females only)..........................................................57

11.2.3 Medical History and Surgical History (other than combined hyperlipidemia)......................................................................................57

11.2.4 Combined hyperlipidemia........................................................................57

11.2.5 Cardiovascular risk factors......................................................................57

11.2.6 Physical Examination...............................................................................57

11.2.7 Vital Signs................................................................................................57

11.2.8 Laboratory Parameters at Baseline..........................................................58

11.2.9 Prior and Concomitant Medications........................................................58

11.2.9.1 Prior and Concomitant Medications during the Selection Phase....58

11.2.9.2 Concomitant Medications during the Efficacy Phase.....................59

11.2.9.3 Concomitant Medications during the Safety Phase........................60

11.3 Measurements of Treatment Compliance.........................................................60

11.4 Efficacy Results and Tabulations of Individual Patient Data...........................61

11.4.1 Analysis of Efficacy.................................................................................61

11.4.1.1 Primary Efficacy Endpoint.............................................................61

11.4.1.2 Secondary Efficacy Endpoint.........................................................63

11.4.2 Statistical/Analytical Issues.....................................................................83

11.4.2.1 Adjustments for Covariates.............................................................83

11.4.2.2 Handling of Dropouts or Missing Data...........................................83

11.4.2.3 Interim Analyses and Data Monitoring...........................................83

11.4.2.4 Multicenter Studies.........................................................................83

11.4.2.5 Multiple Comparisons/Multiplicity................................................83

11.4.2.6 Use of an "Efficacy Subset" of Patients..........................................83

11.4.2.7 Active-Control Studies Intended to Show Equivalence..................84

11.4.2.8 Examination of Subgroups..............................................................84

11.4.3 Tabulation of Individual Response Data..................................................84

11.4.4 Drug Dose, Drug Concentration, and Relationships to Response...........84

11.4.5 Drug-Drug and Drug-Disease Interactions..............................................84


11.4.6 By-Patient Displays.................................................................................84

11.4.7 Efficacy Conclusions...............................................................................84

12 SAFETY EVALUATION.........................................................................................85

12.1 Extent of Exposure............................................................................................85

12.2 Adverse Events.................................................................................................85

12.2.1 Brief Summary of Adverse Events..........................................................85

12.2.1.1 Adverse Events Occurring the 8-week Selection Period................85

12.2.1.2 Adverse Events Occuring during the 12-week Efficacy Phase......85

12.2.1.3 Adverse Events Occuring during the 24/52-week Safety Phase ....87

12.2.1.4 Adverse Events not taken into account in the Safety Analysis.......87

12.2.2 Display of Adverse Events.......................................................................87

12.2.3 Analysis of Adverse Events.....................................................................89

12.2.3.1 Display of Adverse Events During the 8-week Selection Phase....89

12.2.3.2 Display of Adverse Events During the 12-week Efficacy Phase....97

12.2.3.3 Display of Adverse Events During the 24/52-week Safety Phase107

12.2.3.3.1 Display of All Adverse Events during the 24/52-week Efficacy Phase..........................................................................................107

12.2.3.3.2 Display of Adverse Events Related to the Study Treatment during the 24/52-week Efficacy Phase..................................................107

12.2.3.3.3 Display of Adverse Events Occurring During the 24/52-week Efficacy Phase Leading to Treatment Discontinuation.............107

12.2.4 Listing of Adverse Events by Patient.....................................................107

12.3 Deaths, Other Serious Adverse Events, and Other Significant Adverse Events107

12.3.3 Listing of Deaths, Other Serious Adverse Events, and Other Significant Adverse Events....................................................................................107

12.3.3.3 Deaths...........................................................................................107

12.3.3.4 Other Serious Adverse Events......................................................107

12.3.3.5 Other Significant Adverse Events.................................................107

12.3.4 Narratives of Deaths, Other Serious Adverse Events, and Certain Other Significant Adverse Events..................................................................110

12.3.5 Analysis and Discussion of Deaths, Other Serious Adverse Events, and Other Significant Adverse Events........................................................111

12.3.4 Other Significant Adverse Events............Error! Bookmark not defined.

12.4 Clinical Laboratory Evaluation.......................................................................111

12.4.1 Listing of Individual Laboratory Measurements by Patient (Appendix 16.2.8) and Each Abnormal Laboratory Value (see section 14.3.4)....111

12.4.2 Evaluation of Each Laboratory Parameter................................................111

12.4.2.1 Laboratory Values Over Time.........................................................112

12.4.2.2 Individual Patient Changes.............Error! Bookmark not defined.


12.4.2.3 Individual Clinically Significant AbnormalitiesError! Bookmark not defined.

12.5 Vital Signs, Physical Findings, and Other Observations Related to Safety....112

12.5.1 Vital Signs..............................................................................................112

12.5.2 Physical Examinations..........................................................................112

12.6 Safety Conclusions..........................................................................................113

13 DISCUSSION AND OVERALL CONCLUSIONS................................................114

13.3 Discussion.......................................................................................................114

13.4 Conclusions.....................................................................................................115

13.4.4 Efficacy Conclusions.............................................................................115

13.4.5 Safety Conclusions.................................................................................116

14 TABLES, FIGURES, AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE TEXT...............................................................................................................117

15 REFERENCE LIST.................................................................................................126

16 Appendices...............................................................................................................128

LIST OF IN-TEXT TABLES

Table 1. Schedule of Events...............................................................................................39Table 2. Summary of Patient Disposition .........................Error! Bookmark not defined.

LIST OF IN-TEXT FIGURES

Figure 1. Guidelines for Safety in Laboratory ValuesFigure 2. Protocol Deviations During the Efficacy PhaseFigure 3. Patient DemographicsFigure 4. Percent Change during Efficacy Phase: Non-HDL cholesterol by TreatmentFigure 5. Percent Change during Efficacy Phase: LDL cholesterol by TreatmentFigure 6. Percent Change during Efficacy Phase: HDL cholesterol by TreatmentFigure 7. Percent Change during Efficacy Phase: Triglycerides by TreatmentFigure 8. Percent Change during Efficacy Phase: Total cholesterol by TreatmentFigure 9. Percent Change during Efficacy Phase: Apolipoprotein A1 by TreatmentFigure 10. Percent Change during Efficacy Phase: Apolipoprotein B by TreatmentFigure 11. Percent Change during Efficacy Phase: Achievement of Therapeutic Goals Figure 12. Percent Change during Efficacy Phase: 10-Year CHD Risk by TreatmentFigure 13. Summary of Treatment-Emergent Adverse Events During the Efficacy PhaseFigure 14. Listing of All Serious Adverse EventsFigure 15. Listing of All Adverse Events Causing Patient DiscontinuationFigure 16. Summary of Data on Patient Systolic Blood PressureFigure 17. Summary of Data on Patient Diastolic Blood PressureFigure 18. Summary of Data on Patient Heart RateFigure 19. Summary of All Vital SignsFigure 20. Shift Tables for ECG Parameters



4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS

AE Adverse Event

ALT Alanine Aminotransferase

ANCOVA Covariance Analysis

ApoA1 Apolipoprotein A1

ApoB Apolipoprotein B

AST Aspartate Aminotransferase

Beta-HCG Human Chorionic Gonadotropin

BMI Body Mass Index

BUN Blood Urea Nitrogen

CBC Complete Blood Count with Differential and Platelet Count

CFR Code of Federal Regulations

CHD Cardiovascular Heart Disease

CI Confidence interval

CLAM Cholesterol Lowering Agent Myopathy

CPK Creatine Phosphokinase

CRF Case report form

CRO Clinical Contract Organization

CRP C-Reactive Protein

CS Clinically Significant

CVD Cardiovascular Disease

DBP Diastolic Blood Pressure

DSM-IV Diagnostic and Statistical Manual, IV Edition

ECG Electrocardiogram

FDA Food and Drug Administration

GCP Good Clinical Practice

GFR Glomerular filtration rate

Hb Hemoglobin

HbA1c Hemoglobin A1c test

Hct Hematocrit


HDL High-density lipoprotein

HDL-C High-density lipoprotein cholesterol

HIPAA Health Information Portability and Accountability Act

HMG-CoA Beta-hydroxy-beta-methy glutarul-coenzyme A

HR Heart rate

IB Investigator’s Brochure

ICH International Conference on Harmonisation

IEC Independent Ethics Committee

IND Investigational New Drug Application

IRB Institutional Review Board

ITT Intent-to-treat

IUD Intra-uterine device

LDL Low-density lipoprotein

LDL-C Low-density lipoprotein cholesterol

LOCF Last Observation Carried Forward

MedDRA Medical Dictionary for Regulatory Activities

mg Milligram

MI Myocardial Infarction

N Observation count

NCEP ATP III National Cholesterol Education Program Adult Treatment Panel III

NCS Not Clinically Significant

NDA New Drug Application

PE Physical Exam

PI Principal Investigator

PHI Protected Health Information

PP Per Protocol

RBC Red blood cells

SAE Serious Adverse Event

SBP Systolic Blood Pressure


SD Standard deviation

SGOT/ASAT Serum glutamate oxaloacetate transaminase

SGPT/ALAT Serum glutamate pyruvate transiminase

SOP Standard Operating Procedures

TC Total Cholesterol

TG Triglyceride

TSH Thyoid-Stimulating Hormone

μg Microgram

UNL Unit Normal Limit

US United States

VLDL Very low density lipoprotein

WBC White Blood Cells

WHO World Health Organization


5 ETHICS

5.1 Independent Ethics Committee (IEC) or Institutional Review Board (IRB)

The protocol and informed consent form for this study were reviewed and approved by a duly constituted central institutional review board (IRB) before patients were screened for entry. The Sponsor ensured that all aspects of the IRB review were conducted in accordance with current institutional, local, and national regulations. The Sponsor submitted all periodic reports and updates that the IRB required, including any final closeout reports. The Sponsor informed the IRB of any reportable adverse events as required by local regulations.

This study was conducted in accordance with the IRB-approved protocol, the International Conference on Harmonization Consolidated Guideline for Good Clinical Practice, IRB regulations, applicable regulatory requirements, the Sponsor’s standard operating procedures (SOPs), and ethical principles for the protection of human research in patients that have their origins in the Declaration of Helsinki (1964).

All IRB/IEC information is provided in Appendix 16.1.3

5.2 Ethical Conduct of the Study

Prior to the start of the study, the protocol, amendment(s), consent form(s), information sheet (if applicable), any patient advertisements (if applicable), and the Investigator Brochure were submitted to the IRB that provides ethical review for each participating institution, and a copy of the written IRB approval was provided to Scīele™ or designee. The approval referred to the study by date and protocol number/title and provided details of the documents reviewed by the IRB. The Investigator submitted to Scīele™ or designee a list of the IRB members (or IRB assurance number), including their titles or occupations and their institutional affiliations.

During the course of the study, the Investigator was obligated to submit to the IRB the following documents, depending on the requirements of each IRB: amendments to the protocol, new advertisements, serious and unexpected adverse events, site-specific updates as agreed to by the Investigator and respective IRB, and any additional information (e.g., unexpected serious adverse events reported by other investigative sites, amendments to the Investigator Brochure, and administrative changes to the protocol) requested by Scīele™ or designee.

At the end of the study, the Investigator was obligated to inform the IRB in writing that the study has ended and no further activities regarding this protocol will be conducted at the site. A copy of this letter was provided to Scīele™ or designee.

The Investigator was to perform the above responsibilities in accordance with 21-CFR Part 56.


5.3 Patient Information and Consent

The Investigator had both the ethical and legal responsibility for obtaining informed consent from each patient in accordance with Good Clinical Practice (GCP) Guidelines, Section 4, May 1997, the current version of the Declaration of Helsinki (Amended 48 th General Assembly, Somerset West, Republic of South Africa, October 1996), and the U.S. Food and Drug Administration (FDA) Regulations Title 21 Code of Federal Regulations (CFR) Parts 50.20–50.27.

Patients had the study explained to them (in writing and verbally), including the known side effects of Pravastatin, Fenofibrate, and Pravafen, and the risks associated with participating in the trial. The patients were advised that they were free to withdraw from the study at any time and for any reason without prejudice to their future care.

After being fully informed of the implications and constraints of the protocol, the patient gave his or her consent in writing. The Investigator or study staff conducting the informed consent discussion also signed the document. The study monitor reviewed the signed forms during site visits. Each patient was given a copy of the signed consent form.

A sample of the master informed consent and samples of informed consents used by Investigators who did not use the master template, and any other study documents provided to the patients are provided in Appendix 16.1.3.2 and Appendix 16.1.3.3.


6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE

6.1 Coordinating Investigators

A list of all Investigators and associated curricula vitae are provided in Appendix 16.1.4.

The signature(s) of the person(s) responsible for confirming the accuracy of this study report is/are provided in Appendix 16.1.5.

6.2 Sponsor

The sponsor of the study was Scīele™ Pharma, Inc.

6.3 Contract Research Organization (CRO)

Integrium LLC was contracted to assist Scīele with the conduct, analysis and oversight of the study.

6.4 Central Laboratories


7 INTRODUCTION

Background

Cardiovascular disease--CVD (cardiovascular disease, stroke, high blood pressure, heart failure and congenital cardiovascular defects)--is the leading cause of death for American men and women (36.3% of deaths in 2004, the most recent data available). Clinical trial data have demonstrated that lipid-lowering therapy consistently reduces cardiovascular events and overall mortality in those with, and at risk of, cardiovascular heart disease. Although statins may be the class of choice for many patients, some patients cannot be managed with statins alone; some perhaps not at all. Many patients require a combination of classes or a different class entirely.

Early measurement of lipoproteins in community-based studies such as the Framingham Study and the Lipid Research Clinics Cardiovascular Primary Prevention Trial provided prevalence and incidence data about various manifestations of CVD, which were then linked to lipoproteins. [1,2] Elevated low-density lipoprotein cholesterol (LDL-C) concentration was a demonstrable risk factor that appeared to explain most of the association of cardiovascular risk with total plasma cholesterol level. In strong contrast, elevated high-density lipoprotein cholesterol (HDL-C) levels predicted reduced risk and have come to be regarded as a protective factor.

Combined hyperlipidemia is characterized by a combination of either elevated total cholesterol and triglyceride levels or elevation of LDL cholesteral and triglyceride levels. Prevalence of combined hyperlipidemia varies between 10 and 25% [9] and is a contributory factor in the pathogenesis of atherosclerosis.

Among the most notable risk factors for development of atherosclerotic cardiovascular disease are elevated levels of LDL cholesterol and reduced levels of HDL cholesterol. Although the relationship is not as strong, hypertriglyceridemia is also associated with an increased risk of atherosclerotic disease.

Rationale

The two main classes of lipid-lowering agents are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors ("statins") and fibric acid derivatives (“fibrates”). Their effects on these lipid parameters are complementary and provide a rationale for the use of the two drug classes together. [9]

Fenofibrate is an advanced-generation fibric acid derivative that was first used for treatment of dyslipidemia in 1975. Its tolerability and efficacy have been established in clinical trials, as described in more than 260 peer-reviewed publications. Marketed in 78 countries, Fenofibrate became available in the United States in 1998.

In the United States, Fenofibrate is indicated as an adjunct to diet modification for adults with serum triglyceride levels greater than 2,000 mg/dL--specifically, Fredrickson types IV


and V hyperlipidemia patients, whose disease is insufficiently controlled by diet and who are thus at risk for pancreatitis. (Outside the United States, Fenofibrate is indicated for the treatment of Frederickson types II-a and II-b [mixed dyslipidemia] as well as types IV and V.) However, because most researchers regard serum triglyceride levels greater than 250-300 mg/dL as indicative of type IV hyperlipidemia, the National Cholesterol Education Program (NCEP) recommends reducing triglyerides to less than 200 mg/dL. [3]

Fenofibric acid, the active metabolite of Fenofibrate, has a powerful effect on triglycerides as well as HDL-C and is believed to lower plasma triglycerides by (a) inhibiting triglyceride synthesis, which lessens the amount of VLDL released into circulation, and (b) stimulating the catabolism of triglyceride-rich lipoproteins, which changes the composition of LDL-C from small, dense, atherogenic particles to larger, more buoyant, less atherogenic ones, lessening the CVD risk associated with LDL-C. In the St. Thomas Atherosclerosis Regression Study (STARS), the presence of small, dense LDL-C particles was the best predictor of CVD risk evident on arteriography. [4]

Published reports suggest that Fenofibrate is more easily tolerated and more effective than fibrates introduced earlier. Reductions in LDL-C levels of 20% to 25% have been seen in patients receiving Fenofibrates, with triglycerides reduced up to 60% and HDL-C increased up to 23%. [5-7] Effects were most pronounced in patients with the highest baseline triglyceride levels.

The introduction of statins in the early 1990s enabled researchers to answer important questions about the long-term efficacy and safety of LDL reduction. The Scandinavian Simvastatin Survival Study (4S) [3] proved that significant declines in total mortality were achieved through a reduction in LDL-C levels among persons previously recognized as being at high risk because they had cardiovascular heart disease (CHD). After 5 years, cardiovascular death was reduced by 42% and total mortality by 30% among patients in that study. The West of Scotland Cardiovascular Prevention Study [5] (WOSCOPS) found that when a reduction in LDL-C was brought about by Pravastatin use, myocardial infarction (MI) or cardiovascular death was significantly reduced in hypercholesterolemic men, even if they did not have signs of previous MI. Finally, the Cholesterol and Recurrent Events (CARE) trial [8] demonstrated that even in patients with proven MI but only average LDL-C levels, the reduction of LDL-C to average values achieved with Pravastatin produced a reduction in recurrent MI and cardiovascular death over 5 years. These studies and others substantiated the efficacy of pharmacological intervention in controlling hypercholesterolemia when patients are unable to achieve control through changes in lifestyle and diet.

As an example of a study comparing the effects of combining statins and fibrates on lipid parameters, Ducobu [10] demonstrated that micronized fenofibrate lowers total cholesterol and low-density lipoprotein cholesterol to an extent similar to Pravastatin but raises high-density lipoprotein cholesterol and lowers triglycerides to a greater extent. This study compared the efficacy of 3 months' treatment with micronized Fenofibrate (200 mg once daily) or Pravastatin (20 mg once daily) in hypercholesterolemic type IIA and mixed dyslipidemic type IIB patients. Two hundred sixty-five male and female patients (18-75 years) were recruited from 28 European centers and 151 were analyzed. Micronized Fenofibrate was at


least as effective as Pravastatin in reducing levels of LDL-C and total cholesterol in primary dyslipidemia and was significantly more effective than Pravastatin in raising high-density lipoprotein cholesterol (respectively, 13.2% vs. 5.6%; p = 0.0084) and lowering triglycerides (-38.7% vs. -11.8%; p = 0.0001).

Melenovsky [11] compared the effects of atorvastatin and fenofibrate on nonlipidaemic biochemical risk factors and low-density lipoprotein (LDL) particle size in subjects with CHD and found that atorvastatin alone increased fibrinogen by 17.4% and fenofibrate alone reduced C-reactive protein by 51.7%. Steinmetz [12] compared 133 type IIA and IIB hyperlipidaemic patients in a multicenter, parallel group study. His subjects were treated with either fenofibrate (200 mg/day) or simvastin (20 mg/day) for 12 weeks. Improvements in the ratios of total cholesterol to HDL cholesterol and to Apolipoprotein A1 were similar for both groups. However, only Fenofibrate also brought about decreases in fibrinogen and uric acid levels. These findings were similar to those of Farnier, [8] who found that Fenofibrate has a broader spectrum of activity than simvastatin.

A study by Isabelle Lemieux [13] compared the effects of 16-week pharmacotherapy among patients with type IIA dyslipidemia with Fenofibrate (200 mg) or Pravastatin (initially 20 mg for 8-weeks and, if necessary, increased to 40 mg) alone on LDL particle size, as assessed by gradient gel electrophoresis. For that purpose, type IIA dyslipidemic patients (cholesterol, 7.45 ± 1.18 (S.D.) mmol/l; LDL cholesterol, 5.57 ± 1.16 mmol/L; triglycerides (TG), 1.66 ± 0.43 mmol/L) were randomized to either Fenofibrate (n = 36) or Pravastatin (n = 43) therapy for 16 weeks. As Pravastatin treatment had no effect on LDL particle size, Lemieux suggested that Fenofibrate may reduce the risk of cardiovascular heart disease (CHD) beyond what can be expected from Pravastatin’s reduction of LDL cholesterol concentration by increasing LDL particle size in type IIA dyslipidemic patients.

Combining these two agents, Fenofibrate and Pravastatin, may therefore induce greater decreases in LDL cholesterol levels than either monotherapy, and improve other lipid parameters (TG, HDL), in particular on patients at high cardiovascular risk with combined hyperlipidemia.

Some trials were designed to assess the efficacy and safety of a combination statin-fibrate. As an example, the study of Farnier and Dejager [14] compared the efficacy and safety of the fluvastatin-Fenofibrate combination therapy with Fenofibrate monotherapy in severe primary hypercholesterolemia. The authors concluded that the addition of fluvastatin to micronized Fenofibrate results in substantial improvement in atherogenic plasma lipids and is well tolerated.

Ellen and Mc Pherson [15] also demonstrated that combination treatment with fenofibrate and low-dose pravastatin is generally safe and effective for the treatment of combined hyperlipidemia in patients with normal hepatic and renal function.

Athyros [16] investigated the safety and efficacy of combined Pravastatin or simvastatin with fibrates gemfibrozil or ciprofibrate on total cholesterol, LDL, TG, plasma fibrinogen, and Apolipoproteins B and A1 in patients with refractory familial combined hyperlipidemia, with or without cardiovascular artery disease. His data suggests that the statin-fibrate combinations used in the study are safe and have a favorable impact on all major cardiovascular artery disease risk factors in patients with refractory familial combined hyperlipidemia, with or without cardiovascular artery disease.


Iliadis and Rosenson [17] demonstrated also that Pravastatin and gemfibrozil therapy is safe and effective in patients with mixed hyperlipidemia. But some restrictions in the use of combination statin-fibrate therapies have arisen since the early 1990s, following reports of associated severe adverse effects, especially myopathy and rhabdomyolysis. The withdrawal from use of cerivastatin in 2001 intensified the debate over combination statin-fibrate therapy.

Pravastatin is generally well tolerated, and in three large placebo-controlled trials (WOS, CARE, LIPID) involving a total of 19768 patients treated with pravastatin sodium or placebo, the safety and tolerability profile of the pravastatin group was comparable to that of the placebo group over a median 4.8 to 5.9 years of follow-up. In these long-term trials, the most common reasons for discontinuation were mild, non-specific gastrointestinal complaints.

Fenofibrate has been studied since the mid-1970s. It has broad-spectrum utility, with documented efficacy in Fredrickson types IIA, IIB, III, IV, and V hyperlipidemias. It is well tolerated, with digestive and musculoskeletal side effects similar to those of other fibrates.

Pharmacodynamically, there is an increased risk of myopathy when statins are co-administrated with fibrates, most prevalent when cerivastatin is combined with gemfibrozil.

A pilot, crossover study (FENOPRAVA-SD021) was performed by Galephar MF on 6 healthy volunteers who received a single dose of a Pravastatin 20 mg tablet or the test formulation capsule of Fenofibrate 160 mg combined with Pravastatin 20 mg (fenofibrate-pravastatin capsule, Galephar MF) under fed conditions. Similar serum LDL, TG, and other concentration curves resulted from each treatment, and no pharmacokinetic interactions between Pravastatin and Fenofibrate were observed, corroborating Pan’s results from 2000.

Guidelines for the coadministration of statins and fibrates in patients with refractory mixed hyperlipidemia are needed.

Mantel-Teeuwisse [18] estimated the number of cases of myopathy that were expected following administration of lipid-lowering drugs in the Netherlands. Estimates of expected cases of statin-related or fibrate-related idiopathic myopathy were low, and actual incidence (confirmed by data from PHARMO) was even lower.

In a pooled recent analysis of 2592 patients with hypercholesterolemia or mixed dyslipidemia, 1017 of whom received fluvastatin [20, 40 or 80 mg (40 mg twice daily)] in combination with a fibrate (bezafibrate 200 or 400 mg, Fenofibrate 200 mg or gemfibrozil 600 or 1200 mg), Farnier & al [19] found that the frequency of CPK elevation with combination therapy was low and not significantly different from that associated with monotherapy or placebo.

The present phase III study proposes to compare the efficacy and safety of combination therapy Pravafen (a fixed combination of 40 mg of Pravastatin and 160 mg of Fenofibrate) to monotherapy Pravastatin 40mg, once daily, or Fenofibrate 160 mg, once daily. Combination treatment will not be a first intention treatment but will be administered to patients refractory to monotherapy. Pravastatin and Fenofibrate were selected because they act on different enzyme systems, so that in combination they are less likely to interact adversely.


8. Study Objectives

8.1 Primary Objective(s)

The primary objective of this study was to compare the efficacy of a dose of Pravastatin 40 mg alone or Fenofibrate 160 mg alone to daily Pravafen (the combination of Pravastatin and Fenofibrate 40/160 mg) over 12 weeks, followed by an open-label, 52-week safety follow-up, exclusively on Pravefen, for the treatment of combined hyperlipidemia.

8.2 Secondary Objective(s)

The secondary objective was to assess the long-term safety of Prevafen for the treatment of combined hyperlipidemia.

9 INVESTIGATIONAL PLAN

7.1 Overall Study Design and Plan: Description

This was a multi-center, double blind, prospective, longitudinal, randomized, 12-week study to evaluate the safety and efficacy of daily administration of Pravastatin 40 mg, Fenofibrate 160 mg or Pravafen (the combination of Pravastatin and Fenofibrate 40/160 mg) in the treatment of combined hyperlipidemia with a 52-week open-label follow-up during which all patients received Pravafen. An open-label, 8-week Selection Phase took place prior to randomization during which all patients were first stabilized on Pravastatin 40 mg/day. Following this Selection Phase, patients who met all inclusion/exclusion criteria were randomized to a three-arm, double blind, 12-week Efficacy Phase during which they received either Pravastatin 40 mg alone or Fenofibrate 160 mg alone or Pravafen (a combination of Pravastatin and Fenofibrate 40/160 mg). This 12-week Efficacy Phase was followed by an open-label, 52-week Safety Phase, during which all patients who had completed the Efficacy Phase received Pravafen.

The clinical trial protocol (and any changes to the protocol) and a sample case report form are provided in Appendices 16.1.1 and 16.1.2, respectively.

9.1.1 Selection Phase

In order to be enrolled, the patient had to have a documented history of combined hyperlipidemia.

If on Visit 1 the patient was already being treated with a lipid-lowering therapy met the selection criteria, then lipid-lowering therapy was immediately discontinued

If on Visit 1 the patient had never been treated with a lipid-lowering therapy and met the selection criteria, the patient was allowed to participate in the study.

In addition, regardless of prior lipid-lowering therapy, the patient must have met the following LDL cholesterol and TG criteria:


Prior treatment LDL-C TG

Naïve to Treatment* > 130 mg/dL AND ≥ 150 mg/dL and ≤ 400 mg/dL

Lipid-Lowering Monotherapy

> 130 mg/dL AND ≥ 150 mg/dL and ≤ 400 mg/dL

Lipid-Lowering Combination Therapy

> 110 mg/dL AND ≥ 150 mg/dL and ≤ 400 mg/dL

Patients who met all study criteria were enrolled in the Selection Period at Visit 1. Laboratory results were reviewed by the Investigator to ensure that laboratory criteria had been met prior to the administration of Pravastatin at Visit 1D. Patients were instructed to take one capsule of Pravastatin 40 mg (PRAVACHOL 40 mg, Bristol Myers Squibb) with the evening meal each day and to bring their bottles and any unused tablets back to the site during the following visit for drug accountability purposes. At Visit 1D, the investigator introduced the American Heart Association Step II diet. Patients were then required to continue on this diet throughout the remainder of their participation in the study.

9.1.2 Efficacy Phase

After the 8-week Selection Phase, patients who still met all inclusion/exclusion criteria were randomized on a 1:1:2 ratio to Pravastatin 40 mg alone, Fenofibrate 160 mg alone, or Pravafen (the combination of Pravastatin and Fenofibrate 40/160 mg) for a 12 week period. From Visit 3 to Visit 7, all patients were instructed to take two (2) capsules with their evening meal each day, according to the following schema:

One capsule of the active Pravastatin 40 mg and one capsule of the placebo of Pravafen (combination of Pravastatin/Fenofibrate 40/160 mg) OROne capsule of the active Fenofibrate 160 mg and one capsule of the placebo of Pravafen (combination of Pravastatin/Fenofibrate 40/160 mg) OR One capsule of the active Pravafen (combination of Pravastatin/Fenofibrate 40/160 mg) and one capsule of the placebo of Pravastatin 40 mg

At each scheduled study visit, patients returned study medication bottles and all unused medications for drug accountability purposes and were supplied with new bottles. This procedure was repeated until Visit 6.

9.1.3 Safety Phase

After completion of the 12-week Efficacy Phase, all patients, unless they experienced an adverse event that precluded them from further participation in the study and/or had changes in their well being, were rolled-over into the 52-week, open-label, Safety portion of the study.


Beginning with Visit 7 and through the Exit Visit/Visit 11, all patients received one capsule of Pravafen (combination of Pravastatin/Fenofibrate 40/160 mg) with their evening meal each day.

At each scheduled study visit, patients returned study medication bottles and all unused medications for drug accountability purposes and were supplied with new bottles. The final study drug dispensation took place at Visit 10.

9.1.4 Schedule of Study Procedures

A flowchart of scheduled study procedures by week is provided in Appendix A.

In the Selection Phase, screening procedures included the following:

Documentation of history of combined hyperlipidemia according to above criteria

Securing of written informed consent form

Review of inclusion/exclusion criteria

Obtaining of demographics data

Completion of medical, surgical, and concomitant medication history

Measurement of height and weight

Completion of physical examination (PE), including vital sign measurement [blood pressure, heart rate, respiratory and temperature (oral temperature was preferred, when feasible)]

Resting 12-lead ECG

Collection of blood/urine samples for laboratory tests (blood chemistry, hematology, lipid and liver function tests, and urinalysis), including serum pregnancy test for female patients with childbearing potential

Scheduling of the patient for return to the clinic in 2-5 days for drug dispensing if laboratory criteria were met

Efficacy Phase study procedures included the following:

Collection of blood samples for laboratory tests (blood chemistry, CRP, lipid and liver function tests). Urine pregnancy testing of all females of childbearing potential (negative results were required for continued participation in the study)

Resting 12-lead ECG

Completion of physical examination (PE) including vital sign measurements (blood pressure, heart rate, respiratory and temperature)

Review of blood/urine laboratory test results (blood chemistry, hematology, lipid and liver function tests, and urinalysis) from prior visit to ensure no abnormal or clinically significant results were obtained


Dispensing of study medication with review of study medication accountability data and patient compliance

Recording of concomitant medications and AEs/SAEs in the CRF

Review of patient’s diet compliance and reinforcement of study’s diet rules

Safety Phase study procedures included the following:

Performing of physical examination (PE) including vital sign measurements (blood pressure, heart rate, respiratory rate and temperature)

Resting 12-lead ECG

Collection of blood samples for laboratory tests (blood chemistry, CRP, lipid and liver function tests). Urine pregnancy testing of all females of childbearing potential (negative results were required for continued participation in the study)

Review of study medication accountability data and patient’s medication and dietary compliance

Dispensing study medication

Recording of concomitant medications and AEs/SAEs in the CRF

7.2 Discussion of Study Design Including the Choice of Control Groups

This multi-center, double blind, prospective, longitudinal, randomized, 12-week study was designed to evaluate the safety and efficacy of daily administration of Pravastatin 40 mg, Fenofibrate 160 mg, or Pravafen (the combination of Pravastatin and Fenofibrate 40/160 mg) in the treatment of combined hyperlipidemia. The Efficacy Phase was preceded by an open-label, 8-week, Selection Phase in which all patients were stabilized on Pravastatin 40 mg/day prior to randomization. Following the Selection Phase, patients who met all inclusion/exclusion criteria were randomized to a three-arm, double blind, 12-week Efficacy Phase during which each received either Pravastatin 40 mg, Fenofibrate 160 mg, or Pravafen (a combination of Pravastatin and Fenofibrate 40/160 mg). The 12-week Efficacy Phase was followed by an open-label, 52-week Safety Phase, during which all patients who had completed the Efficacy Phase received Pravafen.

The primary endpoint assessed during the Efficacy Phase was the difference in change from baseline in non-HDL-C (TC, HDL-C) between patients receiving Pravafen (the combination of Pravastatin and Fenofibrate) and those receiving Pravastatin or Fenofibrate alone after twelve weeks. During the following 52-week, open-label phase, overall safety of patients receiving Pravafen was assessed.

Secondary endpoints assessed differences in change from baseline in TC, TG, LDL-C, HDL-C (absolute and percentage change), TC/HDL-C, and Apolipoproteins A1 and B (ApoA1 and ApoB) between patients receiving Pravafen and those receiving Pravastatin or Fenofibrate alone at the end of the 12-week Efficacy Phase. During the


52-week, open-label follow-up, change from baseline in TC, TG, LDL-C, HDL-C (absolute and percentage change), TC/HDL-C, Non-HDL-C and ApoA1 and ApoB was assessed every 12 weeks (at Weeks 24, 36, 48 and 64). Both at the end of the Efficacy Phase and at the end of the Safety Phase, the percentage of patients meeting LDL, TG, and combined LDL/TG goals was assessed (LDL ≤ 100 mg/dL, TG ≤ 150 mg/dL, or both).

Differences in change from baseline in ALT, AST, and CK and overall patient safety between patients receiving Pravafen and those receiving Pravastatin or Fenofibrate alone at the end of the 12-week Efficacy Phase were assessed. In addition, change from baseline in ALT, AST, and CK was assessed every 12 weeks (at Weeks 24, 36, 48 and 64) during the 52-week, open-label Safety Phase of the study.

7.3 Selection of Study Population

7.3.1 Inclusion Criteria

At the end of the Selection Phase, each patient must have met the following criteria to be eligible for inclusion in the study:

Male or female patients with a history of a combined hyperlipidemia with an age range of 18-75 years inclusive at the time of initial dosing

LDL cholesterol 100 mg/dL and/or TG 150 mg/dL and 400 mg/dL at Week 1/Visit 2 after taking Pravastatin 40 mg/day from Visit 1

If a sexually active female with childbearing potential, use of an acceptable birth control method was required (abstinence, IUD, oral, transdermal, injectable or implantable contraceptives, at least 2 years post-menopausal, one year post hysterectomy, double barrier device and/or partner at least one year post vasectomy), a negative serum pregnancy test was to be obtained at the Selection Visit (Visit 1), and a negative urine pregnancy test was to be obtained prior to study drug administration at Baseline Visit (Visit 3)

Capable of complying with all study procedures

Written informed consent to participate in the study obtained, signed and dated

Demonstrated compliance ≥80% during the 8-week Selection/Pravastatin phase of the study.

7.3.2 Exclusion Criteria

Patients who met any of the following criteria were excluded from the study:

1. Female of childbearing potential who was pregnant and/or lactating and/or sexually active but not using an acceptable method of contraception

2. History of allergy or contraindications to any of the following: Fenofibrate or similar compounds


HMG-CoA reductase inhibitors

3. History of any of the following uncontrolled or unstable conditions: Diabetes (e.g., diabetic nephropathy) Hepatic impairment/insufficiency Renal impairment/insufficiency (e.g., nephritis, polycystic kidney disease, acute or

chronic renal failure, end-stage renal disease, GFR < 60 mL/min) Neurological Gastrointestinal (e.g., ulcerative colitis, Barrett’s, etc.) Gallbladder disease (patients with prior cholecystectomy were not allowed to

participate), Psychiatric Sleep apnea Any other clinically significant medical or surgical history that could affect the

safety of the patient or hinder the evaluation of the study drug’s effect, at the discretion of the Principal Investigator or Medical Monitor

4. Acute liver disease or persistent elevations in liver function tests (2 times the upper normal limit or greater)

5. Levels of creatine phosphokinase (CK) greater than or equal to 3 times the upper normal limit

6. Change in diuretic or β-blocker treatment for hypertension within 30 days of enrollment in the Selection Phase (Visit 1)

7. Positive personal history of abuse of any of the following: Alcohol (as per the DSM-IV criteria) Recreational drugs (as per the DSM-IV criteria)

8. Usage of any of the following medications (patients were to have discontinued these medications for 5 or more half-lives or for 30 days, whichever was greater prior to study drug administration on Visit 3/ Day 0): Corticosteroids Immunosuppresants Macrolide antibiotics Azole antifungal agents

9. Recent use of any investigational drug. These drugs were to be discontinued for either 5 or more half-lives or for 30 days, whichever was greater prior to Visit 1

10. Hyperlipidemia type I-IIa-IV-V

11. LDL <100 mg/dL

12. TG <150 mg/dL or >400 mg/dL

13. Uncontrolled primary hypothyroidism

14. History of an acute myocardial infarction, stroke within the 6 months immediately prior to Visit 1; unstable angina; or clinically significant heart failure


15. Uncontrolled hypertension, as defined by SBP >160 mmHg or DBP >100 mmHg while on anti-hypertensive medication

16. Type 1 or type 2 diabetes mellitus requiring insulin, and diabetic patients with poor control (HbA1c level >10.5%), abnormal renal function (GFR <60 mL/min), or any renal disease likely to lead to renal dysfunction)

17. Use of any of the prohibited medications listed in the concomitant medication section

18. Non-adherence to the American Heart Association Step II diet introduced at Visit 1

19. Presence of any other condition or illness, that, in the opinion of the Principal Investigator, would interfere with the patient’s participation in the study

7.3.3 Removal of Patients from Therapy or Study Treatment Discontinuation

Patients were free to withdraw from the study at any time, for any reason. Similarly, an Investigator had the right to withdraw patients from the study in the event of intercurrent illness, adverse events, treatment failures, protocol violations, administrative difficulty, or if an Investigator felt it was in the best interest of the patient.

If a patient withdrew or was discontinued from the study, all safety data normally required at the completion of the study was to be obtained when possible. All available details were reported and recorded for any patient who withdrew or was removed from the study. If the reason for removal was an adverse event, intercurrent illness, or abnormal laboratory value requiring medical intervention or considered clinically significant, the specific principal event was also recorded on the adverse event case report form (CRF).

CRFs were required for all patients who signed informed consent and underwent pre-operative procedures for the study but who were subsequently withdrawn from the study before all assessments are completed or treatment with the study agent occurred. Whenever possible, all sections of the CRF were completed up to the time of withdrawal.

7.4 Treatments

7.4.1 Treatments Administered

After the 8-week Selection Phase, patients who met the inclusion/exclusion criteria were randomized for 12 weeks on a 1:1:2 ratio to Pravastatin 40 mg, Fenofibrate 160 mg, or Pravafen (the combination of Pravastatin and Fenofibrate 40/160 mg). From Visit 3 to Visit 7, the patient took two (2) capsules of one of the following regimens with the evening meal each day:

One capsule of active Pravastatin 40 mg and one capsule containing the placebo of Pravafen (combination of Pravastatin/Fenofibrate 40/160 mg) OROne capsule containing active Fenofibrate 160 mg and one capsule containing the placebo of Pravafen OR


One capsule containing active Pravafen (combination of Pravastatin/Fenofibrate 40/160 mg) and one capsule containing the placebo of Pravastatin 40 mg

A flow chart of the study procedure, including randomization and treatments administered, is presented as Appendix 16.1.7.

7.4.2 Identity of Investigational Product(s)

Pravastatin 40 mg

Fenofibrate 160 mg

Pravafen (combination of Pravastatin and Fenofibrate 40/160 mg)

Placebo.

7.4.2.1 Selection Phase

Pravastatin 40 mg: Each patient received one (1) bottle containing 65 tablets.

7.4.2.2 Efficacy Phase

At Visit 3, Visit 4, Visit 5, and Visit 6, each patient received 2 bottles of study drugs: one bottle containing Pravastatin 40 mg, Fenofibrate 160 mg, or Pravafen (combination of Pravastatin and Fenofibrate 40/160 mg), and another bottle containing placebo. The description of the study drugs is as follows:

Active drug: Pravastatin 40 mg, Fenofibrate 160 mg, or Pravafen (combination of Pravastatin and Fenofibrate 40/160 mg): Each patient received one (1) bottle containing 30 capsules at Visit 3, Visit 4, Visit 5, and Visit 6, for a total of 4 bottles and 120 capsules of the active drug to which the patient was randomized during the 12-week Efficacy Phase

Placebo: Each patient received one (1) bottle containing 30 capsules at Visit 3, Visit 4, Visit 5 and Visit 6, for a total of 4 bottles and 120 capsules of placebo during the 12-week Efficacy Phase

7.4.2.3 Safety Phase

During the Safety Phase all patients received Pravafen (combination of Pravastatin and Fenofibrate 40/160 mg): Each patient received one (1) bottle containing 100 capsules at Visit 7, Visit 8 and Visit 9, and each patient received one (1) bottle containing 130 capsules at Visit 10, for a total of 4 bottles and 430 capsules of Pravafen 40/160 mg during the 52-week Safety Phase

7.4.3 Method of Assigning Patients to Treatment Groups

Each patient was given a patient number (a randomization code) that had been assigned to one of the three treatment regimens according to the randomization schedule generated by Integrium LLC, the sponsor’s designee. Decoding envelopes


prepared by Galephar PR, Inc., were supplied with the investigational products. A copy of the decoding envelopes was also made available at Integrium LLC. This system permitted investigators to suspend blinding for medical reasons if necessary.

7.4.4 Selection of Doses in the Study

Study doses of Pravastatin and Fenofibrate, 40 mg and 160 mg, respectively, are within the range of recommended doses for adults. Selection of the study dose of Pravafen, the combination of the statin and fibrate, was based on its likelihood to potentiate therapeutic activity, resulting in efficacy superior to that achievable by a single substance and improving patient compliance by simplifying dosing. The mechanisms of action of statins and fibrates are complementary. Their metabolic effects act efficiently on the lipid triad: LDL, HDL, and triglycerides. Furthermore, the differences in pharmacokinetic profile and metabolic route of this particular statin and fibrate insure that no drug-drug interactions will result.

7.4.5 Selection and Timing of Dose for Each Patient

Patients were instructed to take their study drugs with the evening meal because Pravastatin has been shown to be more effective in the evening and Fenofibrate is more highly bioavailable when administered with food.

7.4.6 Blinding Procedures

Integrium LLC generated the randomization code and Galephar PR, Inc., prepared the decoding envelopes that were supplied with the investigational products. A decoding list containing the codes for all patients included in the study was available at Galephar PR, Inc., and a copy of the decoding envelopes was also made available at Integrium LLC. This system permitted suspension of blinding for medical reasons if necessary.

Integrium LLC was prepared to reveal the identity of the study medication if, in an emergency, a patient couldn’t adequately be treated in the Investigator’s opinion without the identity of the study medication being known. Every effort was to be made to contact the Medical Monitor and/or the Director of Clinical Operations at Sciele™ prior to suspension of blinding. If this was impossible and the situation was an emergency, the Investigator could suspend blinding and was instructed to contact the Medical Monitor as soon as possible. In all cases of unblinding, pertinent information, including the date and reasons for suspension of blinding, were to be recorded in the source documents and on the CRFs.

The Medical Monitor and the Director of Clinical Operations at Sciele™ were to be informed immediately of any suspension of blinding. The Investigator was instructed to document and report all relevant information regarding suspension of blinding on CRFs.


7.4.7 Prior and Concomitant Therapy

All medications and other treatments other than the study drug were considered concomitant medications. All concomitant medications taken during the 12 months prior to Visit 1 for the treatment of hyperlipidemia were recorded in the patient’s medical record and on CRFs.

All concomitant medications, including over-the-counter medications, vitamins, alternative therapies, and herbs, used within four weeks prior to initial administration of the study drug (on Visit 2/Day 0) and/or initiated or changed during the study were to be recorded on the source documents and appropriate CRF pages.

7.4.7.1 Prohibited Concomitant Therapy

Medications prohibited with concomitant administration of the combination of Pravastatin/Fenofibrate included the following:

- Any other lipid-lowering therapy: fibrates, HMG-CoA reductase inhibitors, resins, or fish oil

- Other drugs which were known to affect lipid levels: Oral anticoagulants Any drug known to carry a risk of rhabdomyolysis (e.g., cyclosporine,

macrolides, etc.) New molecules currently under experimentation

7.4.7.2 Permitted Concomitant Therapy Under Certain Conditions

Medications allowed under certain conditions with concomitant administration of the combination of Pravastatin/Fenofibrate included:

- Phenobarbital or anti-epileptics known to be hepatic enzyme inducers, authorized provided that the treatment had been ongoing at least 3 months prior to inclusion in the study and that the same dose was maintained throughout the study.

7.4.8 Treatment Compliance

Compliance of at least 80% during the 8-week Selection Phase was necessary for a patient to be eligible for randomization into the Efficacy Phase. At each visit during the study, the Investigator and/or Designee assessed the patient’s compliance with administration of the study medication.


7.5 Efficacy and Safety Variables

7.5.1 Definition and Timing of Efficacy and Safety Assessments

Blood was collected and values obtained by the designated central laboratory. Patients fasted prior to each scheduled blood collection during the study.

Clinical laboratory evaluations were performed in accordance with the following schedule:

a) Hematology

At Visit 1 (Screening), Visit 7 (Week 12/End of Efficacy Phase), Visit 8 (Week 24), Visit 9 (Week 36), and Visit 11 (Week 64/End of Safety Phase): hemoglobin, hematocrit, red blood cells, white blood cells with differential, and platelet count

b) Blood Chemistry

At Visit 1, only basic metabolic panel was tested: creatinine (GFR calculated), BUN, sodium, potassium, chloride, bicarbonate, glucose, alkaline phosphatase, AST, ALT, GGT, total bilirubin, calcium, phosphorus, uric acid, cholesterol, total protein and albumin.

At Visits 3, 5, 7, 8, 9, 10 and 11, blood chemistry testing included basic metabolic panel (as noted above), ApoA1, and ApoB.

At Visits 3, 7, 8, 9, and 11, C-Reactive Protein (CRP) was drawn.

c) Urinalysis

At Visits 1, 7, 8, 9, and 11: urinalysis (protein, glucose, ketones, blood, leukocytes); if abnormal: microscopic sediment examination (leukocytes, erythrocytes, epithelial cells, bacteria, casts)

d) Urine or blood pregnancy test

At Visit 1: a serum pregnancy test was performed on all females with childbearing potential.At Visits 3, 7, 8, 9, and 11: urine pregnancy test was performed on all females with childbearing potential.Negative pregnancy test results were required before the patient was permitted to continue participation in the study.

e) Lipid/Liver function tests

At Visits 1, 2, 3, 5, 7, 8, 9, 10 and 11: After an overnight fast: total cholesterol (TC), triglycerides (TG), LDL, HDL, non-HDL-C (TC-HDL), TC/HDL, AST, ALT, CK.

f) Other laboratory tests

TSH was drawn at Visit 1.

HbA1c was drawn at Visit 1.


7.5.1.1 Efficacy Measurements

The specific lipid efficacy laboratory assessments performed during the patient’s participation in the study included the following:

LDL Total cholesterol (TC) HDL Non-HDL (TC-HDL) TC/HDL Triglycerides (TG) ApoA1 and ApoB

7.5.1.2 Safety Measurements

The specific laboratory assessments performed to insure the patient’s safety during his participation in the study included the following:

SGPT/ALAT SGOT/ASAT CPK C-Reactive Protein (CRP) Serum creatinine Glomerular filtration rate (GFR) Blood biochemistry and hematology Urinalysis Pregnancy: a serum pregnancy test (beta-HCG) was performed on females with

childbearing potential at Screening Visit (Visit 1) and a urine pregnancy test was performed at Visit 3. A urine pregnancy test was repeated at the end of the Efficacy Phase (Visit 7), at Visit 8, Visit 9, and at the end of the Safety Phase (Visit 11).

9.5.1.2.1 Safety Evaluations

Definition of Safety Variables

Adverse events, physical examination, and laboratory evaluation were assessed in all patients included in the study

Events of myopathy and/or rhabdomyolysis

Increase in transaminase levels ( threefold the upper normal limit)

Increase in CPK ( fivefold the upper normal limit)

Increase in creatinine

Withdrawals/dropouts


9.5.1.2.2. Laboratory Assessment of Safety

Abnormal laboratory test results

The results of all laboratory tests required by the protocol were recorded on the patient’s case report form. All clinically important abnormal laboratory tests that occurred during the study were to be repeated every 2 or 4 weeks at the discretion of the PI until they returned either to baseline or to a level deemed acceptable by the Investigator and the designated Medical Monitor or until a diagnosis that explained them was made. The criteria for determining whether an abnormal laboratory test finding was to be reported as an adverse event were as follows:

Test result was associated with accompanying symptoms, and/or

Test result required additional diagnostic testing or medical/surgical intervention, and/or

Test result led to a change in study dosing or patient’s withdrawal from the study, significant additional concomitant drug treatment, or other therapy, and/or

Test result led to any of the outcomes included in the definition of a serious adverse event, and/or

Test result was considered to be an adverse event by the Investigator or Sponsor.

Special attention was to be paid to patients developing elevated serum transaminase 3 or more times the upper limit of normal, or CPK levels 5 or more times the upper limit of normal. If transaminase was >3 times and/or CPK >5 times ULN, measurements were to be repeated once a week.

Guidelines for safety in laboratory values are presented as Figure 1.


Figure 1. Guidelines for safety in laboratory values

Parameter Critical threshold

Conduct to adoptin 1st intention

Conduct to adoptin 2nd intention

Transaminases @ > 3 UNL Control every week until return to normal

If 2 consecutive assessments > 3 UNL

Treatment discontinuation

CPK $

5 UNL and <10 UNL

Control every week until return to normal

If 3 consecutive assessments 5 UNL


10 UNL with muscular

symptoms *

Immediate treatment discontinuation

10 UNL without muscular

symptoms *

Control within one week If 2 consecutive assessments 10 UNL


Creatinine > 20 mg/l and clearance < 50

ml/min**


TG > 600 mg/dl Control at next assessment(following visit)

If 2 consecutive assessments > 600 mg/dl


LDL-c < 50 mg/dl Control at next assessment(following visit)

If 2 consecutive assessments < 50 mg/dl


Beta-HCG Positive Treatment discontinuation

@ Transaminases normal values (max): - ALAT/SGPT: 41 UI/l for male and 31 UI/l for female- ASAT/SGOT: 37 IU/l for male and 31 UI/l for female

$ CPK normal values (max) : 190 UI/l for male and 167 UI/l for female* In patients presenting muscular symptoms or CPK > 10 UNL, myoglobin levels (in plasma and urine) were to be measured.** The protocol foresaw a patient’s discontinuation when creatinine >20 mg/l or clearance <50 ml/min, but finally, the clearance < 50 ml/min was quite common and the investigators often considered that it was not significant for their older patients, so in these cases, a discontinuation was applied when creatinine > 20 mg/l and clearance < 50 ml/min.

7.5.1.3 Schedule of Events

Table 1 presents the schedule of events for all study visits.


Table 1. Schedule of Events During the Selection, Efficacy, and Safety Phases of the Study

Selection Phase Efficacy Phase Safety Phase

Visit 1Visit 1D Visit 2

Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Visit 10Visit 11Exit Visite

Week -8.5 Week -8

Week -1 ±3 days)

Baseline(Day 0)

Week 3(Day 21±3 days)








Informed Consent X

Inclusion/Exclusion X X

Demographics X

Medical History X

Physical Exama X X X X X

Blood Chemistryf X X X X X X X X

Hemoglobin A1c X

Hematology X X X X X

Urinalysis X X X X X

12-Lead ECG X X X X X X

Pregnancy Testg X X X X X X

Vital Signs X X X X X X X X X X

Lipid/Liver Function Testingb, c

X

XX X X X X X X

Diet Evaluation/Instruction

X X X X X X X X X X X

Study Medication Dispensed

X X X X X X X X X X

Drug Accountability X X X X X X X X X

Concomitant Medications

X X X X X X X X X X

Adverse Events X X X X X X X X Xa Additional physical examinations may be performed during interim visits if the PI has determined that patient well-being has changed. b Lipid/liver function testing (after an overnight fast) will include measurements of lipids and lipoproteins [TC, TG, LDL-C, HDL-C (absolute and percentage), non HDL-C] and AST, ALT, and CK.c Lipid parameters will be measured at the end of the selection period but one week before randomization into the Efficacy Phase.d Patients will be advised to stop medication and contact the PI if muscle symptoms or other possible side effects develop and persist beyond 2 days; if any severe intercurrent disease develops; or if surgery or any other event occurs that could

interfere with the patient’s continuation in the study.

e If patient drops out or is withdrawn early, all exit procedures should be performed at that time.f At Visit 1, only basic metabolic panel. At Visits 3, 5, 7, 8, 9, 10 and 11, in addition to basic metabolic panel, Apolipoprotein A and Apolipoprotein B assessed. At Visits 3, 7, 8, 9, and 11, CRP will also be assessed.g Serum pregnancy test performed at Visit 1. Urine pregnancy test performed at Visits 3, 7, 8, 9, and 11.


7.5.2 Appropriateness of Measurements

The measurements made in this study were standard, and generally acknowledged as reliable, accurate, and relevant indicators of cardiovascular risk.

7.5.3 Efficacy Variable(s)

7.5.3.1 Primary Efficacy Variable(s)

The primary efficacy variable used to assess the study drug’s therapeutic efficacy was the mean percent change from baseline (Visit 1) in plasma non-HDL cholesterol levels at the end of the efficacy period.

7.5.3.2 Secondary Efficacy Variable(s)

The secondary efficacy variables used to assess the study drug’s therapeutic efficacy were the following:

Percentage of patients who achieve therapeutic goals concerning non-HDL and LDL levels as defined in the NCEP ATP III

Change from baseline in LDL levels

Change from baseline in HDL, TG, TC

Change from baseline in ApoA1, ApoB levels

Differences in estimated cardiovascular risk for myocardial infarction (PROCAM risk calculator).

7.6 Data Quality Assurance

7.6.1 Study Administration and Conduct

Integrium LLC was responsible for conducting Clinical Trial Site Quality Assurance (CTSQA) audits at 10% of the clinical trial sites. Such audits not only evaluated practices at the clinical trial sites but also ensured the sites’ compliance with applicable government regulations, local laws, Good Clinical Practices (GCP), and the study protocol.

The first interim monitoring visit (IMV) to study sites occurred 2 weeks after the first patient was screened at that site. Thereafter, IMVs were performed every 8 weeks until the last patient completed the 12-week treatment period. Interim monitoring visits were performed quarterly from the time the last patient completed the 12-week treatment period until the time the last patient completed the last visit.

Each participating site maintained appropriate medical and research records as patient source data for this trial. To ensure that data in the CRFs was accurate, complete, and in accordance with patient source data, site monitors performed verification of source data on 100% of all CRFs, which entailed a comparison of the data in the source documentation and other records relevant to the study to the data reported on the CRFs.


The monitors verified that documentation of informed consent was on file for all screened patients and confirmed whether they had been randomized into the study. Monitors also ensured that the following information had been correctly recorded: trial identification, code, number, and initials of trial patients; trial drugs and doses; inclusion date; name of responsible investigator; name of sponsor; and other information as stipulated in the study protocol.

7.6.2 Data Generation and Analysis

Copies of audit certificates are provided in Appendix 16.1.8. Documentation of inter-laboratory standardization methods and quality assurance procedures are provided in Appendix 16.1.10.

7.7 Statistical Methods Planned in the Protocol and Determination of Sample Size

7.7.1 Statistical and Analytical Plans

7.7.1.1 General Methodology

Efficacy analyses

The percent changes in non-HDL cholesterol levels at 12 weeks were analyzed among the three treatment groups using analysis of covariance (ANCOVA). Factors for this ANCOVA model included site, treatment group, and site-by-treatment-group interaction, and baseline non-HDL cholesterol was the covariate term. Comparisons of the treatment groups [Pravafen (combination of Pravastatin/Fenofibrate 40/160mg) versus Pravastatin 40mg alone and Pravafen (combination of Pravastatin/Fenofibrate 40/160mg) versus Fenofibrate 160mg alone) were carried out using one-sided tests and were considered statistically significant if the p-value was less than 0.025--the Bonferroni adjusted level of significance.

The percent change of all other lipid parameters at 12 weeks also was compared among the three treatment groups by ANCOVA, using the same statistical model as specified for the primary efficacy parameter. Pairwise treatment comparisons with respect to the secondary parameters were carried out using one-sided tests and evaluated at the p<0.05 significance level.

The same methodology as above was used to compare the percent changes at 12 weeks between treatment groups for estimated 10-year CHD risk.

The percentage of patients in each of the three treatment groups who achieved therapeutic goals for levels of non-HDL and LDL at the end of the Efficacy Phase (as defined in the NCEP ATP III: non-HDL cholesterol < 130 mg/dL, LDL < 100 mg/dL) were compared using a chi-square test.


Safety analyses

Overall incidence and types of AEs are summarized by preferred term and body system, including analyses of seriousness, intensity, outcome, and relationship to study medication.

Occurrences of AEs are compared among the three treatment groups using a chi-square test (or Fisher’s exact test if necessary).

Patients withdrawn from the study as a result of specific adverse events (CPK>fivefold UNL, confirmed by redraw; SGOT/SGPT>3 times of the UNL, confirmed by redraw; GFR <60 mL/min) are classified and summarized according to their treatment group. Two-sided 90% CI of the differences among treatment groups is assessed using the z-statistic.

An interim analysis of safety data was performed after the last patient completed 6 months of the Safety Phase (Visit 9/Week 36), at which time the database was locked.

Significance level

Unless otherwise stated, the overall level of significance for the tests is = 5%.

Missing data

For the primary endpoint (percentage variation in non-HDL cholesterol levels at 12 weeks), missing data from withdrawn patients was replaced by the last available value (LOCF procedure). This method was also used for the other lipid parameter levels (LDL cholesterol, HDL cholesterol, triglycerides, total cholesterol, ApoA1, ApoB), for fibrinogen values, and for C-reactive protein values (secondary efficacy endpoints).

Descriptive statistics

Continuous variables are described using: number of observations (N), mean (Mean), standard deviation (SD), median (Median), minimum (Min), maximum (Max) and number of missing data. Categorical and ordinal variables are presented using frequencies (N) and percentages (%).

7.7.1.2 Description of the populations analyzed

A complete list of patients and their classifications by population is presented as Appendix 16.4.

9.7.1.2.1 Efficacy Populations

Primary analysis is based on Intent-To-Treat (ITT) principles and includes all randomized patients who received at least one dose of active study medication.

In addition, a Per Protocol (PP) analysis was performed for all patients from the ITT population who presented no major protocol violations.


9.7.1.2.2 Safety Populations

Safety analyses have been conducted in all patients who received at least one dose of active study medication.

7.7.1.3 Statistical Analysis Methods

Significance level

Unless otherwise stated, the overall level of significance for the tests is = 5%.

Missing data

For the primary endpoint (percentage variation in non-HDL cholesterol levels at 12 weeks), missing data from withdrawn patients has been replaced by the last available value (LOCF procedure). This method was also used for other lipidemic parameter levels (LDL cholesterol, HDL cholesterol, triglycerides, total cholesterol, ApoA1, ApoB), for fibrinogen values, and for C-reactive protein values (secondary efficacy endpoints).

Descriptive statistics

Continuous variables are described using: number of observations (N), mean (Mean), standard deviation (SD), median (Median), minimum (Min), maximum (Max) and number of missing data. Categorical and ordinal variables are presented using the frequencies (N) and percentages (%).

9.7.1.3.1 Primary Efficacy Endpoints

The primary efficacy endpoint is defined as the mean percent change from baseline in non-HDL cholesterol level in patients receiving Pravafen (combination of Pravastatin/Fenofibrate 40/160 mg), compared to patients receiving either Pravastatin 40 mg or Fenofibrate 160 mg alone, at the end of the 12-week Efficacy Phase.

9.7.1.3.2 Secondary Efficacy Endpoints

The secondary efficacy endpoints are:

Mean percent changes of LDL cholesterol levels at the end of the Efficacy Phase compared to the baseline

Percentage of patients who achieved therapeutic goals of non-HDL and LDL levels as defined in the NCEP ATP III at the end of the Efficacy Phase

Mean percent change of the following other lipid parameter levels at the end of the Efficacy Phase, compared to baseline: HDL, triglycerides (TG), total cholesterol (CT), ApoA1, ApoB

Absolute changes in estimated 10-year Cardiovascular Heart Disease (CHD) risk (PROCAM risk calculator) at the end of the Efficacy Phase, compared to baseline


9.7.1.3.4 Safety Endpoints

Safety parameters analyzed are the following:

- Adverse events (AEs), laboratory evaluation, vital signs, and physical examination, assessed in all patients who received at least one dose of active study medication (Pravastatin, Fenofibrate and/or Pravafen)

- Increase of transaminase levels (>3 times the upper normal limit) during the treatment period (SGOT/ASAT and SGPT/ALAT)

- Appearance of myopathy and/or rhabdomyolysis during the treatment period

- Increase of creatine phosphokinase (CPK) levels ( fivefold the upper normal limit) during the treatment period

- Decrease of GFR levels (<60 ml/mn) during the treatment period

- Presence of signs/symptoms of gallbladder disease (i.e., abdominal fullness; severe abdominal pain located on the right upper quadrant or over the epigastrium occurring mostly after meals and worsening during deep intake of breath, radiating to back or below the right shoulder blade, worse after eating fatty foods; fever, nausea, vomiting, heartburn, chest pain under the breastbone, etc.)

- Decrease in the GFR ≤ 60 mL/min/1.73 m2

- Rate of patients withdrawn due to adverse events

A signed copy of the final Statistical and Analytical Plan for this study is provided in Appendix <enter.

7.7.2 Determination of Sample Size

Sample size calculation was done in order to demonstrate the superiority of the combination Pravastatin/Fenofibrate 40/160 mg to Pravastatin 40 mg alone or Fenofibrate 160 mg alone for the analysis of the primary efficacy endpoint--i.e., mean percent changes from baseline in plasma non-HDL cholesterol level at the end of the 12-week Efficacy Period.

To do this, information from other studies on percent changes in plasma non-HDL cholesterol were used. A difference between treatment groups in mean percent changes in plasma non-HDL cholesterol level between baseline and Week 12 (Visit 7) of 7% was considered a clinically meaningful difference [23]. To protect the overall Type I error of = 0.05, the Bonferroni adjustment was used, since there were two comparisons to be made: Pravafen versus Fenofibrate alone and Pravafen versus Pravastatin alone. Assuming a common standard deviation in percent change of 20%, a sample size of 200 patients in the Pravafen group, and 100 patients each in the Fenofibrate-alone and Pravastatin-alone groups > 80% power was provided using a one-tailed test with an adjusted level of significance of = 0.025.


7.8 Changes in the Conduct of the Study or Planned Analyses

Three amendments were made to the original protocol, and a copy of each is included in Appendix 16.1.1.

7.8.1 Changes in the Conduct of the Study

Amendment No. 1, dated 14 March 2007

Clarified lipid parameters for patients entering the Efficacy Phase; defined patients considered naïve to treatment; clarified selection and exclusion criteria; stipulated procedures for laboratory tests and their review; added “exacerbation of prior muscular symptom” to the list of clinically relevant observations to be reported as an AE on the CRF; and elaborated upon study documentation and record retention procedures.

Amendment No. 2, dated 22 June 2007

Stipulated that a sufficient number of patients would be screened to ensure that 640 were enrolled in the Selection Phase, with the aim of randomizing 400 patients into the Efficacy Phase, and that following the 12-week Efficacy Phase, a sufficient number of patients would be enrolled in the Safety Phase to insure that at least 100 completed the 52-week Safety Phase; specified Safety Phase evaluations at 24, 36, and 52 weeks, with lipid profile assessment every 12 weeks; added Apolipoprotein A1 and Apolipoprotein B as secondary efficacy endpoints; modified exclusion criteria; study drug administration during the Safety Phase; abnormal test results; and statistical methods to be employed in the safety and efficacy analyses.

Amendment No. 3, dated 9 November 2007

Reduced number of patients screened for Selection Phase from 640 to 600 to enable randomization of at least 400 into the Efficacy Phase; required sites to ensure that between and 10 and 15% of patients have Type 2 diabetes with HbA1c 10.5%; modified laboratory assessment schedule; stipulated performance of complete PE at visits 8, 9, and conclusion of the study; increased number of ECG evaluations from four to six; and described interim analysis of data after the last patient completed 6 months of the Safety Phase.

7.8.2 Changes in the Planned Analyses

Changes in the planned analyses are detailed in Amendment 2, which is provided in Appendix 16.1.1.


8 STUDY PATIENTS

8.1 Disposition of Patients

A total of 617 patients were screened and entered the Selection Phase and 558 (90.4%) completed the Selection Phase. Seventy-seven patients (12.5%) completed the Selection Phase but were not randomized into the Efficacy Phase. A total of 481 patients entered the Efficacy Phase and 410 patients completed the Efficacy Phase.

Of the patients discontinued, 21 (4.4%) withdrew consent, 8 (1.7%) were lost to follow-up, 20 (4.2%) experienced adverse events, 15 (3.1%) had abnormal laboratory values, and 1 had an abnormal test procedure. There were also 6 protocol violations.

Individual patient data and summaries of patient dispositions during the Efficacy Phase are provided in Appendix 16.4.

A summary of patient dispositions by treatment is found in Table 2.


Table 2. Summary of Dispositions by Treatment

—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Pravastatin 40 mg Fenofibrate 160 mg Pravafen Total (N=116) (N=125) (N=240) n (%) [a] —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Screened and entered selection 617 phase Completed selection phase 558 ( 90.4) Discontinued selection phase 59 ( 9.6) Completed selection phase but not 77 ( 12.5) randomized Entered efficacy phase (randomized) 116 125 240 481 Safety Population [b] 114 ( 98.3) 122 ( 97.6) 239 ( 99.6) 475 ( 98.8) ITT Population [c] 112 ( 96.6) 118 ( 94.4) 237 ( 98.8) 467 ( 97.1) Per-Protocol Population [d] 107 ( 92.2) 116 ( 92.8) 227 ( 94.6) 450 ( 93.6) Completed efficacy phase 103 ( 88.8) 102 ( 81.6) 205 ( 85.4) 410 ( 85.2) Discontinued 13 ( 11.2) 23 ( 18.4) 35 ( 14.6) 71 ( 14.8) Subject withdrew consent 5 ( 4.3) 10 ( 8.0) 6 ( 2.5) 21 ( 4.4) Lost to follow-up 1 ( 0.9) 4 ( 3.2) 3 ( 1.3) 8 ( 1.7) Adverse event 3 ( 2.6) 4 ( 3.2) 13 ( 5.4) 20 ( 4.2) Protocol violation 3 ( 2.6) 2 ( 1.6) 1 ( 0.4) 6 ( 1.2) Abnormal laboratory values 1 ( 0.9) 3 ( 2.4) 11 ( 4.6) 15 ( 3.1) Abnormal test procedures 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) Death 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)

—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— [a] Percents are based on the number of patients entering each phase. [b] The Safety population includes all subjects who took at least one dose of study drug. [c] The ITT population includes all subjects who received study drug and had a baseline and a post-baseline assessment. [d] The Per-Protocol population includes all subjects in the ITT population who presented no major protocol violations.


8.1.1 Description of the Populations Analyses during the Efficacy Phase

A complete list of patients and their classifications by population is presented as Appendix 16.4.

8.1.1.1 Safety Population (Efficacy Phase)

The Safety population totaled 475 (114 to receive Pravastatin 40mg, 122 to receive Fenofibrate 160mg, and 239 to receive Pravafen, the combination of Pravastatin/Fenofibrate 40/160mg) and consisted of all patients who had taken at least one dose of a study drug.

8.1.1.2 Intent-to-Treat Population (ITT) (Efficacy Phase)

The ITT population totaled 467 (112 to receive Pravastatin 40mg, 118 to receive Fenofibrate 160mg, and 237 to receive Pravafen, the combination of Pravastatin/Fenofibrate 40/160mg, and consisted of all patients who had received a study drug and had had a baseline and post-baseline assessment.

8.1.1.3 Per Protocol Population (PP) Efficacy Phase)

The PP population totaled 450 (107 to receive Pravastatin 40mg, 116 to receive Fenofibrate 160mg, and 227 to receive Pravafen, the combination of Pravastatin/Fenofibrate 40/160mg) and included all patients in the ITT population who presented no major protocol violations.

8.1.2 Description of the Populations Analyses during the Safety Phase

8.1.3 Withdrawals from Study during the Efficacy Phase

A total of 71 patients (14.8%) were discontinued from participation in the study during the Efficacy Phase. Of these, 21 (4.4%) withdrew consent, 20 (4.2%) experienced an adverse event, 15 (3.1%) demonstrated abnormal laboratory values, 8 (1.7%) were lost to follow-up, 6 (1.2%) violated the study protocol, and one underwent abnormal test procedures.

8.1.4 Withdrawals from Study during the Safety Phase

8.2 Protocol Deviations

8.2.1 Protocol Violations met at Inclusion and during the Efficacy Phase

There were 19 (4.0%) protocol violations during the Efficacy Phase.

Thirteen patients (2.7%) did not meet the 80% compliance requirement of the Efficacy Phase;

Four (0.8%) took one of the prohibited medications (lipid-lowering agents) concomitantly with the study medications during active treatment;

Two (0.4%) did not meet minimum criteria for hyperlipidemia (LDL <100mg/dL and/or TG <150mg/dL).


A summary of protocol deviations during the Efficacy Phase (Visit 3 through Visit 7) is found in Figure 2.


Figure 2. Summary of Protocol Deviations during the Efficacy Phase

——————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Description N ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————— All Randomized Subjects 481 Major Protocol Deviations 19 ( 4.0) Randomization error: Did not meet lipid criteria (LDL < 100 mg/dL and TG < 150 mg/dL) 2 ( 0.4) Prohibited concomitant medication (lipid lowering agents) during active treatment 4 ( 0.8) Study medication compliance less than 80% (Selection or Efficacy phase) 13 ( 2.7)


8.2.2 Protool Violations met during the Safety Phase

8.3 Data Sets Analyzed

8.3.1 Efficacy Phase Data Sets Analyzed

During the Efficacy Phase of the study, the Pravafen group showed greater decreases in non-HDL cholesterol from baseline (-7.6%) than either the Pravastatin alone or Fenofibrate alone groups (p<0.001). See Figure 3.

Total cholesterol (TC) was also reduced more effectively by the Pravafen combination therapy (-5.6%) than by Pravastatin or Fenofibrate alone (p<0.001). See Figure 7.

Fenofibrate raised HDL cholesterol more effectively than the other two regimens (+2.4%)(p=0.032). See Figure 5.

The combination Pravafen therapy reduced triglycerides (TG) more dramatically that either of the monotherapies (-19.5% vs. -13.8% and +12.9%; p<0.001). See Figure 6.

Higher percentages of patients achieved their therapeutic goals of lowering non-HDL (37.9%)(p<0.001) and LDL cholesterol (19.8%)(p=0.025) while taking the combination Pravafen therapy than while taking either Pravastatin alone (18.7% and 14.0%) or Fenofibrate alone (12.1% and 4.3%). Nearly twice the percentage of patients achieved both therapeutic goals on Pravafen (19.4%) as on Pravastatin alone (10.3%) or Fenofibrate alone (4.3%)(P=0.002). See Figure 10.

Fenofibrate caused LDL cholesterol to increase an average of 17.6% during the Efficacy Phase (p<0.001), while no statistically significant changes in LDL cholesterol were observed in either the Pravafen or Pravastatin groups. See Figure 4.

Similarly, Apolipoprotein A1 (ApoA1) was seen to rise significantly in the Fenofibrate group (+6.4%)(P<0.001) despite the absence of significant changes in ApoA1 in either of the other groups. On the other hand, Apolipoprotein B declined an average of 11.5% in the group on Pravafen, compared to smaller declines in the Pravastatin (-4.0%) and Fenofibrate (-0.6%) groups (P<0.001). See Figures 8 and 9.

No statistically significant declines in 10-year CHD risk were observed in the Pravafen and Pravastatin groups; a small but significant increase in 10-year risk was observed in the group taking Fenofibrate alone (p=0.017). See Figure 11.


8.3.2 Safety Phase Data Sets Analyzed

8.4 Demographic and Other Baseline Characteristics

8.4.1 Demographics of the Efficacy Phase

475 patients were analyzed for safety during the Efficacy Phase of the study; of these, 467 comprised the intent-to-treat population (ITT) and 450 comprised the per protocol population (PP). Demographics for patients participating in the Efficacy Phase are presented as Figure 3.

No significant differences were observed among the three treatment groups in any of these three populations (safety, ITT, PP) for the following variables: age, age category, gender, race, weight, height, HbA1c, or HbA1c category.

In all three populations (analyzed for safety, ITT, PP), the group administered Fenofibrate alone exhibited a statistically higher body mass index (BMI) than either of the other two groups (p<0.031).


Figure 3. Demographics of Efficacy Phase Population

—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Pravastatin 40 mg Fenofibrate 160 mg Pravafen Variable (N=114) (N=122) (N=239) P-value [a] —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Age (years) 0.649 n 114 122 239 Mean 54.5 53.9 53.5 SD 8.69 10.14 9.24 Median 55.0 55.0 54.0 Min, Max 32.0, 75.0 26.0, 75.0 28.0, 73.0 Age Category n (%) n (%) n (%) 0.850 <65 100 ( 87.7) 101 ( 82.8) 207 ( 86.6) 65 to 75 14 ( 12.3) 21 ( 17.2) 32 ( 13.4) >75 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Gender n (%) n (%) n (%) 0.785 Male 55 ( 48.2) 51 ( 41.8) 116 ( 48.5) Female 59 ( 51.8) 71 ( 58.2) 123 ( 51.5) Race n (%) n (%) n (%) 0.805 Caucasian 105 ( 92.1) 113 ( 92.6) 218 ( 91.2) Black 4 ( 3.5) 4 ( 3.3) 7 ( 2.9) Asian 1 ( 0.9) 1 ( 0.8) 6 ( 2.5) American Indian / Alaska Native 0 ( 0.0) 1 ( 0.8) 1 ( 0.4) Other 4 ( 3.5) 3 ( 2.5) 7 ( 2.9) Weight (kg) 0.153 n 114 122 239 Mean 87.5 91.6 90.8 SD 17.65 17.65 17.29 Median 83.9 88.9 90.9 Min, Max 55.0, 142.0 57.0, 137.9 54.5, 142.9 Height (cm) 0.314 n 114 122 238 Mean 169.7 167.9 168.7 SD 10.14 9.81 10.41 Median 168.2 167.6 168.9 Min, Max 147.5, 193.0 142.0, 188.0 142.2, 195.6 BMI (kg/m^2) 0.013 n 114 122 238 Mean 30.4 32.7 31.9 SD 5.87 6.91 5.55 Median 29.4 31.5 31.2 Min, Max 18.5, 58.1 21.7, 54.8 22.0, 52.7


HbA1c 0.348 n 110 119 235 Mean 5.9 5.9 5.8 SD 0.55 0.50 0.50 Median 5.8 5.8 5.8 Min, Max 5.1, 8.3 5.1, 7.8 5.0, 9.6 HbA1c Category n (%) n (%) n (%) 0.457 <8.5% 110 ( 96.5) 119 ( 97.5) 234 ( 97.9) 8.5 to <10.5% 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) >= 10.5% 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) [a] P-values generated from CMH test for categorical variables and ANOVA for continuous variables adjusting for site for the comparison between treatments.


8.4.2 Demographics of the Safety Phase

A complete listing of patients and their demographic data is presented as Appendix 16.2.4.

8.4.3 Medical History and Surgical History (other than combined hyperlipidemia)

A list of patients and their associated medical histories is provided as Appendix 16.2.9.

8.4.4 Combined hyperlipidemia

A list of patients and the results of the lipid tests they underwent is presented as Appendix 16.2.10.

8.4.5 Cardiovascular risk factors

8.4.6 Physical Examination

A summary of data obtained during physical examinations is presented as Appendix 16.2.11.

8.4.7 Vital Signs

8.4.7.1 Vital Signs during the Efficacy Phase

475 patients entered the 12-week Efficacy Phase of the study: 114 patients randomized to Pravastatin 40mg alone, 122 patients randomized to Fenofibrate 160mg alone, and 239 patients randomized to Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg). A summary of patient vital signs taken during the Selection and Efficacy Phases and during the first two months (Visits 8 and 9) of the Safety Phase is presented as Appendix 16.2.12.

Systolic blood pressure averaged a mean of 126.0mmHg in both monotherapy groups at the beginning of the Efficacy Phase and 124.0mmHg in the Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg) group. After 12 weeks in the Efficacy Phase, mean systolic blood pressure was 128.0mmHg in the Pravastatin group, 126.0mmHg in the Fenofibrate group, and 123.9mmHg in the Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg) group.

Diastolic pressure averaged a mean of 79.1mmHg in the Pravastatin alone group at the outset of the Efficacy Phase, 78.2mmHg in the Fenofibrate alone group, and 77.6mmHg in the Pravafen group. By the end of the 12-week Efficacy Phase, diastolic pressure had dropped to 78.1 in the Pravastatin alone group and 76.9mmHg in the Pravafen group for reductions of 1.0% and 0.6%, respectively. The diastolic blood pressure of the group randomized to monotherapy Fenofibrate was unchanged from baseline after 12 weeks of the Efficacy Phase.

Baseline pulse rate at the beginning of the Efficacy Phase (Visit 3) was 69.4bpm in the group randomized to Pravastatin alone, 71.6bpm in the Fenofibrate alone group, and 71.5bpm in the group randomized to combination therapy Pravafen. After 12 weeks in the Efficacy Phase of the study, baseline pulse rate had dropped to a mean


of 70.2bpm in the Pravafen group and had increased to an average of 69.8bpm in the Pravastatin only group and 72.0bpm in the Fenofibrate group.

Over the course of the Efficacy Phase (Visit 3/Baseline to Visit 7), the QRS complexes on ECG of 5 patients (4.4%) taking monotherapy Pravastatin changed from abnormal to normal. Conversely, the QRS complexes of 3 (1.9%) of those taking monotherapy Fenofibrate and 5 (2.1%) taking Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg) changed from normal to abnormal. Safety Phase

8.4.7.2 10.4.7.2 Vital Signs during the Safety Phase

8.4.8 Laboratory Parameters at Baseline

8.4.8.1 Efficacy Phase

8.4.8.2 Safety Phase

8.4.9 Prior and Concomitant Medications

Detailed listings of prior and concomitant medications by patient are provided in Appendix 16.2.13.

8.4.9.1 Prior and Concomitant Medications from the Screening Visit (Visit 1) to Baseline Visit (Visit 3)

8.4.9.2 Prior and Concomitant Medications during the Efficacy Phase (Baseline Visit [Visit 3] through Visit 7)

Of the 475 patients monitored for safety from the beginning of the Efficacy Phase (Visit 3), 57 (50.0%) of those patients randomized to Pravastatin alone had taken at least one medication previously; 52 (42.6%) of those randomized to Fenofibrate alone had taken at least one prior medication; and 119 (49.8%) of those randomized to Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg) had taken at least one medication previously.

Cardiovascular medications had previously been taken by 30.7% of the Pravastatin only group while 27.9% of the Fenofibrate only group and 34.3% of the Pravafen group had previously taken a cardiovascular system medication.

In the Pravastatin only group, 8.8% had taken an anti-infective, and 4.9% of the Fenofibrate only group and 10.0% of the Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg) group had previously taken an anti-infective.

Seven percent of the Pravastatin only group had taken a nervous system medication; 6.6% of the Fenofibrate only group and 5.9% of the Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg) group had previously taken a nervous system medication.


Alimentary tract and metabolic medications had previously been taken by 5.3% of the group randomized to Pravastatin alone, 6.6% of the Fenofibrate alone group, and 5.4% of the Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg) group.

Less than 5% of the patients in any group had previously taken medications for ailments of the respiratory, musculo-skeletal, sensory organ, dermatological, genitourinary-sex hormone, systemic hormone, blood and blood-forming organ, and miscellaneous systems.

8.4.9.3 Concomitant Medications during the Safety Phase

Of the 475 patients monitored for safety during the Efficacy Phase, 88.6% of those randomized to monotherapy Pravastatin, 93.4% of those randomized to monotherapy Fenofibrate, and 92.5% of those randomized to combination therapy Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg) took at least one medication concomitantly with their study medication.

Of these, 57.9% of the Pravastatin only group, 65.6% of the Fenofibrate only group, and 60.7% of the Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg) group were taking medications for ailments of the alimentary tract and metabolism.

For ailments of the nervous system, 56.1% of the monotherapy Pravastatin group were taking medication, 52.5% of the Fenofibrate only group, and 51.9% of the Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg) group.

Musculo-skeletal system medications were being taken by 46.5% of those randomized to Pravastatin alone, 40.2% of those taking Fenofibrate alone, and 38.1% of those taking Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg).

Cardiovascular system medications were taken concomitantly with the study medication by 43.0% of the Pravastatin only group, 45.1% of the Fenofibrate only group, and 43.5% of those randomized to Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg).

Respiratory system medications were being taken during the Efficacy Phase by 28.9% of the Pravastatin only group, 34.4% of the Fenofibrate only group, and 31.8% of those randomized to Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg).

Medications of the blood and blood-forming organs were being taken concomitantly with the study medication during the Efficacy Phase by 23.7% of those randomized to monotherapy Pravastatin; by 27.0% of those taking monotherapy Fenofibrate; and by 28.0% of those randomized to Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg).

Anti-infectives had been administered for systemic use to 14.9% of the Pravastatin only group during the Efficacy Phase; to 18.0% of those randomized to monotherapy Fenofibrate; and to 25.9% of those taking Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg).


Genitourinary and sex hormone therapies had been administered during the Efficacy Phase to 14.9% of those randomized to monotherapy Pravastatin; to 12.3% of those randomized to monotherapy Fenofibrate; and to 16.3% of those randomized to Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg).

Systemic, non-sex and non-insulin hormones were being administered to 9.6% of those randomized to Pravastatin alone during the Efficacy Phase; to 11.5% of those randomized to monotherapy Fenofibrate; and to 13.0% of those taking Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg).

Dermatologicals had been administered concomitantly with the study medication during the Efficacy Phase to 2.6% of those taking Pravastatin alone, 7.4% of those randomized to Fenofibrate alone, and 7.1% of those taking Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg) alone.

Various other medications, many of them herbal, were being taking concomitantly with the study medication by 11.4% of those randomized to monotherapy Pravastatin, 8.2% of those randomized to monotherapy Fenofibrate, and 6.3% of those randomized to Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg).

Smaller numbers of patients (0.8-5.3%) were taking medications for ailments of the sensory organs and medications for which no codes currently exist.

8.5 Measurements of Treatment Compliance

All treatments administered were recorded in the Study Drug Dispensing Record of the CRF and are presented by patient in Appendix 16.3.3.

8.5.1.1 Treatment Compliance during the Efficacy Phase

The data on treatment compliance is remarkably uniform during the Efficacy Phase.

The 113 patients monitored for safety during the Efficacy Phase in the Pravastatin only group spent an average of 81.2 days on study drug treatment; 122 patients in the Fenofibrate only group spent an average of 79.3 days on their study drug; and 239 patients in the Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg) group spent an average of 80.0 days on their study drug.

The Efficacy Phase of the study lasted an average of 82.2 days for the Pravastatin only group, 81.7 days for the Fenofibrate only group, and 82.6 days for those randomized to Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg).

Those randomized to Pravastatin only complied with study protocol 95.8% of the time; those randomized to Fenofibrate showed 95.3% compliance; and those taking Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg) also complied 95.3% of the time.


8.5.1.2 Treatment Compliance during the Safety Phase

8.6 Efficacy Results and Tabulations of Individual Patient Data

8.6.1 Analysis of Efficacy

8.6.1.1 Primary Efficacy Endpoint: Change in non-HDL cholesterol

Over the course of the Selection Phase, while all patients were being stabilized on Pravastatin 40mg, all 3 randomization groups in the ITT population monitored for safety showed statistically uniform reductions in non-HDL-C. The future monotherapy Pravastatin group exhibited 18.5% non-HDL-C reduction; the future monotherapy Fenofibrate exhibited 18.6% reduction in non-HDL-C; and the future Pravafen group showed a 17.8% reduction in non-HDL-C (p<0.001).

During the Efficacy Phase of the study, the Pravafen group showed greater decreases in non-HDL cholesterol from baseline (-7.6%) than either the Pravastatin alone or Fenofibrate alone groups (p<0.001). See Figure 4.

Over the course of the combined Selection and Efficacy phases (Visits 1 through 7), the ITT group monitored for safety and randomized to Pravafen (combination Pravastatin/Fenofibrate 40/160mg) exhibited statistically greater (-25.1%) reduction of non-HDL-C than either monotherapy Pravastatin (-19.2%) or monotherapy Fenofibrate (-10.9%) groups (p<0.001).


Figure 4. Percent Change during Efficacy Phase: Non-HDL Cholesterol (mg/dL) By Treatment

—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Pravastatin 40 mg Fenofibrate 160 mg Pravafen (N=112) (N=118) (N=237) P-value [e] —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Baseline Visit n 112 118 237 Mean 160.2 157.2 157.3 SD 32.63 29.37 29.55 Median 155.5 153.5 155.0 Min, Max 110.0, 290.0 101.0, 274.0 101.0, 250.0 95% CI [154.1, 166.3] [151.9, 162.6] [153.5, 161.1] Final Visit n 112 118 237 Mean 158.4 170.4 143.2 SD 33.55 40.41 35.75 Median 155.0 164.5 140.0 Min, Max 93.0, 310.0 82.0, 302.0 70.0, 252.0 95% CI [152.1, 164.7] [163.0, 177.7] [138.6, 147.8] Percent Change from Baseline [a] n 112 118 237 Mean 0.2 9.3 -7.9 SD 17.78 21.26 20.98 Median -1.6 9.0 -11.1 Min, Max -49.2, 61.5 -41.2, 70.7 -55.7, 70.7 95% CI [-3.1, 3.6] [5.4, 13.2] [-10.6, -5.2] P-value [b] 0.888 <0.001 <0.001 Percent Change from Baseline <0.001 Adjusted for Covariates [c] n 112 118 237 Pairwise: Mean 2.7 10.2 -6.9 P vs PF=<0.001 SE 1.98 1.88 1.38 F vs PF=<0.001 95% CI [2.7, 6.5] [10.2, 13.9] [-6.9, -4.2] P-value [d] 0.180 <0.001 <0.001 —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— [a] Percent change from baseline is calculated by (Final Visit (Visit 7) - Baseline (Visit 3))/Baseline (Visit 3) x 100. [b] P-value is based on the paired t-test. [c] Adjusted difference for each group is based on the least squares means after adjusting for site and baseline value. [d] P-values (within groups) are based on the null hypothesis that the least squares mean is equal to zero. [e] P-values are treatment comparisons from the analysis of covariance with site and baseline value as covariate. Overall p-value is significant if <0.05. Pairwise p-value is significant if < 0.025. P=Pravastatin, F=Fenofibrate, PF=Pravafen


8.6.1.2 Secondary Efficacy Endpoints

10.6.1.2.1 Evolution of LDL cholesterol levels during the whole study period

Over the course of the Selection Phase of the study, while all patients were being stabilized on Pravastatin 40mg, all future treatment groups in the ITT population monitored for safety showed statistically similar reductions in LDL-C. The group to be randomized to Pravastatin alone showed an 18.0% reduction in LDL-C; the group to be randomized to Fenofibrate alone showed an 18.3% reduction, and the group to be randomized to Pravafen (combination Pravastatin/Fenofibrate 40/160mg) exhibited a reduction of 18.0% in LDL-C (P<0.001).

Fenofibrate caused LDL cholesterol to increase an average of 17.6% during the Efficacy Phase (p<0.001), while no statistically significant changes in LDL cholesterol were observed in either the Pravafen or Pravastatin groups. See Figure 5.

Over the course of the combined Selection and Efficacy phases (Visits 1 through 7), the ITT group monitored for safety and randomized to Pravafen (combination Pravastatin/Fenofibrate 40/160mg) exhibited statistically greater reductions in LDL-C (-21.0%) than either monotherapy Pravastatin (-18.9%) or monotherapy Fenofibrate (-3.7%) groups (p<0.001).


Figure 5. Percent Change during Efficacy Phase: LDL Cholesterol (mg/dL) By Treatment

—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Pravastatin 40 mg Fenofibrate 160 mg Pravafen (N=112) (N=118) (N=237) P-value [e] —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Baseline Visit n 112 118 237 Mean 133.7 131.0 131.4 SD 29.64 27.30 27.15 Median 131.0 128.5 128.0 Min, Max 78.0, 236.0 80.0, 213.0 74.0, 209.0 95% CI [128.1, 139.2] [126.1, 136.0] [127.9, 134.8] Final Visit n 112 118 237 Mean 132.3 151.3 126.1 SD 30.23 35.18 31.33 Median 129.0 147.0 125.0 Min, Max 82.0, 254.0 77.0, 269.0 56.0, 238.0 95% CI [126.6, 137.9] [144.9, 157.7] [122.1, 130.1] Percent Change from Baseline [a] n 112 118 237 Mean 0.7 17.6 -2.0 SD 19.12 25.25 24.03 Median -1.1 15.0 -6.0 Min, Max -44.6, 50.0 -35.8, 94.9 -53.7, 74.3 95% CI [-2.9, 4.2] [13.0, 22.2] [-5.1, 1.0] P-value [b] 0.716 <0.001 0.191 Percent Change from Baseline <0.001 Adjusted for Covariates [c] n 112 118 237 Pairwise: Mean 3.5 18.7 -1.1 P vs PF=0.031 SE 2.17 2.07 1.52 F vs PF=<0.001 95% CI [3.5, 7.8] [18.7, 22.8] [-1.1, 1.9] P-value [d] 0.103 <0.001 0.476 —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— [a] Percent change from baseline is calculated by (Final Visit (Visit 7) - Baseline (Visit 3))/Baseline (Visit 3) x 100. [b] P-value is based on the paired t-test. [c] Adjusted difference for each group is based on the least squares means after adjusting for site and baseline value. [d] P-values (within groups) are based on the null hypothesis that the least squares mean is equal to zero. [e] P-values are treatment comparisons from the analysis of covariance with site and baseline value as covariate. Overall p-value is significant if <0.05. Pairwise p-value is significant if < 0.025. P=Pravastatin, F=Fenofibrate, PF=Pravafen


10.6.1.2.2 Evolution of HDL cholesterol levels during the whole study period

Over the course of the Selection Phase, while all patients were being stabilized on Pravastatin 40mg, the ITT patients monitored for safety in all three randomization groups showed statistically unchanged serum levels of HDL-C. The group to be randomized to Pravastatin alone showed an increase of 0.1% in HDL-C; the group to be randomized to Fenofibrate alone showed a reduction of 0.8% in HDL-C; and the group to receive Pravafen (combination Pravastatin/Fenofibrate 40/160mg) showed a 0.2% reduction in HDL-C. None of these changes were statistically significant.

Fenofibrate raised HDL-C more effectively (+2.4%) during the Efficacy Phase (Visits 3 through 7) than the other two regimens (Pravastatin alone [-2.1%] and Pravafen [+0.9%]) (p=0.032). See Figure 6.

Over the course of the combined Selection and Efficacy phases of the study (Visits 1 through 7), the ITT population monitored for safety and randomized to either group taking Fenofibrate (Pravafen combination therapy [+14.89%] or Fenofibrate alone [+14.80%]) exhibited greater reductions in HDL-C than the group randomized to Pravastatin alone (+10.8%)(p=0.011).


Figure 6. Percent Change during Efficacy Phase: HDL Cholesterol (mg/dL) By Treatment

—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Pravastatin 40 mg Fenofibrate 160 mg Pravafen (N=112) (N=118) (N=237) P-value [e] —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Baseline Visit n 112 118 237 Mean 49.8 48.8 48.4 SD 10.69 9.01 10.13 Median 48.0 48.0 47.0 Min, Max 31.0, 82.0 30.0, 78.0 29.0, 86.0 95% CI [47.8, 51.8] [47.2, 50.5] [47.2, 49.7] Final Visit n 112 118 237 Mean 48.5 49.7 48.8 SD 11.01 9.82 11.71 Median 47.0 48.5 47.0 Min, Max 26.0, 76.0 30.0, 81.0 13.0, 81.0 95% CI [46.5, 50.6] [47.9, 51.5] [47.3, 50.2] Percent Change from Baseline [a] n 112 118 237 Mean -2.1 2.4 0.9 SD 12.30 13.68 14.61 Median -2.5 2.0 0.0 Min, Max -31.6, 45.1 -30.0, 47.1 -60.6, 73.2 95% CI [-4.4, 0.2] [0.0, 4.9] [-1.0, 2.7] P-value [b] 0.068 0.054 0.359 Percent Change from Baseline 0.039 Adjusted for Covariates [c] n 112 118 237 Pairwise: Mean -1.8 2.9 0.8 P vs PF=0.052 SE 1.40 1.33 0.98 F vs PF=0.906 95% CI [-1.8, 0.9] [2.9, 5.5] [0.8, 2.7] P-value [d] 0.195 0.032 0.422 —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— [a] Percent change from baseline is calculated by (Final Visit (Visit 7) - Baseline (Visit 3))/Baseline (Visit 3) x 100. [b] P-value is based on the paired t-test. [c] Adjusted difference for each group is based on the least squares means after adjusting for site and baseline value. [d] P-values (within groups) are based on the null hypothesis that the least squares mean is equal to zero. [e] P-values are treatment comparisons from the analysis of covariance with site and baseline value as covariate. Overall p-value is significant if <0.05. Pairwise p-value is significant if < 0.025. P=Pravastatin, F=Fenofibrate, PF=Pravafen


10.6.1.2.3 Evolution of triglyceride levels during the whole study period

Over the course of the Selection Phase, during which all patients were being stabilized on Pravastatin 40mg, ITT patients monitored for safety in all three future randomization groups showed statistically insignificant reductions in TG. The future Pravastatin group showed a 6.1% reduction in TG; the future Fenofibrate group exhibited a 5.5% TG reduction; and the group randomized to take Pravafen (combination Pravastatin/Fenofibrate 40/160mg) showed a 3.0% reduction in TG.

During the Efficacy Phase of the study (Visit 3 to Visit 7), the combination Pravafen therapy reduced triglycerides (TG) more dramatically (-19.5%) than either of the monotherapies, Fenofibrate alone (-13.8%) and Pravastatin alone (+12.9%) (p<0.001). See Figure 7.

Over the course of the combined Selection and Efficacy phases (Visits 1 through 7), the ITT population monitored for safety and randomized to one of the two groups taking Fenofibrate showed greater reductions in TG than the monotherapy Pravastatin group. The Pravafen group exhibited a 25.3% reduction in TG and the monotherapy Fenofibrate group showed a 23.3% reduction in TG, compared to a 2.3% increase in TG exhibited by the group randomized to monotherapy Pravastatin (p<0.001).


Figure 7. Percent Change during Efficacy Phase: Triglycerides (mg/dL) By Treatment —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Pravastatin 40 mg Fenofibrate 160 mg Pravafen (N=112) (N=118) (N=237) P-value [e] —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Baseline Visit n 112 118 237 Mean 199.7 199.5 204.2 SD 88.04 91.42 93.45 Median 177.0 178.5 185.0 Min, Max 59.0, 738.0 77.0, 747.0 77.0, 794.0 95% CI [183.2, 216.2] [182.8, 216.2] [192.3, 216.2] Final Visit n 112 118 237 Mean 208.4 160.7 156.5 SD 81.17 69.23 88.66 Median 198.5 149.0 135.0 Min, Max 92.0, 532.0 56.0, 599.0 56.0, 805.0 95% CI [193.2, 223.6] [148.1, 173.3] [145.2, 167.8] Percent Change from Baseline [a] n 112 118 237 Mean 12.9 -13.8 -19.6 SD 44.78 33.15 31.81 Median 5.6 -21.1 -25.3 Min, Max -60.3, 271.2 -67.3, 96.9 -84.6, 156.2 95% CI [4.5, 21.3] [-19.9, -7.8] [-23.7, -15.6] P-value [b] 0.003 <0.001 <0.001 Percent Change from Baseline <0.001 Adjusted for Covariates [c] n 112 118 237 Pairwise: Mean 13.2 -13.7 -19.7 P vs PF=<0.001 SE 3.46 3.30 2.43 F vs PF=0.064 95% CI [13.2, 20.0] [-13.7, -7.3] [-19.7, -14.9] P-value [d] <0.001 <0.001 <0.001 —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— [a] Percent change from baseline is calculated by (Final Visit (Visit 7) - Baseline (Visit 3))/Baseline (Visit 3) x 100. [b] P-value is based on the paired t-test. [c] Adjusted difference for each group is based on the least squares means after adjusting for site and baseline value. [d] P-values (within groups) are based on the null hypothesis that the least squares mean is equal to zero. [e] P-values are treatment comparisons from the analysis of covariance with site and baseline value as covariate. Overall p-value is significant if <0.05. Pairwise p-value is significant if < 0.025. P=Pravastatin, F=Fenofibrate, PF=Pravafen


10.6.1.2.4 Evolution of total cholesterol levels during the whole study period

Over the course of the Selection Phase (Visits 1 through 3) while all patients were being stabilized on Pravastatin 40mg, ITT patients monitored for safety in all three randomization groups showed statistically insignificant reductions in T. The group to be randomized to Pravastatin exhibited a 15.0% reduction in total cholesterol (TC); the group to be randomized to Fenofibrate exhibited a 15.4% reduction in TC; and the group to take Pravafen (combination Pravastatin/Fenofibrate 40/160mg) in the future showed a 14.6% reduction in TC.

Total cholesterol (TC) was also reduced more effectively by the Pravafen combination therapy (-5.6%) than by Pravastatin (-0.7%) or Fenofibrate alone (+7.5%) (p<0.001). See Figure 8.

Over the course of the combined Selection and Efficacy phases (Visits 1 through 7), the ITT population monitored for safety and randomized to Pravafen (combination Pravastatin/Fenofibrate 40/160mg) exhibited statistically greater reductions in TC (-20.2%) than either the monotherapy Pravastatin group (-16.3%) or the monotherapy Fenofibrate group (-8.9%)(p<0.001).


Figure 8. Percent Change during Efficacy Phase: Total Cholesterol (mg/dL) By Treatment

—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Pravastatin 40 mg Fenofibrate 160 mg Pravafen (N=112) (N=118) (N=237) P-value [e] —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Baseline Visit n 112 118 237 Mean 210.1 206.0 205.8 SD 33.93 31.74 31.25 Median 207.0 205.5 205.0 Min, Max 153.0, 331.0 147.0, 330.0 148.0, 303.0 95% CI [203.7, 216.4] [200.3, 211.8] [201.8, 209.8] Final Visit n 112 118 237 Mean 206.9 220.0 191.9 SD 35.73 39.47 34.44 Median 206.0 217.0 190.0 Min, Max 145.0, 350.0 124.0, 348.0 118.0, 304.0 95% CI [200.2, 213.6] [212.8, 227.2] [187.5, 196.3] Percent Change from Baseline [a] n 112 118 237 Mean -0.7 7.5 -5.8 SD 13.94 15.62 15.89 Median -2.1 5.8 -7.7 Min, Max -46.8, 42.6 -27.5, 60.0 -40.6, 52.2 95% CI [-3.3, 1.9] [4.6, 10.3] [-7.9, -3.8] P-value [b] 0.604 <0.001 <0.001 Percent Change from Baseline <0.001 Adjusted for Covariates [c] n 112 118 237 Pairwise: Mean 1.3 8.2 -5.2 P vs PF=<0.001 SE 1.47 1.40 1.03 F vs PF=<0.001 95% CI [1.3, 4.2] [8.2, 11.0] [-5.2, -3.2] P-value [d] 0.367 <0.001 <0.001 —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— [a] Percent change from baseline is calculated by (Final Visit (Visit 7) - Baseline (Visit 3))/Baseline (Visit 3) x 100. [b] P-value is based on the paired t-test. [c] Adjusted difference for each group is based on the least squares means after adjusting for site and baseline value. [d] P-values (within groups) are based on the null hypothesis that the least squares mean is equal to zero. [e] P-values are treatment comparisons from the analysis of covariance with site and baseline value as covariate. Overall p-value is significant if <0.05. Pairwise p-value is significant if < 0.025. P=Pravastatin, F=Fenofibrate, PF=Pravafen


10.6.1.2.5 Evolution of Apolipoprotein A1 levels during the whole study period

Apolipoprotein A1 (ApoA1) was seen to rise significantly in the Fenofibrate group (6.4%)(P<0.001) during the Efficacy Phase despite the absence of significant changes in ApoA1 in either of the other groups. See Figure 9.


Figure 9. Percent Change during Efficacy Phase: Apolipoprotein A1 (mg/dL) By Treatment

—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Pravastatin 40 mg Fenofibrate 160 mg Pravafen (N=112) (N=118) (N=237) P-value [e] —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Baseline Visit n 107 118 230 Mean 167.0 162.0 161.0 SD 32.57 25.42 27.87 Median 160.0 161.0 157.0 Min, Max 107.0, 281.0 96.0, 265.0 105.0, 248.0 95% CI [160.8, 173.3] [157.3, 166.6] [157.4, 164.6] Final Visit n 112 118 237 Mean 165.2 170.8 164.0 SD 32.95 27.21 32.53 Median 161.5 168.0 162.0 Min, Max 108.0, 268.0 106.0, 264.0 29.0, 263.0 95% CI [159.0, 171.3] [165.8, 175.8] [159.9, 168.2] Percent Change from Baseline [a] n 107 118 230 Mean -0.5 6.2 2.1 SD 13.17 13.16 14.58 Median -1.5 5.3 1.3 Min, Max -27.0, 61.0 -17.8, 59.1 -74.1, 41.8 95% CI [-3.0, 2.0] [3.8, 8.6] [0.2, 4.0] P-value [b] 0.705 <0.001 0.031 Percent Change from Baseline <0.001 Adjusted for Covariates [c] n 112 118 237 Pairwise: Mean -0.8 6.0 1.2 P vs PF=0.887 SE 1.41 1.32 0.98 F vs PF=0.001 95% CI [-0.8, 2.0] [6.0, 8.6] [1.2, 3.1] P-value [d] 0.573 <0.001 0.236 —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— [a] Percent change from baseline is calculated by (Final Visit (Visit 7) - Baseline (Visit 3))/Baseline (Visit 3) x 100. [b] P-value is based on the paired t-test. [c] Adjusted difference for each group is based on the least squares means after adjusting for site and baseline value. [d] P-values (within groups) are based on the null hypothesis that the least squares mean is equal to zero. [e] P-values are treatment comparisons from the analysis of covariance with site and baseline value as covariate. Overall p-value is significant if <0.05. Pairwise p-value is significant if < 0.025. P=Pravastatin, F=Fenofibrate, PF=Pravafen


10.6.1.2.6 Evolution of Apolipoprotein B levels during the whole study period

Apolipoprotein B declined an average of 11.5% in the group on Pravafen during the Efficacy Phase, compared to smaller declines in the Pravastatin (4.0%) and Fenofibrate (-0.6%) groups (P<0.001). See Figure 10.


Figure 10. Percent Change during Efficacy Phase: Apolipoprotein B (mg/dL) By Treatment

—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Pravastatin 40 mg Fenofibrate 160 mg Pravafen (N=112) (N=118) (N=237) P-value [e] —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Baseline Visit n 107 118 230 Mean 118.7 118.2 117.0 SD 21.53 22.06 19.84 Median 116.0 117.0 115.0 Min, Max 81.0, 174.0 65.0, 183.0 66.0, 179.0 95% CI [114.6, 122.9] [114.2, 122.2] [114.4, 119.6] Final Visit n 112 118 237 Mean 112.1 116.0 102.5 SD 23.11 25.00 25.38 Median 110.5 115.0 101.0 Min, Max 66.0, 187.0 55.0, 184.0 45.0, 184.0 95% CI [107.8, 116.5] [111.5, 120.6] [99.2, 105.7] Percent Change from Baseline [a] n 107 118 230 Mean -4.0 -0.6 -11.5 SD 18.62 19.24 21.30 Median -4.7 -0.8 -13.0 Min, Max -45.4, 43.9 -49.1, 50.0 -58.7, 71.4 95% CI [-7.6, -0.5] [-4.1, 2.9] [-14.3, -8.8] P-value [b] 0.027 0.724 <0.001 Percent Change from Baseline <0.001 Adjusted for Covariates [c] n 112 118 237 Pairwise: Mean -2.2 0.4 -11.2 P vs PF=<0.001 SE 1.97 1.85 1.38 F vs PF=<0.001 95% CI [-2.2, 1.7] [0.4, 4.1] [-11.2, -8.5] P-value [d] 0.276 0.810 <0.001 —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— [a] Percent change from baseline is calculated by (Final Visit (Visit 7) - Baseline (Visit 3))/Baseline (Visit 3) x 100. [b] P-value is based on the paired t-test. [c] Adjusted difference for each group is based on the least squares means after adjusting for site and baseline value. [d] P-values (within groups) are based on the null hypothesis that the least squares mean is equal to zero. [e] P-values are treatment comparisons from the analysis of covariance with site and baseline value as covariate. Overall p-value is significant if <0.05. Pairwise p-value is significant if < 0.025. P=Pravastatin, F=Fenofibrate, PF=Pravafen


10.6.1.2.8 Achievement of the therapeutics goals defined by the NCEP ATP III during the whole study period

Higher percentages of patients achieved their therapeutic goals of lowering non-HDL (37.9%)(p<0.001) and LDL cholesterol (19.8%)(p=0.025) while taking the combination Pravafen therapy than while taking either Pravastatin alone (18.7% and 14.0%) or Fenofibrate alone (12.1% and 4.3%).

Nearly twice the percentage of patients achieved both therapeutic goals on Pravafen (19.4%) as on Pravastatin alone (10.3%) or Fenofibrate alone (4.3%)(P=0.002). See Figure 11.


Figure 11. Percent Change during Efficacy Phase: Achievement of Therapeutic Goals

—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Pravastatin 40 mg Fenofibrate 160 mg Pravafen Statistic/Score (N=112) (N=118) (N=237) P-value[2] —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Non-HDL Cholesterol Therapeutic Goal (<130 mg/dL) <.001 Achieved 20 ( 17.9) 14 ( 11.9) 90 ( 38.0) Not Achieved 92 ( 82.1) 104 ( 88.1) 147 ( 62.0) Missing 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) LDL Cholesterol Therapeutic Goal (<100 mg/dL) 0.019 Achieved 15 ( 13.4) 5 ( 4.2) 46 ( 19.4) Not Achieved 97 ( 86.6) 113 ( 95.8) 191 ( 80.6) Missing 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Both Therapeutic Goals 0.002 Achieved 11 ( 9.8) 5 ( 4.2) 45 ( 19.0) Not Achieved 101 ( 90.2) 113 ( 95.8) 192 ( 81.0) Missing 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)


10.6.1.2.9 Evolution of the 10-year cardiovascular heart disease risk during the whole study period

No statistically significant declines in 10-year CHD risk were observed in the Pravafen and Pravastatin groups; a small but significant increase in 10-year risk was observed in the group taking Fenofibrate alone (p=0.017). See Figure 12.


Figure 12. Percent Change During Efficacy Phase: 10-year CHD Risks By Treatment

—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Pravastatin 40 mg Fenofibrate 160 mg Pravafen (N=112) (N=118) (N=237) P-value [e] —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Baseline Visit n 109 112 234 Mean 5.8 5.3 5.6 SD 5.76 5.45 5.30 Median 4.0 3.5 4.0 Min, Max 0.0, 30.0 0.0, 25.0 0.0, 25.0 95% CI [4.7, 6.9] [4.3, 6.3] [4.9, 6.3] Final Visit n 109 112 234 Mean 6.1 5.9 5.4 SD 6.16 6.02 5.80 Median 4.0 4.0 3.0 Min, Max 0.0, 25.0 0.0, 30.0 0.0, 25.0 95% CI [5.0, 7.3] [4.8, 7.0] [4.6, 6.1] Change from Baseline [a] n 109 112 234 Mean 0.3 0.6 -0.2 SD 2.95 3.27 2.73 Median 0.0 0.0 0.0 Min, Max -8.0, 13.0 -9.0, 14.0 -8.0, 13.0 95% CI [-0.2, 0.9] [0.0, 1.2] [-0.6, 0.2] P-value [b] 0.272 0.045 0.262 Change from Baseline Adjusted 0.028 for Covariates [c] n 112 118 237 Pairwise: Mean 0.4 0.7 -0.2 P vs PF=0.050 SE 0.30 0.29 0.21 F vs PF=0.006 95% CI [0.4, 1.0] [0.7, 1.3] [-0.2, 0.2] P-value [d] 0.181 0.017 0.436 —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— [a] Change from baseline is calculated by Final Visit (Visit 7) - Baseline (Visit 3). [b] P-value is based on the paired t-test. [c] Adjusted difference for each group is based on the least squares means after adjusting for site and baseline value. [d] P-values (within groups) are based on the null hypothesis that the least squares mean is equal to zero. [e] P-values are treatment comparisons from the analysis of covariance with site and baseline value as covariate. P=Pravastatin, F=Fenofibrate, PF=Pravafen


9 SAFETY EVALUATION

9.1 Extent of Exposure

Records of patient exposure to study medications and their associated compliance history are provided in Appendix 16.2.5.

9.2 Adverse Events

9.2.1 Brief Summary of Adverse Events

9.2.1.1 Adverse Events Occurring During the 8-week Selection Period

During the Selection Phase and prior to randomization (Visit 1 through Visit 3), 206 of the 617 patients who had entered the Selection Phase (Visit 1) experienced at least one adverse event.

Of these 206, 57 (27.7%) occurred as musculoskeletal and connective tissue disorders (16 cases of extremity pain, 12 of arthralgia, 11 of myalgia, 8 of back pain, and 4 or less of other such disorders)

Infections and infestations were manifested in 51 patients (24.8%) (9 cases of nasopharygnitis, 7 each of sinusitis and upper respiratory tract infections, and 5 of urinary tract infection)

GI disorders occurred in 47 patients (including 12 cases of nausea, 9 of diarrhea, 7 each of upper abdominal pain and dyspepsia, and 5 of constipation)

General disorders were experienced by 29 patients (4.7%), the majority (17) of which were reported as fatigue, with 5 cases of peripheral edema

Nervous system disorders occurred in 28 patients (13.6%) occurred as, with 13 as headache and 7 as dizziness

Smaller numbers of other disorders were reported: 15 respiratory (7.3%); 15 dermatological (7.3%); 12 injury, including 2 poisoning (5.8%); 9 psychiatric (4.4%), of which 5 occurred as insomnia and 4 as depression; 6 renal and urinary (2.9%); and 5 each (2.4%) of eye disorders and neoplasms, only one of which was confirmed malignant

9.2.1.2 Adverse Events Occurring During the 12-week Efficacy Phase

Patients randomized at the beginning of the Efficacy Phase (Visit 3) into the three treatment groups who were then followed for safety totaled 475, including 114 taking Pravastatin alone, 122 taking Fenofibrate alone, and 239 taking Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg).


There were no significant differences between the groups in the number of patients who experienced at least one treatment-related event during the Efficacy Period: 21 (18.4%) of those taking monotherapy Pravastatin, 25 (20.5%) of those taking monotherapy Fenofibrate, and 43 (18.0%) of those administered combination therapy Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg)

Of these 89 patients who experienced an adverse event, 30 events (33.7%) led to investigations, including 8 cases of increases in creatine phosphokinase, 6 of increases in LDL, 4 each of increases in alanine aminotransferase, aspartate aminotransferase, and weight

Gastrointestinal disorders were reported as treatment-related adverse events by 28 patients during the Efficacy Phase (5.9%)

Nervous system disorders were exhibited in 15 patients (3.2%)

Musculoskeletal and connective tissue disorders were exhibited in 14 patients (2.9%)

Ten patients (2.1%) reported general disorders and site condition difficulties, half of these fatigue

Skin and subcutaneous tissue disorders occurred in 7 patients (1.5%)

Metabolism/nutritional complaints and respiratory symptoms were each exhibited by 4 patients (0.8%)

Three patients suffered from infections and infestations (0.6%)

One patient each experienced palpitations, a contusion, anxiety, haematurnia, and pollakiuria, and there was one cholecystectomy

There were no statistically significant differences in any of these categories of treatment-related adverse events among the three randomized treatment groups during the 12-week Efficacy Phase of the study.

There were also no significant differences among the treatment groups in number of subjects discontinuing study participation due to adverse events or experiencing “serious” adverse events, despite the fact that all 3 of the latter occurred in the group taking Pravafen (combination Pravastatin/Fenofibrate 40mg/160mg)(p=0.435): chest pain; abdominal pain/cholecystectomy with post-procedural infection; and in situ malignant melanoma.

9.2.1.3 Adverse Events Occurring During the 24/52 wee Safety Phase

9.2.2 Display of Adverse Events

Adverse events (AEs) during the Efficacy Phase are summarized for all patients in Figure 13.


A summary of adverse events that took place during the 8- week Selection Phase is presented as Appendix 16.2.7.1.


Figure 13. Summary of Treatment-Emergent Adverse Events During Efficacy Phase by Group

System/disorder Pravastatin 40mgN=114

Fenofibrate 160mgN=122

PravafenN=239

TotalsN=475

Infections and infestations 15 26 45 86Musculoskeletal/connective tissue 13 18 37 68Gastrointestinal 16 11 38 65Investigations 11 11 31 53Nervous system 9 10 18 37General & administrative site 8 8 18 34Respiratory, thoracic, mediastinal 5 8 20 33Injury, poisoning, procedural 5 4 10 19Skin & subcutaneous tissue 6 4 9 19Psychiatric 2 2 9 13Metabolic/nutritional 1 2 9 12Cardiac 3 2 3 8Surgical/medical procedures 0 3 5 8Vascular 0 4 3 7Ear/labyrinth 0 1 4 5Blood/lymphatic 2 1 1 4Eye 0 1 3 4Immune system 1 0 3 4Hepatobiliary 1 0 2 3Reproductive 1 1 1 3Neoplasms, benign, malignant, unspecified 0 0 2 2Renal/urinary 1 0 0 1Insomnia 0 1 0 1

TOTALS 100 118 281 399


Appendix 16.2.7.1. Summary of Adverse Events during the Selection Phase

—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Screened and Entered System Organ Class/ Selection Phase Preferred Term [a] (N=617) —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Number of subjects with at least one adverse event 206 ( 33.4) prior to randomization Musculoskeletal and connective tissue disorders 57 ( 9.2) Pain in extremity 16 ( 2.6) Arthralgia 12 ( 1.9) Myalgia 11 ( 1.8) Back pain 8 ( 1.3) Muscle spasms 4 ( 0.6) Muscular weakness 3 ( 0.5) Neck pain 3 ( 0.5) Osteoporosis 3 ( 0.5) Muscle tightness 2 ( 0.3) Musculoskeletal pain 2 ( 0.3) Osteoarthritis 2 ( 0.3) Flank pain 1 ( 0.2) Intervertebral disc protrusion 1 ( 0.2) Joint crepitation 1 ( 0.2) Joint swelling 1 ( 0.2) Musculoskeletal chest pain 1 ( 0.2) Rotator cuff syndrome 1 ( 0.2) Infections and infestations 51 ( 8.3) Nasopharyngitis 9 ( 1.5) Sinusitis 7 ( 1.1) Upper respiratory tract infection 7 ( 1.1) Urinary tract infection 5 ( 0.8) Bronchitis 4 ( 0.6) Tooth infection 3 ( 0.5) Vulvovaginal mycotic infection 3 ( 0.5) Ear infection 2 ( 0.3) Influenza 2 ( 0.3) Oral herpes 2 ( 0.3) Pharyngitis 2 ( 0.3) —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Note: Includes only adverse events with onset date prior to randomization. [a] System organ classes and preferred terms are coded using the MedDRA dictionary (Version 9.1). System organ classes and preferred terms are listed in descending order of frequency by the 75mg BID treatment group. A subject with multiple occurrences of an AE is counted only once in the System Organ Class and Preferred Term category.



—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Screened and Entered System Organ Class/ Selection Phase Preferred Term [a] (N=617) —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Bronchopneumonia 1 ( 0.2) Diverticulitis 1 ( 0.2) Gastroenteritis viral 1 ( 0.2) Herpes zoster 1 ( 0.2) Hordeolum 1 ( 0.2) Lower respiratory tract infection 1 ( 0.2) Postoperative wound infection 1 ( 0.2) Sialoadenitis 1 ( 0.2) Viral infection 1 ( 0.2) Gastrointestinal disorders 47 ( 7.6) Nausea 12 ( 1.9) Diarrhoea 9 ( 1.5) Abdominal pain upper 7 ( 1.1) Dyspepsia 7 ( 1.1) Constipation 5 ( 0.8) Vomiting 4 ( 0.6) Abdominal pain 3 ( 0.5) Flatulence 3 ( 0.5) Gastrooesophageal reflux disease 3 ( 0.5) Abdominal distension 2 ( 0.3) Abdominal pain lower 1 ( 0.2) Diverticulum 1 ( 0.2) Dysphagia 1 ( 0.2) Food poisoning 1 ( 0.2) Gastritis 1 ( 0.2) Gastrointestinal pain 1 ( 0.2) Haematochezia 1 ( 0.2) Haemorrhoids 1 ( 0.2) Hiatus hernia 1 ( 0.2) Paraesthesia oral 1 ( 0.2) —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Note: Includes only adverse events with onset date prior to randomization. [a] System organ classes and preferred terms are coded using the MedDRA dictionary (Version 9.1). System organ classes and preferred terms are listed in descending order of frequency by the 75mg BID treatment group. A subject with multiple occurrences of an AE is counted only once in the System Organ Class and Preferred Term category.



—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Screened and Entered System Organ Class/ Selection Phase Preferred Term [a] (N=617) —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— General disorders and administration site conditions 29 ( 4.7) Fatigue 17 ( 2.8) Oedema peripheral 5 ( 0.8) Asthenia 3 ( 0.5) Chills 2 ( 0.3) Cyst 1 ( 0.2) Influenza like illness 1 ( 0.2) Pain 1 ( 0.2) Pyrexia 1 ( 0.2) Thirst 1 ( 0.2) Nervous system disorders 28 ( 4.5) Headache 13 ( 2.1) Dizziness 7 ( 1.1) Sinus headache 2 ( 0.3) Anosmia 1 ( 0.2) Burning sensation 1 ( 0.2) Cervical myelopathy 1 ( 0.2) Dysgeusia 1 ( 0.2) Hypoaesthesia 1 ( 0.2) Migraine 1 ( 0.2) Nerve compression 1 ( 0.2) Parosmia 1 ( 0.2) Restless legs syndrome 1 ( 0.2) Syncope 1 ( 0.2)



—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Screened and Entered System Organ Class/ Selection Phase Preferred Term [a] (N=617) —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Investigations 15 ( 2.4) Blood creatine phosphokinase increased 6 ( 1.0) Glomerular filtration rate decreased 2 ( 0.3) Alanine aminotransferase increased 1 ( 0.2) Apolipoprotein B increased 1 ( 0.2) Aspartate aminotransferase increased 1 ( 0.2) Blood bilirubin increased 1 ( 0.2) Blood cholesterol increased 1 ( 0.2) Blood pressure increased 1 ( 0.2) Blood thyroid stimulating hormone increased 1 ( 0.2) Blood uric acid increased 1 ( 0.2) Eosinophil count increased 1 ( 0.2) Glucose tolerance test abnormal 1 ( 0.2) Glycosylated haemoglobin increased 1 ( 0.2) High density lipoprotein increased 1 ( 0.2) Low density lipoprotein increased 1 ( 0.2) Neutrophil count abnormal 1 ( 0.2) White blood cell count increased 1 ( 0.2) Respiratory, thoracic and mediastinal disorders 15 ( 2.4) Cough 5 ( 0.8) Nasal congestion 3 ( 0.5) Pulmonary congestion 3 ( 0.5) Pharyngolaryngeal pain 2 ( 0.3) Sinus congestion 2 ( 0.3) Choking sensation 1 ( 0.2) Diaphragmatic hernia 1 ( 0.2) Dysphonia 1 ( 0.2) Dyspnoea 1 ( 0.2) Postnasal drip 1 ( 0.2) Productive cough 1 ( 0.2) Snoring 1 ( 0.2) —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Note: Includes only adverse events with onset date prior to randomization. [a] System organ classes and preferred terms are coded using the MedDRA dictionary (Version 9.1). System organ classes and preferred terms are listed in descending order of frequency by the 75mg BID treatment group. A subject with multiple occurrences of an AE is counted only once in the System Organ Class and Preferred Term category.



—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Screened and Entered System Organ Class/ Selection Phase Preferred Term [a] (N=617) —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Skin and subcutaneous tissue disorders 15 ( 2.4) Hyperhidrosis 2 ( 0.3) Pruritus 2 ( 0.3) Rash 2 ( 0.3) Acne 1 ( 0.2) Dermatitis contact 1 ( 0.2) Eczema 1 ( 0.2) Increased tendency to bruise 1 ( 0.2) Photosensitivity reaction 1 ( 0.2) Skin discolouration 1 ( 0.2) Swelling face 1 ( 0.2) Umbilical erythema 1 ( 0.2) Urticaria 1 ( 0.2) Injury, poisoning and procedural complications 12 ( 1.9) Back injury 2 ( 0.3) Exposure to toxic agent 2 ( 0.3) Ankle fracture 1 ( 0.2) Contusion 1 ( 0.2) Fall 1 ( 0.2) Foot fracture 1 ( 0.2) Joint sprain 1 ( 0.2) Meniscus lesion 1 ( 0.2) Muscle strain 1 ( 0.2) Rib fracture 1 ( 0.2) Scapula fracture 1 ( 0.2) —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Note: Includes only adverse events with onset date prior to randomization. [a] System organ classes and preferred terms are coded using the MedDRA dictionary (Version 9.1). System organ classes and preferred terms are listed in descending order of frequency by the 75mg BID treatment group. A subject with multiple occurrences of an AE is counted only once in the System Organ Class and Preferred Term category.



—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Screened and Entered System Organ Class/ Selection Phase Preferred Term [a] (N=617) —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Psychiatric disorders 9 ( 1.5) Insomnia 5 ( 0.8) Depression 4 ( 0.6) Abnormal dreams 2 ( 0.3) Anxiety 2 ( 0.3) Nervousness 1 ( 0.2) Renal and urinary disorders 6 ( 1.0) Pollakiuria 2 ( 0.3) Haematuria 1 ( 0.2) Nephrolithiasis 1 ( 0.2) Renal impairment 1 ( 0.2) Urine odour abnormal 1 ( 0.2) Eye disorders 5 ( 0.8) Chalazion 1 ( 0.2) Eye pain 1 ( 0.2) Iritis 1 ( 0.2) Ocular hyperaemia 1 ( 0.2) Retinal detachment 1 ( 0.2) Neoplasms benign, malignant and unspecified (incl cysts 5 ( 0.8) and polyps) Basal cell carcinoma 1 ( 0.2) Benign bone neoplasm 1 ( 0.2) Benign neoplasm 1 ( 0.2) Seborrhoeic keratosis 1 ( 0.2) Thyroid neoplasm 1 ( 0.2) —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Note: Includes only adverse events with onset date prior to randomization. [a] System organ classes and preferred terms are coded using the MedDRA dictionary (Version 9.1). System organ classes and preferred terms are listed in descending order of frequency by the 75mg BID treatment group. A subject with multiple occurrences of an AE is counted only once in the System Organ Class and Preferred Term category.



—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Screened and Entered System Organ Class/ Selection Phase Preferred Term [a] (N=617) —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Metabolism and nutrition disorders 4 ( 0.6) Decreased appetite 1 ( 0.2) Diabetes mellitus 1 ( 0.2) Gout 1 ( 0.2) Increased appetite 1 ( 0.2) Vascular disorders 4 ( 0.6) Hypertension 4 ( 0.6) Cardiac disorders 3 ( 0.5) Myocardial infarction 2 ( 0.3) Palpitations 1 ( 0.2) Surgical and medical procedures 3 ( 0.5) Bone lesion excision 1 ( 0.2) Laser therapy 1 ( 0.2) Rotator cuff repair 1 ( 0.2) Tooth extraction 1 ( 0.2) Blood and lymphatic system disorders 2 ( 0.3) Anaemia 1 ( 0.2) Lymphadenopathy 1 ( 0.2) Ear and labyrinth disorders 2 ( 0.3) Deafness unilateral 1 ( 0.2) Vertigo 1 ( 0.2) Endocrine disorders 1 ( 0.2) Benign neoplasm of adrenal gland 1 ( 0.2) Immune system disorders 1 ( 0.2) Hypersensitivity 1 ( 0.2) —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Note: Includes only adverse events with onset date prior to randomization. [a] System organ classes and preferred terms are coded using the MedDRA dictionary (Version 9.1). System organ classes and preferred terms are listed in descending order of frequency by the 75mg BID treatment group. A subject with multiple occurrences of an AE is counted only once in the System Organ Class and Preferred Term category.


9.2.2.1 Display of Adverse Events During the 12-week Efficacy Phase

A summary of adverse events that occurred during the 12-week Efficacy Phase appears as Appendix 16.2.7.2.


Appendix 16.2.7.2. Summary of Adverse Events during the Efficacy Phase

—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— System Organ Class/ Pravastatin 40 mg Fenofibrate 160 mg Pravafen Total Preferred Term [a] (N=114) (N=122) (N=239) (N=475) P-value [b] —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Number of subjects with at least 21 ( 18.4) 25 ( 20.5) 43 ( 18.0) 89 ( 18.7) 0.841 one treatment-related adverse event Investigations 7 ( 6.1) 6 ( 4.9) 17 ( 7.1) 30 ( 6.3) 0.752 Blood creatine phosphokinase 3 ( 2.6) 3 ( 2.5) 2 ( 0.8) 8 ( 1.7) 0.361 increased Low density lipoprotein increased 1 ( 0.9) 0 ( 0.0) 5 ( 2.1) 6 ( 1.3) 0.668 Alanine aminotransferase 0 ( 0.0) 2 ( 1.6) 2 ( 0.8) 4 ( 0.8) 0.606 increased Aspartate aminotransferase 0 ( 0.0) 2 ( 1.6) 2 ( 0.8) 4 ( 0.8) 0.606 increased Weight increased 1 ( 0.9) 0 ( 0.0) 3 ( 1.3) 4 ( 0.8) 1.000 Glomerular filtration rate 0 ( 0.0) 1 ( 0.8) 2 ( 0.8) 3 ( 0.6) 1.000 decreased Hepatic enzyme increased 1 ( 0.9) 1 ( 0.8) 1 ( 0.4) 3 ( 0.6) 0.805 Apolipoprotein B increased 1 ( 0.9) 0 ( 0.0) 1 ( 0.4) 2 ( 0.4) 0.542 Blood cholesterol increased 1 ( 0.9) 0 ( 0.0) 1 ( 0.4) 2 ( 0.4) 0.542 Electrocardiogram QT prolonged 1 ( 0.9) 0 ( 0.0) 1 ( 0.4) 2 ( 0.4) 0.542 Glucose tolerance test abnormal 1 ( 0.9) 1 ( 0.8) 0 ( 0.0) 2 ( 0.4) 1.000 Blood creatinine increased 0 ( 0.0) 1 ( 0.8) 0 ( 0.0) 1 ( 0.2) NE Blood phosphorus abnormal 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Heart rate decreased 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE High density lipoprotein 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE decreased Laboratory test abnormal 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Urine colour abnormal 1 ( 0.9) 0 ( 0.0) 0 ( 0.0) 1 ( 0.2) NE White blood cell count decreased 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE



System Organ Class/ Pravastatin 40 mg Fenofibrate 160 mg Pravafen Total Preferred Term [a] (N=114) (N=122) (N=239) (N=475) P-value [b] —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Gastrointestinal disorders 5 ( 4.4) 6 ( 4.9) 17 ( 7.1) 28 ( 5.9) 0.583 Constipation 1 ( 0.9) 2 ( 1.6) 5 ( 2.1) 8 ( 1.7) 0.896 Diarrhoea 3 ( 2.6) 0 ( 0.0) 3 ( 1.3) 6 ( 1.3) 0.393 Dyspepsia 0 ( 0.0) 1 ( 0.8) 2 ( 0.8) 3 ( 0.6) 1.000 Flatulence 0 ( 0.0) 1 ( 0.8) 2 ( 0.8) 3 ( 0.6) 1.000 Nausea 0 ( 0.0) 1 ( 0.8) 2 ( 0.8) 3 ( 0.6) 1.000 Abdominal pain upper 0 ( 0.0) 0 ( 0.0) 2 ( 0.8) 2 ( 0.4) NE Stomach discomfort 0 ( 0.0) 1 ( 0.8) 1 ( 0.4) 2 ( 0.4) 1.000 Vomiting 1 ( 0.9) 0 ( 0.0) 1 ( 0.4) 2 ( 0.4) 0.542 Abdominal distension 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Abdominal pain 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Dry mouth 1 ( 0.9) 0 ( 0.0) 0 ( 0.0) 1 ( 0.2) NE Dysphagia 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Gastrooesophageal reflux disease 0 ( 0.0) 1 ( 0.8) 0 ( 0.0) 1 ( 0.2) NE Nervous system disorders 2 ( 1.8) 6 ( 4.9) 7 ( 2.9) 15 ( 3.2) 0.397 Dizziness 2 ( 1.8) 1 ( 0.8) 3 ( 1.3) 6 ( 1.3) 0.758 Headache 1 ( 0.9) 2 ( 1.6) 2 ( 0.8) 5 ( 1.1) 0.842 Paraesthesia 0 ( 0.0) 1 ( 0.8) 2 ( 0.8) 3 ( 0.6) 1.000 Lethargy 0 ( 0.0) 1 ( 0.8) 1 ( 0.4) 2 ( 0.4) 1.000 Memory impairment 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Neuropathy peripheral 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Poor quality sleep 0 ( 0.0) 1 ( 0.8) 0 ( 0.0) 1 ( 0.2) NE Musculoskeletal and connective 4 ( 3.5) 3 ( 2.5) 7 ( 2.9) 14 ( 2.9) 0.880 tissue disorders Myalgia 4 ( 3.5) 1 ( 0.8) 1 ( 0.4) 6 ( 1.3) 0.045 Arthralgia 0 ( 0.0) 1 ( 0.8) 4 ( 1.7) 5 ( 1.1) 0.666 Muscle spasms 0 ( 0.0) 1 ( 0.8) 3 ( 1.3) 4 ( 0.8) 1.000 Pain in extremity 0 ( 0.0) 2 ( 1.6) 0 ( 0.0) 2 ( 0.4) NE Joint stiffness 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Musculoskeletal pain 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Osteoarthritis 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— [a] System organ classes and preferred terms are coded using the MedDRA dictionary (Version 9.1). System organ classes and preferred terms are listed in descending order of frequency by the 75mg BID treatment group. A subject with multiple occurrences of an AE is counted only once in the System Organ Class and Preferred Term category. [b] P-values are based on Fisher exact test.


Appendix 16.2.7.2. Summary of Adverse Events during the Efficacy Phase ase

—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— System Organ Class/ Pravastatin 40 mg Fenofibrate 160 mg Pravafen Total Preferred Term [a] (N=114) (N=122) (N=239) (N=475) P-value [b] —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— General disorders and 3 ( 2.6) 1 ( 0.8) 6 ( 2.5) 10 ( 2.1) 0.593 administration site conditions Fatigue 2 ( 1.8) 0 ( 0.0) 3 ( 1.3) 5 ( 1.1) 0.660 Asthenia 0 ( 0.0) 1 ( 0.8) 1 ( 0.4) 2 ( 0.4) 1.000 Hunger 0 ( 0.0) 1 ( 0.8) 0 ( 0.0) 1 ( 0.2) NE Influenza like illness 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Non-cardiac chest pain 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Pain 1 ( 0.9) 0 ( 0.0) 0 ( 0.0) 1 ( 0.2) NE Thirst 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Skin and subcutaneous tissue 3 ( 2.6) 2 ( 1.6) 2 ( 0.8) 7 ( 1.5) 0.416 disorders Rash 0 ( 0.0) 1 ( 0.8) 1 ( 0.4) 2 ( 0.4) 1.000 Urticaria 1 ( 0.9) 1 ( 0.8) 0 ( 0.0) 2 ( 0.4) 1.000 Night sweats 1 ( 0.9) 0 ( 0.0) 0 ( 0.0) 1 ( 0.2) NE Pruritus generalised 1 ( 0.9) 0 ( 0.0) 0 ( 0.0) 1 ( 0.2) NE Rash papular 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Metabolism and nutrition disorders 0 ( 0.0) 1 ( 0.8) 3 ( 1.3) 4 ( 0.8) 1.000 Hypercholesterolaemia 0 ( 0.0) 0 ( 0.0) 2 ( 0.8) 2 ( 0.4) NE Obesity 0 ( 0.0) 0 ( 0.0) 2 ( 0.8) 2 ( 0.4) NE Gout 0 ( 0.0) 1 ( 0.8) 0 ( 0.0) 1 ( 0.2) NE Respiratory, thoracic and 1 ( 0.9) 2 ( 1.6) 1 ( 0.4) 4 ( 0.8) 0.458 mediastinal disorders Choking 0 ( 0.0) 1 ( 0.8) 0 ( 0.0) 1 ( 0.2) NE Dyspnoea 1 ( 0.9) 0 ( 0.0) 0 ( 0.0) 1 ( 0.2) NE Hiccups 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Pharyngolaryngeal pain 0 ( 0.0) 1 ( 0.8) 0 ( 0.0) 1 ( 0.2) NE —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— [a] System organ classes and preferred terms are coded using the MedDRA dictionary (Version 9.1). System organ classes and preferred terms are listed in descending order of frequency by the 75mg BID treatment group. A subject with multiple occurrences of an AE is counted only once in the System Organ Class and Preferred Term category. [b] P-values are based on Fisher exact test.



—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— System Organ Class/ Pravastatin 40 mg Fenofibrate 160 mg Pravafen Total Preferred Term [a] (N=114) (N=122) (N=239) (N=475) P-value [b] —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Infections and infestations 2 ( 1.8) 1 ( 0.8) 0 ( 0.0) 3 ( 0.6) 0.611 Gastroenteritis viral 1 ( 0.9) 0 ( 0.0) 0 ( 0.0) 1 ( 0.2) NE Herpes zoster 1 ( 0.9) 0 ( 0.0) 0 ( 0.0) 1 ( 0.2) NE Pharyngitis 0 ( 0.0) 1 ( 0.8) 0 ( 0.0) 1 ( 0.2) NE Cardiac disorders 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Palpitations 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Injury, poisoning and procedural 0 ( 0.0) 1 ( 0.8) 0 ( 0.0) 1 ( 0.2) NE complications Contusion 0 ( 0.0) 1 ( 0.8) 0 ( 0.0) 1 ( 0.2) NE Psychiatric disorders 1 ( 0.9) 0 ( 0.0) 0 ( 0.0) 1 ( 0.2) NE Anxiety 1 ( 0.9) 0 ( 0.0) 0 ( 0.0) 1 ( 0.2) NE Renal and urinary disorders 1 ( 0.9) 0 ( 0.0) 0 ( 0.0) 1 ( 0.2) NE Haematuria 1 ( 0.9) 0 ( 0.0) 0 ( 0.0) 1 ( 0.2) NE Pollakiuria 1 ( 0.9) 0 ( 0.0) 0 ( 0.0) 1 ( 0.2) NE Surgical and medical procedures 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Cholecystectomy 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— [a] System organ classes and preferred terms are coded using the MedDRA dictionary (Version 9.1). System organ classes and preferred terms are listed in descending order of frequency by the 75mg BID treatment group. A subject with multiple occurrences of an AE is counted only once in the System Organ Class and Preferred Term category. [b] P-values are based on Fisher exact test.


12.2.3.2.1 Display of Adverse Events Occurring During the 12-week Efficacy Phase Leading to Treatment Discontinuation

A summary of adverse events that took place during the 12-week Efficacy Phase and led to discontinuation of the patient in the study is found in Appendix 16.2.7.3.


Appendix 16.2.7.3. Summary of Adverse Events That Led to Patient Discontinuation

—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— System Organ Class/ Pravastatin 40 mg Fenofibrate 160 mg Pravafen Total Preferred Term [a] (N=114) (N=122) (N=239) (N=475) P-value [b] —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Number of subjects with at least 7 ( 6.1) 8 ( 6.6) 22 ( 9.2) 37 ( 7.8) 0.563 one adverse event leading to discontinuation Investigations 2 ( 1.8) 4 ( 3.3) 11 ( 4.6) 17 ( 3.6) 0.469 Glomerular filtration rate 1 ( 0.9) 1 ( 0.8) 5 ( 2.1) 7 ( 1.5) 0.689 decreased Blood creatine phosphokinase 1 ( 0.9) 3 ( 2.5) 0 ( 0.0) 4 ( 0.8) 0.623 increased Alanine aminotransferase 0 ( 0.0) 1 ( 0.8) 1 ( 0.4) 2 ( 0.4) 1.000 increased Glomerular filtration rate 0 ( 0.0) 0 ( 0.0) 2 ( 0.8) 2 ( 0.4) NE increased Aspartate aminotransferase 0 ( 0.0) 1 ( 0.8) 0 ( 0.0) 1 ( 0.2) NE increased Blood creatinine increased 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Carbon dioxide decreased 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Glucose tolerance test abnormal 0 ( 0.0) 1 ( 0.8) 0 ( 0.0) 1 ( 0.2) NE Heart rate decreased 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Laboratory test abnormal 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Musculoskeletal and connective 2 ( 1.8) 3 ( 2.5) 4 ( 1.7) 9 ( 1.9) 0.906 tissue disorders Muscle spasms 0 ( 0.0) 1 ( 0.8) 2 ( 0.8) 3 ( 0.6) 1.000 Myalgia 2 ( 1.8) 1 ( 0.8) 0 ( 0.0) 3 ( 0.6) 0.611 Arthralgia 0 ( 0.0) 0 ( 0.0) 2 ( 0.8) 2 ( 0.4) NE Pain in extremity 0 ( 0.0) 1 ( 0.8) 0 ( 0.0) 1 ( 0.2) NE —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— [a] System organ classes and preferred terms are coded using the MedDRA dictionary (Version 9.1). System organ classes and preferred terms are listed in descending order of frequency by the 75mg BID treatment group. A subject with multiple occurrences of an AE is counted only once in the System Organ Class and Preferred Term category. [b] P-values are based on Fisher exact test.



—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— System Organ Class/ Pravastatin 40 mg Fenofibrate 160 mg Pravafen Total Preferred Term [a] (N=114) (N=122) (N=239) (N=475) P-value [b] —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— Gastrointestinal disorders 2 ( 1.8) 1 ( 0.8) 5 ( 2.1) 8 ( 1.7) 0.809 Nausea 1 ( 0.9) 0 ( 0.0) 2 ( 0.8) 3 ( 0.6) 1.000 Vomiting 2 ( 1.8) 0 ( 0.0) 1 ( 0.4) 3 ( 0.6) 0.245 Abdominal pain 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Diarrhoea 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Dyspepsia 0 ( 0.0) 1 ( 0.8) 0 ( 0.0) 1 ( 0.2) NE General disorders and 0 ( 0.0) 1 ( 0.8) 2 ( 0.8) 3 ( 0.6) 1.000 administration site conditions Asthenia 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Chest pain 0 ( 0.0) 1 ( 0.8) 0 ( 0.0) 1 ( 0.2) NE Influenza like illness 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Nervous system disorders 0 ( 0.0) 1 ( 0.8) 1 ( 0.4) 2 ( 0.4) 1.000 Dizziness 0 ( 0.0) 1 ( 0.8) 0 ( 0.0) 1 ( 0.2) NE Headache 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Ear and labyrinth disorders 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Eustachian tube dysfunction 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Hepatobiliary disorders 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Biliary dyskinesia 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Infections and infestations 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Acute sinusitis 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Metabolism and nutrition disorders 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Hypokalaemia 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Hyponatraemia 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Psychiatric disorders 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Libido decreased 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— [a] System organ classes and preferred terms are coded using the MedDRA dictionary (Version 9.1). System organ classes and preferred terms are listed in descending order of frequency by the 75mg BID treatment group. A subject with multiple occurrences of an AE is counted only once in the System Organ Class and Preferred Term category. [b] P-values are based on Fisher exact test.


—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— System Organ Class/ Pravastatin 40 mg Fenofibrate 160 mg Pravafen Total Preferred Term [a] (N=114) (N=122) (N=239) (N=475) P-value [b] ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————


Skin and subcutaneous tissue 1 ( 0.9) 0 ( 0.0) 0 ( 0.0) 1 ( 0.2) NE disorders Night sweats 1 ( 0.9) 0 ( 0.0) 0 ( 0.0) 1 ( 0.2) NE Surgical and medical procedures 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE Cholecystectomy 0 ( 0.0) 0 ( 0.0) 1 ( 0.4) 1 ( 0.2) NE

—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— [a] System organ classes and preferred terms are coded using the MedDRA dictionary (Version 9.1). System organ classes and preferred terms are listed in descending order of frequency by the 75mg BID treatment group. A subject with multiple occurrences of an AE is counted only once in the System Organ Class and Preferred Term category. [b] P-values are based on Fisher exact test.


9.2.3 Display of Adverse Events During the 24/52-week Safety Phase

9.2.3.1 Display of All Adverse Events during the 24/52-week Safety Phase

9.2.3.2 Display of Adverse Events Related to the Study Treatment during the 24/52-week Safety Phase

9.2.3.3 Display of Adverse Events Occurring During the 24/52-week Safety Phase Leading to Treatment Discontinuation

12.2.3 Listing of Adverse Events by Patient

All treatment-emergent adverse events are listed in Appendix 16.2.7.4 by patient.

12.3 Deaths and Serious and Significant Adverse Events

12.3.1 Listing of Serious or Significant Adverse Events

A list of serious adverse events is presented in Figure 14.

A list of adverse events that led to patient discontinuation in the study is presented in Figure 15.

12.3.1.1 Deaths

There were no treatment-related deaths during the Selection or Efficacy Phases of the study, and no deaths have occurred during the first 3 months of the 12-month Safety Phase as well.

12.3.1.2 Other Serious Adverse Events

Four patients experienced serious adverse events while taking study medication and being monitored for safety.

One experienced chest pain; one suffered the protrusion of an intervertebral disc and associated cervical myelopathy; one experienced lower abdominal pain, surgically received a cholecystectomy, and suffered a post-procedural infection; and one suffered malignant melanoma.

Although all 3 patients had been randomized into the Pravafen (combination Pravastatin/Fenofibrate 40/160mg) treatment group, no statistical significance was attached to these events (p=0.435).

12.3.1.3 Other Significant Adverse Events

Thirty-seven patients experienced at least one adverse event that led to their withdrawal from the study.


Of these, 7 had been randomized to monotherapy Pravastatin, 8 to monotherapy Fenofibrate, and 22 to combination therapy Pravafen (combination Pravastatin/Fenofibrate 40/160mg).

No statistical significance could be attached to the distribution of these adverse events (p=0.563).

A summary of adverse events that led to patient discontinuation in the study by system and patient group can be found in Figure 15.


Figure 15. Treatment-Emergent Adverse Events Leading to Discontinuation During Efficacy Phase

System/disorder Pravastatin 40mgn=114

Fenofibrate 160mgn=122

Pravafenn-239

Totalsn=475

Infections and infestations 0 0 1 1Musculoskeletal/connective tissue 2 3 4 9Gastrointestinal 2 1 5 8Nervous system 0 1 1 2General & administrative site 0 1 2 3Respiratory, thoracic, mediastinal 0 0 0 0Injury, poisoning, procedural 0 0 0 0Skin & subcutaneous tissue 1 0 0 1Psychiatric 0 0 1 1Metabolic/nutritional 0 3 3 6Cardiac 0 0 1 1Surgical/medical procedures 0 0 1 1Vascular 0 0 0 0Ear/labyrinth 0 0 1 1Blood/lymphatic 0 0 0 0Eye 0 0 0 0Immune system 0 0 0 0Hepatobiliary 0 0 1 1Reproductive 0 0 0 0Neoplasms, benign, malignant, unspecified 0 0 0 0Renal/urinary 2 4 8 14Insomnia 0 0 0 0

Number of dc’d subjects with adverse events 7 8 22 37


12.3.2 Narratives of Serious and Significant Adverse Events

12.3.2.1 Narratives of Serious Adverse Events

A list of serious adverse events (AE) associated with the study and their circumstances is presented in Figure 14. All patients suffering these AE were discontinued from the study.

The first listed patient suffered severe chest pain unrelated to the study protocol during his first day of treatment with the study medication. He was taken off the study medication and recovered.

The second listed patient suffered herniation of an intervertebral disc and cervical myelopathy, both symptoms unrelated to the study protocol, on the second day of treatment with the study medication. After she was taken off the medication, she recovered.

A third patient experienced abdominal pain on the second day of treatment with the study medication, unrelated to the study procedure. Examination revealed a gall bladder disorder, and cholecystectomy was performed that same day. The patient was at the same time removed from the study protocol. Infection of the surgical site was revealed on the sixth postoperative day and was treated with antibiotics. The patient soon recovered.

In situ malignant melanoma of the upper right arm, etiology unrelated to the study medication, was discovered in the fourth patient on the 28th day of treatment with the study medication. After being withdrawn from participation in the study, the patient was treated and recovered.

12.3.2.2 Narratives of Significant Adverse Events That Led to Discontinuation

Forty-one patients (8.6% of 475 patients monitored for safety) suffered adverse AE, significant but for the most part not serious, that nevertheless led to their withdrawal from participation in the study. A summary of these events and the circumstances surrounding them is presented in Appendix 16.2.7.3.

Muscle-related disorders--myalgias, muscle spasms, and extremity pain--make up the largest category (24.4%) of patients experiencing discontinuation-causing AE during the study. The study drug was thought to have caused the extremity pain of all 4 patients with this symptom, and all but one recovered after being withdrawn from the study. Myalgias were also attributed to the study drug; two of the three patients suffering from study-related muscle pain recovered after being withdrawn from participation and the circumstances of the third are unknown. Finally, the muscle spasms of 2 of the 3 patients suffering these AE were attributed to the study medication, and discontinuation of that medication resolved these symptoms. The third’s symptoms were thought to have resolved after discontinuation of the study drug.


With a likely etiological relation to these muscle complaints were increases in creatine kinase levels in 4 patients (9.8%). In 3 of these 4, the study drug was thought to be the cause of the symptom. Two of these patients recovered after their study medication was discontinued, another’s high CK levels persist, and a fourth’s circumstances are presently unknown.

Eight (19.5%) of these patients experienced slowing of their glomerular filtration rate early in the course of their treatment with the study medication. All but one of these patients suffered this condition during their first few days of treatment with the study drug and withdrew from the study. The other delayed his symptoms until the 32nd day of treatment and similarly withdrew from study participation. The study drug was thought to be of doubtful or no relation to the symptom in 5 of the 8 cases and to have either possibly or definitely caused the symptom in the other 3. Two patients for whom it was thought the study drug probably did not cause the adverse event have recovered; in the other 6 the AE persists.

Six patients (14.6%) suffered gastrointestinal side effects during the study--nausea, vomiting, and/or dyspepsia--and withdrew from participation. The symptoms of four were thought to be the result of administration of the study drug, and those of the other two probably unrelated. All but the lone dyspepsia patient recovered.

The remaining AE study patients (36.5%) suffered from an assortment of ailments, including 2 with arthralgias, 2 with increases in glomerular filtration rate, and 1 each with fatigue, dizziness, night sweats, decreased libido, sinusitus, bradycardia, biliary dyskinesia, influenza, Eustacian tube dysfunction, asthenia, increases in alanine and aspartate aminotransferases, abnormal glucose tolerance test, hypokalemia, hyponatremia, and diarrhea. Most of these were thought caused by the study medication and resolved following its discontinuation. The cases of increases in glomerular filtration rate, bradycardia, and hepatic dyskinesia persist as of last report.

12.3.3 Analysis and Discussion of Serious and Significant Adverse Events

In a recent review of 16,591 UK patients treated for hyperlipidemia with either statins or fibrates, Molokhia [23] estimates the risk of statin-induced myopathy and myalgias as 11.4%, and of statins and fibrates together at 25.7% (p<0.05). The smaller percentages of muscle-related AE in the present study suggests Molokhia’s study population was comparatively less selective, including, for example, cases in which were combined with statins, circumstances which have repeatedly been associated with myopathy, especially when ATP III guidelines were not met. [24] But as in Molokhia’s review, the present study underlines the potential for persistent myopathy in an extremely small percentage of cases following long-term exposure to statins, fibrates, or combination therapy.

McClure’s statistics [25] are far closer to those obtained in the present study. The prevalence of myositis associated with statins in his 2007 study was 2.8%, and of combination statin-fibrate therapy 9.1%. The incidence of comorbid liver disease with statin-fibrate therapy was 4.3%.


Fenofibrate can raise creatinine and homocysteine levels in some cases, but these effects are reversible, and the risks of myopathy, cholelithiasis, and venous thrombosis together associated with it are less than 1.0%. [26] Preferable to other fibrates because its effects are mediated by the peroxisome proloiferator-activated receptor-alpha (PPARalpha) that is independent of glucose and lipid metabolism and not associated with inhibition of statin metabolism, Fenofibrate not only lowers serum triglycerides and raises HDL cholesterol, complementing the cholesterol-lowering effects of statins, but can reduce and reverse deposition of atherosclerotic plaque as statins do not. [27,28] The FIELD study found that Fenofibrate also reduces the progression of proteinuria and vascular retinopathy in diabetics. [29]

When renal impairment is present or suspected concomitantly with Fenofibrate administration, serum creatinine should be measured and the Fenofibrate dosage adjusted accordingly. Although routine monitoring of serum creatinine levels is unnecessary, increases in creatinine not associated with other causes should compel discontinuation of Fenofibrate administration. [26]

Depression, memory loss, confusion, and aggression have in the past been associated with statin use, [30] although only one case of psychiatric adverse effects—decrease in libido—is cited in the present study. A decrease in the cholesterol made available to brain cell membranes is thought to be the cause of these symptoms, and caution with respect to the evolution of psychiatric symptoms in conjunction with statin and statin-fibrate pharmacotherapy is certainly always indicated. [30]

But on the whole, authors overwhelmingly emphasize that the benefits of combination statin-fibrate therapy far outweigh their potential for adverse effects. Rhabdomyelosis and its associated renal failure, in particular, though usually cited as potentially associated with combination therapy, is actually extremely rare and almost always found associated with predisposing factors, such as diabetes mellitus, renal insufficiency, hypothyroidism, or extreme old age. [31] Gastrointestinal side effects are not only very rare but predominantly reversible.

12.4 Clinical Laboratory Evaluation

12.4.1 Normal Laboratory Ranges

The list of accepted “normal” laboratory ranges is provided in Figure 1.

12.4.2 Listing of Individual Laboratory Measurements by Patient

A list of individual patient laboratory values is provided as Appendix 16.2.8.

12.4.3 Laboratory Values Over Time

12.4.3.1 Laboratory Values Over Time During the 12-week Efficacy Phase

Shift tables during the Efficacy Phase are presented as Appendix 16.2.8.1 as follows:


Blood chemistry values during the Efficacy Phase Hematology values during the Efficacy Phase Liver and liver function tests during the Efficacy Phase Elevation of creatine phosphokinase (CPK) levels during the Efficacy Phase Elevation of transaminase levels (SGOT/SGPT) during the Efficacy Phase Hematology laboratory monocyte levels during the Efficacy Phase

12.4.3.2 Laboratory Values Over Time During the 24/52-week Safety Phase

12.5 Vital Signs, Physical Findings, and Other Observations Related to Safety

12.5.1 Vital Signs

A listing of patient vital signs readings obtained at each visit is presented as Appendix 16.2.12.

Vital signs are summarized as follows:

Systolic blood pressure by patient group: Figure 16. Diastolic blood pressure by patient group: Figure 17. Heart rate by patient group: Figure 18.

12.5.2 Physical Examinations

A summary of the results of physical examinations performed on all patients is presented as Appendix 16.2.11.

In addition, a summary of vital signs obtained at these physical examinations is presented in Figure 19.

12.5.3 ECG Results

A list of patient visits at which ECG’s were performed on all participating study patients is presented in the Schedule of Events for patient visits in Table 1.

The results of these ECG’s are listed in Appendix 16.2.14.

Shifts in ECG values obtained at successive visits are presented in Figure 20.

12.5 Discussion

Recent studies have underlined both the effectiveness of statin therapy in lowering total and LDL cholesterol and cardiovascular heart disease risk, especially in older patients at high risk for ischemic events, [32] and the limitations of monotherapy statin treatment for dyslipidemia and mixed hyperlipidemia: Statins effectively reduce LDL cholesterol and total cholesterol but generally fail to reduce triglycerides, raise HDL cholesterol levels or reduce morbidity and mortality risks of cardiovascular heart disease events. [33-35]


These studies also amply demonstrate the synergies available with combination statin and fibrate therapy and the dangers of combining certain fibrates, such as gemfibrozil, with statins, because gemfibrozil interferes with glucouronidation of statins, leading to elevations of statin plasma concentrations that cause rhabdomyelosis and myopathy. These studies suggest that such dangers are not common to all fibrates and do not, for example, apply to Fenofibrate, bezafibrate, or ciprofibrate because such fibrates do not affect the same metabolic pathways as the statins and do not therefore influence their pharmacokinetics or metabolism. [36]

Combined hyperlipidemia results from hepatic synthesis of Apolipoprotein B in very low- density lipoprotein cholesterol (VLDL) and thereby causes risk factors associated with cardiovascular heart disease. [38] It is therefore important to monitor the effect of pharmacological treatment for mixed hyperlipidemia on levels of Apolipoprotein B. But while Farnier’s study [36] establishes that combination therapy with ezetimibe/atorvastatin and Fenofibrate is superior to either monotherapy in reducing Apolipoprotein B as well as LDL-C, total cholesterol, and total triglycerides, and raising HDL-C and Apolipoprotein A1, and was equally as well tolerated, his study is limited by number of patients and duration of follow-up and does not measure the effect of combination therapy on non-HDL-cholesterol.

May’s recent study [39] underscores the superiority of combination statin-fibrate therapy in lowering VLDL-C and LDL-C pattern B in patients with TG >170mg/dL, lipids that tend to be formed in the presence of these same triglycerides, but his study is limited to patients exhibiting types 1 and 2 diabetes mellitus.

Chatley’s study [35] most closely resembles the present study in aims and demonstrates that combination atorvastatin/Fenofibrate therapy maximizes lowering of LDL-C, TG, and TC and increases HDL-C in comparison to all monotherapies, with no differences in patient safety observed between combination and monotherapy groups, but his study was limited to only ninety patients and was not randomized.

The primary efficacy endpoint of the present study is this particular difference in effect on non-HDL cholesterol between the statin-fibrate combination Pravafen (combination Pravastatin/Fenofibrate 40/160mg) over a 12-week Efficacy Phase, adds as secondary endpoints combination therapy’s effects on the other lipidemic parameters (LDL-C, TG, TC, HDL, therapeutic goals, and 10-year cardiovascular risk), and extends the period of safety follow-up to a Safety Phase 52 weeks beyond the Efficacy Phase, underlining the importance of monitoring long-term statin and combination statin-fibrate patients for development of myopathy and myositis. [23,25,27]

Results of the present study largely repeat the findings of recent as well as older studies:

Non-HDL cholesterol is more effectively reduced by combination Pravafen (Pravastatin/Fenofibrate 40/160mg) than either monotherapy Pravastatin or monotherapy Fenofibrate


Combination therapy Pravafen (Pravastatin/Fenofibrate 40/160mg) reduces total cholesterol more effectively than monotherapy Pravastatin or monotherapy Fenofibrate

Triglycerides are more effectively reduced by combination therapy Pravafen (Pravastatin/Fenofibrate 40/160mg) than either monotherapy Pravastatin or monotherapy Fenofibrate

Apolipoprotein B, the cause of hyperlipidemia, is more effectively reduced by combination therapy Pravafen (Pravastatin/Fenofibrate 40/160mg) than monotherapy Pravastatin or monotherapy Fenofibrate

Apolipoprotein A1 is raised more effectively administration of combination therapy Pravafen (Pravastatin/Fenofibrate 40/160mg) than monotherapy Pravastatin or monotherapy Fenofibrate

Levels of high density lipoprotein cholesterol are raised more effectively by combination therapy Pravafen (Pravastatin/Fenofibrate 40/160mg) than by monotherapy Pravastatin or monotherapy Fenofibrate

Patients administered combination therapy Pravafen (Pravastatin/Fenofibrate 40/160mg) are twice as likely to reach their therapeutic goals for reducing serum levels of low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol as those taking either monotherapy Pravastatin or monotherapy Fenofibrate

12.6 Conclusions

12.6.1 Efficacy Conclusions

Statins and certain fibrates, such as Fenofibrate, act on different metabolic pathways and therefore work synergistically. Statins reduce serum levels of total and low-density lipoprotein cholesterol, while fibrates reduce triglycerides, raise low levels of high-density lipoprotein cholesterol, and reduce overall risk of cardiovascular morbidity and mortality. In particuclar, Pravastatin (PRAVACHOL, Bristol-Meyers Squibb) and Fenofibrate have been shown to be effective against hyperlipidemia without interacting with each other to increase risk of adverse effects. Patients are far more likely to meet with success in attaining dual therapeutic goals of reducing low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol on combination Pravastatin-Fenofibrate therapy than while taking either Pravastatin or Fenofibrate alone. Therapeutic use of Pravafen (combination Pravastatin/Fenofibrate 40/160mg) in the treatment of mixed hyperlipidemia is therefore recommended.

12.6.2 Safety Conclusions

Caution should prevail when combination statin-fibrate therapy is administered concomitantly with other medications and when predisposing conditions, such as diabetes mellitus, renal insufficiency, and hypothyroidism are present or suspected. Dosages should


be adjusted to reflect these conditions. Other lipid-lowering medications must be discontinued when statin-fibrate combinations are administered.

Nevertheless, this particular combination of Pravastatin and Fenofibrate, present in Pravafen (combination Pravastatin/Fenofibrate 40/160mg), offers so many therapeutic advantages, with only slight chances for usually reversible adverse side effects, that it must be considered the preferred therapeutic alternative for hyperlipidemia in the majority of clinical circumstances.


13 REFERENCE LIST

1. Cullen P, Schulte H, Assmann G. The Münster Heart Study (PROCAM). Total mortality in middle-aged men is increased at low total and LDL cholesterol concentrations in smokers but not in non-smokers. Circulation. 1997. 96: 2128-36.

2. Pedersen TR, Olsson AG, Faergeman O, et al. for the Scandinavian Survival Study Group. Lipoprotein changes and reduction in the incidence of major coronary heart disase in the Scandinavian Simvastatin Survival Study (4S). Circulation. 1998; 97 (15): 1453-60.

3. Grundy SM, Members from the Expert Panel. Summary of the second report of the National Cholesterol Education Program (NCEP) expert panel ondetection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel II). JAMA. 1993; 269: 3015-23.

4. Pedersen TR, Berg K, Cook TJ, et al. Safety and tolerability of cholesterol lowering with simvastatin during 5 years in the Scandinavian Simvastatin Survival Study (4S). Arch Intern Med. 1996; 156: 2085-92.

5. Ose L, Kastelein JJP, Scott R, et al. for the WSEDP Research Group. Efficacy and six-month safety of simvastatin 80mg/day: results from theWorldwide Simvastatin Expanded Dose Program (WSEDP). Nutr Metab Cardiovasc Dis. 1998; 8: 135-43.

6. Packard CJ. Overview of fenofibrate. Eur Heart J. 1998; 19 Suppl A: A62-5.

7. Watts GF, Dimmitt SB. Fibrates, dyslipoproteinemia and cardiovascular disease. Curr Opin Lipidol. 1999: 10 (6): 561-74.

8. Farnier M, Bonnefous F, Debbas N, et al. Comparative efficacy and safety of micronized fenofibrate and simvastatin in patients with primary type IIa or IIb hyperlipidemia. Arch Intern Med. 1994: 154: 441-9.

9. Wierzbicki AS, et al. Statin-fibrate combination therapy for hyperlipidaemia: a review. Current Medical Research and Opinion; vol 19: no. 3, 2003.

10. Ducobu J, et al. Comparison of micronized fibrate and Pravastatin in patients with priary hyperlipidemia. J Cardiovasc Pharmacol. 2003; 41: 60-7.

11. Melenovsky V, et al. Comparison of the effects of atorvastatin or fenofibrate on nonlkipid biochemical risk factors and the LDL particle size in subjects with combined hyperlipidemia. Am Heart J. 2002; 144-6.

12. Steinmetz A, et al. Multicenter comparison of micronized fenofibrate and simvastatin in patients with parimary type IIA or IIB hyperlipoproteinemia. J Cardiovasc Pharmacol. 1996; 27: 563-70.

13. Lemieux I, et al. A 16-week fenofibrate treatment increases LDL particle size in type IIA dyslipidemic patients. Atherosclerosis. 2002; 162 (2): 363-71.


14. Farnier M and Dejager S. Effect of combined fluvastatin-fenofibrate therapy compared with fenofibrate monotherapy in severe primary hypercholesterolemia. Am J Card. 2000; 85: 53-7.

15. Ellen R and McPherson R. Long-term efficacy and safety of fenofibrate and a statin in the treatment of combined hyperlipidemia. Am J Cardiol. 1998; 81 ($A): 60B-65B.

16. Athyros VG, et al. Safety and efficacy of long-term statin-fibrate combinations in patients with refractory familial combined hyperlipidemia. Am J Card. 1997; 80: 608-13.

17. Lliadis EA and Rosensono RS. Long-term safety of Pravastatin-gemfibrozil therapy in mixed hyperlipidemia. Clin Card. 1999; 22 (1): 25-8.

18. Mantel-Teeuwisse AK, et al. Myopathy due to statin/fibrate use in the Netherlands. Ann Pharmacother. 2002; 36: 1957-60.

19. Farnier M, et al. Frequency of creatine kinase elevation during treatment with fluvastatin in combination with fibrates (Bezafibrate, Fenofibrate, or Gemfibrozil). Am J Card. 2003; 91: 238-40.

20. Athyros VG, et al. Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined hyperlipidemia. Diabetes Care. 2002; 25: 1198-1202.

21. Assmann G, et al. Simple scoring scheme for calculating the risk of acute coronary events based on the 10-Year follow-up of the Prospective Cardiovascular Munster (PROCAM) Study. Circulation. 2002; 105: 310-15.

22. Laboratories SMB. A Phase II, two-armed, randomized, double-blind, double-dummy, parallel study to compare the therapeutic efficacy of 12 weeks of one combination (Fenofibrate/Pravaastatin 160/40mg) versus Pravastatin 40mg alone, followed by an open-label safety phase of the combination alone of 52 weeks, in high risk patients with combined hyperlipidemia. Clinical Study Report. Unpublished data. 2007

23. Molokhia M, McKeigue P, Curcin V, Majeed A. Statin-induced myopathy and myalgia: time trend analysis and comparison of risk associated with statin class from 1991-2006. PLoS ONE. 2008 Jun 25; 3 (6): e2522.

24. Curtin PO, Jones WN. Therapeutic rationale of combining therapy with gemfibrozil and simvastatin. J. Am Pharm Assoc (2003). 2007 Mar-Apr; 47 (2): 140-6.

25. McClure DL, Valulck RJ, Glanz M, Murphy JR, Hokanson JE. Statin and statin-fibrate use was significantly associated with increased myositis risk in a managed care population. J. Clin Epidemiol. 2007 Aug; 60 (8): 812-8.

26. Davidson MH, Armani A, McKenney JM, Jacobson TA. Safety considerations with fibrate therapy. Am J Cardiol. 2007 Mar 19; 99 (6A): 3C-18C.


27. Remick J, Weintraub H, Setton R, Offenbacher J, Fisher E, Schwartzbard A. Fibrate therapy: an update. Cardiol Rev. 2008 May-Jun; 16 (3): 129-41.

28. Zambon A, Cusi K. The role of fenofibrate in clinical practice. Diab Vasc Dis Res. 2007 Sep; 4 Suppl 3: S15-S20.

29. Brown WV. Expert commentary: the safety of fibrates in lipid-lowering therapy. Curr Opin Lipidol. 2007 Mar 19; 99 (6A): 19C-21C.

30. Tatley M, Savage R. Psychiatric adverse reactions with statins, fibrates, and ezetimibe: implications for the use of lipid-lowering agents. Drug Saf. 2007; 30 (3): 195-201.

31. Tahmaz M, Kumbasar B, ERgen K, Ure U, Karatemiz G, Kazanciogul R. Acute renal failure secondary to fenofibrate monotherapy-induced rhabdomyolysis. Ren Fail. 2007; 29 (7): 927-30.

32. Aronow WS. Treatment of high-risk older persons with lipid lowering drug therapy.Am J Ther. 2008 Mar-Apr; 15(2): 102-7.

33. Avisar I, Brook JG, Wolfovitz E. Atorvastatin monotherapy vs. combination therapy in the management of patients with combined hyperlipidemia. Eur J Intern Med. 2008 May; 19(3): 203-8.

34. Brinton EA. Does the addition of fibrates to statin therapy have a favorable risk to benefit ratio? Curr Atheroscler Res. 2008 Feb; 10(1): 25-32.

35. Chatley P, Badyal DK, Calton R, Khosla PP. Combination therapy of low-dose atorvastatin and fenofibrate in mixed hyperlipidemia. Methods Find Exp Clin Pharmacol. 2007 Apr; 29 (3): 217-21.

36. Farnier M, Roth E, Gil-Extremera B, Mendez GF, Macdonell G, Hamlin C, Perevozskaya I, Davies MJ, Kush D, Mitchel YB; Ezetimibe/Simvastatin + Fenofibrate Study Group.Efficacy and safety of the coadministration of ezetimibe/simvastatin with fenofibrate in patients with mixed hyperlipidemia. Am Heart J. 2007 Feb; 153 (2): 335e1-8.

37. Franssen R, Vergeer M, Stroes ES, Kastelein JJ. Combination statin-fibrate therapy: safety aspects. Diabetes Obes Metab. 2008 Jun 1.

38. Koh KK, Quon MJ, Rosenson RS, Chung WJ, Han SH. Vascular and metabolic effects of treatment of combined hyperlipidemia: focus on statins and fibrates. Int J Cardiol. 2008 Feb 29; 124 (2): 149-59.

39. May HT, Anderson JL, Pearson RR, Jensen JR, Horne BD, Lavasani F, Yannicelli HD, Muhlestein JB. Comparison of effects of simvastatin alone versus fenofibrate alone versus simvastatin plus fenofibrate on lipoprotein subparticle profiles in diabetic patients with mixed dyslipidemia (from the Diabetes and Combined Lipid Therapy Regimen study). Am J Cardiol. 2008 Feb 15; 101 (4): 486-9.


http://www.ncbi.nlm.nih.gov/pubmed/17658632?ordinalpos=9&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum








16 APPENDICES

16.1 STUDY INFORMATION

16.1.1 Protocol and Protocol Amendments

16.1.2 Sample Case Report Form (unique pages only)

16.1.3 List of IEC’s or IRB’s (plus the name of the committee chair if required by the regulatory authority) and Representative Written Information for Patient and Sample Consent Forms

16.1.3.1 List of IEC’s or IRB’s

16.1.3.2 Representative Written Information for the Patient

16.1.3.3 Sample Consent Forms

16.1.4 List and Description of Investigators and Other Important Participants in the Study, Including Brief (one page) CV’s or Equivalent Summaries of Training and Experience Relevant to the Performance of the Clinical Study

16.1.4.1 List and Description of Investigators and Other Important Participants in the Study

16.1.4.2 Brief CV’s or Equivalent Summaries of Training and Experience Relevant to the Performance of the Clinical Study

16.1.5 Signatures of Principal or Coordinating Investigator(s) or Sponsor’s Responsible Medical Officer, Depending on the Regulatory Authority’s Requirement

16.1.5.1 Signatures of Principal or Coordinating Investigator(s) or Sponsor’s Responsible Medical Officer

16.1.5.2 Signatures of the Clinical Study Report Authors

16.1.6 Listing of Patients Receiving Test Drug(s)/Investigational Product(s) from Specific Batches, Where More Than One Batch Was Used

16.1.7 Randomization Scheme and Codes (Patient Identification and Treatment Assigned)

16.1.8 Audit Certificates

16.1.9 Documentation of Statistical Methods

16.1.10 Documentation of Inter-laboratory Standardization Methods and Quality Assurance Procedures If Used

16.1.11 Publications Based on the Study

16.1.12 Important Publications Referenced in the Report

16.2 PATIENT DATA

16.2.1 Discontinued Patients

16.2.2 Protocol Deviations

16.2.3 Patients Excluded From the Efficacy Analysis

16.2.4 Demographic Data

16.2.5 Compliance and/or Drug Concentration Data

16.2.6 Individual Efficacy Response Data


16.2.7 All Adverse Events by Patient 16.2.7.1 Adverse Events Occurring During the Selection Phase 16.2.7.2 Adverse Events Occurring During the Efficacy Phase 16.2.7.3 Adverse Events That Led to Patient Discontinuation in the Study 16.2.7.4 All Treatment-Emergent Adverse Events

16.2.8.1 Individual Laboratory Measurements by Patient16.2.8.2 Shift Values of All Laboratory Measurements During the Efficacy Phase 16.2.9 Individual Medical Histories16.2.10 Individual Lipid Tests16.2.11 Individual Results of their Physical Examinations16.2.12 Individual Vital Signs16.2.13 Individual Prior and Concomitant Medications16.2.14 Individual Results of their ECG’s

16.3 CASE REPORT FORMS (CRF’S)

16.3.1 CRF’s for Deaths, Other Serious Adverse Events, and Withdrawals for Adverse Events

16.3.2 Other CRF’s Submitted 16.3.3 Study Drug Dispensary Record on Case Report Forms

16.4 INDIVIDUAL PATIENT DATA LISTINGS


16.1 STUDY INFORMATION

16.1.1 PROTOCOL AND PROTOCOL AMENDMENTS

The protocol is provided on the following pages.

The revised protocol incorporating all protocol amendments and standalone amendments is provided on the following pages.

The original protocol and individual protocol amendments are provided on the following pages.


16.1.2 SAMPLE CASE REPORT FORM (UNIQUE PAGES ONLY)

The sample case report form is provided on the following pages.

The sample case report form (unique pages only) is provided on the following pages.


16.1.3 LIST OF IEC’S OR IRB’S (PLUS THE NAME OF THE COMMITTEE CHAIR IF REQUIRED BY THE REGULATORY AUTHORITY) AND REPRESENTATIVE WRITTEN INFORMATION FOR PATIENT AND SAMPLE CONSENT FORMS

16.1.3.1 LIST OF IEC’S OR IRB’S

The list of IRBs and IECs is provided on the following pages.

The list of IRBs and IECs is provided in Section <enter of this clinical study report.

Central IRBs/IECs InvestigatorSite

Number

<enter <enter <enter



Chairperson: <enter <enter <enter





Local IRBs/IECs InvestigatorSite

Number










16.1.3.2 REPRESENTATIVE WRITTEN INFORMATION FOR PATIENT

The sample informed consent form(s) is/are provided on the following pages.


16.1.3.3 SAMPLE CONSENT FORMS

A sample patient diary is provided on the following pages.

Samples of other study-related written information given to the patients are provided on the following pages.


16.1.4 LIST AND DESCRIPTION OF INVESTIGATORS AND OTHER IMPORTANT PARTICIPANTS IN THE STUDY, INCLUDING BRIEF (ONE PAGE) CV’S OR EQUIVALENT SUMMARIES OF TRAINING AND EXPERIENCE RELEVANT TO THE PERFORMANCE OF THE CLINICAL STUDY

16.1.4.1 LIST AND DESCRIPTION OF INVESTIGATORS AND OTHER IMPORTANT PARTICIPANTS IN THE STUDY

A list of the Investigators who participated in this study is provided on the following pages.

A list of the Investigators who participated in this study is provided in Section <enter of this clinical study report.

List of Investigators

Site Number

Investigator Role



List of Investigators

Investigator Role Site Number



A list of other important participants in this study is provided on the following pages.

A list of other important participants in this study is provided in Section <enter of this clinical study report.

List of Other Important Participants

Site Number

Other Important Participants Role






Other Important Participants Role Site Number




16.1.4.2 BRIEF (ONE PAGE) CV’S OR EQUIVALENT SUMMARIES OF TRAINING AND EXPERIENCE RELEVANT TO THE PERFORMANCE OF THE CLINICAL STUDY

A curriculum vitae for each Investigator who participated in this study is provided on the following pages.

A list of qualifications for each Investigator who participated in this study is provided on the following pages.


16.1.5 SIGNATURES OF PRINCIPAL OR COORDINATING INVESTIGATOR(S) OR SPONSOR’S RESPONSIBLE MEDICAL OFFICER, DEPENDING ON THE REGULATORY AUTHORITY’S REQUIREMENT

16.1.5.1 SIGNATURES OF PRINCIPAL OR COORDINATING INVESTIGATOR(S) OR SPONSOR’S RESPONSIBLE MEDICAL OFFICER

Signature(s) of the Principal or Coordinating Investigator(s) or Sponsor’s Responsible Medical Officer is/are provided on the following page.

PRINCIPAL OR COORDINATING INVESTIGATORS’ SIGNATURES, OR

RESPONSIBLE MEDICAL OFFICER’S SIGNATURE

Study Title: Error: Reference source not found

Study Number: Error: Reference source not found

Study Report Authors: <enter

I have read this report and confirm that to the best of my knowledge it accurately describes the conduct and results of the study.

Signed: Date: {responsible


16.1.5.2 SIGNATURES OF THE CLINICAL STUDY REPORT AUTHORS

Signature(s) of the study report author(s) and responsible statistician are provided on the following page.


SIGNATURE(S) OF STUDY REPORT AUTHOR(S)

Study Title: Error: Reference source not found

Study Number: Error: Reference source not found

We, the undersigned, confirm that this final clinical study report accurately describes the experimental methods and results.

Signed: Date: <enter<enter<enter




16.1.6 LISTING OF PATIENTS RECEIVING TEST DRUG(S)/INVESTIGATIONAL PRODUCT(S) FROM SPECIFIC BATCHES, WHERE MORE THAN ONE BATCH WAS USED

Only one batch of study drug was administered during this study. The batch number was <enter.

The batch number(s) used for this study are provided in Section <enter of this clinical study report.

The listing of patients receiving study drug from specific batches is provided in Appendix <enter, Data Listing <enter.

Patient Number Treatment Group Lot Number

1 A: <formulation/dose> xxxx

2 C: <formulation/dose> yyyy

3 C: <formulation/dose> yyyy

4 B: <formulation/dose> zzzz

Treatment A Lot Number Patient

5-mg tablets Lot X Patients 1-100

Lot Y Patients 101-200

Treatment B Lot Number Patients

5-mg tablets Lot XX All patients received the same lot


16.1.7 RANDOMIZATION SCHEME AND CODES (PATIENT IDENTIFICATION AND TREATMENT ASSIGNED)

This was an open-label study. The schedule of doses is provided in Appendix <enter, Data Listing <enter.

The randomization schedule and codes are provided in Appendix <enter, Data Listing <enter.

Treatment Group/Dose Randomization Number(s)


16.1.8 AUDIT CERTIFICATES (IF AVAILABLE)

XX audits were conducted during this study.

The audit certificate(s) is/are provided on the following page(s).


16.1.9 DOCUMENTATION OF STATISTICAL METHODS

The Statistical Analysis Plan for this study is provided in the following pages.

No Statistical Analysis Plan was generated for this study.

Statistical methods are described in Section <enter of this clinical study report.


16.1.10 DOCUMENTATION OF INTER-LABORATORY STANDARDIZATION METHODS AND QUALITY ASSURANCE PROCEDURES IF USED

No laboratories were used during this study.

Only one central laboratory was used in the study. Reference ranges for this laboratory are provided in the following pages/in Appendix <enter, Data Listing <enter.

Central Laboratory Investigator’s Name/Site Number

<enter<enter

<enter<enter

Multiple laboratories were used in this study and are listed on the following pages. Reference range lists for each laboratory are also provided on the following pages, followed by a statement explaining the methods and quality assurance procedures used to standardize data between multiple laboratories.

Multiple laboratories were used in this study and are listed on the following pages, followed by a statement explaining the methods and quality assurance procedures used to standardize data between multiple laboratories. The standardized reference range list is provided in Appendix <enter, Data Listing <enter.

Central Laboratories Investigator’s Name/Site Number

<enter<enter

<enter<enter

Local Laboratories Investigator’s Name/Site Number

<enter<enter

<enter<enter


16.1.11 PUBLICATIONS BASED ON THE STUDY

Publications based on the clinical study that are listed in the Reference List of this report are provided in this Appendix to the report, with the exception of the following publications:

1. <enter<enter

No publications based on the clinical study have been written.


16.1.12 IMPORTANT PUBLICATIONS REFERENCED IN THE REPORT

Publications referenced in this report that are cited in the Reference List of this report are provided in this Appendix to the report, with the exception of the following publications:

2. <enter<enter

No publications are being submitted as an appendix to this clinical study report.


16.2 PATIENT DATA LISTINGS

16.2.1 DISCONTINUED PATIENTS

16.2.1.1 <enter

16.2.1.2 <enter


16.2.2 PROTOCOL DEVIATIONS

16.2.2.1 <enter

16.2.2.2 <enter


16.2.3 PATIENTS EXCLUDED FROM THE EFFICACY ANALYSIS

16.2.3.1 <enter

16.2.3.2 <enter


16.2.4 DEMOGRAPHIC DATA

16.2.4.1 <enter

16.2.4.2 <enter


16.2.5 COMPLIANCE AND/OR DRUG CONCENTRATION DATA (IF AVAILABLE)

16.2.5.1 <enter

16.2.5.2 <enter


16.2.6 INDIVIDUAL EFFICACY RESPONSE DATA

16.2.6.1 <enter

16.2.6.2 <enter


16.2.7 ADVERSE EVENT LISTINGS (EACH PATIENT)

16.2.7.1 <enter

16.2.7.2 <enter


16.2.8 LISTING OF INDIVIDUAL LABORATORY MEASUREMENTS BY PATIENT, WHEN REQUIRED BY REGULATORY AUTHORITIES

16.2.8.1 <enter

16.2.8.2 <enter


16.3 CASE REPORT FORMS (CRF’S)

16.3.1 CRF’S FOR DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND WITHDRAWALS FOR ADVERSE EVENTS

16.3.1.1 CRF’S FOR DEATHS

Patient Number: <enter


16.3.1.2 CRF’S FOR OTHER SERIOUS ADVERSE EVENTS



16.3.1.3 CRF’S FOR WITHDRAWALS FOR ADVERSE EVENTS



16.3.2 OTHER CRF’S SUBMITTED



16.4 INDIVIDUAL PATIENT DATA LISTINGS



Documents

Bloom RB. Comprehensive study report, Pravafen, Sciele (now Shionogi Sciele)