Clinical trial NCT02138253
Conditions: Liver Fibrosis Hepatic Fibrosis Liver Cirrhosis Hepatic Cirrhosis
Keywords: liver transplant hepatitis C liver fibrosis hepatic fibrosis liver cirrhosis hepatic cirrhosis
Sponsor: Conatus Pharmaceuticals Inc.
Start date: 2014-05-01; Completion date: 2018-03-09
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a double-blind, multicenter study involving patients with chronic HCV infection who had a liver transplantation; developed HCV-related liver fibrosis and/or incomplete cirrhosis; achieved a sustained virologic response (SVR) following anti-HCV therapy; but still have fibrosis and/or incomplete cirrhosis on liver biopsy to see if treatment with IDN-6556 is better than placebo in reversing or stopping the progression of the damage to the new liver caused by HCV.

Detailed description:
There are data to suggest that with eradication of the HCV virus, improvements in liver fibrosis can be seen in the post-transplant population. However, amelioration of inflammatory activity, and deceleration of fibrosis progression is a gradual process over the course of many years. This placebo-controlled study is designed to evaluate the effects of IDN-6556, compared to placebo, on markers of apoptosis and inflammation, and liver histology.

Arms: arm 1: IDN-6556 25 mg BID arm 2: Placebo BID
Interventions: intervention 1: IDN-6556 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: Placebo control

Protocol documents:
Prot_000.pdf: 
Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
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CLINICAL TRIAL PROTOCOL 
 
 
A Multicenter, Double-Blind, Randomized Trial of IDN-6556 
in Subjects Who had Hepatitis C Virus (HCV) Reinfection 
and Liver Fibrosis or Cirrhosis following Orthotopic Liver 
Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response 
Following anti-HCV Therapy 
 
 
Protocol Number: IDN-6556-07 
 
 
Date:  03 August 2015 
 
 
Developmental Phase: 2 
 
 
 
Sponsor:  Conatus Pharmaceuticals 
 
16745 W. Bernardo Drive, Suite 200 
 
San Diego, CA 92127 
 
United States of America 
 
 
THIS PROTOCOL IS THE PROPERTY OF CONATUS PHARMACEUTICALS AND IS A 
CONFIDENTIAL COMMUNICATION. ACCEPTANCE IMPLIES AN AGREEMENT NOT TO 
DISCLOSE INFORMATION CONTAINED HEREIN THAT IS NOT OTHERWISE PUBLICLY 
AVAILABLE, EXCEPT FOR USE BY AN INSTITUTIONAL REVIEW BOARD (IRB) OR ETHICS 
COMMITTEE (EC) FOR THE PURPOSE OF OBTAINING APPROVAL TO CONDUCT THE STUDY. 
THE IRB/IEC IS REQUESTED AND EXPECTED TO MAINTAIN CONFIDENTIALITY. THIS 
DOCUMENT MAY NOT BE USED OR PUBLISHED IN WHOLE OR IN PART WITHOUT THE 
WRITTEN CONSENT OF CONATUS PHARMACEUTICALS. 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
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LIST OF KEY PERSONNEL 
 
 
Sponsor  
 
 
Conatus Pharmaceuticals 
16745 W. Bernardo Drive, Suite 200 
San Diego, CA 92127 
USA 
 
Medical Monitor 
 
Jean L. Chan, MD 
VP, Clinical Development 
Phone: 
1 858-376-2632 
Mobile: 
1 617-407-5689 
jchan@conatuspharma.com 
 
 
Serious Adverse Event Reporting 
 
 
 
Synteract HCR Safety 
Safety Fax:  +1-760-268-6500 
safetyfax@synteracthcr.com 
 
 
OR 
if not 
available 
Mason Yamashita, MD 
VP, Pharmacovigilance 
Phone:    1 858-376-2617 
Mobile:    1 619 306 2125 
myamashita@conatuspharma.com 
 
 
Clinical Operations 
 
Beth Sheedy 
Associate Director, Clinical Operations 
Office: 
1 858 376 2643 
Fax:  
1 858  432 7721 
Mobile: 
1 619 980 2126 
bsheedy@conatuspharma.com  
 
OR 
if not 
available 
Lisa Grubbs 
VP, Clinical Operations and 
Data Management 
Office:  
1 858 376 2627 
Fax:  
1 858  432 7721 
Mobile: 
1 858 336 7540 
lgrubbs@conatuspharma.com 
 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
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TABLE OF CONTENTS 
Page 
 
1.0 
STUDY SYNOPSIS ......................................................................................... 7 
2.0 
LIST OF ABBREVIATIONS .......................................................................... 12 
3.0 
ETHICS ......................................................................................................... 15 
4.0 
INTRODUCTION ........................................................................................... 15 
4.1 
Background ................................................................................................ 15 
4.2 
Study Rationale .......................................................................................... 16 
5.0 
STUDY OBJECTIVES .................................................................................. 17 
6.0 
STUDY DESIGN ........................................................................................... 17 
7.0 
STUDY POPULATION.................................................................................. 19 
7.1 
Inclusion Criteria ......................................................................................... 20 
7.2 
Exclusion Criteria ........................................................................................ 21 
7.3 
Subject Identification .................................................................................. 22 
7.4 
Randomization Procedure .......................................................................... 22 
7.5 
Blinding/Unblinding Procedures.................................................................. 23 
8.0 
STUDY ASSESSMENTS AND CONDUCT .................................................. 24 
8.1 
Efficacy and Safety Assessments............................................................... 24 
8.1.1 
Liver Biopsy ........................................................................................ 24 
8.1.2 
Medical History and Physical Examinations ....................................... 25 
8.1.3 
Vital Sign Measurements .................................................................... 25 
8.1.4 
Liver and Abdominal Ultrasound, and Other Imaging ......................... 25 
8.1.5 
Transient Elastography (Fibroscan®) ................................................. 26 
8.1.6 
Chest X-Ray ....................................................................................... 26 
8.1.7 
12-Lead Electrocardiogram (ECG) ..................................................... 27 
8.1.8 
Clinical Laboratory Tests .................................................................... 27 
8.1.9 
Additional Laboratory and Clinical Assessments for Safety ................ 28 
8.1.10 
Pharmacokinetic Sampling ................................................................. 29 
8.1.11 
Biomarker Sampling ........................................................................... 30 
8.1.12 
Blood Volume ..................................................................................... 30 
8.2 
Efficacy Assessments ................................................................................. 31 
8.2.1 
Primary ............................................................................................... 31 
8.2.2 
Secondary .......................................................................................... 31 
8.2.3 
Additional ............................................................................................ 31 
8.2.4 
Exploratory ......................................................................................... 32 
8.3 
Specific Study Visit Information .................................................................. 32 
8.3.1 
Screening Phase (Week -6 to Day 0) ................................................. 32 
8.3.2 
Double-Blind Phase (Month 0/Day 1 through to Month 24/ Early 
Termination/ End of Treatment) .......................................................... 33 
8.3.3 
Follow-Up Phase (Month 25, 4 Weeks after Early Termination/End of 
Treatment) .......................................................................................... 35 
8.4 
Prior and Concomitant Medications ............................................................ 35 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
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8.5 
Other Precautions, Restrictions, Drugs, and Alcohol .................................. 36 
8.6 
Subject and Study Termination .................................................................. 36 
8.6.1 
Reasons and Procedures for Early Termination ................................. 36 
8.6.2 
Completion of the Study ..................................................................... 37 
8.6.3 
Termination of the Study .................................................................... 37 
9.0 
INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 38 
9.1 
IDN-6556 and Placebo Supplies................................................................. 38 
9.2 
Investigational Medicinal Product Packaging and Labeling ........................ 38 
9.3 
Investigational Medicinal Product Dispensing and Accountability .............. 39 
9.4 
Investigational Medicinal Product Administration........................................ 39 
10.0 
WARNINGS AND PRECAUTIONS .............................................................. 39 
11.0 
DOCUMENTATION OF DATA ..................................................................... 40 
11.1 Source Documentation ............................................................................... 40 
11.2 Data Entry in Database .............................................................................. 40 
11.3 Query Checks ............................................................................................. 40 
11.4 Coding of Adverse Events, Drugs, and Diseases ....................................... 41 
11.5 Study Language & Translations ................................................................. 41 
12.0 
STATISTICAL METHODS ............................................................................ 41 
12.1 Introduction ................................................................................................. 41 
12.2 Parameters of Interest ................................................................................ 41 
12.2.1 
Safety Variables ................................................................................. 41 
12.2.2 
Efficacy Variables ............................................................................... 42 
12.2.3 
Other Variables .................................................................................. 42 
12.3 Demographics and Baseline Characteristics .............................................. 42 
12.4 Analysis Populations .................................................................................. 42 
12.5 Sample Size ............................................................................................... 43 
12.6 Statistical Analysis ...................................................................................... 45 
12.6.1 
General ............................................................................................... 45 
12.6.2 
Safety Analysis ................................................................................... 45 
12.6.3 
Efficacy Analysis................................................................................. 45 
12.6.4 
Interim Analysis .................................................................................. 46 
12.6.5 
Handling of Missing Data .................................................................... 46 
12.7 Analysis Plan .............................................................................................. 46 
12.8 Statistical Software ..................................................................................... 47 
12.9 Data Monitoring Committee (DMC) ............................................................ 47 
13.0 
ADVERSE EVENTS ..................................................................................... 47 
13.1 Adverse Event Reporting Obligations ......................................................... 47 
13.2 Adverse Event Definitions .......................................................................... 48 
13.2.1 
Anticipated Serious Adverse Events in HCV POLT SVR Subject 
Population .......................................................................................... 50 
13.2.2 
Pre-Treatment-Emergent Adverse Events .......................................... 50 
13.2.3 
Laboratory Abnormalities as Adverse Events ..................................... 50 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
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13.3 Severity of Adverse Events ........................................................................ 51 
13.4 Classification of Adverse Events by Relationship to Study Drug 
Administration ............................................................................................. 51 
13.5 Recording and Reporting Adverse Events .................................................. 52 
13.5.1 
Recording Adverse Events ................................................................. 52 
13.5.2 
Investigator Reporting of a Serious Adverse Event ............................ 53 
13.6 Additional Investigator Responsibilities on Follow-up of Serious Adverse 
Events ........................................................................................................ 54 
13.7 Post-Study Follow-Up of Adverse Events ................................................... 54 
13.8 Notification of Post-Study Serious Adverse Events .................................... 54 
13.9 IRB/IEC Notification of Serious Adverse Events ......................................... 55 
13.10 Health Authority Safety Reports ................................................................. 55 
14.0 
ADMINISTRATIVE ASPECTS ...................................................................... 55 
14.1 Investigator Responsibilities for General Study Conduct ............................ 55 
14.2 Informed Consent ....................................................................................... 56 
14.3 Subject Confidentiality and Data Protection ............................................... 57 
14.4 Laboratory Accreditation ............................................................................. 58 
14.5 Required Documents .................................................................................. 58 
14.6 Study Initiation, Monitoring, and Termination ............................................. 59 
14.7 Data Recording and Case Report Forms ................................................... 60 
14.8 Investigational Medicinal Product Accountability ........................................ 60 
14.9 Record Retention ........................................................................................ 61 
14.10 Investigator’s Final Report .......................................................................... 61 
14.11 Publication Policy ....................................................................................... 61 
14.12 Confidentiality ............................................................................................. 63 
15.0 
REFERENCES .............................................................................................. 65 
APPENDIX I: SCHEDULE OF EVENTS ................................................................. 67 
APPENDIX II: LIVER BIOPSY SCORING AND ASSESSMENT ............................ 70 
APPENDIX III: CLASSIFICATION OF HEPATIC AND RENAL IMPAIRMENT ...... 72 
APPENDIX IV: FIBROSCAN® PROTOCOL ............................................................ 74 
 
LIST OF FIGURES 
Figure 6.1 
Study Schema .................................................................................... 18 
Figure IV.1 
FibroScan® Probe Placement in Relation to Anatomy of a Subject 74 
 
LIST OF TABLES 
Table 7.1 
Treatment Arm Allocation ................................................................... 19 
Table 7.2 
Duration of Subject Participation ........................................................ 20 
Table 8.1 
Clinical Laboratory Tests .................................................................... 28 
Table 8.2 
Serum Biomarkers .............................................................................. 28 
Table 8.3 
Total Blood Volume ............................................................................ 31 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
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Table 12.1 
Probabilities of Study Outcomes According to Various Levels of True 
Treatment Effect (TE) ....................................................................................... 44 
Table II.1 
Ishak Fibrosis Score: Architectural Changes, Fibrosis and Cirrhosis .. 
 
 ........................................................................................................... 70 
Table II.2 
Ishak Modification of Knodell Histological Activity Index: Necro-
inflammatory Scores ........................................................................................ 70 
Table III.1 
Assessment of Hepatic Impairment: Child-Pugh Scale (adapted from 
Pugh et al) ........................................................................................................ 72 
Table III.2 
Classification of Renal Function Based on GFR (eGFR) or Estimated 
Creatinine Clearance (CLcr) ............................................................................. 73 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
7 of 76 
1.0 
STUDY SYNOPSIS 
Protocol: 
IDN-6556-07 
 
Title: 
A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects Who had 
Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis Following 
Orthotopic Liver Transplantation for Chronic HCV Infection and Who Subsequently 
Achieved a Sustained Virologic Response Following anti-HCV Therapy 
 
Phase of Trial:  
Phase 2 
 
Objectives: 
Primary 
 To assess the effect of oral IDN-6556 on fibrosis or cirrhosis using the Ishak 
Fibrosis Score, in subjects with HCV reinfection and liver fibrosis or cirrhosis 
following orthotopic liver transplantation for chronic HCV who subsequently 
achieved a sustained virologic response following anti-HCV therapy  
 
Secondary 
 To determine the effects of oral IDN-6556 on necro-inflammatory sub-score of 
the modified Histological Activity Index 
 To determine the effects of oral IDN-6556 on markers of mechanism of action 
and inflammation 
 To assess the safety and tolerability of oral IDN-6556 in subjects status post 
orthotopic liver transplantation 
 
Centers:  
Multicenter, approximately 35 sites in the US. 
 
Number of Subjects: 
Approximately 60 subjects (40 subjects on IDN-6556: 20 on placebo) will be 
assigned in a 2:1 ratio to IDN-6556 25 mg BID or placebo. Up to 15 subjects with an 
Ishak score of F6 can be enrolled. 
 
Design: 
This is a double-blind, randomized, multicenter study involving subjects with chronic 
HCV who underwent liver transplantation; developed HCV-related liver fibrosis or 
cirrhosis; achieved a sustained virologic response (SVR) following anti-HCV therapy; 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
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and still show demonstrable fibrosis or cirrhosis on liver biopsy.  Upon successful 
screening, subjects will be randomized to receive 25 mg BID of IDN-6556 or placebo 
in a 2:1 ratio. 
 
The randomization will be stratified based on the stage of fibrosis or cirrhosis at 
Baseline: 
1. Ishak F2 
2. Ishak F3 – F5 
3. Ishak 6 
 
The study treatment duration will be two years.  All subjects who complete or 
discontinue from the study, for any reason, will have a follow-up visit four weeks 
after the end of treatment visit.  Subjects who complete the study will have a liver 
biopsy performed at M24.  Subjects who discontinue the study prematurely will be 
contacted and asked to sign a separate consent to return for a Month 24 liver biopsy 
(primary endpoint).   
 
Schema: 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
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Dosage and Administration: 
IDN-6556 will be double-blind with matching placebo.  25 mg of IDN-6556 or placebo 
will be administered orally twice a day, preferably with food. 
 
Drug Supply: 
IDN-6556 will be supplied in bottles containing 60 capsules, each containing 25 mg 
of IDN-6556.  Matching placebo will be supplied in bottles containing 60 capsules.  
 
Subject Entry Criteria (Refer to protocol Sections 7.1 and 7.2 for full entry criteria) 
 
Key Inclusion Criteria: 
1. Male or female subjects of minimum adult legal age (according to local laws for 
signing the informed consent document), able to provide written informed 
consent, and able to understand and willing to comply with the requirements of 
the study 
2. History of orthotopic liver transplantation for HCV-induced liver disease 
Note: Living donor or cadaveric transplantation will be permitted into the 
study. HCV positive donor livers will also be permitted into the study.  
3. Diagnosis of HCV infection (HCV-RNA detectable in serum) and liver fibrosis or 
cirrhosis status post liver transplantation, and achieved a sustained virologic 
response (SVR) with anti-viral HCV treatment within 18 months of Day 1 
Note: For the purposes of this study, subjects must meet the definition of SVR 
as defined by the anti-HCV regimen used. 
4. Liver fibrosis or cirrhosis on liver histology as read by central histopathologist of 
Ishak F2 to F6 within three months of Day 1 
Note: Baseline liver histology in close approximation of the three month 
window may be permitted on a case by case basis after discussion with the 
Medical Monitor. 
5. Willingness to utilize two reliable forms of contraception (for both males and 
females of childbearing potential) from Screening to one month after the last 
dose of study drug 
 
Key Exclusion Criteria: 
1. Known 
active 
infection 
with 
hepatitis B 
virus 
(HBV) 
and/or 
human 
immunodeficiency virus (HIV) 
2. History of renal transplant and/or severe renal impairment defined as eGFR 
(estimated glomerular filtration rate) of less than 30 mL/min/1.73 m2 
3. Evidence of tumor burden >Milan criteria, or evidence of micro- or macrovascular 
invasion in explanted liver 
4. Hepatocellular carcinoma (HCC) at entry into the study 
5. Concurrent sirolimus (rapamycin) use  


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
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6. History or presence of clinically concerning cardiac arrhythmias, or prolongation 
of Screening (pre-treatment) QTcF interval of > 480 milliseconds (msec) 
7. Subjects with diagnosed or suspected systemic lupus erythematosus (SLE) 
and/or rheumatoid arthritis (RA) 
8. If female: known pregnancy, positive urine or serum pregnancy test, or 
lactating/breastfeeding. 
 
Criteria for Evaluation: 
 
Safety Variables: 
Safety evaluations will be based on adverse event (AE) reports.  These will be 
coded using MedDRA to preferred terms, sorted by body system, and compared 
between the two treatment groups. 
 
1. Serious adverse events will be analyzed separately 
2. Clinical laboratory variables will be evaluated in the context of coinciding clinical 
adverse events when necessary 
 
Efficacy Variables: 
Efficacy Endpoints: 
 Ishak Fibrosis Score  
 Necro-inflammatory sub-score of the modified Histological Activity Index 
 Biomarkers of apoptosis   
 Liver function (e.g., ALT, AST, bilirubin)  
 Transient elastography (to be performed at select centers only) 
 
Exploratory Endpoint: 
 Morphometric image analysis to quantify collagen deposition  
 
Statistical Methods: 
All endpoints will be tested at a two-sided statistical significance level of 0.05.   
 
For the comparison of Ishak Fibrosis Scores at 24 months, subjects will be classified 
into one of the following three categories: 
 
 Category 1. Regression at 24 months defined as a greater than or equal to a 
one point improvement in Ishak Fibrosis Score from Baseline. 
 Category 2.  Stable disease at 24 months defined as no change from 
Baseline in the Ishak Fibrosis Score from Baseline. 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
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 Category 3.  Progression at 24 months defined as a greater than or equal to a 
one point worsening from Baseline in the Ishak Fibrosis Score from Baseline 
or death/re-transplantation 
 
Changes in the Ishak Fibrosis Score at 24 months will be analyzed by a logistic 
regression model, appropriate for the analysis of ordinal categorical data, to derive 
the odds ratio and associated 95% confidence interval for IDN-6556 against 
placebo. The model will allow adjustment for the following variables: 
 Baseline Ishak Fibrosis Score 
 Immunosuppression regimen (classified into one of five groups: tacrolimus 
with/without steroids; cyclosporine with/without steroids; other) 
 Age of the transplant donor 
 Age of the recipient  
 
Adverse events, vital signs, ECGs, liver and abdominal ultrasounds, and routine 
laboratory test data will be explored through the use of standard presentations of 
descriptive statistics. 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
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2.0 
LIST OF ABBREVIATIONS 
 
AASLD 
American Association for the Study of Liver Diseases 
AE(s) 
adverse event(s) 
AFP 
-fetoprotein 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
bis in die, twice daily 
BMI 
body mass index 
BUN 
blood urea nitrogen 
Ca 
calcium 
CFR 
Code of Federal Regulations 
C-G 
Cockcroft-Gault 
CIOMS 
Council for International Organization of Medical Sciences 
cCK18 
caspase cleaved cytokeratin 18 
Cl 
chloride 
CO2 
carbon dioxide 
CRA 
Clinical Research Associate 
CRF 
case report form 
CRP 
c-reactive protein 
CS 
clinically significant 
CT 
computed tomography 
dL 
deciliter 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
EDC 
electronic data capture 
e.g. 
exempli gratia, for example 
eGFR 
estimated glomerular filtration rate 
ELF 
Enhanced Liver Fibrosis 
EOT 
end of treatment 
ET 
early termination 
FAS 
full analysis set 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
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FDA 
US Food and Drug Administration 
flCK18 
full length cytokeratin 18 
g 
gram(s) 
GCP 
good clinical practice 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transferase 
GMP 
good manufacturing practice 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
HCG 
human chorionic gonadotropin 
Hct 
hematocrit 
HCV 
hepatitis C virus 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
IB 
investigator’s brochure 
IBC 
iron binding capacity 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
i.e. 
id est, that is 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
intention-to-treat 
IWRS 
Interactive Web Randomization System 
LDH 
lactate dehydrogenase 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
mg 
milligram 
MedDRA 
Medical Dictionary for Regulatory Activities 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
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MDRD 
Modification of Diet in Renal Disease 
Mg 
magnesium 
mL 
milliliter 
mm 
millimeter 
MPV 
mean platelet volume 
MRI 
magnetic resonance imaging 
msec(s) 
millisecond(s) 
Na 
sodium 
NAFLD 
non-alcoholic fatty liver disease 
NASH 
non-alcoholic steatohepatitis 
NCS 
not clinically significant 
OTC 
over-the-counter 
pH 
hydrogen ion concentration 
POLT 
post orthotopic liver transplantation 
PP 
per-protocol 
QD 
quaque die, once daily 
RA 
rheumatoid arthritis 
RBC 
red blood cell 
RNA 
ribonucleic acid 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
sec(s) 
second(s) 
SLE 
systemic lupus erythematosus 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
SVR 
sustained virologic response 
SVR4 
sustained virologic response 4 weeks after therapy 
SVR24 
sustained virologic response 24 weeks after therapy 
ULN 
upper limit of normal 
USA 
United States of America 
WBC 
white blood cell 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
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3.0 
ETHICS 
 
The study will be conducted in accordance with Conatus standards that comply with 
regulations relating to Good Clinical Practice (GCP). These include the EU Clinical 
Trials Directives (2001/20/EC, 2005/28/EC, and subsequent amendments), 
International Conference on Harmonisation Guideline for Good Clinical Practice E6, 
21CFR Part 312, and applicable regulatory requirements. 
 
The ethical requirements of Institutional Review Boards/Independent Ethics 
Committees (IRB/IECs) and the Informed Consent Forms (ICFs) are discussed in 
Section 14, Administrative Aspects. 
 
4.0 
INTRODUCTION 
 
4.1 
Background 
 
Chronic liver disease is associated with increased rates of hepatic lobular 
inflammation and hepatocyte apoptosis. While the etiology of liver diseases differs 
considerably (viral, alcohol, autoimmune, etc.), the pathological disease patterns 
across chronic liver diseases have similar tissue responses to injury. Chronic insults 
cause chronic necro-inflammation with increased apoptotic rates and may induce 
hepatic fibrosis, which typically progresses to cirrhosis. Subjects with cirrhosis may 
develop liver failure and/or hepatocellular carcinoma. 
 
Hepatitis C virus (HCV)-associated liver disease continues to be the most common 
indication for liver transplantation in the US, accounting for nearly 25% of all liver 
transplants1.  In the HCV-infected, HCV recurrence and reinfection of the liver graft 
status post orthotopic liver transplantation (POLT) is almost universal and 
characterized by accelerated progression of liver disease. 
 
The absence of a preventative strategy for HCV reinfection after transplant is a 
major challenge for the HCV-infected recipients undergoing liver transplantation.  
Clinicians have successfully treated HCV-infected POLT population with interferon, 
ribavirin, and/or protease inhibitor-containing regimens, although these regimens 
were complicated by the necessity of close subject monitoring and by enhanced 
adverse effects of the combination treatments2,3,4.  Data presented at the 2013 
annual meeting of the American Association for the Study of Liver Diseases 
(AASLD) showed that an interferon-free combination of sofosbuvir plus ribavirin led 
to early viral clearance (SVR4) in about 75% of those subjects treated after 
transplantation5.  Although it is too early to determine the sustained virologic 
response at Week 24 (SVR24) with this regimen, it is anticipated that a large number 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
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of post-transplant subjects may be treated with this interferon-free, all-oral therapy 
once sofosbuvir is readily available. 
 
There are data to suggest that with eradication of the HCV virus, improvements in 
liver fibrosis can be seen in the post-transplant population6,7,8. However, 
amelioration of inflammatory activity, and deceleration of fibrosis progression is a 
gradual process over the course of many years9.  This placebo-controlled study is 
designed to evaluate the effects of IDN-6556, compared to placebo, on markers of 
apoptosis and inflammation, and liver histology. 
 
4.2 
Study Rationale 
 
The Investigator’s Brochure (IB) contains a summary of the data and information 
collected about IDN-6556 (including principal data and findings from preclinical, 
toxicological, and clinical studies conducted to date).  
 
IDN-6556 is a novel small molecule irreversible caspase inhibitor. Caspases are 
enzymes responsible for executing apoptotic pathways, or programmed cell death, 
and activating cytokines such as IL-1 and IL-18. The apoptotic pathway has been 
previously shown to play an important role in the formation and progression of 
hepatic fibrosis, leading to the hypothesis that inhibition of caspases may have 
significant therapeutic benefit for the treatment of liver fibrosis, independent of the 
underlying disease state (e.g., viral infection, fatty liver, etc.).  Activation of pro-
inflammatory cytokines such as IL-1 has also been shown to play a role in hepatic 
injury.  IDN-6556 has shown specificity in assays measuring caspase inhibition, and 
prevented apoptosis in a variety of cellular assays. IDN-6556 demonstrated efficacy 
in a number of animal models of liver disease, as well as in models of damage to 
other organ systems.  Human studies have demonstrated that IDN-6556 can lower 
serum transaminases after intravenous or oral administration.  Treatment with IDN-
6556 was also associated with statistically significant reductions in elevated 
activated serum caspases and cCK18, a caspase cleaved substrate, indicating that 
IDN-6556 works by the presumed mechanism of action of inhibiting caspases. 
 
In subjects who received a liver transplant and were successfully treated and 
achieved an SVR, fibrosis and inflammation were still present up to 5 years after 
treatment9,10,11.  In general, fibrosis stabilized or regressed in most subjects with 
increases in fibrosis in only a small subset of subjects.  In general, inflammation/ 
necro-inflammation was still present, but reduced as compared to pre-treatment.  A 
caspase inhibitor, such as IDN-6556, could have clinical utility by reducing apoptosis 
rates and inflammation, which would also reduce the stimulus for fibrogenesis.  
Given this rationale, this study will evaluate the efficacy and safety of IDN-6556 in 
subjects with chronic hepatitis C virus (HCV) infection who have undergone 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
17 of 76 
orthotopic liver transplantation, achieved an SVR, and still show demonstrable 
fibrosis or cirrhosis on liver histology. 
 
5.0 
STUDY OBJECTIVES 
 
The objectives of the study are as follows: 
 
Primary 
 To assess the effect of oral IDN-6556 on fibrosis or cirrhosis using the Ishak 
Fibrosis Score, in subjects with HCV reinfection and liver fibrosis or cirrhosis 
following orthotopic liver transplantation for chronic HCV who subsequently 
achieved a sustained virologic response following anti-HCV therapy 
 
Secondary 
 To determine the effects of oral IDN-6556 on necro-inflammatory sub-score of 
the modified Histological Activity Index 
 To determine the effects of oral IDN-6556 on markers of mechanism of action 
and inflammation 
 To assess the safety and tolerability of oral IDN-6556 in subjects status post 
orthotopic liver transplantation 
 
6.0 
STUDY DESIGN 
 
This is a double-blind, randomized, multicenter study involving subjects with chronic 
HCV who underwent liver transplantation; developed HCV-related liver fibrosis or 
cirrhosis; achieved a sustained virologic response (SVR) following anti-HCV therapy; 
and still show demonstrable fibrosis or cirrhosis on liver biopsy.  Upon successful 
screening, subjects will be randomized to receive 25 mg BID of IDN-6556 or placebo 
in a 2:1 ratio. 
 
The subjects will be stratified based on the stage of fibrosis or cirrhosis at Baseline: 
1. Ishak F2 
2. Ishak F3  – F5 
3. Ishak 6 
 
The study schema is outlined is Figure 6.1. 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
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Figure 6.1 
Study Schema 
 
 
Appendix I, the Schedule of Events Table*, indicates which procedures and 
evaluations will be performed throughout the study.  An overview of key events is 
described below. 
 
Screening Phase (Week -6 to Day 0):  Subjects will sign an informed consent form 
(ICF) before any study-related procedures are performed.  Subjects will be screened 
to determine their eligibility.  Medical history and medication record (prior and 
concomitant medications) will be obtained for all subjects.  A physical examination 
and a series of laboratory and diagnostic tests will be performed as described in the 
Schedule of Events.  After confirming initial eligibility criteria, availability of prior liver 
biopsy will be assessed and a liver biopsy conducted if needed.  The liver biopsy 
slides must be submitted to the central histopathologist who will confirm subject’s 
eligibility prior to randomization. 
 
                                                 
* If any discrepancies should be found between the text of the protocol and the Schedule of Events 
Table, the table will predominate. 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
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Double-Blind Phase (Month 0/Day 1 through to Month 24): 
During treatment, for safety and efficacy, all subjects will be evaluated frequently 
through a series of physical examinations, laboratory tests, and diagnostic tests as 
described in the Schedule of Events.   
 
All subjects who prematurely discontinue the study during the Double-Blind Phase, 
regardless of the cause, will be contacted and asked to sign a separate consent to 
return for a Month 24 liver biopsy.  If premature discontinuation is within 
approximately 42 days of the originally scheduled Month 24 visit, the liver biopsy 
may be performed at the time of premature discontinuation.  All liver biopsy slides 
must be submitted to the central histopathologist. 
 
However, all subjects who discontinue prematurely should also undergo all other 
assessments, as outlined for End of Treatment (see Section 8.3.2 and Appendix I).   
 
Follow-up Phase (4 Weeks after End of Treatment): 
All subjects will return for a follow-up visit four weeks after completion of treatment. 
The visit will include a physical examination, updating of medication records, 
reporting of any adverse events, and laboratory tests.  (i.e., four weeks after early 
termination) should occur. 
 
7.0 
STUDY POPULATION 
 
Approximately 60 subjects who underwent orthotopic liver transplantation for chronic 
HCV, developed HCV-related liver fibrosis or cirrhosis, achieved a sustained 
virologic response with anti-viral treatment, and still have demonstrable fibrosis or 
cirrhosis on liver histology will be enrolled.  Up to 15 subjects with an Ishak score of 
F6 can be enrolled. 
 
Table 7.1 
Treatment Arm Allocation 
 
Treatment Arm 
N 
IDN-6556 25 mg BID 
40 
Placebo BID 
20 
TOTAL 
60 
 
Subjects will be enrolled at approximately 35 clinical sites in the US.  Expected 
duration of subject participation is as follows: 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
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Table 7.2 
Duration of Subject Participation 
 
Time expected for all subjects to be enrolled: 
Approximately 12 months 
Duration of individual subject participation: 
Approximately 2.2 years 
(6 weeks Screening, 2 years 
treatment, and 4 weeks for 
follow-up) 
 
7.1 
Inclusion Criteria 
 
To participate in this study, subjects must meet all of the following criteria: 
 
1. Male or female subjects of minimum adult legal age (according to local laws for 
signing the informed consent document), able to provide written informed 
consent, and able to understand and willing to comply with the requirements of 
the study 
2. History of orthotopic liver transplantation for HCV-induced liver disease 
Note: Living donor or cadaveric transplantation will be permitted into the 
study. HCV positive donor livers will also be permitted into the study.  
3. Diagnosis of HCV infection (HCV-RNA detectable in serum) and liver fibrosis or 
cirrhosis status post liver transplantation, and achieved a sustained virologic 
response (SVR) with anti-viral HCV treatment within 18 months of Day 1  
Note: For the purposes of this study, subjects must meet the definition of SVR 
as defined by the anti-HCV regimen used. 
4. Liver fibrosis or cirrhosis on liver histology as read by central histopathologist of 
Ishak F2 to F6 within three months of Day 1 
Note: Baseline liver histology in close approximation of the three month 
window may be permitted on a case by case basis after discussion with the 
Medical Monitor. 
5. Available liver tissue for central read (ten, 4-microns-thick, unstained liver 
sections)  
6. Willing to undergo protocol-determined liver biopsies during the study 
7. Hemoglobin ≥ 11 g/dL, platelet count ≥ 75 x 109/L, WBC ≥ 2.0 x 109/L 
Note: As these parameters may be influenced by immunosuppressive 
therapy, small variances may be permitted on a case by case basis after 
discussion with the Medical Monitor. 
8. On stable doses of immunosuppressant therapy for ≥ 3 months prior to Day 1 
9. Willingness to utilize two reliable forms of contraception (for both males and 
females of childbearing potential) from Screening to one month after the last 
dose of study drug 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
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7.2 
Exclusion Criteria 
 
Subjects who meet any of the following criteria will be excluded from the study: 
 
1. Known 
active 
infection 
with 
hepatitis B 
virus 
(HBV) and/or human 
immunodeficiency virus (HIV) 
2. History of renal transplant and/or severe renal impairment defined as eGFR 
(estimated glomerular filtration rate) of less than 30 mL/min/1.73 m2 
3. Subjects with post-transplant liver fibrosis of any etiology other than chronic HCV 
infection 
4. History of autoimmune hepatitis 
5. History of autoimmune cholestatic disease 
6. Wilson’s disease, defined by ceruloplasmin below the limits of normal and liver 
histology consistent with Wilson’s disease 
7. Alpha-1-antitrypsin deficiency defined by serum alpha-1-antitrypsin level less 
than normal and liver histology consistent with alpha-1-antitrypsin deficiency 
8. Hemochromatosis or secondary iron overload as defined by the following: 
a. Presence of 3+ or 4+ iron on liver biopsy stain or a history of previous 
phlebotomy for iron overload, or 
b. Iron saturation (serum iron/IBCx100%) of greater than 50% 
9. Subjects with diagnosed or suspected systemic lupus erythematosus (SLE) 
and/or rheumatoid arthritis (RA) 
10. Drug induced liver disease defined on the basis of typical exposure and history of 
ingestion of drugs known to produce hepatic injury (including but not limited to 
high dose estrogens, tetracycline or amiodarone) in the previous six months 
11. Cholestatic liver disease 
12. Inflammatory bowel disease 
13. Bile duct obstruction as shown by imaging studies 
14. Alpha-fetoprotein levels > 200 ng/mL  
15. Evidence of tumor burden > Milan criteria, or evidence of micro- or 
macrovascular invasion in explanted liver 
16. Hepatocellular carcinoma (HCC) at entry into the study 
17. Subjects with active or history of non-liver malignancies other than curatively 
treated skin cancer (basal cell or squamous cell carcinomas) 
18. History of alcohol abuse within the last year 
19. History of pancreatitis 
20. Concurrent sirolimus (rapamycin) use 
21. Evidence of rejection of implanted liver within three months of Day 1, unless 
adequately treated and resolved prior to Day 1 
22. Any drugs known to cause fibrosis, with the exception of immunosuppressive 
therapy, six months prior to dosing and throughout the study 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
22 of 76 
23. History or presence of clinically concerning cardiac arrhythmias, or prolongation 
of Screening (pre-treatment) QTcF interval of > 480 milliseconds (msec) 
24. Any subject who has received any investigational drug or device within 30 days 
of dosing or who is scheduled to receive another investigational drug or device in 
the course of the study 
25. Active or latent tuberculosis on chest x-ray at study entry 
26. Significant systemic or major illness other than liver disease, including coronary 
artery disease, cerebrovascular disease, pulmonary disease, renal failure, 
serious psychiatric disease, that, in the opinion of the Investigator would preclude 
the subject from participating in and completing the study 
27. Spontaneous bacterial peritonitis or any other active systemic infection at the 
time of entry into the study unless adequately treated with antibiotics 
28. Decompensated or severe liver disease defined by one or more of the following 
criteria: 
a.    INR > 1.6 
b.    Total bilirubin ≥ 1.5 x ULN 
c.    Serum albumin below normal 
d.    AST or ALT > 10 x ULN during the Screening Phase 
e.   Diuretic-resistant ascites. (Ascites that is well-controlled on stable medication 
is NOT exclusionary) 
f.  Encephalopathy grade 2-4 according to the Child-Turcotte-Pugh score.  
(Encephalopathy that is well-controlled on stable medication is NOT 
exclusionary) 
g.   Untreated esophageal varices that are – in the opinion of the investigator – at 
high risk for bleeding 
h. History of variceal hemorrhage 
29. If female: known pregnancy, positive urine or serum pregnancy test, or 
lactating/breastfeeding. 
 
7.3 
Subject Identification  
 
During the Screening period, subjects will be identified by a unique screening 
number and by either their initials (first, middle, last) or de-identified initials (e.g., 
AAA, BBB, etc.).  On Month 0/Day 1, subjects will be identified by a unique four-digit 
subject number and initials.  Only qualified subjects will be assigned a subject 
number.  
 
7.4 
Randomization Procedure 
 
The assignment to IDN-6556 or placebo will be performed randomly. The 
randomization schedule will be generated using a validated randomization program 
and verified for accuracy using strict quality control procedures. 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
23 of 76 
 
The assignment of subject number and treatment assignment will be centrally 
coordinated through the study’s Interactive Web Randomization System (IWRS) to 
ensure that appropriate stratification, based on stage of Baseline Ishak Fibrosis 
score (Ishak F2, F3 – F5 or F6), occurs at randomization.  Subject numbers will be 
assigned by the IWRS.   
 
7.5 
Blinding/Unblinding Procedures 
 
The Investigators and the Medical Monitor(s) will be able to unblind subjects through 
the IWRS when it is medically imperative to know whether a subject is receiving 
IDN-6556 or placebo.  The emergency unblinding should only be instituted by the 
Investigator or the Medical Monitor(s).  Each Investigator will make arrangements to 
ensure that access to the secure internet site (i.e., individual user name and 
password) is maintained in strict confidence to prevent a compromise of subject 
blinding by non-study or unauthorized individuals. 
 
Only in the event of an adverse event (AE) that the Investigator feels cannot be 
adequately treated without knowing the identity of the study drug should the 
medication code be broken for an individual subject.  Every effort must be made to 
contact Conatus and/or the Medical Monitor before breaking the blind, or if in an 
emergency, as soon as possible thereafter (no later than 24 hours after emergency 
unblinding).  Similarly, if the Medical Monitor breaks the blind for the purpose of 
evaluating an emergent safety issue, the Medical Monitor will document within study 
correspondence the rationale, circumstances, and the person or persons being 
informed about the unblinding. 
 
If the blind is broken, an entry must be made in the case report form (CRF) that 
contains the reason that the blind was broken and the name of the person contacted 
at Conatus or designee. 
 
Access to randomization codes and corresponding treatment assignment will also be 
made available through the IWRS to the appropriate Conatus designee(s) and 
individual(s) who are responsible for reporting serious adverse events (SAEs) and 
suspected unexpected serious adverse reactions (SUSARs) to the regulatory 
authorities and should be accessed only in the event of a medical emergency or as 
needed for regulatory agency notifications.  No other Conatus personnel will have 
access to blinded subject treatment codes until all study data have been entered 
onto the study database and validated, and the database locked. 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
24 of 76 
8.0 
STUDY ASSESSMENTS AND CONDUCT 
 
8.1 
Efficacy and Safety Assessments 
 
8.1.1 Liver Biopsy 
 
A screening liver biopsy must be performed prior to randomization if the prior biopsy 
was done more than 3 months prior to Day 1, or if tissue from the previous biopsy is 
not available.  Ten (10) unstained liver biopsy sections, cut 4-microns-thick, must be 
submitted to the central histopathologist who will confirm subject’s eligibility prior to 
randomization.  Generally, the liver biopsy should be the last assessment performed 
during the Screening Phase prior to randomization and should only be performed in 
subjects who fulfill all other inclusion criteria. 
 
After randomization, yearly (12 months ± 42 day window) liver biopsies will be 
performed during the Double-Blind Phase of the study. In the event that a subject is 
withdrawn from the study prior to the 24 Month visit. The subject will be contacted 
and asked to sign a separate consent to return for the Month 24 liver biopsy.  If 
premature discontinuation is within approximately 42 days of the originally scheduled 
Month 24 visit, the liver biopsy may be performed at the time of premature 
discontinuation.  All reasonable attempts should be made to continue to follow the 
subject for the duration of the study follow-up period. 
 
For all liver biopsies conducted during the Double-Blind Phase, 10 unstained 
sections, cut 4-microns-thick, must be available for analysis by the central 
histopathologist.  In addition, all liver biopsies performed during the study should be 
of adequate quality to enable morphometric quantification of fibrosis and smooth 
muscle actin as well as meaningful interpretation of the histology by the central 
histopathologist.  
 
Lastly, all liver biopsies taken during the course of the study, regardless of the 
indication (i.e., both protocol-defined and those performed for other clinical 
indications) must be assessed at the local institution and forwarded to the central 
histopathologist for assessment as well as being assessed at the local institution.  In 
the event of any discrepancy between the local and central histopathology reports, 
the latter shall prevail. 
 
Additional liver biopsies should be performed for subjects who show signs and 
symptoms of clinical worsening.  Criteria for additional liver biopsy include: 
 If the ALT at Baseline is ≤ 60 IU/L and it is raised to ≥ 3X ULN on two 
separate occasions separated by at least one week 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
25 of 76 
 If the ALT is >60 IU/L at Baseline and it is raised to ≥ 2X Baseline value on 
two separate occasions separated by at least one week 
 Any sustained rise in ALT above either ULN (if Baseline was below ULN) or 
above Baseline (if Baseline was above ULN) together with sustained 
increases in neutrophil count and/or C-reactive protein (CRP) and/or              
-fetoprotein on at least two occasions separated by at least one week 
 Any clinical concerns that the Investigator may have that, in their opinion, 
requires an additional biopsy 
 
8.1.2 Medical History and Physical Examinations 
 
Medical history will be taken at Screening.  A comprehensive physical examination 
will be performed at the Screening visit and on-study visits as specified in the 
Schedule of Events.  The physical examination will include the following:  general 
appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), lymph 
nodes, chest, heart, abdomen (including liver examination), extremities, and nervous 
system.  Weight, assessed in ordinary indoor clothing with shoes off, and height 
(Screening visit only) will be recorded at the specified visits.  Each subject’s body 
mass index (BMI) will be calculated.  If additional physical examinations are 
performed during the study, the results will be captured as study data. 
 
Given that the subjects enrolled in the study are on long-term immunosuppression 
with drugs such as cyclosporine and/or tacrolimus, they have an increased risk of 
development of lymphoma and other malignancies, particularly of the skin, due to 
prolonged immunosuppression.  Thorough clinical evaluations, e.g., assessment of 
symptoms and physical examinations, etc., must be performed during the study and 
at follow-up visits in order to assess for any potential malignancies. 
 
8.1.3 Vital Sign Measurements 
 
Evaluation of the respiratory rate will be measured by counting the inhalations for 
one minute.  Heart rate, systolic and diastolic blood pressure, and temperature 
measurements (‘vital signs’) will be performed.  If clinically significant findings occur, 
as determined by the Investigator, then that measurement will be repeated at 
medically appropriate intervals until the value returns to within an acceptable range. 
 
8.1.4 Liver and Abdominal Ultrasound, and Other Imaging 
 
A comprehensive liver and abdominal ultrasound (including the examination of the 
biliary tree) will be performed at the Screening visit and on-study visits as specified 
in the Schedule of Events.  If the subject had a liver and abdominal ultrasound 
performed within three months of Screening, the prior ultrasound results can be 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
26 of 76 
used for study entry.  If the subject had an abdominal MRI or CT scan within three 
months of Screening, it can be utilized in lieu of the ultrasound at Screening. 
 
If the Investigator deems it medically necessary, additional liver and abdominal 
ultrasounds (or higher resolution imaging), other than those specified by the 
protocol, may be performed during the study.  If additional ultrasounds (or other 
imaging) are performed during the study, the reasons for and results of the 
additional imaging will be captured as study data. 
 
In addition, if any abnormalities are found during on-treatment ultrasounds, the 
Investigator should utilize normal clinical practice for additional subject follow-up and 
discuss treatment (dis)continuation with the Conatus Medical Monitor.  
 
8.1.5 Transient Elastography (FibroScan®) 
 
FibroScan® is a novel, non-invasive, reproducible method for measuring liver 
stiffness.  An ultrasound transducer probe is mounted on the axis of a vibrator; 
vibrations of mild amplitude and low frequency are transmitted by the transducer, 
inducing a wave that propagates through the underlying tissue.  The propagation 
velocity of the wave is then measured.  The velocity is directly related to tissue 
stiffness; the stiffer the tissue, the faster the wave propagates.  Preliminary reports 
suggest that FibroScan® accurately predicts hepatic fibrosis in chronic HCV 
subjects. 
 
FibroScan® measurements will be performed at select centers every six months as 
indicated in the Schedule of Events (see Appendix I), and the results will be 
evaluated against liver biopsy and other biomarkers of disease severity.  The 
protocol for the FibroScan® procedure is provided in Appendix IV.  Centers who 
elect to participate in the FibroScan® measurements will make every effort to collect 
the Screening and post-Screening measurements as indicated in the Schedule of 
Events.    
 
8.1.6 Chest X-Ray 
 
A chest x-ray will be performed at Screening to rule out entry of subjects who have 
radiological evidence of active or latent pulmonary tuberculosis.  If additional chest 
x-rays are medically required and performed during the study, the reasons for and 
results of the additional chest x-rays will be captured as study data. 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
27 of 76 
8.1.7 12-Lead Electrocardiogram (ECG) 
 
A 12-lead ECG will be performed at Screening and at subsequent visits, as specified 
in the Schedule of Events.  Original ECGs with interval printouts and rhythm strips 
run at 25 mm/sec must be provided as source documentation.  
 
Automatically calculated QTc intervals will be reviewed and checked for gross 
inaccuracies by the Investigator or designated ECG reviewer.  If the automatically 
calculated QTc interval is greater than 480 msec, or has increased by 50 msec or 
more over the Baseline value, it will be manually over-read by the Investigator or 
designated ECG reviewer.  The ECG parameters that will be assessed include heart 
rate, PR interval, QRS interval, and QTc interval.  If QTc interval prolongation 
exceeding these limits is verified during treatment, the subject’s medical background 
should be examined closely for risk factors that may have contributed to the event, 
including genotyping for hereditary long QTc syndromes, if appropriate. 
  
Any sign of arrhythmia should be noted.  During treatment, any indication of QTc 
prolongation or Torsade de Pointes, a polymorphic ventricular tachyarrhythmia that 
appears on the ECG as continuous twisting of the vector of the QRS complex 
around the isoelectric baseline, must be recorded as an adverse event and reported 
to the Conatus Medical Monitor. 
  
The decision to continue the treatment of any subject with prolonged QTc interval 
must be discussed and agreed upon by the Investigator and the Conatus Medical 
Monitor.  All such subjects, including subjects with cardiac arrhythmias, should be 
monitored closely.  If appropriate, ECG monitoring should be performed until the 
QTc intervals and waveform morphology have returned to normal.  If the 
QTc interval prolongation or abnormal rhythm persists, the Conatus Medical Monitor 
must be contacted. 
 
8.1.8 Clinical Laboratory Tests 
 
Clinical safety laboratory tests will be analyzed by a central laboratory according to 
standardized, validated assays. The laboratory will supply detailed instructions and 
all containers for blood and urine investigations. Blood and urine sample volumes 
will meet the laboratory’s specification. 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
28 of 76 
Table 8.1 
Clinical Laboratory Tests 
 
Hematology 
Coagulation 
Chemistry 
Urinalysis 
Other 
Liver 
Enzymes & 
Other 
Function 
Tests 
Other 
Chemistry 
Hgb, Hct, 
RBC count, 
WBC count 
and 
differential, 
Platelet 
count, MCV, 
MCH, 
MCHC, MPV 
 
INR, PT, PTT 
AST, ALT, 
GGT, Total 
bilirubin, 
Direct 
bilirubin, AP 
Na+, K+, Cl-, 
Total CO2 
(bicarbonate), 
Ca++, Mg++, 
Phosphate, 
Creatinine, 
Serum 
creatinine 
clearance 
(calculated), 
BUN, Uric 
acid, Glucose, 
Total protein, 
Albumin, 
Globulin, LDH, 
CRP 
Specific 
gravity, pH, 
Blood, 
Protein, 
Glucose, 
Ketones, 
Bilirubin 
-fetoprotein 
 
CA-19-9 
 
-HCG serum 
pregnancy test* 
 
Urine pregnancy test* 
 
Immunosuppressant 
concentration 
*For women of childbearing potential 
 
Table 8.2 
Serum Biomarkers 
 
Serum Biomarkers# 
cCK18/M30, Caspase 3/7, flCK18/M65,  
ELF (component scores also to be reported), 
IL-18 
 
 
#Proposed biomarkers to be studied. Additional biomarkers may be evaluated. 
 
8.1.9 Additional Laboratory and Clinical Assessments for Safety 
 
Additional laboratory and clinical assessments should be performed for subjects who 
show the following signs and symptoms of potential drug induced liver injury.  The 
following laboratory and clinical assessments should be performed: 
 
 If ALT or AST is > ULN at Baseline and an increase of ≥ 2X Baseline occurs 
in ALT, AST and/or total bilirubin, prompt repeat testing within 48 to 72 hours 
must be performed.  In addition, the subject must be evaluated for any 
adverse events, including symptoms suggestive of worsening liver disease 
(e.g., anorexia, nausea, fatigue, right upper abdominal discomfort, vomiting, 
etc.). Subsequent close observation is required.  


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
29 of 76 
 If ALT, AST and total bilirubin are < ULN at Baseline and there is an increase 
of > 3X Baseline in any of these parameters, prompt repeat testing within 48 
to 72 hours must be performed.  In addition, the subject must be evaluated for 
any adverse events including symptoms suggestive of worsening liver 
disease (e.g., anorexia, nausea, fatigue, right upper abdominal discomfort, 
vomiting, etc.). Subsequent close observation is required.  
 
The need for prompt repeat testing is especially critical if ALT or AST is much 
greater than 3X ULN and/or total bilirubin is greater than 2X ULN.  If symptoms 
persist or repeat testing shows ALT or AST >3X ULN for subjects with normal 
Baseline values or 2-fold increases above Baseline values for subjects with elevated 
values before study drug exposure, it is appropriate to initiate close observation to 
determine whether the abnormalities are improving or worsening. If close 
observation and monitoring is not possible, the study drug must be discontinued. 
 
Close observation includes:  
 Repeating liver enzyme and serum bilirubin tests two or three times weekly. 
Frequency of retesting can decrease to once a week or less if abnormalities 
stabilize or the study drug has been discontinued and the subject is 
asymptomatic 
 Obtaining a more detailed history of symptoms and prior or concurrent 
diseases 
 Obtaining a history of concomitant drug use (including nonprescription 
medications and herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and special diets 
 Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or 
alcoholic hepatitis; NASH; hypoxic/ischemic hepatopathy; and biliary tract 
disease 
 Obtaining a history of exposure to environmental chemical agents 
 Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, 
direct bilirubin) 
 Considering further gastroenterology and/or hepatology consultations if 
appropriate 
 
8.1.10 Pharmacokinetic Sampling 
 
8.1.10.1 
IDN-6556 Pharmacokinetic Sampling 
 
Up to 5 mL of whole blood will be collected at each sampling time point by using 
tubes provided by the central laboratory.  Samples will be obtained according to the 
Schedule of Events and processed according to the instructions provided by the 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
30 of 76 
central laboratory.  After processing, each sample is to be harvested, equally divided 
into two aliquots, and transferred into cryotubes.  Aliquots are to be frozen at less 
than or equal to () -70C. 
 
Samples are to be shipped to a central laboratory specified by Conatus.  The 
samples will be assayed at the laboratory using validated methods.  
 
8.1.10.2 
Immunosuppression Pharmacokinetic Sampling 
 
Up to 10 mL of whole blood will be collected at each sampling time point by using 
tubes provided by the central laboratory.  Samples will be obtained according to the 
Schedule of Events and processed according to the instructions provided by the 
central laboratory.  After processing, each sample is to be harvested, equally divided 
into two aliquots, and transferred into cryotubes.  Aliquots are to be frozen at less 
than or equal to () -20C. 
 
Samples are to be shipped to a central laboratory specified by Conatus.  The 
samples will be assayed at the laboratory using validated methods.  
 
8.1.11 Biomarker Sampling 
 
Up to 12 mL of whole blood will be collected at specified visits by using tubes 
provided by the central laboratory.  Samples will be obtained according to the 
Schedule of Events.  After processing, each sample is to be harvested, divided into 
multiple aliquots as specified by the central laboratory, and transferred into 
cryotubes.  Aliquots are to be frozen at less than or equal to () -70C. 
 
Samples are to be shipped to a central laboratory specified by Conatus.  The 
samples will be assayed at the laboratory using validated methods.  
 
8.1.12 Blood Volume 
 
Table 8.3 summarizes the total blood to be collected over the course of the 
Screening, Double-Blind, and the Follow-up Phases of the study. 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
31 of 76 
Table 8.3 
Total Blood Volume 
 
Sample Type 
Sample 
Volume 
(mL) 
Number of Samples Per Study Phase 
Total 
Volume 
(mL) 
Screening 
Double-Blind 
Follow-Up 
Hematology 
5 
1 
10 
1 
60 
Chemistry 
5 
1 
11 
1 
65 
Coagulation 
5 
1 
6 
1 
40 
Immunosuppression 
concentration 
10 
0 
2 
0 
20 
Immunosuppression PK 
80 
0 
1 
0 
80 
-fetoprotein 
5 
1 
4 
0 
25 
CA 19-9 
5 
0 
2 
0 
10 
Biomarkers 
12 
0 
7 
1 
96 
Population IDN-6556 PK 
5 
0 
2 
0 
10 
IDN-6556 PK  
40 
0 
1 
0 
40 
IDN-6556 PK if ALT, AST or 
bilirubin increase* 
5 
0 
1 
0 
5 
Serum pregnancy test** 
5 
1 
9 
1 
55 
TOTAL 
506 
*Assumes a single case requiring PK sampling. 
**For women of childbearing potential only 
 
Note: Total volume does not include discarded blood from pre-draws used to remove fluid from 
flushed catheters.  Additional blood samples may be taken at times specified by Conatus (or due to 
sample/test repeat) or if clinically indicated for safety. 
 
8.2 
Efficacy Assessments 
 
8.2.1 Primary 
 
The primary efficacy endpoint of the study will be change from Baseline in liver 
histology as defined as ≥1 point change in the Ishak Fibrosis Score at 24 months. 
 
8.2.2 Secondary 
 
The secondary efficacy endpoint will be the effects on liver inflammation measured 
by the difference in responder rates in the necro-inflammatory sub-score of the 
modified Histological Activity Index between the two treatment groups (change 
defined as a movement by at least 2 points at 24 months compared with Baseline).   
 
8.2.3 Additional 
 
Effects on biomarkers of mechanism of action and inflammation, and liver function 
will be evaluated as additional endpoints.   


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
32 of 76 
 
8.2.4 Exploratory 
 
An assessment of morphometric image analysis to quantify collagen deposition will 
be performed on liver histology. 
 
8.3 
Specific Study Visit Information 
 
The following sections provide specific details of the assessments to be performed 
at each study visit.  After a subject is entered into the study, the visit window from 
Day 1 to Month 6 will be  seven days.  After Month 6, the visit window will be  14 
days.  However, every effort should be made to maintain the nominal visit schedules 
of subjects as predicated by the date of the Month 0/Day 1 visit. 
 
Except at Screening, the liver biopsy window will be ± 42 days.  In the event that a 
subject is withdrawn from the study prior to the 24 month visit, the subject will be 
contacted and asked to sign a separate consent to return for a Month 24 liver biopsy 
unless a biopsy was performed within 42 days of the Month 24 visit. 
 
8.3.1 Screening Phase (Week -6 to Day 0) 
 
The following study evaluations will be performed during the course of the Screening 
period: 
 Signed informed consent 
 Inclusion and exclusion criteria 
 Complete medical and surgical histories 
 Record of concomitant medication usage, including use of prescription and 
over-the-counter 
medications, 
and 
vitamin, 
mineral, 
and/or 
herbal 
supplements/therapies 
 Subject demographics 
 Vital signs (blood pressure, pulse, respiratory rate, and temperature) 
 Complete physical examination, including height and weight 
 Liver and abdominal ultrasound (prior ultrasound, or superior imaging, may be 
utilized if performed within 3 months of Screening) 
 12-Lead ECG 
 Chest X-ray 
 Liver biopsy (refer to the biopsy window in Section 8.1.1) 
 Transient elastography (at select centers only) 
 Clinical chemistry, hematology, and coagulation 
 Urinalysis 
 -fetoprotein 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
33 of 76 
 Serum pregnancy test (for women of childbearing potential) 
 
Since the Screening Phase can last up to 6 weeks, it is highly recommended that 
only key assessments and laboratory tests initially be conducted to confirm a 
subject’s eligibility after signing of the informed consent document.  The remainder 
of the screening assessments should only be performed for those subjects who pass 
the initial screening assessments. 
 
Clinically meaningful, unexpected findings in the laboratory or clinical tests that may 
interfere with the study conduct need to be discussed with the Medical Monitor prior 
to entry into the study.   
 
Once the subject’s eligibility is confirmed, including confirmation of the fibrosis score 
by the central histopathologist, the subject will be randomized by IWRS to either 
IDN-6556 or placebo, and stratified by degree of Baseline Ishak Fibrosis Score (F2, 
F3-F5 or F6).  
 
Subjects who initially fail screening may be re-screened after discussion with the 
Conatus Medical Monitor.  Reasons for initial screen failure and eligibility for re-
screening will be clearly documented. 
 
8.3.2 Double-Blind Phase (Month 0/Day 1 through to Month 24/ Early 
Termination/ End of Treatment) 
 
The following study evaluations will be performed during Double-Blind Phase as 
noted on the Schedule of Events: 
 Record concomitant medications and therapies 
 Vital signs (blood pressure, respiratory rate, pulse, and temperature)  
 Physical examination, including weight, at yearly intervals 
 12-lead ECG at yearly intervals 
 Liver and abdominal ultrasound every 6 months 
 Transient elastography every 6 months (at select centers only) 
 Liver biopsy at yearly intervals – refer to Section 8.1.1 for requirements for 
additional biopsies 
 Study drug administration and dispensation 
 Compliance assessment (capsule count) 
 Record adverse events 
 Clinical chemistry and hematology. On Day 14, only clinical chemistry will be 
performed – refer to Section 8.1.9 for requirements for additional laboratory 
and clinical assessments for safety 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
34 of 76 
 Coagulation at Month 0/Day 1, Month 1, Month 6, and every 6 months 
thereafter 
 Urinalysis at Month 0/Day 1 and every 6 months thereafter 
 Blood sample for immunosuppressant concentration monitoring (Month 0/Day 
1 and Day 14) 
 Collection of up to 10 mL of blood for immunosuppressant pharmacokinetic 
analysis at predose, and at 0.5, 1, 2, 3, 4, 5, and 8 hours post dose at Month 
1 
 -fetoprotein every 6 months 
 CA 19-9 at Month 0/Day 1 and Month 24 
 Collection of 12 mL of blood for serum biomarkers at Month 0/Day 1, Day 14, 
Months 1, 3, 6, 12, and 24 (Note: ELF test to be conducted every 6 months 
only) 
 Collection of 5 mL of blood for population pharmacokinetic analysis at Months 
12 and 24 
 Collection of 5 mL of blood for pharmacokinetic analysis at predose, and at 
0.5, 1, 2, 3, 4, 5, and 8 hours post dose at Month 1 
 Collection of 5 mL of blood for pharmacokinetic analysis if repeat laboratory 
testing is required for elevated ALT, AST, and/or total bilirubin values 
 Serum pregnancy test (for women of childbearing potential); except Month 
0/Day 1, and Day 14 
 Urine pregnancy test (for women of childbearing potential) at Month 0/Day 1 
prior to study drug administration 
 
The study procedures specified for Month 0/Day 1 should be performed prior to 
dosing with study drug. 
 
In the event that a subject is withdrawn from the study prior to the 24 Month visit, the 
subject will be contacted and asked to sign a separate consent to return for the 
Month 24 liver biopsy.  If premature discontinuation is within approximately 42 days 
of the originally scheduled Month 24 visit, the liver biopsy may be performed at the 
time of premature discontinuation.   
 
 
                                                 
 If elevations occur during the Double-Blind Phase of the study, Investigators should utilize normal 
clinical practice for follow-up of subjects and discuss treatment (dis)continuation with the Conatus 
Medical Monitor. 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
35 of 76 
8.3.3 Follow-Up Phase (Month 25, 4 Weeks after Early Termination/End of 
Treatment) 
 
All subjects will be seen four weeks after end of treatment.  Follow-up procedures 
will consist of the following: 
 Update of concomitant medications and therapies 
 Vital signs (blood pressure, respiratory rate, pulse, and temperature)  
 Physical examination, including weight 
 Update of adverse events 
 Clinical chemistry, hematology, and coagulation  
 Urinalysis  
 Collection of 12 mL of blood for serum biomarkers 
 Serum pregnancy test (for women of childbearing potential) 
 
If the subject discontinues the study early, all reasonable attempts should be made 
to complete the final follow-up phase, which may or may not coincide with the M24 
liver biopsy. 
 
8.4 
Prior and Concomitant Medications 
 
All prescription and ‘over-the-counter’ (OTC) medications, including supplements, 
taken by the subject during the 30 days before Screening will be recorded on the 
Concomitant Medications case report form.  The generic drug name, indication, total 
daily dose, and dates of drug administration will be recorded.  Any additions, 
deletions, or changes in the dose of these medications should be entered on the 
case report form.   
 
Any current ongoing medications, including OTC drugs, will be allowed if not 
prohibited by the protocol and approved by the Investigator. Subjects must be 
instructed not to take any new OTC drugs during the study without first obtaining 
approval from the Investigator. Subjects should also be instructed to contact the 
Investigator if they develop any illnesses or any new medications. 
 
Subjects should not take the following: 
 Potentially hepatotoxic drugs (starting 30 days prior to dosing and throughout 
the study) 
 Any drugs known to cause fibrosis, with the exception of immunosuppressive 
therapy (for six months prior to dosing and throughout the study) 
 
It is expected that all subjects will be receiving immunosuppressant therapy during 
the course of the study.  This should be tailored to the specific subject’s 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
36 of 76 
requirements.  The reasons for any changes in background immunosuppressant 
therapy should be documented in the case report forms and the subject should 
continue with all study related procedures.  In the event that a subject develops liver 
transplant rejection during the study, decisions about a subject’s treatment regimen, 
including whether or not the subject will continue in the study, will be completely at 
the discretion of the Investigator. 
 
8.5 
Other Precautions, Restrictions, Drugs, and Alcohol 
 
All subjects must take appropriate precautions to avoid excessive sun exposure due 
to the increased risk of malignancies, especially skin malignancies, with their 
requisite, long-term use of immunosuppressants.  Subjects should also be advised 
that illicit drugs, drugs of abuse and excessive alcohol use will not be allowed from 
the start of the Screening to the end of the follow-up visits.  If there is clear evidence 
of use of illicit drugs, drugs of abuse, or excessive alcohol use during study drug 
treatment, the Investigator must counsel the subject and determine whether 
continued study participation is appropriate. 
 
8.6 
Subject and Study Termination 
 
8.6.1 Reasons and Procedures for Early Termination 
 
Subjects may be withdrawn from the study at their own request, upon request of the 
Investigator, or by the Sponsor at any time and for any reason.  Reasons for 
removing a subject from the study may include: 
 
 the subject does not adhere to study rules and procedures; 
 the subject wishes to withdraw from the study ; 
 the subject develops an AE necessitating withdrawal, or requires an 
unacceptable concomitant medication; 
 continuation of the subject is in violation of the inclusion and/or exclusion 
criteria; 
 the Investigator feels it is in the subject’s best interest to terminate 
participation; 
 the study is terminated by the Sponsor. 
 
All subjects who discontinue the study because of adverse events (AEs) will be 
followed up at suitable intervals in order to evaluate the course of the AE and to 
ensure the resolution or stabilization of the abnormality.   
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
37 of 76 
All subjects who prematurely discontinue the study, regardless of the cause, will be 
contacted and asked to sign a separate consent to return for a Month 24 liver 
biopsy. If premature discontinuation is within approximately 42 days of the originally 
scheduled Month 24 visit, the liver biopsy may be performed at the time of 
premature discontinuation.  
 
However, subjects should undergo all other assessments during the final visit, 
scheduled for End of Treatment on the date of discontinuation (see Sections 8.3.2 
and Appendix I).    A follow-up visit should be scheduled to occur 4 weeks following 
the early termination visit. 
 
Female subjects who are discontinued prematurely due to a pregnancy should be 
followed as outlined in Section 10.0. 
 
If a subject is lost to follow up (i.e., fails to return for study visits), reasonable efforts 
should be made to contact the subject and complete study termination procedures, 
in addition to the long-term follow-up of the subject.   
 
8.6.2 Completion of the Study 
 
The Investigator will document the completion or the reason for early withdrawal by 
a subject in the case report form.  The following categories should be used to 
describe the early withdrawal reasons in the case report form: 
 
 Subject discretion (document reason) 
 Investigator considers it to be in the best interest of the subject (document 
reason) 
 Adverse event(s) 
 Administrative reasons (e.g., early termination of the study) 
 Subject lost to follow-up 
 Major protocol violation (with approval by the Sponsor) 
 Death 
 
If the study is prematurely terminated by Conatus, all reasonable attempts should be 
made to complete the final follow-up phase for all remaining subjects.  
 
8.6.3 Termination of the Study 
 
The study may be terminated prematurely, for any reason, by the Investigator with 
sufficient advance notice, per the terms of the contract with the Sponsor.  The 
reason should be communicated in writing to the Sponsor. 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
38 of 76 
 
Conatus reserves the right to discontinue the study at any time for clinical or 
administrative reasons.  Such a termination must be implemented by the 
Investigator, if instructed to do so by Conatus, in a time frame that is compatible with 
each subjects’ well-being. 
 
9.0 
INVESTIGATIONAL MEDICINAL PRODUCT 
 
For the purpose of this protocol the term ‘investigational medicinal product (IMP)’ is 
interchangeable with the term ‘study medication’ and/or ‘study drug’. 
 
All study medication (IDN-6556 and matching placebo) will be manufactured 
according to Good Manufacturing Practice (GMP). 
 
9.1 
IDN-6556 and Placebo Supplies 
 
The double-blind supplies of IDN-6556 will be in bottles containing 60 capsules, with 
each capsule containing 25 mg of IDN-6556.  Matching placebo will also be supplied 
in bottles containing 60 capsules.  Therefore, each bottle will contain a 30-day 
supply of study drug (IDN-6556 or placebo). 
 
Subjects should be instructed to take one capsule in the morning and one capsule in 
the evening, preferably with food.  
 
IDN-6556 and placebo supplies must be stored in a secure, lockable area.  Subjects 
should be instructed to store their study drug bottles with the caps tightly closed in a 
safe area at room temperature.  Study drug bottles should not be stored near 
heating devices, at high temperatures or humidity, or where children or pets have 
access to them. 
 
9.2 
Investigational Medicinal Product Packaging and Labeling 
 
The packaging and labeling of study medication supplies will be performed 
according to GMP standards by a designated, qualified vendor. 
 
IDN-6556 and placebo capsules will be dispensed to subjects in the provided bottles 
in sufficient quantities for continuation of treatment to at least the next scheduled 
visit, along with instructions for the proper method of taking the study drug.   
 
All study drug bottles will carry a uniquely numbered label which will also contain the 
drug description and conditions for storage.   
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
39 of 76 
9.3 
Investigational Medicinal Product Dispensing and Accountability 
 
All study drugs must be dispensed in the original containers in order to assure 
stability of the drugs.  At each visit, subjects must be instructed to return all, original, 
study-drug containers (even empty containers) and all unused capsules (in partially 
or completely full bottles) in order to adequately assess each subject’s compliance 
with dosing instructions.  The number of capsules remaining in the bottles should be 
counted at each visit to assess subject compliance with study drug administration.  
Every effort should be made to obtain all unused capsules and all dispensed bottles.   
 
9.4 
Investigational Medicinal Product Administration 
 
Subjects will be instructed to take IDN-6556 or placebo twice daily, about the same 
time in the morning and evening, preferably with food.   
 
Details of dosing information (e.g., dates of dosing, missed doses and dose 
adjustment, if any) are to be captured in the case report forms. 
 
10.0 WARNINGS AND PRECAUTIONS 
 
IDN-6556 has potential to be teratogenic (refer to the Investigator’s Brochure for 
further details).  There have been no studies with this compound in pregnant 
women.  Teratology studies, conducted in rats and rabbits, demonstrated that IDN-
6556 may be teratogenic.  Therefore, IDN-6556 should not be used in pregnant 
women.  IDN-6556 has also been found to reduce male and female fertility in rats.  
There have been no studies on the effect of IDN-6556 on fertility in men and women. 
 
Both male and female subjects of reproductive potential must use two reliable forms 
of contraception from screening to one month after the last dose of study drug.  
Effective contraception is defined as abstinence or two reliable forms of 
contraception, including one barrier method, used simultaneously.   
 
If pregnancy occurs in a female subject taking study drug, the subject should be 
instructed to immediately stop taking the study drug, and the Investigator should 
inform the Sponsor within 24 hours of the Investigator’s learning of the pregnancy.  
If the female subject is in the Double-Blind Phase of the study, the treatment arm 
may be unblinded (after discussion between the Investigator and the Conatus 
Medical Monitor).  If the female subject chooses to terminate the pregnancy, the 
Investigator should document the termination and contact the Conatus Medical 
Monitor to discuss whether continued participation of the subject in the study is 
appropriate.  If the female subject chooses to continue the pregnancy, the 
procedures for withdrawing a subject from the study should be completed, and the 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
40 of 76 
Investigator will attempt to obtain information on the outcome of the pregnancy.  If 
the pregnancy goes to term, then the Investigator should also attempt to obtain 
information on the health of the infant after delivery and provide the information to 
the Sponsor.   
 
If pregnancy occurs in a female subject after the Double-Blind Phase of the study 
but within one month of taking study drug, the Investigator should inform the 
Sponsor immediately.  
 
If pregnancy occurs in the female partner of a male subject during the Double-Blind 
Phase of the study or within one month of taking study drug, the Investigator should 
inform the Sponsor immediately. 
 
11.0 DOCUMENTATION OF DATA 
 
11.1 Source Documentation 
 
All data obtained in this study are source data.  The clinical site study staff members 
will record the data on source documents immediately, except for data that are 
available on original printouts or as data files.   
 
All clinical work conducted under this protocol will be conducted according to GCP 
rules.  This includes an inspection by the Sponsor or their designee(s) and/or health 
authority representative(s) at any time.  The Investigator will agree to the inspection 
of study-related records by representatives of the health authority(ies) and/or the 
Sponsor.  If the study is to be audited by a health authority at a given site, the 
Investigator will agree to immediately notify the Sponsor upon receipt of the audit 
notification. 
 
11.2 Data Entry in Database 
 
All data will be entered electronically by the study personnel using electronic data 
capture (EDC) specifically designed for this study.   
 
11.3 Query Checks 
 
The raw data will be checked by appropriate programs for consistency and 
plausibility according to previously defined query checks documented in a data 
validation plan.  
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
41 of 76 
11.4 Coding of Adverse Events, Drugs, and Diseases 
 
After data entry, the AEs will be coded according to the MedDRA dictionary.  
Concomitant medications will be coded according to the World Health Organization 
Drug Reference List. 
 
11.5 Study Language & Translations 
 
The primary study materials (protocol, correspondence, clinical study report) will be 
prepared in English. However, where the first language of the subject, study 
personnel, or others involved in the study (such as IRBs/IECs) is not English, 
appropriate arrangements will be made to have the relevant documents translated 
into the local language.  In this case, the qualified translator will need to provide 
documentation to attest to the fact that the translated study documents are an 
accurate reflection of the original, English study documents.   
 
Additional documents may need to be translated into English (e.g., transcripts of 
necessary additional hospital tests that may occur), and others (e.g., new safety 
information) may need to be translated into the local language.  The Sponsor, or 
designee, will make arrangements for such translations to occur promptly. 
 
12.0 STATISTICAL METHODS 
 
12.1 Introduction 
 
Detailed methodology for summary and statistical analyses of the data collected in 
this study will be documented in a Statistical Analysis Plan (SAP), which will be 
dated and maintained by the sponsor.  This document may modify the plans outlined 
in the protocol. 
 
Should any of the assumptions of the statistical methods described below not be 
met, alternative methods will be applied and documented in the Clinical Study 
Report. 
 
12.2 Parameters of Interest 
 
12.2.1 Safety Variables 
 
The following parameters will be recorded for the safety evaluation: 
 Adverse events 
 Vital signs (pulse, heart rate, respiration), physical examinations 
 Clinical chemistry, hematology, coagulation, and urinalysis 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
42 of 76 
 ECGs 
 Liver and abdominal ultrasounds 
 
12.2.2 Efficacy Variables 
 
The following parameters will be recorded for the efficacy evaluation: 
 Histologic changes defined as ≥1 point change in the Ishak Fibrosis Score 
 Effects on liver inflammation in the necro-inflammatory sub-score of the 
modified Histological Activity Index.  A responder will be defined as a subject 
who has improved by at least 2 points at 24 months on the necro-
inflammatory sub-score of the modified Histological Activity Index from 
Baseline.  
 Clinical outcomes defined as time to clinical worsening.  Time to 
decompensation, re-transplantation, and/or death will be captured as clinical 
outcomes.  (Note: Decompensation is defined as presence of: bleeding 
varices, encephalopathy, ascites requiring treatment and jaundice.) 
 Effects on biomarkers of apoptosis and mechanism of action 
 Effects on liver function parameters such as ALT, AST, bilirubin 
 Changes in transient elastography (at select centers) 
 
12.2.3 Other Variables 
 
The following parameter will be assessed as an exploratory variable: 
 Effects on liver collagen as measured by morphometric image analysis 
 
12.3 Demographics and Baseline Characteristics 
 
All continuous parameters will be summarized using standard summary statistics as 
appropriate (n, mean, standard deviation, median, minimum and maximum).  
Summary statistics for categorical variables will include frequency counts and 
percentages.   
 
12.4 Analysis Populations  
 
The safety analysis set consists of all randomized subjects who have received at 
least one dose of study medication, i.e., any dose of IDN-6556 or placebo.  If the 
application of any study medication is not certain, the subject will be included in the 
safety analysis set.  The analyses based on the safety analysis set will be conducted 
on an “as treated” basis, i.e., all subjects will be analyzed by the treatment they have 
actually received. 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
43 of 76 
The Full Analysis Set (FAS) population consists of all randomized subjects who have 
received at least one dose of study medication, i.e., any dose of IDN-6556 or 
placebo.  The analyses based on the FAS population will be conducted on an 
intention-to-treat (ITT) principle (i.e., all subjects will be analyzed with the group to 
which they were randomly assigned).   
 
The Per Protocol (PP) population will be used as a sensitivity analysis of the primary 
endpoint. Criteria for assessing the PP population will be detailed in the Statistical 
Analysis Plan (SAP). 
 
All safety analyses will be based on the safety analysis set. All efficacy analyses will 
be based on the intention-to-treat population 
 
12.5 Sample Size 
 
The sample size determination for this study is based on the Phase 2b screening 
methodology presented in Fleming and Richardson12.   
 
A total of 60 subjects will be treated in a 2:1 ratio to IDN-6556 or placebo.  
Treatment duration for all subjects will be two years.  The primary outcome variable 
is change in Ishak Fibrosis Score at 24 months.   
 
The primary analysis of this Phase 2 “screening” study is formally based on a three-
category decision guideline.  To be specific, the decision guideline for this study is 
based on whether the proportion of subjects who show a regression (i.e., 
improvement) of Ishak Fibrosis Score at 24 months for the IDN-6556 arm compared 
to the placebo arm is less than 5%, is from 5% up to 15%, or is at least 15%.   
 
Note that these categories should not be interpreted as providing strict decision rules 
but rather as guidelines that will be factored into a broader scientific assessment of 
the benefit to risk profile of the IDN-6556 regimen.  This broader assessment will 
include consideration of safety, of secondary efficacy endpoints, and of relevant 
information external to this study.  Specifically, the decision guidelines for this study 
are: 
1. If the estimated absolute increase in the proportion of subjects who show 
regression in Ishak Fibrosis Score is less than 5%, (e.g., less than an 
estimated increase from 30% to 35%), then the IDN-6556 regimen is not 
plausibly more efficacious than placebo; the formulation of this IDN-6556 
regimen or its utility in this indication will be reconsidered.  
2. If the estimated absolute increase in the proportion of subjects who show 
regression in Ishak Fibrosis Score is from 5% up to 15%, (e.g., an estimated 
increase from 30% to between 35% and 45%), then the IDN-6556 regimen is 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
44 of 76 
plausibly more efficacious than placebo and if analyses of biomarkers 
suggest utility of the IDN-6556 regimen, should be evaluated definitively in a 
subsequent Phase 3 clinical study.   
3. If the estimated absolute increase in the proportion of subjects who show 
regression in Ishak Fibrosis Score is at least 15%, (e.g., an estimated 
increase from 30% to greater than 45%), then the IDN-6556 regimen will be 
evaluated definitively in a subsequent Phase 3 study. 
 
The operating characteristics for this three-category decision guideline (based on 
100,000 simulated trials) are shown in the table below. 
 
Table 12.1 
Probabilities of Study Outcomes According to Various Levels of 
True Treatment Effect (TE) 
 
 
Probability of obtaining an estimated TE (active – placebo) 
TE 
<5% 
Of >5% but <15% 
>15% 
0 
67% 
22% 
11% 
5 
52% 
26% 
22% 
10 
36% 
27% 
37% 
15 
23% 
24% 
53% 
20 
13% 
19% 
68% 
25 
7% 
13% 
80% 
30 
3% 
8% 
89% 
 
 
Of note: 
1. The false-positive error rate of the screening procedure is low.  In particular, if 
the IDN-6556 regimen truly provides no improvement in the 2-year Ishak 
Fibrosis Score, then there is only an 11% chance of going forward to a Phase 
3 study and only a 2.5% chance of false positive conclusion that the IDN-
6556 regimen has statistically significant improvement in efficacy relative to 
placebo.   
2. The false-negative error rate is acceptable.  If the IDN-6556 regimen truly 
provides an absolute increase of 15%, (e.g., an increase from 30% to 45%), 
then there is only a 23% chance that the combination intervention would be 
discarded, and thus a 77% chance that it would be evaluated in a subsequent 
Phase 3 study.  If the true absolute increase is 15%, there is a 20% chance 
that the IDN-6556 regimen will have a statistically significant  improvement in 
efficacy relative to placebo and a 80% chance of a statistically significant 
difference if the true absolute increase is 37% (at the 2-sided 0.05 level).  
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
45 of 76 
12.6 
Statistical Analysis 
 
12.6.1 
General 
 
Where appropriate, parameters will be analyzed using descriptive methods.  
Continuous parameters will be summarized using standard summary statistics as 
appropriate (n, mean, standard deviation, median, minimum and maximum).  
Summary statistics for categorical variables will include frequency counts and 
percentages.  All subjects within the respective analysis set will be tabulated. 
 
Graphical presentation of data may be performed.   
 
12.6.2 
Safety Analysis 
 
Safety will be assessed by adverse events, laboratory tests, vital signs, physical 
examinations, ECGs, and liver and abdominal ultrasounds.  
 
Adverse events will be tabulated by body system and preferred term.  The number of 
entries, as well as the number of subjects will be reported.  The nature, intensity, 
frequency, and relationship to IDN-6556 or placebo of adverse events will be 
described for all study subjects.  
 
Results of laboratory tests, vital signs, physical examinations, and ECGs will be 
analyzed descriptively.  Abnormal laboratory and ECG findings will be tabulated 
against appropriate cut-off points (e.g., ≥ 2 x ULN) using frequency counts and 
percentages.   
 
Furthermore, any prior and concomitant medication will be described.   
 
Graphical presentation of results will be performed, where appropriate.  
 
12.6.3 Efficacy Analysis 
 
Primary Endpoint:  Change from Baseline in Ishak Fibrosis Score at 2-years 
 
The primary analysis of the primary endpoint will test the change in Ishak Fibrosis 
Scores at 24 months between the treatment groups in the FAS Population using ITT 
principles. 
 
Subjects will be classified into one of the following 3 categories: 
 Category 1. Regression at 24 months defined as a greater than or equal to a 
one point improvement in Ishak Fibrosis Score from Baseline. 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
46 of 76 
 Category 2.  Stable disease at 24 months defined as no change from 
Baseline in the Ishak Fibrosis Score from Baseline. 
 Category 3.  Progression at 24 months defined as a greater than or equal to a 
one point worsening from Baseline in the Ishak Fibrosis Score from Baseline 
or death/re-transplantation. 
 
Changes in the Ishak Fibrosis Score at 24 months will be analyzed by a logistic 
regression model, appropriate for the analysis of ordinal categorical data, to derive 
the odds ratio and associated 95% confidence interval for IDN-6556 against 
placebo.  The model will allow adjustment for the following variables: 
 Baseline Ishak Fibrosis Score 
 Immunosuppression regimen (classified into one of five groups: tacrolimus 
with/without steroids; cyclosporine with/without steroids; other) 
 Age of the transplant donor 
 Age of the recipient  
 
Subgroup analyses of the model covariates, stated above, will also be conducted.  
 
Shift tables of changes in Ishak Fibrosis Score over time will also be presented. 
 
Secondary Endpoint 
 
Estimates of the treatment effect of IDN-6556 versus placebo, and corresponding 
95% confidence intervals of the modified Histological Activity Score will be 
conducted applying the suitable model for ordinal categorical data and detailed in 
the Statistical Analysis Plan.  Shift tables showing changes over time will also be 
presented.  
 
12.6.4 Interim Analysis 
 
No formal interim analyses are planned for this exploratory study. 
 
12.6.5 Handling of Missing Data 
 
Methods for imputing missing data will be detailed within the Statistical Analysis 
Plan. 
 
12.7 Analysis Plan 
 
Prior to the analysis, a detailed SAP for the core study will be developed.  This plan 
will be finalized prior to the database lock and/or study unblinding.  It is intended that 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
47 of 76 
the database will be locked once the last subject completes the 4 week follow-up 
visit.   
 
A detailed analysis plan to determine the exposure effect relationship and the 
population pharmacokinetics will be developed separately.  The results of the 
analysis will be generated as a stand-alone report. 
 
12.8 Statistical Software 
 
Analyses will be done using the validated statistical software of SAS® (version 9 or 
later). 
 
12.9 Data Monitoring Committee (DMC) 
 
An independent Data Monitoring Committee (DMC) is planned for this study.  The 
DMC will review safety data at periodic intervals from this and all other IDN-6556 
studies conducted by the Sponsor.  Members of the DMC will not be allowed to 
participate as Investigators in this study and will not otherwise consult for the 
Sponsor.   
 
A charter, which will include a detailed description of the scope and the extent of the 
DMC’s responsibilities and procedures, will be implemented prior to any data review.  
DMC documents (charter, open and closed meeting minutes, etc.) will be considered 
part of the study documentation, but not part of this protocol.  The DMC will review 
data within its general remit to oversee subject safety in the study, and provide 
recommendations and guidance to the Sponsor in accordance with the procedures 
stated in its charter.  
 
Should the DMC make subject-safety-related recommendations which affect the 
conduct of this study, all Investigators, responsible IRB/IECs, and applicable 
regulatory agencies will be informed of any decisions made by the Sponsor in 
response to such DMC recommendations.  The Investigators will inform the subjects 
of any such decisions, and the protocol and ICF will be revised, as appropriate. 
 
13.0 ADVERSE EVENTS 
 
13.1 Adverse Event Reporting Obligations 
 
The Investigator is responsible for recording adverse events observed during the 
study. In addition, certain adverse events (as described in Section 13.2. below) are 
classified as “serious” and must be reported within 24 hours to Conatus or its 
designee. 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
48 of 76 
 
In the case of certain adverse events, the Investigator and the Medical Monitor, after 
discussing the details of the adverse events, may decide to temporarily interrupt 
dosing, or permanently discontinue study drug treatment in a subset of subjects or in 
entirety. 
 
13.2 Adverse Event Definitions 
 
The following definitions of terms are guided by the International Conference on 
Harmonization and the U.S. Code of Federal Regulations [21 CFR 312.32] and are 
included herein.  
 
An adverse event is any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
 
Adverse events include, but are not limited to: 
 
 Any symptom or condition not previously reported by the subject (medical 
history). 
 An exacerbation of a pre-existing symptom or condition. 
 A significant increase in frequency or intensity of a pre-existing episodic event 
or condition. 
 A drug interaction. 
 A condition first detected or diagnosed after study drug administration even 
though it may have been present prior to the start of the study. 
 
An AE does not include: 
 
 Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, or 
blood transfusion); the condition that leads to the procedure is an adverse 
event (e.g., bleeding esophageal varices, dental caries). 
 Overdose of either study drug or concurrent medication without any clinical 
signs or symptoms. 
 
Suspected adverse reaction means any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event.  For the purposes of 
safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which 
means any adverse event caused by a drug. 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
49 of 76 
An adverse reaction is any adverse event caused by a drug.  Adverse reactions are 
a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event. 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the 
view of either the Investigator or sponsor, it results in any of the following outcomes: 
 
 Death 
 A life-threatening adverse event 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 A congenital anomaly/birth defect 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result 
in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
An adverse event or suspected adverse reaction is considered “life-threatening” if, in 
the view of either the Investigator or sponsor, its occurrence places the subject at 
immediate risk of death.  It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death. 
 
An adverse event or suspected adverse reaction is considered ‘unexpected’ if it is 
not listed in the Investigator’s Brochure or is not listed at the specificity or severity 
that has been observed; or, if an Investigator’s Brochure is not required or available, 
is not consistent with the risk information described in the general investigational 
plan or elsewhere in the current application.  For example, under this definition, 
hepatic necrosis would be unexpected (by virtue of greater severity) if the 
Investigator’s Brochure referred only to elevated hepatic enzymes or hepatitis.  
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected 
(by virtue of greater specificity) if the Investigator’s Brochure listed only cerebral 
vascular accidents.  ‘Unexpected,’ as used in this definition, also refers to adverse 
events or suspected adverse reactions that are mentioned in the Investigator’s 
Brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation. 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
50 of 76 
 
The Sponsor will determine if a suspected, unexpected serious adverse reaction 
(SUSAR) or SAE meets the criteria as being reportable as a 7-day or a 15-day 
safety report.  
 
13.2.1 Anticipated Serious Adverse Events in HCV POLT SVR Subject 
Population 
 
Given the chronic HCV subject population who underwent an orthotopic liver 
transplantation being studied in this protocol, serious adverse events are anticipated 
to occur, despite having achieved HCV viral clearance.  As such, expected events in 
this patient population, with the exception of Immunologic and Infectious Disorders, if 
they become serious, will not be reported in an expedited manner because they may 
occur at some frequency, independent of drug exposure. 
 
The Medical Monitor will review the subject data electronically via the EDC portal on 
an ongoing basis to ensure prompt review of protocol-specified SAEs.  In addition, at 
minimum, quarterly outputs of all adverse events will be provided to the Medical 
Monitor to determine if any serious adverse events remain unreported and to 
establish routine monitoring of all adverse event data.  The Medical Monitor will 
forward a summary of his/her review, if required by the DMC charter, to the DMC for 
additional safety oversight. 
 
13.2.2 Pre-Treatment-Emergent Adverse Events 
 
Conatus considers adverse events that occur between the time the subject signs the 
informed consent form for the study and the time when that subject is first 
administered the study drugs as “pre-treatment-emergent” events. Any pre-
treatment-emergent event should not be recorded as an adverse event but should 
be recorded in the appropriate category of the subject’s medical history case report 
form. 
 
13.2.3 Laboratory Abnormalities as Adverse Events 
 
Many laboratory abnormalities observed during the course of a study will be 
included under a reported adverse event describing a clinical syndrome (e.g., 
elevated BUN and creatinine in the setting of an adverse event of renal failure, or 
decreased hemoglobin in a case of bleeding esophageal varices).  In such cases, 
the laboratory abnormality itself (e.g., elevated creatinine in a setting of renal failure) 
does not need to be recorded as an adverse event.  However, isolated laboratory 
abnormalities should be reported as adverse events if they are considered to be 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
51 of 76 
clinically significant by the Investigator.  Criteria for a “clinically significant” 
laboratory abnormality are: 
 
a) A laboratory abnormality that leads to a dose-limiting toxicity (e.g., an 
abnormality that results in study drug dose suspension or discontinuation), or 
b) A laboratory abnormality that results in any therapeutic intervention (i.e., 
concomitant medication or therapy) 
 
For laboratory abnormalities that do not meet the above criteria but are outside of 
normal range (e.g., < or > normal reference range), the Investigator should indicate 
whether the value is clinically significant (CS) or not clinically significant (NCS) for 
the subject.  
 
13.3 Severity of Adverse Events 
 
The Investigator must categorize the severity of each adverse event according to the 
following guidelines: 
 
Mild:  
Associated with no limitation of usual activities or only slight 
discomfort; generally not requiring alteration or cessation of study drug 
administration; and/or not needing therapeutic intervention. 
 
Moderate: 
Associated with limitation of usual activities or significant discomfort; 
generally requiring alteration or cessation of study drug administration; 
and/or requiring therapeutic intervention. 
 
Severe:  
Associated with inability of subject to carry out usual activities or very 
marked discomfort; considered to be life-threatening; resulting in 
significant 
disability 
or 
incapacity; 
and 
requiring 
therapeutic 
intervention. 
 
13.4 Classification of Adverse Events by Relationship to Study Drug 
Administration 
 
The Investigator must assess whether each adverse event is related to either IDN-
6556 or placebo.  The relationship of each adverse event will be assessed by the 
Investigator after careful consideration, and according to the following guidelines: 
 
Definitely: 
A reaction that follows a reasonable temporal sequence from 
administration of study drug; that follows a known or expected 
response pattern to the study drug; it disappears or decreases on 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
52 of 76 
cessation or reduction in study drug dose; and/or it reappears or 
worsens when the study drug is administered. 
 
Probably: 
A reaction that follows a reasonable temporal sequence from 
administration of study drug; that follows a known or expected 
response pattern to the study drug; and/or that could not be reasonably 
explained by other factors such as underlying disease, complications, 
concomitant drugs, or concurrent treatments. 
 
Possibly: 
A reaction that follows a reasonable temporal sequence from 
administration of study drug; that follows a known or expected 
response pattern to the study drug, but that could reasonably have 
been produced by a number of other factors including underlying 
disease, complications, concomitant drugs, or concurrent treatments. 
 
Unlikely: 
A reaction that does not follow a reasonable temporal sequence from 
administration, and/or that can be reasonably explained by other 
factors, including underlying disease, complications, concomitant 
drugs, or concurrent treatments. 
 
Not Related: A reaction for which sufficient data exist to indicate that the etiology is 
unrelated to the study drug. 
 
13.5 Recording and Reporting Adverse Events 
 
13.5.1 Recording Adverse Events 
 
All adverse events will be recorded in the appropriate section of the case report 
form.  Subjects withdrawn from the study due to adverse events will be followed by 
the Investigator until the outcome is determined and, when appropriate, additional 
written reports and documentation will be provided.  The Investigator should attempt, 
if possible, to establish a diagnosis based on the presenting signs and symptoms.  
 
If the adverse event meets the definition of a serious adverse event, or if the 
Investigator becomes aware of an unexpected adverse event that places the subject 
at risk or a pregnancy at any time after the study drug administration up to the end of 
the study follow-up period, the event must be documented and reported as 
described in Section 13.5.2. 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
53 of 76 
13.5.2 Investigator Reporting of a Serious Adverse Event 
 
In agreeing to the provisions of this protocol, the Investigator accepts all legal 
responsibilities for prompt notification of serious adverse events to the Sponsor’s Medical 
Monitor or designee. 
 
All serious adverse events must be reported to Conatus within 24 hours after the 
Investigator recognizes/classifies the event as a serious adverse event. At a minimum the 
following information should be provided at the time of the initial report:  subject number and 
initials, a description of the event, at least one criterion classifying the event as Serious and 
the name and title of the reporting individual.  Additionally, judgment of causality by the 
Investigator must be provided as soon as possible to ensure timely reporting to regulatory 
authorities by the Sponsor or designee(s) (e.g., CIOMS forms, FDA MedWatch Form 3500A 
or other equivalent form). After the initial report, as necessary, the Investigator must provide 
any additional information on a serious adverse event to the Medical Monitor within 24 hours 
after he/she receives that information. This follow-up information will be a detailed written 
report that will include copies of hospital records, case reports, autopsy reports, and other 
pertinent documents. 
 
Conatus will consider the Investigator’s assessment of the causality assessment; however, 
since Conatus will assess the overall safety of the study medication, Conatus’ causality 
assessment will take precedence, unless the Investigator’s assessment must take 
precedence per country-specific regulations  
 
Contact: 
 
SynteractHCR Safety 
Safety Fax:  +1-760-268-6500 
safetyfax@synteracthcr.com 
 
 
OR 
if not available 
Mason Yamashita, MD 
VP, Pharmacovigilance 
Mobile:    1 619 306 2125 
Fax: 
1 858 432 7720 
myamashita@conatuspharma.com 
 
All serious adverse events must be reported to Conatus within 24 hours after the 
Investigator recognizes/classifies the event as a serious adverse event. At a 
minimum the following information should be provided at the time of the initial 
report:  subject number and initials, a description of the event, at least one criterion 
classifying the event as Serious and the name and title of the reporting individual.  
Additionally, judgment of causality by the Investigator must be provided as soon as 
possible to ensure timely reporting to regulatory authorities by the Sponsor or 
designee(s) (e.g., CIOMS forms, FDA MedWatch Form 3500A or other equivalent 
form). After the initial report, as necessary, the Investigator must provide any 
additional information on a serious adverse event to the Sponsor or designee within 
24 hours after he/she receives that information. This follow-up information will be a 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
54 of 76 
detailed written report that will include copies of hospital records, case reports, 
autopsy reports, and other pertinent documents. 
 
Conatus will consider the Investigator’s assessment of the causality assessment; 
however, since Conatus will assess the overall safety of the study medication, 
Conatus’ causality assessment will take precedence, unless the Investigator’s 
assessment must take precedence per country-specific regulations  
 
13.6 Additional Investigator Responsibilities on Follow-up of Serious 
Adverse Events 
 
The Investigator and supporting personnel responsible for subject care should 
discuss with the Medical Monitor any need for supplemental investigations of serious 
adverse events. The results of these additional assessments conducted must be 
reported to Conatus. If a subject dies during participation in the study and a post-
mortem examination is performed, a copy of the autopsy report must be submitted to 
Conatus. 
 
13.7 Post-Study Follow-Up of Adverse Events 
 
All adverse events, including a worsening of clinically significant laboratory values, 
physical examination findings compared with Baseline values, must be followed until 
the event resolves, the condition stabilizes, the event is otherwise explained, or the 
subject is lost to follow-up.   
 
Adverse events ongoing at the final visit will be followed for as long as necessary to 
adequately evaluate the subject’s safety or until the event stabilizes or resolves. If 
resolved, a resolution date should be documented on the case report form or 
reported to Conatus if the case report forms have been collected.  The Investigator 
is responsible to ensure that follow-up includes any supplemental investigations as 
may be indicated to elucidate the nature and/or causality of the adverse event.  This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals as is practical. 
 
13.8 Notification of Post-Study Serious Adverse Events 
 
Investigators are not obligated to actively follow subjects after the completion of the 
study.  However, if the Investigator becomes aware of a serious adverse event, 
he/she should notify Conatus if such an event is attributable to study drug.  The 
notification to Conatus of a post-study serious adverse event by the Investigator 
should occur within 24 hours of becoming aware of the serious adverse event. 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
55 of 76 
13.9 IRB/IEC Notification of Serious Adverse Events 
 
The Investigator is responsible for promptly notifying her/his IRB/IEC of all serious 
adverse events, including any follow-up information, occurring at her/his site.  In 
addition, the Investigator is responsible for submitting information on SUSARs/SAEs 
received from Conatus to their local IRB/IEC.  Documentation of the submissions to 
IRBs/IECs must be retained in the appropriate study file(s). 
 
However, in some countries, the notification of SUSARs/SAEs to IRB/IEC will be the 
responsibility of the Sponsor or the Sponsor’s designee. 
 
13.10 Health Authority Safety Reports 
 
Conatus, or its representatives, will submit a safety report to the US Food and Drug 
Administration (FDA) and any other appropriate regulatory agencies in accordance 
with country specific requirements, for any serious adverse event that is unexpected 
and related to the study drug within the appropriate time frame.  Conatus or its 
representatives will send copies of each safety report submitted to the FDA and 
other regulatory agencies to the Investigators who are actively participating in 
Conatus-sponsored clinical studies.  Safety reports must be submitted to the 
appropriate IRB/IEC as soon as possible.  In some countries, submission of the 
safety reports to IRB/IEC will be made by Conatus or its representatives.  
Documentation of the submission to the IRB/IEC must be retained for each safety 
report.  As instructed by Conatus or its designee, safety reports should be retained 
in the appropriate study files, or with the Investigator’s Brochure.  
 
14.0 ADMINISTRATIVE ASPECTS 
 
14.1 Investigator Responsibilities for General Study Conduct 
 
It is the Investigator’s responsibility to ensure that: 
 
 The protocol, subject information sheet, the proposed informed consent form, 
trial participation card (if applicable), or any information to the Primary Care 
Physician and any advertisement for subject recruitment are reviewed and 
approved by the appropriate IRB/IEC, prior to the start of the study. 
 The proposed subject information sheet, informed consent form, trial 
participation card (if applicable) and any proposed advertisement are agreed 
to by Conatus. 
 A copy of the IRB/IEC approval letters for the protocol, any amendments, 
subject information sheet, the informed consent form, trial participation card (if 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
56 of 76 
applicable) and any advertisements are supplied to Conatus prior to starting 
the study.   
 During the course of the study, at intervals not exceeding one year, timely 
and accurate reports are submitted to the IRB/IEC on the progress of the 
study and any other local IRB/IEC regulations regarding reporting are 
satisfied. 
 Copies of all reports to and correspondence with and from the IRB/IEC are 
provided to Conatus. 
 At the completion or early termination of the study, a final report is made to 
the IRB/IEC within the applicable IRB/IEC time frames. 
 Any significant deviation in the study protocol or any change that may alter 
subject risk is approved by Conatus (and FDA/other regulatory agency review 
and/or approval is obtained, if required) and is approved in writing by the 
IRB/IEC prior to implementation.  All protocol amendments will be submitted 
to the IRB/IEC.   
 Acknowledge receipt of administrative amendments that are provided for 
information only.   
 An approval/favorable opinion is obtained from the IRB/IEC on substantial 
amendments prior to implementation, unless the amendment is necessary to 
reduce immediate risk to study participants. 
 A written notice of approval from Conatus is obtained prior to initiating 
changes to the study protocol. 
 
A protocol deviation intended to eliminate an apparent immediate hazard may be 
implemented immediately, provided that Conatus is notified and an amendment is 
subsequently provided by Conatus and approved by the IRB/IEC.  Such deviations, 
and their rationale, should be documented. 
 
It is the Investigator’s obligation to maintain an IRB/IEC correspondence file and to 
make this available for review by representatives of Conatus and applicable 
regulatory agencies as part of the study monitoring process. 
 
14.2 Informed Consent 
 
Each site’s proposed informed consent form must be in compliance with applicable 
regulations and must be reviewed and approved by Conatus prior to initiation of the 
study.  The proposed informed consent form must contain a full explanation of the 
purpose and nature of the study, a description of the procedures, the possible 
advantages and risks, alternate treatment options, a statement of confidentiality of 
subject study records, a statement regarding compensation and availability of 
treatment in the case of injury, an explanation of whom to contact about the 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
57 of 76 
research, the subject’s rights, and notification that participation is voluntary and 
refusal will involve no penalty or loss of medical benefits.  These requirements are in 
accordance with the Federal Regulations as detailed in 21 CFR Part 50.25, ICH 
GCP 4.8.10, and the most current revision of the Declaration of Helsinki.  It should 
also indicate by signature that the subject (or, where appropriate, legal 
guardian/representative) permits access to relevant medical records by the Sponsor 
and/or the Sponsor’s duly appointed agent and by representatives of the US Food 
and Drug Administration (FDA) and other applicable regulatory agency and permits 
their data to be used in publications. 
 
The Investigator will be responsible for obtaining written informed consent from 
potential subjects prior to any study specific screening and entry into the study.  A 
copy of the signed document will be provided to the subject.  The original will be 
retained by the Investigator along with the case report forms. 
 
14.3 Subject Confidentiality and Data Protection 
All information obtained during the conduct of the study with respect to the subject 
will be regarded as confidential and confidentiality of all subjects will be maintained.  
Monitors (e.g., CRA, Medical Monitor), auditors and inspectors will require access to 
a subject’s medical notes for the purpose of source document verification but the 
subject’s confidentiality will be maintained at all times.  An agreement for disclosure 
of any such information will be obtained in writing and is included in the statement of 
informed consent.  The study data shall not be disclosed to a third party (with the 
exception of auditors and/or regulatory authorities) without the written consent of the 
Sponsor.  All data shall be secured against unauthorized access. 
 
The Investigator will maintain a list of subject names and identifying information 
(e.g., subject’s hospital number, unique subject number).  This list will not be 
collected by the Sponsor. 
 
The written information sheet will explain that study data will be stored in a computer 
database, maintaining confidentiality in accordance with national data legislation.  All 
data computer processed by the Sponsor or designee will be identified by unique 
subject number / subject initials / site number only.   
 
When personal data on subjects are stored or processed by computer, the data 
must be protected to prevent their disclosure to unauthorized third parties.  The 
pertinent sections of the data protection laws in which the country is being 
conducted will be complied with in full. 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
58 of 76 
The written ICF/subject information sheet will explain that, for data verification 
purposes, authorized representatives of the Sponsor, a regulatory authority, or an 
IRB/IEC may require direct access to parts of the hospital or practice records 
relevant to the study, including subject’s medical history. 
 
14.4 Laboratory Accreditation 
 
Any laboratory facility intended to be used for analysis of clinical laboratory samples 
required by this protocol must provide evidence of adequate licensure or 
accreditation according to the prevailing regulations in that state and/or country. 
Reference values and/or normal ranges for the test results must be provided to 
Conatus.  Conatus must be notified promptly in writing of any reference value 
changes during the course of the study. 
 
This protocol will analyze exploratory serum biomarkers of caspase and apoptotic 
activity.  As such, some of the analytes may be tested at a non-accredited research 
or analytical laboratory.  The requirement for adequate licensure or accreditation will 
not apply to any research or analytical laboratories utilized in this protocol. 
 
14.5 Required Documents 
 
Before the site initiation visit or the enrollment of any subject may occur, the 
Investigator must provide the Sponsor with the following documents (copies of which 
should be kept in the Investigator’s regulatory document binder):    
 
 Signed copy (original) of the approved protocol 
 Completed and signed statement of Investigator (Form FDA 1572) or foreign 
equivalent 
 Financial disclosure of the Investigator and sub-Investigators 
 Curriculum vitae and medical licenses (or equivalent) of the Investigator and 
sub-Investigators 
 Composition (names and representation) of IRB/IEC 
 Letter of approval from the IRB/IEC for both the protocol and the informed 
consent form, and other information provided to study participants  
 Copy of the stamped IRB/IEC-approved written informed consent form or 
subject information sheet to be used 
 For each clinical laboratory utilized in the study: 
 Relevant laboratory certification(s) 
 List of normal laboratory values 
 Curriculum vitae of the laboratory director 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
59 of 76 
In case a laboratory certification is not available, a written statement as to how the 
laboratory complies with quality assurance should be provided.  The Sponsor must 
be notified if the laboratory is changed. 
 
14.6 Study Initiation, Monitoring, and Termination 
 
Prior to commencement of the study, representatives of Conatus will visit the study 
site to verify adequacy of facilities to conduct the protocol, and to review with the 
Investigator the general obligations regarding studies with investigational new drugs. 
 
Upon satisfactory receipt of all required documentation (see Section 14.5), 
representatives of Conatus will arrange for all study materials to be delivered to the 
study site and will schedule a study initiation visit at a mutually convenient time.  
Subject entry must not begin until this initiation visit has been completed. At the 
initiation visit, site personnel will undergo a study-specific orientation, during which 
they will receive instruction in the study protocol, case report form completion, drug 
accountability, study file maintenance, and other study responsibilities. 
 
Throughout the course of the study, the Investigator shall make every reasonable 
effort to maintain the enrollment rate of appropriate subjects at the level 
prospectively estimated to Conatus.  Should the enrollment rate lag or significant 
numbers of clearly non-evaluable subjects be enrolled in the study, Conatus may 
elect to terminate the study at one or more sites.  Conatus also has the right to 
terminate the study at a particular site, at any time, for non-adherence to the 
protocol, lack of Investigator or site personnel availability (to the Sponsor or its 
designated monitoring personnel), or administrative reasons.  If it is necessary to 
terminate the study, Investigators will be compensated for reasonable expenses 
incurred during study termination.  Conatus will not compensate the Investigator (or 
investigative site) for procedures and/or evaluations conducted in a manner other 
than that specified by the protocol. 
 
Throughout the course of the study, representatives of Conatus will make frequent 
contacts with the Investigator and investigative site personnel.  Contacts will include 
e-mails, telephone calls, and/or on-site visits at appropriate and necessary intervals. 
During on-site visits, case report forms will be reviewed for completeness and for 
adherence to the protocol.  As part of the data review, it is expected that source 
documents (e.g., hospital records, office records, etc.) will be made available for 
review by the representatives of Conatus.  The representatives will also perform 
drug accountability checks and may periodically review the Investigator’s study file 
to assure completeness of documentation in all aspects of the conduct of the study. 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
60 of 76 
The Investigator (or appointed delegate) will be available to the representatives of 
Conatus during these on-site visits, will provide necessary study documents for 
inspection, and will respond to all inquiries that may arise as part of this review. On 
completion of the study, the representatives of Conatus will arrange for a final 
review of the study files, after which the study files should be secured for the 
appropriate time period (specified in Section 14.9).  The Investigator will also permit 
inspection of the study files by the Sponsor’s Quality Assurance auditors, IRB/IEC, 
authorized representatives of the FDA, and/or other applicable regulatory agencies. 
 
14.7 Data Recording and Case Report Forms 
 
Electronic case report forms will be provided by Conatus or its designee for the 
collection of all study data.  Forms should be completed in a timely manner, and 
appropriate efforts should be made to have forms completed and up-to-date prior to 
visits by the representatives of Conatus.  It is the obligation of the Investigator, as 
the study’s authority, to review each page of the case report forms and to e-sign the 
designated and appropriate forms.  Case report form completion may be formally 
delegated to other study personnel.  However, Conatus must be informed in writing 
of the name of such persons and the scope of their authority. 
 
14.8 Investigational Medicinal Product Accountability  
 
The investigational drug is to be prescribed only by the Investigator or physician 
sub-Investigators named on the Form FDA 1572 or foreign equivalent.  Under no 
circumstances will the Investigator(s) allow the investigational drug to be used other 
than as directed by this protocol. 
 
The Investigator must maintain accurate records accounting for the receipt of the 
investigational drug supplies and for the disposition of the study drug.  
Documentation of the disposition of the study drug should consist of a dispensing 
record including the identification of the person to whom the study drug is 
dispensed, the quantity and the date of dispensing, and any unused study drug 
returned.  This record is in addition to any drug accountability information recorded 
on the case report forms.  At the termination of the study or at the request of the 
Sponsor, the Investigator must return any unused study medications and all partially 
dispensed or empty containers to the Sponsor or its designee according to 
applicable local and country regulations.  If return of study drugs is not feasible, the 
Sponsor will supply instructions as to how the supplies may be destroyed.  Study 
drug supply destruction must be clearly documented.  Any investigational drug 
return will be documented at Conatus.  The Investigator will also provide a written 
explanation for any missing study drugs. 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
61 of 76 
14.9 Record Retention 
 
Documents that individually and collectively permit evaluation of the conduct of the 
study and the quality of the data produced must be maintained for review by the 
Sponsor’s Quality Assurance auditors and by US and non-US regulatory authorities. 
The period of time these documents must be maintained is governed by US and 
non-US regulations.  International requirements specify that these documents are to 
be maintained for 15 years or longer after a drug is approved for marketing.  
Conatus or its designee(s) will inform the Investigator when these documents may 
be destroyed.  The Sponsor or its designee(s) must be notified in writing at least 6 
months prior to the intended date of disposal of any study record related to this 
protocol to allow the Sponsor to make alternate storage arrangements. 
 
If the Investigator relocates, retires, or for any reason withdraws from the study, 
Conatus should be prospectively notified.  The study records must be transferred to 
an acceptable designee, such as another Investigator, another institution, or to 
Conatus. 
 
14.10 Investigator’s Final Report 
 
Each Investigator will submit, shortly after completion of study participation, a final, 
written report to the Sponsor. 
  
14.11 Publication Policy 
 
Conatus intends to publish the results of all of the clinical studies that it sponsors.  
Consistent with the recommendations of the editors of several leading medical 
journals, the International Committee of Medical Journal Editors (ICMJE), authorship 
of publications resulting from Conatus-sponsored studies should fairly recognize the 
activities of those that have made a significant contribution to the study13. Thus, it is 
anticipated that authorship will reflect the contribution made by the Sponsor 
personnel, the Investigators and others involved such as statisticians.  
 
In recent years, issues about conflicts of interest and accuracy of the study data 
have been raised in the medical press.  Accordingly, Conatus has developed 
publication guidelines for clinical studies that are appropriate for this study.  Key 
issues include: 
 
 Responsibility: Each Investigator is responsible for the accuracy and 
completeness of all data from his/her site. The Sponsor (or its 
representatives) is (are) responsible for the accuracy of the data entered into 
the study databases and for the accuracy of the analyses conducted. 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
62 of 76 
 
 Authorship and Publication Committee:  The Sponsor, in collaboration with 
the Investigators, will establish the appropriate authorship and responsibility 
for drafting study documents in accordance with the principles of the ICMJE.  
It is anticipated that a publication committee will be formed to assume 
oversight of these activities.  All manuscripts will be reviewed and agreed 
upon before submission for publication by all authors.   
 
 Sponsor Review of External Manuscripts: Consistent with the previous 
bullet point, drafts of any and all publications or presentations that may arise 
from this study must be submitted to the Sponsor for review, approval, and to 
ensure consistency with the policy in this protocol.  The Sponsor will have the 
right to request appropriate modification to correct facts and to represent its 
opinions, or the opinions of the publication committee, if these differ with the 
proposed publication.  Any Investigator who plans to submit material for 
publication must adhere to the following procedure for Sponsor review and 
approval: 
 
(a) The Investigator will notify Conatus of his/her intent to publish and/or 
present results of the study at least 30 days prior to submission for 
publication or the scheduled presentation date. The notification should 
be made in writing to Conatus. 
(b)  The Investigator shall provide to Conatus the full details of the proposed 
publication or presentation in electronic format at minimum 14 (fourteen) 
days prior to submission for publication of any paper, letter or similar 
publication, or 7 (seven) days prior to submission for presentation of any 
abstract, poster, talk or any other presentation. 
(c)  The Investigator shall give reasonable consideration to any request by 
Conatus to make changes within the periods mentioned in (b) above. 
(d)  The Investigator shall remove confidential information requested by 
Conatus before finalizing the publication. 
(e) Upon written request from Conatus, the Investigator agrees not to submit 
data for publication/presentation for an additional 60 (sixty) days in order 
to allow for actions to be taken which might be necessary to preserve 
rights for patent protection.  If such written request is not made within the 
periods mentioned in (b) above, Conatus will be deemed to have waived 
the right to delay. 
(f)  In any case, the Investigator will also provide a final version, in exactly 
the form that was submitted for publication, to Conatus simultaneously 
with that submission; this shall also apply to any revised versions that 
are submitted following review by the journal (etc.) in which publication is 
projected. 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
63 of 76 
 
 Confidentiality:  Investigators will conduct all interactions with the Sponsor 
and with third parties consistent with the executed confidentiality agreements.  
While publication, by intention, presents the critical scientific data in a public 
forum, some information (such as future plans, results of nonclinical studies, 
or chemical formulae) may still need to remain confidential. 
 
 Medical Journal Review:  Consistent with the intention of the Sponsor to 
publish the study in a fair and accurate manner, the Sponsor supports 
diligence in the publication review process of medical journals.  Accordingly, 
upon request, all pertinent study data and information will be made available 
as supplemental information for journal editors and reviewers to evaluate and 
audit, e.g., protocol and amendments, data tabulations, etc.  The journal and 
reviewers will need to make arrangements to maintain the confidentiality of 
such supplemental information, where relevant, and the Sponsor will make 
suitable arrangements to ensure that the identity of journal reviewers is kept 
confidential.  Records will be maintained of reviewers and the respective 
documents and datasets that were reviewed by each of them. 
 
 Internet Clinical Study Listing: In addition, also consistent with the 
recommendations of the ICMJE, the Sponsor will make available appropriate 
information regarding the study via the internet. This will include registration 
and listing of the study on www.clinicaltrials.gov, the US National Institutes of 
Health listing of clinical studies. 
 
14.12 Confidentiality 
 
Conatus, its designees, and all clinical site personnel affirm and uphold the principle 
of the subject’s right to protection against invasion of privacy.  Throughout this study, 
all data will be identified only by an identification number and subject initials. 
 
All information concerning this study and Conatus’ development of IDN-6556 that is 
not previously published is considered confidential information.  This confidential 
information shall remain the sole property of Conatus.  It shall not be disclosed to 
others without written consent of Conatus and shall not be used except in the 
performance of this study. 
 
The information compiled during the conduct of this clinical study is also considered 
confidential and may be disclosed and/or used only by Conatus as they deem 
necessary. To allow the use of the information derived from this clinical study and to 
ensure compliance to current federal and international regulations, the Investigator is 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
64 of 76 
obliged to furnish Conatus with complete test results and all data compiled in this 
study. 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
65 of 76 
 
15.0 REFERENCES 
 
1. 
http://srtr.transplant.hrsa.gov/annual_reports/2011/pdf/03_%20liver_12.pdf. 
OPTN & SRTR Annual Data Report 2011. Accessed 27 January 2014. 
 
2. 
Roche B, Samuel D. Treatment of hepatitis B and C after liver transplantation. 
Part 2, hepatitis C. Transpl Int 2005;17:759-766. 
 
3. 
Garg V, van Heeswijk R, Lee JE, et al. Effect of telaprevir on the 
pharmacokinetics of cyclosporine and tacrolimus. Hepatology 2011 Jul; 54(1): 
20-27. 
 
4. 
Hezode C, Dorival C, Zoulim F, et al. Safety of Telaprevir or Boceprevir in 
combination with Peginterferon alfa/Ribavirin, in Cirrhotic Non Responders 
(ANRS CO20-CUPIC). 
5. 
MR Charlton, EJ Gane, MP Manns, et al. Sofosbuvir and ribavirin for the 
treatment of established recurrent hepatitis C infection after liver 
transplantation: preliminary results of a prospective, multicenter study. 64th 
Annual Meeting of the American Association for the Study of Liver Diseases 
(AASLD 2013). Washington, DC, November 1-5, 2013. AbstractLB-2. 
 
6. 
Abdelmalek MF, Firpi RJ, Soldevila-Pico C, et al. Sustained viral response to 
interferon and ribavirin in liver transplant recipients with recurrent hepatitis C. 
Liver Transpl 2004;10:199-207. 
 
7. 
Walter T, Dumortier J, Guillaud O, et al. Factors influencing the progression of 
fibrosis in patients with recurrent hepatitis C after liver transplantation under 
antiviral therapy: a retrospective analysis of 939 liver biopsies in a single 
center. Liver Transpl 2007;13:294-301. 
 
8. 
Bixollon T, Ahmed SNS, Radenne S, et al. Long term histological 
improvement and clearance of intrahepatic hepatitis C virus RNA following 
sustained response to interferon-ribavirin combination therapy in liver 
transplanted patients with hepatitis C virus recurrence.  Gut 2003;52:283-287. 
 
9. 
Bahra M, Neumann UP, Jacob D, et al. Fibrosis progression in hepatitis C 
positive liver recipients after sustained virologic response to antiviral 
combination therapy (interferon-ribavirin therapy). Transpl 2007;83:351-353. 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
66 of 76 
10. 
Nair S, Lipscomb J, Eason J. Efficacy of interferon based antiviral therapy for 
recurrent 
hepatitis 
C 
in 
patients 
who 
received 
steroid 
free 
immunosuppression for liver transplantation. Transpl 2008;86:418-422. 
 
11. 
Roche B, Sebagh M, Canfora ML, et al.  Hepatitis C virus therapy in liver 
transplant recipients: response predictors, effect on fibrosis progression, and 
importance of the initial stage of fibrosis.  Liver Transpl 2008;14:1766-1777. 
 
12. 
Fleming T, Richardson B. Some design issues in trials of microbicides for the 
prevention of HIV infection. J Infectious Diseases 2004;190(4):666-674. 
 
13. 
Davidoff F, DeAngelis CD, Drazen JM, et al. Sponsorship, authorship, and 
accountability.  N Engl J Med, 2001; 345: 825-827. 
 
14. 
Pugh R, Murray-Lyon I, Dawson J, et al. Transection of the oesophagus for 
bleeding oesophageal varices. Brit. J. Surg. 60: 646-649, 1973. 
 
15. 
National Kidney Foundation: KDOQI Clinical Practice Guidelines for Chronic 
Kidney Disease: Evaluation, classification, and stratification. Am J Kidney Dis 
39:S1-S266, 2002 (suppl 1). 
 
16. 
Sandrin L, Fourquet B, Hasquenoph JM, et al. Transient elastography: a new 
noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 
2003; 29(12):1705-1713. 
 
17. 
Ziol M, Handra-Luca A, Kettaneh A, et al.  Noninvasive assessment of liver 
fibrosis by measurement of stiffness in patients with chronic hepatitis C. 
Hepatology 2005; 41(1):48-54. 
 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
67 of 76 
APPENDIX I: SCHEDULE OF EVENTS  
 
STUDY VISITSA 
Screening 
Phase 
(Week -6 
to Day 0) 
Double-Label Phase 
Follow-Up 
Phase 
M0/ 
Day 1 
Day 
14 
M 
1 
M 
3 
M 
6 
M 
9 
M 
12 
M 
15 
M 
18 
M 
21 
M24/ 
ET/EOT 
M25/ 
4 Wks post 
ET/EOT 
Study Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medication/Therapy Record 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination (including weight, height at 
screening only) 
X 
 
 
 
 
 
 
X 
 
 
 
X 
X 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
12 Lead ECG 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Liver and Abdominal Ultrasound 
XB 
 
 
 
 
XC 
 
XC 
 
XC 
 
X 
 
Liver Biopsy 
XD 
 
 
 
 
XE 
 
XF 
 
XE 
 
XF 
 
Transient Elastography (at select centers only) 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Study Drug Administration/Dispense Study Drug 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Compliance Assessment (Capsule Count) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Event Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Laboratory Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Urinalysis 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
Immunosuppressant Concentration Monitoring 
 
X 
X 
 
 
 
 
 
 
 
 
 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
68 of 76 
 
STUDY VISITSA 
Screening 
Phase 
(Week -6 
to Day 0) 
Double-Label Phase 
Follow-Up 
Phase 
M0/ 
Day 1 
Day 
14 
M 
1 
M 
3 
M 
6 
M 
9 
M 
12 
M 
15 
M 
18 
M 
21 
M24/ 
ET/EOT 
M25/ 
4 Wks post 
ET/EOT 
Blood Samples for Immunosuppressant Pharmacokinetic 
Analysis 
 
 
 
XG 
 
 
 
 
 
 
 
 
 
-fetoprotein 
X 
 
 
 
 
XH 
 
XH 
 
XH 
 
X 
 
CA 19-9 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Blood Sample for Biomarkers 
 
XI 
X 
X 
X 
XI 
 
XI 
 
 
 
XI 
X 
Blood Sample for Population Pharmacokinetic Analysis 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Blood Samples for Pharmacokinetic Analysis 
 
 
 
XJ 
 
 
 
 
 
 
 
 
 
Blood Samples for Pharmacokinetic Analysis  
(If Repeat Testing is Required for Elevated ALT, AST, 
and/or Bilirubin) 
 
 
XK 
XK 
XK 
XK 
XK 
XK 
XK 
XK 
XK 
XK 
 
Serum Pregnancy TestL 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy TestL 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
A Acceptable variation for actual study visits from Day 1 to Month 6 is  7 days from nominally scheduled day, and  14 days from nominally scheduled day from 
Month 6 onward.  However, every effort should be made to maintain the nominal visit schedules of subjects as predicated by the date of the Day 1 visit. 
B If the subject had a liver and abdominal ultrasound performed within three months of Screening, the prior ultrasound results can be used for study entry.  If the 
subject had an abdominal MRI or CT scan within three months of Screening, it can be utilized in lieu of the ultrasound at Screening 
C If on-treatment abnormalities in liver and abdominal ultrasound occur, Investigators should utilize normal clinical practice for follow-up of subjects and discuss 
treatment (dis)continuation with the Conatus Medical Monitor. 
D The biopsy should be within 3 months prior to Day 1. 
E If clinically indicated.  Refer to Section 8.1.1 for further details. 
F Yearly biopsy window is ± 42 days. In the event that a subject is withdrawn from the study prior to the 24 month visit, the subject will be contacted and asked to 
sign a separate consent to return for a biopsy at the Month 24 visit 
G Blood samples will be taken at predose, and at 0.5, 1, 2, 3, 4, 5, and 8 hours post dose for immunosuppressant pharmacokinetic analysis. 
H If elevations in -fetoprotein occur during the study, Investigators should utilize normal clinical practice for follow-up of subjects and discuss treatment 
(dis)continuation with the Conatus Medical Monitor. 
I ELF test to be run every 6 months only. 
J Blood samples will be taken at predose, and at 0.5, 1, 2, 3, 4, 5, and 8 hours post dose for pharmacokinetic analysis.   The time window for samples will be: 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
69 of 76 
o 
0.5 hour  5 minutes 
o 
1 hour  5 minutes 
o 
2 hour  5 minutes 
o 
3 hour  10 minutes 
o 
4 hour  10 minutes 
o 
5 hour  10 minutes 
o 
8 hour  10 minutes 
K If repeat laboratory testing is required for elevated ALT, AST, and/or total bilirubin (refer to Section 8.1.9) a single blood sample will be taken for pharmacokinetic 
analysis.   
L For women of childbearing potential only. 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
70 of 76 
APPENDIX II: LIVER BIOPSY SCORING AND ASSESSMENT 
 
Ishak Modified Histological Activity Index (Ishak Fibrosis Score) 
 
Liver biopsy findings are assigned scores for fibrosis as follows: 
 
Table II.1 
Ishak Fibrosis Score: Architectural Changes, Fibrosis and 
Cirrhosis 
 
 
Score 
No fibrosis 
0 
Fibrous expansion of some portal areas, with or without short fibrous septa 
1 
Fibrous expansion of most portal areas, with or without short fibrous septa 
2 
Fibrous expansion of most portal areas, with occasional portal to portal bridging 
3 
Fibrous expansion of portal areas, with marked bridging (portal to portal as well 
as portal to central) 
4 
Marked bridging (portal to portal and/or portal to central) with occasional 
nodules (incomplete cirrhosis) 
5 
Cirrhosis probable or definite 
6 
 
 
Ishak Modification of Knodell Histological Activity Index 
 
Liver biopsy findings will be assigned scores for necro-inflammation as follows: 
 
Table II.2 
Ishak Modification of Knodell Histological Activity Index: 
Necro-inflammatory Scores 
 
 
Score 
A Periportal or periseptal interface hepatitis (piecemeal necrosis) 
 
 
Absent 
0 
 
Mild (focal, few areas) 
1 
 
Mild/moderate (focal, most portal areas) 
2 
 
Moderate (continuous around <50% of tracts or septa) 
3 
 
Severe (continuous around >50% of tracts or septa) 
4 
B Confluent necrosis 
 
 
Absent 
0 
 
Focal confluent necrosis 
1 
 
Zone 3 necrosis in some areas 
2 
 
Zone 3 necrosis in most areas 
3 
 
Zone 3 necrosis + occasional portal-central bridging 
4 
 
Zone 3 necrosis + multiple portal-central bridging 
5 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
71 of 76 
 
Pan acinar or multiacinar necrosis 
6 
C Focal (spotty) lytic necrosis, apoptosis and focal inflammation 
 
 
Absent 
0 
 
One focus or less per 10X objective 
1 
 
Two – Four foci per 10X objective 
2 
 
Five – Ten foci per 10X objective 
3 
 
More than ten foci per 10X objective 
4 
D Portal Inflammation 
 
 
None 
0 
 
Mild, some or all portal areas 
1 
 
Moderate, some or all portal areas 
2 
 
Moderate/marked, all portal areas 
3 
 
Marked, all portal areas 
4 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
72 of 76 
APPENDIX III: CLASSIFICATION OF HEPATIC AND RENAL IMPAIRMENT 
 
Table III.1 
Assessment of Hepatic Impairment: Child-Pugh Scale (adapted 
from Pugh et al)14 
 
 
Points Scored for Observed Findings 
1 
2 
3 
Encephalopathy Grade+ 
None 
1 or 2 
3 or 4 
Ascites 
Absent 
Slight 
Moderate 
Serum Bilirubin (mg/dL) 
< 2.0 
2.0 - 3.0 
> 3.0 
Serum Albumin (g/dL) 
> 3.5 
2.8 - 3.5 
< 2.8 
Prothrombin Time (sec prolonged) 
< 4 
4 - 6 
> 6 
Classification of clinical severity 
 
Class A:  Score 5-6 (mild) 
Class B:  Score 7-9 (moderate) 
Class C:  Score 10-15 (severe) 
 
+Hepatic Encephalopathy grading: 
 
Grade 0: normal 
consciousness, 
personality, 
neurological 
examination, 
electroencephalogram 
Grade 1:  restless, 
sleep 
disturbed, 
irritable/agitated, 
tremor, 
impaired 
handwriting, 5 cps waves 
Grade 2:  lethargic, time-disorientated, inappropriate, asterixis, ataxia, slow 
triphasic waves 
Grade 3: somnolent, stuperous, place-disoriented, hyperactive reflexes, rigidity, 
slower waves 
Grade 4:  unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps 
delta activity 
 
Determination of Encephalopathy for the Calculation of the Child-Pugh Score 
 
Encephalopathy Test (If needed) 
The number connection test will facilitate the diagnosis of hepatic encephalopathy. 
The test should be performed by the subject after the investigator’s verbal 
instructions. The purpose is to correctly combine numbers with a pencil on a test 
chart as fast as possible. If the subject needs more than 40 seconds to perform the 
task, there is a strong indication of a latent hepatic encephalopathy. 
 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
73 of 76 
Table III.2 
Classification of Renal Function Based on GFR (eGFR) or 
Estimated Creatinine Clearance (CLcr)a 
 
Stage  
Descriptionb  
eGFRc  
(mL/min/1.73m2)  
CLcrd  
(mL/min)  
1  
Control (normal) GFR  
≥ 90  
≥ 90  
2  
Mild decrease in GFR  
60 - 89  
60 - 89  
3  
Moderate decrease in 
GFR  
30-59  
30 - 59  
4  
Severe decrease in 
GFR  
15 - 29  
15 - 29  
5  
End Stage Renal 
Disease (ESRD)  
<15 not on dialysis  
<15 not on dialysis  
Requiring dialysis  
Requiring dialysis 
a. In some situations, collection of 24-hour urine samples for measurement of creatinine 
clearance, or measurement of clearance of an exogenous filtration marker, may 
provide better estimates of GFR than the prediction equations. The situations include 
determination of GFR for patients in the following scenarios: undergoing kidney 
replacement therapy; acute renal failure; extremes of age, body size, or muscle mass; 
conditions of severe malnutrition or obesity; disease of skeletal muscle; or on a 
vegetarian diet.  
b. Stages of renal impairment are based on K/DOQI Clinical Practice Guidelines for 
Chronic Kidney Disease (CKD) from the National Kidney Foundation in 200215; GFR: 
glomerular filtration rate 
c. eGFR: estimate of GFR based on an MDRD equation 
d. CLcr: estimated creatinine clearance based on the C-G equation 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
74 of 76 
APPENDIX IV: FIBROSCAN® PROTOCOL 
 
Background 
 
Transient elastography performed with FibroScan® uses a low frequency vibrator 
(50Hz) mounted on 1-D US probe (5MHz). The speed of propagation of the shear 
wave through the liver is proportional to stiffness. The stiffness correlates with the 
severity of fibrosis16,17. 
 
Figure IV.1 FibroScan® Probe Placement in Relation to Anatomy of a 
Subject  
 
 
 
Reproduced from Ziol et al 200517. 
 
There are three images displayed on the monitor: 
 
1. A-mode image 
2. Time movement (TM) image 
3. A 2D elastogram 
 
These images are used by the operator to make sure that the area of the liver 
selected is free of large vascular structures, that lung fields do not encroach on 
inspiration and that the selected area is not over a rib. The elastogram 
demonstrates the depth of the shear wave with time. The slope of the resulting line 
gives speed of propagation. 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
75 of 76 
 
There are four figures displayed on the monitor: 
 
1. The cumulative median liver stiffness value 
2. The current liver stiffness value 
3. The inter-quartile range 
4. The success rate 
 
Method 
 
1. The subject is asked to lie comfortably in the supine position with his/her 
right arm fully abducted and resting on a pillow. 
2. Cover the tip of the probe with a small amount of coupling gel and place on 
the skin, on the right lateral wall of the abdomen between the ribs at the level 
of the right lobe of the liver. 
3. The right lobe of the liver is selected to ensure that the area of the liver to be 
measured is at least 6 cm thick. 
4. The probe must be placed perpendicular to the subject’s abdominal wall. 
5. Pressure should be applied by the operator on the subject and the button is 
pressed to initiate an acquisition. 
a. It is important to apply enough pressure on the subject so that the 
pressure bar display is within the green range. Insufficient pressure will 
be displayed as orange and over pressure will be displayed as red. 
b. Pressure must be released immediately following an acquisition. 
c. When making a measurement, it is also important to ensure that the 
subject is breathing slowly and not moving or speaking. 
6. If a successful reading is not acquired, the probe should be moved up or 
down by one rib space and, if that is not successful, anteriorly or posteriorly 
from the initial site by 1cm. Once a successful reading has been obtained, 
the remaining readings should be taken from the same site. 
7. To obtain a reliable and representative evaluation of the stiffness of the liver, 
10 valid measurements with a success rate of >60% should be acquired. 
8. For each subject the following parameters should be recorded: 
a. The median liver stiffness value (kPa) 
b. The success rate (%) 
c. The inter-quartile range (kPa) 
 
In order to standardize the FibroScan® procedure, the following should be 
implemented to obtain consistent and reproducible measurements. 
 
1. The subject should be NPO for 4 hours prior to the procedure 


Protocol Number: 
IDN-6556-07 
Version: 
3.1 
Title: A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects 
Who had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis or Cirrhosis 
following Orthotopic Liver Transplantation for Chronic HCV Infection and Who 
Subsequently Achieved a Sustained Virologic Response Following anti-HCV 
Therapy 
 
CONFIDENTIAL 
 
76 of 76 
2. The operator should be seated next to the subject, with the hand holding 
the probe, stabilized by the other. This will improve the stability of the 
probe as it is held up against the subject yielding an improved result with a 
low IQR. 
3. The measurement should be taken during expiration.  
 


Signature Page for CTS-CTD-0604 v1.0
Signature Page for CTS-CTD-0604 v1.0
Approved
Lisa Grubbs
Document Owner
14-Aug-2015 00:50:06 GMT+0000
Approved
Cindy Luchetti
RA/QA Approval
14-Aug-2015 16:00:58 GMT+0000
Approved
Jean Chan
Monitoring
14-Aug-2015 16:03:37 GMT+0000
Approved
David Hagerty
Clinical Operations
17-Aug-2015 17:22:01 GMT+0000

SAP_001.pdf: 
 
 
 
CONFIDENTIAL 
IDN-6556 (Emricasan) 
IDN-6556-07 STATISTICAL ANALYSIS PLAN (VERSION 2.0 FINAL) 
  
Protocol Title A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in 
Subjects Who had Hepatitis C Virus (HCV) Reinfection and Liver 
Fibrosis or Cirrhosis following Orthotopic Liver Transplantation for 
Chronic HCV Infection and Who Subsequently Achieved a Sustained 
Virologic Response Following anti-HCV Therapy 
Sponsor Conatus Pharmaceuticals 
16745 W. Bernardo Drive, Suite 200 
San Diego, CA  92127 
Statistician James M Robinson, MS 
Senior Director, Biostatistics 
Version 2.0 18JAN2018 FINAL 
  
  
  
 
 
 


Conatus Pharmaceuticals 
IDN-6556 (Emricasan) 
IDN-6556-07 Statistical Analysis Plan, Version 2.0 
 
CONFIDENTIAL 
2 
TABLE OF CONTENTS 
1 INTRODUCTION .....................................................................................................................5 
2 STUDY OBJECTIVES ..............................................................................................................6 
2.1 
Primary Objective .............................................................................................................6 
2.2 
Secondary Objectives .......................................................................................................6 
3 STUDY DETAILS.....................................................................................................................7 
3.1 
Study Design .....................................................................................................................7 
3.2 
Study Population ...............................................................................................................7 
3.3 
Randomization ..................................................................................................................7 
3.4 
Blinding ............................................................................................................................7 
3.5 
Study Visit Assignments ...................................................................................................8 
4 PLANNED SIZE DETERMINATION .....................................................................................9 
5 STUDY ENDPOINTS .............................................................................................................10 
5.1 
Primary Efficacy Endpoint .............................................................................................10 
5.2 
Secondary Efficacy Endpoints ........................................................................................10 
5.2.1 Ishak Modification of Knodell Histological Activity Index ..................................10 
5.2.2 NASH CRN Fibrosis Stage Scoring ......................................................................11 
5.2.3 Clinical Outcomes ..................................................................................................12 
5.2.4 Biomarkers .............................................................................................................12 
5.2.5 Liver Stiffness ........................................................................................................12 
5.3 
Exploratory Endpoint ......................................................................................................12 
5.4 
Safety Endpoints .............................................................................................................13 
5.4.1 Treatment Compliance ...........................................................................................13 
5.4.2 Extent of Exposure .................................................................................................13 
5.4.3 Adverse Events (AEs) ............................................................................................13 
5.4.4 Liver Ultrasound ....................................................................................................13 
5.4.5 Liver Monitoring ....................................................................................................13 
5.4.6 Laboratory Measurements .....................................................................................14 
5.4.7 Vital Signs, Weight, and Height ............................................................................14 
5.4.8 Electrocardiograms ................................................................................................15 
5.4.9 Medications ............................................................................................................15 
5.4.10 Physical Examination.............................................................................................15 
6 ANALYSIS POPULATIONS .................................................................................................17 
7 GENERAL STATISTICAL CONSIDERATIONS .................................................................18 
8 SUMMARY OF STUDY POPULATION DATA ..................................................................19 
8.1 
Subject Disposition .........................................................................................................19 
8.2 
Protocol Deviations.........................................................................................................19 
8.3 
Demographics .................................................................................................................19 
8.4 
Baseline Characteristics ..................................................................................................19 
8.5 
Transplant and HCV History ..........................................................................................20 


Conatus Pharmaceuticals 
IDN-6556 (Emricasan) 
IDN-6556-07 Statistical Analysis Plan, Version 2.0 
 
CONFIDENTIAL 
3 
9 EFFICACY ANALYSES ........................................................................................................21 
9.1 
Primary Efficacy Analysis ..............................................................................................21 
9.2 
Secondary Efficacy Analyses .........................................................................................21 
9.2.1 Secondary Efficacy Analysis: Testing the Difference in Response Rates Stratified 
by Baseline Ishak Fibrosis Score ...........................................................................22 
9.2.2 Secondary Efficacy Analysis: Change from Baseline in Ishak Fibrosis Score .....22 
9.2.3 Secondary Efficacy Analysis: Ishak Modification of Knodell Histological Activity 
Index ......................................................................................................................22 
9.2.4 Secondary Efficacy Analysis: Clinical Outcomes .................................................22 
9.2.5 Secondary Efficacy Analysis: Biomarkers ............................................................22 
9.2.6 Secondary Efficacy Analysis:  Fibrosis Improvement: NASH CRN ....................22 
9.2.7 Secondary Efficacy Analysis: Liver Stiffness .......................................................22 
9.3 
Exploratory Efficacy Analyses .......................................................................................23 
9.4 
Examination of Subgroups for Efficacy Endpoints ........................................................23 
10 PHARMACOKINETIC (PK) ANALYSES ............................................................................24 
10.1 Emricasan, Metabolites, and Immunosuppression PK profiles ......................................24 
10.2 Population PK Analysis ..................................................................................................24 
11 SAFETY ANALYSES.............................................................................................................25 
11.1 Dosing and Extent of Exposure ......................................................................................25 
11.2 Adverse Events ...............................................................................................................25 
11.3 Liver Ultrasound .............................................................................................................25 
11.4 Potential LIVER INJURY ..............................................................................................26 
11.5 Laboratory Measurements ..............................................................................................26 
11.6 Vital Signs and Weight ...................................................................................................26 
11.7 Electrocardiograms .........................................................................................................26 
11.8 Medications .....................................................................................................................26 
11.9 Physical Exam.................................................................................................................27 
11.10 Examination of Subgroups for Safety Endpoints ...........................................................27 
12 HANDLING OF MISSING DATA .........................................................................................28 
13 DATA MONITORING COMMITTEE ...................................................................................29 
14 CHANGES IN PLANNED ANALYSIS .................................................................................30 
14.1 Changes From Protocol to SAP version 1.0 ...................................................................30 
14.2 changes from SAP Version 1.0 to sap version 2.0 .........................................................30 
15 REFERENCES ........................................................................................................................31 
 
 
 


Conatus Pharmaceuticals 
IDN-6556 (Emricasan) 
IDN-6556-07 Statistical Analysis Plan, Version 2.0 
 
CONFIDENTIAL 
4 
ABBREVIATIONS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical classification 
BID 
Bis in die, twice daily 
BMI 
Body mass index 
CI 
Confidence interval 
DILI 
Drug-induced liver injury 
DMC 
Data monitoring committee 
EAER 
Exposure adjusted adverse event rate 
ELF 
Enhanced Liver Fibrosis Score 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eDISH 
Evaluation of drug-induced serious hepatotoxicity 
ES 
Enrolled Set 
FAS 
Full analysis set 
HCV 
Hepatitis C virus 
IQR 
Interquartile range 
IWRS 
Interactive web randomization system 
LSMeans 
Least-square means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
ms 
Milliseconds 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PPS 
Per-protocol Set 
QTcB 
QTc Bazett’s correction 
QTcF 
QTc Fridericia correction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SMA 
Smooth Muscle Actin 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
SVR 
Sustained virologic response 
TE 
Treatment effect 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of the normal range 


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1 
INTRODUCTION 
Clinical protocol IDN-6556-07 describes the collection and analysis of clinical study data to 
evaluate the use of emricasan (IDN-6556) in subjects who had HCV reinfection and liver fibrosis 
or cirrhosis following orthotopic liver transplantation for chronic HCV infection and who 
subsequently achieved a sustained virologic response (SVR) following anti-HCV therapy. This 
document provides details of the statistical analyses to be performed. All decisions regarding 
handling of data for reporting results will be determined prior to database lock and will be 
described in the relevant sections of this statistical analysis plan (SAP). 
 


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2 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of this clinical trial is to assess the effect of oral emricasan on fibrosis or 
cirrhosis using the Ishak Fibrosis Score, in subjects with HCV reinfection and liver fibrosis or 
cirrhosis following orthotopic liver transplantation for chronic HCV who subsequently achieved 
SVR following anti-HCV therapy. 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives of this clinical trial are: 
 To determine the effects of oral emricasan on necro-inflammatory sub-score of the 
modified Histological Activity Index 
 To determine the effects of oral emricasan on markers of mechanism of action and 
inflammation 
 To assess the safety and tolerability of oral emricasan in subject’s status post orthotopic 
liver transplantation. 
 


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3 
STUDY DETAILS 
3.1 
STUDY DESIGN 
This is a double-blind, randomized, multicenter study involving subjects with chronic HCV who 
underwent liver transplantation; developed HCV-related liver fibrosis or cirrhosis; achieved SVR 
following anti-HCV therapy; and still show demonstrable fibrosis or cirrhosis on liver biopsy. 
Upon successful screening, subjects are randomized to receive 25 mg BID of emricasan or 
placebo in a 2:1 ratio. 
The subjects are stratified based on the stage of fibrosis or cirrhosis at Baseline: 
 Ishak F2  
 Ishak F3-F5 
 Ishak F6 
The duration of each subject’s participation will be approximately 26.5 months and will consist 
of: 
 Screening period of up to 6 weeks  
 Double-blind treatment period of 24 months 
 A follow-up visit 4 weeks after completion of treatment 
The schedule of events is provided in Appendix 1 of the protocol. 
3.2 
STUDY POPULATION 
Approximately 60 subjects who underwent orthotopic liver transplantation for chronic HCV, 
developed HCV-related liver fibrosis or cirrhosis, achieved a SVR with anti-viral treatment, and 
still have demonstrable fibrosis or cirrhosis on liver histology will be enrolled.  Up to 15 subjects 
with an Ishak score of F6 can be enrolled. 
3.3 
RANDOMIZATION 
The assignment to emricasan or placebo will be performed randomly in a 2:1 ratio to emricasan 
25 mg BID or matching placebo BID.  Approximately 60 subjects will be enrolled in this trial 
with 40 assigned to emricasan and 20 assigned to placebo. Randomization will be stratified 
based on baseline Ishak Fibrosis Score: F2, F3-F5, or F6.  
The randomization schedule will be generated using a validated randomization program and 
verified for accuracy using strict quality control procedures. Randomization numbers and study 
drug assignment will be centrally coordinated through the study’s Interactive Web 
Randomization System (IWRS).  
3.4 
BLINDING 
This clinical trial is a double-blind study through the final study visit.  The final randomization 
codes for each subject completing the trial will be provided after all subjects complete their final 
visit and database lock occurs.  
Investigators will be able to unblind individual subjects through the IWRS when it is medically 
imperative to know whether a specific subject is receiving emricasan or placebo, such as in the 
occurrence of an adverse event (AE) that the Investigator feels cannot be adequately treated 


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without knowing the identity of the study drug.  In the event of an individual subject being 
unblinded when medically imperative, the individual subject will have their study drug stopped 
sometime prior to unblinding. Every effort must be made to contact the Medical Monitor to 
discuss the case before breaking the blind, or if in an emergency, as soon as possible thereafter 
(no later than 24 hours after emergency unblinding) to inform the Medical Monitor that 
unblinding was performed but without disclosing the actual study drug assignment.  The 
investigator should make arrangements to ensure that access to the secure internet site 
(i.e., individual user name and password) is maintained in strict confidence to prevent a 
compromise of subject blinding by non-study or unauthorized individuals.  
The Sponsor may access the randomization codes for individual subjects with potential suspected 
unexpected serious adverse reactions (SUSARs) for regulatory reporting or for the purpose of 
evaluating an emergent safety issue.  In such an event, the Sponsor will document the rationale, 
circumstances, and the person or persons being informed about the unblinding. 
If the blind for an individual subject is broken (by the Investigator or the Sponsor), an entry must 
be made in the electronic data capture system that contains the reason that the blind was broken 
and the name of the person contacted at the Sponsor or designee. 
3.5 
STUDY VISIT ASSIGNMENTS 
Study visits are designated on the electronic case report forms (eCRFs) and data will be analyzed 
per the study visit assigned and collected.  All post-baseline biopsies will be assigned and 
collected on the Month 12 and 24 eCRFs.  
For purposes of sensitivity analyses, biopsies will also be assigned to Month 12 and Month 24 
flags, respectively, based on biopsy date.  Biopsies will be classified as Month 12 biopsies flag if 
the biopsy date is collected within ±8 weeks (i.e., ±56 study days, inclusive) from the planned 
Month 12 visit date relative to the Day 1 visit date (i.e., Month 12 visit date – Day 1 visit date + 
1).  Similarly, Month 24 biopsies flag will designate those biopsies at Month 24 that are within 
±8 weeks (i.e., ±56 study days, inclusive) from the planned Month 24 visit date relative to the 
Day 1 visit date (i.e., Month 24 visit date – Day 1 visit date + 1).  


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4 
PLANNED SIZE DETERMINATION 
This study will be conducted at multiple centers at which approximately 60 subjects will be 
enrolled and treated in a 2:1 ratio with emricasan or placebo, respectively.  The sample size 
determination for this study is based on the Phase 2b screening methodology presented in 
Fleming and Richardson (2004).  
The base case for the placebo response rate of 30% was assumed and obtained from George, et al 
(2009), where it stated that 29% of patients showed a response in fibrosis from a mean of 1.6 
years following HCV-SVR. 
Treatment duration for all subjects is expected to be two years. The primary analysis of this 
Phase 2 “screening” study is formally based on a three-category decision guideline. The decision 
guideline for this study is based on whether the difference in the proportions of subjects who 
show a response (i.e., improvement or no change) per their Ishak Fibrosis Score at 24 months for 
emricasan compared to placebo is less than 5%, is from 5% up to 15%, or is more than 15%. 
Specifically, the outcome of the study will determine one of the following three course of action: 
1. If the difference in response rates between emricasan and placebo (i.e., emricasan 
response rate – placebo response rate) is less than 5%, then emricasan regimen is not 
plausibly more efficacious than placebo; hence, emricasan or its utility in this indication 
will be reconsidered. 
2. If the difference in response rates between emricasan and placebo is from 5% up to 15%, 
then emricasan is plausibly more efficacious than placebo in this indication if secondary 
analyses of biomarkers suggest utility of emricasan or a positive safety profile is 
observed; hence, emricasan could be evaluated in a subsequent Phase 3 clinical study. 
3. If the difference in response rates between emricasan and placebo is more than 15%, then 
emricasan could be evaluated in a subsequent Phase 3 study. 
These categories should not be interpreted as providing strict decision rules but rather as 
guidelines that will be factored into a broader scientific assessment of the benefit to risk profile 
for emricasan in this indication. This broader assessment will include consideration of secondary 
efficacy analyses, safety profile, and relevant information external to this study. 
The operating characteristics for this three-category decision guideline are shown in Table 1. 
Table 1. 
Operating Characteristics for Three-Category Decision Guideline  
Probability of Obtaining an Estimated Treatment Effect (Emricasan – Placebo) 
True Treatment Effect (TE) 
≤5% 
5%≤ TE <15% 
≥15% 
0 
67% 
22% 
11% 
5 
52% 
26% 
22% 
10 
36% 
27% 
37% 
15 
23% 
24% 
53% 
20 
13% 
19% 
68% 
25 
7% 
13% 
80% 
30 
3% 
8% 
89% 
Note: 
Based on 100,000 simulations. 


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5 
STUDY ENDPOINTS 
5.1 
PRIMARY EFFICACY ENDPOINT 
The Ishak Fibrosis Score will be determined by liver biopsy as scored by the central 
histopathologist. The Ishak Fibrosis Score classification is defined as:  
 0 = No fibrosis (F0);  
 1 = Fibrous expansion of some portal areas, with or without short fibrous septa (F1);  
 2 = Fibrous expansion of most portal areas, with or without short fibrous septa (F2);  
 3 = Fibrous expansion of most portal areas, with occasional portal to portal bridging (F3);  
 4 = Fibrous expansion of portal areas, with marked bridging (F4);  
 5 = Marked bridging with occasional nodules (F5);  
 6 = cirrhosis probable or definite (F6).  
 
Fibrosis scores of F0 and F1 will be excluded from enrollment. The change from baseline in the 
Ishak Fibrosis Score will be derived for each subject and will be used to classify subjects into 
one of the three following groups: 
 Improvement, defined as having a reduction from baseline of at least 1-point in the Ishak 
Fibrosis Score 
 Stable, defined as having no change from baseline in the Ishak Fibrosis Score 
 Worsening, defined as having an increase from baseline in the Ishak Fibrosis Score 
 
Subjects will be classified as a responder or non-responder based on the above three groups and 
their baseline Ishak Fibrosis score.  The definition of response is based on the following: 
 For subjects with baseline Ishak Fibrosis Score of F2-F5, achieving either improvement 
or remaining stable 
 For subjects with baseline Ishak Fibrosis Score of F6, achieving improvement 
 
The response at Month 24 will be used as the primary endpoint in this study.  Response rates at 
Month 12 using the same definitions as above will also be summarized. 
5.2 
SECONDARY EFFICACY ENDPOINTS 
5.2.1 
Ishak Modification of Knodell Histological Activity Index 
The Ishak modification of Knodell histological activity index will be determined by liver biopsy. 
The four items and their categorizations scores include: 
 interface hepatitis 
o 0 = None 
o 1 = Mild (local, few portal areas) 
o 2 = Mild/moderate (focal, most portal areas) 
o 3 = Moderate (continuous around <50% of tracts or septa) 


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o 4 = Severe (continuous around >50% of tracts or septa) 
 confluent necrosis 
o 0 = None 
o 1 = Focal confluent necrosis 
o 2 = Zone 3 necrosis in some areas 
o 3 = Zone 3 necrosis in most areas 
o 4 = Zone 3 necrosis + occasional portal-central bridging 
o 5 = Zone 3 necrosis + multiple portal-central bridging 
o 6 = Panacinar or multiacinar necrosis 
 parenchymal injury (focal lytic necrosis, apoptosis and focal inflammation) 
o 0 = None 
o 1 = One focus or less per 10× objective 
o 2 = Two to four foci per 10× objective 
o 3 = Five to ten foci per 10× objective 
o 4 = More than ten foci per 10× objective 
 portal inflammation  
o 0 = None 
o 1 = Mild, some or all portal areas 
o 2 = Moderate, some or all portal areas 
o 3 = Moderate/marked, all portal areas 
o 4 = Marked, all portal areas 
The Ishak modification of Knodell histological activity index will be assessed at months 12 and 24.  
5.2.2 
NASH CRN Fibrosis Stage Scoring 
In order to provide a potential comparison to how fibrosis improvement would be viewed in a 
traditional paired biopsy study in NASH, the Ishak fibrosis scores will be mapped to a comparable 
fibrosis stage in the NASH CRN staging system.  The NASH CRN fibrosis stage classification is 
defined as: 0=None (F0); 1a=mild, Zone 3, perisinusoidal fibrosis (F1); 1b=moderate, Zone 3, 
perisinusoidal fibrosis (F1); 1c=portal/periportal fibrosis only (F1); 2=perisinusoidal and 
portal/periportal fibrosis (F2); 3=bridging fibrosis (F3); and 4=cirrhosis (F4).  To map Ishak 
Fibrosis Score to the NASH CRN definitions, Table 2 will be used to map the scores from Ishak 
to NASH CRN: 
Table 2. 
Mapping of fibrosis staging from Ishak to NASH CRN 
Ishak Fibrosis Scoring 
NASH CRN Mapped Score 
F0 
F0 
F1 
F1 
F2 
F2 
F3 
F3 
F4 
F3 
F5 
F4 


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F6 
F4 
The proportion of patients who have at least a one stage improvement in the mapped fibrosis 
stages will be evaluated at Month 12 and Month 24. 
5.2.3 
Clinical Outcomes 
Clinical outcomes will be documented from a blinded medical review of MedDRA coded AEs 
collected from the eCRF prior to database lock.  Clinical outcomes will include decompensation 
events, re-transplantations, and all-cause mortality.  Decompensations events will include 
variceal bleeding, hepatic encephalopathy, ascites, hepato-renal syndrome, and jaundice. The 
following specific MedDRA coded preferred terms to be used are: 
 Liver Transplant, Kidney Transplant 
 Death 
 Oesophageal varices haemorrhage 
 Hepatic encephalopathy 
 Ascites 
 Hepatorenal syndrome 
 Jaundice 
 
5.2.4 
Biomarkers 
The following biomarkers will be collected: 
 ALT  
 AST 
 caspase 3/7 
 cCK18/M30 
 flCK18/M65 
 Enhanced Liver Fibrosis (ELF) score (based on hyaluronic acid, P3NP, TIMP-1) 
The change from baseline will be derived for each of these biomarkers. If any biomarker 
variables are not normally distributed, a log-transformation may be applied to that biomarker 
endpoint prior to analysis.  
5.2.5 
Liver Stiffness 
Liver stiffness will be assessed by transient elastography (FibroScan®) performed at seven sites 
on a subset of the entire study population.  Fibroscan® is collected at screening and Months 6, 12, 
18, and 24. Only values meeting the specific success criteria (interquartile range [IQR] / median 
liver stiffness <30% and success rate >60%) will be summarized. The change from baseline in 
liver stiffness will be derived using all available data. 
5.3 
EXPLORATORY ENDPOINT 
A morphometric assessment will be made on all biopsies collected at screening and Months 12 
and 24.  Effects on liver collagen and smooth muscle actin (SMA) will be assessed by 


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morphometric image analysis.  The change from baseline in percent of liver collagen and SMA 
will be derived. 
5.4 
SAFETY ENDPOINTS 
5.4.1 
Treatment Compliance 
Study drug dispensation information and treatment compliance data will be collected throughout 
the study. The number of capsules dispensed, number of capsules returned, number of missed 
doses and study drug interruptions data will be collected.  Treatment compliance will be 
calculated in the database and is defined as: (the number of capsules dispensed minus the number 
of capsules returned) divided by the number of expected doses. 
5.4.2 
Extent of Exposure 
Overall treatment exposure will be derived as the number of days from the first date of study 
drug administration to the last date of study drug administration (inclusive of the first and last 
dates of dosing), regardless of study drug interruptions.  Person years of exposure will be derived 
as the overall exposure divided by the number of person years observed, where 1 year is equal to 
365.25 days.  
5.4.3 
Adverse Events (AEs) 
Adverse events will be collected during the study and will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). All events with a start date on or after the first 
date of study drug administration to the last study visit date are defined as treatment-emergent 
adverse events (TEAEs). 
Adverse events classified as definitely, probably, and possibly related to study drug will be 
summarized together as related AEs. Adverse events classified as unlikely and not related will be 
summarized together as not related AEs. For summary purposes, the AE relationship will be 
summarized as related, not related, or unknown. 
5.4.4 
Liver Ultrasound 
Liver ultrasounds are performed at Screening, Month 6, Month 12, Month 18, and Month 24. 
Ultrasound data will be reviewed for evidence of any new focal hepatic lesion as well as for any 
evidence of new gallbladder inflammation.   
5.4.5 
Liver Monitoring 
Liver transaminases (ALT, AST) and total bilirubin will be monitored at each study visit during 
the study for any evidence of potential DILI.  The following categories for ALT, AST, and total 
bilirubin will be derived:  
 Maximum post-baseline comparison to upper limit of the normal range (ULN): 
o ALT 
 ≤ULN 
 >ULN and ≤3× ULN 
 >3× ULN and ≤5× ULN 
 >5× ULN and ≤8× ULN 
 >8× ULN 


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o AST 
 ≤ULN 
 >ULN and ≤3× ULN 
 >3× ULN and ≤5× ULN  
 >5× ULN and ≤8× ULN 
 >8× ULN 
o Total bilirubin 
 ≤ULN 
 >ULN and ≤1.5× ULN 
 >1.5× ULN and ≤2× ULN  
 >2× ULN and ≤3× ULN 
 >3× ULN 
 Maximum post-baseline value >2× baseline 
 Maximum post-baseline value >3× baseline 
 Elevated post-baseline ALT and/or AST with concurrent (i.e., same post-baseline visit) 
elevated total bilirubin 
o ALT >3× ULN and concurrent total bilirubin >2× ULN 
o AST >3× ULN and concurrent total bilirubin >2× ULN 
o Either ALT or AST >3× ULN and concurrent total bilirubin >2× ULN 
o Both ALT and AST >3× ULN and concurrent total bilirubin >2× ULN 
 Elevated Post-baseline ALT and/or AST with elevated total bilirubin (not necessarily 
concurrent) 
o ALT >3× ULN and not necessarily concurrent (i.e., across all post-baseline visits) 
total bilirubin >2× ULN 
o AST >3× ULN and not necessarily concurrent total bilirubin >2× ULN 
o Either ALT or AST >3× ULN and not necessarily concurrent total bilirubin >2× ULN 
o Both ALT and AST >3× ULN and not necessarily concurrent total bilirubin >2× ULN 
 
5.4.6 
Laboratory Measurements 
Laboratory tests include measurements across panels of hematology, coagulation, chemistry, and 
urinalysis.  In addition, alpha-fetoprotein is measured at screening and every 6 months during the 
study. All specific laboratory tests are listed in detail in clinical protocol IDN-6556-07.  Normal 
ranges, where applicable, will be provided by the central laboratory and used to identify 
laboratory measurements outside the normal range. 
Changes from baseline will be derived for each continuous laboratory parameter.  Laboratory 
tests with categorical results will have no derivations made. 
5.4.7 
Vital Signs, Weight, and Height 
Vital signs include systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, 
and temperature. Body weight and height will be collected at protocol specified visits (weight at 


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screening, Month 12, and Month 24, height at screening only), and body mass index (BMI) will 
be derived as [weight in kilograms] / [height in meters2].     
Changes from baseline in vital signs, weight, and BMI will be derived. 
5.4.8 
Electrocardiograms 
Electrocardiogram (ECG) data to be reported includes ventricular rate, PR interval, RR interval, 
QRS interval, QT interval, QTc interval, QTcB interval, QTcF interval, and findings (i.e., normal 
or abnormal). Post-dose maximum values in QTcB and QTcF will be classified into the 
following categories, in milliseconds (ms): 
 <450 
 ≥450 to <480 
 ≥480 to <500 
 ≥500 
Changes from baseline in PR interval, QRS interval, QT interval, QTc interval, QTcB interval, 
and QTcF interval will be derived at each respective visit. Changes from baseline values in 
QTcB and QTcF will be classified into the following categories, in ms:  
 <30 
 ≥30 to <60 
 ≥60 
5.4.9 
Medications 
All additional medications taken any time during the study will be recorded at each study visit.  
Medications will be classified into 1 of the following 3 types: 
 Prior Medication: any medication stopped prior to the first date of study drug 
administration 
 Concomitant Medication: any medication started prior to and stopped on or after the first 
date of study drug administration 
 New Concomitant Medication: any medication started on or after the first date of study 
drug administration  
All medications will be coded using the world health organization drug dictionary. 
Immunosuppressant therapy relative to a subject’s liver transplant is collected at screening and 
will be classified as tacrolimus, cyclosporine, or other. 
Previous hepatic treatments were collected at screening.  These medications will be manually 
reviewed and classified as anti-viral, immunotherapy, and anti-viral+immunotherapy.  These 
medications will also be classified as interferon-based or not.  
5.4.10 
Physical Examination 
A comprehensive physical examination will be performed and will include assessments of 
general appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, 
chest, heart, abdomen (including liver and spleen examination), extremities, and nervous system.  
No derivations will be made for physical examination components results. 


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6 
ANALYSIS POPULATIONS 
The Enrolled Set (ES) is defined as the set of subjects who provide a signed informed consent 
form to participate in this study.  
The Full Analysis Set (FAS) consists of all randomized subjects who have received at least one 
dose of study drug. If the administration of study drug is not certain, the subject will be allocated 
to the FAS. The FAS is representative of the intention-to-treat principle assigning subjects to the 
planned randomized study drug assignment and will be analyzed as randomized. 
The Per-Protocol Set (PPS) is defined as the set of subjects included in the FAS who have no 
significant protocol deviations that impact the primary endpoint and who provide a Month 24 
liver biopsy. The PPS will be defined during a blinded data review meeting prior to database 
lock based on considerations like major protocol deviations affecting the primary endpoint, 
inadequate study drug compliance, etc. Meeting minutes and the final deviation tracker will 
serve as documentation for classification of subjects into the PPS. 
The Safety Analysis Set consists of all subjects who are randomized and receive at least one dose 
of study drug. Subjects will be analyzed on an “as treated” basis (i.e., all subjects will be 
analyzed by the treatment they actually received). If no errors in randomization assignments 
occur, then the FAS and Safety Analysis Set will be the same. 


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7 
GENERAL STATISTICAL CONSIDERATIONS 
All biopsy data analyzed by and collected from the central histopathologist will be used in the 
FAS for all efficacy analyses, unless stated otherwise. All biopsy data collected per local 
assessments will be captured in the database and will be provided in a listing by visit. 
Analyses will be conducted using SASv9.3 or higher and pooled across all enrolling sites.  Data 
will be summarized descriptively with categorical variables being summarized using number of 
observations and percentages; continuous variables being summarized by n, mean, median, 
standard deviation, minimum, and maximum, unless otherwise specified.  
All disposition, demographics, and baseline summaries will be based on using the FAS, with the 
disposition table also being summarized using the ES.  The efficacy analyses will be based on 
the FAS, with the primary analysis also performed on the PPS. All safety analyses will be based 
on the Safety Analysis Set. 
All summaries by treatment group will include each of the planned two treatment groups and all 
subjects combined (i.e., total). 
All subjects will be assigned a unique subject number, which will consist of the study site 
identification concatenated with the assigned subject number. 
For purposes of laboratory summaries, baseline is defined as an average all values observed up to 
an including Day 1.  For purposes of abnormality laboratory summaries and all other analyses, 
baseline is defined as the last observed value up to and including Day 1.  
Formatting of numerical results will include the following: 
 Mean values will be reported to 1 decimal place more than the data collected. 
 Standard deviation values will be reported to 2 decimal places more than the data 
collected. 
 Median, minimum, and maximum values will be reported to the same decimal place as 
the data collected.  
 Percentages will be reported to 1 decimal place. 
 Where confidence intervals (CI) are to be reported, CIs for means will be reported to the 
same decimal places as mean values; CIs for percentages will be reported to 1 decimal 
place. 
 All p-values will be reported to 3 decimal places. 
 


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8 
SUMMARY OF STUDY POPULATION DATA 
All study population data will be provided in subject specific listings. The disposition table will 
be produced using the ES and FAS. All other study population data tables will be produced using 
the FAS. 
8.1 
SUBJECT DISPOSITION 
Subject disposition will be summarized descriptively by treatment group.  The disposition 
summary will include results for subjects enrolled, subjects randomized, subjects treated, 
subjects included in each analysis population, discontinuation of study drug, reason for study 
drug discontinuation, study completion status, and reason for study withdrawal. 
8.2 
PROTOCOL DEVIATIONS 
Protocol deviations will include the deviation recorded, the deviation category, and significance 
classification. The deviation category refers to the general aspect of the study the deviation 
affects. Classifications of protocol deviations will be determined by the clinical trial study team 
prior to database lock during a blinded data review meeting. 
Protocol deviations will be summarized descriptively by treatment group. A listing of protocol 
deviations by unique subject number will be provided. 
Reasons for screen failure will also be summarized by treatment group. 
8.3 
DEMOGRAPHICS 
Subject demographics will be summarized descriptively by treatment group.  The demographics 
summary will include results for subject age, age group, gender, race, and ethnic category. Age 
group is defined as the following categories: 
 18 - 40 years 
 ≥40 - 64 years 
 >64 years 
 
8.4 
BASELINE CHARACTERISTICS 
Baseline characteristics include the following: 
 Ishak fibrosis score 
 Knodell histological activity index components (interface hepatitis, confluent necrosis, 
parenchymal injury, and portal inflammation)  
 Liver collagen and SMA 
 biomarkers (ALT, AST, caspase 3/7, cCK18/M30, and flCK18/M65) 
 Laboratory Parameters (platelet count, total bilirubin, albumin, INR) 
 Weight, BMI 
 


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The number and percentage of patients who are receiving either tacrolimus or cyclosporin as 
their immunosuppressant medication at the time or randomization, as well as the type of previous 
hepatic treatment received, will be included as part of the baseline characteristics. 
All baseline characteristics will be summarized descriptively by treatment group. A listing of 
baseline characteristics will be provided by unique subject number. 
8.5 
TRANSPLANT AND HCV HISTORY 
Transplant and HCV history will be summarized by treatment group. The transplant history 
summary will include: 
 Number of years since transplant 
 Liver donor age 
 HCV positive donor Liver 
o Yes 
o No 
 Source of transplant 
o Living 
o Cadaveric 
 Immunosuppression regimen 
o Tacrolimus 
o Cyclosporine  
o Other 
 Time since SVR (calculated as 12 weeks post end of previous hepatic treatment date 
treatment date) 
 Previous HCV treatment post-transplant 
o Treatment Type 
 Antiviral 
 Immunotherapy 
 Antiviral+Immunotherapy 
o Interferon Based Treatment  
 Yes 
 No 


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9 
EFFICACY ANALYSES 
All primary, secondary, and exploratory endpoints will be summarized descriptively by 
treatment group at each study visit, using the FAS.  Also, a sensitivity analysis for the primary 
endpoint will be produced using the PPS. The individual components of the primary endpoint 
will also be summarized descriptively by treatment group at each study visit.   
All efficacy endpoints will be provided in listings by unique subject number and visit. 
9.1 
PRIMARY EFFICACY ANALYSIS 
All screening and post-baseline biopsy data collected will be used in the primary analysis, 
irrespective of the defined protocol visit window.  Classification of the Ishak fibrosis score will 
be summarized descriptively by treatment group at baseline, Month 12, and Month 24. Response 
at Months 12 and 24 will be summarized descriptively by treatment group, along with exact 
(Clopper-Pearson) 95% confidence intervals (CIs).  The risk difference between groups will also 
be provided with its 95% CI. 
For the primary efficacy analysis based on the Month 24 biopsy, subjects with a missing Month 
24 biopsy will have their Ishak fibrosis score imputed.  Imputation of missing Ishak fibrosis 
scores will be conducted using multiple imputation (MI).  Results will be imputed based on age, 
gender, baseline Ishak fibrosis score, and the Month 12 Ishak fibrosis score.  Imputations will be 
based on at least 5 imputed datasets, depending on the percent of missing observations and will 
be documented in the clinical study report. Within each imputed dataset, the change from 
baseline at Month 24 will be derived to allow categorization into response or no response as 
defined in Section 5.1. 
Study success will be determined per the criteria described in Section 0. This primary analysis 
will be conducted using the FAS.   
The following sensitivity analyses will be provided for the primary efficacy endpoint, using 
different methods for the handling of missing liver biopsy results at Month 24: 
 All FAS observed post-baseline biopsies 
 All FAS observed post-baseline at Month 24 (within the sensitivity analysis visit 
window, per Section 3.5) 
 FAS with missing M24 biopsy imputed to ‘No’ response 
 Per-protocol  
 
Response rates at Month 12 will be summarized using the FAS in the same manner as the 
response rates at Month 24 (i.e., using MI). Subjects with a missing Month 12 liver biopsy will 
have their Month 12 Ishak fibrosis score imputed based on age, gender, and baseline Ishak 
fibrosis score.   
9.2 
SECONDARY EFFICACY ANALYSES 
All secondary analyses will be conducted using the FAS.  All secondary endpoints based on the 
Months 12 and 24 liver biopsies will include data as collected (per Section 3.5). All secondary 
endpoints will be summarized using observed cases.  


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No multiplicity adjustments will be made for the analysis of secondary endpoints.   
9.2.1 
Secondary Efficacy Analysis: Testing the Difference in Response Rates 
Stratified by Baseline Ishak Fibrosis Score  
Testing of differences in response rates will be conducted using a Cochran-Mantel-Haenszel test.  
For each of the analyses described in Section 9.1 above, the testing will be stratified separately 
by each of the following: 
 Baseline Ishak fibrosis score strata (F2, F3-F5, F6) 
 Baseline Ishak fibrosis score grouping A (F2-F3, F4-F6) 
 Baseline Ishak fibrosis score (F2-F6) 
 
9.2.2 
Secondary Efficacy Analysis: Change from Baseline in Ishak Fibrosis Score 
Changes from baseline for the Ishak fibrosis score will also be summarized descriptively by 
treatment group using a shift table. 
9.2.3 
Secondary Efficacy Analysis: Ishak Modification of Knodell Histological 
Activity Index 
The four components of the Knodell Histological Activity Index (interface hepatitis, confluent 
necrosis, parenchymal injury, and portal inflammation) will each be summarized descriptively by 
treatment group in two formats.  The first format is descriptively summarizing each category by 
treatment group and visit.  The second format is descriptively summarizing the shift in categories 
between baseline and Months 12 and 24, separately, by treatment group.   
9.2.4 
Secondary Efficacy Analysis: Clinical Outcomes 
Each clinical outcome and type of decompensation event will be summarized descriptively by 
treatment group. This descriptive summary will summarize subjects and events across the entire 
study period (i.e., all post-baseline data collected up through Month 24).  This summary will also 
be provided for all post-baseline data collected through Month 12.   
9.2.5 
Secondary Efficacy Analysis: Biomarkers 
Biomarker endpoints will be summarized descriptively at each visit by treatment group. Change 
from baseline values for each biomarker at each post-baseline visit will be summarized 
descriptively by treatment group.  If log-transformations are applied to any of the biomarker 
endpoints, the geometric mean, coefficient of variation, and percent relative change will also be 
included in the descriptive statistics.   
9.2.6 
Secondary Efficacy Analysis:  Fibrosis Improvement: NASH CRN 
The primary efficacy analysis will be repeated using the mapping from the Ishak Fibrosis Scoring 
System to evaluate the proportion of subjects who have at least at one-point improvement in 
fibrosis based on the mapping to this scoring system at Month 12 and Month 24.  
9.2.7 
Secondary Efficacy Analysis: Liver Stiffness 
Liver stiffness will be summarized descriptively at each visit collected by treatment group. 
Change from baseline values in liver stiffness at each post-baseline visit will also be summarized 
descriptively by treatment group. 


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9.3 
EXPLORATORY EFFICACY ANALYSES 
The percent collagen and percent SMA from morphometric analysis will be summarized 
descriptively at Month 12 and Month 24 by treatment group. Change from baseline values in 
percent collagen and SMA will be summarized descriptively by treatment group and overall. 
9.4 
EXAMINATION OF SUBGROUPS FOR EFFICACY ENDPOINTS 
The primary endpoint will be summarized descriptively using observed cases by treatment group 
for the following subgroups: 
 Gender (Female, Male) 
 Time since transplant (≤median, >median) 
 Time since SVR (≤median, >median) 
 Baseline Ishak fibrosis score strata (F2, F3-F5, F6) 
 Baseline Ishak fibrosis score grouping A (F2-F3, F4-F6) 
 Baseline Ishak fibrosis score grouping B (F2-F3, F3-F4, F5-F6) 
 Baseline Ishak fibrosis score (F2, F3, F4, F5, F6) 
 Investigative site 
 
No statistical hypothesis testing will be conducted for these subgroup analyses. 
 


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10 
PHARMACOKINETIC (PK) ANALYSES 
All concentration levels and collection times for emricasan and its metabolites from the Month 1 
visit will be provided in a listing.  Population PK concentrations will be provided in a listing by 
visit.  
10.1 
EMRICASAN, METABOLITES, AND IMMUNOSUPPRESSION PK 
PROFILES 
Blood samples will be collected at the Month 1 visit for generation of PK profiles for emricasan 
(IDN-6556), three metabolites (IDN-8741, IDN-6556-6, and IDN-6556-9), and four 
immunosuppressants (cyclosporine, everolimus, mycophenolate, and tacrolimus).  The 
concentration levels will be used to derive the PK parameters that will be included in the PK 
analysis.  Theses analyses will be conducted outside the scope of this SAP with a separate PK 
report being generated for inclusion in the clinical study report as an appendix.     
10.2 
POPULATION PK ANALYSIS 
Blood samples will be collected for population PK assessment.  A population analysis of time 
versus emricasan plasma concentration data will be performed using the nonlinear mixed effects 
modeling approach.  The software NONMEM (UCSF, California, USA) will be used to derive 
the population mean and variance values for specific PK parameters.  Additionally, a relationship 
between PK parameters (or dose) and efficacy, as well as AEs, will be investigated. 
In the PK (and pharmacodynamics, PD) analysis, several covariates will be tested and 
incorporated into the structural model if shown to significantly improve the model’s ability to 
describe the data. The final PK/PD model for emricasan will be obtained from this “full” model 
using only the covariate relationships that are thought to result in clinically significant alterations 
in drug PK and/or PD. This model will include data from this study and also from previously 
conducted emricasan studies. 
Results from these population PK/PD models will be provided in a separate report and all 
analyses are outside the scope of this SAP.  
 


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11 
SAFETY ANALYSES 
All safety endpoints will be provided in listings by unique subject number and visit.  All Safety 
related tables will be produced using the Safety Set. 
11.1 
DOSING AND EXTENT OF EXPOSURE 
Study drug capsule counts will be summarized descriptively by treatment group and visit.  
Treatment compliance and extent of treatment exposure endpoints (i.e., days and person years of 
exposure) will be summarized descriptively by treatment group. 
11.2 
ADVERSE EVENTS 
The incidence of TEAEs will be summarized descriptively by treatment group for the following: 
 system organ class (SOC) and preferred term 
 SOC, preferred term, and severity 
 SOC and preferred term for TEAEs classified as related to study drug 
 SOC and preferred term for events having incidence of ≥5% in any treatment group  
 SOC and preferred term for subjects with study discontinuation due to the AE 
 SOC and preferred term for subjects with study drug interruption due to the AE  
 preferred term (alphabetical and highest incidence in all emricasan dose groups) 
 
Missing values for severity, relationship to study drug, action taken with study drug, treatment 
required, and/or outcome will be summarized as unknown. 
The incidence of SAEs for each SAE will be summarized descriptively by treatment group and 
overall for the following: 
 SOC and preferred term 
 SOC, preferred term, and severity 
 SOC and preferred term for SAEs classified as related to study drug 
 preferred term (alphabetical and highest incidence in all emricasan dose groups) 
 
Subject listings by unique subject number and visit will be provided for the listings below: 
 All AEs 
 Subjects who discontinued from the study 
 Subjects who had a study drug interruption 
 Subjects with SAEs 
 Subjects who died 
 
11.3 
LIVER ULTRASOUND 
Incidence of abnormal findings and number of events from the liver ultrasound will be 
summarized by treatment group.  This summary will also include the incidence and events 


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considered to be clinically significant.  The list of abnormal events, as determined by a blinded 
medical review prior to database lock, will also be provided.  
11.4 
POTENTIAL LIVER INJURY 
Subject incidence of the categorizations for ALT, AST, and total bilirubin as described in 
Section 5.4.5 will be summarized descriptively by treatment group and visit. An evaluation of 
drug-induced serious hepatotoxicity (eDISH) plot of all subjects coded by treatment group will be 
provided, which displays the ALT or AST value (on a log 10 scale) versus the total bilirubin value 
(on a log 10 scale). The eDISH plot will be produced with concurrent results for ALT, AST, and 
bilirubin by visit and an additional plot that displays the maximum post-baseline values of ALT, 
AST and total bilirubin (both on a log 10 scale). 
11.5 
LABORATORY MEASUREMENTS 
Hematology, chemistry, coagulation, and alpha-fetoprotein laboratory parameters will be 
summarized descriptively at each visit by treatment group.  Where applicable, change from 
baseline in laboratory tests will also be summarized descriptively at each post-baseline visit by 
treatment group.  
A shift table will be provided for descriptively summarizing the classification around the normal 
range of each hematology, chemistry, coagulation, and alpha-fetoprotein laboratory parameter 
between baseline to each of the minimum and maximum post-baseline values.  
An additional shift table will be provided for descriptively summarizing the classification of 
urinalysis laboratory parameters between baseline and the maximum post-baseline values by 
treatment group and overall. 
11.6 
VITAL SIGNS AND WEIGHT 
Vital signs, weight, and BMI will be summarized descriptively at each visit by treatment group.  
Change from baseline in vital signs, weight, and BMI will also be summarized descriptively at 
each post-baseline visit by treatment group and overall. 
Abnormalities in vital signs will also be summarized descriptively by treatment group and visit. 
11.7 
ELECTROCARDIOGRAMS 
Classifications of observed values and change from baseline values in QTcB and QTcF, as 
described in Section 5.4.8, will be summarized descriptively by treatment group and visit.  
Maximum values and maximum change from baseline values during the treatment period will 
also be summarized descriptively. 
11.8 
MEDICATIONS 
Incidence of prior medications will be summarized descriptively by treatment group, anatomical 
therapeutic chemical classification (ATC) level, and preferred term. This summary will be 
included as part of the study population data summaries described in Section 5.4.9.Incidence of 
concomitant, new concomitant, and all concomitant medications will be summarized 
descriptively by treatment group, ATC level, and preferred term. 
The number and percentage of subjects receiving anti-viral, immunotherapy, and 
immunosuppressants medications prior to the study and during the study will each be summarized 
by ATC classification and preferred term. 


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11.9 
PHYSICAL EXAM 
Physical examination assessments will be summarized descriptively at each visit by treatment 
group.  Changes in physical exam status will be summarized descriptively by treatment group 
using shift tables. 
11.10 
EXAMINATION OF SUBGROUPS FOR SAFETY ENDPOINTS 
Overall AEs will be summarized descriptively by treatment group for the following subgroups: 
 Gender (Female, Male) 
 Age (18-40, ≥40 - ≤64, >64) 
 Baseline Ishak fibrosis score strata (F2, F3-F5, F6) 
 Baseline Ishak fibrosis score grouping A (F2-F3, F4-F6) 
 Baseline Ishak fibrosis score grouping B (F2-F3, F3-F4, F5-F6) 
 Baseline Ishak fibrosis score (F2, F3, F4, F5, F6) 


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12 
HANDLING OF MISSING DATA 
The details of handling missing data for the primary endpoint are provided in Section 9.1.  There 
will be no imputations made for any of the secondary endpoints. 
 
 


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13 
DATA MONITORING COMMITTEE 
An independent Data Monitoring Committee (DMC) will review safety data from this study at 
6-month periodic intervals.  The DMC will review data within its general remit to oversee 
subject safety in the study, and provide recommendations and guidance to the Sponsor in 
accordance with the procedures stated in its charter.  
All Investigators, responsible institutional review boards/institutional ethics committees, and 
applicable regulatory agencies will be informed of any decisions made by the Sponsor based on 
recommendations from the DMC relating to subject safety that affect the conduct of this study.  
The Investigators will inform the subjects of such actions, and the protocol and informed consent 
form will be revised, as appropriate. 


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14 
CHANGES IN PLANNED ANALYSIS 
14.1 
CHANGES FROM PROTOCOL TO SAP VERSION 1.0 
The primary endpoint was clarified from the protocol such that the response rate is declared as 
the primary endpoint to make it consistent with the sample size calculations.  Response is 
defined per Section 5.1 of this SAP. 
The primary analysis was updated to reflect the primary endpoint as defined in Section 5.1.  All 
secondary analyses will be conducted using observed cases in the FAS.   
All biopsy data collected by local assessments will be captured in the database and will not be 
summarized or listed. 
All other details provided in this SAP are intended to provide more detail and clarity to the 
protocol planned analyses.  
14.2 
CHANGES FROM SAP VERSION 1.0 TO SAP VERSION 2.0 
Clarifications were made to text throughout the SAP to help clarify further details.  
A translation of the Ishak Fibrosis Score to NASH CRN Fibrosis Stage Scoring (Section 5.2.3) 
was added with a corresponding planned summary table. 
Local biopsy assessments collected will be provided in a data listing.  
Baseline was redefined for laboratory summaries as the average of all values observed up to and 
including Day 1. 
Age group categories were updated for the baseline characteristics summary table and primary 
endpoint subgroup analysis. 
Details regarding the transplant and HCV history, along with immunosuppressant and previous 
hepatic treatments, collected at screening will be summarized. 
Sensitivity analyses for the primary endpoint were updated. 
An additional summary table of specific concomitant medications will be produced that will 
include immunosuppressants, antivirals, and immunotherapies. 
 


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15 
REFERENCES 
Fleming T, Richardson B. Some design issues in trials of microbicides for the 
prevention of HIV infection. J Infectious Diseases 2004;190(4):666-674. 
 
George et. al. Clinical, virologic, histologic, and biochemical outcomes after successful HCV 
therapy: A 5-year follow-up of 150 patients. Hepatology; 49(3):729-738 
 


Signature Page for CTS-S-0367 v1.0
Signature Page for CTS-S-0367 v1.0
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James Robinson
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Biostatistics
29-Jan-2018 18:41:15 GMT+0000
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David Hagerty
Clinical Operations
30-Jan-2018 22:22:09 GMT+0000
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Regulatory
31-Jan-2018 20:20:00 GMT+0000
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Dan Ripley
Project Management
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