Clinical trial NCT02960204
Conditions: Cirrhosis Portal Hypertension Non-alcoholic Steatohepatitis
Keywords: cirrhosis Portal Hypertension Non-alcoholic Steatohepatitis Liver cirrhosis
Sponsor: Histogen
Start date: 2016-10-17; Completion date: 2019-04-08
Enrollment: 263 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, randomized, double-blind, placebo-controlled trial involving subjects with NASH cirrhosis and severe portal hypertension (defined as HVPG ≥12 mmHg as determined by the central reader assigned to this study). Upon successful screening, subjects will be randomized to receive either emricasan 50 mg BID, 25 mg BID, or 5 mg BID or matching placebo BID.

Detailed description:

Arms: arm 1: Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (5 mg) twice a day. arm 2: Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (25 mg) twice a day. arm 3: Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with emricasan (50 mg) twice a day. arm 4: Subjects with Non-alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension will be administered orally with a matching placebo twice a day.
Interventions: intervention 1: Emricasan intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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CLINICAL TRIAL PROTOCOL 
A Multicenter, Randomized, Double-Blind, Placebo-
Controlled Trial of Emricasan, an Oral Caspase Inhibitor, in 
Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
Protocol Number: 
IDN-6556-14 
EudraCT Number: 
2015-004473-32 
Developmental Phase: 
2 
Amendment 8 (Version 9.0) 
14 March 2018 
Amendment 7 (Version 8.0) 
22 January 2018 
Amendment 6 (Version 7.0) 
18 October 2017 
Amendment 5 (Version 6.0) 
13 July 2017 
Amendment 4 (Version 5.0) 
26 May 2017 
Amendment 3 (Version 4.0) 
10 April 2017 
Amendment 2 (Version 3.0) 
07 March 2017 
Amendment 1 (Version 2.0) 
15 June 2016 
Original Protocol (Version 1.0) 
29 March 2016 
Draft Protocol 
02 February 2016 
Sponsor: 
Conatus Pharmaceuticals Inc. 
16745 W. Bernardo Drive, Suite 200 
San Diego, CA 92127 
USA 
 
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. 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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KEY PERSONNEL 
Sponsor  
Conatus Pharmaceuticals Inc. 
16745 W. Bernardo Drive, Suite 200 
San Diego, CA 92127 
USA 
 
Sponsor Contact 
Jean L. Chan, MD 
VP, Clinical Development 
Office: 
+1-858 376 2632 
Mobile: 
+1-617 407 5689 
jchan@conatuspharma.com 
 
Pharmacovigilance, 24 Hour Emergency Reporting 
SynteractHCR Safety 
Safety Fax: 
+1-760-268-6500 
safetyfax@synteracthcr.com 
OR 
if not 
available 
Mason Yamashita, MD 
VP, Pharmacovigilance 
Office: +1-858 376 2617 
Mobile: +1-619 306 2125 
myamashita@conatuspharma.com 
 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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TABLE OF CONTENTS 
1 
STUDY SYNOPSIS ............................................................................................................... 7 
2 
LIST OF ABBREVIATIONS ................................................................................................. 14 
3 
ETHICS ............................................................................................................................... 17 
4 
INTRODUCTION ................................................................................................................. 18 
4.1 
Background ............................................................................................................. 18 
4.2 
Study Rationale ....................................................................................................... 20 
5 
STUDY OBJECTIVES ......................................................................................................... 26 
6 
STUDY DESIGN ................................................................................................................. 27 
7 
STUDY POPULATION ........................................................................................................ 30 
7.1 
Inclusion Criteria ...................................................................................................... 30 
7.2 
Exclusion Criteria ..................................................................................................... 31 
7.3 
Subject Identification ................................................................................................ 32 
7.4 
Randomization Procedure ....................................................................................... 32 
7.5 
Blinding/Unblinding Procedures ............................................................................... 33 
8 
STUDY ASSESSMENTS AND CONDUCT ......................................................................... 34 
8.1 
Safety Assessments ................................................................................................ 34 
8.1.1 
Adverse Events .................................................................................................. 34 
8.1.2 
Medical History and Physical Examinations ....................................................... 34 
8.1.3 
Vital Sign Measurements ................................................................................... 34 
8.1.4 
12-Lead Electrocardiogram (ECG) ..................................................................... 34 
8.1.5 
Monitoring for Potential Gallbladder Adverse Effects ......................................... 35 
8.1.6 
Monitoring for Evidence of Potential Drug-Induced Liver Injury (DILI) ................ 35 
8.1.7 
Management of Subjects Who Progress to Child-Pugh C .................................. 39 
8.1.8 
Screening and Follow-up Questionnaires for Alcohol Abuse .............................. 39 
8.1.9 
Screening Esophagogastroduodenoscopy (EGD) .............................................. 40 
8.2 
Efficacy Assessments .............................................................................................. 40 
8.2.1 
Hepatic Venous Pressure Gradient (HVPG) ....................................................... 40 
8.2.2 
Model for End Stage Liver Disease [1] Score ..................................................... 41 
8.2.3 
Child-Pugh Score and Classification .................................................................. 42 
8.2.4 
Quality of Life Assessments ............................................................................... 43 
8.2.5 
Clinical Outcome Events .................................................................................... 44 
8.2.6 
Liver Metabolic Function by Methacetin Breath Test .......................................... 45 
8.2.7 
Liver Stiffness by Transient Elastography (using FibroScan®) ............................ 45 
8.3 
Laboratory Tests ...................................................................................................... 46 
8.3.1 
Biomarker Assessments .................................................................................... 48 
8.3.2 
Population Pharmacokinetic (PK) Assessment .................................................. 48 
8.3.3 
OATP Transporter Genotyping........................................................................... 48 
8.3.4 
Blood Volume .................................................................................................... 48 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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8.4 
Specific Study Visit Information ................................................................................ 50 
8.4.1 
Screening Phase (Week -6 to Day 0) ................................................................. 50 
8.4.2 
Double-Blind Phase (Day 1) ............................................................................... 50 
8.4.3 
Double-Blind Phase (Week 4) ............................................................................ 51 
8.4.4 
Initial 24-Week Double-Blind Phase (Week 8, Week 12, Week 16, Week 20) .... 51 
8.4.5 
Initial 24-Week Double-Blind Phase (Week 24) .................................................. 51 
8.4.6 
Continued 24-Week Double-Blind Phase (Week 32 and Week 40) .................... 52 
8.4.7 
Continued 24-Week Double-Blind Phase (Week 48) .......................................... 52 
8.4.8 
Follow-Up Phase (2 weeks after Week 24 or Week 48) ..................................... 53 
8.5 
Prior and Concomitant Medications ......................................................................... 53 
8.6 
Other Precautions and Restrictions during the Study ............................................... 53 
8.7 
Subject and Study Termination ................................................................................ 54 
8.7.1 
Reasons and Procedures for Early Termination ................................................. 54 
8.7.2 
Withdrawal from Study Drug Treatment but Not from Study Participation .......... 54 
8.7.3 
Termination of the Study .................................................................................... 55 
9 
INVESTIGATIONAL MEDICINAL PRODUCT ...................................................................... 56 
9.1 
Emricasan and Placebo Supplies ............................................................................ 56 
9.2 
Investigational Medicinal Product Packaging and Labeling ...................................... 56 
9.3 
Investigational Medicinal Product Dispensing and Accountability ............................. 56 
9.4 
Investigational Medicinal Product Administration ..................................................... 56 
10 WARNINGS AND PRECAUTIONS ..................................................................................... 57 
10.1 
Teratogenicity and Fertility ....................................................................................... 57 
10.2 
Contraception for Female Subjects of Reproductive Potential ................................. 57 
10.3 
Contraception for Male Subjects with Female Partners of Reproductive Potential ... 59 
10.4 
Use of Estrogens in Subjects with Decompensated Cirrhosis .................................. 59 
11 DOCUMENTATION OF DATA ............................................................................................ 60 
11.1 
Source Documentation ............................................................................................ 60 
11.2 
Data Entry in Database ............................................................................................ 60 
11.3 
Query Checks .......................................................................................................... 60 
11.4 
Coding of Adverse Events, Drugs, and Diseases ..................................................... 60 
11.5 
Study Language and Translations ........................................................................... 60 
12 STATISTICAL METHODS ................................................................................................... 61 
12.1 
Introduction .............................................................................................................. 61 
12.2 
Parameters of Interest ............................................................................................. 61 
12.2.1 Safety Variables ................................................................................................. 61 
12.2.2 Efficacy Variables .............................................................................................. 61 
12.3 
Analysis Populations ................................................................................................ 62 
12.4 
Sample Size ............................................................................................................ 62 
12.5 
Statistical Analyses .................................................................................................. 62 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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12.5.1 General .............................................................................................................. 62 
12.5.2 Safety Analysis .................................................................................................. 63 
12.5.3 Efficacy Analysis ................................................................................................ 63 
12.5.4 Timing of Analyses ............................................................................................. 64 
12.6 
Handling of Missing Data ......................................................................................... 64 
12.7 
Data Monitoring Committee (DMC) .......................................................................... 65 
13 SAFETY MONITORING AND REPORTING ........................................................................ 66 
13.1 
Adverse Event Reporting Obligations ...................................................................... 66 
13.2 
Adverse Event Definitions ........................................................................................ 66 
13.2.1 Pre-Treatment-Emergent Adverse Events ......................................................... 68 
13.2.2 Laboratory Abnormalities as Adverse Events ..................................................... 69 
13.3 
Severity of Adverse Events ...................................................................................... 69 
13.4 
Classification of Adverse Events by Relationship to Study Drug Administration ....... 69 
13.5 
Recording and Reporting Adverse Events ............................................................... 70 
13.5.1 Recording Adverse Events ................................................................................. 70 
13.5.2 Investigator Reporting of a Serious Adverse Event ............................................ 70 
13.6 
Additional Investigator Responsibilities on Follow-up of Serious Adverse Events .... 71 
13.7 
Follow-Up of Adverse Events ................................................................................... 71 
13.8 
Notification of Post-Study Serious Adverse Events .................................................. 72 
13.9 
IRB/IEC Notification of Serious Adverse Events ...................................................... 72 
13.10 Health Authority Safety Reports ............................................................................... 72 
14 ADMINISTRATIVE ASPECTS ............................................................................................. 73 
14.1 
Investigator Responsibilities for General Study Conduct .......................................... 73 
14.2 
Protocol Deviations .................................................................................................. 73 
14.3 
Subject Information and Consent ............................................................................. 74 
14.4 
Subject Confidentiality and Data Protection ............................................................. 74 
14.5 
Laboratory Accreditation .......................................................................................... 74 
14.6 
Required Documents ............................................................................................... 75 
14.7 
Study Monitoring ...................................................................................................... 75 
14.8 
Electronic Data Record and Case Report Forms ..................................................... 75 
14.9 
Drug Accountability .................................................................................................. 76 
14.10 Record Retention ..................................................................................................... 76 
14.11 Financial Disclosure ................................................................................................. 76 
14.12 Investigator’s Final Report ....................................................................................... 77 
14.13 Publication Policy..................................................................................................... 77 
14.14 Confidentiality .......................................................................................................... 78 
15 REFERENCES .................................................................................................................... 79 
 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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LIST OF APPENDICES 
Appendix I. 
Schedule of Events ............................................................................................82 
Appendix II. 
Measurement of Liver Metabolic Function with the Methacetin Breath Test .......84 
Appendix III. FibroScan® Protocol ...........................................................................................86 
Appendix IV. Diabetes Mellitus Definition and Metabolic Syndrome Criteria............................88 
 
LIST OF FIGURES 
Figure 1. 
Probability of Clinical Decompensation in Patients with Cirrhosis with and  
without Clinically Significant Portal Hypertension ...............................................19 
Figure 2. 
Natural History of Cirrhosis: Relationship with Increasing Portal Pressure .........22 
Figure 3. 
Dose-Response Modelling of Emricasan using Biomarkers ...............................24 
Figure 4. 
Study Schema ...................................................................................................28 
Figure 5. 
FibroScan® Probe Placement in Relation to Anatomy of a Subject ................86 
 
LIST OF TABLES 
Table 1. 
Liver Monitoring Procedure ................................................................................36 
Table 2. 
Laboratory Tests ................................................................................................47 
Table 3. 
Blood Volume ....................................................................................................49 
Table 4. 
Time-Adjusted Incidence Rate for Anticipated Events in Patient Population.......68 
 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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1 
STUDY SYNOPSIS 
Protocol 
IDN-6556-14 
Title 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, an Oral 
Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) Cirrhosis and Severe 
Portal Hypertension 
Phase of Trial 
Phase 2 
Objectives 
Primary Objective 
• 
To assess whether emricasan compared to placebo leads to a mean decrease in hepatic 
venous pressure gradient (HVPG) at Week 24 in subjects with NASH cirrhosis and 
severe portal hypertension 
Secondary Objectives 
• 
To assess the safety and tolerability of emricasan 
• 
To characterize the dose response of emricasan on portal pressure as assessed by 
HVPG at Week 24 
• 
To assess whether emricasan compared to placebo improves HVPG response at 
Week 24 using a 20% reduction from baseline response definition 
• 
To assess whether emricasan compared to placebo decreases mechanism specific 
(caspase 3/7) and non-specific alanine aminotransferase (ALT) biomarkers at Weeks 24 
and 48 
Exploratory Objectives 
• 
To assess whether emricasan compared to placebo improves HVPG response at 
Week 24 using a 10% reduction from baseline response definition 
• 
To assess whether emricasan compared to placebo improves liver function and 
prognosis at Weeks 24 and 48 as assessed by model for end-stage liver disease [1] and 
Child-Pugh (CP) scores (change in score, progression, regression)  
• 
To assess whether emricasan compared to placebo improves biochemical and 
functional biomarkers (cCK18/M30, flCK18/M65, aspartate aminotransferase [AST], total 
bilirubin, international normalized ratio [INR], and albumin) at Weeks 24 and 48 
• 
To assess whether emricasan compared to placebo improves fibrosis markers at 
Weeks 24 and 48 
• 
To assess whether emricasan compared to placebo improves health-related quality of 
life at Weeks 24 and 48 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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• 
To assess whether emricasan compared to placebo decreases development of 
decompensation or worsening of decompensation at Weeks 24 and 48 
• 
To assess whether emricasan compared to placebo improves liver metabolic function at 
Weeks 24 and 48 as assessed by methacetin breath test (at select sites) 
• 
To assess whether emricasan compared to placebo improves liver stiffness at Weeks 24 
and 48 as assessed by transient elastography (FibroScan®) (at select sites) 
Centers 
Multicenter, approximately 90 sites in North America and Europe 
Number of Subjects 
Approximately 240 subjects (60 subjects/arm) will be randomized in a 1:1:1:1 ratio to emricasan 
50 mg BID, emricasan 25 mg BID, emricasan 5 mg BID, or matching placebo BID. 
Design 
This is a multicenter, double-blind, randomized, placebo-controlled, dose-response study to 
evaluate the safety and efficacy of emricasan in improving portal hypertension in subjects with 
NASH cirrhosis and severe portal hypertension (defined as HVPG ≥12 mmHg). Subjects can 
have compensated (at least 60% of subjects but no more than 75%) or decompensated 
cirrhosis with no more than 1 prior significant decompensating event and must be currently 
clinically stable on stable standard therapy [2] (see Inclusion/Exclusion Criteria). Randomization 
will be stratified by compensated vs. decompensated status at baseline as well as use of 
non-selective beta-blockers (NSBB) or not. Subjects who are otherwise eligible will undergo the 
HVPG procedure as the last qualifying procedure prior to Day 1.  
The study treatment duration will be up to 48 weeks, including an initial 24-week randomized 
treatment phase with follow-up HVPG at Week 24 (primary endpoint) and an additional 24-week 
treatment phase (continuing the same study drug treatment as initially randomized).  Subjects 
completing the initial 24-week randomized treatment phase will be re-consented for the 
additional 24-week treatment phase.  HVPG measurements will be performed at screening and 
Week 24, with additional placebo-controlled safety follow-up and exploratory efficacy 
assessments through Week 48.  Subjects will complete a final follow-up visit approximately 
2 weeks after the end of treatment (i.e., at Week 26 if completing the initial 24-week randomized 
treatment only or at Week 50 if completing the 48-week treatment). 
Subjects with baseline HVPG ≥12 mmHg may experience progression of cirrhosis during the 
48-week study.  Given that the primary endpoint for this study is HVPG rather than a clinical 
event (or clinical composite), subjects who have a decompensating event or worsened 
decompensation during the study will not be required to withdraw and can remain in the study 
unless the investigator feels the subject is too unstable or the subject requires a transjugular 
intrahepatic portal shunt or other portosystemic bypass procedure, which would confound the 
HVPG assessment. Subjects who progress to Child-Pugh C will be withdrawn from study drug 
but are expected to remain in the study and complete all planned study visits (see 
Section 8.1.7).  All subjects who wish to discontinue study drug treatment should remain in the 
study and complete all planned study visits, in order to minimize missing data and protect the 
integrity of the study results.  Subjects who withdraw consent for participating in the study 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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should discontinue study visits.  Subjects for whom the investigator deems that it is not in the 
best interest of the subject to continue participating in the study may also discontinue study 
visits. 
Schema 
 
Dosage and Administration 
Study drug will be double-blind with matching placebo. Emricasan at 50 mg, 25 mg, or 5 mg or 
matching placebo will be administered orally twice a day. 
Drug Supply 
Emricasan (IDN-6556) and matching placebo will be supplied in bottles containing 60 capsules. 
Subject Entry Criteria 
Inclusion Criteria 
1. Male or female subjects 18 years or older, able to provide written informed consent and able 
to understand and willing to comply with the requirements of the study. 
2. Cirrhosis due to NASH with exclusion of other causes of cirrhosis (e.g. chronic viral 
hepatitis, alcoholic liver disease, etc.) 
Screening 
Phase
Follow-up 
Phase
HVPG                                           HVPG
Must be ≥ 12 mmHg 
Follow-
up visit
Screen
E
N
D
T
R
E
A
T
M
E
N
T
Emricasan 5 mg BID
N=60
Placebo BID
N=60
Emricasan 50 mg BID
N=60
Emricasan 25 mg BID
N=60
R
A
N
D
O
M
I
Z
A
T
I
O
N
Initial randomized 
treatment
Double-Blind 
Treatment Phase
Continued 
randomized treatment
Wk -6 to Day 0                          Day 1 - - - - - - - - - - - Wk 24       - - - - - - - - - - - - - - - - Wk 48                    - - - - - Wk 26 or 50


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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• 
Diagnosis of cirrhosis is based on:  
o Biopsy OR 
o Clinical evidence: platelet count <150,000, AST > ALT, and either nodular liver 
surface on imaging or splenomegaly 
• 
NASH is based on at least 1 of the following: 
o Prior or current biopsy showing steatohepatitis (fat, ballooning degeneration, 
inflammation) consistent with NASH  
o At least 2 metabolic risk factors for at least 5 years preceding the diagnosis of 
cirrhosis: diabetes mellitus, impaired fasting glucose, obesity (BMI ≥30 kg/m2 or 
central obesity), hypertension, dyslipidemia (see Appendix IV)  
o Prior or current biopsy showing some but not all diagnostic features of NASH 
(e.g. only fat or ballooning degeneration or inflammation) but with no evidence for 
viral hepatitis or other liver disease AND either fatty liver disease on prior imaging or 
at least 1 metabolic risk factor (as above) for at least 5 years preceding the diagnosis 
of cirrhosis 
Note: 
Previous viral hepatitis that was curatively treated (with sustained viral 
response) is not an exclusion as long as: 1) viral eradication was achieved at least 3 
years prior to the diagnosis of cirrhosis and 2) all other criteria are met for NASH as 
the etiology of cirrhosis 
3. Compensated cirrhosis (no history of or presence of clinically evident ascites, variceal 
hemorrhage, or encephalopathy, and on no medications to treat these complications)  
 
OR  
 
Decompensated cirrhosis with no more than 1 prior significant decompensating event: 
a. If prior decompensating event was variceal hemorrhage, event must have occurred at 
least 3 months prior to Day 1 
b. If prior decompensating event was ascites requiring chronic diuretics, ascites should be 
well controlled (not clinically evident, i.e. no ascites or ascites only detectable by 
ultrasound examination) on a stable dose of diuretics for at least 3 months prior to Day 1 
c. If prior decompensating event was hepatic encephalopathy ≥ grade II or requiring 
hospitalization, encephalopathy should be well-controlled (Stage 0 or 1) on stable 
medication for at least 3 months prior to Day 1 
Note: Previous transient ascites or hepatic encephalopathy in a subject who is currently 
stable without clinically evident ascites or encephalopathy and on no medications for 
these conditions does not count as a prior significant decompensating event 
4. Severe portal hypertension defined as HVPG ≥12 mmHg (see Section 8.4.1 for 
recommendations to identify subjects more likely to meet the HVPG criteria)  
5. Subjects who are on NSBB, nitrates, diuretics, lactulose, rifaximin, or statins must be on a 
stable dose for at least 3 months prior to Day 1 
6. Willingness to utilize effective contraception (for both males and females of reproductive 
potential) from Screening to 4 weeks after the last dose of study drug 
7. Platelet count ≤125 k/mm3 or transient elastography ≥20 kilopascal [3] during screening 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
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8. If on therapeutic dose of vitamin E, stable for 6 months prior to Day 1 
Exclusion Criteria 
1. Evidence of severe decompensation, defined as:  
a. Presence or history of more than one type of significant decompensating event (clinically 
evident ascites requiring chronic diuretics, variceal hemorrhage, and/or overt 
encephalopathy) 
Note: Previous transient ascites or hepatic encephalopathy in a subject who is currently 
stable without clinically evident ascites or encephalopathy and on no medications for 
these conditions does not count towards this exclusion (see Inclusion Criteria #4). 
b. One type of decompensating event with the following characteristics: 
o More than 1 episode of variceal hemorrhage or bleeding from a portal hypertensive 
source (e.g. portal hypertensive gastropathy) 
o Ascites that has required more than 1 large-volume paracentesis (>5 L) for treatment 
or that has been complicated by spontaneous bacterial peritonitis, hyponatremia 
(serum Na <130), and/or hepatorenal syndrome 
o More than 1 episode of overt hepatic encephalopathy requiring hospitalization  
2. Severe hepatic impairment defined as a Child-Pugh score ≥10 
3. ALT >3 times upper limit of normal (ULN) or AST >5 times ULN during screening  
4. Estimated creatinine clearance <30 mL/min 
5. Prior transjugular intrahepatic portosystemic shunt or other porto-systemic bypass 
procedure 
6. Known portal vein thrombosis 
7. Symptoms of biliary colic, e.g., due to symptomatic gallstones, within the last 6 months, 
unless resolved following cholecystectomy, other definitive treatment (e.g., sphincterotomy), 
or medical management (e.g., ursodeoxycholic acid) 
8. Current use of medications that are considered inhibitors of OATP1B1 and OATP1B3 
transporters: atazanavir, cyclosporine, eltrombopag, gemfibrozil, indinavir, lopinavir, 
ritonavir, rifampin, saquinavir, simeprevir, telaprevir, tipranovir, or some combination of 
these medications 
9. Alpha-fetoprotein >50 ng/mL 
10. History or presence of clinically concerning cardiac arrhythmias, or prolongation of screening 
(pre-treatment) QT Interval Corrected by the Fridericia Correction Formula [QTcF] interval of 
>500 msec 
11. History of or active malignancies, other than those successfully treated with curative intent 
and believed to be cured 
12. Significant systemic or major illness other than liver disease that in the opinion of the 
investigator would preclude the subject from participating in and completing the study, 
including but not limited to acute coronary syndrome or stroke within 6 months of screening 
or major surgery within 3 months of screening 
13. Prior liver transplant 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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14. Change in diabetes medications within 3 months of screening, including initiation, 
discontinuation, or change in dose except for medications titrated according to blood 
glucose 
15. Uncontrolled diabetes mellitus (HbA1c >9%) within 3 months of screening 
16. Restrictive bariatric surgery or bariatric device within 1 year of screening or prior 
malabsorptive bariatric surgery 
17. Known human immunodeficiency virus infection 
18. Use of controlled substances (including inhaled or injected drugs) or non-prescribed use of 
prescription drugs within 1 year of screening to the point of interfering with the subject’s 
ability to comply with study procedures and study drug administration in the investigator’s 
judgement 
19. History of significant alcohol consumption (>20 g/day for females and >30 g/day for males 
on average) within the past 5 years 
20. If female: planned or known pregnancy, positive urine or serum pregnancy test, or 
lactating/breastfeeding 
21. Previous treatment with emricasan or active investigational medication (except methacetin) 
in a clinical trial within 3 months prior to Day 1 
Criteria for Evaluation 
Safety Variables 
• 
Adverse events 
• 
Vital signs, physical examination 
• 
Laboratory tests (e.g. chemistry, hematology, coagulation, urinalysis) 
• 
ECGs 
• 
Liver and gallbladder events and ultrasound  
Efficacy Variables 
Primary 
• 
HVPG mean change from baseline at Week 24 
Secondary 
• 
HVPG response (20% reduction from baseline) at Week 24 
• 
Caspase 3/7 and ALT at Weeks 24 and 48 
Exploratory 
• 
HVPG response (10% reduction from baseline) at Week 24 
• 
MELD and Child-Pugh scores, regression, and progression at Weeks 24 and 48 
• 
cCK18/M30, flCK18/M65, AST, total bilirubin, INR, and albumin at Weeks 24 and 48 
• 
Fibrosis markers at Weeks 24 and 48 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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• 
Health-related quality of life, as measured by Short Form-36 (SF-36) and Chronic Liver 
Disease Questionnaire (CLDQ), at Weeks 24 and 48 
• 
Clinical outcomes (development of decompensation or worsening of decompensation) at 
Weeks 24 and 48 
• 
Liver metabolic function assessed by methacetin breath test (at select sites) at 
Weeks 24 and 48 
• 
Liver stiffness by transient elastography (at select sites) at Weeks 24 and 48 
Statistical Methods 
All efficacy analyses will be based on the Full Analysis Set (FAS) and Per Protocol Set.  All 
safety analyses will be based on the Safety Analysis Set. 
The primary endpoint for this study is the change from baseline at Week 24 in HVPG.  The 
change from baseline will be calculated as HVPG at Week 24 minus HVPG at baseline 
(HVPGW24-HVPGBL). Comparisons of the mean change from baseline in HVPG at Week 24 
between each emricasan treatment group and placebo will be analyzed using a fixed effects 
Analysis of Covariance (ANCOVA) model using the FAS.  This model will include the treatment 
group, compensated vs. decompensated status, and NSBB use as fixed effects with baseline 
HVPG as a covariate. Least-square adjusted means (LSMeans) will be reported, along with the 
estimated difference in LSMeans and corresponding 95% confidence intervals. A Dunnett’s test 
will be applied to adjust for the multiple comparisons of each emricasan treatment group with 
placebo. 
Secondary endpoints include the change from baseline at Weeks 24 and 48 in Caspase 3/7 and 
ALT measurements and 20% HVPG response at Week 24.  Exploratory endpoints include 
10% HVPG response at Week 24, change from baseline in MELD and Child-Pugh scores at 
Weeks 24 and 48, regression/progression in MELD and Child-Pugh scores at Weeks 24 and 48, 
biochemical and functional biomarkers at Weeks 24 and 48, fibrosis markers at Weeks 24 and 
48, quality of life at Weeks 24 and 48, clinical outcome events at Weeks 24 and 48, liver 
function at Weeks 24 and 48, and liver stiffness measurements at Weeks 24 and 48. 
Safety endpoints include treatment compliance, exposure, adverse events, gallbladder adverse 
effects and ultrasound, potential drug-induced liver injury, additional laboratory parameters, vital 
signs, and electrocardiogram measurements. 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
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2 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
AUDIT 
Alcohol Use Disorders Identification Test 
BID 
bis in die, twice daily 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
cCK18 
Caspase-cleaved cytokeratin 18 
CFB 
Change from baseline 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CLDQ 
Chronic Liver Disease Questionnaire 
cm 
centimeter 
CP 
Child-Pugh 
CRF 
Case report form 
CSPH 
Clinically significant portal hypertension 
DILI 
Drug-induced liver injury 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EGD 
Esophagogastroduodenoscopy 
ELF 
Enhanced liver fibrosis 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
US Food and Drug Administration 
FHVP 
Free hepatic vein pressure 
flCK18 
Full-length cytokeratin 18 
FSH 
Follicle stimulating hormone 
g 
gram 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GMP 
Good manufacturing practice 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
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HA 
Hyaluronic Acid 
HbA1c 
Glycated Hemoglobin 
HBV 
Hepatitis B virus 
HCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HDL 
High density lipoprotein  
HE 
Hepatic Encephalopathy 
HVPG 
Hepatic venous pressure gradient 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IQR 
Inter-quartile  
ITT 
Intention to treat 
IVC 
Inferior vena cava 
IWRS 
Interactive Web Randomization System 
kg 
Kilogram 
kPa 
Kilopascal 
L 
Liter 
LDL 
Low density lipoprotein 
LOX-L2 
Lysyl oxidase-like 2 
LSMeans 
Least-square adjusted means 
MBT 
Methacetin breath test 
MCS™ 
Molecular Correlation Spectrometry 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for end stage liver disease 
mg 
Milligram 
mL 
Milliliter 
mm 
Millimeter 
mmHg 
Millimeter of mercury 
msec(s) 
Millisecond(s) 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
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NAFLD 
Non-alcoholic fatty liver disease 
NASH 
Non-alcoholic steatohepatitis 
ng 
Nanogram 
NSBB 
Non-selective beta-blocker 
OATP 
Organic anion transporting polypeptide 
P3NP 
Aminoterminal propeptide of type III collagen 
PK 
Pharmacokinetic 
PPS 
Per Protocol Set 
PT 
Prothrombin time 
QOL 
Quality of life 
QTcF 
QT Interval Corrected by the Fridericia Correction Formula 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SF-36 
Short Form 36 
SUSAR 
Suspected unexpected serious adverse reaction 
TIMP-1 
Tissue inhibitor of matrix metalloproteinase 1 
ULN 
Upper limit of normal 
WBC 
White blood cell (count) 
WHVP 
Wedged hepatic vein pressure 
YLD 
Years lived with disability 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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3 
ETHICS 
The study will be conducted in accordance with standards that meet regulations relating to 
Good Clinical Practice (GCP). These include the European Union (EU) Clinical Trials Directive 
(2005/28/EC and subsequent amendments and EU Regulation No. 536/2014), International 
Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (GCP) 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. 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
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4 
INTRODUCTION 
4.1 
BACKGROUND 
Cirrhosis and Portal Hypertension 
Cirrhosis with portal hypertension is a major public health concern. In 2010, cirrhosis was the 
12th leading cause of mortality world-wide, responsible for approximately 1 million deaths 
[4].This estimate was substantiated by the Global Burden of Disease Study 2013, which 
estimated that there were ~1.2 million deaths from cirrhosis in 2013 [5] with an overall 
age-standardized death rate of 18.8/100,000, a rate that is similar in magnitude to all other 
digestive diseases combined (19/100,000), diabetes mellitus (21.6/100,000) and to neoplasms 
such as colorectal cancer (12.8/100,000) and stomach cancer (13.8/100,000). Interestingly, 
cirrhosis predisposes to and is felt to be largely responsible for the development of 
hepatocellular carcinoma. If deaths due to hepatocellular carcinoma from hepatitis B (300,000), 
hepatitis C (342,500) and alcohol use (92,000) were included in the cirrhosis death estimates, 
the number of deaths would almost double. Thus, cirrhosis and portal hypertension are major 
concerns for public health as well as for patients with those diseases. 
Cirrhosis has an important effect upon morbidity and disability. The Global Burden of Disease 
Study 2013 [6] estimated the years lived with disability (YLD) for 301 acute and chronic 
diseases between 1990-2013 since that is an important input into global and national health 
policies. Not surprisingly given the high mortality associated with cirrhosis, cirrhosis was an 
important and large contributor to YLDs in 2013, with approximately 3.3 million prevalent cases 
contributing to 545,000 YLDs in 2013. 
Once a patient with chronic liver disease progresses to cirrhosis and portal hypertension 
develops (defined as a hepatic venous pressure gradient [HVPG] >5 mmHg), survival 
decreases significantly. Cirrhosis consists of at least 2 distinct prognostic stages: compensated 
and decompensated with the development of clinically overt ascites, variceal hemorrhage, 
and/or encephalopathy defining the decompensated stage [7]. When a patient with cirrhosis 
transitions from being “compensated” to “decompensated,” survival is markedly decreased. 
While patients with compensated cirrhosis have a median survival time >12 years, the median 
survival time for patients with decompensated cirrhosis is <2 years [7-9]. 
Portal hypertension is defined as clinically significant portal hypertension (CSPH) once the 
HVPG is ≥10 mmHg. In a study of 213 patients with compensated cirrhosis and portal 
hypertension but without varices followed for a median of 51.1 months, those with a baseline 
HVPG <10 mmHg had a 90% probability of not progressing to the decompensated state during 
the follow-up period while the risk of decompensation was almost 6 times higher in the group 
>10 mmHg (unadjusted hazard ratio of 5.7; P<0.001) [10]. Studies indicate that mortality 
increases ~3% with every 1 mmHg increase in HVPG, such that a patient with an HVPG of 15 
mmHg has a 30% greater risk of death than a patient with an HVPG of 5 mmHg (Figure 1) [10, 
11]. 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
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Figure 1. 
Probability of Clinical Decompensation in Patients with Cirrhosis with and 
without Clinically Significant Portal Hypertension 
 
Solid line: HVPG <10 mmHg; dotted line: HVPG >10 mmHg [10]. 
 
CSPH is accompanied with an increased risk for developing hepatic decompensation, including 
bleeding varices and formation of ascites. Esophageal varices form once the HVPG is 
≥10 mmHg and are present in ~50% of patients with cirrhosis [12]. Variceal bleeding is a 
medical emergency and associated with a 10% to 30% mortality at 6 weeks [2, 7, 12].  
Importantly, reducing the HVPG to <12 mmHg, or by at least 10-20%, significantly decreases 
the risk of variceal bleeding in both primary and secondary prophylaxis settings (for reviews, see 
[13-15]). 
Patients with CSPH are also at risk for developing ascites. Ascites develops in ~50% of patients 
within 10 years of the diagnosis of cirrhosis [8]. Once ascites is present (with or without 
esophageal varices), the mortality rate is approximately 20% per year [7]. Mortality is greater 
when more than one complication is present [9] or when the patient progresses to a stage of 
“further” decompensation characterized by recurrent variceal hemorrhage/encephalopathy, 
refractory ascites, hyponatremia, and hepatorenal syndrome. 
There is clearly a medical need for a drug that would either decrease the risk for developing 
decompensated cirrhosis in a patient with compensated cirrhosis or for a drug that would 
decrease the risk for a patient with a single decompensating event to develop further 
decompensation. This drug would result in an improvement in survival. In both cases, a drug 
that could decrease portal hypertension could be reasonably expected to achieve those goals. 


 
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IDN-6556-14-PRO-1001 
Version: 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
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Standard of Care for Management of Cirrhosis with Portal Hypertension 
There are currently no medications approved for the treatment of cirrhosis or portal 
hypertension. However, non-selective beta blockers (NSBB) are the standard of care used in 
clinical practice to prevent variceal bleeding. The American Association for the Study of Liver 
Diseases recommends that NSBB be used in the following clinical settings [12]: 
• 
Patients with cirrhosis and small varices that have not bled and who are at higher risk for 
bleeding (Child-Pugh B or C; red wale marks on Esophagogastroduodenoscopy [EGD]) 
• 
Patients with cirrhosis and medium/large varices that have not bled 
• 
Patients with cirrhosis who survived an episode of acute variceal hemorrhage 
 
NSBB appear to be effective at decreasing the risk of bleeding from esophageal varices in 
approximately one-third to one-half of patients [14, 16, 17]. However, bleeding from esophageal 
varices remains a significant clinical problem, even with the use of NSBB. While NSBB 
decrease the risk of variceal bleeding to low levels if the HVPG is lowered below 12 mmHg 
(~7% bleeding rate), few patients (less than 15%) achieve that goal [7]. For patients with at least 
a 20% reduction in HVPG who do not achieve an HVPG value <12 mmHg, the risk of bleeding 
remains substantial (bleeding rate ~29%) but is decreased approximately 50%. Clinically, the 
consequences of a variceal bleed are important. Variceal bleeding is a medical emergency and 
associated with a 10-30% mortality at 6 weeks [2, 7, 12].   
NSBB act by decreasing portal flow but have no effect on improving intrahepatic circulation or 
improving liver function. For patients who continue to experience progressive cirrhosis, liver 
transplantation is the only other treatment option. In addition, NSBBs must be used cautiously in 
certain cirrhotic patient populations. For example, propranolol was prospectively shown to 
decrease survival in patients with refractory ascites [18]. These patients often have systemic 
hypotension, and the Baveno VI consensus conference recommended that patients with 
refractory ascites should be monitored closely when placed on NSBBs and that NSBBs should 
be reduced or discontinued in the presence of systolic blood pressure below 90 mmHg, 
hyponatremia with a serum sodium below 130 mEq/L, or acute kidney injury [2]. In addition, 
approximately 15-20% of patients do not tolerate NSBB [14, 17], and another 15% have a 
contraindication to NSBB use [12]. 
4.2 
STUDY RATIONALE 
Emricasan (IDN-6556) is a novel small molecule irreversible caspase inhibitor. Caspases are a 
family of intracellular cysteine protease inhibitors whose function is to mediate apoptosis, a type 
of programmed cell death, and activate some proinflammatory cytokines. Caspases cleave 
cytokeratin-18, an intracellular structural protein, during apoptosis in a very specific manner to 
produce caspase-cleaved cytokeratin-18 (cCK18), which is readily detected by a selective and 
commercially available antibody. Some caspases (e.g., caspase-1) can also process and 
activate pro-inflammatory cytokines such as interleukin-1β and interleukin-18. Caspases 
typically exist as pro-caspases and must be converted to an active form enzymatically. 
Activation of caspases in injured or pre-apoptotic cells leads to cleavage of a number of cell 
proteins, which ultimately results in cell death and activation of some pro-inflammatory 
cytokines. Caspase-mediated apoptotic and inflammatory pathways have been previously 
shown to play an important role in liver diseases, leading to the hypothesis that inhibition of 


 
Document Code: 
IDN-6556-14-PRO-1001 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
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Cirrhosis and Severe Portal Hypertension 
 
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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.) [19]. Emricasan has been 
shown to be an effective inhibitor of liver injury and inflammation in several animal models of 
liver disease and to reduce portal hypertension in a model of cholestasis [20].  
An additional emerging role of caspases is the formation and release of hepatocyte-derived 
microvesicles (also referred to as microparticles). Microvesicles are released by virtually all 
cells, but levels are increased in some pathologic states and different liver diseases, including 
alcohol, viral infection, and metabolic syndrome. Other processes that increase microvesicle 
release include oxidative stress, shear stress, systemic inflammation, and bacterial 
translocation.  Many of these processes are present in patients with chronic liver disease, 
especially cirrhosis. Furthermore, microvesicles are believed to worsen portal hypertension by 
contributing to splanchnic vasodilation, angiogenesis, and vasoconstriction within the liver [21]. 
In support of the notion that caspase inhibition could have a beneficial role in portal 
hypertension, emricasan was recently shown to improve survival and decrease portal pressure 
in a murine model of portal hypertension [20]. Cholestasis followed by liver injury was induced 
by ligation of the common bile duct with resultant increase in portal pressure. Mice received 
either emricasan (10 mg / kg / day) or placebo for two weeks, with repeat measurement of portal 
pressure and removal of the liver for histological assessment. Emricasan treatment resulted in 
decreased microparticles and a statistically significant reduction in portal pressure, as well as a 
decrease in fibrosis, although the decrease in fibrosis did not reach statistical significance, 
suggesting that the effects on portal hypertension were at least in part independent of the 
anti-fibrotic effects of the drug. Importantly, emricasan treatment improved survival. 
In non-cirrhotic patients with chronic liver disease due to two of the most common etiologies 
(chronic hepatitis C virus [HCV] infection and non-alcoholic fatty liver disease [NAFLD]), 
emricasan treatment decreased apoptosis biomarkers and improved transaminases. Emricasan 
treatment was associated with rapid and statistically significant reductions in elevated activated 
serum caspases and cCK18 in subjects with chronic HCV [22]. Importantly, emricasan reduced 
cCK18 levels to within the range typically observed in healthy subjects, but did not affect cCK18 
levels in healthy subjects [23], indicating that emricasan can reduce elevated but not basal 
levels of apoptosis. Emricasan lowered transaminase levels within 1 week and maintained these 
reductions to 12 weeks in patients with chronic HCV infection [24]. Similarly, emricasan 
treatment (at a dose of 25 mg BID) significantly reduced alanine aminotransferase (ALT) levels 
in subjects with NAFLD and elevated ALT in a 28-day, placebo-controlled, multi-center study 
(Study IDN-6556-06). 
Based on the idea that caspases produce hemodynamically active, proinflammatory 
microparticles from apoptotic cells that could increase portal pressure by increasing intrahepatic 
resistance and/or decreasing splanchnic resistance, a recent open-label pilot study 
(Study IDN-6556-11) evaluated whether emricasan (at a dose of 25 mg twice daily [BID]) in 
patients with compensated cirrhosis (primarily due to non-alcoholic steatohepatitis [NASH] or 
HCV) and portal hypertension could lower portal pressure over 28 days. Of 23 subjects enrolled 
with baseline HVPG (5.5 to 32 mmHg), 22 subjects were evaluable for HVPG with data at 
baseline and Day 28.  There was no significant difference in the HVPG response in the overall 
group, but analysis according to the recognized HVPG therapeutic threshold of 12 mmHg 
(indicative of severe portal hypertension) demonstrated a clinically meaningful mean (standard 


 
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Cirrhosis and Severe Portal Hypertension 
 
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deviation [SD]) decrease in HVPG of 3.7 (4.0) mmHg, representing a 17.2% decrease in the 
group with baseline HVPG ≥12 mmHg. Notably, 4/12 had a ≥20% decrease and 8/12 had a 
≥10% decrease; 2/12 had a decrease in HVPG below 12 mmHg.  Ten subjects with baseline 
HVPG <12 mmHg had a non-significant (p=0.12) mean (SD) increase of 1.9 (3.2) mmHg.  
Emricasan was overall well-tolerated with no drug-related serious adverse events (SAEs) and 
1 subject discontinuing the study early for non-serious adverse events.  
The reason for a robust decrease in HVPG in the ≥12 mmHg group and lack of discernable 
effect in the <12 mmHg group could be related to the differing pathophysiology of portal 
hypertension in these 2 groups.  Figure 2, taken from a clinical review of portal hypertension 
[25], shows that as the HVPG increases to >10 mmHg and patients transition from 
compensated to decompensated cirrhosis, the hyperdynamic circulation becomes an 
increasingly important contributor to portal hypertension. 
Portal hypertension is a dynamic process, and in early portal hypertension (HVPG 6-10 mmHg), 
the elevated pressures are largely due to increased intrahepatic resistance to blood flow as a 
result of both intrahepatic vasoconstriction and fibrotic changes associated with cirrhosis [26].  
However, as cirrhosis and portal hypertension progress, splanchnic and systemic vasodilation, 
along with an increased cardiac output, dramatically increase portal venous blood flow [27, 28]. 
These observations explain why NSBBs, which decrease cardiac output and increase 
splanchnic resistance, are ineffective in patients with early stages of portal hypertension (HVPG 
<10 mmHg) when increased cardiac output and decreased splanchnic resistance are not yet 
contributing to the portal hypertension in those patients [29-31]. 
Figure 2. 
Natural History of Cirrhosis: Relationship with Increasing Portal Pressure 
[25] 
 
Thus, there is sound preclinical and clinical rationale to believe that emricasan can decrease 
HVPG in subjects with NASH cirrhosis and severe portal hypertension, based on data in 
humans demonstrating the important pathophysiological role of excessive apoptosis and 
inflammation in cirrhosis and portal hypertension, as well as preclinical data showing that 
emricasan decreases apoptosis, inflammation, and fibrosis in mouse models of chronic liver 


 
Document Code: 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
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disease, and short-term (~1 month) data in humans with cirrhosis and severe portal 
hypertension demonstrating clinically meaningful reductions in HVPG with emricasan.  
Dose Rationale 
Emricasan has been administered to 624 subjects in 15 completed Phase 1 and 2 studies 
(including 169 healthy subjects, 394 subjects with elevated liver transaminases, 8 subjects with 
severe renal impairment, and 53 liver transplant subjects) with administration of single or 
multiple doses of intravenous or oral emricasan ranging from 0.1 to 10 mg/kg/day intravenously 
or 1 to 500 mg/day orally.  Emricasan has been administered orally to 510 subjects, including 
383 subjects with liver disease, most of whom received emricasan up to 50 mg BID for up to 
3 months.  Emricasan has generally been well tolerated with most adverse events being mild to 
moderate in severity, and the most common events (~3-5%) in subjects with liver disease 
receiving oral emricasan being fatigue, nausea, dizziness, and headache, without any clear 
relationship with dose or duration of therapy. 
The relationship between emricasan dose and biomarker responses has been thoroughly 
characterized.  The initial phase 1 and 2 studies assessed the effect of emricasan upon 
biomarkers at oral doses ranging from 0.5 mg BID up to 200 mg BID.  The 0.5 mg BID dose was 
clearly active, decreasing cCK-18 and ALT by nearly 50%, but had less effect upon aspartate 
aminotransferase (AST) and caspase 3/7.  Doses greater than 50 mg BID did not appear to 
have any greater reduction in biomarkers compared to the 50 mg BID dose.  Having therefore 
defined the shape of the dose-response curve, subsequent clinical studies focused on the 5, 25 
and 50 mg BID doses. 
Formal dose-response modeling for emricasan used models based upon reductions of 4 
biomarkers (ALT, AST, cCK18, and caspase 3/7).  Dose response modeling in subjects with 
liver disease predominantly due to HCV who had normal hepatic function indicated that 
emricasan doses >27.6 mg twice daily (BID) provided the greatest probability of leading to 
significant reductions in serum transaminases (reflective of ongoing inflammation) and cCK18 
(reflective of apoptotic activity) (Figure 3). 


 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
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Cirrhosis and Severe Portal Hypertension 
 
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Figure 3. 
Dose-Response Modelling of Emricasan using Biomarkers 
 
 
 
 
The biomarker dose-response curve was relatively flat between 0.5 to 50 mg BID, with doses as 
low as 5 mg BID showing near-maximal reduction for cCK-18 and ALT in subjects with normal 
hepatic function.  Specifically, 5 mg BID reduced cCK18 and ALT by 71.2% to 83.6% of 
maximal but reduced AST and caspase 3/7 by only 36.7% to 46.3% of maximal.  The 25 mg 
BID dosed reduced all 4 biomarkers by 74.4% to 96.2% of maximal, and the 50 mg BID showed 
incrementally greater reduction of AST and caspase 3/7.  In addition, studies conducted in 
subjects with hepatic impairment (IDN-6556-08 and IDN-6556-02) suggested that the biomarker 
dose-response curve may be shifted to the right with severe hepatic impairment, and that the 
50 mg dose might more effectively decrease biomarkers in those subjects than the 25 mg 
dose.  Updating the dose response model with biomarker data from subjects with NAFLD 
indicated that the dose response for the NAFLD population was similar to that for the HCV 
population for subjects with elevated transaminases and normal hepatic function.  
While the relationship between dose and biomarker response has been well-characterized, the 
relationship between emricasan dose and clinical responses has not been thoroughly assessed.  
Understanding that relationship is an important goal of the proposed phase 2b study.  Pilot 
studies conducted only with the 25 mg BID dose of emricasan showed that this dose lowered 
portal vein pressures (HVPG) in subjects with severe portal hypertension following 1 month of 
treatment, and improved model for end stage liver disease [1] scores in subjects with baseline 
Dose 
(mg BID) 
% of maximum response 
CK-18 
ALT 
AST 
Caspase 3/7 
5 
83.6 
71.2 
46.3 
36.7 
15 
93.9 
88.1 
72.1 
63.5 
25 
96.2 
92.5 
81.2 
74.4 


 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
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Cirrhosis and Severe Portal Hypertension 
 
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MELD scores ≥15 following 3 months of treatment and provided the rationale to further explore 
the safety and efficacy of emricasan in patients with cirrhosis.  To better understand the shape 
of the dose-response curve for clinically important endpoints (HVPG and MELD score) in 
subjects with cirrhosis and hepatic impairment (Child-Pugh classes A and B), the Sponsor 
intends to study the 5, 25 and 50 mg BID doses of emricasan. 
Thus, the 5, 25, and 50 mg BID doses proposed for this Phase 2 study were chosen to evaluate 
a dose that is anticipated to be active but likely sub-maximal (5 mg BID) as well as a dose with a 
high likelihood of maximal efficacy based upon the biomarker dose-response curve (50 mg 
BID), with inclusion of an intermediate dose (25 mg BID) that has demonstrated efficacy on 
HVPG and MELD score in prior studies.  This approach is reasonable given the large number of 
subjects exposed to repeat oral doses as high as 200 mg BID, good safety profile to date, lack 
of identified drug-related toxicities, and lack of tolerability issues at doses less than 500 mg (at 
which transient, mild GI symptoms were reported).  Animal toxicology studies identified the 
gallbladder and intestines as having the potential for toxicity.  However, careful assessment of 
pre- and post-dosing gallbladder ultrasound examinations and analysis of safety data for 
adverse events potentially related to either gallbladder or intestinal inflammation has revealed 
no evidence for a safety concern in humans to date. 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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5 
STUDY OBJECTIVES 
The objectives of this study are: 
Primary Objective 
• 
To assess whether emricasan compared to placebo leads to a mean decrease in hepatic 
venous pressure gradient (HVPG) at Week 24 in subjects with NASH cirrhosis and 
severe portal hypertension 
Secondary Objectives 
• 
To assess the safety and tolerability of emricasan  
• 
To evaluate the dose response of emricasan on portal pressure as assessed by HVPG 
at Week 24 
• 
To assess whether emricasan compared to placebo improves HVPG response at 
Week 24 using a 20% reduction from baseline response definition  
• 
To assess whether emricasan compared to placebo decreases mechanism specific 
(caspase 3/7) and non-specific (ALT) biomarkers at Weeks 24 and 48 
Exploratory Objectives 
• 
To assess whether emricasan compared to placebo improves HVPG response at 
Week 24 using a 10% reduction from baseline response definition 
• 
To assess whether emricasan compared to placebo improves liver function and 
prognosis at Weeks 24 and 48 as assessed by model for end-stage liver disease [1] and 
Child-Pugh (CP) scores (change in score, progression, regression) 
• 
To assess whether emricasan compared to placebo improves biochemical and 
functional biomarkers (cCK18/M30, flCK18/M65, AST, total bilirubin, INR, and albumin) 
at Weeks 24 and 48 
• 
To assess whether emricasan compared to placebo improves fibrosis markers at 
Weeks 24 and 48 
• 
To assess whether emricasan compared to placebo improves health-related quality of 
life at Weeks 24 and 48 
• 
To assess whether emricasan compared to placebo decreases development of 
decompensation or worsening of decompensation at Weeks 24 and 48 
• 
To assess whether emricasan compared to placebo improves liver metabolic function at 
Weeks 24 and 48 as assessed by methacetin breath test (at select sites) 
• 
To assess whether emricasan compared to placebo improves liver stiffness at Weeks 24 
and 48 as assessed by transient elastography (FibroScan®) (at select sites) 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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6 
STUDY DESIGN 
This is a multicenter, double-blind, randomized, placebo-controlled, dose-response study to 
evaluate the safety and efficacy of emricasan in improving portal hypertension in subjects with 
NASH cirrhosis and severe portal hypertension (defined as HVPG ≥12 mmHg). Subjects can 
have compensated (at least 60% of subjects but no more than 75%) or decompensated 
cirrhosis with no more than 1 prior significant decompensating event and must be currently 
clinically stable on stable standard therapy [2] (see Inclusion/Exclusion Criteria). Randomization 
will be stratified by compensated vs. decompensated status at baseline as well as use of 
non-selective beta-blockers (NSBB) or not. Subjects who are otherwise eligible will undergo the 
HVPG procedure as the last qualifying procedure prior to Day 1. 
The study treatment duration will be up to 48 weeks, including an initial 24-week randomized 
treatment phase with follow-up HVPG at Week 24 (primary endpoint) and an additional 24-week 
treatment phase (continuing the same study drug treatment as initially randomized).  Subjects 
completing the initial 24-week randomized treatment phase will be re-consented for the 
additional 24-week treatment phase.  HVPG measurements will be performed at screening and 
Week 24, with additional placebo controlled safety follow-up and exploratory efficacy 
assessments through Week 48.  Subjects will complete a final follow-up visit approximately 
2 weeks after the end of treatment (i.e., at Week 26 if completing the initial 24-week randomized 
treatment only or at Week 50 if completing the 48-week treatment). 
Subjects with baseline HVPG ≥12 mmHg may experience progression of cirrhosis during the 
48-week study.  Given that the primary endpoint for this study is HVPG rather than a clinical 
event (or clinical composite), subjects who have a decompensating event or worsened 
decompensation during the study will not be required to withdraw and can remain in the study 
unless the investigator feels the subject is not stable or the subject requires a transjugular 
intrahepatic portal shunt or other portosystemic bypass procedure, which would confound the 
HVPG assessment. Subjects who progress to Child-Pugh C will be withdrawn from study drug 
but are expected to remain in the study and complete all planned study visits (see 
Section 8.1.7).  All subjects who wish to discontinue study drug treatment should remain in the 
study and complete all planned study visits, in order to minimize missing data and protect the 
integrity of the study results.  Subjects who withdraw consent for participating in the study 
should discontinue study visits.  Subjects for whom the investigator deems that it is not in the 
best interest of the subject to continue participating in the study may also discontinue study 
visits. 
Subjects will be randomized in a 1:1:1:1 ratio to emricasan 50 mg BID, emricasan 25 mg BID, 
emricasan 5 mg BID or matching placebo BID.  
For each subject, the study will consist of: 
• 
Screening period of up to 6 weeks  
• 
Double-blind treatment period of 24 or 48 weeks 
• 
A follow-up visit 2 weeks after the Week 24 or Week 48 (or early termination) visit 
 
The duration of each subject’s participation will be approximately 32 or 56 weeks. 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
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Figure 4. 
Study Schema 
 
 
Appendix I, Schedule of Events*, 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 undergo a Screening period of up to 6 weeks; however, the screening could be 
completed within a shorter time frame. Subjects will sign an ICF before any study-related 
procedures are performed. Subjects will be screened to determine their eligibility. 
Medical/surgical history, medication record (prior and concomitant medications and therapy), 
and a physical examination including vitals will be obtained for all subjects. A series of 
laboratory and diagnostic tests will be performed. In general, a qualifying HVPG should be the 
last assessment performed during the Screening phase prior to randomization and should only 
be performed in subjects who meet all other eligibility criteria. 
                                               
*If any discrepancies should be found between the text of the protocol and Appendix I, Schedule of Events, the table 
will predominate. 
Screening 
Phase
Follow-up 
Phase
HVPG                                           HVPG
Must be ≥ 12 mmHg 
Follow-
up visit
Screen
E
N
D
T
R
E
A
T
M
E
N
T
Emricasan 5 mg BID
N=60
Placebo BID
N=60
Emricasan 50 mg BID
N=60
Emricasan 25 mg BID
N=60
R
A
N
D
O
M
I
Z
A
T
I
O
N
Initial randomized 
treatment
Double-Blind 
Treatment Phase
Continued 
randomized treatment
Wk -6 to Day 0                          Day 1 - - - - - - - - - - - Wk 24       - - - - - - - - - - - - - - - - Wk 48                    - - - - - Wk 26 or 50


 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
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Cirrhosis and Severe Portal Hypertension 
 
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Initial 24-Week Double-Blind Treatment Phase (Day 1 to Week 24) 
All subjects will be evaluated regularly through study visits every 4 weeks and laboratory and 
diagnostic tests for safety and efficacy as described in Appendix I, Schedule of Events.  
Continued 24-Week Double-Blind Treatment Phase (Week 25 to Week 48) 
Subjects consenting for continued treatment (continuing the same study drug treatment as 
initially randomized) will be evaluated regularly through study visits every 8 weeks and 
laboratory and diagnostic tests for safety and efficacy as described in Appendix I, Schedule of 
Events. Subjects can be seen more frequently for clinical reasons if indicated, but study 
assessments do not need to be performed at visits that are solely for clinical care. 
Follow-up Phase (Approximately 2 weeks after Week 24 or Week 48) 
Subjects will return approximately 2 weeks after completing Week 24 or Week 48 for a follow-up 
visit (either at Week 26 or Week 50). The visit will include study assessments as specified in the 
Schedule of Events.  This is the final study visit for all subjects. The end of the trial will be when 
the last subject completes the last follow-up visit. 
All subjects who prematurely discontinue the study, regardless of the cause, should undergo a 
follow-up visit (see Section 8.7.1) approximately 2 weeks following the early discontinuation 
visit.  


 
Document Code: 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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7 
STUDY POPULATION 
7.1 
INCLUSION CRITERIA 
To participate in this study, subjects must meet all of the following criteria: 
1. Male or female subjects 18 years or older, able to provide written informed consent and able 
to understand and willing to comply with the requirements of the study. 
2. Cirrhosis due to NASH with exclusion of other causes of cirrhosis (e.g. chronic viral 
hepatitis, alcoholic liver disease, etc.) 
• 
Diagnosis of cirrhosis is based on: 
o Biopsy OR 
o Clinical evidence: platelet count <150,000, AST > ALT, and either nodular liver 
surface on imaging or splenomegaly 
• 
NASH is based on at least 1 of the following: 
o Prior or current biopsy showing steatohepatitis (fat, ballooning degeneration, 
inflammation) consistent with NASH  
o At least 2 metabolic risk factors for at least 5 years preceding the diagnosis of 
cirrhosis: diabetes mellitus, impaired fasting glucose, obesity (Body Mass Index 
(BMI) ≥30 kg/m2 or central obesity), hypertension, dyslipidemia (See Appendix IV)  
o Prior or current biopsy showing some but not all diagnostic features of NASH 
(e.g. only fat or ballooning degeneration or inflammation) but with no evidence for 
viral hepatitis or other liver disease AND either fatty liver disease on prior imaging or 
at least 1 metabolic risk factor (as above) for at least 5 years preceding the diagnosis 
of cirrhosis 
Note: Previous viral hepatitis that was curatively treated (with sustained viral response) is 
not an exclusion as long as: 1) viral eradication was achieved at least 3 years prior 
to the diagnosis of cirrhosis and 2) all other criteria are met for NASH as the 
etiology of cirrhosis 
3. Compensated cirrhosis (no history of or presence of clinically evident ascites, variceal 
hemorrhage, or encephalopathy, and on no medications to treat these complications)  
 
OR  
 
Decompensated cirrhosis with no more than 1 prior significant decompensating event: 
a. If prior decompensating event was variceal hemorrhage, event must have occurred at 
least 3 months prior to Day 1 
b. If prior decompensating event was ascites requiring chronic diuretics, ascites should be 
well controlled (not clinically evident, i.e. no ascites or ascites only detectable by 
ultrasound examination) on a stable dose of diuretics for at least 3 months prior to Day 1 
c. If prior decompensating event was hepatic encephalopathy ≥ grade II or requiring 
hospitalization, encephalopathy should be well-controlled (Stage 0 or 1) on stable 
medication for at least 3 months prior to Day 1  


 
Document Code: 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
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Note: Previous transient ascites or hepatic encephalopathy in a subject who is currently 
stable without clinically evident ascites or encephalopathy and on no medications 
for these conditions does not count as a prior significant decompensating event 
4. Severe portal hypertension defined as HVPG ≥12 mmHg (see Section 8.4.1 for 
recommendations to identify subjects more likely to meet the HVPG criteria) 
5. Subjects who are on NSBB, nitrates, diuretics, lactulose, rifaximin, or statins must be on a 
stable dose for at least 3 months prior to Day 1 
6. Willingness to utilize effective contraception (for both males and females of reproductive 
potential) from Screening to 4 weeks after the last dose of study drug 
7. Platelet count ≤125 k/mm3 or transient elastography ≥20 kilopascal [3] during screening 
8. If on therapeutic dose of vitamin E, stable for 6 months prior to Day 1 
7.2 
EXCLUSION CRITERIA 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Evidence of severe decompensation, defined as: 
• 
Presence or history of more than one type of significant decompensating event (clinically 
evident ascites requiring chronic diuretics, variceal hemorrhage, and/or overt 
encephalopathy) 
Note: Previous transient ascites or hepatic encephalopathy in a subject who is currently 
stable without clinically evident ascites or encephalopathy and on no medications 
for these conditions does not count towards this exclusion 
(See Inclusion Criteria #4). 
 
• 
One type of decompensating event with the following characteristics: 
• 
More than 1 episode of variceal hemorrhage or bleeding from a portal hypertensive 
source (e.g. portal hypertensive gastropathy) 
• 
Ascites that has required more than 1 large-volume paracentesis (>5 L) for treatment or 
that has been complicated by spontaneous bacterial peritonitis, hyponatremia (serum 
Na <130), and/or hepatorenal syndrome 
• 
More than 1 episode of overt hepatic encephalopathy requiring hospitalization 
 
2. Severe hepatic impairment defined as a Child-Pugh score ≥10  
3. ALT >3 times upper limit of normal (ULN) or AST >5 times ULN during screening  
4. Estimated creatinine clearance <30 mL/min 
5. Prior transjugular intrahepatic portosystemic shunt or other porto-systemic bypass 
procedure 
6. Known portal vein thrombosis 
7. Symptoms of biliary colic, e.g. due to symptomatic gallstones, within the last 6 months, 
unless resolved following cholecystectomy, other definitive treatment (e.g., sphincterotomy), 
or medical management (e.g., ursodeoxycholic acid) 


 
Document Code: 
IDN-6556-14-PRO-1001 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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8. Current use of medications that are considered inhibitors of OATP1B1 and OATP1B3 
transporters: atazanavir, cyclosporine, eltrombopag, gemfibrozil, indinavir, lopinavir, 
ritonavir, rifampin, saquinavir, simeprevir, telaprevir, tipranovir, or some combination of 
these medications 
9. Alpha-fetoprotein >50 ng/mL 
10. History or presence of clinically concerning cardiac arrhythmias, or prolongation of screening 
(pre-treatment) QT Interval Corrected by the Fridericia Correction Formula (QTcF) interval of 
>500 msec 
11. History of or active malignancies, other than those successfully treated with curative intent 
and believed to be cured 
12. Significant systemic or major illness other than liver disease that in the opinion of the 
investigator would preclude the subject from participating in and completing the study, 
including but not limited to acute coronary syndrome or stroke within 6 months of screening 
or major surgery within 3 months of screening 
13. Prior liver transplant 
14. Change in diabetes medications within 3 months of screening, including initiation, 
discontinuation, or change in dose except for medications titrated according to blood 
glucose 
15. Uncontrolled diabetes mellitus (HbA1c >9%) within 3 months of screening 
16. Restrictive bariatric surgery or bariatric device within 1 year of screening or prior 
malabsorptive bariatric surgery 
17. Known human immunodeficiency virus infection 
18. Use of controlled substances (including inhaled or injected drugs) or non-prescribed use of 
prescription drugs within 1 year of screening to the point of interfering with the subject’s 
ability to comply with study procedures and study drug administration in the investigator’s 
judgement 
19. History of significant alcohol consumption (>20 g/day for females and >30 g/day for males 
on average) within the past 5 years 
20. If female: planned or known pregnancy, positive urine or serum pregnancy test, or 
lactating/breastfeeding 
21. Previous treatment with emricasan or active investigational medication (except methacetin) 
in a clinical trial within 3 months prior to Day 1 
7.3 
SUBJECT IDENTIFICATION 
During the screening period, subjects will be identified by a unique screening number composed 
of the 3-digit site number and a 2-digit subject identification number that starts with 01.  On 
Day 1, subjects who will be randomized will be identified by a unique 4-digit randomization 
number.  Only qualified subjects will be assigned a randomization number. 
7.4 
RANDOMIZATION PROCEDURE 
The assignment to emricasan 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. 


 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
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Cirrhosis and Severe Portal Hypertension 
 
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The assignment of randomization number and treatment assignment will be centrally 
coordinated through the study’s Interactive Web Randomization System (IWRS).  
Randomization numbers will be assigned by the IWRS. The IWRS will notify sites when 
enrollment for compensated subjects reaches 75% or enrollment for decompensated subjects 
reaches 40%. 
The randomization will be stratified by 2 factors: 
• 
Compensated vs. decompensated status at baseline 
• 
Use of non-selective beta-blockers (NSBB) or not 
7.5 
BLINDING/UNBLINDING PROCEDURES 
Investigators will be able to unblind subjects through the IWRS when it is medically imperative 
to know whether a subject is receiving emricasan or placebo, such as in the event of an adverse 
event (AE) that the Investigator feels cannot be adequately treated without knowing the identity 
of the study drug.  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 treatment assignment.  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 subjects with potential suspected 
unexpected serious adverse reactions (SUSARs) for the purpose of 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 a 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.  If the Investigator becomes 
unblinded to a subject’s study drug assignment, the subject should be withdrawn from the study. 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
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Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
34 of 90 
8 
STUDY ASSESSMENTS AND CONDUCT 
8.1 
SAFETY ASSESSMENTS 
8.1.1 
Adverse Events 
Adverse events verbatim terms will be collected at each study visit.  The start date of the event, 
stop date of the event (if known), severity, relationship to study drug (emricasan or placebo) or 
to methacetin, seriousness, outcome, and action taken for each verbatim term will also be 
collected.  All verbatim terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary for purposes of summarization. AEs (except SAEs, see Section 13.8) 
should be collected for a subject starting from signing of the informed consent until the subject’s 
last study visit (follow-up visit, early termination, or last regularly scheduled study visit). 
8.1.2 
Medical History and Physical Examinations 
Medical and surgical history will be taken at screening.  A comprehensive physical examination 
will be performed at the Screening, Week 24, and Week 48 visits including examination 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. A focused physical examination limited to relevant assessments and based on any 
symptoms or concerns related to a particular body system will be performed at all other visits. 
Weight, assessed in street clothes with shoes and outerwear off, and height (screening visit 
only) will be recorded at the specified visits. Each subject’s body mass index (BMI) will be 
calculated. Assessment of Child-Pugh clinical features will be performed at all visits. 
8.1.3 
Vital Sign Measurements 
Respiratory rate, pulse, systolic and diastolic blood pressure, and temperature measurements 
(‘vital signs’) will be performed. Evaluation of the respiratory rate will be measured by counting 
the inhalations for one minute. Blood pressure and heart rate measured during the HVPG 
procedure will also be collected. 
8.1.4 
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 clinically significant findings occur as 
determined by the Investigator, the Medical Monitor should be contacted.   


 
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8.1.5 
Monitoring for Potential Gallbladder Adverse Effects 
Due to pre-clinical findings that emricasan was associated with gallbladder inflammation, 
specific safety evaluation and monitoring procedures will be followed.  
• 
Subjects with symptoms of biliary colic, e.g. due to symptomatic gallstones, within the 
last 6 months, unless resolved following cholecystectomy, other definitive treatment 
(e.g., sphincterotomy), or medical management (e.g., ursodeoxycholic acid), will be 
excluded from the study.  
• 
All subjects will have a comprehensive liver and gallbladder ultrasound (including 
examination of the biliary tree, assessment of whether gallbladder wall thickening is 
present, and measurement of gallbladder wall thickness) at the Screening visit, unless 
the subject had an ultrasound within 3 months of Screening that captures all the 
assessments noted above.  If source documentation is provided, the prior ultrasound 
can be used in place of the Screening ultrasound.  An anonymized copy of the report 
(and images if needed) from the ultrasound (whether historical or performed for the 
study) should be provided to the Sponsor. 
• 
At each study visit, the Investigator will specifically assess the subject for any symptoms 
consistent with biliary colic, e.g. sharp right upper quadrant pain, nausea, vomiting, fever 
(with cholecystitis), etc. If the subject reports symptoms of biliary colic or other 
symptoms suggestive of gallbladder disease on directed questioning or spontaneously 
reports such symptoms at any other time during the study, a follow-up liver and 
gallbladder ultrasound (including assessment of the biliary tree and any gallbladder 
abnormalities) should be performed.  If additional ultrasounds (or other imaging) are 
performed during the study for evaluation of biliary colic, assessment of the gallbladder 
as noted above should be performed, and an anonymized copy of the report(s) (and 
images if needed) should be provided to the Sponsor.   
• 
Symptoms of biliary colic or other symptoms suggestive of gallbladder disease (such as 
cholecystitis) that trigger a follow-up ultrasound should be recorded as AEs that are 
possibly or probably related to study drug. 
8.1.6 
Monitoring for Evidence of Potential Drug-Induced Liver Injury (DILI) 
Liver transaminases (ALT, AST) and total bilirubin will be monitored regularly (assessed at each 
study visit) during the study not only as mechanism-independent biomarkers of inflammation, 
but also for any evidence of potential DILI.  Given that the patient population to be studied has 
underlying liver disease and therefore is likely to have abnormalities in liver transaminases 
and/or bilirubin at baseline, the guidelines for DILI monitoring in this study have been adapted 
from the US Food and Drug Administration (FDA) guidance on DILI that was based primarily on 
monitoring subjects with normal liver enzymes and bilirubin at baseline and incorporate 
suggestions provided to the Sponsor from the FDA regarding monitoring for DILI in subjects 
who have abnormal baseline values of liver transaminases and/or total bilirubin. 
 


 
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Table 1. 
Liver Monitoring Procedure 
 
Additional Monitoring ONLY 
Additional Monitoring AND Study Medication Interruption 
Criteria 
If any ONE of the following 2 criteria are met:  
• Isolated increase in ALT or AST and minimal or no increase in 
total bilirubin (TB) in the absence of clinical hepatitis 
symptoms (including but not limited to fever, anorexia, nausea, 
vomiting, abdominal pain, rash) 
o ALT >2x baseline if baseline ALT >2x ULN OR  
o ALT >3x ULN if baseline ALT ≤2x ULN OR 
o AST >2x baseline if baseline AST >2x ULN OR  
o AST >3x ULN if baseline AST ≤2x ULN 
o No increase in TB greater than criteria below 
• Isolated increase in TB and minimal or no increase in ALT or 
AST in the absence of clinical hepatitis symptoms (as described 
above) 
o TB >2x baseline if baseline TB >ULN OR 
o TB >2x ULN if baseline TB ≤ULN  
o No increase in ALT or AST greater than criteria above 
If any ONE of the following 6 criteria are met: 
• Isolated transaminase increase 
o ALT OR AST > 8x ULN 
• Increase in TB that is related to an increase in direct bilirubin 
(defined as a direct bilirubin to TB ratio >35%) 
o TB increase >2.0 mg/dL if baseline TB >2.0 mg/dL OR 
o TB >2x baseline or >1.5x ULN, whichever is higher, if 
baseline TB ≤2.0 mg/dL  
• Increases in transaminases and TB  
o ALT >3x baseline if baseline ALT >ULN OR  
o ALT >5x ULN if baseline ALT ≤ULN OR 
o AST >3x baseline if baseline AST >ULN OR  
o AST >5x ULN if baseline AST ≤ULN 
AND 
o TB >2x baseline if baseline TB >ULN OR 
o TB >2x ULN if baseline TB ≤ULN  
• Increase in cholestatic marker (ALP) when the ALP increase is 
due to a hepatic source 
o ALP >2x baseline if baseline ALP >ULN OR 
o ALP >3x ULN if baseline ALP ≤ULN 
• Increase in INR that is refractory to vitamin K administration in 
the absence of a clear reason (e.g. initiation of anticoagulants 
that can affect INR) 
o INR increase of >0.4 if baseline INR >ULN OR 
o INR increase to >1.5 if baseline INR ≤ULN  
• Any increase in transaminases or TB if associated with 
symptoms (e.g., fever, anorexia, nausea, vomiting, abdominal 
pain, rash) and/or >5% eosinophilia 


 
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Confirmation 
of Need for 
Additional 
Liver 
Monitoring 
If either of above criteria met: 
• Repeat liver profile (AST, ALT, total and direct bilirubin, GGT, 
alkaline phosphatase, albumin, CBC, and INR) within 2 to 3 
days to confirm the elevation 
o If a subject lives in a remote area, use of local labs may be 
approved by the Sponsor 
o The Investigator will ensure that local lab results are 
promptly reviewed 
• If not confirmed, resume routine laboratory testing 
If any of above criteria met: 
• Repeat liver profile (AST, ALT, total and direct bilirubin, GGT, 
alkaline phosphatase, albumin, CBC, and INR) within 2 to 3 
days to confirm the elevation 
o If a subject lives in a remote area, use of local labs may be 
approved by the Sponsor 
o The Investigator will ensure that local lab results are 
promptly reviewed 
• If not confirmed, resume routine laboratory testing 
Study 
Medication 
Interruption 
Not applicable 
If elevated tests confirmed: 
• Interrupt study medication 
Work-up for 
Liver Injury 
If elevated tests confirmed: 
• Initiate work-up for other causes of liver injury (see below) 
If elevated tests confirmed: 
• Initiate work-up for other causes of liver injury (see below) 
Close 
Monitoring 
If elevated tests confirmed: 
• Monitor the subject with laboratory testing 2 or 3 times weekly 
with the frequency of testing decreased to once a week or less 
if abnormalities stabilize and the subject is asymptomatic  
o If a subject lives in a remote area, use of local labs may be 
approved by the Sponsor  
o The Investigator will ensure that local lab results are 
promptly reviewed 
• Discontinue frequent lab monitoring and resume usual study 
visit monitoring schedule when  
o ALT and AST decrease to <1.2x baseline (or <1.2x ULN if 
baseline value <ULN) on two consecutive measurements 
o TB decreases to <1.3x baseline (or <1.3x ULN if baseline 
value <ULN) on two consecutive measurements 
• Clinical judgment should determine the intensity and duration of 
close monitoring for subjects who are clinically stable and 
asymptomatic but with elevated test(s) 
If elevated tests confirmed: 
• Monitor the subject with laboratory testing 2 or 3 times weekly 
with the frequency of testing decreased to once a week or less 
if abnormalities stabilize and the subject is asymptomatic  
o If a subject lives in a remote area, use of local labs may be 
approved by the Sponsor  
o The Investigator will ensure that local lab results are 
promptly reviewed  
• Discontinue frequent lab monitoring and resume usual study 
visit monitoring schedule when  
o ALT, AST, ALP decrease to <1.2x baseline (or <1.2x ULN if 
baseline value <ULN) on two consecutive measurements 
o TB, INR decreases to <1.3x baseline (or <1.3x ULN if 
baseline value <ULN) on two consecutive measurements 
• Clinical judgment should determine the intensity and duration of 
close monitoring for subjects who are clinically stable and/or 
asymptomatic but with elevated test(s) 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
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Title: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, an Oral Caspase Inhibitor, in 
Subjects with Non-Alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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Potential 
Restart of 
Study 
Medication 
after 
Interruption 
Not applicable 
• In accordance with the FDA “Guidance for Industry Drug 
Induced Liver Injury (DILI): Premarketing Clinical Evaluation” 
o If a subject has suspected DILI, restarting study medication 
is NOT recommended 
• If DILI is considered unlikely AND liver tests return to levels 
indicated above for discontinuing close monitoring 
o Restarting study medication may be considered according to 
the discretion of the Investigator and after discussion with 
the Sponsor 
Follow-up 
During Restart 
of Study 
Medication 
after 
Interruption 
Not applicable 
• Laboratory tests (as noted above for confirmatory testing) 
should be checked within 2-3 days after restarting study 
medication, followed by weekly lab tests for 2-4 weeks 
(depending on Investigator judgment) and then monthly for 3 
months, which may occur at regular study visits 
• Any subject who meets the criteria for liver monitoring (after 
confirmatory testing) a second time will have study medication 
permanently discontinued 
 
If elevated tests are confirmed, the following work-up should be performed at the first monitoring visit:  
• 
Obtain a more detailed history of symptoms and prior and concurrent diseases 
• 
Obtain further history of concomitant drug use (including non-prescription medications, herbal and dietary supplement 
preparations), alcohol use, recreational drug use, and special diets 
• 
Obtain a history for exposure to environmental chemical agents and travel 
• 
Obtain serology for viral hepatitis (hepatitis A immunoglobulin M [IgM], HBV surface antigen, HCV antibody, hepatitis E IgM, 
cytomegalovirus IgM, Epstein Barr virus antibody panel) and autoimmune hepatitis (e.g. anti-nuclear antibody) 
• 
Perform further testing for Gilbert’s if appropriate (e.g. if total bilirubin is elevated)  
 


 
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an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
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8.1.7 
Management of Subjects Who Progress to Child-Pugh C 
Subjects with Child-Pugh C status at baseline will be excluded. Child-Pugh status will be 
assessed at each visit during the study, and subjects who progress to Child-Pugh C will be 
considered for withdrawal from study drug treatment. However, given the day to day fluctuations 
in clinical laboratory parameters (total bilirubin, albumin, INR) that could transiently change a 
subject’s Child-Pugh status to C, a Child-Pugh C score should be confirmed on repeat testing 
and evaluation before withdrawing study drug treatment.  Laboratory tests and clinical 
evaluation consistently confirming Child-Pugh C status should lead to study drug withdrawal. 
Subjects should, however, remain in the study and complete all scheduled study visits.   
If post-baseline Child-Pugh score is ≥10 
• 
Subject should return for repeat laboratory testing (total bilirubin, albumin, INR) and 
clinical evaluation (ascites, hepatic encephalopathy) ideally within 3 days of the tests 
consistent with Child-Pugh C status but at least within 7 days 
o If repeat Child-Pugh score (2nd test) is <10, the subject should continue study drug 
treatment with the next follow-up occurring at the next regularly scheduled study visit.  
o If repeat Child-Pugh score (2nd test) is ≥11, the subject should be withdrawn from 
the study drug, but should complete all scheduled study visits. 
o If repeat Child-Pugh score (2nd test) is 10 and the investigator feels the subject is 
clinically stable to continue study drug treatment, the subject should return for repeat 
laboratory testing (total bilirubin, albumin, INR) and clinical evaluation (ascites, 
hepatic encephalopathy) in 1-2 weeks 
 
If repeat Child-Pugh score (3rd test) is ≥10, the subject should be withdrawn from 
the study drug, but should complete all scheduled study visits. 
 
If repeat Child-Pugh score (3rd test) is <10, the subject should continue study 
drug treatment with the next follow-up occurring at the next regularly scheduled 
study visit. 
8.1.8 
Screening and Follow-up Questionnaires for Alcohol Abuse 
The Alcohol Use Disorders Identification Test (AUDIT) is a 10-item questionnaire developed to 
screen for excessive drinking, helping to identify whether a person has hazardous (or risky) 
drinking, harmful drinking, or alcohol dependence.  The AUDIT-C is a 3-question version of 
AUDIT that performed similarly to the full AUDIT for detecting heavy drinking and/or active 
abuse or dependence [32]. 
The Skinner Alcohol Dependence scale is a 25-item questionnaire that provides a quantitative 
measure of the severity of alcohol dependence, with scores in the 1st, 2nd, 3rd, and 4th quartiles 
corresponding to low, intermediate, substantial, and severe levels of alcohol dependence being 
likely. 
The AUDIT and Skinner Alcohol Dependence scale will be used during Screening to screen for 
any evidence of alcohol abuse, and the AUDIT-C will be used during the treatment phase of the 
study to monitor for any evidence of active alcohol abuse.  


 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
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Cirrhosis and Severe Portal Hypertension 
 
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8.1.9 
Screening Esophagogastroduodenoscopy (EGD) 
An EGD will be performed during screening, unless the subject had a prior EGD performed 
within an acceptable time frame according to the recommendations outlined in the Baveno VI 
Consensus Workshop on portal hypertension [2], and records from the prior EGD are available. 
For example, if there is ongoing liver injury (e.g. NASH), patients with compensated cirrhosis 
with no varices on screening EGD should have surveillance endoscopy at 2-year intervals while 
patients with decompensated cirrhosis and small varices should have surveillance endoscopy at 
1-year intervals. Subjects with medium or large varices or with decompensated cirrhosis should 
have surveillance endoscopy at 1-year intervals.  
The following information should be available from the EGD: presence or absence of 
esophageal varices, size of varices (small, medium, large), and any high-risk stigmata (e.g. red 
wale signs).  Small varices are defined as those that barely protrude above the esophageal 
mucosa but that persist after air insufflation of the esophagus, large varices are those that 
occupy half of the esophageal lumen, and medium-sized varices are those that are intermediate 
between small and large. 
If the Investigator deems it medically necessary, additional EGDs other than those specified by 
the protocol may be performed during the study.  If additional EGDs are performed during the 
study, the reasons for and results of the additional EGDs will be captured as study data. 
8.2 
EFFICACY ASSESSMENTS 
8.2.1 
Hepatic Venous Pressure Gradient (HVPG) 
The HVPG is the difference between wedged (or occluded) hepatic vein pressure (WHVP) and 
free hepatic vein pressure (FHVP) and represents the gradient between the portal vein and the 
intra-abdominal inferior vena cava (IVC) pressure, with normal HVPG being 3-5 mmHg. It is a 
measure of intrahepatic sinusoidal pressure that correlates directly with direct measurements of 
portal pressure in cirrhosis.  
Measurement of the HVPG is a moderately invasive procedure that involves insertion of a 
catheter via the right internal jugular vein to measure WHVP and FHVP. The WHVP is obtained 
by inflating a balloon at the tip of the catheter to occlude the lumen of the hepatic vein 
(preferably the main right hepatic vein). The FHVP is obtained by deflating the balloon of the 
hepatic vein catheter and is very close to the IVC pressure. If the difference between FHVP and 
IVC is ≥2 mmHg, this usually reflects the catheter advanced too far into the hepatic vein. The 
FHVP should be obtained with the catheter tip 1-3 cm into the hepatic vein; if the point of 
adequate balloon occlusion is further down the hepatic vein, FHVP should be repeated at this 
"withdrawn" position. The WHVP and FHVP are affected equally by intra-abdominal pressure 
(e.g. increased intra-abdominal pressure in ascites), whereas their gradient (HVPG) is not. 
Therefore, the measurement of HVPG incorporates its own zero reference point and is not 
affected by increases in intra-abdominal pressure. Furthermore, the use of the HVPG eliminates 
another very important source of error, the external zero reference point, which should be 
placed at the level of the mid-axillary line and kept constant during the study. 


 
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Cirrhosis and Severe Portal Hypertension 
 
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Practical Considerations for HVPG Measurement 
• 
The procedure is an outpatient procedure (median duration of ~25 minutes) that is 
generally well-tolerated and usually associated with minimal complications (mostly 
hematoma and/or pain at site of puncture).  
• 
WHVP can also be measured by advancing the catheter into the smallest branch of the 
hepatic vein and “wedging” it, but this is less accurate than the “occluded” pressure 
because the balloon catheter occludes a larger hepatic venous branch and can, 
theoretically, measure WHVP over a wider vascular territory of the liver compared with a 
wedged catheter.  
• 
The test should be performed preferably in the morning because there is circadian 
variation of the HVPG (higher during the day, lower at night).  For a given subject, the 
Screening and Week 24 tests should be performed at approximately the same time of 
the day, i.e. after fasting in the morning. 
• 
The test should be performed after an overnight fast as the HVPG increases after food 
ingestion (1-2 hours post-prandial), particularly in cirrhosis.   
• 
The procedure may be done under slight conscious sedation with intravenous 
midazolam, but deep sedation (e.g. with opioids such as fentanyl) must be AVOIDED as 
it can lead to artifacts caused by exaggerated deep breathing.   
• 
At least three sets of WHVP (with continuous recording at least 60 sec [or longer if the 
pressure is still increasing]) and FHVP (with recording at least 20-30 sec) measurements 
should be collected, with the average used to calculate the final HVPG result. 
• 
Adequate occlusion of the hepatic vein should be checked by injecting a small amount 
(0.5 mL) of contrast dye with the balloon inflated.  
• 
After the WHVP and FHVP measurements are obtained, 3 additional pressure 
measurements should be collected as the catheter is being withdrawn (and without 
interrupting the recording): a) at the most proximal portion of the hepatic vein (juncture 
between IVC and hepatic vein), at the IVC (at the level of the hepatic vein) and at the 
right atrium.  
 
HVPG will be performed at Screening and Week 24 visits. A blood sample from the hepatic vein 
and a paired systemic sample (obtained from the jugular vein through the side arm of the 
venous introducer) will be collected for measurement of biomarkers.  
Generally, the HVPG 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. A central reader appointed for this study will ensure that all participating sites are 
qualified to perform the procedure. Original tracings of the pressure measurements will be kept 
at the site as part of source documentation for the study, and redacted copies will be forwarded 
to the Central Reader for evaluation. A manual providing more details on the HVPG procedure 
will be provided to sites. 
8.2.2 
Model for End Stage Liver Disease [1] Score 
The Model for End-Stage Liver Disease, or MELD, is a scoring system for assessing the 
severity of chronic liver disease and short-term mortality.  An earlier version of the formula for 


 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
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MELD used the subject's values for serum bilirubin, serum creatinine, and the international 
normalized ratio (INR) for prothrombin time and was calculated according to the following 
formula (rounded to the nearest whole number): 
Previous MELD = 3.78[Ln serum bilirubin (mg/dL)] + 11.2[Ln INR] 
+ 9.57[Ln serum creatinine (mg/dL)] + 6.43 
 
If the patient was dialyzed twice within the last 7 days, then the value for serum creatinine used 
was set to 4.0. Any value less than 1 was given a value of 1 (i.e. if bilirubin was 0.8, a value of 
1.0 was used) to prevent the occurrence of scores below 0 (the natural logarithm of 1 is 0, and 
any value below 1 would yield a negative result). 
In January 2016, the Organ Procurement and Transplantation Network updated the MELD 
score to include sodium for the purpose of liver organ allocation.  Thus, the MELD score is now 
calculated based on the previous MELD score (provided above) as well as sodium (Na) 
according to the following formula (which will be the one used for the purpose of this study): 
MELD = previous MELD + 1.32 × (137-Na) – [0.033 × previous MELD × (137-Na)] 
 
Sodium values <125 mmol/L will be set to 125, and values >137 mmol/L will be set to 137. 
8.2.3 
Child-Pugh Score and Classification 
The Child-Pugh score (sometimes referred to as the Child-Turcotte-Pugh score) is used to 
assess the prognosis of chronic liver disease and is calculated as the sum of five component 
scores. Total bilirubin, serum albumin, prothrombin time, ascites, and hepatic encephalopathy 
components are scored with values of 1 to 3 points with 3 indicating the greatest severity.  This 
provides a Child-Pugh score of 5 to 15 points.  The Child-Pugh score is used to determine the 
Child-Pugh classification (A, B, or C). 


 
Document Code: 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
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Parameter 
Child-Pugh Score 
1 
2 
3 
Total Bilirubin (mg/dL) 
<2.0 
2.0-3.0 
>3.0 
Albumin (g/dL) 
>3.5 
2.8-3.5 
<2.8 
Ascites 
Currently with no 
ascites or ascites only 
detectable on imaging 
(grade 1) and not on 
diuretics 
Currently ascites only 
detectable on imaging 
(grade 1) and treated 
with diuretics OR with 
overt ascites (grade 2 
or 3) that is diuretic 
responsive 
Currently with overt 
ascites (grade 2 or 3) 
that is not diuretic 
responsive  
Hepatic Encephalopathy 
(HE) 
Currently with no overt 
HE and not on specific 
therapy* 
Currently with no overt 
HE and no asterixis on 
treatment with specific 
therapy OR currently 
with grade 2 HE 
(confused but talking 
and/or with asterixis) 
not on treatment with 
specific therapy 
Currently with grade 2 
HE despite treatment 
with specific therapy or 
currently with grade 3 
HE or grade 4 HE 
Prothrombin time (sec 
prolonged) or INR 
<4 
(INR <1.7) 
4-6 
(INR 1.7-2.3) 
>6 
(INR >2.3) 
 
Child-Pugh Classification 
Child-Pugh Score 
Child-Pugh A 
5-6 
Child-Pugh B 
7-9 
Child-Pugh C 
10-15 
8.2.4 
Quality of Life Assessments 
Health-related quality of life (QOL) will be assessed by using the Short Form 36 (SF-36) and 
Chronic Liver Disease Questionnaire (CLDQ). 
The SF-36 is a generic, validated, widely used QOL assessment survey that has shown good 
psychometric properties in diverse disease states, including patients with advanced liver 
disease. The SF-36 consists of 36 questions that make up 8 subscales (physical function, 
physical role limitation, bodily pain, general health, vitality, social function, emotional role 
limitation, and mental health) with 0 as the worst and 100 as the best possible score.  An overall 
physical health score and mental health score are derived from the subscale scores.  Norm-
based scoring involves a linear transformation to transform scores to a mean of 50 and standard 
deviation of 10, such that a score >50 is interpreted as better health than the US population, 
and a score <50 means poorer health.  In 713 subjects with NAFLD (61% of whom had definite 
NASH) enrolled in the NASH Clinical Research Network, those with NAFLD had worse physical 
and mental health scores compared with the US population with and without chronic illness, and 
those with NASH had lower physical health compared with NAFLD subjects without NASH [33]. 


 
Document Code: 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
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Cirrhosis and Severe Portal Hypertension 
 
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The CLDQ was developed to assess health-related QOL in patients with chronic liver disease 
[34] and includes 29 questions in 6 domains: fatigue, activity, emotional function, abdominal 
symptoms, systemic symptoms, and worry.  Patients found the CLDQ clear and easy to 
complete in 10 minutes.  The CLDQ correlated with disease severity, showing a gradient 
between patients without cirrhosis, patients with Child-Pugh A cirrhosis, and patients with 
Child-Pugh B or C cirrhosis [34].  In a study of 237 patients with chronic liver disease related to 
NAFLD, chronic HCV, or chronic hepatitis B virus (HBV), NAFLD patients had significantly lower 
quality of life scores compared to HCV and HBV patients on multiple CLDQ domains [35]. 
8.2.5 
Clinical Outcome Events 
Clinical outcome events are an efficacy measure and will be defined based on whether the 
subject has compensated cirrhosis or decompensated cirrhosis at study entry, and for the latter, 
depending on what the prior decompensating event was.  Subjects may have more than 
1 clinical outcome event. Subjects who have compensated cirrhosis on study entry and have a 
decompensating event could meet criteria for an additional decompensating event(s) if they 
remain in the study. All clinical outcome events should be reported as AEs. An event reflecting 
progression of chronic liver disease that meets criteria for being adverse but does not qualify as 
a clinical outcome event (e.g. worsening ascites not requiring paracentesis) should still be 
reported as an AE. 
Baseline (Day 1) 
Cirrhosis Stage 
Decompensating Event Prior to 
Day 1 
Qualifying Clinical Outcome Events 
Compensated 
Not applicable 
• New onset clinically evident ascites 
requiring chronic diuretics 
• Variceal hemorrhage 
• New onset overt hepatic encephalopathy 
requiring hospitalization 
Decompensated 
Ascites, not clinically evident (no 
ascites or only detectable by 
ultrasound) on a stable dose of 
diuretics 
• Variceal hemorrhage 
• Worsening ascites requiring paracentesis 
• New onset overt hepatic encephalopathy 
requiring hospitalization 
Decompensated  
Prior variceal hemorrhage 
• Recurrent variceal hemorrhage 
• New onset clinically evident ascites 
requiring chronic diuretics 
• New onset overt hepatic encephalopathy 
requiring hospitalization 
Decompensated 
Hepatic encephalopathy, 
currently with no or mild 
encephalopathy (Stage 1) on 
lactulose and/or rifaximin 
• Variceal hemorrhage 
• New onset clinically evident ascites 
requiring chronic diuretics 
• Worsening overt hepatic encephalopathy 
requiring another hospitalization 


 
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Cirrhosis and Severe Portal Hypertension 
 
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8.2.6 
Liver Metabolic Function by Methacetin Breath Test  
The 13C-methacetin breath test (MBT) is a noninvasive tool to assess liver microsomal capacity 
to metabolize the nonradioactive 13C-labeled Methacetin. The Breath Test System consists of 
the BreathID® Molecular Correlation Spectrometry (MCSTM) device and a test kit containing a 
breath collection nasal cannula and a nonradioactive isotope 13C-methacetin solution. The 
BreathID MCS device measures and computes the 13CO2/12CO2 ratio in the subject’s exhaled 
breath in real time.  Additional details for the procedure are provided in Appendix II. 
The BreathID MCS device is based on an FDA-approved device (510k#: K130524) for 
assessment of Helicobacter pylori infection in the stomach utilizing 13C-urea as a substrate. As 
a standalone device, it is classified by the FDA as Class I, which means that for general use, 
the device is exempt from pre-marketing application. The MBT, which consists of both a device 
and an unapproved drug component, is however considered an investigational device. 
Performance and safety of the device utilizing the 13C-methacetin substrate for assessment of 
liver function have been studied in thousands of subjects worldwide, including in a large US 
pivotal study (G080107) enrolling over 400 subjects with chronic liver disease from 
11 participating sites (including 141 subjects with biopsy proven cirrhosis). This study 
demonstrated an excellent safety profile of the MBT. Furthermore, there are currently 2 ongoing 
MBT studies for detection of clinically significant portal hypertension in subjects with advanced 
liver disease and for assessment of correlation to severity of liver disease in subjects with 
NAFLD. 
Subjects will be asked to sit in a chair with a nasal cannula (a small tube) attached to the 
BreathID MCS device placed inside their nostrils while breathing normally.  The BreathID MCS 
device will measure the subject’s baseline carbon dioxide production for approximately 
10 minutes (up to 25 minutes), after which the subject will be administered 1 cup of a solution of 
a 75 mg Methacetin pre-dissolved in water. Methacetin is exclusively broken up in the liver and 
turns into carbon dioxide and acetaminophen. The subject will remain sitting in a chair with the 
nasal cannula in their nose breathing in a normal fashion for another 60 minutes while the 
BreathID MCS device measures carbon dioxide production. Additional details on the procedure 
as well as the parameters obtained from the MBT are provided in Appendix II. 
The MBT will be performed at select sites at Screening, Week 24, and Week 48. MBT should be 
performed within 1 week of HVPG but not within 24 hours after HVPG. If MBT is performed on 
the same day as the HVPG test, it should be performed before the HVPG test. For the Week 24 
and Week 48 MBT, subjects should take their morning dose of study drug prior to the test. Sites 
who elect to participate in the MBT measurements will perform the test at the specified visits for 
all subjects enrolled at their site.  
8.2.7 
Liver Stiffness by Transient Elastography (using FibroScan®) 
Transient elastography is a non-invasive, reproducible method for measuring liver stiffness that 
correlates with liver fibrosis and will be measured using FibroScan® (manufacturer Echosens).  
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.  The 
protocol for the FibroScan® procedure is provided in Appendix III. 


 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
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Cirrhosis and Severe Portal Hypertension 
 
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Transient elastography measurements will be performed at select sites at Screening, Week 24, 
and Week 48. Sites who elect to participate in the transient elastography measurements will 
perform the test at the specified visits for all subjects enrolled at their site.  
8.3 
LABORATORY TESTS 
Blood and urine collected for laboratory tests will be analyzed according to standardized, 
validated assays.  The central laboratory will supply detailed instructions and all necessary 
containers for blood and urine collections.  Blood and urine sample volumes should meet the 
laboratory’s specification.   
Table 2 presents the laboratory tests to be performed during the study for screening purposes 
and safety and efficacy evaluations, including routine chemistry, hematology (complete blood 
count with automated differential), coagulation, and urinalysis.   
Metabolic 
Given the significant association of cirrhosis with insulin resistance and components of the 
metabolic syndrome (especially fasting plasma glucose and blood pressure) [36], particularly for 
patients with NASH, metabolic parameters will be evaluated in the study including fasting 
plasma glucose, HbA1c, lipid levels (total cholesterol, high density lipoprotein (HDL) cholesterol, 
low density lipoprotein (LDL) cholesterol, triglycerides), and insulin resistance.  Insulin 
resistance will be estimated using a commonly used index based on fasting insulin and glucose 
called the homeostasis model assessment of insulin resistance (HOMA-IR), which provides a 
measure of hepatic insulin resistance [37]. 
Fibrosis Markers 
The Enhanced Liver Fibrosis (ELF) panel is based on 3 serum markers (hyaluronic acid [HA], 
aminoterminal propeptide of type III collagen [P3NP], and tissue inhibitor of matrix 
metalloproteinase 1 [TIMP-1]) and has demonstrated utility in predicting advanced fibrosis in 
patients with chronic liver disease related to NAFLD [38], chronic HCV infection [39], and 
alcoholic liver disease [40].  In addition, a study of 457 patients with chronic liver disease 
followed for a median of 7 years demonstrated that the ELF test predicted clinical liver-related 
outcomes [41]. Ferritin is a component of several scores (based on clinical parameters and lab 
tests) that have demonstrated utility in predicting fibrosis [42]. Lysyl oxidase-like 2 (LOX-L2) is 
an enzyme expressed in the liver that is responsible for crosslinking collagen and consequently 
stabilizing it to degradation.  LOX-L2 activity is an indicator of fibrosis and has recently 
demonstrated utility in predicting clinically significant portal hypertension [43].  


 
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Cirrhosis and Severe Portal Hypertension 
 
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Table 2. 
Laboratory Tests 
Hematology & 
Coagulation 
Chemistry 
Urinalysis 
Metabolic  
Research 
Other 
Hemoglobin 
Hematocrit 
RBC count 
Platelet count 
WBC count 
Neutrophils 
Eosinophils 
Monocytes 
Basophils 
Lymphocytes 
MCV, MCH, 
MCHC, MPV 
Peripheral 
smear1 
 
INR, PT, PTT 
BUN, Creatinine, 
Creatinine 
clearance 
(Cockcroft-Gault), 
Ca, Na, K, Cl, 
Phosphorus, Mg, 
Total CO2 
(Bicarbonate), 
AST2, ALT2, 
Total bilirubin, 
Direct bilirubin 
Alkaline 
phosphatase, 
Uric acid, 
Albumin, 
Total protein, 
Globulin, LDH, 
GGT, Glucose 
 
serum β-HCG and 
urine pregnancy 
test3 
 
DILI 
Confirmation 
(as needed)  
• ALT, AST, 
Total and 
direct 
bilirubin, 
GGT, alkaline 
phosphatase, 
albumin, 
CBC, INR 
pH 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Microscopy4 
 
Protein5 
(quantitative) 
Creatinine5 
(quantitative) 
Hemoglobin A1c  
 
Lipid Panel 
• Total 
cholesterol 
• LDL 
• HDL 
• Triglycerides 
 
Fasting insulin, 
HOMA-IR6 
Fibrosis 
Markers 
ELF Panel 
(Hyaluronic acid,
P3NP, TIMP-1) 
Ferritin 
LOX-L2 
 
Peripheral and 
HVPG 
Biomarkers 
Caspase 3/7 
cCK18 
flCK18 
 
Population PK 
including back-
up 
Etiologic screen7 
• HBsAg 
• Anti-HCV Ab8 
• Ferritin, transferrin 
saturation (calculated from 
iron, TIBC, UIBC) 
• Ceruloplasmin 
• ANA 
• α1-antitrypsin 
 
α–fetoprotein7 
 
Transporter genotyping 
 
DILI Monitoring (as needed) 
First visit after confirmation 
• ALT, AST, Alkaline 
phosphatase, INR, Total 
and direct bilirubin, GGT, 
albumin, CBC 
• HAV IgM, HBsAg, 
Anti-HCV antibody8, HEV 
IgM, CMV IgM 
• EBV panel (VCA-IgM, 
VCA-IgG) 
• Autoimmune hepatitis 
(ANA, SMA, anti-LKM1) 
• Testing for Gilbert’s, as 
needed  
Additional visits (as needed) 
ALT, AST, Alkaline 
phosphatase, INR, Total and 
direct bilirubin, GGT, 
albumin, CBC 
Abbreviations: ANA=antinuclear antibody; anti-LKM1=anti-liver kidney microsomal type 1 antibody; CBC=complete blood count; 
CMV=cytomegalovirus; CO2=carbon dioxide;  EBV=Epstein-Barr virus; HAV = hepatitis A virus; HBsAg= hepatitis B surface 
antigen; HEV=hepatitis E virus; LDH=lactate dehydrogenase; MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular 
hemoglobin concentration; MCV=mean corpuscular volume; MPV=mean platelet volume; PTT=partial thromboplastin time; 
RBC=red blood cell; SMA=smooth muscle antibody; TIBC=total iron binding capacity; UIBC= unsaturated iron binding capacity; 
VCA-IgG=viral capsule antigen immunoglobulin G; VCA-IgM=viral capsule antigen immunoglobulin M 
1 
Lab to complete automatically if necessary 
2 
A second test for ALT and AST is required during Screening at least 2 weeks from the first draw  
3 
For females of reproductive potential 
4 
Only if urine dipstick is positive for blood or protein 
5 
At Screening and Day 1, with subsequent tests as needed (e.g. for evaluation of hepatorenal syndrome) 
6 
Calculated by the central laboratory 
7 
At screening only 
8 
If positive, Hep C confirmation to be completed 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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8.3.1 
Biomarker Assessments 
Peripheral blood samples will be obtained according to the Schedule of Events. The following 
serum biomarkers will be assessed by the central laboratory: caspase 3/7, cCK18/M30, 
flCK18/M65. An aliquot will be stored until the end of the study and then tested for 
microparticles. In addition, effects on biomarkers of mechanism of action and inflammation may 
be measured. 
In addition to collection of peripheral blood samples, 2 blood samples will be collected at the 
time of the HVPG test: a hepatic vein sample, and a paired systemic sample obtained from the 
jugular vein. For the HVPG samples, the central laboratory will test caspase 3/7, cCK18/M30, 
and flCK18/M65. Aliquots from the HVPG samples will be stored until the end of the study and 
then tested for microparticles, coagulation biomarkers, bacterial translocation biomarkers, and 
hepatic vasculature function biomarkers. Samples will be destroyed once all analyses are 
completed.  
Samples should be processed for serum and plasma, divided into the central laboratory-
specified number of aliquots (including back-ups), and frozen at -70 °C or colder.  Samples 
should be shipped on dry ice to the central laboratory. 
8.3.2 
Population Pharmacokinetic (PK) Assessment 
Samples will be obtained according to the Schedule of Events for population pharmacokinetic 
assessment. After processing, samples should be equally divided into 2 aliquots and frozen 
at -70 °C or colder.  Samples should be shipped on dry ice to the central laboratory. One aliquot 
will be forwarded to MicroConstants for analysis, and one will be stored at the central laboratory 
for re-testing if needed. Samples will be destroyed once all analyses are completed. 
8.3.3 
OATP Transporter Genotyping 
The role of genetic variants of OATP1B1 and OATP1B3 transporters on the hepatic uptake of 
emricasan and their effect on the pharmacokinetics and pharmacodynamics of emricasan is 
currently not well understood. Genetic polymorphism(s) can play an important role in the 
pharmacokinetics and pharmacodynamics of many drugs. If the subject provides consent, a 
blood sample will be collected on Study Day 1 to evaluate each subject’s OATP transporter 
genetic variants.  Samples will be shipped to the central laboratory and then to Gentris for 
testing. Samples will be destroyed once all analyses are completed. 
8.3.4 
Blood Volume 
The total blood sampling volume for an individual subject is approximately 231 mL for subjects 
who complete the initial 24-week randomized treatment only and 306 mL for subjects who 
complete the 48-week randomized treatment, as shown in Table 3.  
 


 
Document Code: 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, an Oral Caspase Inhibitor, in 
Subjects with Non-Alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension 
 
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Table 3. 
Blood Volume 
Sample Type 
Sample 
Volume 
(mL) 
Number of Samples Per Study Phase 
24-Week 
Treatment 
48-Week 
Treatment 
Screening 
Treatment 
Follow-Up 
Total 
Volume 
(mL) 
Total 
Volume 
(mL) 
Initial 24 Weeks 
Continued 24 Weeks 
Hematology 
2 
1 
7 
3 
1 
18 
24 
Chemistry 
6 
1 
7 
3 
1 
54 
72 
Coagulation 
3 
1 
7 
3 
1 
27 
36 
Fibrosis markers 
8 
0 
2 
1 
0 
16 
24 
Lipids1 
- 
0 
2 
1 
0 
- 
- 
Insulin 
2 
0 
2 
1 
0 
4 
6 
HbA1c 
2 
0 
2 
1 
0 
4 
6 
Etiologic screen 
10 
1 
0 
0 
0 
10 
10 
α-fetoprotein 
2 
1 
0 
0 
0 
2 
2 
Serum pregnancy test 1, 2 
- 
1 
1 
0 
0 
- 
- 
Population PK 
6 
0 
6 
3 
0 
36 
54 
Biomarkers – peripheral 
blood 
4 
1 
7 
3 
1 
36 
48 
Biomarkers (plasma) – 
HVPG samples (hepatic 
vein, systemic) 
4 
1 
1 
0 
0 
8 
8 
Biomarkers (serum) – 
HVPG samples (hepatic 
vein, systemic) 
4 
1 
1 
0 
0 
8 
8 
OATP transporter 
genotyping 
6 
0 
1 
0 
0 
6 
6 
Second screening liver 
tests 
2 
1 
0 
0 
0 
2 
2 
TOTAL 
231 
306 
1 
Drawn as part of chemistry panel 
2 
For females of reproductive potential only 
Note: 
Additional blood samples may be taken at times specified by the Sponsor or the Investigator (or due to sample/test repeat). 


 
Document Code: 
IDN-6556-14-PRO-1001 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
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8.4 
SPECIFIC STUDY VISIT INFORMATION 
The following sections provide specific details of the assessments to be performed at each 
study visit as noted in the Schedule of Events:  
8.4.1 
Screening Phase (Week -6 to Day 0) 
The following study evaluations will be performed during the course of the Screening phase: 
• 
Signed informed consent 
• 
Eligibility criteria (inclusion and exclusion criteria) 
• 
Medical and surgical history 
• 
Assessment for adverse events, including biliary colic symptoms 
• 
Review of current medications including prescription and nonprescription drugs, 
vitamins, and dietary supplements  
• 
Comprehensive physical examination including vital signs, height, weight 
• 
Assessment of Child-Pugh clinical features  
• 
12-lead ECG 
• 
Screening questionnaires for alcohol dependence: AUDIT, Skinner 
• 
Clinical laboratory evaluations: chemistry, hematology, coagulation, urinalysis, etiologic 
screen, α-fetoprotein, serum pregnancy test (for females of reproductive potential) 
o AST, ALT, and total and direct bilirubin should be measured twice during the 
screening phase (at least 2 weeks apart) 
• 
Blood sample for biomarkers 
• 
Liver and gallbladder ultrasound  
• 
Esophagogastroduodenoscopy 
• 
HVPG, including collection of hepatic vein and systemic blood samples 
• 
Methacetin breath test (at select sites)  
• 
FibroScan® (at select sites) 
 
In general, the HVPG should be performed after the subject meets all other eligibility criteria.  To 
identify subjects more likely to meet the HVPG ≥ 12 mmHg criteria, it is recommended (but not 
required) that subjects have one of the following prior to having the HVPG test: 
1. History or presence of medium or large varices 
2. Evidence of collateral circulation on imaging 
3. History of ascites 
8.4.2 
Double-Blind Phase (Day 1) 
• 
Confirmation of eligibility criteria 
• 
Review concomitant medications and other therapies (vitamins and dietary supplements) 
• 
Assessment for adverse events, including biliary colic symptoms 


 
Document Code: 
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• 
Focused physical examination, vital signs, weight, assessment of Child-Pugh clinical 
features 
• 
Questionnaires: SF-36, Chronic Liver Disease Questionnaire 
• 
Clinical laboratory evaluations (after fasting at least 10 hours): chemistry, hematology, 
coagulation, urinalysis, metabolic parameters (insulin, lipids, HbA1c), fibrosis markers, 
serum and urine pregnancy tests (for females of reproductive potential) 
• 
Blood samples for biomarkers and OATP transporter genotyping 
• 
Study drug dispensation 
 
The study procedures specified for Day 1 should be performed prior to dosing with study drug. 
8.4.3 
Double-Blind Phase (Week 4) 
• 
Review concomitant medications and other therapies (vitamins and dietary supplements) 
• 
Assessment for adverse events, including biliary colic symptoms 
• 
Study drug compliance assessment 
• 
Focused physical examination, vital signs, weight, assessment of Child-Pugh clinical 
features 
• 
12-lead ECG 
• 
Clinical laboratory evaluations: chemistry, hematology, coagulation, urinalysis, urine 
pregnancy test (for females of reproductive potential) 
• 
Blood samples for biomarkers and population PK 
• 
Study drug dispensation 
8.4.4 
Initial 24-Week Double-Blind Phase (Week 8, Week 12, Week 16, Week 20) 
• 
Review concomitant medications and other therapies (vitamins and dietary supplements) 
• 
Assessment for adverse events, including biliary colic symptoms 
• 
Study drug compliance assessment 
• 
Focused physical examination, vital signs, weight, assessment of Child-Pugh clinical 
features 
• 
Questionnaire: AUDIT-C (Week 12 only) 
• 
Clinical laboratory evaluations: chemistry, hematology, coagulation, urinalysis, urine 
pregnancy test (for females of reproductive potential) 
• 
Blood samples for biomarkers and population PK 
• 
Study drug dispensation 
8.4.5 
Initial 24-Week Double-Blind Phase (Week 24) 
• 
Review concomitant medications and other therapies (vitamins and dietary supplements) 
• 
Assessment for adverse events, including biliary colic symptoms 
• 
Study drug compliance assessment  


 
Document Code: 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
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Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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• 
Comprehensive physical examination, vital signs, weight, assessment of Child-Pugh 
clinical features 
• 
12-lead ECG  
• 
Questionnaires: SF-36, Chronic Liver Disease Questionnaire, AUDIT-C 
• 
Clinical laboratory evaluations (after fasting at least 10 hours): chemistry, hematology, 
coagulation, urinalysis, fibrosis markers, metabolic parameters (insulin, lipids, HbA1c), 
urine pregnancy test (for females of reproductive potential) 
• 
Blood samples for biomarkers and population PK 
• 
HVPG, including collection of hepatic vein and systemic blood samples 
• 
Methacetin breath test (at select sites) 
• 
FibroScan® (at select sites) 
• 
Signed informed consent (for subjects who signed consent for the second 24-week 
treatment phase only) 
• 
Study drug dispensation (for subjects who signed consent for the second 24-week 
treatment phase only) 
8.4.6 
Continued 24-Week Double-Blind Phase (Week 32 and Week 40) 
• 
Review concomitant medications and other therapies (vitamins and dietary supplements) 
• 
Assessment for adverse events, including biliary colic symptoms 
• 
Study drug compliance assessment 
• 
Focused physical examination, vital signs, weight, assessment of Child-Pugh clinical 
features 
• 
Clinical laboratory evaluations: chemistry, hematology, coagulation, urinalysis, urine 
pregnancy test (for females of reproductive potential) 
• 
Blood samples for biomarkers and population PK 
• 
Study drug dispensation 
8.4.7 
Continued 24-Week Double-Blind Phase (Week 48) 
• 
Review concomitant medications and other therapies (vitamins and dietary supplements) 
• 
Assessment for adverse events, including biliary colic symptoms 
• 
Study drug compliance assessment  
• 
Comprehensive physical examination, vital signs, weight, assessment of Child-Pugh 
clinical features 
• 
12-lead ECG  
• 
Questionnaires: SF-36, Chronic Liver Disease Questionnaire, AUDIT-C 
• 
Clinical laboratory evaluations (after fasting at least 10 hours): chemistry, hematology, 
coagulation, urinalysis, fibrosis markers, metabolic parameters (insulin, lipids, HbA1c), 
urine pregnancy test (for females of reproductive potential) 
• 
Blood samples for biomarkers and population PK 


 
Document Code: 
IDN-6556-14-PRO-1001 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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• 
Methacetin breath test (at select sites) 
• 
FibroScan® (at select sites) 
8.4.8 
Follow-Up Phase (2 weeks after Week 24 or Week 48) 
Subjects will be seen approximately 2 weeks after Week 24 or Week 48 (either at Week 26 or 
Week 50) or early termination.  Follow-up procedures will consist of the following: 
• 
Review concomitant medications and other therapies (vitamins and dietary supplements) 
• 
Assessment for adverse events, including biliary colic symptoms 
• 
Focused physical examination, vital signs, weight, assessment of Child-Pugh clinical 
features 
• 
12-lead ECG 
• 
Clinical laboratory evaluations: chemistry, hematology, coagulation, urinalysis, urine 
pregnancy test (for females of reproductive potential) 
• 
Blood sample for biomarkers 
8.5 
PRIOR AND CONCOMITANT MEDICATIONS 
Medications to treat complications of portal hypertension (e.g. non-selective beta blockers, 
nitrates, diuretics, lactulose, rifaximin, etc.) as well as statins should be maintained at a stable 
dose during the study if possible but may be adjusted if clinically indicated. Any changes to the 
dose or use of these medications should be entered on the case report form.  Subjects should 
not take any potentially hepatotoxic drugs, herbal preparations, or supplements during the 
Screening period and throughout the study.   
Subjects should avoid taking new herbal preparations and supplements during the study that 
are chronically administered unless medically indicated. All prescription and ‘over-the-counter’ 
medications, including herbal preparations and supplements, taken by the subject at Screening 
and through to study follow-up will be recorded on the Concomitant Medications case report 
form. The generic drug name, indication, 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. All subjects will be questioned about concomitant medication 
usage at each study visit. No other investigational medication should be taken during the study 
except for methacetin as specified in the procedures for the methacetin breath test.  
8.6 
OTHER PRECAUTIONS AND RESTRICTIONS DURING THE STUDY 
Subjects should be contacted prior to each study visit to remind them to take their study drug 
the night before and the morning of the study visit and to remind them to follow directions for 
fasting status for the relevant study visits. Subjects should be fasting (except for morning 
medications including study drug and NSBB which can be taken with water) at least 10 hours 
before study visits at Day 1, Week 24, and Week 48.   


 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
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Cirrhosis and Severe Portal Hypertension 
 
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8.7 
SUBJECT AND STUDY TERMINATION 
8.7.1 
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 or for any reason.  Reasons for removing a subject 
from the study may include: 
• 
subject withdrawal of consent; 
• 
Investigator decision (Investigator feels it is in the subject’s best interest to terminate 
participation) 
• 
the subject develops an AE necessitating withdrawal 
• 
subject non-compliance with study drug and/or study procedures 
• 
subject lost to follow-up 
• 
major protocol violation 
• 
death 
• 
the study is terminated by the Sponsor 
• 
other reasons (e.g. subject requires an unacceptable concomitant medication, or 
pregnancy in a female study subject) 
 
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.  Efforts and means 
used to contact the subject should be recorded in the source documents. 
All subjects who discontinue the study because of AEs will be followed up at suitable intervals in 
order to evaluate the course of the AE and to ensure the reversibility or stabilization of the 
abnormality. 
All subjects who prematurely discontinue the study, regardless of the cause, should have an 
Early Termination visit scheduled as soon as possible after the discontinuation date.  For 
subjects who prematurely discontinue before Week 24, assessments scheduled at the Week 24 
visit should be performed, and for subjects who prematurely discontinue after Week 24, 
assessments scheduled at the Week 48 visit should be performed (see Appendix I, Schedule of 
Events).  Study drug should be continued (unless the subject is discontinuing treatment due to 
an adverse event) until the Early Termination visit is performed. A follow-up visit should then be 
scheduled to occur approximately 2 weeks following the Early Termination visit. 
8.7.2 
Withdrawal from Study Drug Treatment but Not from Study Participation 
All efforts should be made to encourage subjects to continue participation in the study including 
undergoing all protocol-specified assessments even if they discontinue study drug treatment, 
unless they withdraw consent for participating in the study, are lost to follow-up, undergo liver 
transplantation, or the investigator deems that it is not in the best interest of the subject to 
continue participating in the study or becomes unblinded to study drug assignment.  Subjects 
who meet criteria for withdrawal of study drug due to progression to Child-Pugh C or who 
develop a new or worsening decompensation event should continue participation in the study, 


 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
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Cirrhosis and Severe Portal Hypertension 
 
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even if withdrawn from study drug.  Discontinuation of study drug should be documented in the 
database. 
8.7.3 
Termination of the Study 
Participation in the study by an Investigator may be terminated prematurely with sufficient notice 
in advance by the Investigator for any reason as per the terms of the contract with the Sponsor.  
The reason should be communicated in writing to the Sponsor. 
The Sponsor 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 
the Sponsor, in a time frame that is compatible with the subjects’ well-being. 


 
Document Code: 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
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Cirrhosis and Severe Portal Hypertension 
 
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9 
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 (emricasan [IDN-6556] and matching placebo) will be manufactured 
according to Good Manufacturing Practice (GMP). 
9.1 
EMRICASAN AND PLACEBO SUPPLIES 
The double-blind supplies of emricasan will be in bottles containing 60 capsules of emricasan 
(5, 25, or 50 mg).  Placebo will also be supplied in bottles containing 60 capsules. Each bottle 
will contain sufficient supply to dose subjects for four weeks. 
At the investigational site, emricasan and placebo supplies must be stored in a secure, lockable 
area. Excursions that are outside of the 15-30 °C (59 to 86 °F) range will need to be reported.  
Subjects should be instructed to store their study drug bottles with the caps tightly closed in a 
safe area at room temperature (15-30 °C [59 to 86 °F]).  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. 
Emricasan 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 drugs.   
All study drug bottles will carry a uniquely numbered label that will also contain the drug 
description and conditions for storage.   
9.3 
INVESTIGATIONAL MEDICINAL PRODUCT DISPENSING AND 
ACCOUNTABILITY 
All study drugs must be dispensed in the original containers provided by either the Sponsor or 
the drug manufacturer in order to assure stability of the drugs.  At each visit, subjects must be 
instructed to return 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 each bottle should be counted at each visit to assess subject compliance with 
study drug administration.  Also, except at the last dispensing visit, every bottle containing 
capsules should be re-dispensed to subjects, and subjects should be instructed to finish all 
capsules in each bottle before opening a new bottle. At the end of the study, all unused 
capsules and all dispensed bottles (used, unused, or empty) must be returned by every subject 
for accounting. 
9.4 
INVESTIGATIONAL MEDICINAL PRODUCT ADMINISTRATION 
Subjects will be instructed to take emricasan or placebo twice daily about the same time in the 
morning and evening without regard for food.  All study procedures specified at Day 1 should be 
performed prior to administration of the first dose of the investigational medicinal product. 


 
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10 
WARNINGS AND PRECAUTIONS 
10.1 
TERATOGENICITY AND FERTILITY 
Teratology studies conducted in rats and rabbits demonstrated that emricasan was 
teratogenic.  There have been no studies with this compound in pregnant women, but based on 
the preclinical findings, emricasan has the potential to be teratogenic (refer to the Investigator’s 
Brochure for further details).  Therefore, emricasan should not be used in pregnant women or 
women planning to become pregnant.   
Emricasan has also been found to reduce male and female fertility in rats.  There have been no 
studies on the effect of emricasan on fertility in men and women, but based on the preclinical 
findings, emricasan has the potential to reduce fertility in humans. 
10.2 
CONTRACEPTION FOR FEMALE SUBJECTS OF REPRODUCTIVE 
POTENTIAL 
For the purposes of this study, females of reproductive potential are defined as any female who 
has experienced menarche and does not meet one of the following conditions: 
• 
Postmenopausal 
• 
Permanently sterile (i.e,. due to hysterectomy, bilateral salpingectomy or bilateral 
oophorectomy) 
o Tubal ligation is not considered to be a permanent sterilization method 
 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause.  A high follicle stimulating hormone [44] level in the postmenopausal range may be used 
to confirm a post-menopausal state in women not using hormonal contraception or hormone 
replacement therapy.  In the absence of 12 months of amenorrhea, a single FSH measurement 
in the post-menopausal range is not sufficient for a subject to be considered post-menopausal. 
Females of reproductive potential must undergo or adhere to the following procedures during 
the screening, treatment, and follow-up periods of the study to help ensure that they are not 
pregnant prior to starting treatment with study medication as well as to minimize exposure of the 
fetus to study medication should an unintentional pregnancy occur: 
• 
Serum pregnancy test at first screening visit (up to 6 weeks prior to Day 1) 
• 
Serum and urine pregnancy test at Day 1 
o Urine pregnancy test result should be confirmed negative before first dose of study 
drug is administered 
o A serum pregnancy test may detect a very early pregnancy approximately 1 week 
before a urine pregnancy test is positive. Subjects should be contacted as soon as 
possible if the serum pregnancy test is positive.   
• 
Urine pregnancy test at all study visits after Day 1 
• 
Urine pregnancy test should be obtained in the event of a missed period by >7 days OR 
if unusual menstrual bleeding occurs 
• 
Use effective contraception for at least 4 weeks prior to Day 1 and continuing for at least 
4 weeks after the last dose of study drug 


 
Document Code: 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
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Cirrhosis and Severe Portal Hypertension 
 
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Females of reproductive potential are strongly encouraged to use at least one of the following 
highly effective methods of contraception [45]: 
• 
Complete sexual abstinence during the entire duration of the study including the follow-
up period 
• 
Intrauterine device or intrauterine hormone-releasing system, which has been shown to 
have a failure rate <1% within the first year of use under “typical use” conditions  
• 
Bilateral tubal ligation or occlusion 
• 
Partner who had vasectomy at least 3 months prior to Screening (only if the partner is 
the sole sexual partner)  
 
If one of the above highly effective methods of contraception is not used, females of 
reproductive potential must use 2 forms of contraception (1 from each of the following 
2 categories): 
For subjects with compensated cirrhosis: 
1. combined (estrogen and progestogen containing) hormonal contraceptive (oral, transdermal, 
or vaginal) or oral/injectable/implantable progestogen-only hormonal contraception AND  
2. barrier method such as a) male or female condom (with or without spermicide); b) cap, 
diaphragm, or sponge with spermicide 
 
For subjects with decompensated cirrhosis: 
1. oral/injectable/implantable progestogen-only hormonal contraception AND  
2. barrier method such as a) male or female condom (with or without spermicide); b) cap, 
diaphragm, or sponge with spermicide 
 
Notes: 
a) Combined oral contraceptives are considered medical eligibility criteria Category 4 (“A 
condition that represents an unacceptable health risk…”) in patients with 
decompensated cirrhosis [46].  Combined oral contraceptives containing estrogens may 
therefore not be used in decompensated study subjects. 
b) Progestogen-only hormonal contraception, including levonorgestrel-releasing IUDs, is 
considered to be Category 3 (“A condition for which the theoretical or proven risks 
usually outweigh the advantages…”) when used in patients with decompensated 
cirrhosis [46].  If possible, a single highly effective method of contraception should be 
used in decompensated subjects.  However, the risk/benefit of progestogen 
contraception may be more favorable than usual in a decompensated subject treated 
with emricasan who cannot or will not use a single highly effective method of 
contraception, since emricasan is a potentially teratogenic drug. 
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 


 
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double-blind phase of the study, the treatment arm may be unblinded (after discussion between 
the Investigator and the Medical Monitor).  If pregnancy occurs in a female subject after the 
double-blind phase of the study but within 4 weeks of taking study drug, the Investigator should 
inform the Sponsor immediately. 
If the female subject chooses to terminate the pregnancy, the Investigator should document the 
termination and contact the 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 Investigator 
should 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. 
10.3 
CONTRACEPTION FOR MALE SUBJECTS WITH FEMALE PARTNERS OF 
REPRODUCTIVE POTENTIAL 
All males, even those who are permanently sterile through bilateral orchiectomy, should use a 
latex or synthetic condom during any sexual contact while on study drug treatment and for 
4 weeks after the last dose of study medication. 
If pregnancy occurs in the female partner of a male subject during the double-blind phase of the 
study or within 4 weeks of taking study drug, the Investigator should inform the Sponsor 
immediately.  The progress of the pregnancy in a male subject’s partner should be followed until 
the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, additional follow-up information may be 
requested for the infant.  Follow-up will be performed to the extent permitted. 
10.4 
USE OF ESTROGENS IN SUBJECTS WITH DECOMPENSATED CIRRHOSIS 
Estrogens have the potential to cause drug-induced liver injury (DILI) in patients with 
decompensated cirrhosis, and many estrogen product labels carry warnings or precautions for 
that patient population.  There are alternatives to estrogen-based contraceptives that are 
acceptable in decompensated cirrhosis; therefore estrogen-containing contraceptives should not 
be used for decompensated subjects in this study. 
Due to the risk of drug-induced liver injury, it is strongly recommended that estrogens not be 
used as hormone replacement therapy for subjects in this trial.  However, there may not be 
good alternatives to estrogens for the treatment of severe post-menopausal (estrogen-
withdrawal) symptoms.  If the Investigator and subject agree that the potential risk of liver injury 
is outweighed by other benefits in that particular subject, estrogens may be cautiously used.  In 
that case, the lowest estrogen dose that results in adequate control of the most severe 
symptoms should be used. 


 
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11 
DOCUMENTATION OF DATA 
11.1 
SOURCE DOCUMENTATION 
Source data is all information in original records and certified copies of original records of 
clinical findings, observations and other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source documents are any original document, data 
and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, 
subject diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, any electronic medical record).  The clinical site study staff members 
will record the source data in their medical charts, 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 guidelines.  
This includes an inspection by the Sponsor and/or health authority representatives at any time.  
The Investigator will agree to the inspection of study-related records by health authority 
representatives 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 a validated Electronic Data 
Capture [47] database 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.  
11.4 
CODING OF ADVERSE EVENTS, DRUGS, AND DISEASES 
After data entry, the AEs will be coded according to the MedDRA (Medical Dictionary for 
Regulatory Activities) dictionary.  Concomitant medications will be coded according to the World 
Health Organization Drug Reference List. 
11.5 
STUDY LANGUAGE AND 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 Ethics Committees) is not English, appropriate arrangements will be made to 
have translations of the documents in the local language, as necessary.  In any case, a qualified 
translator will need to provide documentation to attest to the fact that the foreign language 
document is an accurate reflection of the respective English language document.  Any subject 
facing documents including the subject informed consent will also need to be translated and 
back translated by a qualified translator. 
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. 


 
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12 
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.  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 variables will be recorded for the safety evaluation: 
• 
Adverse events 
• 
Vital signs, weight, physical examination 
• 
Laboratory tests (e.g. chemistry, hematology, coagulation, urinalysis) 
• 
ECGs 
• 
Liver and gallbladder events and ultrasound 
 
12.2.2 
Efficacy Variables 
The following variables will be recorded for the efficacy evaluation: 
Primary 
• 
HVPG mean change from baseline at Week 24 
Secondary 
• 
HVPG response (based on 20% reduction from baseline) at Week 24 
• 
Caspase 3/7 and ALT at Weeks 24 and 48 
Exploratory 
• 
HVPG response (based on 10% reduction from baseline) at Week 24 
• 
MELD and Child-Pugh scores, regression, and progression at Weeks 24 and 48 
• 
cCK18/M30, flCK18/M65, AST, total bilirubin, INR, and albumin at Weeks 24 and 48 
• 
Fibrosis markers at Weeks 24 and 48 
• 
Health-related quality of life, as measured by SF-36 and CLDQ, at Weeks 24 and 48 
• 
Clinical outcomes (development of decompensation or worsening of decompensation) at 
Weeks 24 and 48 
• 
Liver metabolic function assessed by methacetin breath test (at select sites) at 
Weeks 24 and 48 
• 
Liver stiffness by transient elastography (at select sites) at Weeks 24 and 48 


 
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12.3 
ANALYSIS POPULATIONS  
The Enrolled population will consist of all subjects who signed an informed consent form. 
The Full Analysis Set (FAS) consists of all randomized subjects who have received at least 
one dose of study drug.  The analyses based on the FAS will be conducted on an 
intention-to-treat principle (i.e., all subjects will be analyzed with the group to which they were 
randomly assigned).   
The Per Protocol Set (PPS) consists of all subjects in the FAS who do not have any significant 
protocol deviations. 
The Safety Analysis Set consists of all subjects randomized and have received at least 
one dose of study drug on an “as treated” basis (i.e., all subjects will be analyzed by the 
treatment they have taken).   
All efficacy analyses will be based on the FAS, with the primary analysis also being conducted 
using the PPS.  All safety analyses will be based on the Safety Analysis Set.  
12.4 
SAMPLE SIZE 
It is planned to enroll subjects into this study in order to randomize 240 subjects (60 subjects 
per group) to receive 1 of 3 treatment groups of emricasan or placebo.  Subjects will be 
randomly assigned to received either emricasan 50 mg BID, emricasan 25 mg BID, emricasan 
5 mg BID, or matching placebo in a 1:1:1:1 ratio. Assuming a 20% attrition rate, it is expected 
that approximately 192 subjects (48 subjects per group) will have a Week 24 HVPG 
assessment. 
This sample size will provide 81% power to detect a statistically significant difference between 
at least 1 emricasan treatment group and placebo in the mean change from baseline in HVPG. 
This calculation assumes a mean difference between an active treatment group and placebo of 
3 mmHg and a sample standard deviation of 4.5 mm Hg.  This calculation also applied a 
Dunnett’s adjustment of comparing 3 active treatment groups with placebo.  
The assumptions for the shape of the dose response was based on modelling of cCK18/M30 
data in HCV patients where the estimated ED50 was 1 mg total daily dose.  Based on data in 
the literature and discussion with key experts in the field, a clinically meaningful difference in the 
change from baseline in HVPG is approximately 2.5 - 3 mmHg, depending on the baseline 
value.  Subjects in Study IDN-6556-11 (open-label pilot study evaluating the effect of emricasan 
on HVPG for 28 days) with a baseline HVPG ≥12mmHg had a sample standard deviation of 
4.05 mmHg. 
12.5 
STATISTICAL ANALYSES 
12.5.1 
General 
All parameters will be analyzed using descriptive methods. Continuous parameters will be 
summarized using standard summary statistics as appropriate (n, mean, standard deviation, 
median, minimum, maximum).  Summary statistics for categorical variables will include number 
of observations and percentages.   


 
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Analyses will be done using the validated statistical software of SAS® (version 9.3 or later). 
12.5.2 
Safety Analysis 
Safety will be assessed by treatment compliance, treatment exposure, adverse events, 
gallbladder monitoring, potential DILI, laboratory tests, vital signs, physical examinations, ECGs, 
and prior/concomitant medications. All safety assessments will be summarized descriptively.  
AEs will be tabulated by system organ class and preferred term. Summary of AEs by severity 
and relationship to treatment will also be provided. 
Change from baseline in laboratory parameters and vital signs will also be summarized 
descriptively. Abnormal laboratory and ECG findings will be tabulated against appropriate cut-off 
points using frequency counts and percentages.  Any prior and concomitant medications will be 
described. 
12.5.3 
Efficacy Analysis 
Primary Endpoint:  Mean Change from Baseline at Week 24 in HVPG 
The primary endpoint for this study is the change from baseline (CFB) at Week 24 in HVPG.  
The change from baseline will be calculated as HVPG at Week 24 minus HVPG at baseline 
(HVPGW24-HVPGBL). Hence, a negative value will represent a decrease in HVPG at Week 24. 
Absolute and CFB values for the primary endpoint will be summarized descriptively by treatment 
group. Comparisons of the mean CFB in HVPG at Week 24 between each emricasan treatment 
group and placebo will be analyzed using a fixed effects Analysis of Covariance (ANCOVA) 
model using the FAS.  This model will include the treatment group, compensated vs. 
decompensated status, and NSBB use as fixed effects with baseline HVPG as a covariate. 
Least-square adjusted means (LSMeans) for each treatment group will be reported, along with 
the estimated difference in LSMeans and corresponding 95% confidence intervals (CIs).  A 
Dunnett’s test will be applied to adjust for the multiple comparisons of each emricasan treatment 
group with placebo. 
Missing data for the primary endpoint will be imputed using a multiple imputation technique as 
described in Section 14 of the SAP. Sensitivity analyses of the primary endpoint will be 
conducted using the following: 
• 
Repeat the primary analysis using observed cases 
• 
Repeat the primary analysis using the PPS 
• 
Tipping point analysis assessing impact of missing data 
Secondary Endpoints 
All secondary analyses will be conducted using the FAS.  No multiplicity adjustments will be 
applied within or across analyses of secondary endpoints. 
The dose response of emricasan on portal pressure as assess by HVPG will be characterized 
using a plot of the CFB at Week 24 in HVPG across treatment group.  Treatment groups will be 
ordered as placebo, emricasan 5 mg BID, emricasan 25 mg BID, and emricasan 50 mg BID. 


 
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Absolute and CFB at each visit in Caspase 3/7 and ALT will be summarized descriptively by 
treatment group and visit.  Treatment comparisons for CFB at Weeks 24 and 48 in Caspase 3/7 
and ALT will be conducted using a similar ANCOVA model as described for the primary 
analysis, using the appropriate baseline value. 
If the CFB at each visit in caspase 3/7 and ALT is deemed to be transformed, the geometric 
mean will also be provided.  In this scenario, the relative change from baseline at Weeks 24 and 
48 will be calculated for caspase 3/7 and ALT by back transforming the change from baseline in 
log-transformed data. 
Exploratory Endpoints 
All exploratory endpoints will be summarized descriptively by treatment group and visit.  
Treatment comparisons for continuous endpoints will be conducted at Weeks 24 and 48 in a 
similar ANCOVA model as the primary analysis, using the appropriate baseline value. 
Treatment comparisons for response, regression, and progression endpoints will be analyzed 
using a logistic regression model using treatment group, compensated vs. decompensated 
status, and NSBB use as fixed effects and the appropriate baseline value as a covariate. 
Adjusted odds and risk ratios for each comparison of emricasan with placebo will be provided 
along with the corresponding 95% CI. 
Safety Endpoints 
All safety endpoints will be summarized descriptively by treatment group. 
12.5.4 
Timing of Analyses 
After the last subject completes their Week 24 visit, all data for all subjects across all visits will 
be cleaned, locked, and considered as the main analysis for this study.  This Week 24 analysis 
will include all primary, secondary, and exploratory endpoint analyses.  Although the Sponsor 
will be unblinded for the Week 24 analysis, the investigative sites will remain blinded throughout 
the study.  The purpose of the Week 24 analysis is internal decision making. 
The final analysis of the study (i.e., Week 48 analysis) will be conducted after all subjects have 
completed all study visits up to and including the follow-up visit.  All study data across all 
subjects and visits will be cleaned and locked for this final analysis. 
12.6 
HANDLING OF MISSING DATA 
Missing data for the primary endpoint will be imputed using a multiple imputation analysis, 
assuming that the missing data pattern is missing at random. The pattern and amount of 
missing data pattern will be assessed to determine the number of imputed datasets to be 
derived for the multiple imputation analysis.  The SAS multiple imputation procedure will be 
used to generate multiply imputed datasets (roughly the percent attrition seen in the study), with 
each multiply imputed dataset being analyzed as described for the primary endpoint analysis.  
The results for each imputed dataset analysis will then be summarized using the SAS 
MIANALYZE procedure with the appropriate statistics to be reported.  
Imputed values will be dependent on examination of treatment group and potential risk factors, 
such as age, gender, compensated/decompensated status, use of NSBB, baseline MELD 


 
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score, and baseline C-P classification.  A monotone regression method will be applied to impute 
missing CFB at Week 24 HVPG values.  
An LOCF method will also be applied to the primary endpoint in the cases where an HVPG 
measurement is provided prior to Week 24. 
No imputation methods will be applied for secondary or exploratory efficacy and all safety 
endpoints. 
12.7 
DATA MONITORING COMMITTEE (DMC) 
An independent DMC will review unblinded safety data from this study approximately every 
three months.  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 its 
responsibilities and procedures, will be implemented prior to any data review.  These 
documents (charter, open and closed meeting minutes, etc.) will be considered part of the study 
documentation, but not 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.  
All Investigators, responsible IRB/IECs, 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 ICF will be revised, as appropriate. 


 
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13 
SAFETY MONITORING AND REPORTING 
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. 
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 ICH and 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 study 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. 
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. 


 
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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. 
Hospitalizations that fulfill the serious criterion are generally greater than 24 hours in duration. 
The Investigator should use appropriate medical judgment to determine if a hospitalization less 
than 24 hours in duration should be considered serious. 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
serious, even if the subject is hospitalized, as long as the study site documents all of the 
following: 
• 
The condition that required the prescheduled or elective procedure or routinely 
scheduled treatment was present before and did not worsen or progress in the opinion of 
the Investigator between the subject’s consent to participate in the study and the 
scheduled procedure or treatment 
• 
The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission 
 
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 Brochure (or reference safety information) or is not listed at the specificity or 
severity that has been observed. 
The adverse events and their time-adjusted incidence rates in Table 4 are considered 
anticipated events in patients with cirrhosis and portal hypertension (the study protocol 
population) and will not be individually reported in an expedited fashion by the Sponsor. The 


 
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Investigator is still obligated to report all SAEs whether considered anticipated or not. The 
severity of these events may be up to severe. 
Table 4. 
Time-Adjusted Incidence Rate for Anticipated Events in Patient Population 
Preferred Term 
Time Adjusted 
Incidence Rate  
(per patient-year) 
Preferred Term 
Time Adjusted 
Incidence Rate  
(per patient-year) 
Ascites 
0.121 
Lobar pneumonia 
0.016 
Hepatic encephalopathy 
0.121 
Pleural effusion 
0.016 
Hepatic failure 
0.067 
Bacteremia 
0.012 
Cellulitis 
0.052 
Biliary cirrhosis primary 
0.012 
Hepatic cirrhosis 
0.052 
Dehydration 
0.012 
Renal failure acute 
0.052 
Dyspnea 
0.012 
Hyperkalemia 
0.032 
Gastroenteritis 
0.012 
Hyponatremia 
0.032 
Hydrothorax 
0.012 
Pneumonia 
0.032 
Mental impairment 
0.012 
Urinary tract infection 
0.032 
Respiratory failure 
0.012 
Hepatorenal syndrome 
0.030 
Septic shock 
0.012 
Oesophageal varices 
haemorrhage 
0.030 
Dizziness 
0.008 
Hepatic neoplasm 
malignant 
0.028 
Hypoglycemia 
0.008 
Peritonitis bacterial 
0.028 
Liver transplant rejection 
0.008 
Clostridium colitis 
0.020 
Metabolic 
encephalopathy 
0.008 
Hyperglycemia 
0.020 
Syncope 
0.008 
Renal failure 
0.020 
Hypotension 
0.004 
 
There are no anticipated AEs with methacetin. 
The Sponsor will determine if a SUSAR or SAE meets the criteria of being reportable as a 7-day 
or a 15-day safety report.  
13.2.1 
Pre-Treatment-Emergent Adverse Events 
The Sponsor considers adverse events that occur between the time that 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. The start date (and time if necessary) of any 
adverse events that occur between signing of the informed consent form and the first dose of 
study drug should be recorded to allow correct classification of these adverse events as 
pre-treatment-emergent. 


 
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13.2.2 
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 blood urine nitrogen 
[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) should not be recorded 
as an adverse event.  However, isolated laboratory abnormalities should be reported as adverse 
events if they are considered adverse by the Investigator.  Criteria for an adverse laboratory 
abnormality in this study include: 
1. A laboratory abnormality that leads to a dose-limiting toxicity (e.g., an abnormality that 
results in study drug dose reduction, suspension or discontinuation), or 
2. A laboratory abnormality that results in any therapeutic intervention (i.e., concomitant 
medication or therapy), or 
3. Other laboratory abnormality judged by the Investigator to be of any particular clinical 
concern (e.g., significant fall in hemoglobin not requiring transfusion). 
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 determine whether each adverse event is related to study drug 
(emricasan or placebo) and whether each adverse event is related to methacetin 
(investigational drug for the methacetin breath test).  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 cessation or reduction in study drug dose; and/or it 
reappears or worsens when the study drug is administered. 


 
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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. 
For the purposes of regulatory reporting, AEs assessed as definitely, probably, and possibly 
related are considered related to 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. AEs 
(except SAEs, see Section 13.8) should be collected for a subject starting from signing of the 
informed consent until the subject’s last study visit (follow-up visit, early termination, or last 
regularly scheduled study visit). 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 always 
group signs and symptoms into a single term that constitutes a single unifying diagnosis if 
possible. 
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. 
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 or designee in the EDC of the 
study and at the contact listed below.  


 
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Contact 
SynteractHCR Safety 
Safety Fax: 
+1-760-268-6500 
safetyfax@synteracthcr.com 
OR 
if not available 
Mason Yamashita, MD 
VP, Pharmacovigilance 
Office: 
+1-858 376 2617 
Mobile: 
+1-619 306 2125 
myamashita@conatuspharma.com 
 
All serious adverse events must be reported to the Sponsor or designee within 24 hours after 
the Investigator recognizes/classifies the event as a serious adverse event. The following 
information should be provided at the time of the initial report:  subject number, a description of 
the event, the Investigator judgment of study drug causality, at least one criterion classifying the 
event as serious, and the name and title of the reporting individual.   
After the initial report, as necessary, the Investigator will provide follow-up information on a 
serious adverse event to the Sponsor or designee within 24 hours after he/she receives that 
information. Examples of follow-up information include hospital records, case reports, autopsy 
reports, and other pertinent documents. 
The Sponsor will consider the Investigator’s assessment of the causality; however, since the 
Sponsor will assess the overall safety of the study medication, the Sponsor’s 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 the Sponsor. 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 the Sponsor. 
13.7 
FOLLOW-UP OF ADVERSE EVENTS 
All SAEs must be followed until the event resolves, the condition stabilizes, the event is 
otherwise explained, or the subject is lost to follow-up.  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. 
All non-serious adverse events must be followed until the final study visit, at which point the 
status of the event (e.g. ongoing, stabilized, resolved) should be documented on the case report 
form, with date of resolution if the event is resolved.  


 
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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 
the Sponsor if such an event is attributable to study drug. The notification to the Sponsor of a 
post-study serious adverse event by the Investigator should occur within 24 hours of becoming 
aware of the serious adverse event. 
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 the Sponsor to her/his 
local IRB/IEC.  However, in some countries, the notification of SUSARs/SAEs to the IRB/IEC 
will be the responsibility of the Sponsor or Sponsor’s designee.  Documentation of the 
submissions to IRB/IEC must be retained in the appropriate study file(s). 
13.10 
HEALTH AUTHORITY SAFETY REPORTS 
The Sponsor 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.  The Sponsor 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 Sponsor clinical studies.  Safety reports must be submitted to the 
appropriate IRB/IEC as soon as possible.  Documentation of the submission to the IRB/IEC 
must be retained for each safety report.  As instructed by the Sponsor or its designee, safety 
reports should be retained in the appropriate study files or with the Investigator’s Brochure.  


 
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14 
ADMINISTRATIVE ASPECTS 
14.1 
INVESTIGATOR RESPONSIBILITIES FOR GENERAL STUDY CONDUCT 
It is the Investigator’s responsibility to ensure that: 
• 
The protocol, subject information sheet, 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 the Sponsor. 
• 
A copy of the IRB/IEC approval letter for the protocol, any amendments, the subject 
information sheet, the informed consent form, the trial participation card (if applicable) 
and any advertisements are supplied to the Sponsor 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 
the Sponsor. 
• 
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 the Sponsor (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.   
• 
Receipt of administrative amendments provided for information only are acknowledged.   
• 
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 the Sponsor is obtained prior to initiating changes to 
the study protocol. 
14.2 
PROTOCOL DEVIATIONS 
Unless there is a safety concern, there should be no deviations or violations of the study 
protocol.  In the event of a safety concern, the Investigator or designee must document and 
explain the reason for any deviation from the approved protocol.  The Investigator may 
implement a deviation from, or a change to, the protocol to eliminate an immediate hazard to 
study participants without prior IRB/IEC approval.  Immediately after the implemented deviation 
or change, the Investigator must submit a report explaining the reasons for the protocol violation 
or deviation to the IRB/IEC, Conatus, and to the regulatory authorities, if required. 


 
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14.3 
SUBJECT INFORMATION AND CONSENT 
Prior to participation in any study-specific procedures, the subject must sign an IRB/IEC-
approved written Informed Consent Form in his/her native language (note: all references to 
“subject” in this section refers to the study subject or his/her legally acceptable representative).  
The approved written informed consent must adhere to all applicable laws in regards to the 
safety and confidentiality of the subjects.  To obtain and document informed consent, the 
Investigator should comply with applicable regulations and adhere to ICH GCP standards and 
the ethical principles in the Declaration of Helsinki (October 2008). 
The language in the written information about the study should be as non-technical as practical 
and should be understandable to the subject.  Before informed consent is obtained, the 
Investigator should provide the subject ample time and opportunity to inquire about the study 
and to decide whether or not to participate. 
All questions about the study should be answered to the satisfaction of the subject.  The written 
Informed Consent Form should be signed and personally dated by the subject and the person 
who conducted the informed consent discussion, with any additional signatures obtained as 
required by applicable local regulations and IRB/IEC requirements.  Each subject will be 
informed that participation is voluntary and that he/she can withdraw from the study at any time.  
All subjects will receive a copy of the signed and dated Informed Consent Form.  
14.4 
SUBJECT CONFIDENTIALITY AND DATA PROTECTION 
The processing of personal data in pursuit of this study will be limited to those data that are 
reasonably necessary to investigate the utility of the study medications used in this study.  
These data will be processed with adequate precautions to ensure confidentiality according to 
local laws.  
The Sponsor ensures that the personal data are:  
• 
collected for a specified and legitimate purpose 
• 
processed fairly and lawfully 
• 
accurate and up to date 
 
Explicit consent for the processing of personal data will be obtained prospectively from the 
participating subject.  The Sponsor and/or designees whose responsibilities require access to 
personal data agree to keep the identity of study subjects confidential.  This confidentiality will 
be maintained throughout the complete data processing.  Study subjects will be entitled to 
request confirmation of the existence of personal data held by the Sponsor and will have the 
right to rectify erroneous or inaccurate data prior to database lock. 
14.5 
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 the Sponsor.  The Sponsor must be notified promptly in 
writing of any reference value changes during the course of the study. 


 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
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This protocol will analyze pharmacokinetics of emricasan and exploratory serum biomarkers of 
caspase 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. 
14.6 
REQUIRED DOCUMENTS 
The Investigator and affiliated institution shall maintain the study documents and records as 
specified in “Essential Documents for the Conduct of a Clinical Trial” (ICH E6 Section 8), and as 
required by the applicable regulatory requirement(s).  This includes, but is not limited to the 
protocol, Case Report Forms (CRF)s, AE reports, subject source data (original records or 
certified copies), correspondence with health authorities and IRB/IEC, consent forms, 
Investigator’s curriculum vitae, monitor visit logs, laboratory reference ranges and laboratory 
certification or quality control procedures and laboratory director curriculum vitae.  Subject 
source data must be maintained as original records or copies certified after verification as being 
accurate and complete.  The Investigator and affiliated institution should take measures to 
prevent accidental or premature destruction of documents. 
14.7 
STUDY MONITORING 
The Sponsor or designee will monitor this clinical study through study site visits scheduled to 
check the adequacy of site staff and facilities and to ensure adherence to the protocol, study 
procedures, and applicable regulations.  The site monitor will also assess proper CRF 
completion and source document retention.  The Investigator and study site staff are expected 
to provide adequate space for monitoring visits and to allocate sufficient time to permit adequate 
review of the study’s progress.  The Investigator will permit study-related monitoring, audits, 
IRB/IEC review and regulatory inspection(s), providing direct access to source data/documents 
including electronic medical records and study related facilities (e.g., pharmacy, diagnostic 
laboratories). 
14.8 
ELECTRONIC DATA RECORD AND CASE REPORT FORMS 
Where referenced in this protocol, CRFs refer to electronic CRFs, as defined for the study.  A 
CRF must be completed for each subject who has given informed consent.  In the case of 
screening failure, the following data will be entered into the CRF at a minimum: visit date, 
demography and reason for screen failure.  All entries into the CRF are ultimately the 
responsibility of the Investigator before adding his/her signature. 
The CRF must be completed at the time of, or shortly after the subject's visit, with the exception 
of results of tests performed outside the Investigator's office, so that they always reflect the 
latest observations of the subjects participating in the study.  If certain information is Not Done, 
Not Available or Not Applicable, the Investigator must record this according to the CRF 
completion instructions. 
The CRF and source documents must be made available to the site monitor.  During monitoring 
visits, the site monitor will review the CRF entries and evaluate them for completeness and 
consistency.  The CRF entries will also be compared with the source documents to ensure that 
there are no discrepancies for critical data.  All entries, corrections, and alterations are to be 
made by the responsible Investigator or his/her designee.  The site monitor may query the data, 


 
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but cannot edit CRF entries recorded by the site designee.  A copy of each subject’s CRF will be 
maintained by the Investigator. 
14.9 
DRUG ACCOUNTABILITY  
The investigational drug is to be prescribed only by the Principal 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 drug.  Documentation of the disposition of the drug 
should consist of a dispensing record including the identification of the person to whom the drug 
is dispensed, the quantity and the date of dispensing, and any unused 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 drugs is not feasible, 
the Sponsor will supply instructions as to how the supplies may be destroyed.  Drug supply 
destruction must be clearly documented. Any investigational drug return will be documented at 
the Sponsor.  The Investigator will also provide a written explanation for any missing study 
drugs. 
14.10 
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.  The Sponsor 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, the Sponsor 
should be prospectively notified.  The study records must be transferred to an acceptable 
designee, such as another Investigator, another institution, or to the Sponsor. 
14.11 
FINANCIAL DISCLOSURE 
The Investigator’s disclosable financial interests must be obtained prior to initiation of the study 
site, at completion of the study at the investigational site, and 1 year following study completion.  
It is the investigator’s responsibility to promptly update this information if any relevant changes 
occur during the above described period.  Any disclosable financial interests will be recorded on 
the Investigator Financial Disclosure Form.  
Any Investigator(s) added as investigational staff to the form FDA 1572 must complete the 
Investigator Financial Disclosure Form at the beginning of his/her participation in the study.   


 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
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14.12 
INVESTIGATOR’S FINAL REPORT 
Each Investigator will submit, shortly after completion of study participation, a final, written 
report to the Sponsor. 
14.13 
PUBLICATION POLICY 
The Sponsor 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 Sponsor studies should fairly recognize the activities of those that have made a significant 
contribution to the study [48]. 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, the Sponsor has developed publication guidelines for 
clinical studies that are appropriate for this study.  Key issues include: 
• 
Responsibility: Each Principal 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. 
• 
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 by all authors before submission for 
publication.  
• 
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 and 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 the Sponsor 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 the Vice 
President, Clinical Development. 
b. The Investigator shall provide to the Sponsor 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 the Sponsor 
to make changes within the periods mentioned in (b) above. 


 
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d. The Investigator shall remove confidential information requested by the Sponsor 
before finalizing the publication. 
e. Upon written request from the Sponsor, 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, the 
Sponsor 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 the Sponsor 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. 
• 
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. 
14.14 
CONFIDENTIALITY 
The Sponsor, 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. 
All information concerning this study and the Sponsor’s development of emricasan that is not 
previously published is considered confidential information.  This confidential information shall 
remain the sole property of the Sponsor.  It shall not be disclosed to others without written 
consent of the Sponsor 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 the Sponsor 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 obliged to furnish the Sponsor with 
complete test results and all data compiled in this study. 


 
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18. Serste, T., et al., Deleterious effects of beta-blockers on survival in patients with cirrhosis 
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19. Guicciardi, M.E. and G.J. Gores, Apoptosis as a mechanism for liver disease progression. 
Semin Liver Dis, 2010. 30(4): p. 402-10. 
20. Eguchi, A., et al., Emricasan, a pan caspase inhibitor, improves survival and portal 
hypertension in a murine model of long-term common bile-duct ligation. Hepatology, 2015. 
62(S1): p. 952A. 
21. Lemoinne, S., et al., The emerging roles of microvesicles in liver diseases. Nat Rev 
Gastroenterol Hepatol, 2014. 11(6): p. 350-61. 
22. Spada, A., P. Contreras, and G. Burgess. Inhibition of caspase activity with emricasan in 
HCV patients: Potential implications for chronic dosing and long term safety. in AASLD. 
2012. Hepatol. 
23. Spada, A., et al. Physiologically normal levels of apoptosis in healthy volunteers are not 
reduced by the pan caspase inhibitor emricasan. in AASLD. 2013. Hepatol. 
24. Shiffman, M.L., et al., Clinical trial: the efficacy and safety of oral PF-03491390, a 
pancaspase inhibitor - a randomized placebo-controlled study in patients with chronic 
hepatitis C. Aliment Pharmacol Ther, 2010. 31(9): p. 969-78. 
25. Albillos, A. and G. Garcia-Tsao, Classification of cirrhosis: the clinical use of HVPG 
measurements. Dis Markers, 2011. 31(3): p. 121-8. 
26. Iwakiri, Y., Pathophysiology of portal hypertension. Clin Liver Dis, 2014. 18(2): p. 281-91. 
27. Iwakiri, Y. and R.J. Groszmann, The hyperdynamic circulation of chronic liver diseases: from 
the patient to the molecule. Hepatology, 2006. 43(2 Suppl 1): p. S121-31. 
28. Bolognesi, M., et al., Splanchnic vasodilation and hyperdynamic circulatory syndrome in 
cirrhosis. World J Gastroenterol, 2014. 20(10): p. 2555-63. 
29. Vorobioff, J.D. and R.J. Groszmann, Prevention of portal hypertension: from variceal 
development to clinical decompensation. Hepatology, 2015. 61(1): p. 375-81. 
30. Qamar, A.A., et al., Lack of effect of non-selective beta-blockers on the hepatic vein 
pressure gradient (HVPG) in patients with mild portal hypertension: A tale of two studies. 
Hepatology, 2010. 52(4). 
31. Villanueva, C., et al., Development of hyperdynamic circulation and response to beta-
blockers in compensated cirrhosis with portal hypertension. Hepatology, 2015. 
32. Bush, K., et al., The AUDIT alcohol consumption questions (AUDIT-C): an effective brief 
screening test for problem drinking. Ambulatory Care Quality Improvement Project 
(ACQUIP). Alcohol Use Disorders Identification Test. Arch Intern Med, 1998. 158(16): p. 
1789-95. 
33. David, K., et al., Quality of life in adults with nonalcoholic fatty liver disease: baseline data 
from the nonalcoholic steatohepatitis clinical research network. Hepatology, 2009. 49(6): p. 
1904-12. 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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34. Younossi, Z.M., et al., Development of a disease specific questionnaire to measure health 
related quality of life in patients with chronic liver disease. Gut, 1999. 45(2): p. 295-300. 
35. Dan, A.A., et al., Health-related quality of life in patients with non-alcoholic fatty liver 
disease. Aliment Pharmacol Ther, 2007. 26(6): p. 815-20. 
36. Scaglione, S., et al., The Epidemiology of Cirrhosis in the United States: A Population-based 
Study. J Clin Gastroenterol, 2015. 49(8): p. 690-6. 
37. Muniyappa, R., et al., Current approaches for assessing insulin sensitivity and resistance in 
vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab, 2008. 
294(1): p. E15-26. 
38. Guha, I.N., et al., Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: 
Validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology, 
2008. 47(2): p. 455-60. 
39. Parkes, J., et al., Enhanced Liver Fibrosis (ELF) test accurately identifies liver fibrosis in 
patients with chronic hepatitis C. J Viral Hepat, 2011. 18(1): p. 23-31. 
40. Parkes, J., et al., Systematic review of the diagnostic performance of serum markers of liver 
fibrosis in alcoholic liver disease. Comp Hepatol, 2012. 11(1): p. 5. 
41. Parkes, J., et al., Enhanced liver fibrosis test can predict clinical outcomes in patients with 
chronic liver disease. Gut, 2010. 59(9): p. 1245-51. 
42. Machado, M.V. and H. Cortez-Pinto, Non-invasive diagnosis of non-alcoholic fatty liver 
disease. A critical appraisal. J Hepatol, 2013. 58(5): p. 1007-19. 
43. Sanyal, A.J., et al., Clinical and Histologic Correlates of the Hepatic Venous Pressure 
Gradient (HVPG) in Patients with Compensated Cirrhosis due to Nonalcoholic 
Steatohepatitis (NASH). Hepatology, 2015. 62(1 (Suppl)): p. 577A. 
44. Ghosh, S., et al., Moderate exercise attenuates caspase-3 activity, oxidative stress, and 
inhibits progression of diabetic renal disease in db/db mice. Am J Physiol Renal Physiol, 
2009. 296(4): p. F700-8. 
45. Trussell, J., Contraceptive failure in the United States. Contraception, 2011. 83(5): p. 397-
404. 
46. CDC-U.S. Selected Practice Recommendations for Contraceptive Use, 2016. Morbidity and 
Mortality Weekly Report, 2016. 65(4): p. 1-66. 
47. Pais, R., et al., A systematic review of follow-up biopsies reveals disease progression in 
patients with non-alcoholic fatty liver. J Hepatol, 2013. 59(3): p. 550-6. 
48. Davidoff, F., et al., Sponsorship, authorship, and accountability. N Engl J Med, 2001. 
345(11): p. 825-6; discussion 826-7. 
49. Alberti, K.G., et al., Harmonizing the metabolic syndrome: a joint interim statement of the 
International Diabetes Federation Task Force on Epidemiology and Prevention; National 
Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; 
International Atherosclerosis Society; and International Association for the Study of Obesity. 
Circulation, 2009. 120(16): p. 1640-5. 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, an Oral Caspase Inhibitor, in 
Subjects with Non-Alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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Appendix I. 
Schedule of Events 
 
Screening 
Wk -6 to Day 0 
Double-blind Treatment Phase 
Follow-up 
Initial 24 weeks 
Continued 24 weeks 
Day 1 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
Wk 20 
Wk 24 
Wk 32 
Wk 40 
Wk 48 
2 wks after 
Wk 24 or 48  
±5 
Days 
±7 
Days 
±7 
Days 
±7 
Days 
±7 
Days 
±7 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±7  
Days 
Study Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
X 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs, weight, Child-Pugh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationA  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12 Lead ECG 
X 
 
X 
 
 
 
 
X 
 
 
X 
X 
AUDIT, Skinner questionnaires 
X 
 
 
 
 
 
 
 
 
 
 
 
AUDIT-C questionnaire 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Liver/gallbladder ultrasoundB 
X 
 
 
 
 
 
 
 
 
 
 
 
EsophagogastroduodenoscopyC 
X 
 
 
 
 
 
 
 
 
 
 
 
SF-36 and CLDQ 
 
X 
 
 
 
 
 
X 
 
 
X 
 
HVPG (with blood samples) 
X 
 
 
 
 
 
 
X 
 
 
 
 
Adverse event assessmentD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensation  
 
X 
X 
X 
X 
X 
X 
XE 
X 
X 
 
 
Compliance assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Methacetin breath testF 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Transient elastographyF  
X 
 
 
 
 
 
 
X 
 
 
X 
 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, an Oral Caspase Inhibitor, in 
Subjects with Non-Alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
83 of 90 
 
Screening 
Wk -6 to Day 0 
Double-blind Treatment Phase 
Follow-up 
Initial 24 weeks 
Continued 24 weeks 
Day 1 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
Wk 20 
Wk 24 
Wk 32 
Wk 40 
Wk 48 
2 wks after 
Wk 24 or 48  
±5 
Days 
±7 
Days 
±7 
Days 
±7 
Days 
±7 
Days 
±7 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±7  
Days 
Laboratory Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry 
XG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
XH 
XH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
α-fetoprotein, etiologic screen 
X 
 
 
 
 
 
 
 
 
 
 
 
MetabolicI  
 
X 
 
 
 
 
 
X 
 
 
X 
 
Fibrosis markers 
 
X 
 
 
 
 
 
X 
 
 
X 
 
Transporter genotyping 
 
X 
 
 
 
 
 
 
 
 
 
 
Population PK 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Biomarkers (peripheral blood) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy testJ 
X 
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testJ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
A 
Comprehensive physical examination at Screening, Week 24, Week 48. Focused physical examination at all other visits. Height at Screening only. 
B 
If subject had a liver and gallbladder ultrasound within three months of Screening and a report with the required information is available, the prior ultrasound 
can be used for the study.  
C 
If subject had a prior esophagogastroduodenoscopy (EGD) according to Baveno VI recommendations and a report with the required information is available, 
the prior EGD can be used for the study. 
D 
Includes assessment for biliary colic symptoms and qualifying clinical outcome events. 
E 
For subjects who sign consent for the second 24-week treatment phase only. 
F 
At select sites. 
G 
AST, ALT, and total and direct bilirubin measured twice during screening at least 2 weeks apart.  
H 
Including quantitative protein and creatinine  
I 
After fasting at least 10 hours.  
J 
For females of reproductive potential. 
 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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Appendix II. Measurement of Liver Metabolic Function with the Methacetin Breath Test 
The 13C-methacetin breath test (MBT) is a noninvasive tool to assess liver microsomal capacity 
to metabolize the nonradioactive 13C-labeled Methacetin. The Breath Test System consists of 
the BreathID® MCS device and a test kit containing a breath collection nasal cannula and a 
nonradioactive isotope 13C-methacetin solution. The BreathID MCS device measures and 
computes the 13CO2/12CO2 ratio in the subject’s exhaled breath in real time. 
Subject will be asked to sit in a chair and the nasal cannula (a small tube) will be placed beside 
their nostrils. Attached to the nasal cannula will be the BreathID MCS device. The BreathID 
MCS device will be activated for approximately 10 minutes and it will collect the subject’s carbon 
dioxide while breathing normally. This process can take up to a maximum of 25 minutes if the 
device needs to self-calibrate. 
One cup of a solution of a 75mg Methacetin pre-dissolved in water will be administered to the 
subject.  Methacetin is exclusively broken up in the liver and turns into carbon dioxide and 
acetaminophen (Tylenol®). The amount of carbon dioxide is measured by the BreathID MCS 
device, and will indicate the liver’s metabolic capacity to metabolize 13C-Methacetin. 
Subjects will be asked to remain sitting in a chair with the nasal cannula in their nose breathing 
in a normal fashion for the next 60 minutes. Then the nasal cannula will be removed and 
subjects may leave the testing room. 
The full breath test procedure could take up to 1.5 hours. 
The actual MBT measure that will be used is the cPDR30, which is the cumulative percentage 
dose recovery of the metabolized 13C-methacetin 30 minutes after ingestion of the test 
substrate. It is obtained using the following steps: 
1. All delta over baseline (DOB) measures with corresponding time-point (Tn) will be noted on 
the CRF. Each DOB will be plotted by the BreathID MCS device using the following formula:  
DOB = 13CO2/12CO2 @Tn - 13CO2/12CO2 @T0 
 
Where T0 is the baseline sample time (0) and Tn is the time of the post ingestion sample in 
minutes. 
 
2. The DOBs will be transformed into percentage dose recovery rates (PDR) at a specific time 
point (n) by using the following formula: 
PDRn=0.01817853 × DOBn × w0.5378  × h0.3963 
 
While: w = weight (in kg), h = height (in cm) 
 
3. The following formula will be used to obtain cPDR30: 
𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐30 = 
𝑇𝑇1
60 ∙𝑃𝑃𝑃𝑃𝑃𝑃1
2
+ ෍
𝑇𝑇𝑛𝑛−𝑇𝑇𝑛𝑛−1
60
∙(𝑃𝑃𝑃𝑃𝑃𝑃𝑛𝑛− 𝑃𝑃𝑃𝑃𝑃𝑃𝑛𝑛−1)
2
𝑛𝑛
𝑖𝑖=2
+ 𝑇𝑇𝑛𝑛−𝑇𝑇𝑛𝑛−1
60
∙𝑃𝑃𝑃𝑃𝑃𝑃𝑛𝑛−1 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
85 of 90 
The company developing the breath test, Exalenz Bioscience, will obtain access to the subject’s 
study data including all the breath test parameters as well as the subject’s demographic, 
imaging, and laboratory data. Exalenz Bioscience will be using these data in order to develop 
and validate diagnostic and/or prognostic, and/or monitoring algorithms for this study population. 
Exalenz Bioscience may segregate a portion of the subject data for use of approval of the 
breath test and its algorithm(s). 
The following precautions should be observed prior to the MBT: 
• 
Subject should be fasting, including all oral morning medications (except for beta 
blockers and study drug [emricasan or placebo]), for at least 8 hours prior to the MBT  
• 
Subject should not smoke on the day of the breath test prior to the MBT 
• 
Subject should not take any of the following drugs within 48 hours prior to the MBT: 
acyclovir, allopurinol, carbamazepine, cimetidine, ciprofloxacin, daidzein (herbal), 
disulfiram, echinacea, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, 
montelukast, norfloxacin, phenylpropanolamine, phenytoin, propafenone, rifampin, 
terbinafine, ticlopidine, thiabendazole, verapamil, zileuton or any medication that might 
interfere with methacetin metabolism or might affect CYP1A2 (cytochrome P450 1A2)  
• 
Subject should not take amiodarone within 30 days prior to the MBT 
• 
Subject should not take paracetamol (acetaminophen) related medications within the 
24 hours prior to the MBT 
• 
Subjects should not perform the MBT if allergic or hypersensitive to methacetin or its 
metabolites (paracetamol, acetaminophen) 
• 
Subject should not consume any alcohol or caffeine within 24 hours prior to the MBT 
• 
Subject should not have general anesthesia or sedation within 24 hours prior to the MBT 
• 
Subjects on beta-blockers or statins should be on stable dose at least 30 days prior to 
the MBT 
 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
86 of 90 
Appendix III. 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 fibrosis. 
Figure 5. 
FibroScan® Probe Placement in Relation to Anatomy of a Subject 
 
Source: 
Reproduced from Ziol et al 2005 
 
There are three images displayed on the monitor: 
1. A-mode image 
2. Time movement image 
3. 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. 
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. 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
87 of 90 
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. For each subject, the following parameters should be recorded: 
a. The median liver stiffness value kPa 
b. The inter-quartile (IQR) range kPa 
c. Success rate (%) 
8. To obtain a reliable and representative evaluation of the stiffness of the liver, the following 
criteria should be met:  
a. 10 valid measurements should be acquired 
b. Success rate >60% 
c. IQR/median <30% 
If any of these criteria are not met, the test should be repeated. 
Additional Recommendations 
The following recommendations are being provided in order to improve standardization of the 
FibroScan® procedure. Please implement these recommendations to obtain consistent and 
reproducible measurements. 
1. The subject should be NPO for 4 hours prior to the procedure 
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 
patient yielding an improved result with a low IQR. 
3. The measurement should be taken during expiration.  
4. Investigators should use the appropriate probe (normal or XL) for a subject according to 
their level of adiposity and use the same probe consistently for all measurements for that 
subject during the course of the study.  
 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
88 of 90 
Appendix IV. Diabetes Mellitus Definition and Metabolic Syndrome Criteria  
The diagnosis of diabetes mellitus is based on criteria established by the American Diabetes 
Association: 
• 
HbA1c ≥6.5% (using a certified method standardized to the Diabetes Control and 
Complications Trial assay) OR 
• 
Fasting plasma glucose ≥126 mg/dL (7 mmol/L) (confirmed by repeat testing unless 
there is unequivocal hyperglycemia) OR 
• 
2-hr plasma glucose (≥200 mg/dL [11.1 mmol/L) after 75-gram oral glucose tolerance 
test OR 
• 
Random plasma glucose ≥200 mg/dL (11.1 mmol/L) with symptoms of hyperglycemia or 
hyperglycemic crisis 
 
The metabolic syndrome is a cluster of risk factor for cardiovascular disease and type 2 
diabetes mellitus including elevated blood pressure, dyslipidemia (elevated triglycerides and low 
HDL cholesterol), elevated fasting glucose, and central obesity.  Various diagnostic criteria have 
been proposed by different scientific organizations in the past, with the main difference 
concerning the measure for central obesity.  In 2009, the International Diabetes Federation Task 
Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American 
Heart Association; World Heart Federation; International Atherosclerosis Society; and 
International Association for the Study of Obesity issued a joint statement proposing a 
harmonized definition of the metabolic syndrome [49].  The criteria for diagnosis are 
summarized in Table 1 and Table 2. 


 
Document Code: 
IDN-6556-14-PRO-1001 
Version: 
9.0 
Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
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Source: Alberti et al. Circulation, 2009. 120(16): p. 1640-5. 


 
Document Code: 
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Version: 
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Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Emricasan, 
an Oral Caspase Inhibitor, in Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Cirrhosis and Severe Portal Hypertension 
 
CONFIDENTIAL 
 
90 of 90 
 
Source: Alberti et al. Circulation, 2009. 120(16): p. 1640-5. 
 


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SAP_001.pdf: 
Conatus Pharmaceuticals 
IDN-6556 (Emricasan) 
IDN-6556-14 Statistical Analysis Plan, Version 2.0 
 
CONFIDENTIAL 
1 
 
 
 
CONFIDENTIAL 
IDN-6556 (Emricasan) 
IDN-6556-14 STATISTICAL ANALYSIS PLAN (VERSION 1) 
  
Protocol Title A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial 
of Emricasan, an Oral Caspase Inhibitor, in Subjects with Non-
Alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal 
Hypertension 
  
Sponsor Conatus Pharmaceuticals Inc. 
16745 W. Bernardo Drive, Suite 200 
San Diego, CA 92127 
Statistician James M Robinson, M.S. 
Senior Director, Biostatistics & Data Management 
Version 2.0 10 JUL 2018 
  
  
  
 
 


Conatus Pharmaceuticals 
IDN-6556 (Emricasan) 
IDN-6556-14 Statistical Analysis Plan, Version 2.0 
 
CONFIDENTIAL 
2 
TABLE OF CONTENTS 
1 
INTRODUCTION ...............................................................................................................7 
2 
STUDY OBJECTIVES ........................................................................................................8 
2.1 
Primary Objective ..........................................................................................................8 
2.2 
Secondary Objectives.....................................................................................................8 
2.3 
Exploratory Objectives ..................................................................................................8 
3 
STUDY DETAILS...............................................................................................................9 
3.1 
Study Design ..................................................................................................................9 
3.2 
Study Population ..........................................................................................................10 
3.3 
Randomization .............................................................................................................10 
3.4 
Blinding........................................................................................................................10 
3.5 
Analysis Windows .......................................................................................................11 
4 
PLANNED SAMPLE SIZE DETERMINATION.............................................................12 
5 
STUDY ENDPOINTS .......................................................................................................13 
5.1 
Primary Efficacy Endpoint ..........................................................................................13 
5.2 
Secondary Efficacy Endpoints .....................................................................................13 
5.2.1 HVPG Response 20% Reduction...........................................................................13 
5.2.2 Caspase 3/7 ............................................................................................................13 
5.2.3 ALT ........................................................................................................................13 
5.3 
Exploratory Endpoints .................................................................................................14 
5.3.1 HVPG Response 10% Reduction...........................................................................14 
5.3.2 Model for End-Stage Liver Disease Score, Regression, and Progression .............14 
5.3.3 Child-Pugh Score, Regression, and Progression....................................................15 
5.3.4 Biochemical and Functional Biomarkers ...............................................................16 
5.3.5 Fibrosis Markers ....................................................................................................16 
5.3.6 CLDQ .....................................................................................................................16 
5.3.7 SF-36 Quality of Life .............................................................................................16 
5.3.8 Clinical Outcome Events (Decompensation) .........................................................16 
5.3.9 Liver Function by Methacetin Breath Test ............................................................17 
5.3.10 Liver Stiffness by Transient Elastography (using FibroScan®) .............................18 
5.4 
Compliance, Exposure, and Safety Endpoints .............................................................18 
5.4.1 Treatment Compliance ...........................................................................................18 
5.4.2 Extent of Exposure .................................................................................................18 
5.4.3 Adverse Events ......................................................................................................18 
5.4.4 Gallbladder Events and Ultrasound .......................................................................19 
5.4.5 Liver Monitoring ....................................................................................................19 
5.4.6 Laboratory Measurements .....................................................................................20 
5.4.7 Vital Signs and Weight ..........................................................................................20 


Conatus Pharmaceuticals 
IDN-6556 (Emricasan) 
IDN-6556-14 Statistical Analysis Plan, Version 2.0 
 
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5.4.8 Electrocardiograms ................................................................................................20 
5.4.9 Medications ............................................................................................................21 
5.4.10 Physical Examination.............................................................................................21 
5.4.11 Alcohol Assessments .............................................................................................21 
6 
ANALYSIS POPULATIONS ...........................................................................................23 
7 
GENERAL STATISTICAL CONSIDERATIONS ...........................................................24 
8 
SUMMARY OF STUDY POPULATION DATA ............................................................25 
8.1 
Subject Disposition ......................................................................................................25 
8.2 
Protocol Deviations ......................................................................................................25 
8.3 
Demographics, Height, and Weight .............................................................................25 
8.4 
Baseline Characteristics ...............................................................................................25 
8.5 
Medical History ...........................................................................................................26 
8.6 
Alcohol scales ..............................................................................................................26 
9 
EFFICACY ANALYSES ..................................................................................................27 
9.1 
Primary Efficacy Analysis ...........................................................................................27 
9.2 
Secondary Efficacy Analyses ......................................................................................27 
9.2.1 Secondary Efficacy Analysis: HVPG Response 20% Reduction ..........................27 
9.2.2 Secondary Efficacy Analysis: Caspase 3/7 ............................................................27 
9.2.3 Secondary Efficacy Analysis: ALT .......................................................................28 
9.3 
Exploratory Efficacy Analyses ....................................................................................28 
9.3.1 Exploratory Efficacy Analysis: HVPG Response 10% Reduction ........................28 
9.3.2 Exploratory Efficacy Analysis: MELD Score, Regression, and Progression ........28 
9.3.3 Exploratory Efficacy Analysis: C-P Score and Response .....................................28 
9.3.4 Exploratory Efficacy Analysis: Biochemical, Fibrosis, and Functional 
Biomarkers .............................................................................................................29 
9.3.5 Exploratory Efficacy Analysis: CLDQ and SF-36 ................................................29 
9.3.6 Exploratory Efficacy Analysis: Clinical Outcome Events (Decompensation) ......29 
9.3.7 Exploratory Efficacy Analysis: Liver Metabolic Function (Methacetin Breath 
Test) .......................................................................................................................29 
9.3.8 Exploratory Efficacy Analysis: Liver Stiffness .....................................................29 
9.4 
Examination of Subgroups for Efficacy Endpoints .....................................................29 
10 
POPULATION PHARMACOKINETICS (PK) ................................................................31 
11 
SAFETY ANALYSES.......................................................................................................32 
11.1 
Dosing and Extent of Exposure ...................................................................................32 
11.2 
Adverse Events ............................................................................................................32 
11.3 
Gallbladder Events and Ultrasound .............................................................................33 
11.4 
Liver monitoring ..........................................................................................................33 
11.5 
Laboratory Measurements ...........................................................................................33 
11.6 
Vital Signs and weight .................................................................................................34 


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11.7 
Electrocardiograms ......................................................................................................34 
11.8 
Medications ..................................................................................................................34 
11.9 
Physical ExAMination .................................................................................................34 
11.10 AUDIT-C .....................................................................................................................34 
12 
HANDLING OF MISSING DATA ...................................................................................35 
13 
DATA MONITORING COMMITTEE .............................................................................36 
14 
SUMMARY OF CHANGES TO PLANNED PROTOCOL ANALYSIS ........................37 
14.1 
Changes fROm Protocol to SAP v1.0 ..........................................................................37 
14.2 
Changes from SAP V1.0 to sap v2.0 ...........................................................................37 
15 
REFERENCES ..................................................................................................................38 
 
LIST OF TABLES 
Table 1. 
Analysis Visit Windows ....................................................................................... 11 
Table 2. 
Child-Pugh Score by Parameter ............................................................................ 15 
Table 3. 
Child-Pugh Classification ..................................................................................... 15 
Table 4. 
Clinical Outcome Events ...................................................................................... 17 
 
 
 
 


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ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical Classification 
AUDIT 
Alcohol Use Disorders Identification Test 
BID 
bis in die, twice daily 
BMI 
Body Mass Index 
CFB 
Change from Baseline 
CI 
Confidence Interval 
CLDQ 
Chronic Liver Disease Questionnaire 
C-P 
Child-Pugh 
cPDR30 
Cumulative Percentage Dose Recovery of 13C-methacetin 30 min after ingestion of test substrate 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
eDISH 
Evaluation of Drug-Induced Serious Hepatotoxicity 
E0 
Basal study drug effect 
ED50 
Median effective dose 
ELF 
Enhanced Liver Fibrosis 
Emax 
Maximum study drug effect 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
HVPG 
Hepatic Venous Pressure Gradient 
ICF 
Informed Consent Form 
IWRS 
Interactive Web Randomization System 
LSMean 
Least-Square Mean 
MBT 
13C-methacetin breath test 
MCS 
SF-36 mental-component summary score 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End-stage Liver Disease 
MI 
Multiple Imputation 
Na 
Sodium 
NASH 
Non-alcoholic steatohepatitis 
NSBB 
Non-selective beta-blockers 
PCS 
SF-26 physical-component summary score 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PPS 
Per-protocol set 
QTcB 
Bazett’s QT correction 


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QTcF 
Fridericia’s QT correction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SF-36 
Short form 36 questionnaire 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
ULN 
Upper Limit of Normal range 
WHODRL 
World Health Organization Drug Reference List 


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1 
INTRODUCTION 
IDN-6556-14 Protocol describes the collection and analysis of clinical study data to evaluate the 
use of IDN-6556 (emricasan), an oral caspase inhibitor, in subjects with non-alcoholic 
steatohepatitis (NASH) cirrhosis and severe portal hypertension. 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 study is to assess whether emricasan compared to placebo leads to 
a mean decrease in hepatic venous pressure gradient (HVPG) at Week 24 in subjects with NASH 
cirrhosis and severe portal hypertension. 
2.2 
SECONDARY OBJECTIVES 
Secondary objectives of this study are: 
 To assess the safety and tolerability of emricasan  
 To evaluate the dose response of emricasan on portal pressure as assessed by HVPG at 
Week 24 
 To assess whether emricasan compared to placebo improves HVPG response at Week 24 
using a 20% reduction from baseline response definition 
 To assess whether emricasan compared to placebo decreases mechanism specific 
(caspase 3/7) and non-specific (alanine aminotransferase [ALT]) biomarkers at Weeks 24 
and 48 
 
2.3 
EXPLORATORY OBJECTIVES 
Exploratory objectives of this study, as defined by the study protocol, are: 
 To assess whether emricasan compared to placebo improves HVPG response at Week 24 
using response criteria of 10% reduction from baseline response definition 
 To assess whether emricasan compared to placebo improves liver function and prognosis 
at Weeks 24 and 48 as assessed by model for end-stage liver disease (MELD) and 
Child-Pugh (C-P) scores (change in score, progression and regression)  
 To assess whether emricasan compared to placebo improves biochemical and functional 
biomarkers (cCK18/M30, flCK18/M65, aspartate aminotransferase (AST), total bilirubin, 
international normalized ratio (INR), and albumin) at Weeks 24 and 48 
 To assess whether emricasan compared to placebo improves fibrosis markers at 
Weeks 24 and 48 
 To assess whether emricasan compared to placebo improves health-related quality of life 
at Weeks 24 and 48  
 To assess whether emricasan compared to placebo decreases development of 
decompensation or worsening of decompensation at Weeks 24 and 48 
 To assess whether emricasan compared to placebo improves liver metabolic function at 
Weeks 24 and 48 as assessed by methacetin breath test (at select sites) 
 To assess whether emricasan compared to placebo improves liver stiffness at Weeks 24 
and 48 as assessed by transient elastography (FibroScan®) (at select sites) 


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3 
STUDY DETAILS 
3.1 
STUDY DESIGN 
This is a multicenter, double-blind, randomized, placebo-controlled, dose-response study to 
evaluate the safety and efficacy of emricasan in improving portal hypertension in subjects with 
NASH cirrhosis and severe portal hypertension (defined as HVPG ≥12 mmHg). Subjects can 
have compensated (at least 60% of subjects but no more than 75%) or decompensated cirrhosis 
with no more than 1 prior significant decompensating event and must be currently clinically 
stable on stable standard therapy (see Inclusion/Exclusion criteria). Randomization will be 
stratified by compensated vs. decompensated status at baseline as well as use of non-selective 
beta-blockers (NSBB) or not. Subjects who are otherwise eligible will undergo the HVPG 
procedure as the last qualifying procedure prior to Day 1. 
The study treatment duration will be up to 48 weeks, including an initial 24-week randomized 
treatment phase with follow-up HVPG at Week 24 (primary endpoint) and an additional 24-week 
treatment phase (continuing the same study drug treatment as initially randomized). Subjects 
completing the initial 24-week randomized treatment phase will be re-consented for the 
additional 24-week treatment phase. HVPG measurements will be performed at screening and 
Week 24, with additional placebo controlled safety follow-up and exploratory efficacy 
assessments through Week 48. Subjects will complete a final follow-up visit approximately 
2 weeks after the end of treatment (i.e., at Week 26 if completing the initial 24-week randomized 
treatment only, or at Week 50 if completing the 48week treatment).  
Subjects with baseline HVPG ≥12 mmHg may experience progression of cirrhosis during the 
48-week study. Given that the primary endpoint for this study is HVPG rather than a clinical 
event (or clinical composite), subjects who have a decompensating event or worsened 
decompensation during the study will not be required to withdraw and can remain in the study 
unless the investigator feels the subject is not stable or the subject requires a transjugular 
intrahepatic portal shunt or other portosystemic bypass procedure, which would confound the 
HVPG assessment. Subjects who progress to Child-Pugh class C will be discontinued from study 
drug but are expected to remain in the study and complete all planned study visits. All subjects 
who wish to discontinue study drug treatment should remain in the study and complete all 
planned study visits, in order to minimize missing data and protect the integrity of the study 
results. Subjects who withdraw consent for participating in the study should discontinue study 
visits. Subjects for whom the investigator deems that it is not in the best interest of the subject to 
continue participating in the study may also discontinue study visits. 
Subjects will be randomized in a 1:1:1:1 ratio to emricasan 50 mg BID, emricasan 25 mg BID, 
emricasan 5 mg BID or matching placebo BID. For each subject, the study will consist of: 
 Screening period of up to 6 weeks  
 Double-blind treatment period of 24 weeks, single-blind after Week 24 and up to 
Week 48 (i.e., Investigative site staff, subjects, and third-party vendors will remain 
blinded) 
 A follow-up visit 2 weeks after the Week 24 or Week 48 (or early termination) visit  
 
The duration of each subject’s participation is intended to be approximately 32 or 56 weeks. 


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The schedule of events is provided in IDN-6556-14 Protocol, Appendix I. 
There will be two analyses conducted for this study, a primary analysis and a final analysis.  The 
primary analysis to be conducted after all randomized subjects have either discontinued prior to 
week 24 or completed the Week 24 planned study visit.  This primary analysis will be considered 
as a database freeze and will include all data collected at the time of the database freeze (i.e., will 
include data collected after the Week 24 study visit).  The final analysis will include all subjects 
and all completed study visits.  The clinical study report will be written after the final analysis is 
conducted.  
3.2 
STUDY POPULATION 
The study population is subjects with NASH cirrhosis and severe portal hypertension (defined as 
HVPG ≥12 mmHg). Subjects can have compensated (at least 60% of subjects but no more than 
75%) or decompensated cirrhosis with no more than 1 prior significant decompensating event 
and must be currently clinically stable on stable standard therapy (see Inclusion/Exclusion 
criteria). 
3.3 
RANDOMIZATION 
Subjects will be randomized in a 1:1:1:1 ratio to emricasan 50 mg BID, emricasan 25 mg BID, 
emricasan 5 mg BID or matching placebo BID.  The assignment to emricasan 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. 
The assignment of randomization number and treatment assignment will be centrally coordinated 
through the study’s Interactive Web Randomization System (IWRS).  Randomization numbers 
will be assigned by the IWRS. 
The randomization will be stratified by 2 factors: 
 Compensated vs. decompensated status at baseline 
 Use of non-selective beta-blockers (NSBB)   
3.4 
BLINDING 
This clinical trial is a double-blind study. The sponsor will be unblinded after the completion of 
the Week 24 study visit with sites and subjects remaining blinded until the completion of the 
final study visit.  Information on individual treatment assignments will not be allowed outside of 
the sponsor until the final analysis conducted after all subjects complete their final visit (i.e., 
when the last active subject has either discontinued the study or completed their Week 50 study 
visit).  
Investigators will be able to unblind subjects through the IWRS when it is medically imperative 
to know whether a subject is receiving emricasan or placebo, such as in the event of an adverse 
event (AE) that the Investigator feels cannot be adequately treated without knowing the identity 
of the study drug.  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 treatment assignment.  Investigators should make arrangements 
to ensure that access to the secure internet site (i.e., individual user name and password) is 


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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 subjects with potential suspected 
unexpected serious adverse reactions (SUSARs) for the purpose of 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 a 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 
ANALYSIS WINDOWS 
Although study visits are designated on the electronic case report forms (eCRFs), data from all 
visits (i.e., scheduled and unscheduled) will be classified into analysis visit windows for 
purposes of analysis. Target dates for each subject’s scheduled visit throughout the study will be 
derived based on their first dose date (i.e., Day 1). Each study visit date will then be classified 
into the analysis visit windows as listed in Table 1. The priority within an analysis window is 
that the regular scheduled visit will be used. In the event any data assessments are missing from 
the regular scheduled visit, data from the unscheduled visit closest to the target date will be used 
for each missing assessment. Baseline values are defined in Section 7. 
In addition, post-baseline HVPG values will also be assigned to a Week 24 flag based on the 
HVPG date and will be classified as being Week 24 if the HVPG date is collected within ±8 
weeks (i.e., 56 days, inclusive) from the target date for the Week 24 visit  
Table 1. 
Analysis Visit Windows 
Visit 
Target Study Day 
Analysis Window 
Screening 
<Day -1 
≤ Day -1 
Day 1 
Day 1 
Day 1 
Week 4 
Day 28 
> Day 1 and ≤ Day 42 
Week 8 
Day 56 
> Day 42 and ≤ Day 70 
Week 12 
Day 84 
> Day 70 and ≤ Day 98 
Week 16 
Day 112 
> Day 98 and ≤ Day 126 
Week 20 
Day 140 
> Day 126 and ≤ Day 154 
Week 24 
Day 168 
> Day 154 and ≤ Day 196 
Week 26a 
Day 182 
> Day 182 
Week 32 
Day 224 
> Day 196 and ≤ Day 252 
Week 40 
Day 280 
> Day 252 and ≤ Day 308 
Week 48 
Day 336 
> Day 308 and ≤ Day 350 
Week 50b 
Day 350 
> Day 350 
aWeek 26 analysis window only applies to subjects that do not consent to the Weeks 28 – 48 study visits. 
bWeek 50 analysis window only applies to subjects that consented to the Weeks 28 – 48 study visits. 


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4 
PLANNED SAMPLE SIZE DETERMINATION 
It is planned to  randomize 240 subjects (60 subjects per group) to receive 1 of 3  emricasan 
doses or placebo. Subjects will be randomly assigned to receive either emricasan 50 mg BID, 
emricasan 25 mg BID, emricasan 5 mg BID, or matching placebo in a 1:1:1:1 ratio. Assuming a 
20% attrition rate, it is expected that approximately 192 subjects (48 subjects per group) will 
have a Week 24 HVPG assessment. 
This sample size will provide 81% power to detect a statistically significant difference, using a 2-
sided test with alpha of 0.05, between at least 1 emricasan treatment group and placebo in the 
mean change from baseline in HVPG. This calculation assumes a mean difference between an 
active treatment group and placebo of 3 mmHg and a sample standard deviation of 4.5 mm Hg. 
This calculation also applied a one-step Dunnett’s adjustment for comparing 3 active treatment 
groups with placebo.  
Based on data in the literature and discussion with key experts in the field, a clinically 
meaningful difference in the change from baseline in HVPG is approximately 2.5-3 mmHg, 
depending on the baseline value (D’Amico 2006). Subjects in Study IDN-6556-11 (open-label 
pilot study evaluating the effect of emricasan on HVPG for 28 days) with a baseline HVPG ≥12 
mm Hg had a sample standard deviation of 4.05 mm Hg. 
The sample size and power were calculated using the IndividualPower SAS macro provided in 
“Multiple Comparisons and Multiple Tests using SAS” (Westfall 2003).   


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5 
STUDY ENDPOINTS 
5.1 
PRIMARY EFFICACY ENDPOINT 
The primary endpoint for this study is the change from baseline (CFB) at Week 24 in HVPG. 
The change from baseline will be calculated as HVPG at Week 24 minus HVPG at baseline 
(HVPGW24-HVPGBL). Hence, a negative value will represent a decrease in HVPG at Week 24.   
The HVPG measurement is the difference between wedged (or occluded) hepatic vein pressure 
and free hepatic vein pressure and represents the gradient between the portal vein and the intra-
abdominal inferior vena cava pressure, with normal HVPG being 3-5 mmHg. It is a measure of 
intrahepatic sinusoidal pressure that correlates directly with direct measurements of portal 
pressure in cirrhosis. 
HVPG will be measured at the Screening and Week 24 visits. Original tracings of the pressure 
measurements will be kept at the site as part of source documentation for the study, and copies 
will be forwarded to the Central Reader for evaluation.  
5.2 
SECONDARY EFFICACY ENDPOINTS 
The CFB at each study visit for all continuous secondary endpoints will be calculated as the post-
baseline value minus the baseline value. Hence, a negative value will represent a decrease at the 
post-baseline visit. 
5.2.1 
HVPG Response 20% Reduction 
 HVPG response is defined as having at least a 20% reduction at Week 24 (i.e., pCFB HVPG ≤ -
20%) from baseline in HVPG. This response variable will be used as a secondary endpoint in 
this study. 
5.2.2 
Caspase 3/7 
 Caspase 3/7 data will be log-transformed for purposes of analysis. The CFB on the log-
transformed values at each study visit for the mechanistic biomarker caspase 3/7 will be derived 
and analyzed, with Week 24 and 48 considered as secondary endpoints for this study.  
Back transformation of the results will be conducted to provide percent relative change on the 
original scale. 
5.2.3 
ALT 
Measurements of ALT will be collected at each study visit. ALT data will be log-transformed for 
purposes of analysis. The CFB on the log-transformed value at each study visit for the functional 
biomarker ALT will be derived and analyzed, with Week 24 and 48 considered as  secondary 
endpoints for this study. 
Back transformation of the results will be conducted to provide percent relative change on the 
original scale.  


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5.3 
EXPLORATORY ENDPOINTS 
The CFB at each study visit for all continuous exploratory endpoints will be calculated as the 
post-baseline value minus the baseline value. Hence, a negative value will represent a decrease at 
the post-baseline visit. 
5.3.1 
HVPG Response 10% Reduction 
HVPG response is defined as having a decrease of at least 10% from baseline in HVPG 
(i.e., pCFB HVPG ≤ -10%), and will be summarized at Week 24. 
5.3.2 
Model for End-Stage Liver Disease Score, Regression, and Progression 
The MELD is a scoring system for assessing the severity of chronic liver disease and short-term 
mortality. An earlier version of the formula for MELD used the subject's values for serum 
bilirubin, serum creatinine, and the international normalized ratio (INR) for prothrombin time 
and was calculated according to the following formula (rounded to the nearest whole number): 
Previous MELD =3.78[ln total bilirubin (mg/dL)] + 11.2[ln INR] + 9.57[ln serum creatinine (mg/dL)] + 
6.43 
where ln is the natural logarithm, mg/dL is milligrams per deciliter 
If the patient was dialyzed twice within the last 7 days, then the value for serum creatinine used 
was set to 4.0. Any value less than one is given a value of 1 (i.e. if bilirubin was 0.8, a value of 
1.0 was used) to prevent the occurrence of scores below 0 (the natural logarithm of 1 is 0, and 
any value below 1 would yield a negative result). 
In January 2016, the Organ Procurement and Transplantation Network updated the MELD score 
to include sodium for the purpose of liver organ allocation.  Thus, the MELD score is now 
calculated based on the previous MELD score (provided above) as well as sodium (Na) 
according to the following formula (which will be used for this study): 
MELD = (previous MELD) + 1.32 × (137-Na) – [0.033 × (previous MELD) × (137-Na)] 
Sodium values <125 mmol/L will be set to 125, and values >137 mmol/L will be set to 137. 
The exploratory endpoint of change from baseline in MELD score at Weeks 24 and 48 will be 
derived. CFB on the log-transformed value will also be derived and explored. 
Regression of MELD will be derived as having a decrease of at least 2 points from baseline in 
MELD score (i.e., CFB MELD ≤-2) at Weeks 24 and 48. Progression of MELD will be derived 
as having an increase of at least 4 points from baseline in MELD score (i.e., CFB MELD ≥4) at 
Weeks 24 and 48. 
The components of MELD will be measured at each study visit and the MELD scores will be 
derived for each study visit by the central laboratory. 
Baseline MELD is defined as the last observed value up to and including Day 1.  


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5.3.3 
Child-Pugh Score, Regression, and Progression 
The C-P score is used to assess the prognosis of chronic liver disease and is calculated as the sum 
of the following five component scores: total bilirubin, serum albumin, ascites, hepatic 
encephalopathy, and INR.  Each component is scored with values of 1 to 3 points with 3 
indicating the greatest severity.  This provides a range for the C-P score of 5 to 15 points and this 
score is used to determine the C-P classification of A, B, or C, with C being the most severe 
(Table 2 and Table 3). 
Table 2. 
Child-Pugh Score by Parameter 
Parameter 
Child-Pugh Score 
1 
2 
3 
Total Bilirubin (mg/dL) 
<2.0 
2.0-3.0 
>3.0 
Albumin (g/dL) 
>3.5 
2.8-3.5 
<2.8 
Ascites 
Currently with no ascites 
or ascites only detectable 
on imaging (grade 1) and 
not on diuretics 
Currently ascites only 
detectable on imaging 
(grade 1) and treated with 
diuretics OR with overt 
ascites (grade 2 or 3) that 
is diuretic responsive 
Currently with overt 
ascites (grade 2 or 3) that 
is not diuretic responsive 
Hepatic Encephalopathy 
Currently with no overt 
HE and not on specific 
therapy (Rifaxmin) 
Currently with no overt 
HE and no asterixis on 
treatment with specific 
therapy OR currently with 
grade 2 HE (confused but 
talking and/or with 
asterixis) not on treatment 
with specific therapy 
Currently with grade 2 
HE despite treatment with 
specific therapy or 
currently with grade 3 HE 
or grade 4 HE 
INR 
<1.7 
1.7-2.3 
>2.3 
 
Table 3. 
Child-Pugh Classification 
Child-Pugh Classification 
Child-Pugh Score 
Child-Pugh A 
5-6 
Child-Pugh B 
7-9 
Child-Pugh C 
10-15 
 
The exploratory endpoint of change from baseline in C-P at Weeks 24 and 48 will be derived. 
Regression of C-P will be derived as having a decrease of at least 2 points from baseline in C-P 
score (i.e., CFB C-P ≤ -2) at Weeks 24 and 48. Progression of C-P will be derived as having an 
increase of at least 2 points from baseline in C-P score (i.e., CFB C-P ≥ 2) at Weeks 24 and 48. 
The components of C-P will be measured at and the C-P score will be derived for each study 
visit. 


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5.3.4 
Biochemical and Functional Biomarkers 
Biochemical and functional biomarker measurements will be collected at each study visit. 
Exploratory biochemical and functional biomarkers include cCK18/M30, flCK18/M65, AST, total 
bilirubin, INR, and albumin. These measurements will all be log-transformed for purposes of 
analysis.  The log-transformed CFB at each study visit will be derived for each biomarker.  
Back transformation of the results will be conducted to provide percent relative change on the 
original scale. 
5.3.5 
Fibrosis Markers 
Exploratory fibrosis markers include the Enhanced Liver Fibrosis (ELF) panel (based on 
hyaluronic acid, P3NP, TIMP-1), ferritin, and LOX-L2.  The CFB at Week 24 and Week 48 for 
each fibrosis marker will be derived. Fibrosis marker measurements will be collected at the Day 1 
and Week 24 visits. 
5.3.6 
CLDQ 
The Chronic Liver Disease Questionnaire (CLDQ) was developed as an evaluative instrument to 
measure longitudinal change in health status within individuals with chronic liver disease. In 
addition to measuring both physical and mental health, the instrument was designed to be a 
disease-specific tool for assessing areas of function important to patients with chronic liver 
disease. The instrument contains 29 items within six domains including abdominal symptoms, 
fatigue, systemic symptoms, activity, emotional function and worry. A Likert scale response 
format is used for all items ranging from 1 (most impairment) to 7 (least impairment). Scoring of 
the questionnaire is performed by dividing each domain score by the number of items per 
domain. Overall CLDQ score is obtained by adding scores for each item and dividing by the total 
number of items (n=29).  
The change from baseline in the overall CLDQ score and each of the 6 domains will be derived 
for each visit. The change from baseline at Weeks 24 and 48 will be considered as the 
exploratory endpoints for CLDQ. 
5.3.7 
SF-36 Quality of Life 
The SF-36 consists of 36 items, 35 of which are aggregated to evaluate eight dimensions of 
health: physical function, bodily pain, general and mental health, vitality, social function, and 
physical and emotional role functioning. Scores on the eight subscales are aggregated to derive 
the physical-component summary score (PCS) and the mental-component summary score 
(MCS). Scores of each question can range from 0 to 10, and the summary and subscale scores 
can range from 0 to 100, with higher scores indicating better health.   
The change from baseline of each component summary and subscales will be derived for each 
visit. The change from baseline at Weeks 24 and 48 will be considered as the exploratory endpoints 
for the component summary and subscales. 
5.3.8 
Clinical Outcome Events (Decompensation) 
Clinical outcome events will be defined based on whether the subject has compensated cirrhosis 
or decompensated cirrhosis at study entry, and for the latter, depending on what was the prior 
decompensating event. Subjects may have more than 1 clinical outcome event. Subjects who 


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have compensated cirrhosis on study entry and have a decompensating event could meet criteria 
for an additional decompensating event(s) if they remain in the study. 
Qualifying clinical outcome events, listed in Table 4 below, will be considered as development 
of decompensation or worsening of decompensation. Investigators will decide if a subject 
qualifies for an event as defined in Table 4   and record their assessment of a qualifying clinical 
outcome event on the eCRF. 
Whether or not a subject is classified as having developed decompensation or worsening of 
decompensation and the number of decompensation events will be exploratory endpoints for this 
study. 
Table 4. 
Clinical Outcome Events 
Cirrhosis Stage 
Prior Decompensating Event 
Qualifying Clinical Outcome Events 
Compensated 
Not applicable 
 New onset clinically evident ascites requiring chronic 
diuretics 
 Variceal hemorrhage 
 New onset overt hepatic encephalopathy requiring 
hospitalization 
Decompensated 
Ascites, not clinically evident 
(no ascites or only detectable 
by ultrasound) on a stable 
dose of diuretics 
 Variceal hemorrhage 
 Worsening ascites requiring paracentesis 
 New onset overt hepatic encephalopathy requiring 
hospitalization 
Decompensated  
Prior variceal hemorrhage 
 Recurrent variceal hemorrhage 
 New onset clinically evident ascites requiring chronic 
diuretics 
 New onset overt hepatic encephalopathy requiring 
hospitalization 
Decompensated 
Hepatic encephalopathy, 
currently with no or mild 
encephalopathy (Stage 1) on 
lactulose and/or rifaxmin 
 Variceal hemorrhage 
 New onset clinically evident ascites requiring 
diuretics 
 Worsening overt hepatic encephalopathy requiring 
another hospitalization 
 
Subjects will be evaluated for clinical outcome events at each study visit. 
5.3.9 
Liver Function by Methacetin Breath Test 
The 13C-methacetin breath test (MBT) is a noninvasive tool to assess liver microsomal capacity 
to metabolize the nonradioactive 13C-labeled methacetin. Details of the MBT are provided in 
IDN-6556-14 Protocol, Appendix II. The change from baseline in cumulative percentage dose 
recovery of the metabolized 13C-methacetin 30 minutes after ingestion of the test substrate 
(cPDR30) will be considered as an exploratory endpoint. 
The MBT will be performed at select sites at Screening and Weeks 24 and 48. Sites who elect to 
participate in the MBT measurements will perform the test at the specified visits for all subjects 
enrolled at their site. 


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5.3.10 
Liver Stiffness by Transient Elastography (using FibroScan®) 
Transient elastography is a non-invasive, reproducible method for measuring liver stiffness that 
correlates with liver fibrosis and will be measured using FibroScan®. Transient elastography 
measurements will be performed at select sites at Screening and Week 24 and 48. Sites who elect 
to participate in the transient elastography measurements will perform the test at the specified visits 
for all subjects enrolled at their site. 
The value for liver stiffness is collected on the eCRF and is the median out of at least 10 successful 
measurements taken, based on the definition of reliable and representative evaluation of the 
stiffness of the liver (i.e., success rate of >60% and IQR/median <30%, per IDN-6556-14 Protocol, 
Appendix III). The change from baseline in liver stiffness at Weeks 24 and 48 will be considered 
as an exploratory endpoint. 
5.4 
COMPLIANCE, EXPOSURE, AND 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. Expected doses will be the same 
for all subjects regardless of when they complete/discontinue study and will be the number of 
doses to be taken through week 24 and 48, that is 336 doses by Week 24 visit and 672 doses by 
Week 48.   
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 (days) divided by 365.25 days. 
5.4.3 
Adverse Events 
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 or worsening 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. 
Exposure-adjusted AE rate (EAER) is defined as the number of events divided by subject years 
of exposure. Exposure-adjusted AE rate will be provided for summarizing AEs overall. 


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5.4.4 
Gallbladder Events and Ultrasound 
At each study visit, investigator will assess the subject for any symptoms potentially consistent 
with biliary colic (e.g., sharp right upper quadrant pain, nausea, vomiting, fever [with 
cholecystitis], etc.), indicated as “yes or no” on the eCRF. 
If the subject reports symptoms of potential biliary colic or other symptoms suggestive of 
gallbladder disease on directed questioning or spontaneously reports such symptoms at any other 
time during the study, a follow-up liver and gallbladder ultrasound (including assessment of the 
biliary tree and any gallbladder abnormalities) should be performed.   
5.4.5 
Liver Monitoring 
Liver transaminases (ALT, AST), total bilirubin, cholestatic marker (ALP), INR, and eosinophils 
will be monitored at each study visit during the study.  Given that the patient population to be 
studied has underlying liver disease and therefore is likely to have abnormalities in liver 
transaminases and/or bilirubin at baseline, the guidelines for liver monitoring applied in this 
study incorporate suggestions provided to the Sponsor from the Food and Drug Administration 
regarding liver monitoring for subjects who have abnormal baseline values of liver transaminases 
and/or total bilirubin. 
In addition, the following categories for ALT, AST, and total bilirubin will be derived for 
baseline to Week 24, baseline to Week 48, and Week 24 to Week 48.  
 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 
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 
o and baseline >ULN 


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 Maximum post-baseline value >3× baseline 
o and baseline <ULN 
 Post-baseline ALT / AST with concurrent (i.e., same post-baseline visit) total bilirubin 
o ALT >3× ULN and concurrent total bilirubin >2× ULN 
o AST >3× ULN and concurrent total bilirubin >2× ULN 
o ALT or AST >3× ULN and concurrent total bilirubin >2× ULN 
o ALT and AST >3× ULN and concurrent total bilirubin >2× ULN 
 Possible Hy’s Law 
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 ALT or AST >3× ULN and not necessarily concurrent total bilirubin >2× ULN 
o ALT and AST >3× ULN and not necessarily concurrent total bilirubin >2× ULN 
5.4.6 
Laboratory Measurements 
Laboratory tests include measurements of parameters included in hematology and coagulation, 
chemistry, and metabolic panels. All specific laboratory tests are listed in detail in the protocol.  
Normal ranges will be provided by the central laboratory and used to derive classifications of 
laboratory measurements outside of the normal range. 
Hematology and coagulation and chemistry panel tests will be collected at each visit. The 
metabolic panel will be collected on Day 1, Week 24, and Week 48.  Changes from baseline will 
be derived for each applicable laboratory test.  Laboratory tests with categorical results will have 
no derivations made. 
5.4.7 
Vital Signs and Weight 
Vital signs include systolic and diastolic blood pressure, pulse, respiratory rate, and temperature. 
Body weight and height will be collected at protocol specified visits (weight at all visits, height 
at screening only), and body mass index (BMI) will be derived as [weight in kilograms (kg)] / 
[height in meters (m)2].     
Changes from baseline at each study visit in vital signs, weight, and BMI will be derived. 
5.4.8 
Electrocardiograms 
A 12-lead ECG will be performed at Screening, Week 4, Week 24, Week 48, and Follow-up. 
Electrocardiogram data to be collected includes ventricular rate, PR interval, RR interval, QRS 
interval, QT interval, QTc interval, and findings (i.e., normal or abnormal).  Derivations for 
Bazett’s QT correction (QTcB) and Fridericia’s QT correction (QTcF) intervals will be 
conducted in the study database. 
Post-dose maximum values in QTcB and QTcF will be classified into the following categories, 
in milliseconds (ms): 
 <450 
 >=450 to <480 


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 >=480 to <500 
 ≥500 
 
Changes from baseline in PR interval, QRS interval, QT interval, QTc interval, QTcB interval, 
and QTcF interval will be derived. Changes from baseline values in QTcB and QTcF will be 
classified into the following categories, in ms:  
 <0 
* >=0 to <30 
 >=30 to <60 
 ≥60 
5.4.9 
Medications 
All additional medications taken any time during the study will be collected 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 WHODRL.  
5.4.10 
Physical Examination 
A comprehensive physical examination will be performed at the Screening, Week 24, and Week 
48 visits including examination 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. A focused physical examination limited to 
relevant assessments and based on any symptoms or concerns related to a particular body system 
will be performed at all other visits. Each subject’s weight,  in street clothes with shoes and 
outerwear off, will be assessed at each study visit and BMI will be calculated.  Assessment of 
Child-Pugh clinical features will be performed at all visits. 
No derivations will be made for physical examination components results. 
5.4.11 
Alcohol Assessments 
The Alcohol Use Disorders Identification Test (AUDIT) is a 10-item questionnaire developed to 
screen for excessive drinking, helping to identify whether a person has hazardous (or risky) 
drinking, harmful drinking, or alcohol dependence.  The AUDIT-C is a 3-question version of 
AUDIT that performed similarly to the full AUDIT for detecting heavy drinking and/or active 
abuse or dependence. 
The Skinner Alcohol Dependence scale is a 25-item questionnaire that provides a quantitative 
measure of the severity of alcohol dependence with scores in the 1st, 2nd, 3rd, and 4th quartiles 


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corresponding to low, intermediate, substantial, and severe levels of alcohol dependence being 
likely.  
The AUDIT and Skinner Alcohol Dependence scale will be used during Screening to screen for 
any evidence of alcohol abuse, and the AUDIT-C will be collected at Weeks 12, 24 and 48 to 
monitor for any evidence of active alcohol abuse. 
No derivations of the Skinner Alcohol Dependence scale, AUDIT, or AUDIT-C will be made.  
 


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6 
ANALYSIS POPULATIONS 
The Enrolled Set consists of all subjects who signed an informed consent form. 
The randomized set consists of all subjects randomized. 
The Full Analysis Set (FAS) consists of all randomized subjects who have received at least one 
dose of study drug.  The analyses based on the FAS population will be conducted on an 
intention-to-treat principle (i.e., all subjects will be analyzed with the group to which they were 
randomly assigned).   
The Per Protocol Set (PPS) consists of all subjects in the FAS population who have a post-
baseline HVPG measurement and do not have any significant protocol deviations. Designation 
into the PPS will be determined by a blinded data review prior to database lock. 
The Safety Analysis Set consists of all randomized subjects who have received at least one dose 
of study drug on an “as treated” basis (i.e., all subjects will be analyzed by the treatment they 
have taken). 


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7 
GENERAL STATISTICAL CONSIDERATIONS 
There will be two analyses conducted for this study, a primary analysis and a final analysis.  The 
primary analysis to be conducted after all randomized subjects have either discontinued prior to 
week 24 or completed the Week 24 planned study visit.  This primary analysis will be considered 
as a database freeze and will include all data collected at the time of the database freeze (i.e., will 
include data collected after the Week 24 study visit).  The final analysis will include all subjects 
and all completed study visits.  The clinical study report will be written after the final analysis is 
conducted. 
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, and 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 the Enrolled set, 
Randomized set and FAS. The efficacy analyses will be based on the FAS, with the supportive 
analysis of the primary endpoint also based on the PP. All safety analyses will be based on the 
Safety Analysis set. 
All summaries by treatment group will include each of the planned 3 treatment groups, along 
with the 3 emricasan treatment groups combined (i.e., all emricasan) and all subjects combined 
(i.e., total). 
The baseline for the HVPG, MELD, and Child-Pugh score is defined as the last non-missing 
value observed prior to and including Day 1. All other continuous endpoints will have their 
baseline defined as the average of all observed values collected prior to and including Day 1. For 
programming purposes, 7 days will be defined as 1 week. 
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. 
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 (at both Week 24 and Week 48), and reason for 
study withdrawal. 
A separate table will also be provided using the enrolled set that summarizes enrollment, 
randomizations, mis-randomizations, stratifications, and mis-stratifications.   
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 the data review meeting. 
Protocol deviations will be summarized descriptively by treatment group. A listing of protocol 
deviations by unique subject number will be provided. 
8.3 
DEMOGRAPHICS, HEIGHT, AND WEIGHT 
Subject demographics will be summarized descriptively by treatment group.  The demographics 
summary will include results for subject age, age group, gender, race, ethnicity category, height, 
weight, and BMI. Age group is defined as the following categories: 
 ≥18 - <40 years 
 ≥40 - <65 years 
 ≥65 years 
8.4 
BASELINE CHARACTERISTICS 
Baseline characteristics include the following: 
 Baseline results for HVPG 
 Stratum - baseline NSBB use (Yes, No) 
 Stratum - baseline compensation status 
o Compensated 
o Decompensated 
 Decompensation type (i.e., ascites, variceal bleed, and/or encephalopathy) 
 Varices (none, small, medium, large)  
 Compensated status with varices 
o Compensated with none or small varices 
o Compensated with medium or large varices 


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o Decompensated with none or small varices 
o Decompensated with medium or large varices 
 MELD score, MELD classification (i.e., ≤14, ≥15), and MELD score components (i.e., 
total bilirubin, serum creatinine, and INR)  
 C-P score, C-P classification (Section 5.3.3), and C-P score components (i.e., total 
bilirubin, serum albumin, ascites, hepatic encephalopathy, and INR) 
 
All baseline characteristics will be summarized descriptively by treatment group. A listing of 
baseline characteristics will be provided by unique subject number. 
8.5 
MEDICAL HISTORY 
In addition to general medical history, specific medical history conditions to be collected at 
baseline will include type 2 diabetes mellitus, impaired fasting glucose, impaired glucose 
tolerance, obesity, dyslipidemia (hypertriglyceridemia, low HDL-C), hypercholesterloaemia 
(high LDL-C), hypertension, gallstones, biliary colic, cholecystectomy, polycystic ovary 
syndrome, gout, coronary artery disease, myocardial infarction, angina, and stroke.  
The percentage of subjects with these specific medical history conditions will be summarized 
descriptively by treatment group.  A listing of medical history events will be provided by unique 
subject number. 
8.6 
ALCOHOL SCALES 
The AUDIT and Skinner Alcohol Dependence Scale will be collected at baseline.  These scales 
will be summarized descriptively by treatment group and will include the classification for level 
of alcohol dependence.  
The AUDIT-C will be collected post-baseline and will be summarized descriptively at each visit 
by treatment group.  
 


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9 
EFFICACY ANALYSES 
All efficacy endpoints will be provided in listings by unique subject numbers and visit.   
9.1 
PRIMARY EFFICACY ANALYSIS 
The observed HVPG at screening, Week 24, and change from baseline to Week 24 will be 
summarized descriptively by treatment groups. Treatment comparisons for continuous change 
from baseline in HVPG will be conducted using a fixed effects analysis of covariance model 
(ANCOVA) using treatment (4 levels), baseline HVPG, baseline compensated/decompensated 
status, and NSBB use as fixed effects. Least-square adjusted means (LSMeans) and 95% CIs at 
Week 24 will be provided for each treatment, along with the estimated difference in LSMeans 
and 95% CIs between each emricasan treatment group and placebo. A one-step Dunnett’s test 
will be applied to adjust for the multiple comparisons of each emricasan treatment group with 
placebo. Missing data for the primary endpoint will be imputed using a multiple imputation (MI) 
approach, as described in Section 12, for the primary analysis. 
The primary analysis will include all subjects classified into the FAS, and will not exclude 
subjects for study drug interruptions or discontinuations. The measure of intervention will be 
HVPG at Week 24 and the magnitude of the treatment effect will be estimated by the LSMeans 
difference relative to placebo at Week 24.  
Sensitivity analyses of the primary endpoint may include other methods for the handling of 
missing data such as observed cases, log-scale, PPS, and as well as emerging methods (if 
applicable) 
Model-based dose response analysis will be conducted outside the scope of this SAP and results 
will be summarized in a separate report. 
9.2 
SECONDARY EFFICACY ANALYSES 
All secondary analyses will be conducted using the FAS.  No multiplicity adjustments will be 
made for any secondary analyses. 
9.2.1 
Secondary Efficacy Analysis: HVPG Response 20% Reduction 
The HVPG response 20% reduction will be summarized descriptively by treatment group at 
baseline and Week 24. Treatment comparisons for HVPG response 20% reduction will be 
conducted using a fixed effects logistic regression model using treatment (4 levels), baseline 
HVPG, baseline compensated/decompensated status, and NSBB use as fixed effects. The odds 
ratios and risk differences between any two treatment groups will be reported with their 
corresponding asymptotic 95% CIs.    
9.2.2 
Secondary Efficacy Analysis: Caspase 3/7 
Data for caspase 3/7 will be summarized descriptively for raw values, CFB, and pCFB at each 
visit by treatment group.   
Treatment comparisons will be based on the analysis of CFB on log-transformed caspase 3/7 at 
Week 24 and 48. It will be conducted using a linear mixed-effects model using treatment (4 
levels), baseline value, visit, treatment-by-visit interaction, baseline compensated/decompensated 
status, and NSBB use as fixed effects. The unstructured covariance model will be used. The 


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LSMeans and 95% CIs at 24 and 48 weeks will be reported for each treatment group, along with 
the estimated difference in LSMeans and 95% CIs for each pairwise comparison.  This model 
will use all available information for all subjects; hence no imputations for missing data will be 
implemented.  
Results will be back-transformed to provide a between-treatment ratio on the post-to-baseline 
ratio. If log-transformations do not allow for this parametric model to be conducted, then a non-
parametric method will be conducted and documented in the clinical study report. 
9.2.3 
 Secondary Efficacy Analysis: ALT 
Data for ALT will be summarized descriptively for raw values, CFB, and pCFB at each visit by 
treatment group.  Treatment comparisons will be based on the analysis of CFB on log-
transformed ALT. It will be conducted using the same type of mixed-effects model as described 
in Section 9.2.2. 
9.3 
EXPLORATORY EFFICACY ANALYSES 
All exploratory analyses will be conducted using the FAS population.  No multiplicity 
adjustments will be made for any exploratory analyses. 
9.3.1 
Exploratory Efficacy Analysis: HVPG Response 10% Reduction 
The exploratory endpoint of HVPG response, defined in Section 5.3.1 above, will be 
summarized descriptively by treatment group and visit. Treatment comparisons for the HVPG 
response defined as 10% reduction at Week 24 will be conducted using the same type of fixed-
effects model as described in Section 9.2.1. 
9.3.2 
 Exploratory Efficacy Analysis: MELD Score, Regression, and Progression 
The observed, CFB, and pCFB in MELD scores will be summarized descriptively by treatment 
group and visit. Similarly, each definition of MELD regression and progression at Week 24 and 
48, defined in Section 5.3.2 above, will be summarized descriptively by treatment group and 
visit.  
Treatment comparisons at Weeks 24 and 48 for change from baseline in MELD score will be 
conducted using the same type of mixed-effects model as described in Section 9.2.2. This same 
analysis will also be conducted for the change from baseline in MELD score. 
9.3.3 
Exploratory Efficacy Analysis: C-P Score and Response 
The C-P score and each component will be summarized descriptively 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 Week 24 and 48 
by treatment group.  
Each definition of regression and progression for C-P score will be summarized descriptively at 
Weeks 24 and 48. 


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9.3.4 
Exploratory Efficacy Analysis: Biochemical, Fibrosis, and Functional 
Biomarkers 
Biomarker endpoints will be summarized descriptively at each visit by treatment group on raw 
value, CFB, and pCFB. Treatment comparisons at Weeks 24 and 48 for change from baseline in 
the raw values and the log-transformed raw values of biomarker endpoints will be conducted 
using the same type of mixed-effects model as described in Section 9.2.2. 
9.3.5 
Exploratory Efficacy Analysis: CLDQ and SF-36 
The overall CLDQ score, each CLDQ domain score, SF-36 PCS, SF-36 MCS, and each SF-36 
subscale score will be summarized descriptively at each visit by treatment group. Change from 
baseline values for each domain at each post-baseline visit will be summarized descriptively by 
treatment group and overall. Treatment comparisons at Weeks 24 and 48 for change from 
baseline in CLDQ and SF-36 scores will be conducted using the same type of mixed-effects 
model as described in Section 9.2.2. 
9.3.6 
Exploratory Efficacy Analysis: Clinical Outcome Events (Decompensation) 
Classification of a clinical outcome event will be summarized descriptively by treatment group 
for the treatment period. Treatment comparisons for clinical outcome events through Weeks 24 
and 48 will be conducted separately using the same type of fixed-effects model as described in 
Section 9.2.1. 
9.3.7 
Exploratory Efficacy Analysis: Liver Metabolic Function (Methacetin Breath 
Test) 
Liver metabolic function will be summarized descriptively at each visit by treatment group. 
Change from baseline values in liver metabolic function at each post-baseline visit will be 
summarized descriptively by treatment group and overall. Treatment comparisons at Weeks 24 
and 48 for change from baseline in liver metabolic function will be conducted using the same 
type of mixed-effects model as described in Section 9.2.2.  
9.3.8 
Exploratory Efficacy Analysis: Liver Stiffness 
Liver stiffness will be summarized descriptively at each visit by treatment group. Change from 
baseline values in liver stiffness at each post-baseline visit will be summarized descriptively by 
treatment group and overall. Treatment comparisons for change from baseline for liver stiffness 
will be conducted using the same type of mixed-effects model as described in Section 9.2.2. 
9.4 
EXAMINATION OF SUBGROUPS FOR EFFICACY ENDPOINTS 
The primary endpoint will be summarized descriptively by treatment group and overall for the 
following subgroups: 
 Gender (Female, Male) 
 Baseline compensation status (compensated, decompensated) 
 NSBB use (Yes, No) 
 Baseline varices (none/small, medium/large)  
 Baseline MELD score (≤14, ≥15) 
 Baseline Child-Pugh classification (A, B) 


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 BMI (<30 kg/m2, ≥30 kg/m2) 
 Type II Diabetes (Yes, No) 
 Investigative Site 
 Region (United State, Outside of United States) 
 
Additional subgroup analyses will be conducted as exploratory analyses but will be handled 
outside of these planned analyses.  Ad hoc exploratory analyses conducted outside of the SAP 
may be reported and discussed in the clinical study report, as appropriate. 


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10 
POPULATION PHARMACOKINETICS (PK) 
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 Conatus 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 numbers and visit.   
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 
An overall summary of TEAEs will be summarized descriptively. The incidence of TEAEs will 
be summarized descriptively by treatment group and overall for each of the following: 
 by system organ class (SOC) and preferred term (including EAER) 
 by SOC 
 by SOC, preferred term, and severity 
 by SOC and preferred term for subjects with TEAEs classified as related to study drug 
 by SOC and preferred term with events having incidence of ≥5% in any treatment group  
 by SOC and preferred term for subjects with study discontinuation 
 by SOC and preferred term for subjects with study discontinuation due to AE 
 by SOC and preferred term for subjects with study drug discontinuation 
 by SOC and preferred term for subjects with study drug discontinuation due to AE 
 by SOC and preferred term for subjects with study drug interruption 
 by preferred term (alphabetically) 
 by preferred term (decreasing  incidence in total emricasan group) 
 by preferred term for events classified with severity as moderate (decreasing incidence in 
total emricasan group) 
 by preferred term for events classified with severity as severe (decreasing incidence in 
total emricasan group) 
 by preferred term for events classified with severity as moderate or severe (decreasing 
incidence in total emricasan group) 
The incidence of SAEs for SAEs will be summarized descriptively by treatment group and 
overall for the following: 
 by SOC and preferred term 
 by SOC and preferred term for subjects with SAEs classified as related to study drug 
 by preferred term (alphabetically) 
 by preferred term (decreasing incidence in total emricasan group) 
Subject listings by unique subject number and visit will be provided for the listings below: 
 All AEs 
 Subjects who discontinued from the study due to AE 


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 Subjects who discontinued from study drug due to AE 
 Subjects who had a drug interruption due to AE 
 Subjects with SAEs 
  Subjects with an event of death  
11.3 
GALLBLADDER EVENTS AND ULTRASOUND 
Baseline gallbladder findings on ultrasound will be summarized descriptively by treatment 
group. The number and percentage of subjects identified as having potential biliary colic 
symptoms (at least once during the study) based on “biliary colic symptoms” checked yes on 
eCRF will be summarized descriptively by treatment group.  This descriptive summary will also 
include the number and percentage of subjects with evidence of new gallbladder wall thickening 
on ultrasound and those with likely gallbladder inflammation events, which will be evaluated by 
medical review during the blinded data review meeting prior to database lock. 
A listing will be provided displaying the baseline medical history related to gallbladder, findings 
from baseline and follow-up ultrasounds, adverse events from the gastrointestinal SOC, and 
temperature, white blood cell count, gamma-glutamyl transferase, alkaline phosphatase, total 
bilirubin, AST, and ALT results during the study for each subject identified as having potential 
biliary colic symptoms. 
11.4 
LIVER MONITORING 
The baseline value used for purposes of liver monitoring is defined as the mean of all screening 
and Day 1 values within 70 days of the Day 1 visits, inclusive. Confirmed triggers of liver 
monitoring as described in Protocol Section 8.1.6 will be summarized descriptively by treatment 
group. 
 
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 value (as a multiple of ULN, on a log 
10 scale) versus the total bilirubin value (as a multiple of ULN, 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 values of ALT and total bilirubin (as a multiple of 
ULN, both on a log 10 scale).  
11.5 
LABORATORY MEASUREMENTS 
Hematology, coagulation, chemistry, metabolic, and urinalysis 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. Box and Line plots by treatment group will be produced across visits for 
laboratory parameters of interest. 


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A shift table will be provided for descriptively summarizing the classification around the normal 
range of each hematology, coagulation, metabolic, and chemistry 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. 
Listings will be provided for hematology, coagulation, metabolic, and chemistry laboratory 
parameters. 
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 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 coded term. Incidence of concomitant, new 
concomitant, and all concomitant medications will also be summarized descriptively by 
treatment group, ATC level, and coded term. 
11.9 
PHYSICAL EXAMINATION 
The comprehensive physical examination assessments conducted at baseline, Week 24, and 
Week 48 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 
AUDIT-C 
Each alcohol assessment will be summarized descriptively by treatment group and at each visit 
collected. 


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12 
HANDLING OF MISSING DATA 
Missing data for the primary endpoint of change from baseline in HVPG at Week 24 will be 
imputed using an MI analysis. The amount of missing data will dictate the number of imputed 
datasets to be derived for the MI analysis.   
Assuming an arbitrary missing data pattern, imputed values will be dependent on examination of 
potential risk factors, such as age, gender, compensated/decompensated status, use of NSBB, and 
baseline HVPG score. An arbitrary data missing pattern will be assumed and a fully conditional 
specification regression method will be used to impute missing CFB at Week 24 HVPG values.   
The SAS MI procedure will be used to generate multiply imputed datasets with each multiply 
imputed dataset being analyzed separately as described in the primary analysis.  The results for 
each imputed dataset analysis will then be summarized using the SAS MIANALYZE procedure 
with the appropriate statistics to be reported.  
There will be no imputations made for missing secondary or exploratory endpoints  
 
 


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13 
DATA MONITORING COMMITTEE 
An independent Data Monitoring Committee (DMC) will review unblinded safety data from this 
study at periodic intervals.  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 
responsibilities and procedures, will be implemented prior to any data review. These DMC 
documents (i.e., charter, open and closed meeting minutes, etc.) will be considered part of the 
study documentation, but not part of the study 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.  
As part of the remit of the Data Monitoring Committee, an independent Liver Adjudication 
Committee will assess in a blinded manner the cases of all subjects who: 
 Have confirmed elevations in liver parameters that meet the most recent protocol-defined 
criteria for liver monitoring 
 Have adverse events of hepatic injury or failure 
 Have serious adverse events that map to the Hepatobiliary system organ class 
 Hepatocellular carcinoma (HCC) 
The Liver Adjudication Committee will provide an opinion as to whether the elevations in liver 
parameters are likely drug-induced, and whether the elevation was likely related to blinded study 
drug.  With regard to AEs and SAEs, the Committee will provide an opinion as to whether that 
event was likely related to the underlying liver disease, other co-morbid conditions or to study 
medication. 
 
Adjudication responses from the Committee will be logged outside of the study database by the 
third-party adjudication project manager and sponsor.  This log will be used to provide a 
summary table and listing of subjects reviewed by the Committee and associated outcomes. 
 
All Investigators, responsible IRB/IECs, 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 
SUMMARY OF CHANGES TO PLANNED PROTOCOL ANALYSIS 
14.1 
CHANGES FROM PROTOCOL TO SAP V1.0 
The planned treatment pairwise comparisons adjustment method planned for secondary and 
exploratory endpoints will not be applied as part of this SAP. 
14.2 
CHANGES FROM SAP V1.0 TO SAP V2.0 
 Clarifications made to text throughout the SAP to help clarify further details   
 Analysis windows defined for programming purposes of applying unscheduled visit data 
when planned visit data are missing 
 Updated definition of MELD score 
 Percent change from baseline variables defined for secondary and exploratory endpoints 
 Clarified liver stiffness data to be used based on reliable criteria 
 Removed dose response analysis from SAP 
 Included treatment comparisons for exploratory endpoints 
 Added a diabetes subgroup for efficacy 
 Included additional AE summary tables and listings 
 Added plots for laboratory parameters of interest 
 Clarified details regarding MI analysis 
  


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15 
REFERENCES 
D’Amico G, Garcia-Pagan JC, Luca A, and Bosch J. (2006), Hepatic Vein Pressure Gradient 
Reduction and Prevention of Variceal Bleeding in Cirrhosis: A Systematic Review. 
Gastroenterology, 131:1611-1624. 
Westfall P, Tobias R, and Wolfinger R. Multiple Comparisons and Multiple Testing Using SAS. 
2003, SAS Institute. 
 


Signature Page for CTS-S-0366 v2.0
Signature Page for CTS-S-0366 v2.0
Approved
James Robinson
Document Owner
10-Jul-2018 23:00:38 GMT+0000
Approved
David Hagerty
Clinical Operations
10-Jul-2018 23:04:40 GMT+0000
Approved
Jean Chan
Monitoring
10-Jul-2018 23:11:25 GMT+0000
Approved
Dan Ripley
Project Management
12-Jul-2018 17:03:01 GMT+0000
Approved
Edward Smith
Regulatory
13-Jul-2018 17:52:54 GMT+0000