Clinical trial NCT03053063
Conditions: Nonalcoholic Steatohepatitis
Sponsor: Gilead Sciences
Start date: 2017-01-30; Completion date: 2019-05-06
Enrollment: 883 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate whether selonsertib (SEL; GS-4997) can cause fibrosis regression and reduce associated complications in adults with cirrhosis due to NASH.

Detailed description:

Arms: arm 1: Randomized Phase: SEL 6 mg plus placebo to match SEL 18 mg for up to 240 weeks.

Open-Label (OL) Phase: Participants who experienced a hepatic clinical event during the randomized phase prior to completing the Week 240 visit, will be offered the option to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the Randomized Phase. arm 2: Randomized Phase: SEL 18 mg plus placebo to match SEL 6 mg for up to 240 weeks.

Open-Label Phase: Participants who experienced a hepatic clinical event during the randomized phase prior to completing the Week 240 visit, will be offered the option to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the Randomized Phase. arm 3: Randomized Phase: Placebo to match SEL 6 mg plus placebo to match SEL 18 mg for up to 240 weeks.

Open-Label Phase: Participants who experienced a hepatic clinical event during the randomized phase prior to completing the Week 240 visit, will be offered the option to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the Randomized Phase.
Interventions: intervention 1: SEL intervention 2: Placebo to match SEL 6 mg intervention 3: Placebo to match SEL 18 mg
Intervention descriptions: intervention 1: Tablets administered orally once daily intervention 2: Tablets administered orally once daily intervention 3: Tablets administered orally once daily

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Safety and Efficacy of Selonsertib in Subjects with 
Compensated Cirrhosis due to Nonalcoholic Steatohepatitis (NASH)
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
125393
2016-004148-13
NCT03053063
Indication:
Nonalcoholic Steatohepatitis
Protocol ID:
GS-US-384-1944
Gilead Sciences
Medical Monitor:
Name:
Telephone:
Fax:
Email:
Gilead Sciences 
Study Director:
Name:
Telephone:
Fax:
Email:
Protocol Version/Date:
Original:
19 December 2016
Original 0.1:    
11 April 2017 (VHP Only)
Original 0.1.1: 
25 August 2017 (Portugal Only)
Original 0.1.2:
01 September 2017 (Germany Only)
Original 0.2:
13 April 2017 (Japan Only)
Amendment 1: 
24 May 2017
Amendment 1.1: 03 October 2017 (Portugal Only)
Amendment 1.2: 20 December 2017 (Germany Only)
Amendment 2: 
31 May 2018
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You will not disclose any of the information to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
GILEAU 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................6
LIST OF IN-TEXT FIGURES ......................................................................................................................................6
PROTOCOL SYNOPSIS ..............................................................................................................................................7
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................16
1.
INTRODUCTION ..............................................................................................................................................21
1.1.
Background ............................................................................................................................................21
1.2.
General Information for SEL .................................................................................................................22
1.2.1.
SEL.......................................................................................................................................22
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................24
1.2.3.
Clinical Trials of SEL...........................................................................................................24
1.2.4.
A Phase 2, Double-blind, Placebo-controlled, Dose-ranging Study 
Evaluating the Efficacy, Safety, and Tolerability of Selonsertib in 
Subjects with Diabetic Kidney Disease (Study GS-US-223-1015)......................................25
1.2.5.
A Phase 2, Dose-ranging, Randomized, Double-blind, Placebo-controlled 
Study of Selonsertib in Subjects with Pulmonary Arterial Hypertension 
(Study GS-US-357-1394).....................................................................................................26
1.2.6.
Study GS-US-416-2124: A Phase 2, Double-Blind, Randomized Study 
Evaluating the Safety, Tolerability, and Efficacy of SEL in Combination 
with Prednisolone versus Prednisolone Alone in Subjects with Severe 
Alcoholic Hepatitis...............................................................................................................27
1.2.7.
A Phase 2, Randomized, Open Label Study Evaluating the Safety, 
Tolerability, and Efficacy of Selonsertib alone or in Combination with 
Simtuzumab (SIM) in Subjects with Nonalcoholic Steatohepatitis 
(NASH) and Fibrosis (F2-F3) (GS-US-384-1497)...............................................................29
1.2.8.
Study GS-US-384-3914: A Phase 2, Proof-of-Concept, Open-Label Study 
Evaluating the Safety, Tolerability, and Efficacy of Regimens in Subjects 
with Nonalcoholic Steatohepatitis........................................................................................34
1.2.9.
Adverse Events Pooled Across Nonalcoholic Steatohepatitis 
Studies GS-US-384-1497 and GS-US-384-3914 .................................................................35
1.2.10.
Study GS-US-384-1943: A Phase 3, Randomized, Double-Blind,
Placebo-Controlled Study Evaluating the Safety and Efficacy of SEL in 
Subjects with Nonalcoholic Steatohepatitis and Bridging (F3) Fibrosis..............................35
1.2.11.
Study GS-US-384-1944: A Phase 3, Randomized, Double-Blind, 
Placebo-Controlled Study Evaluating the Safety and Efficacy of SEL in 
Subjects with Compensated Cirrhosis due to Nonalcoholic Steatohepatitis ........................36
1.3.
Rationale for This Study ........................................................................................................................37
1.4.
Rationale for Dose Selection of SEL .....................................................................................................38
1.4.1.
Rationale for Study Population ............................................................................................38
1.5.
Risk/Benefit Assessment for the Study..................................................................................................39
1.6.
Compliance ............................................................................................................................................40
2.
OBJECTIVES.....................................................................................................................................................41
3.
STUDY DESIGN................................................................................................................................................43
3.1.
Study Design..........................................................................................................................................43
3.2.
Treatment Plan and Regimen .................................................................................................................43
3.3.
Adjudication Committees.......................................................................................................................44
3.3.1.
Hepatic Events Adjudication Committee .............................................................................44


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3.3.2.
Cardiovascular Events Adjudication Committee..................................................................45
3.3.3.
Drug-Induced Liver Injury (DILI) Adjudication Committee ...............................................45
3.4.
Biomarker Testing..................................................................................................................................45
3.4.1.
Biomarker Samples to Address the Study Objectives ..........................................................45
3.4.2.
Biomarker Samples for Optional Future Research...............................................................46
3.4.3.
Biomarker Samples for Optional Genomic Research...........................................................47
4.
SUBJECT POPULATION..................................................................................................................................48
4.1.
Number of Subjects and Subject Selection ............................................................................................48
4.2.
Inclusion Criteria....................................................................................................................................48
4.3.
Exclusion Criteria...................................................................................................................................49
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................51
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................51
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................51
5.2.
Description and Handling of Selonsertib (SEL).....................................................................................52
5.2.1.
Formulation..........................................................................................................................52
5.2.2.
Packaging and Labeling .......................................................................................................52
5.2.3.
Storage and Handling...........................................................................................................53
5.3.
Dosage and Administration of Selonsertib (SEL)/ PTM Selonsertib (SEL) ..........................................53
5.3.1.
Selonsertib (SEL)/PTM Selonsertib (SEL) ..........................................................................53
5.4.
Prior and Concomitant Medications.......................................................................................................53
5.5.
Accountability for Selonsertib (SEL)/PTM Selonsertib (SEL)..............................................................55
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................56
6.
STUDY PROCEDURES ....................................................................................................................................57
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................57
6.2.
Pretreatment Assessments......................................................................................................................57
6.2.1.
Screening Visit .....................................................................................................................57
6.3.
Baseline Assessments.............................................................................................................................59
6.3.1.
Day 1 Randomization and Assessments...............................................................................59
6.4.
Treatment Assessments..........................................................................................................................61
6.4.1.
Week 1 Visit.........................................................................................................................61
6.4.2.
Week 4, Week 12, Week 24, Week 72, Week 120, Week 168 and 
Week 216 Visits...................................................................................................................62
6.4.3.
Week 8, Week 36, Week 44, Week 60, Week 84, Week 108, Week 132, 
Week 156, Week 180, Week 204 and Week 228 Visits.......................................................63
6.4.4.
Week 16, Week 20, Week 28, Week 32 and Week 40 Visits...............................................64
6.4.5.
Week 48, Week 96, Week 144, Week 192 and Week 240 (End of 
Treatment [EOT]) Visits ......................................................................................................65
6.4.6.
Early Termination (ET) Visit ...............................................................................................67
6.4.7.
Unscheduled Visits...............................................................................................................68
6.5.
Post-treatment Assessments ...................................................................................................................69
6.5.1.
Follow-Up Visit....................................................................................................................69
6.5.2.
Telephone Follow-Up Visit..................................................................................................69
6.6.
Visit Windows........................................................................................................................................70
6.7.
Open-Label Phase ..................................................................................................................................70
6.8.
Criteria for Discontinuation of Study Treatment....................................................................................71
6.9.
Assessments for Premature Discontinuation from Study.......................................................................71
6.10.
Optional Intensive PK Substudy ............................................................................................................71
6.11.
Description of Assessments ...................................................................................................................72
6.11.1.
Clinical Laboratory Analytes ...............................................................................................72
6.11.2.
Physical Examination...........................................................................................................73
6.11.3.
Vital Signs............................................................................................................................73


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6.11.4.
Medical History....................................................................................................................73
6.11.5.
Clinical Liver Assessments ..................................................................................................74
6.11.6.
Creatinine Clearance/eGFR..................................................................................................75
6.11.7.
Genomic Testing ..................................................................................................................75
6.11.8.
Pregnancy Testing................................................................................................................76
6.11.9.
Health Related Quality of Life (HRQoL).............................................................................76
6.11.10.
Health Resource Utilization Questionnaire ..........................................................................77
6.11.11.
Electrocardiogram................................................................................................................77
6.11.12.
Liver Stiffness Measurement by Elastography.....................................................................77
6.11.13.
Liver Biopsy.........................................................................................................................77
6.11.14.
Stool Frequency Assessment................................................................................................78
6.12.
Lifestyle Modification Counseling.........................................................................................................78
6.13.
End of Study Definition .........................................................................................................................78
6.14.
Sample Storage.......................................................................................................................................78
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................79
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................79
7.1.1.
Adverse Events.....................................................................................................................79
7.1.2.
Serious Adverse Events........................................................................................................79
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................80
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................80
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................81
7.2.2.
Assessment of Severity ........................................................................................................81
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................81
7.4.
Gilead Reporting Requirements.............................................................................................................83
7.5.
Toxicity Management ............................................................................................................................83
7.6.
Special Situations Reports......................................................................................................................86
7.6.1.
Definitions of Special Situations..........................................................................................86
7.6.2.
Instructions for Reporting Special Situations.......................................................................86
8.
STATISTICAL CONSIDERATIONS................................................................................................................88
8.1.
Analysis Objectives and Endpoints........................................................................................................88
8.1.1.
Analysis Objectives..............................................................................................................88
8.1.2.
Primary Efficacy Endpoint...................................................................................................89
8.1.3.
Clinical Efficacy Endpoint ...................................................................................................89
8.1.4.
Secondary Endpoint .............................................................................................................89
8.1.5.
Exploratory Endpoints..........................................................................................................89
8.2.
Analysis Conventions.............................................................................................................................90
8.2.1.
Analysis Sets ........................................................................................................................90
8.3.
Data Handling Conventions ...................................................................................................................91
8.4.
Multiple Testing.....................................................................................................................................92
8.5.
Demographic Data and Baseline Characteristics ...................................................................................94
8.6.
Efficacy Analysis ...................................................................................................................................94
8.6.1.
Primary Efficacy Endpoints Analysis ..................................................................................94
8.6.2.
Secondary Efficacy Endpoint Analysis................................................................................95
8.7.
Assessment of Noninvasive Measures of Fibrosis .................................................................................96
8.8.
Safety Analysis.......................................................................................................................................96
8.8.1.
Extent of Exposure...............................................................................................................97
8.8.2.
Adverse Events.....................................................................................................................97
8.8.3.
Laboratory Evaluations ........................................................................................................97
8.8.4.
Other Safety Evaluations......................................................................................................97
8.9.
Pharmacokinetic Analysis......................................................................................................................98


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8.9.1.
Exploratory Biomarker Analyses .........................................................................................98
8.10.
Sample Size............................................................................................................................................98
8.11.
Data Monitoring Committee ..................................................................................................................99
9.
RESPONSIBILITIES........................................................................................................................................100
9.1.
Investigator Responsibilities ................................................................................................................100
9.1.1.
Good Clinical Practice........................................................................................................100
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Ethics Committee (EC) Review and Approval ........................................................100
9.1.3.
Informed Consent...............................................................................................................100
9.1.4.
Confidentiality....................................................................................................................101
9.1.5.
Study Files and Retention of Records ................................................................................101
9.1.6.
Electronic Case Report Forms............................................................................................102
9.1.7.
Investigational Medicinal Product Accountability and Return...........................................103
9.1.8.
Inspections..........................................................................................................................103
9.1.9.
Protocol Compliance..........................................................................................................103
9.2.
Sponsor Responsibilities ......................................................................................................................104
9.2.1.
Protocol Modifications.......................................................................................................104
9.2.2.
Study Report and Publications ...........................................................................................104
9.3.
Joint Investigator/Sponsor Responsibilities .........................................................................................104
9.3.1.
Payment Reporting.............................................................................................................104
9.3.2.
Access to Information for Monitoring................................................................................105
9.3.3.
Access to Information for Auditing or Inspections ............................................................105
9.3.4.
Study Discontinuation........................................................................................................105
10.
REFERENCES .................................................................................................................................................106
11.
APPENDICES ..................................................................................................................................................111
Appendix 1.
Investigator Signature Page..................................................................................................112
Appendix 2.
Study Procedures Tables ......................................................................................................113
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................119
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE)............................................122
Appendix 5.
West Haven Criteria .............................................................................................................123


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LIST OF IN-TEXT TABLES
Table 1-1.
GS-US-384-1497: Selected Histologic Endpoints at Week 24 (Evaluable Subjects, 
Full Analysis Set) ...................................................................................................................31
Table 3-1.
Exploratory Biomarkers .........................................................................................................46
Table 5-1.
List of Disallowed and Use with Caution Medicationsa.........................................................55
Table 6-1.
Visit Windows........................................................................................................................70
Table 6-2.
Child-Pugh Classification of the severity of cirrhosis............................................................75
Table 6-3.
Stool Frequency Subscore of Partial Mayo Score ..................................................................78
LIST OF IN-TEXT FIGURES
Figure 1-1.
ASK1 Signaling in NASH......................................................................................................22
Figure 1-2.
GS-US-384-1497: NASH CRN Fibrosis Response at Week 24 (Evaluable Subjects, 
Full Analysis Set) ...................................................................................................................32
Figure 3-1.
Overall Study Design .............................................................................................................43
Figure 7-1.
On-Treatment ALT/AST Monitoring Requiring Close Observation......................................84
Figure 7-2.
On-Treatment ALT/AST Monitoring Requiring Study Drug Withholding............................85
Figure 8-1.
Multiple Testing Flow Chart ..................................................................................................93


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Dr.
Foster City, CA 94404 USA
Study Title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study
Evaluating the Safety and Efficacy of Selonsertib in Subjects with 
Compensated Cirrhosis due to Nonalcoholic Steatohepatitis (NASH)
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
125393
2016-004148-13
NCT03053063
Study Centers 
Planned:
Approximately 430 centers globally
Number of Subjects 
Planned:
Approximately 800 subjects
Target Population:
Males and non-pregnant, non-lactating females between 18 – 70 years of 
age with NASH and compensated cirrhosis.
Duration of 
Treatment:
Subjects will be treated for up to 240 weeks.
Duration of Study:
Individual subject participation in the study can last up to 260 weeks, 
which includes an 8-week Screening period, a 240-week treatment 
period, a 4-week Follow-Up period and a Telephone Follow-Up visit 
12 weeks after the Week 240 or Early Termination (ET) visit, as 
applicable.
The total study duration is anticipated to be approximately 7 years, 
including an enrollment period of approximately 2 years.
Objectives:
The primary objective of this study is:

To evaluate whether selonsertib (SEL, previously known as 
GS-4997) can cause fibrosis regression and reduce associated 
complications in subjects with cirrhosis due to NASH
The secondary objective of this study is: 

To assess the safety and tolerability of SEL in subjects with NASH 
and cirrhosis


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Study Design:
This is a Phase 3, randomized, double-blind, placebo-controlled study 
evaluating the safety and efficacy of SEL in subjects with compensated 
cirrhosis due to NASH.
Subjects meeting the study’s entry criteria will be randomly assigned in 
a 2:2:1 ratio to 1 of 3 treatment groups as shown in the figure below:
Randomized Study Phase
Randomization will be stratified by the presence or absence of diabetes 
mellitus (as determined by medical history or based on Screening lab 
values if previously undiagnosed [i.e. hemoglobin A1c (HbA1c) ≥6.5% 
or fasting plasma glucose ≥126 milligram/deciliter [mg/dL]) and by 
Enhanced Liver Fibrosis (ELF™) score ≥ 11.27 or < 11.27 during 
Screening. Study drugs will be administered for up to a total of 
240 weeks.
A key primary objective of this study is to prevent complications
attributable to cirrhosis. A composite of clinical events that constitute 
the clinical efficacy endpoint have been identified and include:
1) Events of hepatic decompensation including:
a) Clinically apparent ascites requiring treatment
b) Hepatic encephalopathy (HE) of Grade 2 or above (according to 
the West Haven criteria as defined in Appendix 5) requiring 
treatment
c) Portal hypertension-related upper gastrointestinal bleeding 
identified by endoscopy and requiring hospitalization, including 
events of bleeding from esophageal varices, gastric varices, and 
portal hypertensive gastropathy
Week 48 
1° Endpoint 
Histology 
Group A 
One SEL 6 mg tablet + 
One PTM SEL IS mg tablet 
administered orally once dail (n=320) 
Group B 
One PTM SEL 6 mg tablet + 
One SEL 18 mg tablet 
administered orall once dail (n=320) 
Group C 
One PTM SEL 6 mg tablet + 
One PTM SEL 18 mg tablet 
administered orall once dail (n=160) 
240Weeks 
Week 240 
Clinical 
Outcomes 
and 
Histology 


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2) Liver transplantation or qualification for liver transplantation, 
defined as a Model for End-stage Liver Disease (MELD) score 
≥15 on at least 2 consecutive occasions at least 4 weeks apart
3) All-cause mortality
Subjects who experience a confirmed hepatic clinical event prior to 
completing the Week 240 Visit of the Randomized Phase will be offered 
the option to rollover into an Open-Label (OL) Phase of the study. Each 
of the clinical events (except all-cause mortality and liver 
transplantation) will require confirmation by a Hepatic Events 
Adjudication Committee. All deaths will be reviewed by this committee 
to determine if they are liver-related.
Once the clinical event (except all-cause mortality and liver 
transplantation) is confirmed by the Hepatic Events Adjudication 
Committee, the subject will no longer participate in the Randomized 
Phase and will be offered the option to receive SEL 18 mg in the OL 
Phase for a total treatment duration of 240 weeks inclusive of the 
Randomized Phase. Rollover into the OL Phase of the study must occur 
within 60 days of confirmation of the event. 
 
 
. Hepatic 
clinical events will be adjudicated and deaths will be reviewed by the 
Hepatic Events/DILI Adjudication Committee only during the 
Randomized Phase of the study; potential DILI events and 
cardiovascular events including deaths will continue to be adjudicated in 
the OL Phase by the Hepatic Events/DILI Adjudication Committee and 
the Cardiovascular Events Adjudication Committee, respectively.
Cardiovascular events including cardiovascular death, myocardial 
infarction, stroke, hospitalization for unstable angina, hospitalization for 
cardiac failure, and coronary revascularization will be adjudicated by an 
independent Cardiovascular Events Adjudication Committee. Subjects 
experiencing a cardiovascular event will continue in the Randomized 
Phase and not rollover into the OL Phase. Cardiovascular events will be 
adjudicated and deaths will only be reviewed during the Randomized 
Phase and the OL Phase of the study.
CCI


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Diagnosis and 
Main Eligibility 
Criteria:
Key Inclusion Criteria
1) Liver biopsy consistent with NASH (defined as the presence of at 
least grade 1 steatosis, hepatocellular ballooning, and lobular 
inflammation according to the NAFLD Activity Score [NAS]) and 
cirrhosis (F4 fibrosis) according to the NASH Clinical Research 
Network (CRN) classification, in the opinion of the central reader
a) A historical liver biopsy within 12 months of the Screening visit 
may be accepted as the Screening biopsy if the sample is deemed 
acceptable for interpretation by the central reader 
b) If a subject is deemed ineligible for this study, the liver biopsy, if 
performed according to protocol specifications and is within 
6 months of the Screening visit, may be used to determine 
eligibility for study GS-US-384-1943
2) Subject has the following laboratory parameters at the Screening 
visit, as determined by the central laboratory:
a) Alanine aminotransferase (ALT) ≤ 8 x ULN 
b) Creatinine Clearance (CLcr) ≥ 30 milliliter/minute (mL/min), as 
calculated by the Cockcroft-Gault equation
c) HbA1c ≤ 9.5% (or serum fructosamine ≤381 µmol if HbA1c is 
unable to be resulted)
d) INR ≤ 1.4, unless due to therapeutic anti-coagulation
e) Platelet count ≥ 100,000/µL
Key Exclusion Criteria
1) Prior history of decompensated liver disease including ascites, HE, 
or variceal bleeding
2) CP score > 7, as determined at Screening, unless due to therapeutic 
anti-coagulation
3) MELD score > 12, as determined at Screening, unless due to 
therapeutic anti-coagulation
4) Chronic hepatitis B virus (HBV) infection (hepatitis B surface 
antigen [HBsAg] positive)
5) Chronic hepatitis C virus (HCV) infection (HCV Ab and 
HCV ribonucleic acid [HCV RNA] positive). Subjects cured of 
HCV infection less than 5 years prior to the Screening visit are not 
eligible.
6) Other causes of liver disease including, but not limited to, alcoholic 
liver disease, hepatitis B, hepatitis C, autoimmune disorders (e.g., 
primary biliary cholangitis, primary sclerosing cholangitis, and 
autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, 
iron overload, and alpha-1-antitryspin deficiency, based on medical 
history and/or centralized review of liver histology.


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7) History of liver transplantation
8) Current or history of HCC
9) Any weight reduction surgery in the 2 years prior to Screening or 
planned during study (weight reduction surgery is disallowed during 
the study), and malabsorptive weight loss surgery (e.g., Roux-en-Y 
or distal gastric bypass) at any time prior to Screening
10) Weight loss > 10% within 6 months of Screening 
11) Human immunodeficiency virus (HIV) infection
12) Unstable cardiovascular disease
Study Procedures/
Frequency: 
Screening assessments will include complete medical history, physical 
exam (PE), vital signs, laboratory assessments, pregnancy tests 
(for females of child-bearing potential), liver biopsy (if required), 
abdominal ultrasound for HCC surveillance, standard 12-lead 
electrocardiogram (ECG), 
 
 and review of adverse events (AEs)
and concomitant medications. 
Eligible subjects will be randomized to one of the three treatment 
groups: SEL 6 mg, SEL 18 mg or placebo to match (PTM). Prior to 
initial dosing, the following Day 1 assessments will be performed:  
symptom driven PE, vital signs, laboratory assessments, pregnancy tests 
(for females of child-bearing potential), liver stiffness measurement by 
elastography (if available), stool frequency assessment, Health Related 
Quality of Life (HRQoL) and Health Resource Utilization 
questionnaires, and review of AEs and concomitant medications.
After the Screening period and a randomization visit at Day 1, study 
visits will occur on Weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 
48 and every 12 weeks thereafter until Week 240 with a Follow-Up visit
and a Telephone Follow-Up visit. At minimum, review of AEs and 
concomitant medications and safety laboratory tests will be performed at 
every visit.  
 
 
 
While on study, subjects will undergo the following procedures and 
laboratory assessments:

Liver biopsy at Week 48 and Week 240 in the Randomized Phase 
only
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
Abdominal ultrasound for HCC surveillance at Weeks 24, 48, 72, 
96, 120, 144, 168, 192, 216, and 240

Single PK sampling:
Randomized Phase at Weeks 1, 4, 12, 24, and 48 in all subjects
OL Phase, at all visits in subjects with severe hepatic impairment 
(Child-Pugh [CP] Class C) in combination with renal impairment 
(eGFR < 30 mL/min)

Record subject’s stool frequency 

Blood and urine for Biomarkers at Weeks 12, 24, 48, 96, 144, 192, 
and 240

HbA1c at Weeks 4, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 
240

Insulin and Lipids at Weeks 4, 12, 24, 48, 72, 96, 120, 144, 168, 
192, 216, and 240 

Symptom driven PE, vital signs, body weight, and lifestyle 
modification counseling

Waist circumference at Weeks 4, 12, 24, 48, 72, 96, 120, 144, 168, 
192, 216, and 240

HRQoL questionnaires: Short Form 36 [SF-36] Health Survey, 
Chronic Liver Disease Questionnaire-Nonalcoholic Fatty Liver 
Disease [CLDQ-NAFLD], Work Productivity and Activity 
Impairment [WPAI], EuroQol five dimensions [EQ-5D], and Health 
Resource Utilization questionnaire at Weeks 12, 24, 48, 72, 96, 120, 
144, 168, 192, 216, and 240 
All subjects will complete the Follow Up visit and a Telephone 
Follow-Up visit. At the Follow Up visit, subjects will have a symptom 
driven PE, vital signs, review of concomitant medications and AEs, 
stool frequency assessment, and safety laboratory tests. A urine 
pregnancy test will be performed for females of childbearing potential 
only.
Test Product:
SEL 18 mg oral tablet once daily
SEL 6 mg oral tablet once daily
Reference Therapy 
Dose:
PTM SEL 18 mg oral tablet once daily
PTM SEL 6 mg oral tablet once daily


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Dose, and Mode of 
Administration:

Treatment Group A: one SEL 6 mg tablet + one PTM SEL 18 mg 
tablet administered orally once daily

Treatment Group B: one PTM SEL 6 mg tablet + one SEL 18 mg 
tablet administered orally once daily

Treatment Group C: one PTM SEL 6 mg tablet + one PTM SEL
18 mg tablet administered orally once daily
Criteria for 
Evaluation:
Efficacy:
The primary efficacy endpoint at Week 48 includes the proportion of 
subjects who achieve a ≥ 1-stage improvement in fibrosis (according to 
the NASH CRN classification) without worsening of NASH (defined as 
a ≥ 1-point increase in hepatocellular ballooning or lobular 
inflammation).
The clinical efficacy endpoint at Week 240 is event-free survival (EFS). 
EFS will be assessed by time to the first clinical event including liver 
decompensation events, liver transplantation, or all-cause mortality.
Secondary Endpoints:

Proportion of subjects who have a ≥ 1-stage improvement in fibrosis 
without worsening of NASH at Week 240;

Proportion of subjects who have a ≥ 1-stage improvement in fibrosis
at Week 48 and Week 240;

Proportion of subjects who have NASH resolution at Week 48 and 
Week 240. 
Safety:
The safety of SEL in subjects with cirrhosis due to NASH will be 
assessed during the study through the reporting of AEs, clinical 
laboratory tests, vital sign assessments and concomitant medication
usage. 
An external Data Monitoring Committee (DMC) that consists of 
three hepatologists and a PhD statistician will review the progress of the 
study. They will convene after 50 subjects have completed the Week 4 
visit and approximately every 6 months thereafter to monitor the study 
for safety events.


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Statistical Methods:
Primary Efficacy Endpoints Analysis:
A stratified Mantel-Haenszel (MH) test will be used to compare the 
differences in proportion of subjects who achieve a ≥ 1-stage 
improvement in fibrosis without worsening of NASH at Week 48 
between each of the SEL arms and the placebo arm, adjusting for 
stratification factors. The point estimates and 95% confidence intervals 
for the differences in proportions will be calculated. 
Clinical Endpoint Analysis:
The clinical efficacy endpoint at Week 240 is EFS. EFS will be assessed 
by time to the first clinical event in the Randomized Phase. Differences 
in time to the first clinical events between each of the SEL arms and the
placebo arm will be assessed using the stratified log-rank test. The 
clinical efficacy endpoint will only be evaluated at Week 240 for the 
SEL arm if the SEL arm demonstrates superiority for the primary 
efficacy endpoint at Week 48.
Secondary Efficacy Endpoint Analyses:
A stratified MH test will be performed to compare the differences in 
proportions between each SEL arm and the placebo arm for the 
following endpoints:

Proportion of subjects who have a ≥ 1-stage improvement in fibrosis 
without worsening of NASH at Week 240;

Proportion of subjects who have a ≥ 1-stage improvement in fibrosis 
at Week 48 and Week 240;

Proportion of subjects who have NASH resolution at Week 48 and 
Week 240
Assessment of Noninvasive Measures of Fibrosis:
Receiver operating characteristic (ROC) curves and measures of 
diagnostic test performance (e.g., sensitivity and specificity) will be 
used to determine whether baseline noninvasive measures of fibrosis 
and their change from baseline can predict histological fibrosis 
regression and development of clinical complications.
Safety Analysis: 
Safety analyses include summaries of extent of exposure, AEs, 
laboratory evaluations and vital sign assessments.
Pharmacokinetic 
Analysis:
Plasma concentrations of SEL and GS-607509 will be listed and 
summarized.
 
 
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Sample Size:
With a sample size of 320 subjects in each active treatment arm and 
160 subjects in the placebo arm, the study has 97% of power to detect a 
difference in the proportion of subjects with a ≥ 1-stage improvement in 
fibrosis without worsening of NASH of 12% or more at Week 48 at a 
significance level of 0.025 (two-sided), assuming the proportion of 
subjects that meet the endpoint in the placebo arm is 4%.
With regard to the clinical efficacy endpoint, subjects will be followed 
for a period of up to 240 weeks. The estimate of the expected event rate 
is 30% in untreated patients, producing an expected EFS rate of 70% at 
240 weeks in the placebo arm. SEL is expected to improve the EFS rate 
to 83.7% (expected event rate of 16.3%) compared with placebo (hazard 
ratio (HR), 0.50). We also expect an overall dropout rate of 20%. Given 
the above assumptions, for comparison of each of the SEL arms versus 
the placebo arm, together with a total sample size of 800 subjects 
(2:2:1 ratio), and assuming the log-rank test statistic is evaluated using a 
two-sided 0.025 significance level, the study will have 85% power to 
evaluate the superiority of each SEL arm versus the placebo arm with 
respect to EFS. 
Therefore, the overall power for the trial, assuming independence 
between the primary efficacy endpoint and clinical efficacy endpoint, is 
82% (97% × 85%). It should be noted that this is a lower bound estimate 
because these two endpoints are expected to be positively correlated.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
AE
adverse event
AH
alcoholic hepatitis
AICD
automatic implantable cardioverter defibrillator
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
APTT 
Activated Partial Thromboplastin Time
ASK1
apoptosis signal-regulating kinase 1
AST
aspartate aminotransferase
AUC
area under the curve 
α-SMA
α-smooth muscle actin
BAP
Biomarker Analysis Plan
BCRP
Breast cancer resistance protein
BL
Baseline
BUN
blood urea nitrogen
CCR
Chemokine Receptor
CFR
Code of Federal Regulations
CI
confidence interval
c-Jun
c-Jun protein
CK18
Cytokeratin-18
CLcr
creatinine clearance
CLDQ-NAFLD
Chronic Liver Disease Questionnaire-Nonalcoholic Fatty Liver Disease
Clast
last observed quantifiable plasma/serum concentration of the drug
Cmax
maximum observed plasma/serum concentration of drug
CMH
Cochran-Mantel-Haenszel
CPK
Creatine phosphokinase
CP
Child-Pugh Score
CRF
Case Report Form
CRN
Clinical Research Network
CRO
contract (or clinical) research organization 
CRP
c-reactive protein
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CXCL1
chemokine (C-X-C motif) ligand 1
CYP3A
cytochrome P4503A
CYP3A4
cytochrome P4503A4
DDI
drug-drug interaction
dL
deciliter


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DILI
Drug-Induced Liver Injury
DKD
Diabetic Kidney Disease
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
EFS
event-free survival
eGFR
estimated glomerular filtration rate
EDC
electronic data capture
e.g.
example
ELF™
enhanced liver fibrosis 
EQ-5D
EuroQol five dimensions
EU
European Union
EudraCT
European clinical trial database
F3
Bridging Fibrosis
FAS
Full analysis set
FDA
(United States) Food and Drug Administration
FSH
Follicle stimulating Hormone
FXR
Farnesoid X Receptor
GCP
Good Clinical Practice
GI
Gastrointestinal 
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
Hgb
Hemoglobin
HbA1c
Hemoglobin A1c
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular Carcinoma
Hct
Hematocrit
HCV
Hepatitis c virus
HCV Ab
Hepatitis c virus antibody
HCV RNA
Hepatitis c virus ribonucleic acid
HDPE
High-density polyethylene
HE
Hepatic encephalopathy
HIV
Human immunodeficiency virus
HIV Ab
Human immunodeficiency virus antibody
HIV RNA
Human immunodeficiency virus ribonucleic acid
HLT
high-level term
HLGT
high-level group term


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HOMA-IR
homeostatic assessment of insulin resistance
HPAH
Heritable pulmonary arterial hypertension
HR
hazard ratio
HRQoL
Health Related Quality of Life
IB
investigator’s brochure
IBD
inflammatory bowel disease
ICF
Informed Consent Form
ICH
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
ID
Identification
IEC
independent ethics committee
IL-1
interleukin 1b
IL-6
interleukin-6
IMP
Investigational Medicinal Product
INR
IRB
international normalized ratio
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
JNK
c-Jun N-terminal kinase
kPa
kilopascal
LLT
lower-level term
MATE1
Multidrug and toxin extrusion protein 1
MCP-1
monocyte chemoattractant protein-1
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MELD
Model for End-stage Liver Disease
g
Microgram
Mg
Milligram
MH
Mantel-Haenszel
min
Minute
mL
Milliliter
mm
Millimeter
mmHg
Millimeter of Mercury
MQC
Morphometric quantitative collagen
MRE
magnetic resonance elastography
MRI
magnetic resonance imaging
MRI-PDFF
magnetic resonance imaging-proton density fat fraction
n
number
NAFLD
nonalcoholic fatty liver disease
NAS
NAFLD Activity Score


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NASH
nonalcoholic steatohepatitis
OATP
Organic anion-transporting polypeptide
OCT1
Organic cation transporter 1
OCT2
Organic cation transporter 2
OL
Open-Label
PAH
Pulmonary arterial hypertension
PD
Pharmacodynamic
PE
Physical exam
PK
Pharmacokinetic 
P-gp
P-glycoprotein
p38
mitogen-activated protein kinase
p-p38
phospho-p38
PPAR
Peroxisome Proliferator-Activated Receptor
PRED
prednisolone
PT
Prothrombin time / Preferred Term
PTM
Placebo-to-Match
PVE
Pharmacovigilance and Epidemiology
PVR
pulmonary vascular resistance
Q
Every
QoL
Quality of Life
QT
electrocardiographic interval between the beginning of the Q wave and termination of the 
T wave, representing the time for both ventricular depolarization and repolarization to occur
QTc
QT interval corrected for heart rate
RBC
red blood cell count
RHC
right heart catheterization
RNA
ribonucleic acid
ROC
receiver operating characteristic
ROS
reactive oxygen species
SADR
serious adverse drug reaction
SAE
serious adverse event
SAF
steatosis, activity, fibrosis
SAP
statistical analysis plan
SAS®
Statistical Analysis System
SEL
Selonsertib
SD
standard deviation
SF-36
Short Form 36 Health Survey
SIM
Simtuzumab
SOC
System Organ Class
SOP
standard operating procedure
SREBP1c
sterol regulatory element binding protein-1c


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SUSAR
Suspected Unexpected Serious Adverse Reaction
t½
An estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant (λz)
TEAEs
Treatment-emergent adverse events
TGF-β
Transforming growth factor beta
TIMP1
tissue inhibitor of metalloprotease 1
Tlast
last measured concentration
Tmax
time (observed time point) of Cmax
TNF-
tumor necrosis factor-alpha
UGT1A1
UDP glucuronosyltransferase family 1 member A1
ULN
upper limit of the normal range
US
United States
VAS
Visual Analog Scale
WBC
white blood cell count
WPAI
Work productivity and activity impairment questionnaire 


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1.
INTRODUCTION
1.1.
Background
Chronic liver disease and the consequences of end-stage liver disease are increasing globally 
despite improved prevention and treatment of viral hepatitis. This is due to the emerging 
epidemics of obesity and metabolic syndrome that are leading to an increased incidence of 
NASH. Prevalence rates of hepatic steatosis or fatty liver, an entity that has been termed 
nonalcoholic fatty liver disease (NAFLD), range from 6% to 37% worldwide {Ong 2007, 
Vernon 2011} with a recent pooled overall global prevalence of 25% reported {Younossi 2016}.
NASH, the form of NAFLD associated with increased liver-related mortality, affects 
approximately 30% of all patients with NAFLD {Ong 2007, Williams 2011, Younossi 2016}. In 
the United States (US), it has been estimated that 2% to 5% of the population have NASH 
{Vernon 2011}, which is equivalent to approximately 16 million adults. Furthermore, as NASH 
is a manifestation of the metabolic syndrome, associated elevated cardiovascular risk factors 
(e.g., atherosclerotic disease, cardiac arrhythmogenicity) likely coexist in patients with NASH 
{Dietrich 2014, Faramawi 2008, Voulgari 2010}. NASH represents a significant and growing 
unmet medical need for which there are no currently approved therapies.  
NASH is primarily thought to occur as the result of the metabolic syndrome: the impact of 
obesity, hepatic insulin resistance, and dyslipidemia. Fatty liver, or simple steatosis, is not 
sufficient to cause liver injury; it is the presence of inflammation and hepatocellular injury on the 
background of steatosis that produces NASH and may result in the progression to cirrhosis and 
its complications including end-stage liver disease. The “2-hit” hypothesis of NASH suggests 
that in the setting of steatosis and metabolic dysfunction, increased oxidative stress and the 
generation of reactive oxygen species (ROS) likely mediate the inflammatory changes in the 
liver (steatohepatitis) with progressive liver fibrosis {Dowman 2010, Koek 2011, Rolo 2012, 
Sumida 2013}. The major pathways in NASH disease progression include those involved in 
metabolic dysfunction in the hepatocyte, activation of hepatic stellate cells, and activation and 
recruitment of macrophages leading to hepatic inflammation and fibrosis. Advanced fibrosis and 
cirrhosis are characterized by extensive collagen deposition and remodeling of the extracellular 
matrix. Additionally, there is evidence which suggests that lipotoxic intermediates of fatty acids 
likely contribute to the etiology of NASH {Neuschwander-Tetri 2010}.
Over time, NASH may result in progressive liver fibrosis, ultimately resulting in cirrhosis. 
Advanced liver fibrosis (bridging fibrosis or cirrhosis) is associated with increased morbidity and 
mortality {Ekstedt 2014, Yeh 2014}. Cirrhosis increases the risk of developing hepatocellular 
carcinoma (HCC) and other complications of end-stage liver disease, including jaundice, fluid
retention (edema and ascites), portal hypertension and variceal hemorrhage, impaired 
coagulation, and HE. Decompensated liver disease, as defined by the development of one of the 
above complications, has a high mortality rate and the only effective treatment is liver 
transplantation. With the increasing prevalence of obesity and obesity-related diseases, NASH is 
expected to become the leading indication for liver transplantation and the leading etiology of 
HCC among liver transplant recipients in the US {Afzali 2012, Wong 2014}.


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1.2.
General Information for SEL
1.2.1.
SEL
SEL is a potent and selective small molecule inhibitor of apoptosis signal-regulating kinase 1 
(ASK1). ASK1 is an ubiquitously expressed serine/threonine kinase that is primarily activated by 
pathological oxidative stress {Makie 2007, Takeda 2008, Tobiume 2002}. ASK1 in turn 
phosphorylates and activates mitogen-activated protein kinase (p38) and c-Jun N-terminal (JNK) 
kinases. p38 and JNK mediate metabolic, pro-inflammatory, and pro-fibrotic changes in the 
liver, which are central to disease progression in NASH. By inhibiting ASK1 signaling in 
patients with NASH, SEL is expected to halt progressive liver fibrosis and reverse existing 
fibrosis, thus preventing the development of cirrhosis-related complications. The mechanism of 
ASK1 signaling in NASH is presented graphically in Figure 1-1.
Figure 1-1.
ASK1 Signaling in NASH
Oxidative Stress 
i Reactive oxygen species 
i Insulin resistance 
i Lipogenesis 
i Apoptosis, Necrosis 
f Cytokines 
f Chemokines 
Fibroblast 
i Activation 
j Fibrotic genes 


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Increased ASK1 signaling is observed in liver biopsy specimens of patients with NASH, as 
demonstrated by increased levels of phosphorylated p38, which correlates with progression of 
fibrosis. ASK1 promotes a pathological cycle between oxidative stress, metabolic dysfunction, 
and hepatocellular damage and inflammation that ultimately promotes fibrosis and organ failure.  
These effects are the result of known roles of p38 and JNK signaling in hepatocytes, 
macrophages, hepatic stellate cells and fibroblasts, which have been demonstrated in preclinical 
studies.  

In hepatocytes, JNK and p38 signaling induces metabolic dysfunction that promotes lipid 
accumulation and hepatic steatosis. JNK serine phosphorylates the insulin receptor substrate 
1 (IRS1) promoting hepatic insulin resistance {Imoto 2006, Vallerie 2010}. Additionally, 
JNK phosphorylates and activates the liver X receptor (LXR) to increase transcription of 
sterol regulatory element binding protein-1c (SREBP1c) {Kim 2010}. SREBP1c is a core 
regulator of hepatic lipid metabolism that increases de novo lipogenesis and promotes hepatic 
steatosis. Additionally, p38 and JNK directly phosphorylate SREBP1c and SREBP1a to 
promote lipogenesis in the liver {Knebel 2014, Kotzka 2012}. In a mouse model of NASH, 
ASK1 inhibition reduced SREPB1c RNA expression and hepatic steatosis.

Sustained p38 and JNK activation in hepatocytes induces mitochondrial dysfunction, ROS 
production and cell death by apoptosis or necrosis. JNK signaling at the mitochondria 
inhibits respiration and increases ROS production, leading to a feed forward cycle of 
sustained ASK1 and JNK activation and oxidative stress{Win 2016, Xie 2015}. p38 and JNK 
phosphorylate BCL-2 family members to promote hepatocyte apoptosis or necrosis, both of 
which exacerbate hepatic inflammation and fibrosis in NASH {Canbay 2004, Ichijo 1997, 
Kaufmann 2009, Nakagawa 2008, Wissing 2014}. In liver injury models, ASK1 inhibition 
reduced hepatocyte apoptosis and necrosis {Nakagawa 2011, Nakagawa 2008, Xie 2015}.

p38 and JNK signaling in macrophages and other immune cells promote hepatic 
inflammation. JNK is required for polarization of macrophages to a pro-inflammatory state 
{Han 2013, Sabio 2014}. In addition, p38 phosphorylates AP1 transcription factors including 
ATF4, promoting the expression and secretion of inflammatory cytokines {Arthur 2013, 
Sabio 2014}.  In mouse models of NAFLD and liver fibrosis, p38 and JNK promote 
expression of cytokines such as tumor necrosis factor-alpha (TNF-, interleukin 1b (IL-1) 
and interleukin-6 (IL-6), chemokines such as monocyte chemoattractant protein-1 (MCP-1) 
and chemokine C-X-C motif ligand 1(CXCL1), and profibrotic mediators such as TGF
{Gonzalez-Teran 2016, Vallerie 2010}. In rodent models of NASH, ASK1 inhibition 
reduced hepatic inflammation and the hepatic RNA expression of TNFand MCP1.  

In NASH, hepatic stellate cells differentiate into myofibroblasts, which are a primary source 
of collagen and extracellular matrix production. JNK signaling is required for differentiation 
of hepatic stellate cells into myofibroblasts in vitro and in mice {Kluwe 2010}. p38 signaling 
in myofibroblasts promotes the transcription of collagen 1 and increases the expression of  
tissue inhibitor of metalloprotease 1 (TIMP1) to inhibit digestion and turnover of 
extracellular matrix by metalloproteases {Nieto 2006}. In a rodent model of NASH, ASK1 
inhibition led to decreased phospho-p38 (p-p38) expression in fibroblasts and decreased 
RNA levels of collagen 1 and TIMP1. In vitro, SEL inhibited JNK phosphorylation and 
fibroblast activation in response to TGF-2 stimulation. 


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
Therefore, ASK1 signaling through p38 and JNK in hepatocytes, macrophages and hepatic 
stellate cells promotes hepatocellular steatosis, apoptosis, necrosis, inflammation and 
fibrosis. SEL, by inhibiting oxidative stress-driven ASK1 signaling characteristic of NASH, 
is expected to halt progressive fibrosis and lead to regression of pre-existing fibrosis, thereby 
reducing progression to cirrhosis and its associated complications.
For further information on SEL, refer to the Investigator’s Brochure (IB).
1.2.2.
Preclinical Pharmacology and Toxicology
SEL has high oral bioavailability, moderate volume of distribution and low systemic clearance in 
nonclinical species and humans. SEL is modestly bound in human plasma. Elimination of SEL
and its metabolites is likely to occur through a mixture of urinary, biliary and intestinal 
excretion. The main route of metabolism of SEL involves N-dealkylation. Human metabolism 
appears to be largely catalyzed by cytochrome P4503A (CYP3A) enzymes. After oral dosing of 
SEL significant concentrations of GS-607509, inactive N-dealkylation metabolite, are found in 
plasma. SEL is an inhibitor of CYP3A and UDP glucuronosyltransferase family 1 member A1 
(UGT1A1) enzymes; however, clinically relevant inhibition of CYP3A was not observed in 
humans. SEL is a weak inhibitor of the transporters breast cancer resistance protein (BCRP), 
OATP1B1, and OATP1B3 and a more potent inhibitor of P-glycoprotein (P-gp), Organic cation 
transporter 1 (OCT1), Organic cation transporter 2 (OCT2), and Multidrug and toxin extrusion 
protein 1 (MATE1). The metabolite GS-607509 did not inhibit any of the CYP enzymes and was 
a very weak inhibitor of UGT1A1. GS-607509 shows little inhibition of all tested transporters 
apart from MATE1.  
SEL has been extensively evaluated in nonclinical toxicology studies. Findings attributed to SEL
administration were primarily related to the cardiovascular system (mild decrease blood pressure 
and mild QT interval corrected for heart rate [QTc] prolongation), GI tract (profuse diarrhea) and 
kidney (tubular basophilia, eosinophilic droplets, and pigment), embryofetal effects (visceral 
and/or skeletal malformations) and occurred at exposures that were in excess of the targeted 
human exposure at 18 mg/day. Similar findings have not been observed to date in clinical studies 
of SEL at doses of up to 100 mg/day. Self-limiting diarrhea has been observed in subjects across 
the clinical studies. However, the low grade and self-limiting nature of the diarrhea suggests the 
diarrhea in the clinical studies is different from what was observed in monkeys.  
Please refer to the SEL IB for additional details.
1.2.3.
Clinical Trials of SEL
As of 16 February 2018, 15 Phase 1 and 2 clinical studies have been conducted/are ongoing in 
which 390 healthy subjects, 248 subjects with diabetic kidney disease (DKD), 145 subjects with 
pulmonary arterial hypertension (PAH), 50 subjects with alcoholic hepatitis (AH), and 
122 subjects with NASH have been dosed with SEL. In addition, as of 12 January 2018, 
approximately 865 subjects with NASH have been dosed with SEL in this Phase 3 study and the 
Phase 3 GS-US-384-1943 study which are evaluating SEL in patients with advanced fibrosis due 
to NASH (treatment assignment remains blinded).
Information on the Phase 1 clinical studies and additional details on the Phase 2 and 3 studies
can be found in the IB.


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1.2.4.
A Phase 2, Double-blind, Placebo-controlled, Dose-ranging Study Evaluating 
the Efficacy, Safety, and Tolerability of Selonsertib in Subjects with Diabetic 
Kidney Disease (Study GS-US-223-1015)
Study GS-US-223-1015 is a Phase 2, double-blind, placebo-controlled, dose-ranging study that 
evaluated the efficacy, safety, and tolerability of SEL in subjects with DKD. Three-hundred and 
thirty-three subjects with type 2 diabetes mellitus and Stage 3 or Stage 4 renal impairment and 
albuminuria receiving standard of care treatment for DKD were randomized (1:1:1:1) to 1 of 
4 treatment groups: SEL 2, 6, or 18 mg or matching placebo administered once daily for 
48 weeks. The primary objective of this study was to determine the effect of SEL on the decline 
of estimated glomerular filtration rate (eGFR) in subjects with DKD.
1.2.4.1.
Subject Disposition
Of the 334 randomized subjects, 333 subjects were treated with placebo or study drug: 
85 subjects with placebo and 248 subjects with active treatment (81, 84, and 83 subjects with 
SEL 2, 6, and 18 mg, respectively).
A total of 256 subjects (76.9%) completed treatment and 76 subjects (22.8%) discontinued study 
drug (19 subjects [22.4%] in the placebo group and 57 subjects [23.0%] in the pooled active 
treatment group [18.5%, 21.4%, and 28.9% for SEL 2, 6, and 18 mg, respectively]). The most 
frequent reason for discontinuation of study drug was due to an AE (4 subjects [4.7%] in the 
placebo group and 18 subjects [7.3%] in the pooled active treatment group), followed by 
progression to end-stage renal disease (4 subjects [4.7%] in the placebo group and 13 subjects 
[5.2%] in the pooled active treatment group), and withdrawal of consent (3 subjects [3.5%] in the 
placebo group and 13 subjects [5.2%] in the pooled active treatment group).
1.2.4.2.
Safety Analyses
Overall 80.8% of subjects had a treatment-emergent adverse event with a frequency of 83.5% in 
the placebo group and 79.8% in the pooled active group (79%, 84.5%, and 75.9% for 2 mg, 6 mg 
and 18 mg, respectively). Adverse events related to study drug occurred in 9.4% of subjects in 
the placebo group and 12.5% of subjects in the pooled active treatment group (8.6%, 11.9%, and 
16.9% for 2 mg, 6 mg and 18 mg, respectively). Overall, deaths occurred in 1.2% of subjects 
with a frequency of 1.2% in the placebo group and 1.2% in the pooled active treatment group 
(1.2%, 1.2%, and 1.2% for 2 mg,   6 mg and 18 mg, respectively). SEL treatment was well 
tolerated and no dose-limiting toxicity was observed.
1.2.4.3.
Efficacy Analyses
The primary endpoint measure of eGFR change from baseline at Week 48 was -3.20 (SE 0.85), -
2.83 (0.86), -2.37 (0.87), and -4.07 (0.89) mL/min/1.73 m2 for placebo, 2 mg, 6 mg and 18 mg 
SEL respectively (p= NS). The study did not demonstrate that SEL lead to a statistically 
significant decrease in eGFR after 48 weeks of treatment compared to placebo.


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1.2.5.
A Phase 2, Dose-ranging, Randomized, Double-blind, Placebo-controlled 
Study of Selonsertib in Subjects with Pulmonary Arterial Hypertension 
(Study GS-US-357-1394)
Study GS-US-357-1394 is a Phase 2, randomized, double-blind, placebo-controlled, multicenter, 
dose-ranging study of SEL in subjects with PAH receiving background stable PAH therapy. 
One-hundred and fifty-one subjects with a diagnosis of idiopathic PAH (IPAH), heritable PAH 
(HPAH), or PAH associated with connective tissue disease (PAH-CTD), congenital heart defects 
(repaired), drug and toxin use, or HIV infection were randomized 1:1:1:1 to receive either SEL 2,
6, or 18 mg or placebo, orally, once daily, for 24 weeks (Period 1). Subjects continued to receive 
their background PAH therapy throughout the study. Subjects who completed the 24-week 
blinded treatment period were eligible to continue (or initiate) treatment with SEL at 2, 6, or 
18 mg during the blinded, long-term treatment extension of this study (Period 2). The Active 
Period was defined for individuals who received at least 1 SEL dose, including subjects who 
received SEL in Period 2 only. The primary objective of this study was to evaluate the effect of 
SEL on pulmonary vascular resistance (PVR), as measured by right heart catheterization (RHC) 
in subjects with PAH.
1.2.5.1.
Subject Disposition
Of the 151 randomized subjects, 150 subjects were treated with placebo or study drug in 
Period 1: 37 subjects with placebo and 113 subjects with active treatment (39, 37, and 
37 subjects with SEL 2, 6, and 18 mg, respectively). A total of 129 subjects (97 from the 
SEL groups and 32 from the placebo group) continued into Period 2 of the study. All subjects 
discontinued study drug during Period 2, primarily because the sponsor terminated the study 
(82.9% of subjects overall).
A total of 132 subjects (88.0%) completed Period 1 treatment and 18 subjects (12.0%) 
discontinued study drug before reaching Week 24 (5 subjects [13.5%] in the placebo group and 
13 subjects [11.5%] in the pooled active treatment group [12.8%, 16.2%, and 5.4% for SEL 2, 6, 
and 18 mg, respectively]). The most frequent reason for discontinuation of study drug was due to 
an AE (2 subjects [5.4%] in the placebo group and 6 subjects [5.3%] in the pooled active 
treatment group), followed by investigator’s discretion (0 subjects in the placebo group and 
3 subjects [2.7%] in the pooled SEL group), death (1 subject [2.7%] in the placebo group and 
2 subjects [1.8%] in the pooled active treatment group), and increase in dose of PAH medication 
or new PAH medication added (1 subject [2.7%] in the placebo group and 2 subjects [1.8%] in 
the pooled SEL group).
1.2.5.2.
Safety Analyses
In Period 1, AEs were reported with a frequency of 97.3% in the placebo group and 90.3% in the 
pooled active group (89.7%, 91.9%, and 89.2% for 2 mg, 6 mg and 18 mg, respectively). 
Adverse events related to study drug occurred in 48.6% in placebo and 42.5% in the pooled 
active treatment group (25.6%, 56.8%, and 45.9% for 2 mg, 6 mg and 18 mg, respectively). In 
the Active Period, AEs were reported for 98.0%, 93.9%, and 97.9% of subjects in the SEL 2, 6, 
and 18 mg groups, respectively. In both Period 1 and the Active Period, the most commonly 
reported AEs were headache, diarrhea, and nausea.


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Over the course of the study and during follow-up vital status checks, a total of 12 subjects died 
(3, 5, and 2 subjects in the SEL 2, 6, and 18 mg groups, respectively, and 2 subjects in the 
placebo group). Nine of the deaths (7 subjects who received SEL and 2 subjects who received 
placebo only) were treatment emergent. Of the treatment-emergent deaths, 6 occurred during 
Period 1 and 3 occurred during the Active Period (after Period 1).
There were no dose-related trends in AE reporting across the SEL doses evaluated.  
1.2.5.3.
Efficacy Analyses
The primary efficacy endpoint (change in PVR from baseline to Week 24) and secondary 
efficacy endpoints were not met. 
1.2.6.
Study GS-US-416-2124: A Phase 2, Double-Blind, Randomized Study 
Evaluating the Safety, Tolerability, and Efficacy of SEL in Combination with 
Prednisolone versus Prednisolone Alone in Subjects with Severe Alcoholic 
Hepatitis
1.2.6.1.
Study Design
Study GS-US-416-2124 is an ongoing Phase 2, double-blind, randomized study evaluating the 
safety, tolerability, and efficacy of SEL in combination with prednisolone (PRED) versus PRED 
alone in subjects with severe, histologically-confirmed AH. The study is fully enrolled. Subjects 
were required to have a clinical diagnosis of severe AH (Maddrey’s discriminant function 
[DF] ≥32) based on a history of excessive alcohol consumption (> 40 g/day for women; 
> 50 g/day for men) and onset of jaundice during the past 3 months, AST ≥50 and ≤400 U/L, 
ALT ≤ 300 U/L, and AST/ALT ratio ≥1.5. Model for End-Stage Liver Disease (MELD) score 
was to be ≤ 30 and Maddrey’s DF ≤ 60 at screening. Up to 120 subjects were to be randomized 
in a 1:1 ratio to 1 of 2 treatment groups: SEL 18 mg once daily + PRED 40 mg once daily for 
28 days (Group A) or SEL placebo once daily + PRED 40 mg once daily for 28 days (Group B). 
Subjects will be followed for an additional 20-week posttreatment period. The primary endpoint 
is the safety of SEL in combination with PRED versus PRED alone.
Preliminary safety data from the primary analysis, based on a data cutoff date of 
16 February 2018 (date of the Week 8 visit for the last subject), are presented below.
1.2.6.2.
Subject Disposition
As of 16 February 2018, a total of 104 subjects were randomized (52 in each group). Of the 
randomized subjects, 102 received at least 1 dose of study drug (50 and 52 in the SEL + PRED 
and placebo + PRED groups, respectively). A total of 77 subjects (75.5% overall) completed 
treatment with SEL or placebo; 18 subjects (36.0%) discontinued SEL and 7 subjects (13.5%)
discontinued placebo treatment in the SEL + PRED and placebo + PRED groups, respectively. 
The reasons for discontinuation of SEL were AE (14.0%), lack of efficacy (12.0% met protocol
stopping criteria and 4.0% at investigator’s discretion), and subject or proxy decision, death, and 
liver biopsy inconsistent with diagnosis of severe AH (each 2.0%). In the placebo + PRED 


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group, the reasons for discontinuation of placebo were AE (7.7%), subject or proxy decision 
(3.8%), and protocol violation (1.9%). Thirty subjects (60.0%) in the SEL + PRED group and 
40 subjects (76.9%) in the placebo + PRED group completed treatment with PRED. 
As of 16 February 2018, 16 subjects (32.0%) in the SEL + PRED and 23 subjects (44.2%) in the
placebo + PRED groups remain on study in the posttreatment follow-up period. 
1.2.6.3.
Safety Results
The frequency of AEs was similar for both treatment groups: 47 subjects (94.0%) and 
49 subjects (94.2%) in the SEL + PRED and placebo + PRED groups, respectively. The 
frequency of treatment-related AEs was similar for both groups: 13 subjects (26.0%) and 
14 subjects (26.9%) in the SEL + PRED and placebo + PRED groups, respectively. Adverse 
events leading to discontinuation of SEL or placebo were reported for 9 subjects (18.0%) in the 
SEL + PRED group and 4 subjects (7.7%) in the placebo + PRED group.
At the time of the data cutoff date of 16 February 2018, a total of 20 subjects had died: 
14 subjects (28.0%) in the SEL + PRED group and 6 subjects (11.5%) in the placebo + PRED 
group. The majority of these deaths occurred after subjects had completed or prematurely 
discontinued study drug. Four deaths (2 in each group) occurred up to Day 28 (i.e., during the 
planned duration of treatment). Most deaths involved complications of severe alcoholic hepatitis, 
including infections. 
The most commonly reported AEs in the SEL + PRED group were ascites and hyponatremia 
(each 16 subjects [32.0%]), hepatic encephalopathy (14 subjects [28.0%]), and edema peripheral 
(13 subjects [26.0%]). In the placebo + PRED group, the most commonly reported AEs were 
ascites (15 subjects [28.8%]), edema peripheral (11 subjects [21.2%]), and hepatic 
encephalopathy (10 subjects [19.2%]).
A greater percentage of subjects in the SEL + PRED group (25 subjects [50.0%]) experienced 
SAEs compared with the placebo + PRED group (21 subjects [40.4%]). The most common SAEs 
overall were hepatic encephalopathy, acute kidney injury, cellulitis, coagulopathy, hepatorenal 
syndrome, hyponatremia, and pneumonia. A greater percentage of subjects in the SEL + PRED 
group (12 subjects [24.0%]) experienced SAEs of infections compared with the placebo + PRED 
group (5 subjects [9.6%]), which included SAEs of brain abscess reported in 2 subjects in the 
SEL + PRED group at the same study site (PTs: brain abscess and fungal abscess central nervous 
system, 1 subject each).
Overall, rates of AEs were similar between subjects in the SEL + PRED and placebo + PRED 
groups. However, higher rates of serious infections and hyponatremia were seen in subjects with 
severe AH who received SEL + PRED compared with placebo + PRED.


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1.2.7.
A Phase 2, Randomized, Open Label Study Evaluating the Safety, 
Tolerability, and Efficacy of Selonsertib alone or in Combination with 
Simtuzumab (SIM) in Subjects with Nonalcoholic Steatohepatitis (NASH) 
and Fibrosis (F2-F3) (GS-US-384-1497)
This multicenter, randomized, open-label study evaluated the safety, tolerability, and efficacy of 
SEL (6 mg or 18 mg) alone or in combination with simtuzumab (SIM, a monoclonal antibody 
directed against LOXL2 evaluated for the treatment of NASH) for 24 weeks in subjects with 
NASH and fibrosis stages F2 or F3. 
The primary objective of this study was to evaluate the safety and tolerability of SEL alone or in
combination with SIM in subjects with NASH and fibrosis stages F2 or F3.
Subjects were randomized in a 2:2:1:1:1 ratio to 1 of 5 treatment groups:

SEL 6 mg orally once daily (N = 20)

SEL 18 mg orally once daily (N = 22)

SEL 6 mg orally once daily + SIM 125 mg subcutaneous injection weekly (N = 10)

SEL 18 mg orally once daily + SIM 125 mg subcutaneous injection weekly (N = 10)

SIM 125 mg subcutaneous injection weekly (N = 10)
Randomization was stratified by the presence or absence of diabetes mellitus as determined by 
medical history or based on screening laboratory values if previously undiagnosed 
(i.e., hemoglobin A1c [HbA1c] ≥ 6.5% or fasting plasma glucose ≥126 mg/dL).
Overall, after 24 weeks of treatment, no additional benefit was observed with the addition of 
SIM 125 mg to the SEL (18 or 6 mg) study treatment regimens. Moreover, data from the SIM 
Phase 2b program (studies GS-US-321-0105 and GS-US-321-0106) showed that SIM has no 
anti-fibrotic effect in subjects with advanced fibrosis due to NASH. Therefore, preliminary 
efficacy results are presented by the following pooled groups: SEL 18 mg ± SIM 125 mg, SEL 
6 mg ± SIM 125 mg, and SIM 125 mg alone. 
1.2.7.1.
Subject Disposition and Demographics
A total of 72 subjects were randomized and treated across 23 sites (21 in the US and 2 in 
Canada); 67 subjects (93.1%) completed study treatment. Of the 5 subjects who did not complete 
study treatment, 3 subjects discontinued due to AEs, 1 subject withdrew consent, and 1 subject 
was lost to follow-up.


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1.2.7.2.
Safety Results 
Overall, 79.2% of subjects had a treatment-emergent adverse event with a frequency of 70% in 
the SIM alone group and 80.6% in the pooled active group (85%, 68.2%, 90%, and 90% in the 
SEL 6 mg, SEL 18 mg, SEL 6 mg + SIM, and SEL 18 mg + SIM, respectively). Adverse events 
related to study drug occurred in 0% of the SIM alone group and 33.9% in the pooled active 
treatment group (40%, 31.8%, 20%, and 40% in the SEL 6 mg, SEL 18 mg, SEL 6 mg + SIM, 
and SEL 18 mg + SIM, respectively).
Overall, SEL 6 mg or 18 mg ± SIM 125 mg administered for 24 weeks was generally well 
tolerated in study GS-US-384-1497. The majority of subjects reported at least 1 AE, and most 
AEs were mild or moderate in severity. Three subjects discontinued study treatment due to AEs: 
2 subjects (9.1%) in the SEL 18 mg group (diarrhea and hypoesthesia in 1 subject and increased 
hepatic enzymes in 1 subject) and 1 subject (5.0%) in the SEL 6 mg group (worsened 
schizophrenia). A total of 11 SAEs were reported in 5 subjects during the study. Of these, only 
1 SAE (hypoesthesia) was considered related to study drug by the investigator. No trends in SAE 
type or onset were observed. There were no deaths reported. Treatment-emergent Grade 3 and 4 
laboratory abnormalities were infrequent. There were 4 subjects who developed an increase of 
ALT or AST of at least 2 baseline and at least 3 ULN, leading to permanent discontinuation 
of study drug in 1 subject. No trends in ECG findings suggestive of cardiac abnormalities were 
observed.
1.2.7.3.
Efficacy Results 
1.2.7.3.1.
Histology 
1.2.7.3.1.1.
Change in Liver Fibrosis including NASH CRN Fibrosis Stage and Hepatic 
Collagen Content 
Table 1-1 presents a summary of selected histologic endpoints following 24 weeks of treatment 
with SEL 18 mg ± SIM 125 mg, SEL 6 mg ± SIM 125 mg, or SIM 125 mg alone. Figure 1-2
presents fibrosis response for subjects with evaluable NASH CRN fibrosis stage data at 
Week 24.
At Week 24, there were more subjects with fibrosis improvement (≥ 1 stage decrease in NASH 
CRN fibrosis stage from baseline) in the SEL 18 mg ± SIM 125 mg group (43.3%, 13 of 
30 subjects) and in the SEL 6 mg ± SIM 125 mg group (29.6%, 8 of 27 subjects) compared with 
the SIM 125 mg alone group (20.0%, 2 of 10 subjects). The proportion of SEL treated subjects 
with fibrosis improvement was greater in those with baseline F3 fibrosis (50.0%, 10 of 
20 subjects in the SEL 18 mg ± SIM 125 mg group and 35%, 7 of 20 subjects in the SEL 6 mg 
± SIM 125 mg group) compared to those with baseline F2 fibrosis (30%, 3 of 10 subjects in the 
SEL 18 mg ± SIM 125 mg group and 14.3%, 1 of 7 in the SEL 6 mg ± SIM 125 mg group).
No additional benefit was observed with the addition of SIM 125 mg to the SEL (18 or 6 mg) 
study treatment regimens. At Week 24, the number of subjects with fibrosis improvement 
without worsening of NASH inflammation or ballooning was 42.9% (9 of 21 subjects) in the 


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SEL 18 mg alone group and 23.5% (4 of 17 subjects) in the SEL 6 mg alone group compared 
with the SEL 18 mg + SIM group (11.1%, 1 of 9 subjects) and the SEL 6 mg + SIM group (30%, 
3 of 10 subjects).
Fewer subjects had worsening in the NASH CRN fibrosis stage at Week 24 or progressed to 
cirrhosis in the SEL 18 mg ± SIM 125 mg group (6.7%, 2 of 30 subjects or 3.3%, 1 of 
30 subjects, respectively) and the SEL 6 mg ± SIM 125 mg group (14.8%, 4 of 27 subjects or 
7.4%, 2 of 27 subjects, respectively) compared with the SIM 125 mg alone group (40.0%, 4 of 
10 subjects or 20.0%, 2 of 10 subjects, respectively).
Table 1-1.
GS-US-384-1497: Selected Histologic Endpoints at Week 24 
(Evaluable Subjects, Full Analysis Set)
SEL 18 mg
± SIM 125 mg
(N = 32)
SEL 6 mg
± SIM 125 mg
(N = 30)
SIM 125 mg
(N = 10)
Subjects with Fibrosis Improvement at Week 24
13/30 (43.3%)
8/27 (29.6%)
2/10 (20.0%)
95% CI
25.5% to 62.6%
13.8% to 50.2%
2.5% to 55.6%
Subjects with Fibrosis Improvement without 
Worsening in NASH inflammation or ballooning 
at Week 24
10/30 (33.3%)
7/27 (25.9%)
2/10 (20.0%)
95% CI
17.3% to 52.8%
11.1% to 46.3%
2.5% to 55.6%
Subjects with Worsening of Fibrosis at Week 24
2/30 (6.7%)
4/27 (14.8%)
4/10 (40.0%)
95% CI
0.8% to 22.1%
4.2% to 33.7%
12.2% to 73.8%
Subjects with Progression to Cirrhosis at Week 24
1/30 (3.3%)
2/27 (7.4%)
2/10 (20.0%)
95% CI
0.1% to 17.2%
0.9% to 24.3%
2.5% to 55.6%
Subjects with NAS Response at Week 24
7/31 (22.6%)
5/27 (18.5%)
2/10 (20.0%)
95% CI
9.6% to 41.1%
6.3% to 38.1%
2.5% to 55.6%
Subjects with NAS Response and without 
Worsening of Fibrosis at Week 24
7/31 (22.6%)
5/27 (18.5%)
1/10 (10.0%)
95% CI
9.6% to 41.1%
6.3% to 38.1%
0.3% to 44.5%
Fibrosis improvement was defined as at least 1-stage decrease in NASH CRN fibrosis stage from baseline at Week 24.
No worsening was defined as postbaseline - baseline ≤ 0.
Progression to cirrhosis was defined as NASH CRN fibrosis stage increase to 4 from 2 or 3 at baseline.
NAS Response was defined as NAS decrease by 2 or more from baseline.
Within-group CI was based on Clopper-Pearson method.
Median percent change from baseline at Week 24 in morphometric collagen content for subjects 
treated with SEL 18 mg ± SIM 125 mg or SEL 6 mg ± SIM 125 mg were −8.7% and −8.2%, 
respectively, compared with an increase of 2.1% in subjects treated with SIM 125 mg alone.


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Figure 1-2.
GS-US-384-1497: NASH CRN Fibrosis Response at Week 24 
(Evaluable Subjects, Full Analysis Set)
Fibrosis improvement was defined as ≥ 1-stage decrease in NASH CRN fibrosis stage from baseline at Week 24.
Fibrosis worsening was defined as ≥1-stage increase in NASH CRN fibrosis stage from baseline at Week 24.
1.2.7.3.1.2.
Change in NAFLD Activity Score (NAS)
There were improvements (≥ 1 point) in the NAS for subjects in the SEL 18 mg ± SIM 125 mg 
group (51.6%, 16 of 31 subjects), the SEL 6 mg ± SIM 125 mg group (40.7%, 11 of 27 subjects), 
and the SIM 125 mg alone group (60.0%, 6 of 10 subjects). Improvements in the NAS resulted
from improvements in all 3 subscores of steatosis, lobular inflammation, and hepatocyte 
ballooning, without a clear predominance of improvement in any single subscore. There was a 
greater proportion of subjects in the SEL 18 mg ± SIM 125 mg group (32.3%, 10 of 31 subjects) 
and the SEL 6 mg ± SIM 125 mg group (22.2%, 6 of 27 subjects), that achieved a ≥1-point 
improvement in the lobular inflammation subscore than in the SIM 125 mg alone group (20.0%, 
2 of 10 subjects). Fewer subjects in the SEL 18 mg ± SIM 125 mg group (9.7%, 3 of 31 subjects) 
and the SEL 6 mg ± SIM 125 mg group (18.5%, 5 of 27 subjects) had worsening in the NAS 
compared with the SIM 125 mg alone group (30.0%, 3 of 10 subjects).
1.2.7.3.1.3.
Change in Cytokeratin-18
Cytokeratin-18 (CK18) is an intracellular protein expressed at high levels in most cell types of 
epithelial origin, including hepatocytes, which can be used as a marker of hepatocyte death. The 
CK18 M30 subfraction represents a caspase cleavage product that indicates apoptotic cell death, 
while CK18 M65 indicates total soluble CK18 released from dead (apoptotic and necrotic) 
hepatocytes {Feldstein 2009}. Across all groups, decreases from baseline in CK18 M30 and 
CK18 M65 fractions were observed at Week 24. Greater median relative decreases in CK18 M30 
Change 
100% 
90% 
80% 
.l!l 70% 
50% 
g 
B 
60% -
56% 
::I 
(/) - 50% 
0 -
C 
40% 
40% 
Q) 
0 '-
Q) 30% 
Q_ 
20% 
43% 
30% 
10% 
20% 
0% 
SEL 18 mg 
SEL 6 mg 
SIM 125 mg 
± SIM 125 mg 
± SIM 125 mg 
(N = 10) 
(N = 30) 
(N = 27) 


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and M65 were observed in the SEL 18 mg ± SIM 125 mg group (−31% and −44%, respectively) 
and the SEL 6 mg ± SIM 125 mg group (−6% and −35%, respectively) compared with the SIM 
125 mg alone group (22% and −4%, respectively).
1.2.7.3.1.4.
Summary of Efficacy Results
Treatment with SEL in GS-US-384-1497 resulted in histologic improvements in subjects with 
biopsy proven NASH and F2-F3 fibrosis. Although the small size of the study precluded formal 
statistical comparisons between treatment groups, numerically superior improvements were also 
consistently observed in the following endpoints in SEL treated compared with SIM-treated 
subjects:

Subjects treated with SEL (18 or 6 mg) ± SIM 125 mg had a ≥ 1 stage decrease in NASH 
CRN fibrosis stage from baseline in 43.3 % and 29.6 % of subjects, respectively, compared 
with 20.0% of subjects treated with SIM 125 mg alone. 

Subjects treated with SEL (18 or 6 mg) ± SIM 125 mg were less likely to have worsening of 
fibrosis (6.7% and 14.8%, respectively) or progression to cirrhosis (3.3% and 7.4%, 
respectively) compared with subjects treated with SIM 125 mg alone (40.0% with worsening 
of fibrosis and 20.0% with progression to cirrhosis).

Consistent with fibrosis stage improvement, subjects treated with SEL (18 or 6 mg) ± SIM 
125 mg had reductions in hepatic collagen content as measured by MQC (−8.7% and −8.2%, 
respectively) versus an increase of 2.1% in subjects treated with SIM 125 mg alone 

Greater reductions in CK18 M30 and M65 fractions in subjects treated with SEL (18 or 
6 mg) ± SIM 125 mg versus SIM 125 mg alone, indicate reduced rates of hepatocellular 
apoptosis and necrosis, and are consistent with improvements in fibrosis stage and liver 
biochemistry tests. The dose-dependent reductions in CK18 M30 and M65 fractions also 
support the mechanism of action of SEL.
Across all treatment groups, no clinically significant worsening in metabolic or cardiovascular 
risk factors from baseline and no significant change in weight were observed at Week 24.
Collectively, these data support that SEL treatment results in fibrosis regression, improvements 
in liver biochemistry, and reductions in hepatic fat, inflammation, and apoptosis in subjects with 
NASH and moderate to severe liver fibrosis.


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1.2.8.
Study GS-US-384-3914: A Phase 2, Proof-of-Concept, Open-Label Study 
Evaluating the Safety, Tolerability, and Efficacy of Regimens in Subjects 
with Nonalcoholic Steatohepatitis
1.2.8.1.
Study Design
Study GS-US-384-3914 is an ongoing Phase 2, proof-of-concept, open-label study evaluating 
the safety, tolerability, and efficacy of SEL, GS-0976, and GS-9674 in subjects with NASH as 
assessed by magnetic resonance imaging proton density fat fraction (MRI-PDFF) and magnetic 
resonance elastography (MRE). Cohorts 1 through 6 and 9 will evaluate treatments in 
noncirrhotic subjects and Cohorts 7 and 8 will evaluate treatments in cirrhotic subjects.
A total of approximately 120 subjects will be enrolled in 1 of 9 cohorts to receive SEL 18 mg 
once daily (Cohort 1), GS-0976 20 mg once daily (Cohort 2), GS-9674 30 mg once daily with 
food (Cohort 3), SEL 18 mg + GS-9674 30 mg once daily with food (Cohort 4), SEL 18 mg + 
GS-0976 20 mg once daily (Cohort 5), GS-9674 30 mg + GS-0976 20 mg once daily with food 
(Cohort 6), GS-0976 20 mg once daily (Cohort 7), GS-9674 30 mg once daily with food 
(Cohort 8), or SEL 18 mg + GS-0976 20 mg + GS-9674 30 mg once daily with food (Cohort 9) 
for 12 weeks.
The primary endpoint is the safety of the study drug(s). 
 
 
Preliminary safety data cohorts evaluating treatments with SEL (Cohorts 1, 4, 5, and 9) from an 
interim analysis as of 31 January 2018 are presented below. 
1.2.8.2.
Subject Disposition
As of 31 January 2018, a total of 61 subjects have been enrolled in Cohort 1 (10 subjects), 
Cohort 4 (20 subjects), Cohort 5 (20 subjects), and Cohort 9 (11 subjects). Among these subjects, 
1 enrolled subject in Cohort 9 did not receive study drug. All subjects in Cohorts 1, 4, and 5 have 
completed study drug, and all 10 subjects in Cohort 9 remain on treatment.
1.2.8.3.
Preliminary Safety Results
Adverse events were reported for 5 subjects (50.0%) in Cohort 1, 5 subjects (25.0%) in Cohort 4, 
8 subjects (40.0%) in Cohort 5, and 4 subjects (40.0%) in Cohort 9. No deaths or AEs leading to 
premature discontinuation of study drug were reported.
The 3 most commonly reported AEs across Cohorts 1, 4, 5, and 9 were headache, diarrhea, and 
constipation. Treatment-related AEs were reported for 3 subjects (30.0%) in Cohort 1, 2 subjects 
(10.0%) in Cohort 4, 5 subjects (25.0%) in Cohort 5, and 3 subjects (30.0%) in Cohort 9. 
Treatment-related AEs reported for > 1 subject in Cohorts 1, 4, 5, or 9 included diarrhea 
(2 subjects [10.0%] in Cohort 5) and headache (2 subjects [20.0%] in Cohort 9).  
Serious adverse events were cellulitis in 1 subject in Cohort 4 and tooth abscess in 1 subject in 
Cohort 5. Neither of these events was considered treatment related.
CCI


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1.2.9.
Adverse Events Pooled Across Nonalcoholic Steatohepatitis
Studies GS-US-384-1497 and GS-US-384-3914
In a pooled analysis of AEs across the 2 NASH Studies GS-US-384-1497 and GS-US-384-3914, 
72 of 122 (59.0%) subjects who received SEL reported AEs: 46 (50.0%) of those who received 
SEL 18 mg and 26 (86.7%) of those who received SEL 6 mg. The most common AEs in the 
pooled SEL group were headache (18 [14.8%] subjects), nausea (12 [9.8%] subjects), 
constipation, fatigue, and sinusitis (each with 8 [6.6%] subjects).
1.2.10.
Study GS-US-384-1943: A Phase 3, Randomized, Double-Blind, 
Placebo-Controlled Study Evaluating the Safety and Efficacy of SEL in 
Subjects with Nonalcoholic Steatohepatitis and Bridging (F3) Fibrosis
1.2.10.1.
Study Design
Study GS-US-384-1943 is an ongoing Phase 3, randomized, double-blind, placebo-controlled 
study evaluating the safety and efficacy of SEL in subjects with NASH (defined as the presence 
of at least grade 1 steatosis, hepatocellular ballooning, and lobular inflammation according to the 
NAS) and bridging (F3) fibrosis.
A total of approximately 800 subjects will be randomized in a 2:2:1 ratio into 1 of 3 treatment 
groups: SEL 6 or 18 mg, or matching placebo administered once daily for 240 weeks.
The primary efficacy endpoint at Week 48 is the proportion of subjects who achieve a ≥1-stage 
improvement in fibrosis (according to the NASH CRN classification) without worsening of 
NASH (defined as a ≥ 1-point increase in hepatocellular ballooning or lobular inflammation).
The clinical efficacy endpoint at Week 240 is event-free survival (EFS), which will be assessed 
by the time to the first clinical event including progression to cirrhosis, liver decompensation 
events, liver transplantation, or all-cause mortality.
Subjects who experience a hepatic clinical event (except histologic progression to cirrhosis, 
all-cause mortality, and liver transplantation) prior to completing the Week 240 visit of the 
randomized phase will be offered the option to rollover into an open-label phase of the study. 
Each of these clinical events will require confirmation by a Hepatic Events Adjudication 
Committee. 
Preliminary safety data from an interim analysis as of 12 January 2018 are presented below.
1.2.10.2.
Subject Disposition
As of 12 January 2018, a total of 458 subjects have been randomized and 425 subjects have been 
treated in the randomized phase of the study for a median (min, max) of 11.9 (0.1, 44.1) weeks. 
Three subjects prematurely discontinued study drug: 2 subjects due to subject decision and 
1 subject due to AE. A total of 421 subjects remain on treatment. Because the study is ongoing 
and blinded, the treatment received by these subjects is unknown.


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1.2.10.3.
Preliminary Safety Results
This ongoing study is blinded and subject treatment assignment is unknown; therefore, data 
presented below are pooled across treatment groups.
A total of 217 subjects (51.1%) had at least 1 AE. The majority of AEs were Grade 1 in severity. 
The most commonly reported AEs were diarrhea (30 subjects, 7.1%), fatigue (24 subjects, 
5.6%), and headache (23 subjects, 5.4%). Treatment-related AEs were reported for a total of 
85 subjects (20.0%). 
One subject experienced an AE (Grade 2 myalgia) leading to discontinuation of study drug. No 
deaths were reported.
Serious adverse events were reported for 11 subjects (2.6%). No SAE was reported in more than 
1 subject, and none of the events were considered treatment related by the investigator.
1.2.11.
Study GS-US-384-1944: A Phase 3, Randomized, Double-Blind, 
Placebo-Controlled Study Evaluating the Safety and Efficacy of SEL in 
Subjects with Compensated Cirrhosis due to Nonalcoholic Steatohepatitis
Preliminary safety data from an interim analysis of this Phase 3 study in subjects with F4 fibrosis 
due to NASH as of 12 January 2018 are presented below.
1.2.11.1.
Subject Disposition
As of 12 January 2018, a total of 696 subjects have been randomized and 656 subjects have been 
treated in the randomized phase of the study for a median (min, max) of 12.1 (0.1, 51.9) weeks. 
Four subjects prematurely discontinued study drug: 2 subjects due to investigator’s discretion 
and 2 subjects due to subject decision. A total of 646 subjects remain on treatment in the 
randomized phase. Six subjects experienced protocol-specified clinical events during the 
randomized phase and entered the open-label phase of the study; these 6 subjects remain on 
treatment in the open-label phase. 
1.2.11.2.
Preliminary Safety Results
This ongoing study is blinded and subject treatment assignment is unknown; therefore, data 
presented below are pooled across treatment groups.
A total of 357 subjects (54.4%) had at least 1 AE. The majority of AEs were Grade 1 in severity. 
The most commonly reported AEs were nausea (57 subjects, 8.7%), headache (49 subjects, 
7.5%), and diarrhea (40 subjects, 6.1%). Treatment-related AEs were reported for a total of 
126 subjects (19.2%). 
Adverse events leading to discontinuation of study drug in the randomized phase were reported 
for 7 subjects (1.1%), 6 of whom met criteria for protocol-specified clinical events and entered 
the open-label phase of the study. 


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Serious adverse events were reported for 24 subjects (3.7%). The most common type of SAEs 
was gastrointestinal disorders (6 subjects, 0.9%). Serious adverse events that were reported in 
> 1 subject included sepsis (3 subjects, 0.5%) and chest pain and hepatic encephalopathy (each 
2 subjects, 0.3%). No SAEs were assessed as treatment related by the investigator. No deaths 
were reported.
For further information on SEL, refer to the IB for SEL.
1.3.
Rationale for This Study
NASH is an increasingly prevalent cause of cirrhosis for which there is no currently approved 
therapy. The greatest morbidity and mortality due to NASH are observed in patients with 
advanced fibrosis {Ekstedt 2014, Yeh 2014}. As described by Angulo et al., advanced fibrosis is 
the only independent prognostic factor associated with mortality and liver-related morbidity in 
NASH {Angulo 2015}. SEL is a potent and selective small molecule inhibitor of ASK1, a kinase 
which contributes to oxidative stress-mediated hepatocellular damage, apoptosis, inflammation, 
and fibrosis in NASH. By inhibiting ASK1 signaling, SEL is expected to cause regression of 
fibrosis and prevent hepatic complications in subjects with cirrhosis due to NASH. In Phase 2 
study GS-US-384-1497, treatment with SEL 18 mg or 6 mg (± SIM 125 mg) led to a ≥1-stage 
decrease in NASH CRN fibrosis stage from baseline in 43% and 30% of subjects, respectively, 
compared with 20% of subjects treated with SIM alone. Progression to cirrhosis was also less 
frequent with both SEL doses (3% and 7% for 18 mg and 6 mg, respectively) compared with 
SIM alone (20%).
To confirm the anti-fibrotic activity of SEL, this Phase 3 study has been designed as a 
multicenter, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy 
of SEL for 240 weeks in subjects with NASH and compensated cirrhosis. Eight hundred subjects 
with histologically-confirmed NASH and cirrhosis (F4 according to the NASH CRN 
classification) will be randomized in a 2:2:1 ratio to receive SEL at a dose of 6 mg or 18 mg 
orally once daily or placebo. Randomization will be stratified by the presence of diabetes 
mellitus, a common comorbidity in this condition, and ELF™score (< 11.27 vs. ≥11.27) during 
Screening. In the Phase 2b study GS-US-321-0106 of SIM, an ELF™score ≥11.27 was 
associated with an increased risk of death or liver-related clinical events (area under the receiver 
operating characteristic [AUROC] curve, 0.706). The primary objective of this study is to 
evaluate whether SEL can cause fibrosis regression and prevent complications of cirrhosis in this 
high-risk patient population. Efficacy will be determined by changes in liver histology and 
adjudicated hepatic clinical event rates that include hepatic decompensation, liver 
transplantation, and all-cause mortality. Due to the increased risk of cardiovascular morbidity 
and mortality in NASH {Angulo 2015, Ekstedt 2015, Targher 2016}, the impact of SEL on 
metabolic parameters (e.g., lipids and insulin resistance) will be monitored and cardiovascular 
events will be prospectively recorded and adjudicated.


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1.4.
Rationale for Dose Selection of SEL
The doses of SEL chosen for evaluation in this study, 6 mg and 18 mg once daily, are supported 
by a combination of safety and efficacy data from Phase 1 and 2 studies in the clinical 
development program, and pharmacokinetic (PK)/pharmacodynamic (PD) modeling of predicted 
inhibition of p38 phosphorylation, a downstream marker of ASK1 pathway activation. In Phase 2 
studies in subjects with PAH and DKD, SEL reduced blood phosphorylated (activated) p38 in a 
dose-dependent fashion. Based on this exposure-response model, plasma SEL exposures 
observed in the NASH patients in study GS-US-384-1497 after administration of SEL 6 mg or 
18 mg (± SIM 125 mg) would be expected to be associated with 54% and 78% maximal 
inhibition (Emax) of phosphorylated p38, respectively. While the level of inhibition of p38 
phosphorylation that is necessary to achieve beneficial effects in NASH is currently unknown, 
both doses of SEL 6 mg and 18 mg (± SIM 125 mg) administered for 24 weeks in study 
GS-US-384-1497 demonstrated improved efficacy over SIM alone. For example, the proportion 
of subjects that achieved a ≥1-stage reduction in NASH CRN fibrosis stage was higher than 
observed in subjects treated with SIM alone (see above). Progression to cirrhosis was also less 
frequent among SEL-treated subjects. While these data may suggest a dose response, the 6 mg 
dose had better responses than the 18 mg dose for some endpoints (e.g., ≥ 15% reduction in liver 
stiffness by magnetic resonance elastography [MRE]) and the results with prolonged dosing have 
not yet been established. A study of SEL in subjects with cirrhosis and hepatic impairment 
demonstrated no clinically relevant differences in SEL exposure which allows for treatment 
without dose adjustment in patients with cirrhosis. Across the clinical development program, 
SEL administered for up to 48 weeks has been well tolerated with no clear dose-safety 
relationships for incidences or severity of AEs or laboratory abnormalities. However, the 
complete safety profile of SEL has not been fully characterized given the relatively small number 
of subjects treated to date. In order to determine a safe and effective dose for patients with 
NASH-related cirrhosis, it is important to establish the correct balance of efficacy and safety in 
larger studies in this population. For these reasons, testing of both 6 mg and 18 mg SEL once 
daily in this Phase 3 study is planned to further optimize dose selection for the treatment of 
NASH cirrhosis. 
1.4.1.
Rationale for Study Population
The SEL Phase 3 development program is focused on patients with NASH and advanced fibrosis 
due to the significant risk of liver-related complications in this patient population. As reported in 
the PRELHIN study {Angulo 2015}, which examined the natural history of 619 patients with 
histologically-confirmed NAFLD for a median duration of 12.6 years, the cumulative risk of 
liver-related events (defined as ascites, varices/variceal bleeding, HE, and HCC) was 14% in 
patients with F3 fibrosis and 24% in patients with cirrhosis (F4). Event rates in patients with F0, 
F1, and F2 fibrosis were significantly lower at 1.6%, 2.8%, and 7.1%, respectively. Compared to 
patients with F0 fibrosis, the adjusted risk of liver-related events was increased over 13-fold in 
patients with F3 fibrosis and 47-fold in patients with cirrhosis. Similar data have been reported 
by other groups {Ekstedt 2006, Ekstedt 2015, Hagstrom 2016, Younossi 2011}. At present, no 
treatment exists for this high risk patient population. Thus, the NASH subjects with the highest 
unmet need are not currently eligible for any therapy. Targeting interventions to help this 
population would be expected to have the greatest impact on morbidity and mortality. 


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1.5.
Risk/Benefit Assessment for the Study
This study will provide information regarding the safety and efficacy of SEL for the treatment of 
patients with cirrhosis due to NASH. The potential benefits of SEL for the treatment of NASH 
were shown in the Phase 2 study GS-US-384-1497. As described above, rapid fibrosis regression 
was observed in a greater proportion of SEL-treated versus SIM-treated subjects after only 
24 weeks of treatment. Although this study did not include a placebo control arm, these response 
rates to SEL are substantially higher than reported in the placebo groups of Phase 2 trials for 
other compounds in development for NASH {Neuschwander-Tetri 2014, Ratziu 2016}. In 
addition, reductions in liver biochemistries (e.g., ALT, aspartate aminotransferase [AST], gamma 
glutamyl transferase [GGT], liver fat content by magnetic resonance imaging-proton density fat 
fraction [MRI-PDFF], lobular inflammation, liver stiffness by magnetic resonance elastography 
[MRE], and biomarkers of apoptosis and necrosis (serum CK-18 M30 and M65 levels) were 
observed, particularly in fibrosis responders.
Cirrhotic subjects randomized to the placebo control arm in the study may benefit from frequent 
medical monitoring and close assessment of their NASH (e.g., surveillance for HCC and hepatic 
decompensation) and associated pathologies during the duration of placebo treatment. Moreover, 
all subjects, including those treated with placebo during the Randomized Phase, have the 
opportunity to receive SEL treatment during the Open-Label Phase in the event of disease 
progression.
Potential risks of this study include those related to the fact that SEL is a new chemical entity 
with a long term safety profile that has yet to be established. While reductions in NASH CRN 
fibrosis stage were shown in the Phase 2 study of patients with NASH and F2-F3 fibrosis 
(GS-US-384-1497), SEL has not been tested for efficacy in patients with cirrhosis (F4) and a 
similar response in this subgroup is not guaranteed. However, immunohistochemical data 
suggest that the level of ASK1 pathway activation (p38 phosphorylation) is increased in subjects 
with cirrhosis compared with non-cirrhotic fibrosis, suggesting that SEL may also have efficacy 
in this patient subgroup. Moreover, nonclinical studies in rodent models of cirrhosis have shown 
that SEL causes regression of fibrosis and reductions in elevated portal pressure in these animals. 
In nonclinical studies, profuse diarrhea was the dose limiting toxicity in cynomolgus monkeys. 
In Phase 2 clinical studies in AH, PAH, DKD, and NASH, a greater proportion of subjects 
treated with SEL (66 of 565 [11.7%]) had an adverse event of diarrhea compared to placebo or 
SIM-treated subjects (13 of 184 [7.1%]). However, diarrhea was generally mild and self-limited.
Across the development program, drug discontinuation rates were low and not attributable to a 
single AE with increased frequency. In Phase 2 clinical studies in subjects with NASH, AH, 
DKD, or PAH, rates of elevations in liver tests (ALT or AST > 3 upper limit of normal [ULN] 
and > 2 baseline for the NASH studies; ALT or AST > 5 baseline for the AH study; ALT or 
AST > 3 ULN for the DKD and PAH studies) were observed in SEL-treated subjects (17 of 
564 [3.0%]) and placebo-treated subjects (4 of 182 [2.2%]). In many of these cases, an 
alternative and/or confounding etiology was identified including alcohol use, intercurrent illness, 
or concomitant treatment with medications known to cause hepatotoxicity. However, in some 
cases, a plausible alternate etiology was not identified. To mitigate the potential risk of liver 
injury in the planned Phase 3 NASH program, subjects will be monitored closely; defined rules 


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for close observation and drug cessation due to elevated liver tests have been specified in 
Section 7.5; and all potential cases of drug-induced liver injury (DILI) will be adjudicated by an 
independent DILI adjudication committee. In addition, embryofetal toxicity was observed in 
nonclinical studies; therefore to prevent potential fetal exposure, adherence to effective methods 
of contraception will be required during the Phase 3 program.  
Additional risks to study subjects include those attributable to study participation in general, 
including risks associated with frequent clinic visits and laboratory blood draws, and the 
associated pain and discomfort of phlebotomy. Strategies to mitigate these risks include close 
monitoring of lab values as well as AEs. Parameters for discontinuation of the study drugs due to 
AEs and non-hepatic laboratory abnormalities are also defined and will be closely followed.
While the potential benefits and risks described above must be confirmed during the Phase 3 
program, available data in NASH patients treated for 24 weeks, as well as the favorable safety 
profile seen across the Phase 2 studies in NASH, DKD, and PAH, provide strong rationale for a 
positive benefit/risk ratio in support of the study in subjects with cirrhosis due to NASH.
1.6.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES
The primary objective of this study is:

To evaluate whether SEL can cause fibrosis regression and reduce associated complications
in subjects with cirrhosis due to NASH. 
The secondary objective of this study is:

To assess the safety and tolerability of SEL in subjects with NASH and cirrhosis.
The exploratory objectives of this study are as follows:
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3.
STUDY DESIGN
3.1.
Study Design
This is a Phase 3, randomized, double-blind, placebo-controlled study evaluating the safety and 
efficacy of SEL in subjects with compensated cirrhosis due to NASH.
The overall study design is presented graphically in Figure 3-1.
Figure 3-1.
Overall Study Design
3.2.
Treatment Plan and Regimen
Subjects meeting the study’s entry criteria will be randomly assigned in a 2:2:1 ratio to 1 of 
3 treatment groups: Group A, Group B and Group C as shown in Figure 3-1. Randomization will 
be stratified by the presence or absence of diabetes mellitus (as determined by medical history or 
based on Screening lab values if previously undiagnosed [i.e. hemoglobin A1c (HbA1c) ≥6.5% 
or fasting plasma glucose ≥126 milligram/deciliter [mg/dL]) and by ELF™score ≥11.27 or 
< 11.27 during Screening. Study drugs will be administered for up to a total of 240 weeks.
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3.3.
Adjudication Committees
3.3.1.
Hepatic Events Adjudication Committee
A key primary objective of this study is to prevent associated complications attributable to 
cirrhosis. A composite of clinical events that constitute the clinical efficacy endpoint have been 
identified and include:
1) Events of hepatic decompensation including:
a) Clinically apparent ascites requiring treatment
b) HE of Grade 2 or above (according to the West Haven criteria defined in Appendix 5)
requiring treatment
c) Portal hypertension-related upper gastrointestinal bleeding identified by endoscopy and 
requiring hospitalization, including events of bleeding from esophageal varices, gastric 
varices, and portal hypertensive gastropathy
2) Liver transplantation or qualification for liver transplantation, defined as MELD score 
≥15 on at least 2 consecutive occasions at least 4 weeks apart
3) All-cause mortality
Each of the clinical events (except all-cause mortality and liver transplantation) will require 
confirmation by a Hepatic Events Adjudication Committee. All deaths will be reviewed by this 
committee to determine if they are liver-related. Subjects who experience one of these confirmed 
clinical events prior to completing the Week 240 Visit of the Randomized Phase will be offered 
the option to rollover into an Open-Label (OL) Phase of the study. The committee will also 
review all cases of HCC in the Randomized phase as an event of special interest.
Once the clinical event (except all-cause mortality and liver transplantation) is confirmed by the 
Hepatic Events Adjudication Committee, the subject will no longer participate in the 
Randomized Phase and will be offered the option to receive SEL 18 mg in the OL Phase for a 
total treatment duration of 240 weeks inclusive of the Randomized Phase. Rollover into the OL 
Phase of the study must occur within 60 days of confirmation of the event. Subjects starting the 
OL Phase of the study will complete the same study procedures as during the Randomized Phase 
of the study, starting with the Day 1 visit with the exception of the liver biopsy,
 
. Hepatic clinical events will be adjudicated and deaths will be reviewed by the Hepatic 
Events/DILI Adjudication Committee only during the Randomized Phase of the study; potential 
DILI events and cardiovascular events including deaths will continue to be adjudicated in the OL 
Phase by the Hepatic Events/DILI Adjudication Committee and the Cardiovascular Events 
Adjudication Committee, respectively.
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3.3.2.
Cardiovascular Events Adjudication Committee
Cardiovascular events including cardiovascular death, myocardial infarction, stroke, 
hospitalization for unstable angina, hospitalization for cardiac failure, and coronary 
revascularization will be adjudicated by an independent Cardiovascular Events Adjudication 
Committee. Subjects experiencing a cardiovascular event will continue in the Randomized Phase 
and not rollover into the OL Phase. Cardiovascular events will be adjudicated during the 
Randomized Phase and the OL Phase of the study.
3.3.3.
Drug-Induced Liver Injury (DILI) Adjudication Committee
Due to the challenge of recognizing and diagnosing DILI in subjects with pre-existing hepatic 
dysfunction, a DILI Adjudication Committee will review potential cases of DILI (refer to 
Section 7.5). Subjects will be categorized as those for whom DILI or worsening of hepatic 
function attributable to study drug could be excluded (e.g., a clear, alternative explanation 
exists); those for whom DILI or worsening of hepatic function attributable to study drug could 
not be excluded (e.g., no clear, alternative explanation exists); and those with insufficient data to 
make a determination. Potential cases of DILI will be adjudicated during the Randomized Phase 
and the OL Phase of the study.
3.4.
Biomarker Testing
3.4.1.
Biomarker Samples to Address the Study Objectives
The biological specimens collected in this study will be used to evaluate the association of 
exploratory systemic biomarkers with study drug response, including efficacy and/or adverse 
events and to increase knowledge and understanding of the biology of how inhibition of ASK-1 
affects the downstream markers of the pathway. Biological specimens will also be used to 
increase the knowledge of diseases such as NAFLD, liver fibrosis, inflammatory diseases, and/or 
the validation of a companion diagnostic. The specific analyses will include, but will not be 
limited to, the biomarkers and assays described in Table 3-1. Because biomarker science is a 
rapidly evolving area of investigation, and adverse events in particular are difficult to predict, it 
is not possible to specify prospectively all tests that will be performed on the specimens 
provided.  


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Table 3-1.
Exploratory Biomarkers
The testing outlined is based upon the current state of scientific knowledge. It may be modified 
during or after the end of the study to remove tests no longer indicated and/or to add new tests 
based upon the growing state of art knowledge. If a test will no longer be performed, sample 
collection may also be withdrawn to reduce burden on subjects.
Samples will be destroyed no later than 15 years after the end of the study. The specimen storage 
period will be in accordance with the IRB/IEC/EC approved Informed Consent Form (ICF) and 
applicable laws (e.g., health requirements).
3.4.2.
Biomarker Samples for Optional Future Research
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.4.3.
Biomarker Samples for Optional Genomic Research
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
This study will enroll approximately 800 subjects with NASH and compensated cirrhosis.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Willing and able to give informed consent prior to any study specific procedures being 
performed
2) Liver biopsy consistent with NASH (defined as the presence of at least grade 1 steatosis, 
hepatocellular ballooning, and lobular inflammation according to the NAFLD Activity Score 
[NAS]) and cirrhosis (F4 fibrosis) according to the NASH CRN classification, in the opinion 
of the central reader
a) A historical liver biopsy within 12 months of the Screening visit may be accepted as the 
Screening biopsy if the sample is deemed acceptable for interpretation by the central 
reader
b) If the subject is deemed ineligible for this study, the liver biopsy, if performed according 
to protocol specifications and is within 6 months of the Screening visit, may be used to 
determine eligibility for study GS-US-384-1943
3) Subject has the following laboratory parameters at the Screening visit, as determined by the 
central laboratory:
a) ALT ≤ 8 x ULN
b) CLcr ≥ 30 mL/min, as calculated by the Cockcroft-Gault equation
c) HbA1c ≤9.5% (or serum fructosamine ≤ 381 µmol if HbA1c is unable to be resulted)
d) INR ≤ 1.4, unless due to therapeutic anti-coagulation
e) Platelet count ≥ 100,000/µL
4) Body Mass Index (BMI) ≥ 18 kg/m2 at Screening
5) Males and non-pregnant, non-lactating females between 18-70 years of age; inclusive based 
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6) Females of childbearing potential (as defined in Appendix 3) must have a negative pregnancy 
test at Screening and Day 1
7) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in 
Appendix 3
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Prior history of decompensated liver disease, including clinical ascites, HE, or variceal 
bleeding
2) CP score > 7, as determined at Screening, unless due to therapeutic anti-coagulation
3) MELD score > 12, as determined at Screening, unless due to therapeutic anti-coagulation
4) Chronic HBV infection (HBsAg positive)
5) Chronic HCV infection (HCV Ab and HCV RNA positive). Subjects cured of HCV infection 
less than 5 years prior to the Screening visit are not eligible
6) Other causes of liver disease including, but not limited to, alcoholic liver disease, hepatitis B, 
hepatitis C, autoimmune disorders (e.g., primary biliary cholangitis, primary sclerosing 
cholangitis, and autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, iron 
overload, and alpha-1-antitryspin deficiency, based on medical history and/or centralized 
review of liver histology
7) History of liver transplantation
8) Current or history of HCC
9) Any weight reduction surgery in the 2 years prior to Screening or planned during the study 
(weight reduction surgery is disallowed during the study), and malabsorptive weight loss 
surgery (e.g., Roux-en-Y or distal gastric bypass) at any time prior to Screening
10) Weight loss > 10% within 6 months of Screening
11) HIV infection (HIV Ab and HIV ribonucleic acid [HIV RNA] positive) 
12) Current alcohol consumption greater than 21 oz/week for males or 14 oz/week for females 
(1oz/30mL of alcohol is present in 1 12oz/360mL beer, 1 4oz/120mL glass of wine, and a 
1 oz/30 mL measure of 40 proof alcohol)
13) Positive urine drug screen for amphetamines, cocaine or opiates (i.e. heroin, morphine) at 
Screening. Subjects on stable methadone or buprenorphine maintenance treatment for at least 
6 months prior to Screening may be included in the study. Subjects with a positive urine drug 
screen due to prescription opioid-based medication are eligible if the prescription and 
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14) Unstable cardiovascular disease as defined by any of the following:
a) Unstable angina, myocardial infarction, coronary artery bypass graft surgery or coronary 
angioplasty within 6 months prior to Screening
b) Transient ischemic attack or cerebrovascular accident within 6 months prior to Screening
c) Symptomatic obstructive valvular heart disease or hypertrophic cardiomyopathy
d) Symptomatic congestive heart failure 
e) Uncontrolled or recurrent ventricular tachycardia or other arrhythmia requiring an 
automatic implantable cardioverter defibrillator (AICD). Stable, controlled atrial 
fibrillation is allowed.
15) Use of any prohibited concomitant medication as described in Section 5.4. Subjects on 
Vitamin E must be on a stable dose for at least 6 months prior to the diagnostic liver biopsy
and subjects on antidiabetic medications must be on a stable dose for at least 3 months prior 
to diagnostic liver biopsy
16) History of a malignancy within 5 years of Screening with the following exceptions:
a) Adequately treated carcinoma in situ of the cervix
b) Adequately treated basal or squamous cell cancer or other localized non-melanoma skin 
cancer
17) Unable to safely undergo a liver biopsy
18) Participation in another investigational study of a drug or device within 30 days or within 
5 half-lives of the prior investigational agent (whichever is longer) prior to Screening
19) Concurrent participation in another therapeutic clinical study
20) Known hypersensitivity to SEL, the metabolites, or formulation excipient
21) Any laboratory abnormality or condition that, in the investigator’s opinion, could adversely 
affect the safety of the subject or impair the assessment of study results
22) Presence of any condition that could, in the opinion of the investigator, compromise the 
subject’s ability to participate in the study, including a history of substance abuse or a 
psychiatric condition requiring hospitalization or emergency room visit within 2 years of 
Screening
23) Unavailable for follow-up assessment or concern for subject’s compliance with the protocol 
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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
This is a randomized, double-blind, placebo-controlled study. Subjects meeting the study’s entry 
criteria will be randomly assigned in a 2:2:1 ratio to 1 of 3 treatment groups as described in 
Section 5.3.
5.1.
Randomization, Blinding and Treatment Codes
An Interactive Web Response System (IWRS) will be used for centralized randomization and 
treatment assignment. Randomization will be stratified by the presence or absence of diabetes 
mellitus (as determined by medical history or based on Screening lab values if previously 
undiagnosed [i.e., HbA1c ≥ 6.5% or fasting plasma glucose ≥126 mg/dL]) and by ELF™score 
≥11.27 or < 11.27 during Screening.
ELF™score will not be provided to the sites. Stratification will be performed by the IWRS.
Investigative site personnel will obtain the subject’s identification number and study drug 
assignment from the IWRS. Subjects and all personnel directly involved in the conduct of the 
study will be blinded to treatment assignment.
Study drugs during the Randomized Phase will be dispensed by the study pharmacist, or 
designee, in a blinded fashion to the subjects.
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IWRS system 
for that subject (refer to Study Reference Binder for IWRS unblinding instructions). Gilead 
recommends, but does not require, that the investigator contact the Gilead Medical Monitor 
before breaking the blind. Treatment assignment should remain blinded unless that knowledge is 
necessary to determine subject emergency medical care. The rationale for unblinding must be 
clearly explained in source documentation and on the electronic case report form (eCRF), along 
with the date on which the treatment assignment was obtained. The investigator is requested to 
contact the Gilead Medical Monitor promptly in case of any treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead Pharmacovigilance and Epidemiology (PVE) may independently unblind cases for 
expedited reporting of suspected unexpected serious adverse reactions (SUSARs).


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5.2.
Description and Handling of Selonsertib (SEL)
5.2.1.
Formulation
5.2.1.1.
Selonsertib (SEL) 6 mg 
SEL 6 mg tablets will be supplied as pentagon-shaped, film-coated gray tablets debossed with an 
underscored “6” on one side and “GSI” on the other side. The tablets have dimensions of 
approximately 6.4 mm x 6.4 mm. In addition to the active ingredient, SEL 6 mg tablets contain 
the following inactive ingredients: 
 
 
PTM SEL 6 mg tablets are available for blinding purposes. Each placebo tablet is identical to 
SEL 6 mg tablets in their size, shape, and appearance and contains the same inactive ingredients.
5.2.1.2.
Selonsertib (SEL) 18 mg 
SEL 18 mg tablets will be supplied as round, film-coated gray tablets debossed with an 
underscored “18” on one side and “GSI” on the other side. The tablets are approximately 
7.14 mm in diameter. In addition to the active ingredient, SEL 18 mg tablets contain the 
following inactive ingredients: 
 
PTM SEL 18 mg tablets are available for blinding purposes. Each placebo tablet is identical to 
SEL 18 mg tablets in their size, shape, and appearance and contains the same inactive 
ingredients.
5.2.2.
Packaging and Labeling
SEL and PTM SEL tablets are packaged in white, high-density polyethylene (HDPE) bottles. 
Each bottle contains 30 tablets, silica gel desiccant and polyester packing material. Each bottle is 
enclosed with a white, continuous-thread, child-resistant polypropylene screw cap fitted with an 
induction-sealed and aluminum-faced liner.
Study drugs to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), European Union (EU) Guideline to Good Manufacturing Practice - Annex 13 
(Investigational Medicinal Products), and/or other local regulations.
CCI
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5.2.3.
Storage and Handling
SEL and PTM SEL tablets should be stored at controlled room temperature of 25°C (77°F); 
excursions are permitted between 15°C and 30°C (59°F and 86°F). Storage conditions are 
specified on the label. Until dispensed to the subjects, all bottles of study drugs should be stored 
in a securely locked area, accessible only to authorized site personnel. To ensure the stability and 
proper identification, study drugs should not be stored in a container other than the container in 
which they were supplied. Keep the bottle tightly closed to protect from moisture.
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling.
5.3.
Dosage and Administration of Selonsertib (SEL)/ PTM Selonsertib (SEL)
The administration of study drug will be recorded in the source documentation and in the eCRF.
5.3.1.
Selonsertib (SEL)/PTM Selonsertib (SEL)
SEL and PTM SEL tablets will be provided by Gilead Sciences. Subjects will take one tablet 
each of SEL (18 mg or PTM 18 mg and 6 mg or PTM 6 mg) once daily at approximately the 
same time each day. Study drug should be swallowed whole with water and may be taken with or 
without food. A dose will be considered missed if the subject cannot take the dose within 
12 hours of their regular dosing time. If a subject misses a dose, the subject should take their next 
dose at the regular dosing time.
Study drug dosing and administration will occur as follows, based on treatment group 
randomization:

Treatment Group A: one SEL 6 mg tablet + one PTM SEL 18 mg tablet administered orally 
once daily

Treatment Group B: one PTM SEL 6 mg tablet + one SEL 18 mg tablet administered orally 
once daily

Treatment Group C: one PTM SEL 6 mg tablet + one PTM SEL 18 mg tablet administered 
orally once daily 
5.4.
Prior and Concomitant Medications
All concomitant medication will be recorded in the source documents and eCRFs. This includes 
concomitant medications taken within 30 days prior to Screening and any taken during the study 
to the end of the follow-up period.


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The following medications are prohibited for all treatment groups:

Any investigational medication or device within 30 days or within 5 half-lives of the prior 
investigational agent (whichever is longer) prior to Screening and throughout the study.
Subjects enrolled in the current protocol may participate concurrently in a HepQuant™ 
sponsored investigational device study at participating US sites only (Investigational Device 
Exemption # G170034/S002), once approved by the applicable IRB/IEC. 

Strong cytochrome P4503A4 (CYP3A4) inducers may decrease the exposure of SEL and 
could lead to decreased efficacy. Use of strong CYP3A4 inducers is prohibited from 2 weeks 
prior to Day 1 through end of treatment.
Caution should be exercised when co-administering sensitive P-gp substrates with narrow 
therapeutic index with SEL as it may increase the concentrations of these agents. The 
investigator should review the prescribing information of the concomitant medication for 
guidance on co-administration with a weak P-gp inhibitor.
Subjects on Vitamin E must be on a stable dose for at least 6 months prior to the diagnostic liver 
biopsy and subjects on antidiabetic medication(s) must be on stable dose(s) for at least 3 months 
prior to the diagnostic liver biopsy. If possible, the doses of these medications should remain 
stable through the End of Treatment.
Examples of representative medications that are prohibited from 2 weeks prior to Day 1 as well 
as specific medications which are prohibited or which should be used with caution from 30 days 
prior to Day 1 are listed below in Table 5-1.


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Table 5-1.
List of Disallowed and Use with Caution Medicationsa
Agents Disallowed
Drug Class
Medications Disallowed 2 weeks prior to Day 1 through the end of 
treatment
Anticonvulsantsb
phenobarbital, phenytoin, carbamazepine
Antimycobacterialsb
rifampin, rifabutin, rifapentinec
Herbal/Natural Supplementsb
St. John’s Wort, Echinacea
Drug Class
Medications Disallowed 30 days prior to Day 1 through the end of 
treatment
Select chronic immunosuppressants
Chronic systemicd corticosteroids, tacrolimus, sirolimus, cyclosporine, 
mycophenolate mofetil, and methotrexate
Farnesoid X receptor (FXR) agonists, 
Peroxisome Proliferator-Activated 
Receptor (PPAR) agonists, Chemokine 
Receptor (CCR) 2/5 inhibitors
obeticholic acidc, elafibranorc, and cenicrivirocc
Agents to be used with Caution
Drug Class
Agents to be used with Caution from 30 days prior to Day 1 
through end of treatment
Cardiac Medicationse
digoxinf, ranolazinec, dabigatran etexilate, aliskiren
a
Not all of these example medications may be approved in each of the countries where the study is being conducted; please 
refer to local product information
b
May result in a decrease in the concentration of SEL
c
Not approved in Japan
d
Intra-articular, topical, nasal, epidural or inhaled routes are allowed. Chronic systemic use of corticosteroids equivalent to 
prednisone > 10mg/day for > 2 weeks is not allowed.
e
SEL may increase the exposure of these medications
f
For subjects on digoxin at start of study: obtain digoxin level prior to starting study drug and at the Week 1 Visit with 
digoxin level checks during the study period per investigator discretion. Monitor and adjust digoxin dose as necessary based 
on prescribing information.
5.5.
Accountability for Selonsertib (SEL)/PTM Selonsertib (SEL)
The investigator or designee (e.g., pharmacist) is responsible for ensuring adequate 
accountability of all used and unused study drug bottles. This includes acknowledgement of 
receipt of each shipment of study drug (quantity and condition), subject dispensing records, and 
returned or destroyed study product. Dispensing records will document quantities received from 
Gilead Sciences and quantities dispensed to subjects, including the lot/kit number, date 
dispensed, subject identification number, subject initials, and the initials of the person dispensing 
the medication. All used and unused study drug bottles dispensed to subjects must be returned to 
the site.


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5.5.1.
Investigational Medicinal Product Return or Disposal
At the start of the study, the study monitor will evaluate the study center’s study drug disposal 
procedures and provide appropriate instruction for return or destruction of unused study drug 
supplies. If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, 
the site may destroy used (empty bottles) and unused study drug supplies performed in 
accordance with the site’s (hospital/pharmacy) SOP. If the site does not have acceptable 
procedures in place for drug destruction, arrangements will be made between the site and 
Gilead Sciences (or Gilead Sciences’ representative) for return of unused study drug supplies. A 
copy of the site’s SOP will be obtained for central files. Where possible, study drug will be 
destroyed at the site. Upon study completion, a copy of the Investigational Drug Accountability 
records must be filed at the site. Another copy will be returned to Gilead Sciences. If drug is 
destroyed on site, the investigator must maintain accurate records for all study drug bottles 
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and person who disposed of the drug. All study drug records must be maintained 
at the site and copies must be submitted to Gilead Sciences at the end of the study.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. Additional information is 
provided in the study procedures manual.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the investigator to ensure that subjects are eligible to participate in the 
study prior to enrollment and throughout the study. 
Documentation of the personally signed and dated informed consent of each subject, using the 
study-specific ICF, is required before initiating the Screening process.
After written informed consent has been obtained and eligibility to participate established, 
investigative site personnel will obtain the subject’s identification number and study drug 
assignment from the interactive web response system (IWRS).
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 8 weeks prior to randomization to determine eligibility for 
participation in the study. The Screening period may be extended under special circumstances 
with the explicit approval of the Gilead Medical Monitor.
Screening labs may be repeated once within the Screening period, at the discretion of the 
investigator, prior to administration of study drugs. 
Screening information from Study GS-US-384-1943 of SEL in NASH may be used to determine 
eligibility and fulfill Screening visit assessments for this study if obtained within the Screening 
window.
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Screening visit to ensure an 
approximate 8-hour fast prior to the blood sample collection the next morning.
The following will be performed and documented at Screening:

Obtain written informed consent before initiation of any Screening procedures

Review and record whether the subject meets inclusion and exclusion criteria


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
Obtain Screening number from IWRS

Obtain medical history

Complete PE

Record vital signs, waist circumference, body weight, and height

Conduct standard 12-Lead ECG

Perform abdominal ultrasound for HCC surveillance

Obtain blood samples for:
Chemistry
Hematology 
Coagulation Panel 
HIV-1, HBV and HCV serology 
HbA1c 
eGFR
Biomarkers
Serum pregnancy test (only for female subjects of childbearing potential; see 
Appendix 3)

Collect urine samples for:
Urine drug screen for amphetamines, cocaine and opiates (i.e., heroin, morphine)

Assess ascites and HE

CP and MELD scores

Perform liver biopsy and provide liver tissue for central reading (if required). A historical 
biopsy within 12 months of the Screening visit may be accepted as the Screening biopsy if 
the sample is deemed acceptable for interpretation and consistent with NASH-related 
cirrhosis by the central reader

Record all concomitant medications that the subject has taken within 30 days prior to 
Screening

 
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From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events eCRF. 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 8 weeks after Screening for randomization into the study.
6.3.
Baseline Assessments
6.3.1.
Day 1 Randomization and Assessments
Subjects returning to the clinic for randomization at Day 1 should be instructed to fast (no food 
or drink, except water), starting from midnight (00:00) or earlier, as appropriate, on the evening 
prior to the Day 1 visit to ensure an approximate 8-hour fast prior to the blood sample collection 
the next morning.  
After review of inclusion and exclusion criteria to confirm continued eligibility, subjects will be 
randomized to study drug assignment and receive their Subject Identification Number via the 
IWRS prior to their first dose of study drugs.
Randomization will be stratified by the presence or absence of diabetes mellitus (as determined 
by medical history or based on Screening lab values if previously undiagnosed [i.e., HbA1c 
≥6.5% OR fasting plasma glucose ≥126 mg/dL]) and by ELF™score ≥ 11.27 or < 11.27 during 
Screening.
The following will be performed and documented at the Day 1 visit prior to dosing:

HRQoL Questionnaires (SF-36, WPAI, CLDQ-NAFLD, and EQ-5D)
Note: It is recommended that HRQoL Questionnaires be completed prior to any study 
procedures being performed and prior to the subject seeing a health care provider. 

Health Resource Utilization Questionnaire

Symptom driven PE

Record vital signs, waist circumference, and body weight

Record subject’s stool frequency 

Provide lifestyle modification counseling

Obtain blood samples for:
Chemistry
Hematology


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Coagulation Panel
Insulin and Lipids
HbA1c 
eGFR
Single PK sampling:

OL Phase, in subjects with severe hepatic impairment (Child-Pugh Class C) in 
combination with renal impairment (eGFR < 30 mL/min)
Biomarkers

Collect urine samples for:
Urine pregnancy test for females of childbearing potential only 
Biomarkers, albumin, creatinine and albumin/creatinine ratio


Assess ascites and HE

MELD score

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring since the Screening visit

Dispense study drugs to the subject and provide instruction on appropriate dosing and 
administration; subject will take the Day 1 dose of study drugs on-site

 
CCI
CCI


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6.4.
Treatment Assessments
6.4.1.
Week 1 Visit
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Week 1 visit to ensure an 
approximate 8-hour fast prior to the blood sample collection the next morning.
The following assessments will be performed and documented at this visit:

Symptom driven PE

Record vital signs, and body weight

Record subject’s stool frequency 

Provide lifestyle modification counseling

Obtain blood samples for:
Chemistry
Hematology
Coagulation Panel
eGFR
Single PK sampling:

Randomized Phase at Week 1 in all subjects

OL Phase, in subjects with severe hepatic impairment (Child-Pugh Class C) in 
combination with renal impairment (eGFR < 30 mL/min)

Assess ascites and HE

MELD score

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events occurring since the previous visit

Review of study drug dosing compliance (pill count)


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6.4.2.
Week 4, Week 12, Week 24, Week 72, Week 120, Week 168 and Week 216
Visits
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the visit to ensure an approximate 
8-hour fast prior to the blood sample collection the next morning.
The following will be performed and documented at this visit:

HRQoL Questionnaires (SF-36, WPAI, CLDQ-NAFLD, and EQ-5D, not performed at 
Week 4)

Health Resource Utilization Questionnaire (not performed at Week 4)

Symptom driven PE

Record vital signs, waist circumference, and body weight

Record subject’s stool frequency 

Provide lifestyle modification counseling

Obtain blood samples for:
Chemistry
Hematology
Coagulation Panel
Insulin and Lipids
HbA1c 
eGFR
Biomarkers (Weeks 12 and 24)
Single PK sampling:

Randomized Phase at Weeks 4, 12, and 24 in all subjects

OL Phase, at all visits in subjects with severe hepatic impairment (Child-Pugh 
Class C) in combination with renal impairment (eGFR < 30 mL/min)

 
CCI


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
Collect urine samples for:
Urine pregnancy test for females of childbearing potential only
Biomarkers, albumin, creatinine and albumin/creatinine ratio (Week 12 and Week 24
only)

Assess ascites and HE

MELD score

Perform liver stiffness measurement by elastography (if available, Week 24 only)

Perform an abdominal ultrasound for HCC surveillance (Weeks 24, 72, 120, 168, and 216)

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events occurring since the previous visit

Review of study drug dosing compliance (pill count)

Dispense study drugs to the subject and provide instruction on appropriate dosing and 
administration
6.4.3.
Week 8, Week 36, Week 44, Week 60, Week 84, Week 108, Week 132, 
Week 156, Week 180, Week 204 and Week 228 Visits
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the visit to ensure an approximate 
8-hour fast prior to the blood sample collection the next morning.
The following will be performed and documented at this visit:

Symptom driven PE

Record vital signs, and body weight

Record subject’s stool frequency 

Provide lifestyle modification counseling

Obtain blood samples for:
Chemistry
Hematology


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Coagulation Panel
eGFR
Single PK sampling:

OL Phase, at all visits in subjects with severe hepatic impairment (Child-Pugh 
Class C) in combination with renal impairment (eGFR < 30 mL/min)

Collect urine sample for:
Urine pregnancy test for females of childbearing potential only

Assess ascites and HE

MELD score

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events occurring since the previous visit

Review of study drug dosing compliance (pill count)

Dispense study drugs to the subject and provide instruction on appropriate dosing and 
administration
6.4.4.
Week 16, Week 20, Week 28, Week 32 and Week 40 Visits
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the visit to ensure an approximate 
8-hour fast prior to the blood sample collection the next morning.
The following will be performed and documented at this visit:

Symptom driven PE

Record vital signs, and body weight

Record subject’s stool frequency 

Provide lifestyle modification counseling

Obtain blood samples for:
Chemistry
Hematology


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Coagulation Panel
eGFR
Single PK sampling:

OL Phase, at all visits in subjects with severe hepatic impairment (Child-Pugh Class 
C) in combination with renal impairment (eGFR < 30 mL/min)

Collect urine sample for:
Urine pregnancy test for females of childbearing potential only

Assess ascites and HE

MELD score

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events occurring since the previous visit

Review of study drug dosing compliance (pill count)

Dispense study drugs to the subject and provide instruction on appropriate dosing and 
administration
6.4.5.
Week 48, Week 96, Week 144, Week 192 and Week 240 (End of Treatment
[EOT]) Visits
Subjects in the Randomized or OL phase who are completing 240 weeks on study should 
complete the Week 240/EOT visit assessments.
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the visit to ensure an approximate 
8-hour fast prior to the blood sample collection the next morning.
The following will be performed and documented at this visit:

HRQoL Questionnaires (SF-36, WPAI, CLDQ-NAFLD, and EQ-5D)

Health Resource Utilization Questionnaire

Symptom driven PE

Record vital signs, waist circumference, and body weight

Record subject’s stool frequency 


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
Provide lifestyle modification counseling

Obtain blood samples for:
Chemistry
Hematology
Coagulation Panel
Insulin and Lipids
HbA1c 
eGFR
Biomarkers
Single PK sampling:

Randomized Phase at Week 48 in all subjects

OL Phase, at all visits in subjects with severe hepatic impairment (Child-Pugh Class 
C) in combination with renal impairment (eGFR < 30 mL/min)

 

Collect urine samples for:
Urine pregnancy test for females of childbearing potential only
Biomarkers, albumin, creatinine and albumin/creatinine ratio

Assess ascites and HE

MELD score

Perform liver biopsy and provide liver tissue for central reading (Randomized Phase at 
Week 48 and Week 240 Visits only)

Perform an abdominal ultrasound for HCC surveillance 

Perform liver stiffness measurement by elastography (if available)

Dispense study drugs to the subject and provide instruction on appropriate dosing and 
administration (not performed at Week 240/EOT)
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
Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events occurring since the previous visit

Review of study drug dosing compliance (pill count)
6.4.6.
Early Termination (ET) Visit
Subjects prematurely discontinuing from the study should complete an ET visit within 30 days of 
last dose.
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the visit to ensure an approximate 
8-hour fast prior to the blood sample collection the next morning.
The following will be performed and documented at this visit:

HRQoL Questionnaires (SF-36, WPAI, CLDQ-NAFLD, and EQ-5D)

Health Resource Utilization Questionnaire

Symptom driven PE

Record vital signs, waist circumference, and body weight

Record subject’s stool frequency 

Provide lifestyle modification counseling

Obtain blood samples for:
Chemistry
Hematology
Coagulation Panel
Insulin and Lipids
HbA1c 
eGFR
Biomarkers
Single PK sampling (all subjects in Randomized Phase and subjects in OL Phase who 
have severe hepatic impairment [Child-Pugh Class C] and renal impairment [eGFR 
< 30 mL/min])


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
 

Collect urine samples for:
Urine pregnancy test for females of childbearing potential only
Biomarkers, albumin, creatinine and albumin/creatinine ratio

Assess ascites and HE

MELD score

At the discretion of the investigator, perform liver biopsy and provide liver tissue for central 
reading

Perform an abdominal ultrasound for HCC surveillance 

Perform liver stiffness measurement by elastography (if available)

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events occurring since the previous visit

Review of study drug dosing compliance (pill count)
6.4.7.
Unscheduled Visits
Additional unscheduled assessments may be performed at the discretion of the investigator.
At a minimum, the following will be performed and documented:

Symptom driven PE

Obtain blood samples for:
Chemistry
Hematology
eGFR

Record vital signs, and body weight

Record all concomitant mediations that the subject has taken since the previous visit

Record any serious adverse events and all adverse events occurring since the previous visit

If the Unscheduled visit is performed for the sole purpose of distribution of study drug, the 
assessments noted above do not need to be performed
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6.5.
Post-treatment Assessments
6.5.1.
Follow-Up Visit 
Subjects will return for a Follow-Up visit, four weeks after the Week 240/EOT or ET visit.
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Follow-Up visit to ensure an 
approximate 8-hour fast prior to the blood sample collection the next morning.
The following will be performed and documented at this visit:

Symptom driven PE

Record vital signs, and body weight

Record subject’s stool frequency 

Obtain blood samples for:
Chemistry
Hematology
Coagulation Panel
eGFR

Collect urine sample for:
Urine pregnancy test for female subjects of childbearing potential only 

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse occurring since the previous visit
6.5.2.
Telephone Follow-Up Visit 
A Telephone Follow-Up visit will be performed 12 weeks after the Week 240/EOT or ET visit. 
The following will be performed and documented at this visit:

Record any serious adverse events and all adverse events occurring since the previous visit
At the discretion of the investigator, an unscheduled visit may be completed if the subject reports 
abnormal or concerning symptoms.


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6.6.
Visit Windows
The study visit windows are listed below in Table 6-1.
Table 6-1.
Visit Windows
Study Visit
Window
Screening Visit
≤ 8 weeks prior to Day 1, window begins with the signing of the 
informed consent.
Day 1 
Day of randomization and first dose of study drugs. All on-treatment 
study visits are calculated based on the Day 1 date.
Week 48 and Week 240/EOT
(-) 14 days
ET Visit
Within 30 days of last dose of study drug
All study visits prior to Week 48 
± 3 days
All other study visits 
± 7 days
6.7.
Open-Label Phase 
Subjects who experience a hepatic clinical event (refer to Section 3.2) prior to completing the 
Week 240 Visit of the Randomized Phase will be offered the option to rollover into an 
Open-Label (OL) Phase of the study. Each of the clinical events (except death and liver 
transplantation) will require confirmation by a Hepatic Events Adjudication Committee. All
deaths will be reviewed by this committee to determine if they are liver-related.
Subjects who undergo liver transplantation are not eligible to participate in the OL Phase of the 
study and should discontinue from the study immediately. Subjects who have permanently 
discontinued study drugs are not eligible for the OL Phase of the study.
Once a clinical event (except death and liver transplantation) is confirmed by the Hepatic Events 
Adjudication Committee, the subject will no longer participate in the Randomized Phase and will 
be offered the option to receive SEL 18 mg in the OL Phase for a total treatment duration of 
240 weeks inclusive of the Randomized Phase. Rollover into the OL Phase of the study must 
occur within 60 days of confirmation of the event.
 
 Hepatic 
clinical events will be adjudicated and deaths will be reviewed by the Hepatic Events/DILI 
Adjudication Committee only during the Randomized Phase of the study; potential DILI events 
and cardiovascular events including deaths will continue to be adjudicated in the OL Phase by 
the Hepatic Events/DILI Adjudication Committee and the Cardiovascular Events Adjudication 
Committee, respectively.
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6.8.
Criteria for Discontinuation of Study Treatment
Study medication must be discontinued in the following instances:

Subject who develops a serious adverse event consisting of a serious hypersensitivity 
reaction to study drug

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator

Unacceptable toxicity or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest

Subject or investigator request to discontinue for any reason

Significant subject noncompliance

Significant protocol violation that impacts subject safety

Pregnancy during the study; refer to Appendix 3

Discontinuation of the study at the request of Gilead, a regulatory agency or IRB/IEC/EC
Subjects who discontinue study treatment should be encouraged to complete study visits 
through Week 240, Follow-Up and a Telephone Follow-Up.
6.9.
Assessments for Premature Discontinuation from Study
Subjects prematurely discontinuing from the study should complete an ET visit within 30 days of 
last dose, Follow-Up visit 4 weeks later and a Telephone Follow-Up visit 12 weeks after the ET
visit. 
If a subject is lost to follow-up, survival data may be gathered from public records such as 
government census or death records (if permitted by local regulations) prior to the completion of 
the study. 
6.10.
Optional Intensive PK Substudy 
 
 
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6.11.
Description of Assessments
6.11.1.
Clinical Laboratory Analytes
Fasting is required prior to all study visits.
Chemistry:
ALT, AST, albumin, ALP, bicarbonate, blood urea nitrogen (BUN), calcium, chloride, 
creatinine, glucose, magnesium, phosphorus, potassium, sodium, total and direct bilirubin, 
total protein, uric acid and GGT.
Hematology:  
Hematocrit (Hct), hemoglobin (Hgb), platelet count, red blood cell count (RBC), white blood 
cell count (WBC) with differential (absolute and percentage) including lymphocytes, monocytes, 
neutrophils, eosinophils, basophils, and mean corpuscular volume (MCV).
Coagulation Panel:
INR, prothrombin time (PT), and activated partial thromboplastin time (APTT).
Additional Tests:
HIV-1 (reflex to HIV-1 RNA), HBV (HBsAg), HCV (reflex to HCV RNA) serology, urine drug 
screen (for amphetamines, cocaine, methadone, opiates), homeostasis model assessment of 
insulin resistance (HOMA-IR, based on fasting glucose and insulin), eGFR as calculated by 
Cockcroft-Gault, C-peptide, lipid panel, insulin, free fatty acids, digoxin (for those taking 
digoxin), creatine phosphokinase, and HbA1c (or serum fructosamine if HbA1c is unable to be 
resulted).
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Biomarker Tests: 
Including but are not limited to C-reactive protein (CRP), ELF™, and FibroSURE/FibroTest®.
Urine samples:
Will be collected for albumin, creatinine, albumin/creatinine ratio and stored for future 
biomarker testing.
Pharmacokinetic (PK) Assessments:
Single PK samples will be collected for PK analysis of SEL and other metabolites, as applicable.
6.11.2.
Physical Examination
A complete PE should include source documentation of general appearance, and the following 
body systems: head, neck, and thyroid; eyes, ears, nose, throat, mouth, and tongue; chest 
(excluding breasts); respiratory; cardiovascular; lymph nodes; abdomen; skin, hair, nails; 
musculoskeletal; neurological. 
The focus of a symptom driven PE will be determined by the investigator based on subject 
complaint. For example, if a subject complains of a cough, a lung exam should be performed. If 
consistent with pneumonia (rales/crackles on exam) then an AE would be documented.
Height, body weight, and waist circumference will be collected at specified time points.
6.11.3.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate and temperature.
Blood pressure will be measured using the following standardized process:

Subject should sit for ≥ 5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;
Measure and record the blood pressure to the nearest 2 millimeter of mercury (mmHg) mark on 
the manometer or to the nearest whole number on an automatic device.
6.11.4.
Medical History
Medical history, including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing, and medication history will be collected on all subjects during 
Screening. 


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6.11.5.
Clinical Liver Assessments
The MELD and CP scores will be calculated from the central laboratory values attained at each 
visit. CP will be calculated by the site at Screening to assess eligibility; MELD may also be 
calculated by the sites at Screening to determine eligibility if the central laboratory is unable to 
perform the calculation. During the OL phase, if the previous eGFR < 30 mL/min, then CP will 
be calculated by the site (using labs from previous visit and current assessment of HE and 
ascites); if CP class is C, single PK samples are required for all remaining OL visits through 
EOT and CP does not need to be calculated at subsequent OL visits. MELD will be monitored by 
site at each visit for hepatic clinical events requiring adjudication. Assessment of ascites and HE 
will be determined by the site at all visits, except the Follow-Up and the Telephone Follow-Up 
visit, as in the Table 6-2 and will be entered into the eCRF. Dialysis in the preceding week will 
also be determined by the site at each visit. HE will also be assessed using the West Haven 
Criteria (Appendix 5).
MELD will be calculated using the following formula:
MELD score = 10 X ([0.378 x ln total bilirubin mg/dL] + [1.12 x ln INR] + [0.957 x ln serum 
creatinine mg/dL] + 0.643). 

Serum creatinine in µmol/L will be converted to mg/dL by multiplying by 0.01131. The 
resulting value will be rounded to 2 decimal places.
If the serum creatinine is <1.00 mg/dL, use 1.00 as the serum creatinine value.
If the serum creatinine is >4.00 mg/dL or if the subject has had 2 or more dialysis 
treatments within the preceding week, use 4.00 as the serum creatinine value.
If the “Creatinine (Rate Blanked)” is resulted as “Icteric – Test Not Performed” by the 
central lab, use the serum enzymatic creatinine value.

Total bilirubin in µmol/L will be converted to mg/dL by multiplying by 0.05848 and the 
resulting total bilirubin value to 1 decimal place. 
If the total bilirubin is <1.0 mg/dL, use 1.0 as the total bilirubin value.  

If the INR is <1.0, use 1.0 as the INR value.
The online calculator https://www.mdcalc.com/meld-score-original-pre-2016-model-end-stage-
liver-disease may also be used.


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Table 6-2.
Child-Pugh Classification of the severity of cirrhosis
1
2
3
Hepatic 
Encephalopathy
(HE)
None
No encephalopathy and 
not on any treatment for 
hepatic encephalopathy
Medication-Controlled
Subject is lethargic, may 
have moderate confusion
Subject is receiving medical 
therapy for HE  
Medication-Refractory
Marked confusion/incoherent, 
rousable but sleeping or 
comatose
Ascites
None
No ascites and not on 
treatment for ascites
Mild/Moderate
Cross sectional imaging 
showing ascites
   
Abdominal distension 
  
Medication for ascites
Severe
(diuretic-refractory)
Visible clinically
Bilirubin (mg/dL)
< 2
2-3
> 3
Albumin (g/dL)
> 3.5
2.8-3.5
< 2.8
INR
< 1.7
1.7-2.3
> 2.3
CP score is obtained by adding the score for each parameter.
CP class:   A = 5-6 points
B = 7-9 points
C = 10-15 points
Records of concomitant medications for ascites and HE will be collected in the eCRF.  
6.11.6.
Creatinine Clearance/eGFR
eGFR is estimated by creatinine clearance calculated by the Cockcroft-Gault equation 
{Cockcroft 1976}.
Male:
CLcr (mL/min) = [140 −age (years)] BW(kg)
                                                        72 Scr
Female: CLcr (mL/min) = [140 −age (years)] BW(kg) 0.85
                                                        72 Scr
Scr = serum creatinine (mg/dL)
Actual body weight will be used for the CLcr.
6.11.7.
Genomic Testing
From subjects who agree to participate and provide consent, blood samples will be collected at 
the Day 1 visit and at Weeks 48, 96, 144, 192, 240, and ET (if applicable) for genomic testing, 
including DNA methylation.  


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6.11.8.
Pregnancy Testing
All females of childbearing potential will have a serum pregnancy test at Screening. Urine 
pregnancy testing will occur at Day 1 (prior to dosing) and every 4 weeks thereafter. Starting at 
the Week 48 visit, urine pregnancy testing kits will be provided for home testing every 4 weeks, 
between in-clinic study visits. All females of childbearing potential will be contacted every 
4 weeks and asked to report the result of the urine pregnancy tests. In the event of a positive 
urine pregnancy result, subjects will be instructed to stop study drug immediately (if applicable) 
and return to the clinic as soon as possible for a serum pregnancy test.
6.11.9.
Health Related Quality of Life (HRQoL)
It is recommended that these questionnaires be completed prior to the clinical and laboratory 
assessments. The subject should read the questionnaires by himself/herself and record the 
answers by himself/herself.
6.11.9.1.
SF-36
The SF-36 asks 36 questions to measure functional health and well-being from the subject’s 
point of view and consists of eight health domains (physical functioning, role-physical, bodily 
pain, general health, vitality, social functioning, role-emotional, and mental health). These health 
domain scales contribute to the physical health and mental health summary measures.
6.11.9.2.
CLDQ-NAFLD
The CLDQ-NAFLD asks questions related to liver disease, and specifically NAFLD, to measure 
health related quality of life in subjects with chronic liver disease.
6.11.9.3.
WPAI
The Work Productivity and Activity Impairment (WPAI) questionnaire asks 6 questions 
regarding the effect of NASH on a person’s ability to work and perform regular activities. 
6.11.9.4.
EQ-5D
The EQ-5D questionnaire is a standard measure of health status developed by the EuroQol 
Group to provide a simple, generic measure of health for clinical and economical appraisal {The 
EuroQol Group 1990}. The EQ-5D is not disease specific and has been validated in numerous 
health states. The tool consists of the EQ-5D descriptive system and the EQ Visual Analog Scale 
(VAS). The descriptive part comprises 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression). Each of these 5 dimensions has 5 levels (no problem, 
slight problems, moderate problems, severe problems and unable to). Results for each of the 
5 dimensions are combined into a 5-digit number to describe the subject’s health state. The VAS 
records the subject’s health on a 0-100 mm VAS scale, with 0 indicating “the worst health you 
can imagine” and 100 indicating “the best health you can imagine”.


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6.11.10.
Health Resource Utilization Questionnaire
The Healthcare Resource Utilization Questionnaire is designed to assess healthcare usage during 
the previous three months across a number of direct medical cost domains. This questionnaire 
should be completed by the patient prior to any procedures being performed at the visit, if 
possible.
6.11.11.
Electrocardiogram
Standard 12-lead ECG assessments will be performed. The investigator will review the ECGs for 
any clinically significant abnormalities to ensure subject safety. Abnormal ECG findings that are 
considered clinically significant by the Investigator and meet the definition of an AE should be 
reported and recorded in the AE eCRF page.
6.11.12.
Liver Stiffness Measurement by Elastography
Acceptable elastographic methods include transient elastography (FibroScan®), MRE, acoustic 
radiation force impulse (ARFI) imaging, and shear-wave elastography (SWE). At each visit, 
median liver stiffness (in kilopascals (kPa) and/or shear wave velocity (in m/s) will be recorded 
as applicable. For individual subjects, the same device must be used for all assessments. If
FibroScan® is used, liver stiffness should be measured using both the M and XL probes, if 
available, at the same location on the body. Where available, the median Controlled Attenuation 
Parameter (CAP) value will be recorded from FibroScan® examinations. Two to 3 hours of 
fasting is recommended prior to all elastography assessments.
6.11.13.
Liver Biopsy
All possible attempts should be made to acquire a liver biopsy specimen of at least 2.0 cm in 
length to ensure accurate staging of fibrosis and other histological lesions. A historical biopsy 
within 12 months of the Screening visit may be accepted as the Screening biopsy. The liver 
biopsy sample must be deemed adequate for evaluation by the central reader for inclusion. 
Liver biopsies will be sent to a central laboratory and then will be read by a central reader. The 
central reader will read all Screening biopsies for eligibility. This assessment will include an 
assessment of the adequacy of the specimen as well as the fibrosis stage and a determination that 
the biopsy is consistent with NASH. Histology results from local readers will be collected, if 
available.
If the liver biopsy is deemed unacceptable by the central reader, it may be repeated. On-
treatment liver biopsy results will be blinded to the investigator and subject. If on-treatment liver 
biopsy results are deemed unevaluable by the central reader for fibrosis, hepatocellular 
ballooning, and/or lobular inflammation, an optional, repeat biopsy may be requested.  
If a liver biopsy is performed per standard of care outside of protocol mandated assessments, all 
possible attempts should be made to submit the biopsy specimen to the central reader for 
evaluation. 
Please refer to the Study Procedures Manual for additional information.


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6.11.14.
Stool Frequency Assessment
The partial Mayo Score is a survey for the assessment of inflammatory bowel disease (IBD) that 
contains domains for stool frequency, rectal bleeding, and physician’s global assessment. For 
this study, only the stool frequency subscore will be collected and “0” should be recorded if a 
subject has fewer stools than normal. Subject reported scores will be documented in the source 
documents.
Table 6-3.
Stool Frequency Subscore of Partial Mayo Score
Domain
Description
Score
Stool Frequency 
(based on the past 3 days)
Normal number of stools
0
1-2 stools more than normal
1
3-4 stools more than normal
2
5 or more stools more than normal
3
6.12.
Lifestyle Modification Counseling
Lifestyle modifications such as weight loss via diet and increased exercise can be effective in the 
treatment of NASH. All subjects will receive counseling regarding lifestyle modifications 
including the maintenance of a healthy diet and participation in regular exercise.
6.13.
End of Study Definition
End of study is considered to be completion of the Telephone Follow-Up visit.
6.14.
Sample Storage
Residual biological samples from all visits will be frozen and stored if specific consent is 
obtained. These stored samples may be used by Gilead or research partners of Gilead to help 
answer questions about the study drugs, NASH, and its associated conditions, or clinical 
laboratory testing to provide additional safety data. No human genetic testing will be performed 
without express consent of the study subjects. At the conclusion of this study, these samples may 
be retained in storage for Gilead for a period of up to 15 years.


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, overdose, drug abuse/misuse reports, or occupational 
exposure. Preexisting events that increase in severity or change in nature during or as a 
consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an adverse event and must be reported

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
Screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.6.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history case 
report form (CRF)
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe)

In-patient hospitalization or prolongation of existing hospitalization


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. 
Examples of medically important events include:
intensive treatment in an emergency room or at home for allergic bronchospasm
blood dyscrasias or convulsions that do not result in hospitalization
development of drug dependency or drug abuse
For the avoidance of doubt, infections resulting from contaminated medicinal product will be 
considered a medically important event and subject to expedited reporting requirements.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (e.g., clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to investigational medicinal product (IMP)
interruption, modification, or discontinuation must be recorded as an AE, as well as an SAE, if 
applicable. In addition, laboratory or other abnormal assessments (e.g., electrocardiogram, 
x-rays, vital signs) that are associated with signs and/or symptoms must be recorded as an AE or 
SAE if they meet the definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the 
laboratory abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., anemia), 
not the laboratory result (i.e., decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.


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7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment describing the event as either unrelated (No) or related (Yes) 
consistent with the following definitions:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (e.g., pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication)

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship of an AE or SAE to study procedures (e.g., invasive procedures such as 
venipuncture or biopsy) should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure

Yes: The adverse event occurred as a result of protocol procedures, (e.g., venipuncture)
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, 4, or 5 according to the 
Common Terminology Criteria for Adverse Events (CTCAE). Refer to the Study Reference 
Binder for additional CTCAE information (see Appendix 4).
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.
The distinction between the seriousness and the severity of an adverse event should be noted. 
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For 
example, a headache may be severe in intensity, but would not be classified as serious unless it 
met one of the criteria for serious events listed above.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the eCRF: all SAEs and AEs related to protocol-mandated procedures.


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Adverse Events
Following initiation of study medication and throughout the duration of the study, including the 
protocol-required post-treatment follow-up period, all AEs, regardless of cause or relationship, 
must be collected and reported on the eCRF as instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (i.e., signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
eCRF database and PVE as instructed. This also includes any SAEs resulting from 
protocol-associated procedures performed after informed consent is signed.
Any SAEs and deaths that occur throughout the duration of the study, including the 
protocol-required post-treatment follow-up period, regardless of causality, should also be 
reported. Investigators are not obligated to actively seek SAEs after the protocol defined follow 
up period however, if the investigator learns of any SAEs that occur after study participation has 
concluded and the event is deemed relevant to the use of IMP, he/she should promptly document 
and report the event to Gilead PVE.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead PVE within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines

If for any reason it is not possible to record the SAE information electronically, i.e., the 
eCRF database is not functioning, record the SAE on the paper serious adverse event 
reporting form and submit within 24 hours to:
      Gilead Sciences PVE: 
Fax: 
Email: PPD
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As soon as it is possible to do so, any SAE reported via paper must be transcribed into the eCRF 
database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary 

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers

Additional information may be requested to ensure the timely completion of accurate safety 
reports

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
SUSARs. In accordance with the EU Clinical Trials Directive (2001/20/EC), Gilead or a 
specified designee will notify worldwide regulatory agencies and the relevant IRB/IEC/EC in 
concerned Member States of applicable SUSARs as outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB/IEC/EC of SUSAR reports as soon 
as is practical, where this is required by local regulatory agencies, and in accordance with the 
local institutional policy.
7.5.
Toxicity Management 
At baseline, some subjects may have liver biochemistry levels above the upper limit of normal 
(ULN). Baseline values for liver tests (ALT, AST, and total bilirubin) will be determined by 
averaging the values obtained at Screening and Day 1. 
If no other cause of the laboratory abnormalities is immediately apparent, on-treatment 
elevations of ALT and/or AST should be confirmed with repeat testing within 48-72 hours. 
Subjects with ALT or AST elevations as per Figure 7-1 must be placed into close observation (as 
described below).


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Figure 7-1. 
On-Treatment ALT/AST Monitoring Requiring Close Observation 
What are the subject's Baseline ALT and AST 
(average of all Screening & Day 1 values)? 
Note: ALT and AST are evaluated independently. 
Normal 
{~ ULN) 
i' 
Does the on-treatment ALT or AST 
meet this criterion: 
• 
> 3 x ULN 
I 
Yes 
t 
Close observation includes: 
Elevated 
(>1 to <5 x ULN) 
Does the on-treatment ALT or AST 
meet any one of these criteria: 
• 
> 2 x Baseline 
• 
> 300 U/L 
Yes 
t 
Enter Subject into Close Observat ion 
I 
Elevated 
(~ 5 x ULN) 
Does the on-treatment ALT or AST 
meet this criterion: 
• 
> 2 x Baseline 
Yes 
• 
Repeating liver biochemistries (ALT, AST, ALP, GGT, total bilimbin, INR) and obtaining a 
creatine phosphokinase (CPK) level within 48-72 hours of results 
• 
Obtaining a more detailed history of symptoms and prior or concunent disease 
• 
Obtaining a history of concomitant drng use (including nonprescription medications and 
herbal and dieta1y supplement preparations), alcohol use, recreational drug use, and special 
diets 
• 
Obtaining a history of exposure to environmental chemical agents 
• 
Ruling out other causes of liver disease as needed ( obtain viral hepatitis panel, imaging for 
evaluation of biliary tract disease, etc. if required in the opinion of the primary investigator) 
• 
Continue to monitor liver biochemistries at least t\¥ice weekly. Frequency can decrease to 
once a week or less if abn01malities stabilize or study mug has been discontinued and the 
subject is asymptomatic 
During close observation, study mug can be continued, if desired, at the discretion of the Gilead 
Medical Monitor and the Principal Investigator. 
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If on-freatment elevations of ALT and/or AST exceed the values shown in Figme 7-2, are 
confumed on repeat testing within 48-72 hours of results, and no alternative cause is 
immediately apparent, the subject must be placed into close observation and study drug must be 
withheld. 
Figure 7-2. 
On-Treatment ALT/AST Monitoring Requiring Study Drug 
Withholding 
I 
Normal 
(:,-; ULN) 
While on-treatmen , does the subject meet 
any one of these criteria: 
• 
Symptoms of drug-related hepatotoxicity 
• 
ALT orAST >8xULN 
• 
ALT or AST > S x ULN for 2 weeks 
• 
ALT or AST> 3 x ULN and (TB > 2 x ULN* 
Qt INR > 1.s••J 
Yes 
i 
What are the subject's Baseline ALT and AST 
(average of all Screening & Day 1 values)? 
Note: ALT and AST are evaluated independently. 
I 
I 
Elevated 
(>l to <5 X ULN) 
• 
While on-t reatment, does the subject meet any 
one of these criteria: 
• 
Symptoms of drug-related hepatotoxicity 
• 
ALT or AST > 8 x Baseline 
• 
ALT or AST> 500 U/L 
• 
[ALT or AST > 3 x Basellnem:300 U/L) and 
[TB > 2x ULN., ru: INR > 1.5° ] 
I 
Yes 
i 
I 
Elevated 
(~S x ULN) 
+ 
While on-treatment, does the subject meet 
any one of these criteria: 
• 
Symptoms of drug-related 
hepatotoxicity 
• 
ALT or AST > 500 U/L 
I 
Yes 
Withhold Study Drug and Enter Subject into Close Observation 
¥ Unless sub;ect has Gilbert's syndrome, in whkh c-ase a direct bilirubin "> 2 ,c baseline (ave rage of screening & Day 1 values.) will be used instead of total bilirubin. 
••1f not on therapeutic anticoagulation {e.g. warfarin). If on t herapeutk anticoagulation, INR criteria i.s di.sregarded. 
Abbreviations: 
ULN - Upper limit of normal ra nge 
TB -Total Bllirubln 
Subjects who develop signs or symptoms of liver toxicity (such as right upper quadrant 
discomfoli, fever, nausea, vomiting, jaundice, rash, or eosinophilia > 5%) which are suspected 
by the principal investigator to be chug-related, must have study ch1.1g withheld and be placed into 
close observation. 
If study ch1.1g is withheld, it may be reintroduced with approval from the Medical Monitor if 
another etiology of elevated liver tests is identified. Study chug must be discontinued if close 
monitoring is not possible or if total bilirnbin, ALT or AST elevation recurs following 
re-challenge with study chug. Subjects who discontinue study chug due to suspected 
hepatotoxicity must be followed until symptoms subside, any abno1mal laborat01y values have 
resolved or returned to baseline levels, until there is a satisfact01y explanation for the changes 
observed, or for 3 months after drug discontinuation, whichever is longer. 
Treatment-emergent toxicities will be noted by the Investigator and brought to the attention of 
the Medical Monitor. Whether or not considered treatment-related, all subjects experiencing AEs 
must be monitored periodically until symptoms subside, any abno1mal laboratory values have 
resolved or returned to baseline levels or they are considered ineversible, or until there is a 
satisfactory explanation for the changes observed. 
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Other than in the case of the liver enzymes noted above, Grade 3 or 4 clinically significant 
laboratory AEs should be confirmed by repeat testing as soon as practical to do so, and 
preferably within 3 calendar days of receipt of the original test results.
Any questions regarding toxicity management should be directed to the Medical Monitor.
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, occupational exposure with an AE, 
pregnancy reports regardless of an associated AE and AE in an infant following exposure from 
breastfeeding.  
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
Occupational exposure with an AE defined as exposure to a medicinal product as a result of 
one’s professional or non-professional occupation.
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to Gilead PVE using the paper pregnancy report form within 24 hours of becoming aware 
of the pregnancy. Reports should be sent directly to Gilead PVE at fax number 
 
or email 
Refer to the eCRF completion guidelines for full instructions on the mechanism of pregnancy 
reporting.
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The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (e.g., a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.3. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must 
be reported to Gilead PVE.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead PVE using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead PVE. Gilead PVE contact information is as follows:
Email: 
 and Fax: 
 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead PVE using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the female partner 
should continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after 
the study has been completed, the outcome should be reported directly to Gilead PVE, fax 
number 
 or email 
Refer to Appendix 3 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead PVE within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.
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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
Details will be provided in the statistical analysis plan (SAP).
8.1.1.
Analysis Objectives
The primary objective of this study is as follows:

To evaluate whether SEL can cause fibrosis regression and reduce associated complications
in subjects with cirrhosis due to NASH.
The secondary objective of this study is: 

To assess the safety and tolerability of SEL in subjects with NASH and cirrhosis
The exploratory objectives of this study are as follows:
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8.1.2.
Primary Efficacy Endpoint
The primary efficacy endpoint at Week 48 includes the proportion of subjects who achieve a 
≥1-stage improvement in fibrosis (according to the NASH CRN classification) without 
worsening of NASH (defined as a ≥ 1-point increase in hepatocellular ballooning or lobular 
inflammation).
8.1.3.
Clinical Efficacy Endpoint
The clinical efficacy endpoint at Week 240 is EFS. EFS will be assessed by time to the 
first clinical event including liver decompensation events, liver transplantation, or all-cause 
mortality.
8.1.4.
Secondary Endpoint
The secondary endpoints of this study are as follows: 

Proportion of subjects who have a ≥ 1-stage improvement in fibrosis without worsening of 
NASH at Week 240;

Proportion of subjects who have a ≥ 1-stage improvement in fibrosis at Week 48 and 
Week 240;

Proportion of subjects who have NASH resolution at Week 48 and Week 240.
8.1.5.
Exploratory Endpoints
 
 
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8.2.
Analysis Conventions
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be performed using Statistical Analysis System (SAS®) software (SAS Institute, Cary, 
North Carolina, USA).
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The primary analysis set for efficacy analyses will be the Full Analysis Set (FAS) which includes 
all subjects who were randomized into the study and received at least one dose of study drug.
Subjects who receive study drug other than that to which they were randomized will be analyzed 
according to the treatment group to which they were randomized.
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8.2.1.2.
Safety
The primary analysis set for safety analyses will include all subjects who received at least one 
dose of study drug. Treatment-emergent data will be analyzed and defined as data collected from 
the first dose of study drug through the date of last dose of study drug plus 30 days. Subjects 
who received study drug other than that to which they were randomized will be analyzed 
according to the study drug received.
8.2.1.3.
Pharmacokinetics
The PK analysis set will include all randomized subjects who took at least one dose of study 
drugs and for whom concentration data of analytes SEL (and its metabolite GS-607509 as 
applicable) are available. The PK of other SEL metabolites may be explored. 
 
 
8.2.1.4.
Biomarkers
The Biomarker Analysis Set will include data from subjects in the Safety Analysis Set who have 
the necessary baseline and on-study measurements to provide interpretable results for the 
specific parameters of interest.
8.3.
Data Handling Conventions
Missing data can have an impact on the interpretation of the trial data. In general, values for 
missing data will not be imputed.
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example, if a subject received study medication, the subject will be 
included in a summary of adverse events according to the treatment received; otherwise, if the 
subject is not dosed then they will be excluded from the summary. If safety laboratory results for 
a subject are missing for any reason at a time point, the subject will be excluded from the 
calculation of summary statistics for that time point. If the subject is missing a pre-dose value, 
then the subject will be excluded from the calculation of summary statistics for the pre-dose 
value and the change from pre-dose values.
Values for missing safety laboratory data will not be imputed; however, a missing baseline result 
will be replaced with a Screening result, if available. If no pre-treatment laboratory value is 
available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) for the 
summary of graded laboratory abnormalities.  
Values for missing vital signs data will not be imputed; however, a missing baseline result will 
be replaced with a Screening result, if available.
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8.4.
Multiple Testing
When the primary histology efficacy endpoint is compared between each of the SEL arms and
the placebo arm at Week 48, it will be tested at a two-sided 0.025 significance level to control an 
overall Type I error rate of 0.05 by Bonferroni adjustment. 
The testing strategy for the clinical efficacy endpoint (EFS) is described below and is presented 
graphically in Figure 8-1.
1) If the primary histology efficacy endpoint is significant in both SEL arms, the EFS endpoint 
will be tested for both SEL arms against placebo at Week 240 at a two-sided 
0.05 significance level by the Hochberg procedure {Hochberg 1988}. If the larger p-value of 
SEL18 mg vs. placebo and SEL 6 mg vs. placebo is less than or equal to 0.05, the EFS 
endpoint for both SEL arms will be a success; if the larger p-value is > 0.05, the treatment 
arm with the larger p-value fails, and the smaller p-value will be compared with the 
significance level of 0.025 to determine the success of the treatment arm. 
2) If the primary histology efficacy endpoint is significant in the SEL 18 mg but not the SEL 
6 mg arm, the EFS endpoint will be tested for SEL 18 mg against placebo at Week 240 at a 
two-sided 0.025 significance level. 
3) If the primary histology efficacy endpoint is significant in SEL 6 mg but not SEL18 mg arm, 
the EFS endpoint will be tested for SEL 6 mg against placebo at Week 240 at a two-sided 
0.025 significance level. 
4) If the primary histology efficacy endpoint is not significant in both the SEL 18 mg and SEL 
6 mg arms, the trial will be terminated.


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Figure 8-1.
Multiple Testing Flow Chart
*
Nominal alpha will be adjusted using Haybittle-Peto approach
Both SEL 18mg 
and SEL 6 mg arms 
succeed 
1) Histology 
EFS at Week 
Yes 
Only the arm 
endpoint at 
240: 
with smaller 
Week 48: 
Maxp-value / 
Yes 
p-value 
SEL 18mg v s. 
of (SEL 18 
suc.ceeds 
placebo:::; 0.025 
Yes 
mgvs. 
and 
placebo, SEL 
SEL 6 mg v s. 
6 mgvs. 
Is the arm with 
placebo :::; 0.025 
---+ 
placebo) 
____. 
smaller p-value 
:::; 0.05* 
:::; 0.025*? 
----.. 
No 
Both SEL arms 
fail 
0 
Yes 
2) Histology 
EFS at Week ____. 1 
Only SEL 18 mg succeeds 
endpoint at 
Yes 
240: 
Week 48: 
__. 
SEL 18mg v s. 
SEL 18mg v s. 
I Both SEL arms fail 
placebo:::; 0.025 
placebo 
and 
:::; 0.025* 
0 
SEL 6 mg v s. 
placebo>0.025 
3) Histology 
EFS atWeek 
Yes 
I 
Only SEL 6 mg succeeds 
endpoint at 
240: 
/ 
\Veek48: 
Yes 
SEL 18mg v s. 
__. 
SEL 6mg v s. 
placebo >0.025 
placebo 
I Both SEL arms fail 
and 
:::; 0.025* 
SEL 6 mg v s. 
No 
placebo :::; 0.025 
4) Histology 
endpoint at 
Week 48: 
Yes 
SEL 18mg vs. 
Both SEL arms 
__. 
placebo>0.025 
fail 
and 
SEL 6 mgvs. 
placebo>0.025 


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Although no formal statistical inference on EFS is planned at the Week 48 analysis, the actual 
nominal significance level for the EFS endpoint at the Week 240 analysis will be adjusted using 
the Haybittle-Peto approach {Haybittle 1971}. The adjustment will be based on the number of 
events at both the Week 48 and Week 240 analyses, assuming an allocation of a two-sided 
significance level of 0.001 at the Week 48 analysis.
8.5.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods. 
Demographic summaries will include sex, race/ethnicity, and age.
Baseline data will include a summary of body weight, height, BMI, and randomization 
stratification groups (presence or absence of diabetes; ELF™score ≥ 11.27 or < 11.27), and other 
disease characteristic variables.
Any discrepancies between the IWRS randomization stratification groups and the group assigned 
based on data entered in the database will be listed.
8.6.
Efficacy Analysis
8.6.1.
Primary Efficacy Endpoints Analysis
Primary Histology Efficacy Endpoint Analysis
A stratified MH test will be used to compare the differences in proportions of subjects who 
achieve a ≥ 1-stage improvement in fibrosis without worsening of NASH at Week 48 between 
each of the SEL arms and the placebo arm, adjusting for stratification factors. Subjects with 
missing data regarding fibrosis stage and NAS elements used to define worsening of NASH 
(hepatocellular ballooning and lobular inflammation) at Week 48 will be analyzed as treatment 
failures. The point estimates and 95% confidence intervals for the differences in proportions will 
be calculated. 
Clinical Efficacy Endpoint Analysis
The clinical efficacy endpoint at Week 240 is EFS. EFS will be assessed by time to the 
first clinical event in the Randomized Phase. Differences in time to the first clinical events 
between each of the SEL arms and the placebo arm will be assessed using the stratified log-rank 
test. A sensitivity analysis of EFS that includes hepatic clinical events and liver-related death 
will also be performed. The clinical efficacy endpoint will only be evaluated at Week 240 for a 
SEL arm if the SEL arm demonstrates superiority over placebo for the primary efficacy endpoint 
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8.6.2.
Secondary Efficacy Endpoint Analysis
A stratified MH test will be performed to compare the differences in proportions between the 
each of the SEL arms and the placebo arm adjusting for stratification factors for the following
endpoints:

Proportion of subjects who have a ≥ 1-stage improvement in fibrosis without worsening of 
NASH at Week 240;

Proportion of subjects who have a ≥ 1-stage improvement in fibrosis at Week 48 and 
Week 240;

Proportion of subjects who have NASH resolution at Week 48 and Week 240. 
8.6.2.1.
Exploratory Endpoint Analyses
 
 
 
 
   
 
 
 
 
 
 
 
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8.7.
Assessment of Noninvasive Measures of Fibrosis
Receiver operating characteristic (ROC) curves and measures of diagnostic test performance 
(e.g., sensitivity and specificity) will be used to determine whether baseline noninvasive 
measures of fibrosis and their change from baseline can predict histological regression of fibrosis 
or the development of clinical complications due to cirrhosis.
8.8.
Safety Analysis
Safety will be assessed during the study through the reporting of AEs, and by clinical laboratory 
tests and vital sign assessments at various time points during the study. Concomitant medication 
usage will also be assessed throughout the study. 
All safety data collected on or after the date that SEL or PTM SEL was first dispensed up to the 
date of last dose of SEL or PTM SEL plus 30 days will be summarized by treatment group, 
including extent of exposure, adverse events, laboratory evaluations, and immunogenicity. 
Safety data from the OL Phase will be summarized for overall subjects who roll-over into the OL 
Phase for safety review.
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8.8.1.
Extent of Exposure
Data for a subject’s extent of exposure will be generated from the study drug administration 
eCRF. Exposure data will be summarized by treatment group and by study phase.
8.8.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database. Adverse event severity will be graded using the CTCAE.
Events will be summarized on the basis of the date of onset for the event. Treatment-emergent 
adverse events (TEAEs) are defined as 1 or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days
after permanent discontinuation of study drug.

Any AEs leading to premature discontinuation of study drug.
Summaries (number and percentage of subjects) of TEAEs by SOC and PT will be provided.  
Treatment-emergent AEs will also be summarized by relationship to study drug and severity. In 
addition, TEAEs leading to premature discontinuation of study drug and study will be 
summarized and listed.
All AEs collected during the course of the study will be presented in data listings with a field for 
treatment-emergent event (yes/no).
8.8.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) by treatment group and study visit along with the corresponding change from 
baseline values.
Graded laboratory abnormalities will be defined using the grading scheme in the CTCAE (refer 
to Appendix 4).
The incidence of treatment-emergent laboratory abnormalities, defined as values that increase at 
least one toxicity grade from baseline at any time post baseline up to and including the date of 
last dose of study drug plus 30 days, will be summarized by treatment group. If baseline data are 
missing, then any graded abnormality (i.e., at least a Grade 1) will be considered 
treatment-emergent.
8.8.4.
Other Safety Evaluations
Vital sign measurements will be summarized by treatment arm and listed by subject.


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8.9.
Pharmacokinetic Analysis
SEL and GS-607509 plasma concentrations will be listed and summarized.
 
 
 
 
8.9.1.
Exploratory Biomarker Analyses
 
 
 
8.10.
Sample Size
With a sample size of 320 subjects in each active treatment arm and 160 subjects in the placebo 
arm, the study has 97% power to detect a difference in the proportion of subjects with a ≥1-stage 
improvement in fibrosis without worsening of NASH of 12% or more at Week 48 at a 
significance level of 0.025 (two-sided), assuming the proportion of subjects that meet the 
endpoint in the placebo arm is 4%.
With regard to the clinical efficacy endpoint, subjects will be followed for a period of up to 
240 weeks. The estimate of the expected event rate is 30% in untreated patients, producing an 
expected EFS rate of 70% at 240 weeks in the placebo arm. SEL is expected to improve the EFS 
rate to 83.7% (expected event rate of 16.3%) compared with placebo (hazard ratio (HR), 0.50). 
We also expect a 20% overall dropout rate. Given the above assumptions, for comparison of
each of the SEL arms versus the placebo arm, together with a total sample size of 800 subjects 
(2:2:1 ratio), and assuming the log-rank test statistic is evaluated using a two-sided 
0.025 significance level, the study will have 85% power to evaluate the superiority of each SEL
arm versus placebo with respect to EFS. 
Therefore, the overall power for the trial, assuming independence between the primary efficacy 
endpoint and clinical efficacy endpoint, is 82% (97% × 85%). It should be noted that this is a 
lower bound estimate as these two endpoints are expected to be positively correlated.
CCI
CCI


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8.11.
Data Monitoring Committee
An external Data Monitoring Committee (DMC) that consists of three hepatologists and a PhD 
statistician will review the progress of the study, perform interim reviews of safety data, and 
provide recommendations to Gilead whether the nature, frequency, and severity of AEs 
associated with study treatment warrant the early termination of the study in the best interests of 
the participants, whether the study should continue as planned, or the study should continue with 
modifications. 
The initial meeting of the DMC will occur after 50 subjects have completed their Week 4 visit
and approximately every 6 months thereafter to monitor the study for safety events.
The DMC’s specific activities will be defined by a mutually agreed upon charter, which will 
define the DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki, International Conference on Harmonisation (ICH) guidelines, or with 
the laws and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the study subject. These standards are consistent with the European Union 
Clinical Trials Directive 2001/20/EC and GCP 2005/28/EC.
The investigator will ensure adherence to the basic principles of GCP, as outlined in 21 the Code 
of Federal Regulations (CFR) 312, subpart D, “Responsibilities of Sponsors and Investigators,” 
21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Ethics Committee (EC) Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC/EC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC/EC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC/EC approval, with the exception of those necessary 
to reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB/IEC/EC approved consent form for documenting 


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written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB/IEC/EC 
or local requirements. The consent form will inform subjects about genomic testing and sample 
retention, and their right to receive clinically relevant genomic analysis results.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law), and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor IRB/IEC/EC, or laboratory. Laboratory 
specimens must be labeled in such a way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The 
investigator must keep a screening log showing codes, names, and addresses for all subjects 
screened and for all subjects enrolled in the trial. Subject data will be processed in accordance 
with all applicable regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, eCRF, the IMP, and any other study information, remain the 
sole and exclusive property of Gilead during the conduct of the study and thereafter. This 
information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, 
IRB/IEC/EC and governmental approval with correspondence, informed consent, drug records, 
staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, i.e., history, PE, and confirmation of 
diagnosis (to support inclusion and exclusion criteria);


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
Documentation of the reason(s) a consented subject is not enrolled;

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (i.e., United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Electronic Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received. Subsequent to data entry, a study monitor will perform source data 


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verification within the electronic data capture (EDC) system. Original entries as well as any 
changes to data fields will be stored in the audit trail of the system. Prior to database lock (or any 
interim time points as described in the clinical data management plan), the investigator will use 
his/her log in credentials to confirm that the forms have been reviewed, and that the entries 
accurately reflect the information in the source documents. The eCRF captures the data required 
per the protocol schedule of events and procedures. System-generated or manual queries will be 
issued to the investigative site staff as data discrepancies are identified by the monitor or internal 
Gilead staff, who routinely review the data for completeness, correctness, and consistency. The 
site coordinator is responsible for responding to the queries in a timely manner, within the 
system, either by confirming the data as correct or updating the original entry, and providing the 
reason for the update (e.g., data entry error). At the conclusion of the trial, Gilead will provide 
the site with a read-only archive copy of the data entered by that site. This archive must be stored 
in accordance with the records retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be sent to the designated disposal facility
for eventual destruction. The study monitor will provide instructions for return. If return is not 
possible, the study monitor will evaluate each study center’s IMP disposal procedures and 
provide appropriate instruction for destruction of unused IMP supplies. If the site has an 
appropriate SOP for drug destruction as determined by Gilead, the site may destroy used 
(empty or partially empty) and unused IMP supplies in accordance with that site’s approved 
SOP. A copy of the site’s approved SOP will be obtained for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP that is
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences and its representatives, to the
IRB/IEC/EC, or to regulatory authority or health authority inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.


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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/IEC/EC
in accordance with local requirements and receive documented IRB/IEC/EC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases.
After conclusion of the study and without prior written approval from Gilead Sciences, 
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

The results of the study in their entirety have been publicly disclosed by or with the consent 
of Gilead in an abstract, manuscript, or presentation form; or 

The study has been completed at all study sites for at least 2 years.
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. The investigator will comply with Gilead’s request to delete 
references to its confidential information (other than the study results) in any paper or 
presentation and agrees to withhold publication or presentation for an additional 60 days in order 
to obtain patent protection if deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g., attendance at Investigator's Meetings. If required under the applicable statutory 
and regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.


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9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead Medical Monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, IECs, and ECs. In terminating the study, Gilead and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.


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Wissing ER, Boyer JG, Kwong JQ, Sargent MA, Karch J, McNally EM, et al. P38alpha MAPK 
underlies muscular dystrophy and myofiber death through a Bax-dependent 
mechanism. Human molecular genetics 2014;23 (20):5452-63.


Selonsertib (SEL; GS-4997)
Protocol GS-US-384-1944
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
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Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing 
indication for liver transplantation in patients with hepatocellular carcinoma in the 
U.S. Hepatology 2014;59 (6):2188-95.
Xie Y, Ramachandran A, Breckenridge DG, Liles JT, Lebofsky M, Farhood A, et al. Inhibitor of 
apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver 
injury. Toxicol Appl Pharmacol 2015;286 (1):1-9.
Yeh MM, Brunt EM. Pathological features of fatty liver disease. Gastroenterology 2014;147 
(4):754-64.
Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of 
nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, 
incidence, and outcomes. Hepatology 2016;64 (1):73-84.
Younossi ZM, Stepanova M, Rafiq N, Makhlouf H, Younoszai Z, Agrawal R, et al. Pathologic 
criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to 
predict liver-related mortality. Hepatology 2011;53 (6):1874-82.


Selonsertib (SEL; GS-4997)
Protocol GS-US-384-1944
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
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31 May 2018
11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Tables
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE)
Appendix 5.
West Haven Criteria


PPD
PPD
Selonsertib (SEL; GS-4997) 
Protocol GS-US-384-1944 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Final 
Amendment 2 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and 
Efficacy of Selonsertib in Subjects with Compensated Cirrhosis due to Nonalcoholic 
Steatohepatitis (NASH) 
GS-US-384-1944, Amendment 2, 31 May 2018 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval . ..,..-----------~ 
Signature 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully infom1ed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDfa TIAL 
Page 112 
31 May 2018 


Selonsertib (SEL; GS-4997)
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Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
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31 May 2018
Appendix 2.
Study Procedures Tables
Study Procedures Table – Screening to Week 48
Assessments
Screening
Day 
1a
On-treatment Visits
Week 
1
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
24
Week 
28
Week 
32
Week 
36
Week 
40
Week 
44
Week 
48
Clinical Assessments
Written Informed 
Consent
X
Determine Eligibility
X
Medical History
X
Physical Examination
X
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Vital Signs including 
Body Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Waist Circumference
X
X
X
X
X
X
12-lead ECG
X
CP/MELD Scoresc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess Ascites and 
Hepatic 
Encephalopathy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver Biopsyd
X
X
Abdominal Ultrasound
for HCC Surveillance
X
X
X
Elastography 
(if available)
Xe
Xf
X
X
I 
I 


Selonsertib (SEL; GS-4997)
Protocol GS-US-384-1944
Final
Gilead Sciences, Inc. 
Amendment 2
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Assessments
Screening
Day 
1a
On-treatment Visits
Week 
1
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
24
Week 
28
Week 
32
Week 
36
Week 
40
Week 
44
Week 
48
Health Related Quality 
of Life Questionnairesg
X
X
X
X
Health Resource 
Utilization 
Questionnairesg
X
X
X
X
Stool Frequency 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lifestyle Modification  
Counseling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
Xh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Study Drug
X
X
X
X
X
X
X
X
X
X
X
X
X
Review of Study Drug 
Dosing Compliance 
(Pill Count)
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Subject Fasting
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistryi, 
Hematology, 
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Insulin and Lipids 
X
X
X
X
X
HbA1c
X
X
X
X
X
X
eGFR
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Testingj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Single PK Sampling
Xl
Xk
Xk
Xl
Xk
Xl
Xl
Xk
Xl
Xl
Xl
Xl
Xl
Xk


Selonsertib (SEL; GS-4997)
Protocol GS-US-384-1944
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
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Assessments
Screening
Day 
1a
On-treatment Visits
Week 
1
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
24
Week 
28
Week 
32
Week 
36
Week 
40
Week 
44
Week 
48
Blood Collection 
(Biomarkers)
X
X
X
X
X
Urine Collection
X
X
X
X
Urine Drug Screen
X
HIV-1, HBV, HCV 
Serology
X
Approximate amount of 
blood drawn (mL)n
70
65
15
15
12
60
12
12
60
12
12
12
12
12
65
CCI
CCI


Selonsertib (SEL; GS-4997)
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Gilead Sciences, Inc. 
Amendment 2
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Study Procedures Table – Week 60 to Follow Up
Assessments
On-treatment Visits
Follow 
Upo
Tele-
phone 
Follow-
Upp
Week
60
Week 
72
Week 
84
Week 
96
Week 
108
Week 
120
Week 
132
Week 
144
Week 
156
ETo
Week 
168
Week 
180
Week 
192
Week 
204
Week 
216
Week 
228
Week 
240(EOT)
Physical Examination
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Vital Signs including Body Weight
X
X
X
X
X
X
X
X
X
X
X
Waist Circumference
X
X
X
X
X
Liver Biopsyd
Xq
Xr
CP/MELD scoresc
X
X
X
X
X
X
X
X
X
X
Assess Ascites and Hepatic 
Encephalopathy
X
X
X
X
X
X
X
X
X
X
Abdominal Ultrasound for 
HCC Surveillance
X
X
X
X
X
Elastography (if available)
X
X
X
Health Related Quality of Life 
Questionnairesg
X
X
X
X
X
Health Resource Utilization 
Questionnairesg
X
X
X
X
X
Stool Frequency Assessment
X
X
X
X
X
X
X
X
X
X
X
Lifestyle Modification Counseling
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Dispense Study Drug
X
X
X
X
X
X
X
Xs
X


Selonsertib (SEL; GS-4997)
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Gilead Sciences, Inc. 
Amendment 2
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Assessments
On-treatment Visits
Follow 
Upo
Tele-
phone 
Follow-
Upp
Week
60
Week 
72
Week 
84
Week 
96
Week 
108
Week 
120
Week 
132
Week 
144
Week 
156
ETo
Week 
168
Week 
180
Week 
192
Week 
204
Week 
216
Week 
228
Week 
240(EOT)
Review of Study Drug Dosing 
Compliance (Pill Count)
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Subject Fasting
X
X
X
X
X
X
X
X
X
X
X
Chemistryi, Hematology, Coagulation
X
X
X
X
X
X
X
X
X
X
X
Insulin and Lipids
X
X
X
X
X
HbA1c
X
X
X
X
X
eGFR
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Testingj
X
X
X
X
X
X
X
X
X
X
X
Single PK samplingl
X
X
X
X
X
X
X
X
X
Xt
Blood Collection (Biomarkers)
X
X
X
Urine Collection 
X
X
X
Approximate amount of blood drawn 
(mL)n
12
15
12
65
12
15
12
65
12
65
10
a
Subjects starting the OL Phase of the study will complete the same study procedures as during the Randomized Phase of the study, starting with the Day 1 visit
b
Symptom-driven PE
c
CP score to be calculated only at Screening
d
Not to be performed during the OL Phase of the study
 
g
For subjects with questionnaires available at Day 1
h
Adverse Events reporting during Screening is limited to serious adverse events and adverse events related to study procedures
i
Additional testing: digoxin level at Day 1 and Week 1 and as needed in subjects taking digoxin (refer to Section 5.4) and CPK level for subjects in close observation for DILI 
(refer to Section 7.5)
CCI
CCII 


Selonsertib (SEL; GS-4997)
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Amendment 2
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j
Females of childbearing potential only (refer to Appendix 3). Serum pregnancy test at Screening and urine pregnancy test at Day 1 and every 4 weeks thereafter. Starting at 
the Week 48 visit, urine pregnancy testing kits will be provided for home testing every 4 weeks, between in-clinic study visits. All females of childbearing potential will be 
contacted every 4 weeks and asked to report the result of the urine pregnancy tests. FSH testing as per Appendix 3
k
To be performed during the Randomized Phase in all subjects and during the OL Phase, only in subjects with severe hepatic impairment (Child-Pugh Class C) in combination 
with renal impairment (eGFR < 30 mL/min)
l
To be performed during the OL Phase, only in subjects with severe hepatic impairment (Child-Pugh Class C) in combination with renal impairment (eGFR < 30 mL/min)
m
n
For specific blood volumes at each visit, please refer to the current approved ICF
o
Subjects prematurely discontinuing from the study should complete an ET visit within 30 days of last dose, Follow-Up visit 4 weeks later and a Telephone Follow-Up visit 
after the ET visit
p
To be performed 12 weeks after the Week 240/EOT or ET visit. At the discretion of the investigator, an unscheduled visit may be completed if the subject reports abnormal or 
concerning symptoms
q
Not to be performed at the Week 144 visit
r
To be performed at the discretion of the investigator
s
Not to be performed at the Week 240/EOT visits
t
To be collected in all subjects that ET in either Randomized or OL Phase
CCI


Selonsertib (SEL; GS-4997)
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Final
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Amendment 2
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Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a) Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause. In 
addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b) Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchiectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a) Study Drug Effects on Pregnancy and Hormonal Contraception
SEL is contraindicated in pregnancy as a malformation effect is suspected, based on non-clinical 
data. In rats and rabbits, SEL administration was associated with effects on embryo-fetal 
development at maternally toxic doses.
Preclinical and clinical drug-drug interaction (DDI) data indicate that SEL is unlikely to alter the 
exposure of hormonal contraceptives through induction of human drug metabolizing enzymes or 
drug transporters. 
Please refer to the latest version of the IB for additional information.
b) Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures. They must have a negative serum pregnancy test at Screening and a 
negative pregnancy test on the Day 1 visit prior to randomization. Pregnancy tests will be 
performed at monthly intervals thereafter. Female subjects must agree to one of the following 
from Screening until 30 days following the last dose of study drug.


Selonsertib (SEL; GS-4997)
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Final
Gilead Sciences, Inc. 
Amendment 2
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
Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below
Intrauterine device (IUD) with a failure rate of <1% per year
Tubal sterilization
Essure® micro-insert system (provided confirmation of success 3 months after procedure) *
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
The above described methods are considered preferred methods of highly effective 
contraception in this protocol.

Should female subjects wish to use a hormonally based method, use of a male condom by the 
female subject's male partner is required. Subjects who utilize a hormonal contraceptive as 
one of their birth control methods must have used the same method for at least three months 
prior to study dosing. Hormonally-based contraceptives permitted for use in this protocol are 
as follows:
Hormonal methods (each method must be used with a condom in the male partner):
Oral contraceptives (either combined or progesterone only)
Injectable progesterone*
Implants of levonorgestrel*
Transdermal contraceptive patch*
Contraceptive vaginal ring*
Not all of these methods may be approved in each of the countries where the study is being 
conducted: please refer to local product information. Additional local regulatory requirements 
may apply.
*
Not approved in Japan
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the last dose of study drug.


Selonsertib (SEL; GS-4997)
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Gilead Sciences, Inc. 
Amendment 2
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3) Contraception Requirements for Male Subjects
It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure of the male subject’s seminal fluid. Therefore, male subjects with female 
partners of childbearing potential must use condoms during treatment until 30 days after the last 
dose of study drug. Female partners of male study subjects are asked to select one of the above 
methods.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM). Female condom and male condom should not 
be used together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study or within 30 days of last study 
drug must report the information to the investigator. Instructions for reporting pregnancy, partner
pregnancy, and pregnancy outcome are outlined in Section 7.6.2.1.


Selonsertib (SEL; GS-4997)
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Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
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31 May 2018
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) 
Refer to the Study Reference Binder for additional CTCAE information. 


Selonsertib (SEL; GS-4997)
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Final
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Amendment 2
CONFIDENTIAL
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Appendix 5.
West Haven Criteria
http://www.mdcalc.com/hepatic-encephalopathy-grades-stages/
Grade of Hepatic 
Encephalopathy
Description
Suggested Operative Criteria
Grade I
Trivial lack of awareness
Euphoria or anxiety
Shortened attention span
Impairment of addition or subtraction
Altered sleep rhythm
Despite oriented in time and space (see below), 
the patient appears to have some cognitive/ 
behavioral decay with respect to his or her 
standard on clinical examination or to the 
caregivers
Grade II
Lethargy or apathy
Disorientation for time
Obvious personality change
Inappropriate behavior
Dyspraxia
Asterixis
Disoriented for time (at least three of the 
followings are wrong: day of the month, day of 
the week, month, season, or year) ± the other 
mentioned symptoms
Grade III
Somnolence to semistupor
Responsive to stimuli
Confused
Gross disorientation
Bizarre behavior
Disoriented also for space (at least three of the 
following wrongly reported: country, state [or 
region], city, or place) ± the other mentioned 
symptoms
Grade IV
Coma
Does not respond even to painful stimuli
Adapted from {Vilstrup 2014}

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled 
Study Evaluating the Safety and Efficacy of Selonsertib in 
Subjects with Compensated Cirrhosis due to Nonalcoholic 
Steatohepatitis (NASH)
Name of Test Drug:
Selonsertib
Study Number:
GS-US-384-1944
Protocol Version (Date):
Amendment 2 (31 May 2018)
Analysis Type:
Interim and Final Analysis
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
23 January 2019
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
PPD
(r) GILEAU 


Selonsertib
GS-US-384-1944 Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 2
23 January 2019
TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
LIST OF IN-TEXT FIGURES ......................................................................................................................................4
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................................................................................5
1.
INTRODUCTION ................................................................................................................................................8
1.1.
Study Objectives ......................................................................................................................................8
1.2.
Study Design............................................................................................................................................9
1.3.
Sample Size and Power..........................................................................................................................11
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................12
2.1.
DMC Interim Analyses ..........................................................................................................................12
2.2.
Interim (Week 48) Analysis ...................................................................................................................12
2.3.
Final (Week 240) Analysis.....................................................................................................................12
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................13
3.1.
Analysis Sets..........................................................................................................................................13
3.1.1.
All Randomized Analysis Set...............................................................................................13
3.1.2.
Full Analysis Set ..................................................................................................................13
3.1.3.
Safety Analysis Set...............................................................................................................13
3.1.4.
Pharmacokinetic Analysis Set..............................................................................................13
3.2.
Subject Grouping ...................................................................................................................................14
3.3.
Strata and Covariates..............................................................................................................................14
3.4.
Examination of Subject Subgroups........................................................................................................15
3.5.
Multiple Testing.....................................................................................................................................15
3.6.
Missing Data and Outliers......................................................................................................................18
3.6.1.
Missing Data ........................................................................................................................18
3.6.2.
Outliers.................................................................................................................................20
3.7.
Data Handling Conventions and Transformations .................................................................................20
3.8.
Analysis Visit Windows.........................................................................................................................22
3.8.1.
Definition of Study Day .......................................................................................................22
3.8.2.
Analysis Visit Windows.......................................................................................................22
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window................................................................................................................................26
4.
SUBJECT DISPOSITION ..................................................................................................................................29
4.1.
Subject Enrollment and Disposition.......................................................................................................29
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................30
4.2.1.
Duration of Exposure to Study Drug....................................................................................30
4.2.2.
Adherence to Study Drug.....................................................................................................31
4.2.2.1.
Randomized Phase..........................................................................................31
4.3.
Protocol Deviations................................................................................................................................32
5.
BASELINE CHARACTERISTICS....................................................................................................................33
5.1.
Demographics ........................................................................................................................................33
5.2.
Other Baseline Characteristics ...............................................................................................................33
5.3.
Medical History......................................................................................................................................35
6.
EFFICACY ANALYSES ...................................................................................................................................36
6.1.
Primary Histology Efficacy Endpoint ....................................................................................................36
6.1.1.
Definition of Primary Histology Efficacy Endpoint.............................................................36


Selonsertib
GS-US-384-1944 Statistical Analysis Plan
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23 January 2019
6.1.2.
Statistical Hypothesis for Primary Histology Efficacy Endpoint .........................................36
6.1.3.
Analysis of Primary Histology Efficacy Endpoint ...............................................................37
6.2.
Clinical Efficacy Endpoint.....................................................................................................................38
6.2.1.
Definition of Clinical Efficacy Endpoint..............................................................................38
6.2.2.
Statistical Hypothesis for Clinical Efficacy Endpoint..........................................................38
6.2.3.
Analysis of Clinical Efficacy Endpoint................................................................................39
6.3.
Secondary Efficacy Endpoints ...............................................................................................................40
6.3.1.
Definition of Secondary Efficacy Endpoints........................................................................40
6.3.2.
Analysis of the Secondary Efficacy Endpoints ....................................................................40
6.4.
Exploratory Efficacy Endpoints.............................................................................................................41
6.4.1.
Definition of Exploratory Efficacy Endpoints......................................................................41
6.4.2.
Analysis Methods for Exploratory Efficacy Endpoints........................................................44
6.5.
Change From Protocol-Specified Efficacy Analyses .............................................................................46
7.
SAFETY ANALYSES........................................................................................................................................47
7.1.
Adverse Events and Deaths....................................................................................................................47
7.1.1.
Adverse Event Dictionary ....................................................................................................47
7.1.2.
Adverse Event Severity........................................................................................................47
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................47
7.1.4.
Serious Adverse Events........................................................................................................47
7.1.5.
Treatment-Emergent Adverse Events...................................................................................47
7.1.5.1.
Definition of Treatment-Emergent Adverse Events .......................................47
7.1.5.2.
Definition of Adverse Events > 30 Days Posttreatment .................................48
7.1.5.3.
Incomplete Dates ............................................................................................48
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................48
7.1.7.
Additional Analysis of Adverse Events ...............................................................................50
7.1.7.1.
Cardiovascular Events ....................................................................................50
7.2.
Laboratory Evaluations ..........................................................................................................................51
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................51
7.2.2.
Graded Laboratory Values ...................................................................................................52
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities.............................................52
7.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities ...............................52
7.2.2.3.
Summaries of Laboratory Abnormalities........................................................53
7.2.3.
Liver-related Laboratory Evaluations...................................................................................53
7.2.4.
Drug-Induced Liver Injury (DILI)........................................................................................55
7.3.
Body Weight and Vital Signs.................................................................................................................55
7.4.
Prior and Concomitant Medications.......................................................................................................56
7.4.1.
Prior Medications .................................................................................................................56
7.4.2.
Concomitant Medications.....................................................................................................56
7.5.
Electrocardiogram Results .....................................................................................................................57
7.6.
Other Safety Measures ...........................................................................................................................57
7.6.1.
Stool Frequency....................................................................................................................57
7.7.
Changes From Protocol-Specified Safety Analyses...............................................................................57
8.
PHARMACOKINETIC ANALYSES ................................................................................................................58
9.
REFERENCES ...................................................................................................................................................59
10.
SOFTWARE.......................................................................................................................................................60
11.
SAP REVISION..................................................................................................................................................61
12.
APPENDICES ....................................................................................................................................................62


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Appendix 1.
Study Procedures Table – Screening to Week 48...................................................................63
Appendix 2.
CTCAE Grade for Laboratory Parameters .............................................................................69
Appendix 3.
Pooled Cohort Risk and Score Calculation ............................................................................73
Appendix 4.
Liver Function Prognostic Scores...........................................................................................75
Appendix 5.
Health Related QoL Score Calculation...................................................................................76
Appendix 6.
NAFLD Activity Score (NAS) and Steatosis, Activity, and Fibrosis (SAF) Score 
Calculation..............................................................................................................................78
Appendix 7.
Noninvasive markers for Fibrosis...........................................................................................79
Appendix 8.
SAS Program for Tipping Point Analysis for Binary Endpoint .............................................80
LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Visit Windows for Chemistry, Hematology, Coagulation, CP/MELD 
scores, Vital Signs, Body Weight, and Stool Frequency........................................................23
Table 3-2.
Analysis Visit Windows for Waist Circumference, Insulin, Homeostasis Model 
Assessment of Insulin Resistance (HOMA-IR), Lipids and Hemoglobin A1c ......................24
Table 3-3.
Analysis Visit Windows for ELF test score and components, FibroSure/FibroTest, 
α2-Macroglobin, Haptoglobin, Apolipoprotein A1, C-Reactive Protein (CRP) and 
Total Bile Acids......................................................................................................................24
Table 3-4.
Analysis Visit Windows for Elastography and Pooled Cohort Risk and Score......................25
Table 3-5.
Analysis Visit Windows for Cytokeratin-18 (CK-18) M30 and CK-18 M65 ........................25
Table 3-6.
Analysis Visit Windows for Biopsy Data...............................................................................25
Table 7-1.
Stool Frequency Subscore of Partial Mayo Score ..................................................................57
LIST OF IN-TEXT FIGURES
Figure 1-1.
Overall Study Design .............................................................................................................10
Figure 3-1.
Multiple Testing Flow Chart ..................................................................................................17


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ARFI
acoustic radiation force impulse
APRI
AST to platelet ratio index
AST
aspartate aminotransferase
α-SMA
α-smooth muscle actin
BLQ
below the limit of quantitation
BMI
body mass index
BP
blood pressure
CI
confidence interval
CLDQ
chronic liver disease questionnaire
CK-18
cytokeratin-18
CMH
Cochran-Mantel-Haenszel
CP 
Child-Pugh
CRF
case report form
CRN
clinical research network
CRP
C-reactive protein
CSR
clinical study report
CTCAE
Common Toxicity Criteria for Adverse Events
DILI
drug-induced liver injury
DMC
data monitoring committee
eCRF
electronic case report form
ECG
electrocardiogram
EFS
event-free survival
ELF™
enhanced liver fibrosis 
ET
early termination
EQ-5D
EuroQol five dimensions
FAS
Full Analysis Set
FIB-4
fibrosis-4
Gilead
Gilead Sciences
GGT
gamma glutamyl transferase
HbA1c
Hemoglobin A1c
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HE
hepatic encephalopathy
Hgb
hemoglobin
HDL
high density lipoprotein


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HLGT
high-level group term
HLT
high-level term
HOMA-IR
homeostasis model assessment of insulin resistance
HR
hazard ratio
HRQoL
Health Related Quality of Life
HRUQ
Health Resource Utilization Questionnaires
ID 
identification
IFG 
impaired fasting glucose
INR
international normalized ratio
ITT
intent to treat
IWRS
interactive web response system
KM
Kaplan-Meier
KMMI
Kaplan-Meier multiple imputation
LDL
low density lipoprotein
LLT
lower-level term
LOCF
last observation carried forward
LOQ
limit of quantitation
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MELD
model for end-stage liver disease
MH
Mantel-Haenszel
MI
multiple imputation
MRE
magnetic resonance elastography
NAFLD
non-alcoholic fatty liver disease
NAS
NAFLD activity score
NASH
non-alcoholic steatohepatitis 
NFS
NAFLD fibrosis score
NRI
non-responder imputation
OL
open-label
PK
Pharmacokinetic
PIIINP
procollagen III N-terminal propeptide
PT
preferred term
PTM
placebo-to-match
PVE
Pharmacovigilance and Epidemiology
Q1, Q3
first quartile, third quartile
QoL
quality of life
SAE
serious adverse event
SAF
steatosis, activity, and fibrosis
SAP
statistical analysis plan
SD
standard deviation
SEL 
selonsertib


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SF-36
Short Form (36) Health Survey
SI (units)
international system of units
SWE
shear-wave elastography
SOC
system organ class
SVR
sustained virologic response
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
TIMP1
tissue inhibitor of metalloproteinase 1
VLDL
very low density lipoprotein
ULN
upper limit of normal
WBC
white blood cell count
WHO
World Health Organization
WPAI
work productivity and activity impairment questionnaire


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures and listings (TFLs) for the interim analysis at Week 48
and final analysis at Week 240 for Study GS-US-384-1944.
This analysis plan is based on the study protocol Amendment 2 dated 31 May 2018 and the 
electronic case report form (eCRF). The SAP will be finalized before breaking the blind for the 
interim analysis. Any changes made after the finalization of the SAP will be documented in the 
clinical study report (CSR).
1.1.
Study Objectives
The primary objective of this study is as follows:

To evaluate whether selonsertib (SEL) can cause fibrosis regression and reduce associated 
complications in subjects with cirrhosis due to NASH.
The secondary objective of this study is as follows:

To assess the safety and tolerability of SEL in subjects with NASH and cirrhosis
The exploratory objectives of this study are as follows:
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1.2.
Study Design
This is a Phase 3, randomized, double-blind, placebo-controlled study evaluating the safety and 
efficacy of SEL in subjects with compensated cirrhosis due to NASH.
The overall study design is presented graphically in Figure 1-1.
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Figure 1-1.
Overall Study Design

EOT = end of treatment; ET = early termination; PTM = Placebo-to-Match
Subjects meeting the study’s entry criteria were randomly assigned in a 2:2:1 ratio to 1 of 
3 treatment groups: Group A, Group B and Group C, respectively, as shown in Figure 1-1. 
Randomization was stratified by the presence or absence of diabetes mellitus (as determined by 
medical history or based on Screening laboratory values if previously undiagnosed [i.e.,
hemoglobin A1c (HbA1c) ≥ 6.5% or fasting plasma glucose ≥126 mg/dL) and by Enhanced 
Liver Fibrosis (ELF™) test score ≥ 11.27 or < 11.27 during Screening. Study drugs will be 
administered for up to a total of 240 weeks. 
Subjects who experience a clinical event (except all-cause mortality and liver transplantation) 
prior to completing the Week 240 Visit of the Randomized Phase will be offered the option to 
rollover into an Open-Label (OL) Phase for a total treatment duration of 240 weeks inclusive of 
the Randomized Phase. Rollover into the OL Phase of the study must occur within 60 days of 
confirmation of the event. Subjects starting the OL Phase of the study will complete the same 
study procedures as during the Randomized Phase of the study, 
 
The schedule of assessments is provided as an appendix to this analysis plan (Appendix 1).
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One PTM SEL 6 mg tablet 
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1.3.
Sample Size and Power
With a sample size of 320 subjects in each active treatment arm and 160 subjects in the placebo 
arm, the study has 97% power to detect a difference in the proportion of subjects with a ≥1-stage 
improvement in fibrosis without worsening of NASH of 12% or more at Week 48 at a 
significance level of 0.025 (2-sided), assuming the proportion of subjects that meet the endpoint 
in the placebo arm is 4%.
With regard to the clinical efficacy endpoint, subjects will be followed for a period of up to 
240 weeks. The estimate of the expected event rate is 30% in untreated patients, producing an 
expected EFS rate of 70% at 240 weeks in the placebo arm. SEL is expected to improve the EFS 
rate to 83.7% (expected event rate of 16.3%) compared with placebo (hazard ratio [HR], 0.50). 
We also expect a 20% overall dropout rate. Given the above assumptions, for comparison of the 
SEL arms versus the placebo arm, together with a total sample size of 800 subjects (2:2:1 ratio), 
and assuming the log-rank test statistic is evaluated using a 2-sided 0.025 significance level, the 
study will have 85% power to evaluate the superiority of each SEL arm versus placebo with 
respect to EFS. 
Therefore, the overall power for the trial, assuming independence between the primary efficacy 
endpoint and clinical efficacy endpoint, is 82% (97% × 85%). It should be noted that this is a 
lower bound estimate as these 2 endpoints are expected to be positively correlated.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
DMC Interim Analyses
An external Data Monitoring Committee (DMC) that consists of 3 hepatologists and a PhD 
statistician will review the progress of the study, perform interim reviews of safety data, and 
provide recommendations to Gilead whether the nature, frequency, and severity of adverse 
events (AEs) associated with study treatment warrant the early termination of the study in the 
best interests of the participants, whether the study should continue as planned, or whether the 
study should continue with modifications. 
The initial meeting of the DMC will occur after 50 subjects have completed their Week 4 visit 
and approximately every 6 months thereafter to monitor the study for safety events.
The DMC’s specific activities will be defined by a mutually agreed upon charter, which will 
define the DMC’s membership, conduct, and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.
2.2.
Interim (Week 48) Analysis 
When all subjects have completed the Randomized Phase Week 48 visit, or have a clinical event 
before Randomized Phase Week 48 visit, or have prematurely discontinued from the study, 
superiority of each SEL arm relative to the placebo arm will be assessed with respect to the 
primary histology efficacy endpoint.  
2.3.
Final (Week 240) Analysis
After all subjects have completed the study, or have prematurely discontinued from the study, 
outstanding data queries have been resolved or adjudicated as unresolvable, and the data have 
been cleaned and finalized, the study blind will be broken and the final analysis of the data will 
be performed. The final analysis will assess the superiority of each SEL arm relative to placebo 
with respect to the primary clinical efficacy endpoint of EFS.  


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD), median, first quartile (Q1), third 
quartile (Q3), minimum, and maximum will be presented.
By-subject listings will be presented for all subjects in the All Randomized Analysis Set and 
sorted by subject identification (ID) number, visit date, and time (if applicable). Data collected 
on log forms, such as AEs, will be presented in chronological order within subject. The treatment 
group to which subjects were initially assigned will be used in the listings. Age, sex at birth, 
race, and ethnicity will be included in the listings, as space permits.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. Subjects included in each analysis set will be determined before the 
study blind is broken for analysis. The analysis set will be identified and included as a subtitle of 
each table, figure, and listing. Subjects who have been randomized but never dosed will also be 
summarized.
A listing of reasons for exclusion from analysis sets will be provided by subject.
3.1.1.
All Randomized Analysis Set
All Randomized Analysis Set includes all subjects who were randomized in the study.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all subjects who were randomized in the study and 
received at least 1 dose of study drug. This is the primary analysis set for efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least 1 dose of study drug. This is the 
primary analysis set for safety analyses.
Safety analysis set for the OL Phase (OL Safety Analysis Set) includes all subjects who were 
enrolled into the OL Phase and received at least 1 dose of OL study drug. This is the primary 
analysis set for OL Phase safety analyses.
3.1.4.
Pharmacokinetic Analysis Set
The PK Analysis Set will include all randomized subjects who took at least 1 dose of study drug 
and had at least 1 nonmissing postdose concentration of SEL (and/or its metabolite GS-607509) 
reported by the bioanalytical laboratory. This is the primary analysis set for all PK analyses.


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3.2.
Subject Grouping
For analyses based on the FAS, subjects will be grouped according to the treatment to which 
they were randomized. For analyses based on the Safety Analysis Set, subjects will be grouped 
according to actual treatment received. The actual treatment received will differ from the 
randomized treatment only when the actual treatment differs from the randomized treatment for 
the entire treatment duration. In this case, the actual treatment received is defined as the 
treatment received for the entire treatment duration. 
For safety analyses, subjects will be grouped into the following:
Randomized Phase (only Randomized Phase data will be summarized for these groups)
1) SEL 18 mg: This group includes all subjects who received SEL 18 mg in the Randomized 
Phase. 
2) SEL 6 mg: This group includes all subjects who received SEL 6 mg in the Randomized 
Phase. 
3) SEL Pooled: This group includes all subjects who received SEL 18 mg or SEL 6 mg in the 
Randomized Phase. 
4) Placebo: This group includes all subjects who received only placebo in the Randomized 
Phase. 
Open-Label Phase (only OL Phase data will be summarized for this group):
OL SEL 18 mg:  This group includes all subjects who received OL study drug.
3.3.
Strata and Covariates
An Interactive Web Response System (IWRS) will be used for centralized randomization and 
treatment assignment. Randomization will be stratified by:

Presence or absence of diabetes mellitus (as determined by medical history or based on 
Screening laboratory values if previously undiagnosed [i.e. HbA1c ≥ 6.5% or fasting plasma 
glucose ≥126 mg/dL]) 

ELF test score ≥11.27 or < 11.27 during Screening.
If there are discrepancies in stratification factor values between the IWRS and the clinical 
database, the baseline values recorded in the clinical database will be used for analyses.
Efficacy endpoints will be evaluated using stratification factors as covariates for analyses, as 
specified in Section 6. 


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3.4.
Examination of Subject Subgroups
The primary and key secondary efficacy endpoints as defined in Section 6 will be examined 
using the following subgroups:

Subjects with diabetes at baseline;

Subjects without diabetes at baseline;

Subjects with ELF test score ≥ 11.27 at baseline;

Subjects with ELF test score < 11.27 at baseline;

Subjects with body weight loss ≥ 5% at Week 48/Week 240 (for Week 48/240 analysis, 
respectively);

Subjects with body weight loss < 5% or body weight gain at Week 48/Week 240 (for Week 
48/240 analysis, respectively).

Subjects treated with Vitamin E at baseline;

Subjects not treated with Vitamin E at baseline;

Subjects with a history of sustained virologic response (SVR) to therapy for chronic 
hepatitis C virus (HCV);

Subjects without a history of SVR to therapy for chronic HCV.
For the comparison of the treatment differences in each subgroup, point estimate and 95% 
confidence intervals (CIs) based on the primary analysis approach will be presented. 
3.5.
Multiple Testing
When the primary histology efficacy endpoint is compared between each of the SEL arms and 
the placebo arm at Week 48, it will be tested at a 2-sided 0.025 significance level to control an 
overall Type I error rate of 0.05 by Bonferroni adjustment. 


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The testing strategy for the clinical efficacy endpoint (EFS) is described below and is presented 
graphically in Figure 3-1. 
1) If the primary histology efficacy endpoint is significant in both SEL arms, the EFS endpoint 
will be tested for both SEL arms against placebo at Week 240 at a 2-sided 0.05 significance 
level by the Hochberg procedure {Hochberg 1988}. If the larger p-value of SEL18 mg vs. 
placebo and SEL 6 mg vs. placebo is less than or equal to 0.05, the EFS endpoint for both 
SEL arms will be a success; if the larger p-value is > 0.05, the treatment arm with the larger 
p-value fails, and the smaller p-value will be compared with the significance level of 0.025 to 
determine the success of the treatment arm. 
2) If the primary histology efficacy endpoint is significant in the SEL 18 mg arm but not the 
SEL 6 mg arm, the EFS endpoint will be tested for SEL 18 mg against placebo at Week 240 
at a 2-sided 0.025 significance level. 
3) If the primary histology efficacy endpoint is significant in the SEL 6 mg arm but not the SEL
18 mg arm, the EFS endpoint will be tested for SEL 6 mg against placebo at Week 240 at a 
2-sided 0.025 significance level. 
4) If the primary histology efficacy endpoint is not significant in either the SEL 18 mg or SEL 
6 mg arms, the trial will be terminated.


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Figure 3-1.
Multiple Testing Flow Chart
*
Nominal alpha will be adjusted using the Haybittle-Peto approach
1) Histology 
endpoint at 
Week 48: 
SEL 18 mg vs. 
placebo ≤ 0.025
and
SEL 6 mg vs. 
placebo ≤ 0.025
EFS at Week 
240: 
Max p-value 
of (SEL 18
mg vs. 
placebo, SEL 
6 mg vs. 
placebo) 
≤ 0.05*
Yes
Both SEL 18 mg 
and SEL 6 mg arms 
succeed
Is the arm with 
smaller p-value 
≤ 0.025*? 
Yes
No
Only the arm 
with smaller 
p-value
succeeds
Yes
Both SEL arms 
fail
No
2) Histology endpoint at 
Week 48: 
SEL 18 mg vs. placebo ≤ 
0.025 and 
SEL 6 mg vs. placebo 
>0.025
EFS at Week 
240: 
SEL 18 mg vs. 
placebo 
≤ 0.025*
Yes
Only SEL 18 mg succeeds
Yes
Both SEL arms fail
No
4) Histology 
endpoint at 
Week 48: 
SEL 18 mg vs. 
placebo >0.025 
and 
SEL 6 mg vs.
placebo >0.025 
Both SEL arms 
fail 
Yes
3) Histology 
endpoint at 
Week 48: 
SEL 18 mg vs. 
placebo >0.025 
and 
SEL 6 mg vs.
placebo ≤ 0.025
EFS at Week 
240: 
SEL 6 mg vs. 
placebo
≤ 0.025*
Yes
Only SEL 6 mg succeeds
Yes
Both SEL arms fail
No
\ I 
\/ 
\ 
r 
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Although no formal statistical inference on EFS is planned for the Week 48 Interim Analysis, the 
actual nominal significance level for the EFS endpoint at the Week 240 Analysis will be adjusted 
using the Haybittle-Peto approach {Haybittle 1971}.  The adjustment will be based on the 
number of events at both the Week 48 and Week 240 analyses, assuming an allocation of a 
two-sided significance level of 0.001 at the Week 48 Interim Analysis.
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
For missing last dosing date of study drug, imputation rules are described in Section 4.2.1. The 
handling of missing or incomplete dates for AE onset is described in Section 7.1.5.3, and for 
prior and concomitant medications in Section 7.4.
The following imputation approaches will be applied to efficacy endpoints as specified:
1) Non-Responder Imputation (NRI) 
For purpose of analysis at a defined time point, when NRI is used, all subjects with missing 
values will be analyzed as not meeting the corresponding endpoint. The NRI method will be 
applied to subjects with or without baseline value.
2) Multiple Imputation (MI):
The MI procedure replaces each missing data point of the binary primary histology efficacy 
endpoint (defined in Section 6.1.1) with a set of plausible values that represent the 
uncertainty about the right value to impute under the missing at random (MAR) assumption. 
The imputation model used to impute missing data points will be based on the logistic 
regression with the treatment arms and the 2 stratification factors as covariates. A total of 
50 imputed datasets will be generated by the imputation model. That is, each missing data 
point will be imputed 50 times. Each imputed data set will be analyzed by the method for the 
primary analysis as specified in Section 6.1.3. The results from these 50 imputed data sets 
will be combined using Rubin’s rule {Rubin 1987}.  
3) Tipping Point Analysis (TPA): 
If any significant result in favor of SEL 18 mg or SEL 6 mg is detected in the primary 
analysis of the binary primary histology efficacy endpoint (described in Section 6.1.3), a 
delta-adjusting pattern-mixture approach for TPA {Ratitch 2013} will be conducted to assess 
the robustness of the primary analysis results under missing not at random assumption for 
SEL arms. Specifically, it is assumed that a systematic difference exists between the 
conditional distributions of the missing and observed data in the SEL arms. To reflect such a 
systematic difference, a shift parameter δ will be applied to the imputation model (i.e., the 
logistic regression with the treatment arms and the 2 stratifications factors as covariates) 
when the missing data points in the SEL arms are imputed. For each value of δ, multiply 
imputed data sets will be generated, each data set will be analyzed by the same method for 
the primary analysis, and analysis results will then be combined by Rubin’s rule. Thus, by 


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varying the values of δ, the impact from missing data on the analysis results will be examined 
to identify tipping points (i.e., the values at which conclusions from statistical inference 
change from being significant to being insignificant for SEL arm(s)). 
4) Last Observation Carried Forward (LOCF)
For purpose of analysis at a defined time point, if the value is missing, the last observed 
value prior to the time point will be used to impute the missing value. Refer to Section 3.8.2
for the handling of the data to be included in efficacy analysis.  The LOCF approach will be 
applied to those subjects who have a baseline value. No imputation will be performed if the 
value at baseline is missing.
5) Observed Case (OC)
Only subjects with observed Baseline and Week 48/240 values will be included at the 
corresponding Week 48/240 analysis.
6) Kaplan-Meier Multiple Imputation (KMMI)
Sensitivity analysis will be performed under the KMMI strategy {Zhao 2014} if there are 
significant differences in the Kaplan-Meier (KM) estimates of survival rates between SEL 18 
mg or SEL 6 mg and placebo. This method introduces a sensitivity parameter, , defined as 
the fixed hazard ratio of a subject who dropped out having the event after being censored at a 
certain centering time relative to subjects who remain on treatment having the event after that 
censoring time. The MAR-like assumption (i.e., noninformative independent censoring) 
corresponds to  = 1.  > 1 implies a higher hazard after censoring for subjects who drop
out compared their counterparts who remain on treatment. By varying the values of , the 
KMMI strategy addresses departures from the MAR-like assumption when unobserved time-
to-event data are multiply imputed. 
The KMMI approach can be summarized as follows:
i)
Calculate KM estimates of survival rates for each treatment group within each stratum 
separately.
ii) Obtain the survival estimate at each censoring time by linear interpolation of the KM 
survival rates corresponding to the 2 event times immediately before and after. The KM 
survival function may be extrapolated to calculate the survival estimates at censoring 
time which is after the event time of the last observed event up to the maximum 
follow-up time (i.e., 252 weeks [or 58 months]).  
iii) Apply each value of  to impute the unobserved event time for a dropout who will 
experience the event after the time being censored for a total of 50 times.


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After the multiple imputation, the pairwise logrank test will be performed to compare the 
survival rates between SEL 18 mg or SEL 6 mg and placebo on each complete data set 
(described in Section 6.2.3). Then, by combining the normalized chi-square statistics using 
Rubin’s rule, the impact of departures from noninformative censoring can be investigated by 
the combined treatment effect inference, which is a function of . Thus, the robustness of the 
significant results can be assessed.
The NRI approach will be used for the primary analysis of the primary histology efficacy 
endpoint and secondary endpoints evaluated at Week 48. LOCF analysis and OC analysis will be 
carried out as sensitivity analyses for these endpoints at Week 48 using the same analysis method 
as defined in Section 6.1.3. ‘Last observation’ includes both baseline and postbaseline records, 
and only the records eligible for efficacy analysis will be carried forward.
The MI and TPA approaches will be used for the sensitivity analyses for the primary histology 
efficacy endpoint. KMMI approach will be used for the sensitivity analysis for the clinical 
efficacy endpoint.
The NRI approach will be used for the primary analysis for the secondary endpoints evaluated at 
Week 240.  The LOCF and OC approaches will be used for sensitivity analysis of these 
endpoints.  
 
 
 
 
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process. All data, 
including outliers, will be included in analyses. 
3.7.
Data Handling Conventions and Transformations
In general, age (in years) on the date of the first dose of study drug will be used for analyses and 
presentation in listings. If an enrolled subject was not dosed with any study drug, the 
randomization date will be used instead of the first dosing date of study drug. For screen failures, 
the date the informed consent was signed will be used for age calculation. If only birth year is 
collected on the eCRF, “01 July” will be used for the unknown birth day and month for the 
purpose of age calculation. If only birth year and month are collected, “01” will be used for the 
unknown birth day.
CCI


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Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ)
or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used for calculation of descriptive statistics if 
the datum is reported in the form of “x” (where x is considered the LOQ). For example, if 
the values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used for 
calculation of summary statistics. An exception to this rule is any value reported as < 1 or 
<0.1, etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used 
for calculation of summary statistics.

A value that is 1 unit above the LOQ will be used for calculation of descriptive statistics if 
the datum is reported in the form of “> x” (where x is considered the LOQ). Values with 
decimal points will follow the same logic as above.

The LOQ will be used for calculation of descriptive statistics if the datum is reported in the 
form of “≤ x” or “≥ x” (where x is considered the LOQ).
When any ELF component (hyaluronic acid, procollagen III N-terminal propeptide [PIIINP]  and 
tissue inhibitor of metalloproteinase 1 [TIMP1]) is less than the lower LOQ or above the upper 
LOQ, the ELF components will be imputated based on the rules described above, and the ELF 
test score will be calculated based on the imputed value of the component(s) as defined in 
Appendix 7.
Natural logarithm transformation will be used for plasma concentrations and analysis of PK 
parameters. Plasma concentration values that are below the limit of quantitation (BLQ) will be 
presented as “BLQ” in the concentration data listing. Values that are BLQ will be treated as 0 at 
predose time points, and one-half the value of the LOQ at postbaseline time points.
The following conventions will be used for the presentation of summary and order statistics: 

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as “BLQ.”

If more than 25% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ.”

If more than 50% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ.”

If more than 75% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.”

If all subjects have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”


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3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day/OL study day will be calculated from the first dosing date of study drug in the 
corresponding phase (Randomized or OL) and derived as follows:

For postdose study days: Assessment Date – First Dosing Date + 1

For days prior to the first dose: Assessment Date – First Dosing Date
Study Day 1/OL Study Day 1 is the day of first dose of study drug administration in the 
corresponding phase.
3.8.2.
Analysis Visit Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows.
On-treatment visit windows will be calculated from Study Day 1/OL Study Day 1 for selected 
efficacy measures, vital signs, elastography, and safety laboratory data.
Selected safety and efficacy data, unless otherwise specified, collected up to and including the 
last dosing date in the Randomized Phase + 30 days and before OL Study Day 1 for the 
Randomized Phase, whichever is earlier, or OL last dosing date + 30 days for the OL Phase, will 
be mapped according to the following analysis windows unless the nominal visit name is Follow-
Up or OL Follow-Up. 
All biopsy data and elastography data collected will be mapped to Randomized Phase visit 
windows unless on or after OL Study Day 1. HRQoL questionnaires and HRUQ will not be 
windowed, and will be summarized by nominal visit. For those endpoints, missing (OL) 
Baseline/Day 1 values will not be imputed.
The analysis windows for select measures are provided in Table 3-1 to Table 3-6.


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Table 3-1.
Analysis Visit Windows for Chemistry, Hematology, Coagulation, 
CP/MELD scores, Vital Signs, Body Weight, and Stool Frequency
Analysis Visit
Nominal Day
Lower Limit
Upper Limit
Baseline/OL-Baseline
1
(none)
1
Week 1/OL-Week 1
8
2
18
Week 4/OL-Week 4
29
19
42
Week 8/OL-Week 8
57
43
70
Week 12/OL-Week 12
85
71
98
Week 16/OL-Week 16
113
99
126
Week 20/OL-Week 20
141
127
154
Week 24/OL-Week 24
169
155
182
Week 28/OL-Week 28
197
183
210
Week 32/OL-Week 32
225
211
238
Week 36/OL-Week 36
253
239
266
Week 40/OL-Week 40
281
267
294
Week 44/OL-Week 44
309
295
322
Week 48/OL-Week 48
337
323
378
Week 60/OL-Week 60
421
379
462
Week 72/OL-Week 72
505
463
546
Week 84/OL-Week 84
589
547
630
Week 96/OL-Week 96
673
631
714
Week 108/OL-Week 108
757
715
798
Week 120/OL-Week 120
841
799
882
Week 132/OL-Week 132
925
883
966
Week 144/OL-Week 144
1009
967
1050
Week 156/OL-Week 156
1093
1051
1134
Week 168/OL-Week 168
1177
1135
1218
Week 180/OL-Week 180
1261
1219
1302
Week 192/OL-Week 192
1345
1303
1386
Week 204/OL-Week 204
1429
1387
1470
Week 216/OL-Week 216
1513
1471
1554
Week 228/OL-Week 228
1597
1555
1638
Week 240/OL-Week 240
1681
1639
≥1681


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Table 3-2.
Analysis Visit Windows for Waist Circumference, Insulin, 
Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), 
Lipids and Hemoglobin A1c
Analysis Visit
Nominal Day
Lower Limit
Upper Limit
Baseline/OL-Baseline
1
(none)
1
Week 4/OL-Week 4
29
2
56
Week 12/OL-Week 12
85
57
126
Week 24/OL-Week 24
169
127
252
Week 48/OL-Week 48
337
253
420
Week 72/OL-Week 72
505
421
588
Week 96/OL-Week 96
673
589
756
Week 120/OL-Week 120
841
757
924
Week 144/OL-Week 144
1009
925
1092
Week 168/OL-Week 168
1177
1093
1260
Week 192/OL-Week 192
1345
1261
1428
Week 216/OL-Week 216
1513
1429
1596
Week 240/OL-Week 240
1681
1597
≥1681
Table 3-3.
Analysis Visit Windows for ELF test score and components, 
FibroSure/FibroTest, α2-Macroglobin, Haptoglobin, Apolipoprotein
A1, C-Reactive Protein (CRP) and Total Bile Acids
Analysis Visit
Nominal Day
Lower Limit
Upper Limit
Baseline/OL-Baseline
1
(none)
1
Week 12/OL-Week 12
85
2
126
Week 24/OL-Week 24
169
127
252
Week 48/OL-Week 48
337
253
420
Week 72/OL-Week 72
505
421
588
Week 96/OL-Week 96
673
589
756
Week 120/OL-Week 120
841
757
924
Week 144/OL-Week 144
1009
925
1092
Week 168/OL-Week 168
1177
1093
1260
Week 192/OL-Week 192
1345
1261
1428
Week 216/OL-Week 216
1513
1429
1596
Week 240/OL-Week 240
1681
1597
≥1681


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Table 3-4.
Analysis Visit Windows for Elastography and Pooled Cohort Risk and 
Score
Analysis Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1 (28*)
Week 24
169
2(29*)
252
Week 48
337
253
420
Week 72
505
421
588
Week 96
673
589
840
Week 144
1009
841
1176
Week 192
1345
1177
1512
Week 240
1681
1513
≥1681
*
for Elastography.
Table 3-5.
Analysis Visit Windows for Cytokeratin-18 (CK-18) M30 and 
CK-18 M65
Analysis Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1 
Week 24
169
2
252
Week 48
337
253
504
Week 96
673
505
840
Week 144
1009
841
1176
Week 192
1345
1177
1512
Week 240
1681
1513
≥1681
Table 3-6.
Analysis Visit Windows for Biopsy Data
Analysis Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 48
337
169
504
Week 240
1681
505
≥1681
Data relating to unscheduled visits and early termination visits may be assigned to a particular 
visit or time point based on the visit windows. The following conventions will be followed:

An unscheduled visit prior to the first dosing of study drug may be included in the calculation 
of the baseline value, if applicable.


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
Unscheduled visits after the first dose of study drug will be included in determining the 
maximum postbaseline toxicity grade.

Data collected on a follow-up visit will be summarized as a separate visit, and labeled 
“Follow-up Visit” of each phase.
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window.
If multiple, valid nonmissing, continuous measurements exist in an analysis window, records 
will be chosen based on the following rules if a single value is needed:

In general, the baseline value will be the last nonmissing value on or prior to the first dosing 
date of study drug in the corresponding phase. If multiple measurements occur on the same 
day, the last nonmissing value prior to the time of first dosing of study drug will be 
considered as the baseline value. If these multiple measurements occur at the same time or 
the time is not available, the average of these measurements (for continuous data) will be 
considered as the baseline value. Baseline values for liver tests (ALT, AST, total bilirubin, 
and direct bilirubin) in the Randomized Phase will be determined by averaging the values 
obtained between and including Screening and Day 1; baseline values for liver tests (ALT, 
AST, total bilirubin, and direct bilirubin) in the OL Phase will be determined by averaging 
the values obtained between OL Study Day - 55 and OL Study Day 1 (inclusive); baseline 
values for elastography will be determined as the last non missing values on or prior to (OL) 
Day 28. Missing (OL) Baseline/Day 1 values of HRQoL questionnaires and HRUQ will not 
be imputed.

For postbaseline visits:
1) The record closest to the nominal day for that visit will be selected.
2) If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
3) In general, if there is more than 1 record on the selected day, the average will be taken. For 
serum creatinine, if both enzymatic and regular creatinine are collected from the same blood 
sample and are analyzable, regular creatinine will be selected for analysis.


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If multiple, valid, nonmissing, categorical measurements exist in an analysis window, records 
will be chosen based on the following rules if a single value is needed:

For baseline, the last available record on or prior to the date of the first dose of study drug
will be selected in the corresponding phase. If there are multiple records on the same day, the 
value with the lowest severity will be selected (e.g., normal will be selected over abnormal 
for safety electrocardiogram [ECG] findings).

For postbaseline visits, if there are multiple records on the same day, the value with the worst 
severity within the window will be selected (e.g., abnormal will be selected over normal for 
safety ECG findings).
Postbaseline parameters used to define histology endpoints will be selected in each visit window 
according to the following rules:

Histology endpoints including ≥1-stage improvement in fibrosis without worsening of 
NASH, ≥1-stage improvement in fibrosis, NASH resolution without worsening of fibrosis, 
NAS and elements, SAF and elements will be derived based on parameters collected from 1
biopsy sampling date if  the following 4 parameters are available: NASH CRN fibrosis stage, 
lobular inflammation, hepatocellular ballooning, and steatosis grades. 

When the set of the 4 parameters (NASH CRN fibrosis stage, lobular inflammation, 
hepatocellular ballooning, and steatosis grades) is available for multiple biopsy samples 
obtained on different dates in 1 visit window, the set with the biopsy sample collection date 
closest to the nominal day will be chosen for analysis. When 2 samples are equidistant from 
the nominal day, the later value will be selected.

When the set of the 4 parameters is not complete for any biopsy sample from a single day, 
the histology endpoints will be derived based on the nonmissing value of each individual 
parameter closest to the nominal day for that visit window. When 2 records are equidistant 
from the nominal day, the later record will be selected.

For Ishak fibrosis stage, the nonmissing value from the biopsy sample collection date closest 
to the nominal day for the visit window will be selected regardless of the missing status of 
other parameters. When 2 records are equidistant from the nominal day, the later record will 
be selected.

When an endpoint cannot be derived based on all biopsy samples in a visit window, the 
histology endpoint will be considered missing, and imputation methods listed in 
Section 3.6.1 will apply.


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Liver stiffness by transient elastography data in each analysis visit window will be chosen based 
on the following rules:

For baseline, measurements by XL probe will be selected for analysis if available, otherwise 
measurements by M probe will be selected.

For postbaseline visits, measurements by the same probe type (XL or M) selected for the 
subject at baseline will be selected in each analysis visit window. If no measurement by the 
same probe type as baseline is available, the analysis value for the corresponding
postbaseline visit will be considered missing. If there are multiple postbaseline records by the 
same probe type as baseline, the rules to choose postbaseline continuous measurements as 
described above will apply.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided by treatment group and overall for each
country and investigator within country. The summary will present the number and percentage of 
subjects enrolled. For each column, the denominator for the percentage calculation will be the 
total number of subjects analyzed for that column.
A similar enrollment table will be provided by randomization stratum. The denominator for the 
percentage of subjects in the stratum will be the total number of randomized subjects. If there are 
discrepancies in the value used for stratification assignment between the IWRS and the clinical 
database, the value collected in the clinical database will be used for the summary. A listing of 
subjects with discrepancies in the value used for stratification assignment between the IWRS and 
the clinical database at the time of data finalization will be provided.
The randomization schedule used for the study will be provided as a by-subject listing to the 
CSR.
A summary of subject disposition will be provided by treatment group. This summary will 
present the number of subjects screened, the number of subjects randomized, and the number of 
subjects in each of the categories (as applicable) listed below:

Safety Analysis Set 

Full Analysis Set 

Continuing randomized study drug (for interim analysis)

Completed randomized study drug

Did not complete randomized study drug with reasons for premature discontinuation of study 
drug in the Randomized Phase

OL Safety Analysis Set

Continuing OL study drug (for interim analysis)

Completed OL study drug

Did not complete OL study drug with reasons for premature discontinuation of study drug in 
the OL Phase

Continuing study (for interim analysis)


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
Completed study

Did not complete study with reasons for premature discontinuation of study
For the Randomized Phase, 2 additional categories will be summarized under “Completed study 
drug”:

Completed study drug due to protocol-specified clinical events 

Completed 240 weeks of study drug
For the status of study drug and study completion and reasons for premature discontinuation, the 
number and percentage of subjects in each category will be provided. The denominator for the 
percentage calculation will be the total number of subjects in the Safety Analysis Set 
corresponding to that column in the corresponding study phase. In addition, a flowchart will be 
provided to depict the disposition by study phase.
In the Week 48 interim analysis, subject disposition will be summarized by study phase in 
2 tables. The table for the Randomized Phase will be provided by treatment group and include 
items listed above, except for those based on the OL Safety Analysis Set, or the study completion 
status.  The table for the OL Phase will be provided on the OL Safety Analysis Set, and will 
include study drug completion status. The flowchart will also be provided by study phase. 
The following by-subject listings will be provided by subject ID number in ascending order to 
support the above summary tables:

Reasons for premature study drug or study discontinuation

Reasons for screen failure will be provided by screening ID number in ascending order

Lot number and bottle ID
4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug and the level of adherence to the study drug specified in the protocol.
4.2.1.
Duration of Exposure to Study Drug
For each study phase, duration of exposure to study drug will be defined as last dosing date 
minus first dosing date plus 1 and then divided by 7, regardless of any temporary interruptions in 
study drug administration, and will be expressed in weeks using up to 1 decimal place (e.g., 
4.5 weeks). For the Randomized Phase, first dosing date is the earlier date between the 2 drug 
types; last dosing date is the later date between the 2 drug types. If the last study drug dosing 
date is missing, the latest date among the study drug end date, clinical visit date, laboratory 
sample collection date, and vital signs assessment date that occurred during the corresponding 
phase will be used in the final analysis. At the time of an interim analysis, the missing last dosing


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date will be imputed by the data snapshot date (or data cut date if applicable) for subjects who 
are still on treatment.
The duration of exposure to study drug will be summarized using descriptive statistics and using 
the number (i.e., cumulative counts) and percentage of subjects exposed through the following 
time periods: 1 day, 1 week, 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, and every 24 
weeks thereafter. Summaries will be provided by treatment group for the Safety Analysis Set in 
each study phase as defined in Section 3.2.
No formal statistical testing is planned.
4.2.2.
Adherence to Study Drug
The total number of tablets administered will be summarized using descriptive statistics. 
The presumed total number of tablets administered to a subject will be determined by the data 
collected on the drug accountability eCRF using the following formula:
Total Number of Doses Administered =
No. of Doses Dispensed
No. of Doses Returned















The level of on-treatment adherence to study drug regimen will be determined by the total 
amount of study drug administered relative to the total amount of study drug expected to be 
administered in each treatment phase during a subject’s actual on-treatment period based on the 
study drug regimen.
The level of on-treatment adherence will be expressed as a percentage using the following 
formula:
Total Amount of Study Drug Administered
On-Treatment Adherence (%) = 
 x 100
Study Drug Expected to be Administered on Treatment






4.2.2.1.
Randomized Phase 
Study drug expected will be calculated as treatment duration in days (one tablet per day for each 
drug type) as defined in Section 4.2.1. The adherence rates of SEL 18 mg tablet for SEL 18 mg 
treatment group and SEL 6 mg tablet for SEL 6 mg treatment group, and the average of the 
adherence rates between PTM 18 mg and PTM 6 mg tablets for placebo group will be 
summarized by treatment group (1, 2 and 4) as defined in Section 3.2. 


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
Open-Label Phase
On-treatment adherence will be calculated for OL SEL 18 mg. Study drug expected will be 
calculated as treatment duration in days (1 tablet per day). Adherence rates will be summarized 
for the OL SEL 18 mg group as defined in Section 3.2.
At interim analyses, if the subject is ongoing, the number of tablets administered and expected to 
be administered on treatment will be calculated based on study drug accountability data.
No formal statistical testing is planned.  Descriptive statistics for the level of on-treatment 
adherence with the number and percentage of subjects belonging to adherence categories 
(< 75%, ≥ 75 to < 90%, ≥ 90%) will be provided.
By-subject listing of study drug administration and drug accountability will be provided 
separately by subject ID number (in ascending order) and visit (in chronological order).
4.3.
Protocol Deviations 
Subjects who did not meet the eligibility criteria for study entry, but enrolled in the study will be 
summarized. No exemptions will be granted for this study. The summary will present the number 
and percentage of subjects who did not meet at least 1 eligibility criterion and the number of 
subjects who did not meet specific criteria by treatment group based on the All Randomized 
Analysis Set. A by-subject listing will be provided for those subjects who did not meet at least 1 
eligibility (inclusion or exclusion) criterion. The listing will present the eligibility criterion (or 
criteria if more than 1 deviation) that subjects did not meet and related comments, if collected.
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. The number and percentage of subjects with important protocol deviations by 
deviation reason will be summarized by treatment group in the Randomized and OL Phases for 
the All Randomized Analysis Set and OL Safety Analysis Set, respectively. A by-subject listing 
will be provided for those subjects with any important protocol deviation.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics
Subject demographic variables (i.e., age, sex, race, and ethnicity) will be summarized by 
treatment group and overall for each study phase using descriptive statistics for age, and using 
number and percentage of subjects for sex, race, and ethnicity. Age in the Randomized/OL Phase 
summary is calculated in years at the date of first study drug administration in the 
Randomized/OL Phase. The summary of demographic data will be provided for the Safety 
Analysis Set and OL Safety Analysis Set, respectively.
A by-subject demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order for the All Randomized Analysis Set.
5.2.
Other Baseline Characteristics
For the Randomized Phase, baseline characteristics include:

Fibrosis stage score (fibrosis stages according to the NASH CRN classification and Ishak 
method will be summarized separately)

Hepatic collagen content

NAS

Steatosis grade

Lobular inflammation grade

Hepatocellular ballooning grade

ALT

AST

GGT

ALP

Total bilirubin

Direct bilirubin

INR

Platelets


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
MELD score

Child-Pugh (CP) score

Height

Body weight

Body mass index (BMI) as a continuous variable and as categories (18 to < 25 kg/m2, 25 to 
< 30 kg/m2  and ≥30 kg/m2)

Diabetes mellitus (absence or presence)

Fasting glucose

HbA1c

ELF™test score 

Fibrosis-4 (FIB-4) index

NAFLD Fibrosis Score (NFS)

Liver stiffness by transient elastography

Use of Vitamin E

History of SVR to therapy for chronic HCV

Use of Vitamin E is defined as treatment with Vitamin E on Day 1. Sustained virologic 
response is defined as HCV antibody positive and HCV virus negative at baseline.
For the OL Phase baseline characteristics include:

ALT

AST

GGT

ALP

Total bilirubin

INR

Platelets


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
Body weight

BMI as a continuous variable and for categories (< 18 kg/m2 [if applicable], 18 to 
< 25 kg/m2, 25 to < 30 kg/m2  and ≥30 kg/m2)

Fasting glucose

HbA1c
All baseline characteristics will be summarized by treatment group and overall for the Safety 
Analysis Set and OL Safety Analysis Set as defined in Section 3.2. Descriptive statistics for 
continuous variables and number and percentage of subjects for categorical variables will be 
used. No formal statistical testing is planned.
A by-subject listing of baseline characteristics will be provided by subject ID number in 
ascending order for the All Randomized Analysis Set.
5.3.
Medical History
General medical history data will be collected at Screening. General medical history data will be 
coded using the current version of Medical Dictionary for Regulatory Activities (MedDRA). 
System organ class (SOC), high-level group term (HLGT), high-level term (HLT), preferred 
term (PT), and lower-level term (LLT) will be provided in the medical history dataset.


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6.
EFFICACY ANALYSES
Efficacy analyses will include data collected in the Randomized Phase only. All data on or after 
the first dose of OL study drug will be excluded from efficacy analyses.  
6.1.
Primary Histology Efficacy Endpoint
6.1.1.
Definition of Primary Histology Efficacy Endpoint
The primary histology efficacy endpoint at Week 48 is the proportion of subjects who achieve a 
≥1-stage improvement in fibrosis (according to the NASH CRN classification) without 
worsening of NASH (defined as a ≥ 1-point increase in hepatocellular ballooning or lobular 
inflammation).
6.1.2.
Statistical Hypothesis for Primary Histology Efficacy Endpoint
The statistical hypotheses to be tested can be stated as:
	
: 
 = 0 versus 
: 
 ≠0 ,  = 1  2
Where 
1
s
(
2
s
) is the difference in the proportion of subjects who achieve a ≥ 1-stage 
improvement in fibrosis without worsening of NASH at Week 48 between SEL 18 mg (SEL 
6 mg) and placebo.  The hypotheses will be tested in the FAS with α = 0.025 for the comparison 
between each SEL arm and the placebo arm.  The study will evaluate if each SEL arm performs 
better (i.e., has a higher proportion of subjects who achieve a ≥1-stage improvement in fibrosis 
without worsening of NASH) than the placebo arm.


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6.1.3.
Analysis of Primary Histology Efficacy Endpoint
A stratified Mantel-Haenszel (MH) test will be used to compare the differences in proportions of 
subjects who achieve a ≥ 1-stage improvement in fibrosis without worsening of NASH at 
Week 48 between SEL 18 mg (SEL 6 mg) and placebo, adjusting for presence or absence of 
diabetes mellitus at baseline and ELF™test score ≥ 11.27 or < 11.27 at baseline. Subjects 
missing data regarding fibrosis stage and NAS elements used to define worsening of NASH 
(hepatocellular ballooning and lobular inflammation) at Week 48 will be analyzed as treatment 
failures for this endpoint. The 2-sided 95% CIs on the difference in proportions between SEL 
18 mg (SEL 6 mg) and placebo will be constructed based on stratum-adjusted MH proportions as 
follows {Koch 1989}:
pA – pB Z(1-α/2 )* SE(pA – pB),
where 

(pA – pB) = 

h
h
h
w
d
w
, is the stratum-adjusted MH proportion difference, where 
h
d
=
Bh
Ah
p
p

is the difference in the proportion of subjects who achieved a ≥ 1-stage 
improvement in fibrosis without worsening of NASH between SEL 18 mg (SEL 6 mg) and 
placebo in stratum h.  

h
w =
Bh
Ah
Bh
Ah
n
n
n
n

, is the weight based on the harmonic mean of sample size per treatment group 
for each stratum where 
Ah
n
and 
Bh
n are the sample sizes of SEL 18 mg (SEL 6 mg) and 
placebo in stratum h.

SE(pA – pB) = 
2
*
*
*
*
2
)
(
1
)
1(
1
)
1(













h
Bh
Bh
Bh
Ah
Ah
Ah
h
w
n
p
p
n
p
p
w
, where 

1
5.0
*



Ah
Ah
Ah
n
m
p
and 
1
5.0
*



Bh
Bh
Bh
n
m
p
, and 

Ah
m
and 
Bh
m
are the number of subjects who achieved a ≥ 1-stage improvement in 
fibrosis without worsening of NASH in SEL 18 mg (SEL 6 mg) and placebo in stratum h.

α = 0.05 for the calculation of 95% CI 

Z(1-α/2 ) = Z0.975 = 1.96 is the 97.5th percentile of the normal distribution

Z score = 
()
()
J--


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If the computed lower confidence bound is less than –1, the lower bound is defined as –1. If the 
computed upper confidence bound is greater than 1, then the upper bound is defined as 1. 
The point estimates, 95% CIs, and corresponding p-values based on Z tests for the differences in 
proportions, and the 95% CIs for proportion of responders in each treatment group based on the 
Clopper-Pearson method will be calculated. 
A logistic regression analysis will also be performed to assess the odds ratio between each of the 
SEL arms and the placebo arm, adjusting for stratification factors.  The point estimate of odds 
ratio, 95% CIs of odds ratio, and corresponding p-values for each SEL arm versus the placebo 
arm will be reported.
Forest plots of the treatment differences in the proportion of subjects who achieved primary 
histology endpoint will be generated for the subgroup analyses as described in Section 3.4 and 
sensitivity analyses as described in Section 3.6.1, respectively.
6.2.
Clinical Efficacy Endpoint
6.2.1.
Definition of Clinical Efficacy Endpoint
A composite of clinical events that constitute the clinical efficacy endpoint include: 
1. Events of hepatic decompensation including:
a) Clinically apparent ascites requiring treatment
b) Hepatic encephalopathy (HE) of Grade 2 or above (according to the West Haven criteria 
defined in Appendix 5 of the protocol) requiring treatment
c) Portal hypertension-related upper gastrointestinal bleeding identified by endoscopy and 
requiring hospitalization, including events of bleeding from esophageal varices, gastric 
varices, and portal hypertensive gastropathy
2. Liver transplantation or qualification for liver transplantation (defined as MELD score  ≥ 15 
on at least 2 consecutive occasions at least 4 weeks apart)
3. All-cause mortality
Each of these clinical events (except all-cause mortality and liver transplantation) will require 
confirmation by a Hepatic Events Adjudication Committee. The onset date of the first clinical 
event (death, liver transplantation or adjudication-confirmed event) will be used in the analysis.
6.2.2.
Statistical Hypothesis for Clinical Efficacy Endpoint
The null statistical hypotheses to be tested can be stated as the survival and hazard functions 
being identical between SEL 18 mg (SEL 6 mg) and placebo.


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6.2.3.
Analysis of Clinical Efficacy Endpoint
Differences in EFS between SEL 18 mg (SEL 6 mg) and placebo will be assessed using the 
log-rank test stratified by presence or absence of diabetes mellitus and ELF test score ≥11.27 or 
< 11.27 at baseline.  
Time (in months) up to the first clinical event/censoring date will be calculated as: [first clinical 
event date or censoring date - randomization date + 1] / 30.4375.  
Censoring date will be the later date between the last visit date and latest AE onset date in the 
Randomized Phase for subjects who have prematurely discontinued from the Randomized Phase, 
or who have completed the Randomized Phase.  In the Week 48 Interim Analysis, the data cut 
date will be used as the censoring date for ongoing subjects in the Randomized Phase.
For the purpose of analysis, if the onset date of a clinical event or an AE is incomplete, the first 
day of the month (if date is missing) or the first day of the year (if date and month are missing) 
will be used to derive the clinical event or censoring date. If such imputation leads to an imputed 
event date that is earlier than the randomization date, the randomization date should be used to 
impute the incomplete event date.
In the following code, Months is the number of months from randomization date to the first 
clinical event or to the censoring date for subjects who don’t have clinical events. Status is a 
binary variable with 1 representing no clinical event observed and 0 representing a clinical event 
observed.  
proc lifetest data=efs_2groups;
time Months*Status(1);
strata BL_Diabetes BL_ELF_category / group=treatment;
run;
A proportional hazards model will be used to calculate the point estimate and 95% CI for the 
hazard ratio between SEL 18 mg (SEL 6 mg) and placebo controlling for stratification factors. 
Proportional hazard assumption will be evaluated.
proc phreg data=efs_3groups;
class treatment BL_Diabetes BL_ELF_category;
model Months*Status(1) =  treatment / RL;
strata BL_Diabetes BL_ELF_category;
run;
For each treatment group, the KM estimates of EFS probability at 3-month intervals, i.e., at 
Month 3, 6, 9, etc and 95% CIs will be provided.  The 95% CI will be calculated based on 
Greenwood’s formula and log-log transformation of the survival function.


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Median, Q1 and Q3 of the EFS will be provided for each treatment group.  The 95% CI for 
median EFS based on Brookmeyer-Crowley method {Brookmeyer 1982}of inverting a 
generalization of the sign test for censored data will also be provided for each treatment group. 
KM curves will be plotted for the clinical EFS by treatment arm.  A by-subject listing of clinical 
events will be provided.
A sensitivity analysis of EFS will be performed where mortality only includes liver-related 
death. All deaths will be reviewed by the Hepatic Event Adjudication Committee to determine if 
they are liver-related.
In addition, a sensitivity analysis for the clinical efficacy endpoint will be performed by using the 
KMMI approach as described in Section 3.6.1 if the survival functions of SEL 18 mg (SEL 
6 mg) and placebo are demonstrated to be significantly different.
Forest plots of the treatment effect in the clinical efficacy endpoints, assessed by the hazard ratio 
between each SEL arm and placebo arm, will be generated for the Week 48 interim analysis and 
the Week 240 final analysis. Forest plots for subgroup analyses will be generated in the final 
analysis at Week 240.
6.3.
Secondary Efficacy Endpoints
6.3.1.
Definition of Secondary Efficacy Endpoints
The secondary endpoints of this study are as follows: 
1) Proportion of subjects who have a ≥ 1-stage improvement in fibrosis (according to the NASH 
CRN classification) without worsening of NASH at Week 240;
2) Proportion of subjects who have a ≥ 1-stage improvement in fibrosis (according to the NASH 
CRN classification) at Week 48 and Week 240;
3) Proportion of subjects who have NASH resolution (defined as lobular inflammation of 0 or 1 
from at least 1 at baseline and hepatocellular ballooning reduced to 0 from at least 1 at 
baseline; both criteria are necessary conditions) at Week 48 and Week 240. 
6.3.2.
Analysis of the Secondary Efficacy Endpoints
For the secondary efficacy endpoints, the stratified MH test defined for the primary histology 
efficacy endpoint in Section 6.1.3 will be used to compare the differences in proportions between 
SEL 18 mg (SEL 6 mg) and placebo, adjusting for presence or absence of diabetes mellitus at 
baseline and ELF™test score ≥ 11.27 or < 11.27 at baseline. The point estimates, 95% CIs and 
the corresponding p-values based on a Z test for the differences in proportions, and 95% CI for 
proportion of responder in each treatment group based on Clopper-Pearson method will be 
calculated. 


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A logistic regression analysis will also be performed to assess the odds ratio between each of the 
SEL arms and the placebo arm, adjusting for stratification factors. The point estimates of odds
ratio, 95% CIs of odds ratio, and corresponding p-values for each SEL arm versus placebo arm 
will be reported.
Forest plots of the treatment differences in proportion of subjects who achieved each secondary 
efficacy endpoint will be generated for subgroup analyses as described in Section 3.4 and 
sensitivity analyses as described in Section 3.6.1, respectively.
The point estimates and 95% CIs based on stratified MH tests of NRI data will be provided in the 
subgroup analysis for the primary histology endpoint and secondary endpoints. The point 
estimates and 95% CIs based on proportional hazard model will be provided in the subgroup 
analysis for the primary clinical efficacy endpoint. When the grouping variable is identical to one 
of the stratification factors (i.e., subgroups by baseline diabetes status or baseline ELF category), 
this stratification factor will not be adjusted in the modeling. 
6.4.
Exploratory Efficacy Endpoints
6.4.1.
Definition of Exploratory Efficacy Endpoints
 
 
CCI


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6.4.2.
Analysis Methods for Exploratory Efficacy Endpoints
 
 
 
 
 
  
  
 
 
 
 
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I 
I 
I 
I 
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6.5.
Change From Protocol-Specified Efficacy Analyses
The analyses for the objective to determine whether noninvasive measures of fibrosis can predict 
histological regression and/or progression of fibrosis and clinical complications of cirrhosis will 
be included in the statistical analysis plan for noninvasive tests.
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7.
SAFETY ANALYSES
Subjects will be grouped as defined in Section 3.2.
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory AEs will be coded using the current version of MedDRA. SOC, HLGT, 
HLT, PT, and LLT will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, 4, or 5 according to Common 
Terminology Criteria for Adverse Events (CTCAE). The severity grade of events for which the 
investigator did not record severity will be categorized as “missing” for tabular summaries and 
data listings. The most severe grade will be considered in data summary if a subject experienced 
multiple events under the same category. The missing category will be listed last in summary 
presentation when applicable.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the investigator’s 
choice, not that of the medical monitor. Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs met the definitions 
of SAEs that were specified in the study protocol. Serious adverse events captured and stored in 
the clinical database will be reconciled with the SAE database from the Gilead 
Pharmacovigilance and Epidemiology before data finalization.
7.1.5.
Treatment-Emergent Adverse Events 
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) for the Randomized/OL Phase are defined as 1 or 
both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug in the Randomized Phase (and before the first 
dosing date in the OL Phase)/OL Phase.

Any AEs leading to premature discontinuation of study drug in the Randomized/OL Phase.


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7.1.5.2.
Definition of Adverse Events > 30 Days Posttreatment
Adverse events > 30 days posttreatment for the Randomized/OL Phase are defined as any AEs 
with an onset date later than 30 days after permanent discontinuation of study drug in the 
Randomized Phase (and before the first dosing date in the OL Phase)/OL Phase.
7.1.5.3.
Incomplete Dates
If the onset date of an AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent in the corresponding treatment phase. The event 
is considered treatment emergent if both of the following 2 criteria are met:

The AE onset is the same as or after the month and year (or year) of the first dosing date of 
study drug, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after the date of the last dose of study drug in the Randomized 
Phase (and before the first dosing date in the OL Phase)/OL Phase.

An AE with completely missing onset and stop dates, or with the onset date missing and a 
stop date later than the first dosing date of study drug, will be considered to be treatment 
emergent. In addition, an AE with the onset date missing and incomplete stop date with the 
same or later month and year (or year alone if month is not recorded) as the first dosing date 
of study drug will be considered treatment emergent.  In above cases if an AE is considered 
as treatment-emergent, it will not be considered as > 30 days posttreatment.  
7.1.6.
Summaries of Adverse Events and Deaths
TEAEs and AEs > 30 days posttreatment will be summarized based on the Safety Analysis 
Set/OL Safety Analysis Set.
The number and percentage of subjects who experienced at least 1 TEAE will be provided and 
summarized by SOC, HLT, PT, and treatment group. For other AEs described below, summaries 
will be provided by SOC, PT, and treatment group:

TEAEs by severity grade

TEAEs of Grade 3 or higher (by maximum severity)

TEAEs of Grade 2 or higher

All TE treatment-related AEs

TE Treatment-related AEs of Grade 3 or higher (by maximum severity)

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
All TE SAEs

All TE treatment-related SAEs 

All TE treatment-related AEs by severity grade

All TEAEs leading to death

All TEAEs leading to discontinuation of study drug (In the Randomized Phase, TEAEs 
leading to discontinuation of study drug include 2 categories: protocol-specified clinical 
events, and TEAEs leading to premature discontinuation of study drug. Summary table of 
premature discontinuation of study drug will be provided.) 
A brief, high-level summary of AEs described above (except for the summary by severity grade)
will be provided by treatment group and by the number and percentage of subjects who 
experienced the above AEs. All deaths observed in the study and subjects who completed 
randomized study drug due to protocol-specified clinical events will be also included in this 
summary.
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetic order of SOC and HLT within SOC (if applicable), and 
then in descending order of PTs by frequency in the (OL) SEL 18 mg group within each SOC or 
HLT in the Randomized/OL Phase. For summaries by severity grade, the most severe grade will 
be used for those AEs that occurred more than once in an individual subject in the 
Randomized/OL Phase. 
In addition to the above summary tables, the following tables will be summarized by PT only, in 
descending order of frequency in the (OL) SEL 18 mg group for the Randomized/OL Phase:

All TEAEs 

TEAEs of Grade 3 or higher (by maximum severity)

TEAEs of Grade 2 or higher

TE treatment-related AEs

TE Treatment-related AEs of Grade 3 or higher (by maximum severity)

TE Treatment-related AEs of Grade 2 or higher 

All TESAEs

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The following tables for AEs > 30 days posttreatment will be summarized by PT only, in 
descending order of frequency in the (OL) SEL 18 mg group for Randomized/OL Phase:

All AEs > 30 days posttreatment

Treatment-related AEs > 30 days posttreatment

SAEs > 30 days posttreatment 
A brief, high-level summary of AEs > 30 days posttreatment described above will be provided 
by treatment group and by the number and percentage of subjects who experienced the above 
AEs.
In addition, data listings will be provided for the following:

All AEs, indicating whether the event is treatment-emergent

All AEs of Grade 3 or higher

SAEs

Deaths

AEs leading to discontinuation of study drug 
7.1.7.
Additional Analysis of Adverse Events
7.1.7.1.
Cardiovascular Events
Proportion of subjects with adjudication-confirmed cardiovascular events will be summarized by 
treatment group for the Randomized and OL Phase. Multiple events will be counted only once 
per subject in each summary for each phase.  All adjudicated cardiovascular events will be listed 
for All Randomized Analysis set.
Time to the first cardiovascular event will be assessed in Randomized Phase. Time up to the first 
cardiovascular event/censoring date (in months) will be calculated as: (first cardiovascular event 
date or censoring date − randomization date + 1) / 30.4375. Censoring date will be the latest date 
among the last visit date in the Randomized Phase, the latest AE onset date in the Randomized 
Phase, the day prior to OL Study Day 1 for subjects discontinued from the Randomized Phase, 
and the data cut date for ongoing subjects in the Randomized Phase (for the Week 48 Interim 
Analysis only). 
For the purpose of analysis, if the onset date of a cardiovascular event or an AE is incomplete, 
the first day of the month (if date is missing) or the first day of the year (if date and month are 
missing) will be used to derive the first cardiovascular event/censoring date. If such imputation 
leads to an imputed event date that is earlier than the randomization date, the randomization date 
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Proportional hazards model will be used to calculate the point estimate and 95% CI for the 
hazard ratio between SEL 18 mg (SEL 6 mg) and placebo controlling for stratification factors. 
For each treatment group, the KM estimates of cardiovascular event probability at 3-month 
intervals, i.e., at Month 3, 6, 9… and 95% CIs will be provided.  The 95% CI will be calculated 
based on Greenwood’s formula and log-log transformation of the survival function.
Median, Q1 and Q3 of the time to the first cardiovascular event will be provided for each 
treatment group.  The 95% CI for median EFS based on Brookmeyer-Crowley method 
{Brookmeyer 1982} of inverting a generalization of the sign test for censored data will also be 
provided for each treatment group. 
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of any study drug in the 
Randomized/OL Phase plus 30 days for subjects who have permanently discontinued study drug
in the Randomized (and before the first dosing date in the OL Phase)/OL Phase. The analysis 
will be based on values reported in conventional units. When values are below the LOQ, they 
will be listed as such, and the closest imputed value will be used for the purpose of calculating 
summary statistics as specified in Section 3.7. 
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, and coagulation separately. Values falling 
outside of the relevant reference range and/or having a severity grade of 1 or higher on the 
CTCAE severity grade as described in Appendix 2 will be flagged in the data listings, as 
appropriate.
No formal statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
ALT, AST, albumin, ALP, glucose, total bilirubin, direct bilirubin, GGT, HOMA-IR, HbA1c, 
and INR in the Randomized Phase will be summarized as efficacy endpoints. Descriptive 
statistics will be provided by treatment group for ALT, AST, albumin, ALP, glucose, total 
bilirubin, direct bilirubin, GGT, HOMA-IR, HbA1c, INR in the OL Phase, and creatinine,  
creatinine clearance (Cockroft-Gault), white blood cells (WBC), neutrophils, lymphocytes, 
hemoglobin, platelets in the Randomized/OL Phase as follows:

Baseline value 

Value at each postbaseline visit

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Change from baseline at a postbaseline visit will be defined as the visit value minus the baseline 
value in the corresponding study phase. The mean, median, Q1, Q3, minimum, and maximum 
values will be displayed to the reported number of digits; SD values will be displayed to the 
reported number of digits plus 1.
Baseline and postbaseline CP score in the OL Phase will be summarized by counts of subjects 
and percentages at each category level.  Change from baseline will be summarized in the 
following 3 ordered categories: improvement, no change, and worsening.  Worsening refers to an 
increase in the score while improvement refers to a decrease in the score.  
Median (Q1, Q3) of the observed values for WBC, neutrophils, lymphocytes, hemoglobin, and 
platelets will be plotted using a line plot by treatment group (1, 2 and 4) and visit for the 
Randomized Phase.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3.
7.2.2.
Graded Laboratory Values
The CTCAE Version 5.0 will be used for assigning toxicity grades (0 to 4) to laboratory results 
for analysis. Grade 0 includes all values that do not meet the criteria for an abnormality of at 
least Grade 1. For laboratory tests with criteria for both increased and decreased levels, analyses 
for each direction (i.e., increased, decreased) will be presented separately.
For the baseline ALT, AST, total bilirubin and direct bilirubin toxicity grades of each phase, the 
CTCAE version 5.0 will be used to assign grades to the derived average values.
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase by at least 
1 toxicity grade from baseline at any postbaseline time point in the corresponding study phase, 
up to and including the date of the last dose of study drug plus 30 days for subjects who 
permanently discontinued study drug (and before OL Study Day 1 for abnormalities in the 
Randomized Phase), or the last available date in the database snapshot for subjects who were still 
on treatment at the time of an interim analysis. If the relevant baseline laboratory value is 
missing, any abnormality of at least Grade 1 observed within the time frame specified above will 
be considered treatment emergent.
7.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities
Treatment-emergent marked laboratory abnormalities are defined as values that increase from 
baseline by at least 3 toxicity grades at any postbaseline time point, up to and including the date 
of the last dose of study drug in the corresponding study phase plus 30 days for subjects who 
permanently discontinued study drug (and before OL Study Day 1 for abnormalities in the 
Randomized Phase) or the last available date in the database snapshot for subjects who were still 
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missing, any Grade 3 or above values observed within the timeframe specified above will be 
considered treatment-emergent marked abnormalities.
7.2.2.3.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at corresponding baseline and each scheduled 
postbaseline visit for the Randomized/OL Phase.
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by laboratory test and treatment group; subjects will be 
categorized according to the most severe postbaseline abnormality grade for a given laboratory 
test:

Graded laboratory abnormalities

Grade 3 or 4 laboratory abnormalities

Marked laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 30 days after the last dosing date (and before OL Study 
Day 1 for the Randomized Phase) of the reporting phase.
A by-subject listing of treatment-emergent Grade 3 or 4 laboratory abnormalities will be 
provided by subject ID number and visit in chronological order. This listing will include all test 
results that were collected throughout the study for the laboratory test of interest, with all 
applicable severity grades or abnormal flags displayed.
7.2.3.
Liver-related Laboratory Evaluations
The summary will be provided by 3 subgroups of subjects according to their baseline ALT/AST 
level in the Randomized/OL Phase:

Normal

Elevated (>1 to < 5 × upper limit of normal [ULN]) 

Elevated (≥ 5  × ULN)


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Liver-related abnormalities after initial study drug dosing will be examined and summarized 
using the number and percentage of subjects who were reported to have the following laboratory 
test values for postbaseline measurements:
For subjects with normal baseline ALT/AST:

Subjects meeting criteria for close observation
○
ALT/AST > 3 × ULN

Subjects meeting criteria for holding study drug
○
ALT/AST > 8 × ULN
○
ALT/AST > 5 × ULN for 2 weeks
○
ALT/AST > 3 × ULN and total bilirubin > 2 × ULN (or direct bilirubin 2 × baseline in 
subjects with Gilbert’s syndrome)
○
ALT/AST > 3 × ULN and INR > 1.5 (if not on anticoagulation)
For subjects with baseline ALT/AST between 1 and 5 × ULN

Subjects meeting criteria for close observation
○
ALT/AST > 2 × Baseline or > 300 U/L

Subjects meeting criteria for holding study drug
○
ALT/AST > 8 × Baseline or > 500 U/L
○
ALT/AST > 3 × Baseline or > 300 U/L, and total bilirubin > 2 × ULN (or direct bilirubin 
2 x Baseline in subjects with Gilbert’s syndrome)
○
ALT/AST > 3 × Baseline and INR > 1.5 (if not on anticoagulation)
For subjects with baseline ALT/AST ≥ 5 × ULN 

Subjects meeting criteria for close observation
○
ALT/AST > 2 × Baseline 

Subjects meeting criteria for holding study drug
○
ALT/AST > 500 U/L


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The above summary will include data from all postbaseline visits up to 30 days after the last dose 
of study drug for subjects who permanently discontinued study drug (and before OL Study Day 1 
for abnormalities in the Randomized Phase) in the reporting phase, or the last available date in 
the database snapshot for subjects who were still on treatment at the time of an interim analysis. 
The denominator is the number of subjects in the (OL) Safety Analysis Set who have nonmissing 
postbaseline values of all relevant tests at the same postbaseline visit date in the summarizing 
group. A listing of subjects meeting any of the criteria above will be provided.
7.2.4.
Drug-Induced Liver Injury (DILI)
Due to the challenge of recognizing and diagnosing DILI in subjects with pre-existing hepatic 
dysfunction, a DILI Adjudication Committee will review potential cases of DILI identified based 
on laboratory parameters listed in Section 7.2.3. Proportion of subjects with DILI events 
determined by the Adjudication Committee, including confirmed DILI events (or worsening of 
hepatic function attributable to study drug could not be excluded) and insufficient data, will be 
summarized by treatment group for the Randomized and OL Phase. Multiple events will be 
counted only once per subject for each phase. All adjudicated DILI events will be listed for All 
Randomized Analysis set.
7.3.
Body Weight and Vital Signs
Descriptive statistics will be provided by treatment group for body weight, waist circumference, 
BMI and vital signs (systolic and diastolic blood pressure [mmHg], pulse [bpm], respiratory rate
[breath/min] and temperature [°C]) in the Randomized/OL Phase as follows:

Baseline value

Value at each postbaseline visit

Change from baseline at each postbaseline visit

Percent change from baseline at each postbaseline visit (only for body weight)
A baseline value in the Randomized/OL Phase will be defined as the last available value 
collected on or prior to the date/time of first dose of study drug in the corresponding treatment 
phase. Change from baseline to a postbaseline visit will be defined as the postbaseline value 
minus the baseline value. Vital signs measured at unscheduled visits will be included for the 
baseline value selection.
 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. No formal statistical testing is planned.
A by-subject listing of vital signs will be provided by subject ID number and visit in 
chronological order. A separate by-subject listing of body weight, height, waist circumference
and BMI will be provided.
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7.4.
Prior and Concomitant Medications
Medications collected at Screening and during the study will be coded using the current version 
of the World Health Organization (WHO) Drug dictionary.
7.4.1.
Prior Medications
Prior medications are defined as any medication taken before a subject took the first study drug
in the Randomized Phase.
Prior medications will be summarized by preferred name using the number and percentage of 
subjects for each treatment group and overall. A subject reporting the same medication more 
than once will be counted only once when calculating the number and percentage of subjects 
who received that medication. The summary will be ordered by preferred name in order of 
descending overall frequency. For drugs with the same frequency, sorting will be done 
alphabetically.
For the purposes of analysis, any medication with a start date prior to the first dosing date of 
study drug will be included in the prior medication summary regardless of when the stop date is. 
If a partial start date is entered the medication will be considered prior unless the month and year 
(if day is missing) or year (if day and month are missing) of the start date are after the first 
dosing date. Medications with a completely missing start date will be included in the prior 
medication summary, unless otherwise specified.
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned.
7.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a subject took study drug. Use 
of concomitant medications will be summarized by preferred name using the number and 
percentage of subjects for each treatment group in the Randomized/OL Phase. A subject 
reporting the same medication more than once will be counted only once when calculating the 
number and percentage of subjects who received that medication. The summary will be ordered 
by preferred name in descending frequency in the (OL) SEL 18 mg group for the Randomized 
/OL Phase. For drugs with the same frequency, sorting will be done alphabetically.
For the purposes of analysis, any medication with a start date prior to or on the first dosing date 
of study drug and continued to take after the first dosing date, or started after the first dosing date 
but prior to or on the last dosing date of study drug will be considered concomitant medications. 
Medications started and stopped on the same day as the first dosing date or the last dosing date of 
study drug will also be considered concomitant. Medications with a stop date prior to the date of 
first dosing date of study drug or a start date after the last dosing date of study drug will be 
excluded from the concomitant medication summary. If a partial stop date is entered, any 
medication with the month and year (if day is missing) or year (if day and month are missing) 
prior to the date of first study drug administration will be excluded from the concomitant 
medication summary. If a partial start date is entered, any medication with the month and year (if 
day is missing) or year (if day and month are missing) after the study drug stop date will be 


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excluded from the concomitant medication summary. Medications with completely missing start 
and stop dates will be included in the concomitant medication summary, unless otherwise 
specified. Summaries will be based on the (OL) Safety Analysis Set. No formal statistical testing 
is planned.
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.
7.5.
Electrocardiogram Results
Electrocardiogram (ECG) data will not be presented in the CSR since ECGs were not assessed in 
this study other than as part of the screening process for potential new subjects.
7.6.
Other Safety Measures
7.6.1.
Stool Frequency
Stool frequency subscore from the partial Mayo Score will be summarized by visit and treatment 
group. Change from baseline will be summarized in the following 3 ordered categories: 
increased, no change, and decreased.  A baseline value in the Randomized/OL Phase will be 
defined as the last available value collected on or prior to the date/time of first dose of study drug
in the corresponding treatment phase.
Table 7-1.
Stool Frequency Subscore of Partial Mayo Score
Domain
Description
Score
Stool Frequency
(based on the past 3 days)
Normal number of stools
0
1-2 stools more than normal
1
3-4 stools more than normal
2
5 or more stools more than normal
3
7.7.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses in this SAP.


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8.
PHARMACOKINETIC ANALYSES
A single PK blood sample will be collected during the Randomized Phase at Week 1, 4, 12, 24, 
and 48 visits in all subjects and during the OL Phase at all visits only in subjects with severe 
hepatic impairment (Child-Pugh Class C) in combination with renal impairment (eGFR 
< 30 mL/min)
 
 
 
Concentrations of SEL and GS-607509 in plasma will be determined using validated 
bioanalytical assays. A population PK model will be developed to characterize the PK of SEL 
and its metabolite (as applicable). Data from this study (single PK and 
) will be 
combined with data from other studies in a meta-population analysis using nonlinear 
mixed-effects modeling techniques. Details of the population PK analysis will be provided in a 
separate population PK analysis report.
The following listing will be provided for both single and intensive PK samples:

PK sampling details by subject and analyte including actual dosing time and actual draw 
time, calculated time postdose of sample collection, differences in scheduled and actual draw 
times, sample age, and sample concentration.
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9.
REFERENCES
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29-41.
Goff DC, Jr., Lloyd-Jones DM, Bennett G, Coady S, D'Agostino RB, Gibbons R, et al. 2013 
ACC/AHA guideline on the assessment of cardiovascular risk: a report of the 
American College of Cardiology/American Heart Association Task Force on 
Practice Guidelines. Circulation 2014;129 (25 Suppl 2):S49-73.
Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Br J Radiol 
1971;44 (526):793-7.
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika 
1988;75 (4):800-2.
Koch GG, Carr GJ, Amara IA, Stokes ME, Uryniak TJ. Categorical Data Analysis. Chapter 13 in 
Berry, D.A. (ed.).  Statistical Methodology in the Pharmaceutical Sciences. New 
York: Marcel Dekker, Inc., 1989:pp. 414-21. 
Ratitch B, O'Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharm Stat 2013;12 (6):337-47.
Rubin DB. Multiple Imputation for Nonresponse in Surveys.  New York, NY: John Wiley & 
Sons, Inc, 1987.
Zhao Y, Herring AH, Zhou H, Ali MW, Koch GG. A Multiple Imputation Method for Sensitivity 
Analyses of Time-to-Event Data with Possibly Informative Censoring [Author 
Manuscript]. J Biopharm Stat 2014;24 (2):229-53.


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10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.
nQuery +nTerim Version 4.0. Statistical Solutions, Cork, Ireland.
EAST Version 6. Cytel. Cambridge, MA, USA.


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11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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12.
APPENDICES
Appendix 1.
Study Procedures Table – Screening to Week 48
Appendix 2.
CTCAE Grade for Laboratory Parameters
Appendix 3.
Pooled Cohort Risk and Score Calculation
Appendix 4.
Liver Function Prognostic Scores
Appendix 5.
Health Related QoL Score Calculation
Appendix 6.
NAFLD Activity Score (NAS) and Steatosis, Activity, and Fibrosis (SAF) Score 
Calculation
Appendix 7.
Noninvasive markers for Fibrosis
Appendix 8.
SAS Program for Tipping Point Analysis for Binary Endpoint


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Appendix 1.
Study Procedures Table – Screening to Week 48
Assessments
Screening
Day 
1a
On-treatment Visits
Week 
1
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
24
Week 
28
Week 
32
Week 
36
Week 
40
Week 
44
Week 
48
Clinical Assessments
Written Informed 
Consent
X
Determine Eligibility
X
Medical History
X
Physical Examination
X
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Vital Signs including 
Body Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Waist Circumference
X
X
X
X
X
X
12-lead ECG
X
CP/MELD Scoresc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess Ascites and 
Hepatic 
Encephalopathy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver Biopsyd
X
X
Abdominal Ultrasound
for HCC Surveillance
X
X
X
Elastography 
(if available)
Xe
Xf
X
X
I 
I 


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Assessments
Screening
Day 
1a
On-treatment Visits
Week 
1
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
24
Week 
28
Week 
32
Week 
36
Week 
40
Week 
44
Week 
48
Health Related Quality 
of Life Questionnairesg
X
X
X
X
Health Resource 
Utilization 
Questionnairesg
X
X
X
X
Stool Frequency 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lifestyle Modification  
Counseling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
Xh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Study Drug
X
X
X
X
X
X
X
X
X
X
X
X
X
Review of Study Drug 
Dosing Compliance 
(Pill Count)
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Subject Fasting
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistryi, 
Hematology, 
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Insulin and Lipids 
X
X
X
X
X
HbA1c
X
X
X
X
X
X
eGFR
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Testingj
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Assessments
Screening
Day 
1a
On-treatment Visits
Week 
1
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
24
Week 
28
Week 
32
Week 
36
Week 
40
Week 
44
Week 
48
Single PK Sampling
Xl
Xk
Xk
Xl
Xk
Xl
Xl
Xk
Xl
Xl
Xl
Xl
Xl
Xk
Blood Collection 
(Biomarkers)
X
X
X
X
X
Urine Collection
X
X
X
X
Urine Drug Screen
X
HIV-1, HBV, HCV 
Serology
X
Approximate amount of 
blood drawn (mL)n
70
65
15
15
12
60
12
12
60
12
12
12
12
12
65
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Study Procedures Table – Week 60 to Follow Up
Assessments
On-treatment Visits
Follow 
Upo
Tele-
phone 
Follow-
Upp
Week
60
Week 
72
Week 
84
Week 
96
Week 
108
Week 
120
Week 
132
Week 
144
Week 
156
ETo
Week 
168
Week 
180
Week 
192
Week 
204
Week 
216
Week 
228
Week 
240(EOT)
Physical Examination
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Vital Signs including Body Weight
X
X
X
X
X
X
X
X
X
X
X
Waist Circumference
X
X
X
X
X
Liver Biopsyd
Xq
Xr
CP/MELD scoresc
X
X
X
X
X
X
X
X
X
X
Assess Ascites and Hepatic 
Encephalopathy
X
X
X
X
X
X
X
X
X
X
Abdominal Ultrasound for 
HCC Surveillance
X
X
X
X
X
Elastography (if available)
X
X
X
Health Related Quality of Life 
Questionnairesg
X
X
X
X
X
Health Resource Utilization 
Questionnairesg
X
X
X
X
X
Stool Frequency Assessment
X
X
X
X
X
X
X
X
X
X
X
Lifestyle Modification Counseling
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Dispense Study Drug
X
X
X
X
X
X
X
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X


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Assessments
On-treatment Visits
Follow 
Upo
Tele-
phone 
Follow-
Upp
Week
60
Week 
72
Week 
84
Week 
96
Week 
108
Week 
120
Week 
132
Week 
144
Week 
156
ETo
Week 
168
Week 
180
Week 
192
Week 
204
Week 
216
Week 
228
Week 
240(EOT)
Review of Study Drug Dosing 
Compliance (Pill Count)
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Subject Fasting
X
X
X
X
X
X
X
X
X
X
X
Chemistryi, Hematology, Coagulation
X
X
X
X
X
X
X
X
X
X
X
Insulin and Lipids
X
X
X
X
X
HbA1c
X
X
X
X
X
eGFR
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Testingj
X
X
X
X
X
X
X
X
X
X
X
Single PK samplingl
X
X
X
X
X
X
X
X
X
Xt
Blood Collection (Biomarkers)
X
X
X
Urine Collection 
X
X
X
Approximate amount of blood drawn 
(mL)n
12
15
12
65
12
15
12
65
12
65
10
a
Subjects starting the OL Phase of the study will complete the same study procedures as during the Randomized Phase of the study, starting with the Day 1 visit
b
Symptom-driven PE
c
CP score to be calculated only at Screening
d
Not to be performed during the OL Phase of the study
e
f
 
g
For subjects with questionnaires available at Day 1
h
Adverse Events reporting during Screening is limited to serious adverse events and adverse events related to study procedures
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i
Additional testing: digoxin level at Day 1 and Week 1 and as needed in subjects taking digoxin (refer to Section 5.4 of the protocol) and CPK level for subjects in close 
observation for DILI (refer to Section 7.5 of the protocol)
j
Females of childbearing potential only (refer to Appendix 3 of the protocol). Serum pregnancy test at Screening and urine pregnancy test at Day 1 and every 4 weeks 
thereafter. Starting at the Week 48 visit, urine pregnancy testing kits will be provided for home testing every 4 weeks, between in-clinic study visits. All females of 
childbearing potential will be contacted every 4 weeks and asked to report the result of the urine pregnancy tests. FSH testing as per Appendix 3 of the protocol.
k
To be performed during the Randomized Phase in all subjects and during the OL Phase, only in subjects with severe hepatic impairment (Child-Pugh Class C) in combination 
with renal impairment (eGFR < 30 mL/min)
l
To be performed during the OL Phase, only in subjects with severe hepatic impairment (Child-Pugh Class C) in combination with renal impairment (eGFR < 30 mL/min)
m
n
For specific blood volumes at each visit, please refer to the current approved ICF
o
Subjects prematurely discontinuing from the study should complete an ET visit within 30 days of last dose, Follow-Up visit 4 weeks later and a Telephone Follow-Up visit 
after the ET visit
p
To be performed 12 weeks after the Week 240/EOT or ET visit. At the discretion of the investigator, an unscheduled visit may be completed if the subject reports abnormal or 
concerning symptoms
q
Not to be performed at the Week 144 visit 
r
To be performed at the discretion of the investigator
s
Not to be performed at the Week 240/EOT visits
t
To be collected in all subjects that ET in either Randomized or OL Phase
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Appendix 2.
CTCAE Grade for Laboratory Parameters
CTCAE 5.0
CTCAE Grade
CTCAE Term
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Anemia
Hemoglobin (Hgb) 
<LLN - 10.0 g/dL; 
<LLN - 6.2 mmol/L; 
<LLN - 100 g/L
Hgb <10.0 - 8.0 g/dL; <6.2 -
4.9 mmol/L; 
<100 - 80g/L
Hgb <8.0 g/dL; 
<4.9 mmol/L; <80 g/L; 
transfusion indicated
Life-threatening consequences; 
urgent intervention indicated
Death
Activated partial 
thromboplastin time 
prolonged
>ULN - 1.5 x ULN
>1.5 - 2.5 x ULN
>2.5 x ULN; bleeding
-
-
Alanine aminotransferase 
increased
>ULN - 3.0 x ULN if baseline 
was normal; 
1.5 - 3.0 x baseline if baseline 
was abnormal
>3.0 - 5.0 x ULN if baseline 
was normal; 
>3.0 - 5.0 x baseline if 
baseline was abnormal
>5.0 - 20.0 x ULN if baseline 
was normal; 
>5.0 - 20.0 x baseline if 
baseline was abnormal
>20.0 x ULN if baseline was 
normal; 
>20.0 x baseline if baseline 
was abnormal
-
Alkaline phosphatase 
increased
>ULN - 2.5 x ULN if baseline 
was normal; 
2.0 - 2.5 x baseline if baseline 
was abnormal
>2.5 - 5.0 x ULN if baseline 
was normal; 
>2.5 - 5.0 x baseline if 
baseline was abnormal
>5.0 - 20.0 x ULN if baseline 
was normal; 
>5.0 - 20.0 x baseline if 
baseline was abnormal
>20.0 x ULN if baseline was 
normal; 
>20.0 x baseline if baseline 
was abnormal
-
Aspartate 
aminotransferase 
increased
>ULN - 3.0 x ULN if baseline 
was normal; 
1.5 - 3.0 x baseline if baseline 
was abnormal
>3.0 - 5.0 x ULN if baseline 
was normal; 
>3.0 - 5.0 x baseline if 
baseline was abnormal
>5.0 - 20.0 x ULN if baseline 
was normal; 
>5.0 - 20.0 x baseline if 
baseline was abnormal
>20.0 x ULN if baseline was 
normal; 
>20.0 x baseline if baseline 
was abnormal
-
Blood bicarbonate 
decreased
<LLN and no intervention 
initiated
-
-
-
-
Blood bilirubin increased
>ULN - 1.5 x ULN if baseline 
was normal; 
> 1.0 - 1.5 x baseline if baseline 
was abnormal
>1.5 - 3.0 x ULN if baseline 
was normal; 
>1.5 - 3.0 x baseline if 
baseline was abnormal
>3.0 - 10.0 x ULN if baseline 
was normal; 
>3.0 - 10.0 x baseline if 
baseline was abnormal
>10.0 x ULN if baseline was 
normal; 
>10.0 x baseline if baseline 
was abnormal
-
Cholesterol high
>ULN - 300 mg/dL; 
>ULN - 7.75 mmol/L
>300 - 400 mg/dL; 
>7.75 - 10.34 mmol/L
>400 - 500 mg/dL; 
>10.34 - 12.92 mmol/L
>500 mg/dL; 
>12.92 mmol/L
-
CPK increased
>ULN - 2.5 x ULN
>2.5 x ULN - 5 x ULN
>5 x ULN - 10 x ULN
>10 x ULN
-


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CTCAE 5.0
CTCAE Grade
CTCAE Term
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Creatinine increased
>ULN - 1.5 x ULN
>1.5 - 3.0 x baseline; 
>1.5 - 3.0 x ULN
>3.0 x baseline; 
>3.0 - 6.0 x ULN
>6.0 x ULN
-
GGT increased
>ULN - 2.5 x ULN if baseline 
was normal; 
2.0 - 2.5 x baseline if baseline 
was abnormal
>2.5 - 5.0 x ULN if baseline 
was normal; 
>2.5 - 5.0 x baseline if 
baseline was abnormal
>5.0 - 20.0 x ULN if baseline 
was normal; 
>5.0 - 20.0 x baseline if 
baseline was abnormal
>20.0 x ULN if baseline was 
normal; 
>20.0 x baseline if baseline 
was abnormal
-
Haptoglobin decreased
<LLN
-
-
-
-
Hemoglobin increased
Increase in >0 - 2 g/dL
Increase in >2 - 4 g/dL
Increase in >4 g/dL
-
-
INR increased
>1.2 - 1.5; >1 - 1.5 x baseline if 
on anticoagulation; monitoring 
only indicated
>1.5 - 2.5; >1.5 - 2.5 x 
baseline if on 
anticoagulation; dose 
adjustment indicated
>2.5; >2.5 x baseline if on 
anticoagulation; bleeding
-
-
Lipase increased
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN; 
>2.0 - 5.0 x ULN and 
asymptomatic
>2.0 - 5.0 x ULN with signs or 
symptoms; >5.0 x ULN and 
asymptomatic
>5.0 x ULN and with signs or 
symptoms
-
Lymphocyte count 
decreased
<LLN - 800/mm3; 
<LLN - 0.8 x 10e9/L
<800 - 500/mm3; 
<0.8 - 0.5 x 10e9 /L
<500 - 200/mm3; 
<0.5 - 0.2 x 10e9 /L
<200/mm3; <0.2 x 10e9 /L
-
Lymphocyte count 
increased
-
>4000/mm3 - 20,000/mm3
>20,000/mm3
-
-
Neutrophil count 
decreased
<LLN - 1500/mm3; 
<LLN - 1.5 x 10e9 /L
<1500 - 1000/mm3; 
<1.5 - 1.0 x 10e9 /L
<1000 - 500/mm3; 
<1.0 - 0.5 x 10e9 /L
<500/mm3; <0.5 x 10e9 /L
-
Platelet count decreased
<LLN - 75,000/mm3; 
<LLN - 75.0 x 10e9 /L
<75,000 - 50,000/mm3; 
<75.0 - 50.0 x 10e9 /L
<50,000 - 25,000/mm3; <50.0 
- 25.0 x 10e9 /L
<25,000/mm3; 
<25.0 x 10e9 /L
-
Serum amylase increased
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN; 
>2.0 - 5.0 x ULN and 
asymptomatic
>2.0 - 5.0 x ULN with signs or 
symptoms; >5.0 x ULN and 
asymptomatic
>5.0 x ULN and with signs or 
symptoms
-
White blood cell 
decreased
<LLN - 3000/mm3; 
<LLN - 3.0 x 10e9 /L
<3000 - 2000/mm3; 
<3.0 - 2.0 x 10e9 /L
<2000 - 1000/mm3; 
<2.0 - 1.0 x 10e9 /L
<1000/mm3; <1.0 x 10e9 /L
-


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CTCAE 5.0
CTCAE Grade
CTCAE Term
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Hypercalcemia
Corrected serum calcium of 
>ULN - 11.5 mg/dL; 
>ULN - 2.9 mmol/L; Ionized 
calcium >ULN - 1.5 mmol/L
Corrected serum calcium of 
>11.5 - 12.5 mg/dL; 
>2.9 - 3.1 mmol/L; Ionized 
calcium 
>1.5 - 1.6 mmol/L; 
symptomatic
Corrected serum calcium of 
>12.5 - 13.5 mg/dL; >3.1 - 3.4 
mmol/L; Ionized calcium >1.6 
- 1.8 mmol/L; hospitalization 
indicated
Corrected serum calcium of 
>13.5 mg/dL; >3.4 mmol/L; 
Ionized calcium 
>1.8 mmol/L; life-threatening 
consequences
Death
Hyperkalemia
>ULN - 5.5 mmol/L
>5.5 - 6.0 mmol/L; 
intervention initiated
>6.0 - 7.0 mmol/L; 
hospitalization indicated
>7.0 mmol/L; life-threatening 
consequences
Death
Hypermagnesemia
>ULN - 3.0 mg/dL; 
>ULN - 1.23 mmol/L
-
>3.0 - 8.0 mg/dL; 
>1.23 - 3.30 mmol/L
>8.0 mg/dL; >3.30 mmol/L; 
life-threatening consequences
Death
Hypernatremia
>ULN - 150 mmol/L
>150 - 155 mmol/L; 
intervention initiated
>155 - 160 mmol/L; 
hospitalization indicated
>160 mmol/L; life-threatening 
consequences
Death
Hypertriglyceridemia
150 mg/dL - 300 mg/dL; 
1.71 mmol/L - 3.42 mmol/L
>300 mg/dL - 500 mg/dL; 
>3.42 mmol/L - 5.7 mmol/L
>500 mg/dL - 1000 mg/dL; 
>5.7 mmol/L - 11.4 mmol/L
>1000 mg/dL; 
>11.4 mmol/L; 
life-threatening consequences
Death
Hyperuricemia
>ULN without physiologic 
consequences
-
>ULN with physiologic 
consequences
Life-threatening consequences
Death
Hypoalbuminemia
<LLN - 3 g/dL; <LLN - 30 g/L
<3 - 2 g/dL; <30 - 20 g/L
<2 g/dL; <20 g/L
Life-threatening consequences; 
urgent intervention indicated
Death
Hypocalcemia
Corrected serum calcium of 
<LLN - 8.0 mg/dL; 
<LLN - 2.0 mmol/L; Ionized 
calcium <LLN - 1.0 mmol/L
Corrected serum calcium of 
<8.0 - 7.0 mg/dL; 
<2.0 - 1.75 mmol/L; Ionized 
calcium <1.0 - 0.9 mmol/L; 
symptomatic
Corrected serum calcium of 
<7.0 - 6.0 mg/dL; 
<1.75 - 1.5 mmol/L; Ionized 
calcium <0.9 - 0.8 mmol/L; 
hospitalization indicated
Corrected serum calcium of 
<6.0 mg/dL; <1.5 mmol/L; 
Ionized calcium <0.8 mmol/L; 
life-threatening consequences
Death
Hypoglycemia
<LLN - 55 mg/dL; 
<LLN - 3.0 mmol/L
<55 - 40 mg/dL; 
<3.0 - 2.2 mmol/L
<40 - 30 mg/dL; 
<2.2 - 1.7 mmol/L
<30 mg/dL; <1.7 mmol/L; 
life-threatening 
consequences; seizures
Death
Hypokalemia
<LLN - 3.0 mmol/L
Symptomatic with 
<LLN - 3.0 mmol/L; 
intervention indicated
<3.0 - 2.5 mmol/L; 
hospitalization indicated
<2.5 mmol/L; life-threatening 
consequences
Death


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CTCAE 5.0
CTCAE Grade
CTCAE Term
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Hypomagnesemia
<LLN - 1.2 mg/dL; <LLN - 0.5 
mmol/L
<1.2 - 0.9 mg/dL; <0.5 - 0.4 
mmol/L
<0.9 - 0.7 mg/dL; <0.4 - 0.3 
mmol/L
<0.7 mg/dL; <0.3 mmol/L; 
life-threatening consequences
Death
Hyponatremia
<LLN - 130 mmol/L
125-129 mmol/L and 
asymptomatic
125-129 mmol/L 
symptomatic; 
120-124 mmol/L regardless 
of symptoms
<120 mmol/L; 
life-threatening consequences
Death
*
Since anticoagulation medication is NOT captured in lab data, the condition for anticoagulation medication is ignored in the grade derivation. 
a
Note: Refer to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, which can be found at https://evs nci nih.gov/ftp1/CTCAE/CTCAE_5.0


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GS-US-384-1944 Statistical Analysis Plan 
Version 1.0 
Appendix 3. 
Pooled Cohort Risk and Score Calculation 
Coefficient 
Female 
Male 
White 01· Othe1· 
African 
White or 
African 
No. 
Parameters 
Amel'ica 
Other 
Amel'ica 
1 
In Age (y) 
-29.799 
17.114 
12.344 
2.469 
2 
In Age, Squared 
4.884 
NIA 
NIA 
NIA 
3 
In Total Cholesterol (mg/dL) 
13.540 
0.940 
11.853 
0.302 
4 
In Age x In Total Cholesterol 
-3.114 
NIA 
-2.664 
NIA 
5 
In HDL Cholesterol (mg/dL) 
-13.578 
-18.920 
-7.990 
-0.307 
6 
In Age x In HDL Cholesterol 
3.149 
4.475 
1.769 
NIA 
7 
In Treated Systolic BP 
2.019 
29.291 
1.797 
1.916 
8 
In Age x In Treated Systolic BP 
IA 
---6.432 
NIA 
NIA 
9 
In Untreated Systolic BP 
1.957 
27.820 
1.764 
1.809 
10 
In Age x In Untreated Systolic BP 
NIA 
---6.087 
NIA 
NIA 
11 
Current Smoker (l=Yes, O=No) 
7.574 
0.691 
7.837 
0.549 
12 
In Age x CwTent Smoker 
-1.665 
NIA 
-1.795 
NIA 
13 
Diabetes (l=Yes O=No) 
0.661 
0.874 
0.658 
0.645 
A 
Baseline Survival 
0.9665 
0.9533 
0.9144 
0.8954 
For each individual patient, individual sum is summation of product 
of each parameter and its con-esponding coefficient for that sex-race 
Individual Sum = 
group for all parameters listed above (#1 - #13). 
B 
I C 
coefficientxparameter) 
Note: NIA indicates that the specific coefficient is not available thus 
the coJTesponding parameter will not be included in calculation. 
C 
Population Mean 
-29.18 
I 
86.61 
61.18 
19.54 
=B-C 
D 
Pooled Cohort SCORE 
= Individual Sum - Population Mean 
Pooled Cohort Risk = Estimated 
= 1 - Allexp(B-C) 
E 
probability of a first hard ASCVD* 
= l - Baseline Survival II exp (Individual Sum- Population Mean) 
event within l 0 years 
ASCVD = atherosclerotic cardiovascular disease· BP= blood pressure; Ln = nattu-al logarithm. 
CONFIDENTIAL 
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23 Januaiy 2019 


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
Age is the actual age when the laboratory parameters are collected for the visit. Smoker is
collected at Screening/Baseline of the Randomized Phase.

If a subject had diabetes at baseline, the diabetic status will be yes for all the postbaseline 
visits.  If the subject does not have diabetes at baseline, the diabetic status will be determined 
based on the AE start date.  If the AE start date is on or prior to the laboratory date of a 
specific visit, then the diabetic status will be yes for that visit and later visits. If the day of the 
AE start date is missing, it will be imputed using the 1st day of the month. 

Treatment status of hypertensives will be determined by the usage of anti-hypertensive 
medications on the dates when blood pressures are collected. Anti-hypertensive medication 
with a start date prior to or on the date of blood pressures taken and a stop date on or after it. 
Systolic BP will be considered as treated Systolic BP. 

Total Cholesterol and HDL Cholesterol need to be measured from the same blood draw.
Systolic BP record closest to the date when Total Cholesterol and HDL Cholesterol are 
measured will be used for the risk and score calculation.

Round Pooled Cohort Risk Score to 0.001. 


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Appendix 4.
Liver Function Prognostic Scores

Child-Pugh Score Calculation:
1
2
3
HE 
None
No encephalopathy and 
not on any treatment for 
hepatic encephalopathy
Medication-Controlled
Subject is lethargic, may 
have moderate confusion
Subject is receiving medical 
therapy for HE  
Medication-Refractory
Marked confusion/incoherent, 
rousable but sleeping or 
comatose
Ascites
None
No ascites and not on 
treatment for ascites
Mild/Moderate
Cross sectional imaging 
showing ascites
   
Abdominal distension 
  
Medication for ascites
Severe
(diuretic-refractory)
Visible clinically
Total Bilirubin 
(mg/dL)
< 2
2-3
> 3
Albumin (g/dL)
> 3.5
2.8-3.5
< 2.8
INR
< 1.7
1.7-2.3
> 2.3
There are 5 components for CP score as seen in the first column. Each will be assigned a 
subscore ranging between 1 and 3 based on the matching condition as described in the 
corresponding row and the value in the header row of the corresponding column. For example, 
when total bilirubin value is 2.5 mg/dL, the total bilirubin subscore will be 2. 
CP score is obtained by adding the subscore for each parameter, ranging between 5 and 15.
For Screening, HE and ascites closest to laboratory collection date will be used; for Day 1 and 
postbaseline visits, HE and ascites will be from the same day as laboratory data collected. If 
baseline CP score is missing due to unevaluable laboratory data, baseline CP score will be 
calculated using the last laboratory values collected prior to (OL) Day 1.

MELD Score Calculation
MELD score = 3.78 [Ln total bilirubin (mg/dL)] + 11.2 [Ln INR] + 9.57 [Ln serum creatinine 
(mg/dL)] + 6.43. If the serum creatinine, the total bilirubin or the INR value is < 1.00 mg/dL, 
the calculation will use 1.00 as the test value. If the serum creatinine is > 4.00 mg/dL or subjects 
on dialysis, the calculation will use 4.00 as the serum creatinine value. 


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Appendix 5.
Health Related QoL Score Calculation

SF-36
Scoring of the SF-36 scales will be performed as described in Chapter 6 of the SF-36 Health 
Survey Manual and Interpretation Guide, Version 2.  Summary will be done for 8 domains of the 
SF-36 (physical functioning, role-physical, bodily pain, general health, vitality, social 
functioning, role-emotional, and mental health), and for the physical component score and 
mental component summary. 

CLDQ-NAFLD
CLDQ-NAFLD scores are calculated using subject responses to 36 questions in the 
questionnaire. If Ri is the score for the patient’s response to the item i, for i=1, 2, …., 36 then the 
6 domain scores are calculated as follows:
Abdominal = Mean of {R1, R5, R17}
Fatigue = Mean of {R2, R4, R8, R11, R13, R35}
Systemic = Mean of {R3, R6, R21, R23, R27, R36}
Activity = Mean of {R7, R9, R14, R30, R31}
Emotion = Mean of {R10, R12, R15, R16, R19, R20, R24, R26, R34}
Worry = Mean of {R18, R22, R25, R28, R29, R32, R33}
Here “Mean” is the average of nonmissing items (SAS mean function). Each score is calculated 
only if at least half of corresponding items are not missing. Otherwise, the score will be missing.
Overall CLDQ score is calculated by taking the mean of 6 domain scores {abdominal, fatigue, 
systemic, activity, emotion, worry}.  Overall CLDQ score will be summarized.

WPAI: NASH
The response to Question 1 of this questionnaire provides the binary endpoint whether or not the 
subject had been in a paid employment during the week prior to assessment.
If the subject had been in a paid employment (Response to Q1 is “Yes”) at the visit when 
questionnaire was given, then following three scores are derived:

Percent work time missed = 100 × Q2 / (Q2 + Q4)

Percent impairment while working = 100 × Q5 / 10


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
Percent overall work impairment = 
Question 6 is applicable to all subjects:
Percent activity impairment = 100 × Q6 / 10.
Percent overall work impairment and percent activity impairment will be summarized.

EQ-5D
Scoring of EQ-5D will be performed as described in EQ-5D-5L user guide. Summary will be 
done for 5 dimensions in descriptive system (mobility, self-care, usual activities, pain/discomfort 
and anxiety/depression) and the EQ Visual Analogue Scale.

HRUQ
The number of visits/days for the following questions will be summarized.
Outpatient non-emergent clinic visits (number of visits)
Outpatient non-emergent clinic visits related to disease (number of visits)
Outpatient emergent department visits (number of visits)
Outpatient emergent department visits related to disease (number of visits)
Outpatient surgeries and procedures (number of visits)
Outpatient surgeries and procedures related to disease (number of visits)
Inpatient surgeries and procedures (number of visits)
Inpatient surgeries and procedures related to disease (number of visits)
Number of days hospitalized (number of days)
Number of days hospitalized related to disease (number of days)


















10
5
)
4
2
2
1
)
4
2
(
2
100
Q
Q
Q
Q
Q
Q
Q


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Appendix 6.
NAFLD Activity Score (NAS) and Steatosis, Activity, and Fibrosis
(SAF) Score Calculation
NAS score is calculated as the sum of steatosis, lobular inflammation and hepatocellular 
ballooning.  SAF score is calculated as the sum of steatosis (same as NAS calculation), activity 
and fibrosis (according to the NASH CRN classification) subscores. Activity subscore is defined 
as sum of lobular inflammation and hepatocellular ballooning, where both grade 2 and 3 of 
lobular inflammation will be treated as 2.


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Appendix 7.
Noninvasive markers for Fibrosis

Enhanced Liver Fibrosis (ELF)
ELF™test score = 2.278 + 0.851× ln (hyaluronic acid) + 0.751 × ln (PIIINP) + 0.394 × ln 
(TIMP1);
Note: All ELF™test score components (hyaluronic acid, PIIINP and TIMP1) need to be 
measured from the same blood draw. ELF™ test score will only be calculated when ELF™test 
score is missing and components are less than the LOQ or above the upper LOQ. Individual 
components are to be imputed per data handling conventions in Section 3.7, and ELF™test score 
will be calculated based on the imputed values of components. 

Fibrosis-4 (FIB-4) Index Calculation:
FIB-4 Index = round ((age × AST ) / (platelet × sqrt (ALT)), 0.01);

AST to Platelet Ratio Index (APRI) Calculation:
APRI = round (AST/ASTULN × 100 / platelet, 0.1);
Note: for FIB-4 index and APRI calculation, the laboratory parameters need to be measured from 
the same blood draw.  Age should be the actual age at the date when laboratory values are taken.

NAFLD fibrosis score (NFS) Calculation:
NFS = -1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m2) + 1.13 × IFG (impaired fasting
glucose) / pre-diabetes or diabetes (yes=1,no=0) + 0.99 × AST / ALT ratio - 0.013 × platelet
(×109/L) - 0.66 × albumin (g/dL).  Keep 3 decimal places.
The laboratory parameters need to be measured from the same blood draw.  The last non-missing
BMI on or prior to laboratory date should be used. Age should be the actual age at the date when 
laboratory values are taken.  Status of pre-diabetes/diabetes should also be decided on the 
laboratory date.  If a subject had pre-diabetes/diabetes at baseline, the pre-diabetes/diabetic status 
will be yes for all the postbaseline visits.  If the subject does not have pre-diabetes/diabetes at 
baseline, the pre-diabetic/diabetic status will be determined based on the start date AEs of pre-
diabetes and diabetes, and the collection date when fasting glucose is greater than 100 (IFG).  If 
the AE start date or the fasting glucose collection date is on or prior to the laboratory date of a 
specific visit, then the pre-diabetic/diabetic status will be yes for that visit and later visits. If the 
day of the AE start date is missing, it will be imputed using the 1st day of the month. 


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Appendix 8.
SAS Program for Tipping Point Analysis for Binary Endpoint
The following %tp_binary macro generates multiple imputed data and a set of the shift
parameters that adjust the imputed values will be examined.
/*-----------------------------------------------------------------------------------------------------------------------*/
/*--- Delta-Adjusting Method for Tipping Point Analysis for Binary Endpoint 
---*/
/*--- Generate imputed data set for specified shift parameters 
---*/
/*--- data= input data set 
---*/
/*--- smin= min shift parameter for active drug 
---*/
/*--- smax= max shift parameter for active drug
---*/
/*--- sinc= increment of the shift parameter for active drug
---*/
/*--- trt= treatment group indicator 
---*/
/*--- out= output imputed data set 
---*/
/*-----------------------------------------------------------------------------------------------------------------------*/
%macro tp_binary( data=, smin=, smax=, sinc=, trt=, out=);
data &out;
    set _null_;
run;
/*------------ # of shift values ------------*/
%let ncase= %sysevalf( (&smax-&smin)/&sinc, ceil );
/*------- Imputed data for each shift -------*/
%do jc=0 %to &ncase;
%let sj= %sysevalf( &smin + &jc * &sinc);
proc mi data=&data seed=20190000 nimpute=50 out=outmi;
var trt01pn strat1V strat2V pe48;
class trt01pn strat1V strat2V pe48;
monotone logistic (pe48 / link=logit);
mnar adjust( pe48(event='1') / adjustobs=(trt01pn="&trt") shift= &sj);
run;
data outmi;
    set outmi;
Shift_Trt= &sj;
run;
data &out;
    set &out outmi;
run;
%end;
%end;
%mend tp_binary;


SAP GS-US-384-1944
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical eSigned
23-Jan-2019
21:32:13
Biostatistics eSigned
25-Jan-2019
02:04:45
PPD
PPD--