A Phase 2, Double-Blind, Randomized Study Evaluating the Safety, Tolerability, and Efficacy of GS-4997 in Combination With Prednisolone Versus Prednisolone Alone in Subjects With Severe Alcoholic Hepatitis (AH)
Phase: PHASE2
Conditions: Alcoholic Hepatitis (AH)
Sponsor: Gilead Sciences



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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................19
1.
INTRODUCTION ..............................................................................................................................................23
1.1.
Background ............................................................................................................................................23
1.2.
GS-4997 .................................................................................................................................................24
1.2.1.
General Information .............................................................................................................24
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................25
1.2.3.
Clinical Trials of GS-4997 ...................................................................................................25
1.2.4.
A Phase 2, Double-blind, Placebo-controlled, Dose-ranging Study 
Evaluating the Efficacy, Safety, and Tolerability of GS-4997 in Subjects 
with Diabetic Kidney Disease (Study GS-US-223-1015)....................................................26
1.2.5.
A Phase 2, Dose-ranging, Randomized, Double-blind, Placebo-controlled 
Study of GS-4997 in Subjects with Pulmonary Arterial Hypertension 
(Study GS-US-357-1394).....................................................................................................27
1.2.6.
A Phase 2, Randomized, Open Label Study Evaluating the Safety, 
Tolerability, and Efficacy of GS-4997 alone or in Combination with 
Simtuzumab (SIM) in Subjects with Nonalcoholic Steatohepatitis 
(NASH) and Fibrosis (F2-F3) (GS-US-384-1497)...............................................................28
1.3.
Rationale for This Study ........................................................................................................................29
1.4.
Rationale for Dose Selection..................................................................................................................30
1.5.
Risk/Benefit Assessment for the Study..................................................................................................31
1.6.
Compliance ............................................................................................................................................31
2.
OBJECTIVES.....................................................................................................................................................32
3.
STUDY DESIGN................................................................................................................................................34
3.1.
Study Design..........................................................................................................................................34
3.2.
Treatment Plan and Regimen .................................................................................................................34
3.3.
Biomarker Testing..................................................................................................................................35
3.3.1.
Biomarker Samples to Address the Study Objectives ..........................................................35
3.3.2.
Biomarker Samples for Optional Future Research...............................................................37
3.3.3.
Biomarker Samples for Optional Genomic Research...........................................................38
4.
SUBJECT POPULATION..................................................................................................................................40
4.1.
Number of Subjects and Subject Selection ............................................................................................40
4.2.
Inclusion Criteria....................................................................................................................................40
4.3.
Exclusion Criteria...................................................................................................................................41
5.
INVESTIGATIONAL AND NON-INVESTIGATIONAL MEDICINAL PRODUCTS...................................44
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................44
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................44
5.2.
Description and Handling of Study Drugs .............................................................................................44
5.2.1.
Formulation..........................................................................................................................44
5.2.2.
Packaging and Labeling .......................................................................................................45
5.2.3.
Storage and Handling...........................................................................................................45
5.3.
Dosage and Administration of Study Drugs...........................................................................................46

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5.3.1.
GS-4997 ...............................................................................................................................46
5.3.2.
Prednisolone.........................................................................................................................46
5.4.
Prior and Concomitant Medications.......................................................................................................46
5.5.
Prohibited Medications ..........................................................................................................................47
5.6.
Study Drug Accountability.....................................................................................................................48
5.6.1.
Investigational Medicinal Product Return or Disposal.........................................................48
6.
STUDY PROCEDURES ....................................................................................................................................49
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................49
6.2.
Pretreatment Assessments......................................................................................................................49
6.2.1.
Screening Visit .....................................................................................................................49
6.2.2.
Baseline / Day 1 Assessments and Randomization ..............................................................52
6.3.
Treatment Assessments..........................................................................................................................54
6.3.1.
Week 1 Visit (±3 Days)........................................................................................................54
6.3.2.
Week 2 Visit (±3 Days)........................................................................................................55
6.3.3.
Week 3 Visit (±3 Days)........................................................................................................56
6.3.4.
Week 4 / End of Treatment Visit (EoT) (±3 days) ...............................................................57
6.3.5.
Follow Up Visit (±5 Days)...................................................................................................58
6.4.
Pharmacokinetic Assessments................................................................................................................59
6.4.1.
Sparse PK.............................................................................................................................59
6.4.2.
Intensive PK Substudy .........................................................................................................60
6.5.
Post-Treatment Assessments..................................................................................................................60
6.5.1.
Week 6 (± 3 Days) ...............................................................................................................60
6.5.2.
Weeks 8, 16, and 20 / Post Treatment Visits (± 5 Days)......................................................61
6.5.3.
Weeks 12 and 24 / Post Treatment Visits (± 5 Days)...........................................................62
6.6.
Unscheduled Visits.................................................................................................................................63
6.7.
Assessments for Premature Discontinuation from Study.......................................................................63
6.8.
Criteria for Discontinuation of Study Treatment....................................................................................64
6.9.
Description of Assessments ...................................................................................................................65
6.9.1.
Liver Biopsy.........................................................................................................................65
6.9.2.
Electrocardiogram................................................................................................................65
6.9.3.
AUDIT / SADQ Questionnaires...........................................................................................65
6.9.4.
Quality of Life (QoL) Measures...........................................................................................65
6.9.5.
Hepatic Encephalopathy (HE)..............................................................................................66
6.9.6.
Ascites..................................................................................................................................66
6.9.7.
Maddrey’s DF, MELD and Child-Pugh-Turcotte Scores.....................................................66
6.9.8.
Hepatorenal Syndrome (HRS)..............................................................................................67
6.9.9.
Infection ...............................................................................................................................68
6.9.10.
Screening Laboratory Assessments......................................................................................69
6.9.11.
FibroScan® ...........................................................................................................................70
6.9.12.
Lille Score ............................................................................................................................70
6.10.
End of Study Definition .........................................................................................................................70
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................71
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................71
7.1.1.
Adverse Events.....................................................................................................................71
7.1.2.
Serious Adverse Events........................................................................................................71
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................72
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................72
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................72
7.2.2.
Assessment of Severity ........................................................................................................73
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................73

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7.4.
Gilead Reporting Requirements.............................................................................................................75
7.5.
Toxicity Management ............................................................................................................................75
7.5.1.
Assessment of Potential Drug-Induced Liver Injury by an Independent 
Adjudicator...........................................................................................................................76
7.6.
Special Situations Reports......................................................................................................................77
7.6.1.
Definitions of Special Situations..........................................................................................77
7.6.2.
Instructions for Reporting Special Situations.......................................................................78
8.
STATISTICAL CONSIDERATIONS................................................................................................................80
8.1.
Analysis Objectives and Endpoints........................................................................................................80
8.1.1.
Primary Endpoint .................................................................................................................80
8.2.
Secondary Endpoints..............................................................................................................................80
8.2.1.
Exploratory Endpoints..........................................................................................................81
8.3.
Analysis Conventions.............................................................................................................................81
8.3.1.
Analysis Sets ........................................................................................................................81
8.4.
Data Handling Conventions ...................................................................................................................82
8.5.
Demographic Data and Baseline Characteristics ...................................................................................83
8.6.
Primary Analysis....................................................................................................................................83
8.7.
Efficacy Analysis ...................................................................................................................................83
8.7.1.
Exploratory Analysis............................................................................................................83
8.8.
Safety Analysis.......................................................................................................................................83
8.8.1.
Extent of Exposure...............................................................................................................84
8.8.2.
Adverse Events.....................................................................................................................84
8.8.3.
Laboratory Evaluations ........................................................................................................84
8.8.4.
Other Safety Evaluations......................................................................................................85
8.9.
Pharmacokinetic Analysis......................................................................................................................85
8.9.1.
Other Exploratory Analyses .................................................................................................85
8.10.
Sample Size............................................................................................................................................85
8.11.
Data Monitoring Committee ..................................................................................................................85
9.
RESPONSIBILITIES..........................................................................................................................................87
9.1.
Investigator Responsibilities ..................................................................................................................87
9.1.1.
Good Clinical Practice..........................................................................................................87
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Ethics Committee (EC) Review and Approval ..........................................................87
9.1.3.
Informed Consent.................................................................................................................87
9.1.4.
Confidentiality......................................................................................................................88
9.1.5.
Study Files and Retention of Records ..................................................................................88
9.1.6.
Electronic Case Report Forms..............................................................................................89
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................90
9.1.8.
Inspections............................................................................................................................90
9.1.9.
Protocol Compliance............................................................................................................90
9.2.
Sponsor Responsibilities ........................................................................................................................91
9.2.1.
Protocol Modifications.........................................................................................................91
9.2.2.
Study Report and Publications .............................................................................................91
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................91
9.3.1.
Payment Reporting...............................................................................................................91
9.3.2.
Access to Information for Monitoring..................................................................................92
9.3.3.
Monitoring and Oversight of Biomarker Specimens............................................................92
9.3.4.
Access to Information for Auditing or Inspections ..............................................................92
9.3.5.
Study Discontinuation..........................................................................................................92
10.
REFERENCES ...................................................................................................................................................93
11.
APPENDICES ....................................................................................................................................................97

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Appendix 1.
Investigator Signature Page....................................................................................................98
Appendix 2.
Study Procedures Table..........................................................................................................99
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................103
Appendix 4.
Child-Pugh-Turcotte (CPT) Classification of the severity of cirrhosis ................................106
LIST OF IN-TEXT TABLES
Table 3-1.
Biomarkers .............................................................................................................................36
Table 5-1.
List of Prohibited Medications ...............................................................................................47
LIST OF IN-TEXT FIGURES
Figure 3-1.
Overall Study Design .............................................................................................................34

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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 2, Double-Blind, Randomized Study Evaluating the 
Safety, Tolerability, and Efficacy of GS-4997 in Combination with 
Prednisolone versus  Prednisolone Alone in Subjects with Severe
Alcoholic Hepatitis (AH)
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
129570
2016-000821-37
NCT02854631
Study Centers Planned:
Multiple centers in North America and Europe
Number of Subjects 
Planned:
Up to 120 subjects will be randomized in order to obtain 
100 subjects with biopsy-proven severe AH
Target Population:
Males and non-pregnant, non-lactating females between 
18-70 years of age with histologically-confirmed severe alcoholic 
hepatitis (Maddrey’s Discriminant Function [Maddrey’s DF]
≥32).
Duration of Study:
Participation in the study can last up to 26 weeks, which includes a
2-week Screening period, a 4-week treatment period, and a 
20-week post treatment period.
Objectives:
The primary objective of this study is as follows:
To evaluate the safety and tolerability of GS-4997 in combination 
with prednisolone versus prednisolone alone in subjects with 
severe AH.
The secondary objectives of this study are as follows: 

To assess changes in hepatic synthetic function [liver 
biochemistry, Model for End-Stage Liver Disease [MELD] 
score, Child-Pugh score, the Lille model, and Maddrey’s 
Discriminant Function (Maddrey’s DF)];

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Study Design:
This is a Phase 2, double blind, proof-of-concept, randomized 
study evaluating the safety, tolerability, and biological activity of 
GS-4997 in combination with prednisolone versus prednisolone 
alone in subjects with severe, histologically-confirmed AH.
Up to 120 subjects (for 100 evaluable AH subjects) will be 
randomized within strata (1:1) to either:
1. Group A (n = 50-60):
GS-4997 18 mg once daily + prednisolone 40 mg once daily 
for 28 days
OR
2. Group B (n = 50-60):
GS-4997 placebo once daily + prednisolone 40 mg once daily 
for 28 days
Randomization will be stratified by MELD < or ≥25 at Screening
(based on local laboratory testing).
To allow for diagnoses inconsistent with severe AH in up to 20%
of subjects based on liver biopsy findings, we will target 
randomization of up to 120 subjects into the study.
Diagnosis and Main 
Eligibility Criteria:
Inclusion Criteria:
1) Males and non-pregnant, non-lactating females between 
18-70 years of age, inclusive based on the date of the 
Screening visit;
2) Willing and able to give informed consent prior to any study 
specific procedures being performed. In subjects with hepatic 
encephalopathy (HE) which may impair decision-making, 
consent will be obtained per hospital procedures (eg, by 
Legally Authorized Representative);
3) Clinical diagnosis of severe AH based on all of the following:
a) History of excessive alcohol consumption during the past 
3 months (average of > 40 g/d of alcohol for women and 
> 50 g/d for men);
b) Aspartate aminotransferase (AST) ≥50 U/L, based on local 
laboratory results;
c) AST/alanine aminotransferase (ALT) ratio (AST/ALT)
≥1.5, based on local laboratory results;
d) Onset of jaundice within the past 3 months;
e) Maddrey’s DF ≥32 at Screening, based on local laboratory 
results;

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4) All female subjects of childbearing potential must agree to use 
a highly effective method of contraception during intercourse 
from the Screening visit throughout the study period and for 
90 days following the last dose of study drug.  If females 
utilize hormonal agents as one of their contraceptive methods, 
the same hormonal methods must have been used for at least 
3 months before study dosing. Females on hormonal methods 
must also utilize a barrier method as another form of 
contraception as described in Appendix 3;
5) Male subjects must agree to use condoms during intercourse 
from Screening through study completion and for 90 days 
following the last dose of study drug;
6) Male subjects must refrain from sperm donation from 
Screening through at least 90 days following the last dose of 
study drug;
7) Female subjects must refrain from egg donation or harvest for 
90 days after last dose of study drug;
8) Willing and able to comply with scheduled visits, drug 
administration plan, laboratory tests, other study procedures, 
and study restrictions.
Exclusion Criteria:
1) Pregnant or lactating females;
2) Other causes of liver disease including chronic hepatitis B 
(hepatitis B surface antigen [HBsAg] positive), chronic 
hepatitis C (HCV RNA positive), acetaminophen 
hepatotoxicity, biliary obstruction, and autoimmune liver 
disease;
3) Serum AST > 400 U/L or ALT > 300 U/L, based on local 
laboratory results;
4) MELD > 30 at Screening, based on local laboratory results;
5) Maddrey’s DF > 60 at Screening, based on local laboratory 
results;
6) Grade 4 HE by West Haven criteria;
7) Concomitant or previous history of hepatocellular carcinoma;
8) History of liver transplantation;
9) HIV Ab positive;
10) Clinical suspicion of pneumonia;

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11) Uncontrolled sepsis;
12) Uncontrolled gastrointestinal (GI) bleeding or controlled GI 
bleeding within 7 days of Screening that was associated with 
shock or required transfusion of more than 3 units of blood;
13) Type 1 hepatorenal syndrome (HRS) or renal failure defined as 
a serum creatinine > 221 μmol/L (> 2.5 mg/dL) or the 
requirement for renal replacement therapy;
14) Subjects dependent on inotropic (eg, epinephrine or 
norepinephrine) or ventilatory support (ie, endotracheal
intubation or positive-pressure ventilation);
15) Portal vein thrombosis;
16) Acute pancreatitis;
17) Cessation of alcohol consumption for more than 2 months 
before Baseline/Day1;
18) Severe associated disease (eg, cardiac failure, acute myocardial 
infarction, severe cardiac arrhythmias, severe pulmonary 
disease, neurologic disease) that may lead to premature 
mortality within the study period;
19) Malignancy within the 2 years prior to Screening, with the 
exception of specific cancers that have been cured by surgical 
resection (eg, basal cell skin cancer).  Subjects under 
evaluation for possible malignancy are not eligible;
20) Positive urine screen for amphetamines, cocaine or opiates 
(ie, 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 positive cannabis drug screen 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 diagnosis are reviewed and approved by the 
investigator;
21) Treatment with immunosuppressive drugs [budesonide, 
tacrolimus, sirolimus, cyclosporine, azathioprine, 
mycophenolate mofetil, and methotrexate], pentoxifylline, 
N-acetylcysteine (NAC), or granulocyte (macrophage) 
colony-stimulating factor within 6 months of Screening. 
Subjects will be eligible to enroll if systemic corticosteroids 
were started within 3 days prior to the Baseline/Day 1 visit.  
Inhaled and topical corticosteroids are allowed;

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22) Use of strong CYP3A4 inducers (eg carbamazepine, 
phenytoin, rifampin, St. John’s wort) within 2 weeks of the 
Baseline/Day 1visit;
23) Active ocular herpes simplex;
24) 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;
25) Participation in another investigational study of a drug or 
device within 1 month prior or within 5 half-lives of the prior 
investigational agent (whichever is longer) prior to Screening;
26) Concurrent participation in another therapeutic clinical study;
27) Known hypersensitivity to the study drugs (GS-4997 and 
prednisolone), the metabolites, or formulation excipients;
28) Presence of any condition that could, in the opinion of the 
investigator, compromise the subject’s ability to participate in 
the study, such as history of substance abuse other than alcohol 
use or a psychiatric or medical condition;
29) Unavailable for follow-up assessment or concern for subject’s 
compliance with the protocol procedures;
Study Procedures/
Frequency:
Screening assessments should be completed within 14 days of 
Baseline/Day 1 visit.  Eligibility will be based on local laboratory 
testing. Refer to Section 6.9.10 Screening Laboratory Assessments 
for additional details.
After the Screening period and a randomization visit at 
Baseline/Day 1, study visits will occur on Weeks 1, 2, 3, 4, 6, 8, 
12, 16, 20, and 24. At minimum, vital signs, physical examination 
(PE), HE and ascites assessment, safety laboratory tests, alcohol 
consumption, and concomitant medications will be done at every 
visit. AEs will be collected up to 30 days after the last dose of any 
study drug and SAEs will be collected throughout the study.  
During the hospitalization period, subjects will be evaluated daily 
with assessments to include a review of adverse events, 
concomitant medications, study drug adherence, and a 
symptom-directed PE including assessments for ascites and HE. 
Findings based on these assessments and laboratory investigations 
obtained by treating physicians as part of routine care will be 
assessed by the investigator for triggers that may necessitate
further evaluation and/or treatment discontinuation and managed 
per Section 7 of the protocol.

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
ADR
adverse drug reaction
AE
adverse event
AH
Alcoholic Hepatitis
ALT
alanine aminotransferase
ARA
acid reducing agent
ASK1
apoptosis signal-regulating kinase 1
ASK1-/-
apoptosis signal-regulating kinase 1 deficient
AST
aspartate aminotransferase
ATP
Adenosine triphosphate
AUCtau
area under the plasma concentration versus time curve over the dosing 
interval (tau)
AUDIT
Alcohol Use Disorders Identification Test
-hCG
beta human chorionic gonadotropin
BAP
Biomarker Analysis Plan
BMI
body mass index
BUN
blood urea nitrogen
CBC
complete blood count
cc
cubic centimeter
CI
confidence interval
CK18
cytokeratin (C18)
CLcr
creatinine clearance
Clast
last observed quantifiable plasma/serum concentration of the drug
Cmax
maximum observed plasma/serum concentration of drug
CLDQ
Chronic Liver Disease Questionnaire
CRO
contract (or clinical) research organization 
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CYP3A4
cytochrome P4503A
DKD
Diabetic kidney disease
dL
Deciliter
DMC
Data Monitoring Committee
DSPH
Drug Safety and Public Health
DF
(Maddrey’s) Discriminant Function
DP
drug product
EC
ethics committee
ECG
electrocardiogram

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eCRF
electronic case report form
EDC
electronic data capture
eg
example
ELF™Test
enhanced liver fibrosis test
EoT
End of Treatment
EU
European Union
FAS
Full analysis set
FDA
(United States) Food and Drug Administration
FIO2 
Fraction of Inspired Oxygen
FSH
Follicle-stimulating hormone
GGT
gamma glutamyl transferase
GI
gastrointestinal
GMP
Good Manufacturing Practice
GSI
Gilead Sciences, Inc.
HbA1c
Hemoglobin A1c
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular Carcinoma
hCG
human chorionic gonadotropin
Hct
Hematocrit
HCV
Hepatitis c virus
HDL
High-density lipoprotein
HDPE
High-density polyethylene
HE
hepatic encephalopathy
Hg
Hemoglobin
HIV
Human immunodeficiency virus
HLT
high-level term
HLGT
high-level group term
HOMA-IR
homeostatic assessment of insulin resistance
HRS
Hepatorenal Syndrome
IB
Investigator’s Brochure
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
IEC
institutional ethics committee
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
INR
international normalized ratio

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IRB
institutional review board
IUD
intrauterine device
IVD
In vitro diagnostic
IWRS
interactive web response system
kg
Kilogram
LOX
Lysyl oxidase
LOXL1
Lysyl oxidase-like 1
LOXL2
Lysyl oxidase-like 2
LOXL3
Lysyl oxidase-like 3
LOXL4
Lysyl oxidase-like 4
LPS
lipopolysaccharide
mAB
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MELD
Model for End-Stage Liver Disease
g
Microgram
mg
Milligram
min
Minute
mL
Milliliter
mm
Millimeter
mm Hg
millimeters of mercury
NAC
N-acetylcysteine
NASH
Nonalcoholic steatohepatitis
PAH
Pulmonary arterial hypertension
PE
Physical Exam
PK
Pharmacokinetic
pH
measure of the acidity 
PT
preferred term
PT
prothrombin time
PTM
Placebo to match
PTT
Partial prothrombin time
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
RNA
ribonucleic acid
ROW
rest of world
SADQ
Severity of Alcohol Dependence Questionnaire
SADR
serious adverse drug reaction
SAE
serious adverse event

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SAP
statistical analysis plan
SBP
Spontaneous bacterial peritonitis
SC
Subcutaneous
SOP
standard operating procedure
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
Tlast
last measured concentration
Tmax
time (observed time point) of Cmax
TQT
thorough QT
ULN
upper limit of the normal range
US
United States
UTI
Urinary tract infection
wks
weeks

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1.
INTRODUCTION
1.1.
Background
Alcoholic liver disease (ALD) encompasses a spectrum of disease ranging from reversible fatty 
liver to alcoholic hepatitis (AH) and cirrhosis. In the United States, ALD remains the second 
most common cause of liver cirrhosis after Hepatitis C virus (HCV) infection and is responsible 
for approximately 20% to 25% cases of liver cirrhosis {Gao 2011, Singal 2013}. In Western 
Europe, ALD is the most prevalent cause of advanced liver disease and cirrhosis is the leading 
cause of alcohol-related death among adults {European Association for the Study of the Liver 
(EASL) 2012}. 
AH represents one of the most serious forms of ALD and remains a significant cause of 
morbidity and mortality in North America and Europe. Approximately 60% of patients with 
ALD in the United Kingdom will have evidence of an alcohol-related hepatitis at presentation 
{Hislop 1983}. In the United States (US), the burden of AH is increasing, with an estimated 
326,000 hospitalizations (0.8% of all admissions) in 2010, a 30% increase compared with 2002 
{Jinjuvadia 2015}. The mean length of a hospital stay is 5 to 7 days with an average health care 
cost of $35,000 to $41,000. In patients with severe AH (typically defined by a Maddrey’s
Discriminant Function (DF) ≥32, short-term mortality rates are high (approximately 25% to 
45%) {Akriviadis 2000, Mathurin 2011}. 
AH is a syndrome characterized by infiltration of the liver by inflammatory cells and 
hepatocellular injury.  Several studies in rodent models and histopathological studies in humans 
suggest that lipopolysaccharide (LPS)-induced inflammation and oxidative stress are key drivers 
of hepatocyte death in AH {Chayanupatkul 2014, Lucey 2009, Meagher 1999}. Alcohol 
consumption increases intestinal permeability and bacterial translocation to the liver, resulting in 
LPS-induced hepatic inflammation. Subsequent hepatocellular injury occurs by neutrophil 
oxidative bursts, and FAS ligand and TNF-induced hepatocyte apoptosis. In addition, ethanol 
strongly induces the expression of CYP2E1, which produces reactive oxygen species (ROS) as a 
by-product of ethanol metabolism, and reduces hepatic antioxidant capacity. Oxidative stress 
occurs as a result of these changes and directly induces hepatocyte mitochondrial dysfunction 
and necrosis and also sensitizes hepatocytes to apoptosis induced by TNF-and FAS ligand 
{Cederbaum 2012}.  
Pharmacologic agents that modulate these pathways have been used in the treatment of AH with 
limited success. Corticosteroid therapy which abrogates the inflammatory process is the current 
standard of care therapy for patients with severe AH. Compared with no treatment, a 28-day 
course of prednisolone improves 1-month mortality (approximately 35% vs. 20%), but shows 
limited impact on longer term outcomes {O'Shea 2010}. Indeed, 6-month mortality remains high 
despite prednisolone therapy {Mathurin 2011, Thursz 2015}. In addition to the limited efficacy 
of corticosteroids, there remains a high risk of infection in patients with severe AH who receive 
prednisolone {Louvet 2009}. In a cohort of 162 patients with AH (established by biopsy), 20% 
of patients had infections at hospital admission and 52% of those treated with corticosteroids 

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developed infections, including some patients with invasive aspergillosis {Michelena 2015}. In 
infected patients, the incidence of multiorgan failure (MOF, approximately 60%) and mortality 
(approximately 45% at 90 days) are substantially increased compared to uninfected patients
(approximately 5% at 90 days). High-dose corticosteroids may also exacerbate glycemic control 
in diabetic patients and lead to an increased risk of gastrointestinal hemorrhage {Rudler 2015}. 
Other therapies that have been evaluated including pentoxifylline which modulates TNF-α
transcription, N-acetylcysteine (an antioxidant), TNF inhibitors and antifibrotics, but none have
shown convincing clinical benefit and/or are considered harmful {Mathurin 2011, Nguyen-Khac 
2011, O'Shea 2005, Spahr 2002}. In light of the increasing burden of disease and limited 
therapeutic options, there remains a significant unmet medical need for alternative therapies with 
improved safety and efficacy for patients with severe AH.
1.2.
GS-4997
1.2.1.
General Information
GS-4997 is a small molecule that is a potent and selective inhibitor of apoptosis signal-regulating 
kinase 1 (ASK1).  ASK1, a critical serine/threonine kinase, is an important signaling node 
through which oxidative stress promotes inflammation, proliferation, apoptosis, and fibrosis 
{Fujisawa 2007, Takeda 2008, Tobiume 2001, Watanabe 2005}.  The ASK1 protein is 
ubiquitously expressed and is normally bound and repressed by thiol-containing antioxidant 
proteins in the cytosol and mitochondria {Fujino 2007, Takeda 2008, Zhang 2004}. In settings of 
elevated oxidative stress, ASK1 is autophosphorylated {Tobiume 2002}.  The phosphorylated 
ASK1 then phosphorylates mitogen-activated protein kinase kinases (MAPKKs) 3, 4, 6, and 7, 
which in turn phosphorylate and activate the mitogen-activated protein kinases (MAPKs) p38 
and c-Jun N-terminal kinase (JNK) {Nagai 2007, Takeda 2008}.
In pathological settings of oxidative stress, ASK1 is required for sustained activation of p38 and 
JNK, which promotes the expression of inflammatory cytokines (eg, interleukins 1β, 2, and 6), 
chemokines (eg, monocyte chemotactic protein 1, chemokine ligands 1 and 2), and matrix 
remodeling genes (ie, transforming growth factor beta, tissue inhibitor of metalloproteinase, and 
plasminogen activator inhibitor-1) {Matsuzawa 2005, Mnich 2010, Nakamura 2009, Takeda 
2008, Terada 2007, Tobiume 2001, Yokoi 2006}. Activation of the ASK1 pathway also 
increases the expression of nicotinamide adenine dinucleotide phosphate-oxidase and induces 
mitochondrial damage leading to an increase in the production of reactive oxygen species (ROS), 
apoptosis, necrosis, and in certain contexts, insulin resistance {Adachi 2013, Gerczuk 2012, 
Imoto 2006, Nakagawa 2008, Takeda 2008, Toldo 2012, Watanabe 2005}.  
A potential role for ASK1 in AH is supported by nonclinical studies demonstrating that oxidative 
stress, Fas ligand and TNF-signaling activate ASK1 in the mouse liver {Nakagawa 2011}. In 
addition, ASK1-/- mice are resistant to acute liver injury caused by Fas activation, TNF-
(induced by LPS plus D-galactosamine), bile duct ligation, or acetaminophen overdose
{Nakagawa 2011, Nakagawa 2008, Noguchi 2014}. Moreover, pharmacological inhibition of 
ASK1 in mice reduces hepatocellular injury and necrosis induced by acetaminophen overdose, as 
well as cardiac and renal apoptosis and necrosis induced by acute ischemia/reperfusion injury

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{Toldo 2012, Xie 2015}. These effects correlated with reduced activation/phosphorylation of 
ASK1, p38, and JNK, and reduced mitochondrial dysfunction which could translate into 
improved liver function and resultant improved mortality in severe AH.
1.2.2.
Preclinical Pharmacology and Toxicology
GS-4997 has high oral bioavailability, moderate volume of distribution and low systemic 
clearance in nonclinical species and humans. GS-4997 is modestly bound in human plasma.  
Elimination of GS-4997 and its metabolites is likely to occur through a mixture of urinary, 
biliary and intestinal excretion. The main route of metabolism of GS-4997 involves 
N-dealkylation. Human metabolism appears to be largely catalyzed by cytochrome P4503A 
(CYP3A) enzymes. After oral dosing of GS-4997 significant concentrations of GS-607509, 
inactive N-dealkylation metabolite, are found in plasma. GS-4997 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. GS-4997 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.  
GS-4997 has been extensively evaluated in nonclinical toxicology studies.  Findings attributed to 
GS-4997 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 GS-4997 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 GS-4997 IB for additional details.
1.2.3.
Clinical Trials of GS-4997
As of 14 October 2016, 13 Phase 1 and 2 clinical studies have been conducted/are ongoing in 
which 359 healthy subjects, 248 subjects with diabetic kidney disease (DKD), 113 subjects with 
pulmonary arterial hypertension (PAH), 72 subjects with NASH have been dosed with GS-4997.
Information on the completed and ongoing Phase 1 clinical 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 GS-4997 in Subjects with Diabetic 
Kidney Disease (Study GS-US-223-1015)
Study GS-US-223-1015 is an ongoing Phase 2, double-blind, placebo-controlled, dose-ranging 
study evaluating the efficacy, safety, and tolerability of GS-4997 in subjects with Diabetic 
Kidney Disease (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: GS-4997 2, 6, or 18 mg or matching 
placebo administered once daily for 48 weeks. The primary objective of this study is to 
determine the effect of GS-4997 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 
GS-4997 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 GS-4997 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.
Preliminary 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% in placebo and 
12.5% 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).
1.2.4.3.
Preliminary 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 GS-4997 respectively (p= NS). The study did not demonstrate that GS-4997 led 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 GS-4997 in Subjects with Pulmonary Arterial Hypertension 
(Study GS-US-357-1394)
Study GS-US-357-1394 is an ongoing Phase 2, randomized, double-blind, placebo-controlled, 
multicenter, dose-ranging study of GS-4997 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 GS-4997 2, 6, or 18 mg or placebo, orally, once daily, for 24 weeks. 
Subjects continued to receive their background PAH therapy throughout the study. Subjects who 
complete the 24-week blinded treatment period will be eligible to continue (or initiate) treatment 
with GS-4997 at 2, 6, or 18 mg during the blinded, long-term treatment extension of this study. 
The primary objective of this study is to evaluate the effect of GS-4997 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: 
37 subjects with placebo and 113 subjects with active treatment (39, 37, and 37 subjects with 
GS-4997 2, 6, and 18 mg, respectively).
A total of 134 subjects (89.3%) completed Period 1 treatment and 16 subjects (10.7%) 
discontinued study drug before reaching Week 24 (5 subjects [13.5%] in the placebo group and 
11 subjects [9.7%] in the pooled active treatment group [10.3%, 13.5%, and 5.4% for GS-4997 2, 
6, and 18 mg, respectively]). The most frequent reason for discontinuation of study drug was due 
to an AE (3 subjects [8.1%] in the placebo group and 6 subjects [5.3%] in the pooled active 
treatment group), followed by death (1 subject [2.7%] in the placebo group and 3 subjects [2.7%] 
in the pooled active treatment group), and investigator’s discretion (2 subjects [1.8%] in the 
pooled active treatment group).
1.2.5.2.
Preliminary Safety Analyses
Overall, 91.3% of subjects had a treatment-emergent adverse event with a frequency of 97.3% in 
the placebo group and 89.4% in the pooled active group (87.2%, 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). Overall, deaths occurred in 6.0% of subjects with a frequency of 
8.1% in the placebo group and 5.3% in the pooled active treatment group (2.6%, 8.1%, and 5.4% 
for 2 mg, 6 mg and 18 mg, respectively).

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1.2.5.3.
Preliminary Efficacy Analyses
The primary efficacy endpoint was change in PVR from baseline to Week 24. The primary 
endpoint measure of median change in PVR from baseline to Week 24 was -43 (CI -99, 86), 
23 (-45, 146), -39 (-97, 36) and -40 (-74, -7) dynes*sec/cm5 for placebo, 2 mg, 6 mg and 18 mg 
GS-4997, respectively (p=0.36). The study thus did not demonstrate that GS-4997 led to a 
statistically significant change in PVR after 24 weeks of treatment compared to placebo.
1.2.6.
A Phase 2, Randomized, Open Label Study Evaluating the Safety, 
Tolerability, and Efficacy of GS-4997 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 
GS-4997 (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 GS-4997 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:

GS-4997 6 mg orally once daily (N = 20)

GS-4997 18 mg orally once daily (N = 22)

GS-4997 6 mg orally once daily + SIM 125 mg subcutaneous injection weekly (N = 10)

GS-4997 18 mg orally once daily + SIM 125 mg subcutaneous injection weekly (N = 10)

SIM 125 mg subcutaneous injection weekly (N = 10)
Overall, after 24 weeks of treatment, no additional benefit was observed with the addition of 
SIM 125 mg to the GS-4997 (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: GS-4997 18 mg ± SIM 125 mg, 
GS-4997 6 mg ± SIM 125 mg, and SIM 125 mg alone.
1.2.6.1.
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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1.2.6.2.
Preliminary 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 
GS-4997 6 mg, GS-4997 18 mg, GS-4997 6 mg + SIM, and GS-4997 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 GS-4997 6 mg, 
GS-4997 18 mg, GS-4997 6 mg + SIM, and GS-4997 18 mg + SIM, respectively).
Overall, GS-4997 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 GS-4997 18 mg group (diarrhea and hypoesthesia in 1 subject and 
increased hepatic enzymes in 1 subject) and 1 subject (5.0%) in the GS-4997 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.
1.2.6.3.
Preliminary Efficacy Results 
Subjects treated with GS-4997 (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 GS-4997
(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).
For further information on GS-4997, refer to the IB for GS-4997.
1.3.
Rationale for This Study
ASK1 is a serine/threonine kinase that is activated by oxidative stress and stimulates apoptotic, 
fibrogenic, and inflammatory pathways via p38 and JNK activation. In mouse models of 
non-alcoholic acute liver injury, ASK-1 has been shown to promote hepatocyte apoptosis and 
necrosis {Nakagawa 2011}. In an internal study, liver biopsies from 9 patients with severe AH 
were shown to have significantly higher p-p38 immunoreactivity (an indicator of ASK1 pathway 
activation) compared to biopsies from patients with NASH and PSC suggesting that ASK1 
inhibition may be a potential therapeutic target in severe AH.  GS-4997 is a small molecule,
potent and selective inhibitor of ASK1. Inhibition of ASK1 with GS-4997 and resultant 
reduction of oxidative stress-induced hepatocyte apoptosis and necrosis, which are key 
mediators of AH pathogenesis {Ziol 2001} is hypothesized to improve efficacy and safety 

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compared with corticosteroid treatment in patients with AH. Moreover, data from the Phase 2 
study GS-US-384-1497 in patients with NASH and moderate to severe fibrosis that demonstrated 
an anti-fibrotic effect of GS-4997 (18 mg or 6 mg daily ± SIM) support its evaluation in patients 
with severe AH, the majority of whom have advanced fibrosis.
Mortality in AH is associated with acute loss of liver function and accompanying complications 
of advanced liver disease, including encephalopathy, sepsis, and/or MOF including renal failure.
Data generated at Gilead have demonstrated that ASK1 inhibition does not directly reduce 
LPS-mediated signaling and cytokine release by macrophages, nor does it reduce oxidative 
burst by neutrophils. These pathways are considered important mechanisms in the 
pathophysiology of severe AH. However it is hypothesized that the hepatoprotective effects of 
GS-4997 via other mechanisms could translate into improved liver function and resultant 
improved mortality in severe AH. Early improvement in liver function is associated with better 
survival (eg, 1-6 months following presentation) {Louvet 2015, Louvet 2007}.Prednisolone is 
the standard of care for severe AH and has been shown to reduce systemic levels of cytokines 
(ie, TNF-, IL-8) and reduce neutrophil activity (oxidative burst) in patients with severe AH
{Taieb 2000}. The complementary mechanisms of action of GS-4997 and prednisolone suggest a 
potential benefit could be gained via their combination. Given the distinct mechanism of action 
of GS-4997 and the totality of the preclinical evidence of modulating pathways involved in liver 
damage in AH, evaluating the combination of GS-4997 and prednisolone in patients with AH is 
of merit. 
1.4.
Rationale for Dose Selection
GS-4997 tablets will be administered orally once daily at a dose of 18 mg.
In preclinical models of DKD, PAH, NASH, and acute acetaminophen overdose, maximal 
efficacy is achieved with a dose that provides near complete suppression of the ASK1 pathway 
in target tissues (> EC95). For this Phase 2 proof-of-concept study, the dose selected (18 mg once 
daily) is projected to provide a plasma concentration that is expected to cause near complete 
inhibition of ASK1 (> EC95) at trough based on an ex vivo CXCL1 assay in human whole blood 
(CXCL1 EC95 = 130 ng/mL) to maximize potential for efficacy in this severe acute indication. 
This dose selection is supported by a preliminary review of unblinded biomarker data from an 
ongoing double-blind Phase 2 study in DKD (GS-US-223-1015) evaluating doses of 2 mg, 6 mg, 
and 18 mg of GS-4997 once daily. Moreover, data from the Phase 2 study GS-US-384-1497 in 
patients with NASH and moderate to severe fibrosis demonstrated a numerically greater 
likelihood of fibrosis regression in subjects treated with 18 mg versus 6 mg of GS-4997 daily.
GS-4997 has been evaluated at doses up to 100 mg in Phase 1 studies and up to 18 mg in Phase 2 
studies and, based on currently available blinded and unblinded safety data, is well tolerated. 
Based on in vitro and in vivo DDI results with probe drugs, GS-4997 PK is not expected to be 
significantly altered when coadministered with prednisolone as planned for this Phase 2 study. In 
the Phase 1 hepatic impairment study (GS-US-223-1018), there were minimal to modest changes 
in GS-4997 PK across varying degrees of hepatic impairment (mild, moderate, and severe). A 
43% increase in GS-4997 exposure (AUC) in subjects with severe hepatic impairment is less 
than what was observed in Study GS-US-223-1434 with the strong CYP3A4 inhibitor ritonavir 

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(79% increase). The small increase in exposure observed with severe hepatic impairment is not 
considered clinically meaningful as the observed changes are less than or comparable to the 
expected effect of a moderate CYP3A4 inhibitor on GS-4997 exposure; moderate and strong
CYP3A4 inhibitors are currently allowed in ongoing Phase 2 and Phase 3 studies evaluating 
doses of GS-4997 of up to 18 mg once daily. Based on the current safety/tolerability profile for 
GS-4997 at doses more than 5-fold higher than the dose proposed for this study, the increase in 
GS-4997 exposure in subjects with severe hepatic impairment is not considered clinically 
relevant and does not require dose adjustment. Taken together, these data support evaluation of 
GS-4997 18 mg once daily in subjects with severe AH.
1.5.
Risk/Benefit Assessment for the Study
The primary risk of study participation relates to the proposed initiation of prednisolone ± 
GS-4997 prior to the histologic confirmation of AH. The rationale for this approach is two-fold. 
First, in many centers, performance of liver biopsy in subjects with suspected severe AH is not 
standard of care prior to initiating treatment, typically with prednisolone. Second, the planned 
approach will allow the rapid initiation of therapy which is deemed vital to optimize outcomes in 
subjects with severe AH. Importantly, a clinical diagnosis of AH (as per standard of care) will be 
made and contraindications to prednisolone (e.g. untreated infection) will be excluded in all 
subjects prior to starting treatment.
Another related risk of study participation is that some subjects who do not have alcoholic 
hepatitis will be exposed to prednisolone ± GS-4997 therapy for up to 7 days before the 
diagnosis is refuted on biopsy. Based on prior studies, an estimated 20% of subjects who are 
suspected of severe alcoholic hepatitis do not have confirmation of the diagnosis on biopsy. As 
mentioned above, the initiation of prednisolone in subjects with suspected alcoholic hepatitis 
without performance of a liver biopsy is standard practice in many centers. The plan to 
discontinue treatment in subjects in whom the biopsy does not confirm alcoholic hepatitis is a 
potential benefit of study participation because it will limit exposure to prednisolone, which has 
toxicities including infection and worsened glycemic control The risk of short-term exposure to 
GS-4997 is low based on the results of prior Phase 1 and 2 studies (as outlined in Section 1.2.3), 
including the hepatic impairment study (GS-US-223-1018) that included subjects with mild, 
moderate, and severe hepatic dysfunction.
In view of the potential for GS-4997 to reduce major mechanisms of liver injury in subjects with 
severe alcoholic hepatitis, the limitations in available therapy, existing safety data, and the 
proposed study design to carefully monitor patient safety, the benefit/risk balance for this study 
is considered positive.
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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3.
STUDY DESIGN
3.1.
Study Design
The overall study design is presented graphically in Figure 3-1.
Figure 3-1.
Overall Study Design
*
Up to 60 subjects will be randomized leading to 50 subjects in each arm for the full analysis set (ie, histologically-proven 
severe AH and took at least one dose of study drug)
3.2.
Treatment Plan and Regimen
This is a Phase 2 double blind, randomized study evaluating the safety, tolerability, and 
biological activity of GS-4997 in combination with prednisolone versus prednisolone alone in 
subjects with severe, histologically-confirmed AH.
Up to 120 subjects will be randomized in a 1:1 ratio (within strata) to 1 of 2 treatment groups:

Group A (n = 50-60): GS-4997 18 mg once daily + prednisolone 40 mg once daily for 
28 days

Group B (n = 50-60): GS-4997 placebo once daily + prednisolone 40 mg once daily once 
daily for 28 days
Randomization will be stratified by MELD < 25 or ≥25 at Screening as calculated using local 
laboratory tests and an online MELD calculator (see Section 6.9.7).

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longer indicated and/or to add new tests based upon the growing state of the art knowledge. If a 
test will no longer be performed because the assay is not robust, sample collection may also be 
withdrawn to reduce burden on subjects.
Specimens will be collected from all 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 (eg, health 
requirements).
Table 3-1.
Biomarkers
Biomarker Focus
Planned Biomarkers
Rational
Specimen Collected
Liver tissue surrogate 
marker panel
ELF Test
Assess potential changes 
in liver fibrosis due to 
treatment
Blood
Liver tissue damage 
marker
Serum LOXL2
Assess potential changes 
in liver tissue damage  due 
to treatment
Blood
Apoptosis and Necrosis 
markers
Circulating Cytokeratin 18 
(CK18) fragments, M30 
for apoptosis and  M65 for 
all dying cells)
Determine changes in liver 
cell death  due to 
treatment
Blood
Inflammatory involvement
Serum cytokines
Determine changes in the 
inflammatory status  due 
to treatment
Blood
Infection
Lipopolysaccharide  
(LPS)/endotoxin
Assess changes in gut 
barrier function  due to 
treatment
Blood
Infection
Procalcitonin
Assess changes in gut 
barrier function due to 
treatment
Blood
Metabolome
Circulating metabolite 
profiles (open platform)
Assess changes in the 
metabolome due to 
treatment
Blood
ASK1 pathway activity
phospho-p38*
blood marker of ASK1 
pathway activity to 
monitor PD effects
Blood
Intestinal microbial 
composition
Stool microbiome 
determined by 16S 
ribosomal DNA 
sequencing
Assess changes in 
microbial populations due 
to treatment
Stool
ASK1 pathway activity
Focused panel gene 
expression (Nanostring)
Assess gene expression in 
disease at baseline
Liver Biopsy
ASK1 pathway activity
phospho-p38  IHC
Assess ASK1 pathway 
activation at baseline
Liver Biopsy

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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
The full analysis set will comprise 100 subjects, males and non-pregnant, non-lactating females 
between 18-70 years of age with histologically-confirmed severe AH (Maddrey’s DF ≥ 32). Up 
to 20 additional subjects will be randomized to account for subjects in whom AH is not 
histologically-confirmed.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Males and non-pregnant, non-lactating females between 18-70 years of age, inclusive based 
on the date of the Screening visit;
2) Willing and able to give informed consent prior to any study specific procedures being 
performed. In subjects with HE, which may impair decision-making, consent will be 
obtained per hospital procedures (eg, by legal Authorized Representative);
3) Clinical diagnosis of severe AH based on all of the following:
a) History of excessive alcohol consumption during the past 3 months (average of > 40 g/d 
of alcohol for women and > 50 g/d for men);
b) Aspartate aminotransferase (AST) ≥50 U/L, based on local laboratory results; 
c) AST/alanine aminotransferase (ALT) ratio (AST/ALT) ≥1.5, based on local laboratory 
results;
d) Onset of jaundice within the past 3 months;
e) Maddrey’s DF ≥32 at Screening, based on local laboratory results;
4) All female subjects of childbearing potential must agree to use a highly effective method of 
contraception during intercourse from the Screening visit throughout the study period and for 
90 days following the last dose of study drug.  If females utilize hormonal agents as one of 
their contraceptive methods, the same hormonal methods must have been used for at least 
3 months before study dosing. Females on hormonal methods must also utilize a barrier 
method as another form of contraception as described in Appendix 3;
5) Male subjects must refrain from sperm donation from Screening through at least 90 days 
following the last dose of study drug;

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6) Male subjects must agree to use condoms during intercourse from Screening through study 
completion and for 90 days following the last dose of study drug;
7) Female subjects must refrain from egg donation or harvest for 90 days after last dose of study 
drug;
8) Willing and able to comply with scheduled visits, drug administration plan, laboratory tests, 
other study procedures, and study restrictions
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Pregnant or lactating females;
2) Other causes of liver disease including chronic hepatitis B (hepatitis B surface antigen 
[HBsAg] positive), chronic hepatitis C (HCV RNA positive), acetaminophen hepatotoxicity, 
biliary obstruction, and autoimmune liver disease
3) Serum AST > 400 U/L or ALT > 300 U/L, based on local laboratory results;
4) MELD > 30 at Screening, based on local laboratory results;
5) Maddrey’s DF > 60 at Screening, based on local laboratory results;
6) Grade 4 HE by West Haven criteria;
7) Concomitant or previous history of hepatocellular carcinoma;
8) History of liver transplantation;
9) HIV Ab positive;
10) Clinical suspicion of pneumonia;
11) Uncontrolled sepsis;
12) Uncontrolled gastrointestinal (GI) bleeding or controlled GI bleeding within 7 days of 
Screening that was associated with shock or required transfusion of more than 3 units of 
blood;
13) Type 1 hepatorenal syndrome (HRS) or renal failure defined as a serum creatinine 
>221 μmol/L (> 2.5 mg/dL) or the requirement for renal replacement therapy;
14) Subjects dependent on inotropic (eg, epinephrine or norepinephrine) or ventilatory support 
(ie, endotracheal intubation or positive-pressure ventilation);

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15) Portal vein thrombosis;
16) Acute pancreatitis;
17) Cessation of alcohol consumption for more than 2 months before Baseline/Day 1;
18) Severe associated disease (eg, cardiac failure, acute myocardial infarction, severe cardiac 
arrhythmias, severe pulmonary disease, neurologic disease,) that may lead to premature 
mortality within the study period;
19) Malignancy within the 2 years prior to Screening, with the exception of specific cancers that 
have been cured by surgical resection (basal cell skin cancer, etc).  Subjects under evaluation 
for possible malignancy are not eligible.
20) Positive urine screen for amphetamines, cocaine or opiates (ie, 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 positive cannabis
drug screen 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 diagnosis are 
reviewed and approved by the investigator;
21) Treatment with immunosuppressive drugs [budesonide, tacrolimus, sirolimus, cyclosporine, 
azathioprine, mycophenolate mofetil, and methotrexate], pentoxifylline, N-acetylcysteine 
(NAC), or granulocyte (macrophage) colony-stimulating factor within 6 months of 
Screening. Subjects will be eligible to enroll if systemic corticosteroids were started within 
3 days prior to the Baseline/Day 1 visit.  Inhaled and topical corticosteroids are allowed;
22) Use of strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s Wort) 
within 2 weeks of the Baseline/Day 1 visit;
23) Active ocular herpes simplex;
24) 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;
25) Participation in another investigational study of a drug or device within 1 month prior or 
within 5 half-lives of the prior investigational agent (whichever is longer) prior to Screening;
26) Concurrent participation in another therapeutic clinical study;
27) Known hypersensitivity to the study drugs (GS-4997 and prednisolone), the metabolites, or 
formulation excipient;

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28) Presence of any condition that could, in the opinion of the investigator, compromise the 
subject’s ability to participate in the study, such as history of substance abuse other than 
alcohol use or a psychiatric or medical condition;
29) Unavailable for follow-up assessment or concern for subject’s compliance with the protocol 
procedures.

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The matching placebo tablets are identical in physical appearance and contain the same inactive 
ingredients as the GS-4997 18 mg tablets. 
5.2.1.2.
Prednisolone
Commercially available prednisolone will be used for the study. Further information regarding 
formulation is available in the Prescribing Information for commercial product.
5.2.2.
Packaging and Labeling
5.2.2.1.
GS-4997 18 mg and GS-4997 PTM
GS-4997 18 mg and GS-4997 PTM 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 with an induction-sealed and aluminum-faced liner.
Study drug 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), EU 
Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal Products), 
and/or other local regulations.
5.2.2.2.
Prednisolone
Commercially available prednisolone 10 mg tablets will be used for the study.
5.2.3.
Storage and Handling
5.2.3.1.
GS-4997 and GS-4997 PTM
GS-4997 18 mg and GS-4997 PTM 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 drug 
should be stored in a securely locked area, accessible only to authorized site personnel.  To 
ensure the stability and proper identification, study drug should not be stored in containers other 
than the containers in which they were supplied.
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.
5.2.3.2.
Prednisolone
Commercially available prednisolone 10 mg tablets will be used for the study. Further 
information regarding storage and handling are available in the Prescribing Information for 
commercial product.

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5.3.
Dosage and Administration of Study Drugs
5.3.1.
GS-4997
GS-4997 18 mg and GS-4997 PTM tablets will be provided by Gilead Sciences. Once daily, at 
approximately the same time each morning, the study drug should be taken orally with water, 
swallowed whole, and with or without food. A dose will be considered missed if the subject 
cannot take the dose within 8 hours of their regular dosing time. If a subject misses a dose, the 
subject should take their next dose at the regular dosing time. For subjects who initiate dialysis, 
GS-4997/PTM should be administered following dialysis on days of the procedure and at the 
usual time on non-dialysis days. Please note that study drug should not be taken on mornings of 
sparse PK and biomarker assessments as outlined in Appendix 2. The dose should be taken as 
soon as possible after the trough PK and trough biomarker assessments are completed.
5.3.2.
Prednisolone
Commercially available prednisolone 10 mg tablets will be provided by Gilead Sciences. 
Subjects will take 40 mg prednisolone (4 x 10 mg) orally with water, once a day, with or without 
meals. The study drug should be swallowed whole and taken at approximately the same time 
each day. A dose will be considered missed if the subject cannot take the dose within 8 hours of 
their regular dosing time. The timing of prednisolone dosing should remain unchanged in 
subjects on dialysis. If a subject misses a dose, the subject should take their next dose at the 
regular dosing time. Prednisolone administration will not exceed 28 days from Baseline/Day 1 (a 
tapering course of prednisolone after the 28-day treatment period will not be allowed).
5.4.
Prior and Concomitant Medications
In vitro data suggests that GS-4997 has the potential to inhibit P-glycoprotein (P-gp). GS-4997 
has the potential to increase the exposure of sensitive P-gp substrates (eg, aliskiren, dabigatran 
etexilate, digoxin, fexofenadine, ranolazine). In a drug-drug interaction study of GS-4997 
co-administered with digoxin (0.5 mg), exposure of digoxin (AUC) was increased by less than 
30%. GS-4997 may increase the exposure of other P-gp substrates; however, the clinical 
relevance of such interactions has not been determined. Co-administration of P-gp substrates 
with study drug is allowed, with specific guidance provided for the following:

Digoxin: Follow digoxin level at baseline and at the Week 1 visit with digoxin level checks 
during the study period per investigator discretion (as frequently as needed).

Dabigatran etexilate: Consult Medical Monitor

Ranolazine: Monitor for side effects

Aliskiren: Use with caution, dose may need to be reduced
All concomitant medication will be recorded in the source documents. This includes concomitant 
medications taken within 30 days prior to Screening and any taken during the study to the end of 

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5.6.
Study Drug Accountability
The investigator or designee (eg, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug. This includes acknowledgement of receipt of each shipment 
of study drug (quantity and condition), subject administration and dispensing records, and 
returned or destroyed study product. Administration and dispensing records will document 
quantities received from Gilead Sciences and quantities administered/dispensed to subjects, 
including the lot number, date administered/dispensed, subject identification number, subject 
initials, and the initials of the person dispensing the medication. All used and unused study drug 
administered/dispensed to subjects must be returned to the site.
Investigational Drug Accountability records will be provided to each study site to:

Record the date and quantity of study drug received

Record the date, subject number, subject initials, and the study drug assigned

Record the date, quantity of used and unused study drug. Dispensing records will include the 
initials of the person recording the information.
5.6.1.
Investigational Medicinal Product Return or Disposal
At the start of the study, the study monitor will evaluate each 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. 
The site 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. In subjects with HE, 
which may impair decision-making, consent will be obtained per hospital procedures (eg, by 
Legally Authorized Representative).
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 IWRS.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Local laboratory results obtained within one day of Screening may be used to determine 
eligibility.
Chest x-rays, local laboratory testing for Hepatitis B and C and HIV Serology, and urine drug 
testing done during the current hospitalization (which includes transfers from other institutions)
and within 10 days of Screening may be used to determine eligibility. A urine pregnancy test 
must be done locally on the day of the Screening visit.
NOTE: All subjects will require an additional set of Screening labs drawn for central lab 
processing.
Subjects will be screened within 14 days prior to randomization to determine eligibility for 
participation in the study. 
The interval between hospitalization and Baseline/Day 1 must be ≤ 14 days. This window may 
be extended under special circumstances with explicit approval from the Medical Monitor.
Subjects who fail to meet eligibility criteria due to an abnormal laboratory result may undergo 
re-testing of the abnormal analyte once during the Screening window. 

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Note: Eligibility will be based on local laboratory results.  
However, subjects whose HIV or hepatitis B or C serologies from the central laboratory are 
positive must stop study drug within 3 days of receipt of results. All subjects stopping study 
drug for these reasons should attend an EoT visit as soon as possible and have a follow up 
visit 30 days after their last dose of study drug, prior to being withdrawn from the study.
The following tests will be performed by the local laboratory only:
Urine samples for urinalysis (routine and microscopic) and culture
Urine Pregnancy Test (only for female subjects of childbearing potential)
Blood cultures
Note:  Subjects may be eligible based on their local urine pregnancy test; however, if the 
subject has a positive serum pregnancy test from central laboratory testing (see below), the 
subject must stop study drug immediately upon receipt of the central laboratory result, attend 
an EoT visit as soon as possible, and have a follow-up visit 30 days after their last dose of 
study drug, prior to being withdrawn from the study.

Obtain blood samples for the following to be sent to the central laboratory only:
Blood for Biomarkers
Insulin
Lipid Profile 
Serum Pregnancy Test (only for females subjects of childbearing potential)

Assessments for HE, ascites, Hepatorenal Syndrome (HRS), and infection

Perform chest x-ray (posteroanterior [PA] film is mandatory and a lateral film should be 
performed if feasible). Chest x-rays performed during the current hospitalization (which 
includes transfers from other institutions) and within 10 days of Screening are acceptable.

Perform liver ultrasound (it is acceptable to use a liver ultrasound previously performed
during the current hospitalization, including transfers between hospitals.)

Perform paracentesis (ascitic fluid tap) with ascitic fluid cell count, differential, and culture if 
clinically-detectable ascites is present (laboratory specimens to be analyzed by the local 
laboratory only)

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
Perform liver biopsy
Note: Can be performed up to 7 days post Baseline/Day 1. Liver biopsy obtained during the 
current hospitalization (including transfers between hospitals) prior to Screening is 
acceptable. However, if biopsy results are not consistent with AH, the subject will stop study 
drug within 3 days of receipt of the liver biopsy result, attend an EoT visit as soon as 
possible, and have a follow-up visit 30 days after their last dose of study drug, prior to being 
withdrawn from the study. If the liver biopsy sample is inadequate to confirm a pathologic 
diagnosis of AH and no alternative diagnosis is suggested on biopsy, then the subject may 
remain in the study. 

Record any serious adverse events (SAEs) and all adverse events related to 
protocol-mandated procedures occurring after signing of the consent form
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all SAEs, as well as any adverse events related to protocol-mandated 
procedures on the adverse events case report form (eCRF).  All other untoward medical 
occurrences observed during the Screening period, including exacerbation or changes in medical 
history are to be captured on the medical history eCRF.  See Section 7 Adverse Events and 
Toxicity Management for additional details.
Subjects must meet all of the inclusion criteria and none of the exclusion criteria prior to 
randomization into the study.
6.2.2.
Baseline / Day 1 Assessments and Randomization
After review of inclusion and exclusion criteria to confirm 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 drug.
Randomization will be stratified by MELD < or ≥ 25 at Screening as calculated using local 
laboratory tests and an online MELD calculator (see Section 6.9.7).  
During the entire hospitalization period, subjects will be evaluated daily with assessments to 
include a review of adverse events, concomitant medications, study drug adherence, and a 
symptom-directed PE including assessments for ascites and HE. Findings based on these 
assessments and laboratory investigations obtained by treating physicians as part of routine care 
will be assessed by the investigator for triggers that may necessitate further evaluation and/or 
treatment discontinuation and managed accordingly per Section 7.5 of the protocol.
The following will be performed and documented at the randomization visit prior to dosing:

Review inclusion/exclusion criteria and confirm eligibility

QoL Questionnaire (CLDQ)

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6.3.4.
Week 4 / End of Treatment Visit (EoT) (±3 days)
If the subject meets criteria for discontinuation of treatment (see Section 6.8 of this protocol), the 
subject should complete an EoT visit as soon as possible after all study drugs are discontinued
and attend post-treatment visits as outlined in Appendix 2. Subjects discontinued prior to Week 2 
should attend a 30-day FU visit to collect safety data within 30 days of their last dose of study 
drug. Subjects that have their scheduled Week 4/End of Treatment visit prior to Day 28 will 
require a phone contact between Study Days 28-35 to assess mortality and liver transplantation.
Subjects should be instructed not to take study drug in the morning of the Week 4 Visit. The 
dose should be taken as soon as possible after the trough PK (Sparse PK sample collected prior 
to dosing) and biomarker assessments are completed.
The following will be performed and documented at this visit:

QoL Questionnaire (CLDQ)

Assess alcohol consumption

Complete PE including, vital signs, and body weight

Perform standard 12-lead ECG

Assessments for HE, ascites, HRS, and infection.

Obtain blood samples for:
Hematology
Chemistry: ALT, AST, albumin, alkaline phosphatase, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, LDH, magnesium, phosphorus, potassium, sodium, total 
and direct bilirubin, total protein, uric acid, GGT. Samples should be drawn for central 
and local laboratory testing for the calculation of the Lille Score (Section 6.9.12)
Coagulation Tests: PT, PTT, and INR
Blood and Urine for Biomarkers
ELFTM Test and LOXL2
Insulin 
Lipid Profile 
Sparse PK Sample

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
Urine pregnancy test (for females of childbearing potential)

Collect stool for microbiome testing

Record all concomitant medications that the subject has taken since the previous visit

Record any SAEs and all adverse events occurring since the previous visit

Assess for study drug adherence

Perform study drug accountability

FibroScan (if available and for subjects without ascites)

Record local laboratory results for total bilirubin so that Lille score can be calculated using 
local laboratory data.
6.3.5.
Follow Up Visit (±5 Days)
Subjects should return for a Follow-Up Visit 30 days after their last dose of study drug.
Subjects whose liver biopsy results are not consistent with AH or whose HIV or hepatitis B or C 
serologies from the central laboratory are positive, must stop study drug within 3 days of receipt 
of results. If the liver biopsy sample is inadequate for pathologic diagnosis of AH and no 
alternative diagnosis is suggested on biopsy, then the subject may remain in the study. Subjects 
whose serum pregnancy testing from the central laboratory is positive at Screening must stop 
study drug immediately upon receipt of this result.  All subjects stopping study drug for these 
reasons should attend an EoT visit as soon as possible and have a follow up visit 30 days after 
their last dose of study drug, prior to being withdrawn from the study. Subjects discontinuing 
both study drugs prior to Week 2 should complete an end of treatment visit after stopping drug, a
30-day safety FU visit, and all post-treatment follow-up visits. Subjects discontinued after Week 
2 should complete an end of treatment visit, and all post-treatment assessments as outlined in 
Appendix 2.

Record all concomitant medications that the subject has taken since the previous visit

Record any SAEs and all adverse events occurring since the previous visit

Assessments for HE, ascites, HRS and infection

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
Obtain blood samples for:
Hematology
Chemistry: ALT, AST, albumin, alkaline phosphatase, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, LDH, magnesium, phosphorus, potassium, sodium, total 
and direct bilirubin, total protein, uric acid, GGT
Coagulation Tests: PT, PTT, and INR
6.4.
Pharmacokinetic Assessments
6.4.1.
Sparse PK
Blood samples for PK assessments will be collected for all subjects on Baseline/Day 1 and 
Weeks 1, 2, and 4.

Baseline/Day 1 - sample should be collected 2 (±1) hrs postdose. 

Weeks 1 and 4 - samples should be collected at 24 (±4) hrs after previous dose (prior to 
dosing on visit day). Subjects should not dose until the PK sample is collected.

Week 2 - samples should be collected at 24 (±4) hrs after prior dose (prior to dosing on visit 
day) AND at 2 (±1) hrs postdose. Subjects should dose in office after the first PK sample is 
collected.
If a subject requires hemodialysis/hemoperfusion/peritoneal/CRRT dialysis therapy, additional 
PK samples will be collected on a single occasion during the 4 week treatment period as 
described below. The start and stop date and time of dialysis, the type of dialysis, and, where 
applicable, the flow rate of dialysate, will be recorded.
If a subject requires hemodialysis/hemoperfusion/peritoneal dialysis therapy,  PK samples should 
be collected at any single session at the following timepoints:

Within 30 minutes prior to initiation of the procedure (0 hr)

Where possible, a single sample from arterial side and a single sample from venous side of 
the dialyzer approximately 1 hr prior to conclusion of dialysis

Upon completion of the procedure (within 15 minutes)

Approximately 1 hr after completion of the procedure.

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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
6.5.2.
Weeks 8, 16, and 20 / Post Treatment Visits (± 5 Days)
During the Week 8, 16, and 20 post treatment visits, the following will be performed and 
documented:

Assess alcohol consumption

Complete PE including, vital signs

Perform standard 12-lead ECG (Week 8 only)

Assessments for HE, ascites, HRS and infection

Obtain blood samples for:
Hematology
Chemistry: ALT, AST, albumin, alkaline phosphatase, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, LDH, magnesium, phosphorus, potassium, sodium, total 
and direct bilirubin, total protein, uric acid, GGT
Coagulation Tests: PT, PTT, and INR
Blood for Biomarkers (Week 8 only)

Urine pregnancy test (for females of childbearing potential)

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
(Week 8 only)

Record procedure-related adverse events and procedure-related SAEs as well as any SAEs 
that the investigator deems relevant to the use of study drug for Weeks 16 and 20 only

Subjects that have their scheduled Week 8 visit prior to Day 56 will require a phone contact 
between Day 56-63 respectively, to assess for mortality and liver transplantation.

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6.5.3.
Weeks 12 and 24 / Post Treatment Visits (± 5 Days)
Subjects that have their scheduled Week 12 or Week 24 visit prior to Day 84 or Day 168, will 
require a phone contact between Day 84-91 or Day 168-175 respectively, to assess for mortality
and liver transplantation.
During the Week 12 and Week 24 post treatment visits, the following will be performed and 
documented:

QoL Questionnaire (CLDQ, week 24 only)

Assess alcohol consumption

Assessments for HE, ascites, HRS and infection

Complete PE including, vital signs, and body weight

Obtain blood samples for:
Hematology
Chemistry: ALT, AST, albumin, alkaline phosphatase, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, LDH, magnesium, phosphorus, potassium, sodium, total 
and direct bilirubin, total protein, uric acid, GGT
Coagulation Tests: PT, PTT, and INR
Blood for Biomarkers; Urine for Biomarkers (Week 24 only)
ELFTM Test and LOXL2
Insulin 
Hemoglobin A1c
Lipid Profile 

Stool for microbiome testing (week 24 only)

Urine pregnancy test (for females of childbearing potential)

Record all concomitant medications that the subject has taken since the previous visit

Record all serious adverse events and any study related adverse events occurring since the 
previous visit

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
Record procedure-related adverse events and procedure-related SAEs as well as any SAEs 
that the investigator deems relevant to the use of study drug (Week 24 only)

FibroScan (if available and for subjects without ascites [Week 24 only])
6.6.
Unscheduled Visits
Additional unscheduled assessments may be performed at the discretion of the investigator.  At a 
minimum, the following will be performed and documented, unless the unscheduled visit is only 
to refill medication, then the following procedures are not necessary.

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

Assessments for HE, ascites, HRS and infection

Obtain blood samples for:
Hematology
Chemistry: ALT, AST, albumin, alkaline phosphatase, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, LDH, magnesium, phosphorus, potassium, sodium, total 
and direct bilirubin, total protein, uric acid, GGT
Coagulation Tests: PT, PTT, and INR
6.7.
Assessments for Premature Discontinuation from Study
Discontinuation from study drug dosing and discontinuation from the study (including follow-up 
visits and phone contact at Week 8, Week 12, and Week 24) are 2 distinct actions.   
Subjects with histologically confirmed AH who discontinue study drug (for any reason other 
than death) prior to completion of the assigned dosing period, should complete an EoT visit, a 
30 day follow up visit, and all required follow-up study visits.  
Subjects whose liver biopsy results are not consistent with AH or whose HIV or hepatitis B or C 
serologies from the central laboratory are positive, must stop study drug within 3 days of receipt 
of results.  Subjects whose serum pregnancy testing from the central laboratory is positive at 
Screening must stop study drug immediately upon receipt of this result.  All subjects stopping 
study drug for these reasons should attend an EoT visit as soon as possible and have a follow up 
visit 30 days after their last dose of study drug, prior to being withdrawn from the study.  These 
subjects will not complete the remaining follow-up study visits.
Subjects are considered to have completed the study after the Follow up Week 24 visit, 
regardless of treatment duration and/or early termination from study drug.

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6.8.
Criteria for Discontinuation of Study Treatment
Study medication must be discontinued in the following instances:

Liver biopsy inconsistent with diagnosis of AH. If the liver biopsy sample is inadequate for 
pathologic diagnosis of AH and no alternative diagnosis is suggested on biopsy, then the 
subject may remain in the study.

Serologies for HIV, hepatitis B, or hepatitis C from central laboratory testing are positive

Serum pregnancy test at Screening from central laboratory testing is positive , and /or 
pregnancy during the study; refer to Appendix 3

Subject who develops a SAE consisting of a serious allergic reaction to the study drug

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 request to discontinue for any reason

Discontinuation of the study at the request of Gilead, a regulatory agency or an institutional 
review board or independent ethics committee (IRB/IEC/EC)
Study medication may be discontinued with discretion in the following instances:

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 after discussion with the 
Medical Monitor

Potential drug-related hepatotoxicity; refer to Section 7.5

Subject noncompliance

Sponsor discretion

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6.9.
Description of Assessments
6.9.1.
Liver Biopsy
A core liver biopsy via either the percutaneous or transjugular route will be performed at 
Screening. Liver biopsy obtained during the current hospitalization (including transfers between 
hospitals) prior to Screening is acceptable. Liver biopsy can be performed up to 7 days following 
the Baseline/Day 1 visit. Subjects may start treatment prior to receipt of the liver biopsy result if 
the subject has met all other eligibility criteria. In such cases, if a diagnosis consistent with AH is 
not confirmed on the liver biopsy, the subject must stop study drugs within 3 days of receipt of 
the liver biopsy result, attend an EoT visit as soon as possible, and have a follow-up visit 30 days 
after their last dose of study drug, prior to being withdrawn from the study. At minimum, a 
histological diagnosis of AH consists of the presence of hepatocellular injury characterized by 
hepatocyte ballooning, neutrophilic infiltration, and steatosis {Lucey 2009}.  Grading of liver 
biopsies according to the Alcoholic Hepatitis Histologic Score (AHHS) is preferred {Angeli 
2015}. If the liver biopsy sample is inadequate for a pathologic diagnosis of AH, but does not 
reveal another etiology, the subject may remain in the study.
6.9.2.
Electrocardiogram
Standard 12-lead electrocardiogram (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 on the AE case report form.
6.9.3.
AUDIT / SADQ Questionnaires 
The Alcohol Use Disorders Identification Test (AUDIT) is a 10-question test to determine if the 
subject may be at risk for alcohol abuse problems.
The Severity of Alcohol Dependence Questionnaire (SADQ) is a 20-question test to measure the 
presence of alcohol dependence.
AUDIT and SADQ will be completed by subjects at the Screening visit. A Legally Authorized 
Representative may assist the subject in completing the questionnaires. It is recommended to 
administer these questionnaires prior to the clinical and laboratory assessments. If the subject is 
unable or refuses to complete a questionnaire, this should be documented on the relevant eCRF.
6.9.4.
Quality of Life (QoL) Measures
The Chronic Liver Disease Questionnaire (CLDQ) will be collected at Baseline/Day 1, Week 4,
and Week 24. It is recommended to administer this questionnaire prior to the clinical and
laboratory assessments. Legally Authorized Representative may assist the subject in completing 
the questionnaires. If the subject is unable or refuses to complete a questionnaire, this should be 
documented on the relevant eCRF. The CLDQ asks 29 questions related to liver disease to 
measure health related quality of life in subjects with chronic liver disease.

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6.9.5.
Hepatic Encephalopathy (HE)
The severity of HE should be graded according to the West Haven Criteria, which are based on 
changes of consciousness, intellectual function, and behavior. 
Grade 1 - Trivial lack of awareness; euphoria or anxiety; shortened attention span; impaired 
performance of addition 
Grade 2 - Lethargy or apathy; minimal disorientation for time or place; subtle personality 
change; inappropriate behavior; impaired performance of subtraction
Grade 3 - Somnolence to semistupor, but responsive to verbal stimuli; confusion; gross 
disorientation
Grade 4 - Coma (unresponsive to verbal or noxious stimuli)
Medications used to treat HE should be recorded on the concomitant medications case report 
form. 
6.9.6.
Ascites
The severity of ascites should be graded according to the following modification of the 
International Ascites Club Criteria.
Grade 0 – No ascites detectable clinically or by ultrasound
Grade 1 – Mild ascites only detectable by ultrasound
Grade 2 – Moderate ascites evident by moderate symmetrical distension of abdomen
Grade 3 – Large or gross ascites with marked abdominal distension
Medications used to treat ascites should be recorded on the concomitant medications case report
form. If a subject has Grade 0 or 1 ascites, but is taking diuretic therapy for treatment, record 
ascites as Grade 2.
6.9.7.
Maddrey’s DF, MELD and Child-Pugh-Turcotte Scores
For purposes of inclusion/exclusion criteria, local laboratory results and online calculators will 
be used to calculate the Maddrey’s DF and MELD scores at Screening. Specifically, Maddrey’s 
DF will be calculated at the Screening visit based on local laboratory results for PT, PT control, 
and serum total bilirubin. The following online calculator will be used: 
http://www.gastrotraining.com/calculators/maddreys-discriminant.
The screening MELD score will be calculated based on the local laboratory results for INR, 
serum creatinine, and total bilirubin in appropriate units (SI or conventional) at the Screening

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visit using the following online calculator:  http://www.mdcalc.com/original-meld-score-pre-
2016-model-for-end-stage-liver-disease.
NOTE: The MELD online calculator uses the original pre-2016 MELD formula without the 
adjustment for Sodium.
MELD score, Child-Pugh-Turcotte (CPT) score, and Maddrey’s DF will be assessed at each 
study visit (see Appendix 4 for more information regarding the CPT scoring and classification).
Components of the MELD, CPT, and Maddrey’s DF scores which are based on laboratory 
values, the data will be obtained from the central laboratory within the clinical database for 
analysis.
6.9.8.
Hepatorenal Syndrome (HRS)
The occurrence of HRS should be confirmed based on the following diagnostic criteria from the
International Ascites Club (IAC) {Angeli 2015}. The date of diagnosis/resolution and specific 
therapies for HRS should be recorded.

Cirrhosis with ascites

Diagnosis of acute kidney injury (AKI) according to the ICA-AKI criteria
Definition of AKI:  Increase in serum creatinine ≥0.3 mg/dL (≥26.5 μmol/L) within 48 
hours or a percentage increase of ≥50% from Baseline/Day 1.
Stages:
■
1:  Increase in serum creatinine ≥0.3 mg/dL (≥26.5 μmol/L) or an increase 
≥1.5x to 2x from Baseline/Day 1.
■
2:  Increase in serum creatinine > 2-3x from Baseline/Day 1.
■
3:  Increase in serum creatinine > 3x from Baseline/Day 1 or serum creatinine
≥4.0 mg/dL (353.6 μmol/L) with an acute increase ≥0.3 mg/dL (≥26.5 μmol/L) from 
Baseline/Day 1 or initiation of renal replacement therapy.
Stage 2 or 3 AKI without improvement of serum creatinine to stage 1 AKI after at least 
2 days with diuretic withdrawal and volume expansion with albumin.  The recommended 
dose of albumin is 1 g/kg of body weight per day up to a maximum of 100 g/day.

Absence of shock

No current or recent treatment with nephrotoxic drugs

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
Absence of parenchymal renal disease as indicated by proteinuria >500 mg/day, 
microhematuria (> 50 red blood cells per high power field) and/or abnormal renal 
ultrasonography.
After the diagnosis of HRS, treatment with vasoconstrictors and albumin is recommended.  
Where available, terlipressin is recommended based on the EASL Clinical Practice Guidelines
(http://www.easl.eu/research/our-contributions/clinical-practice-guidelines/detail/management-
of-ascites-spontaneous-bacterial-peritonitis-and-hepatorenal-syndrome-in-cirrhosis/report/6);
norepinephrine or midodrine plus octreotide are acceptable alternatives based on AASLD 
Practice Guidelines
(http://www.aasld.org/sites/default/files/guideline_documents/adultascitesenhanced.pdf).  
6.9.9.
Infection
The occurrence of bacterial, fungal, or viral infections should be recorded as adverse events. 
Relevant data to be recorded include the source of infection, date of onset/resolution, presence of 
fever (temperature ≥38ºC/100.4ºF), laboratory investigations (e.g. white blood cell count, 
cultures, chest x-ray), and anti-microbial therapy. An infection will be considered definite in 
subjects with clinical evidence of infection and a positive culture from a normally sterile source 
(with the exception of spontaneous bacterial peritonitis [SBP] as below). All other infections will 
be considered probable. In subjects with ascitic fluid neutrophils ≥250 cells/mm3, definite SBP 
will be recorded irrespective of culture positivity.
If pneumonia develops during the study, treatment according to the following guidelines is 
recommended:

Community-Acquired Pneumonia: Infectious Diseases Society of America/American 
Thoracic Society Consensus Guidelines (2007) 
(http://cid.oxfordjournals.org/content/44/Supplement_2/S27.full)
The minimum recommended duration of antibiotic treatment is 5 days.

Hospital-Acquired Pneumonia (HAP): Infectious Diseases Society of America/American 
Thoracic Society Consensus Guidelines (2016) 
(http://www.idsociety.org/Guidelines/Patient_Care/IDSA_Practice_Guidelines/Infections_by
_Organ_System/Lower/Upper_Respiratory/Hospital-Acquired_Pneumonia_(HAP)/)
HAP is defined as a pneumonia not incubating at the time of hospital admission and 
occurring ≥48 hours after admission.
The minimum recommended duration of antibiotic treatment is 7 days.

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SBP, UTI, and other infections that develop during the study should be treated according to the 
following guidelines:

SBP: AASLD Practice Guidelines:  Management of Adult Patients with Ascites Due to 
Cirrhosis:  Update 2012.  (http://www.aasld.org/publications/practice-guidelines-
0#practice_guidelines_accordion-block-2). The minimum recommended duration of 
antibiotic treatment is 5 days. Patients with SBP who also have a serum creatinine 
> 1 mg/dL, blood urea nitrogen > 30 mg/dL, or total bilirubin > 4 mg/dL should also receive
1.5 g albumin per kg body weight within 6 hours of detection and 1.0 g/kg 2 days later.

UTI: American Urological Association Adult UTI Guidelines (2016) 
(https://www.auanet.org/education/adult-uti.cfm).  The minimum recommended duration of 
antibiotic treatment is 5 days for uncomplicated UTI, 7 days for uncomplicated UTI in 
patients with diabetes, and 14 days for complicated UTI.

Other infections: Investigator’s discretion.
In subjects with documented infection, interruption of prednisolone should be considered at the 
discretion of the investigator (see Section 7.5: Toxicity Management). GS-4997/placebo does not 
require dose modification in subjects with infection.
6.9.10.
Screening Laboratory Assessments
All samples for laboratory assessments will be sent to the central laboratory with the exception 
of urine samples for urinalysis and culture, blood cultures and urine pregnancy tests which will 
be completed at the site.
The following laboratory tests will be collected at Screening for testing at both the local and 
central laboratories:  urine drug screen, hematology, chemistry, coagulation tests, hepatitis B 
serology, hepatitis C serology, and HIV serology. 
Chest-x-rays and local laboratory testing for Hepatitis B and C and HIV Serology and urine drug 
testing done during the current hospitalization (which includes transfers from other institutions)
and within 10 days of Screening may be used to determine eligibility. A urine pregnancy test 
must be done locally on the day of the Screening visit. An additional set of Screening labs must
be drawn for central laboratory processing.  
However, for hepatitis B serology, hepatitis C serology, and HIV serology, eligibility is 
confirmed based on central laboratory testing. Subjects may be enrolled based on local urine 
pregnancy testing, but serum pregnancy testing via the central laboratory will be the basis for 
final eligibility to continue the subject in the study.  Refer to Section 6.7 for assessments to be 
completed for premature discontinuation from the study.
Specific instructions for processing, labelling, and shipping samples will be provided in a central 
laboratory manual.

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6.9.11.
FibroScan®
Where available, liver stiffness measurement by FibroScan® will be performed at 
Baseline/Day 1, Week 4 and Week 24.  Liver stiffness measurement should not be performed in 
subjects with ascites. At each visit, median liver stiffness (in kilopascals (kPa)), and where 
available, the median Controlled Attenuation Parameter (CAP) value will be recorded.
6.9.12.
Lille Score
The Lille score should be calculated at Day 7 using local laboratory results from Baseline/Day 1 
(albumin, total bilirubin, creatinine, PT) and Week 1 (total bilirubin) for all subjects utilizing the 
following calculator (http://www.mdcalc.com/lille-model-alcoholic-hepatitis/), in appropriate 
units (SI or conventional).  
Prednisolone should be discontinued in subjects with a Lille Score ≥0.56 at Day 7 (null 
response); these subjects may continue GS-4997/placebo treatment.  
For safety monitoring of the stopping criteria of Lille score > 0.85, sites should also collect local 
laboratory results for total bilirubin at Weeks 2, 3, and 4 and use the same calculator to calculate 
the Lille Score compared to baseline values.  When performing the calculation, ensure the Day 7 
total bilirubin is changed to Week 2, 3, and 4 values at the appropriate time points. 
If a subject’s Lille score is > 0.85 at any time, they should stop both study drugs.  If the central 
laboratory Lille score calculation is different from the local laboratory results, the stopping 
criteria will be based on central laboratory results.
6.10.
End of Study Definition
The end of the study will be the last subject’s last observation (or visit).

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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, lack of efficacy, 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 (eg, hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae 

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 
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 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; and 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 (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to 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 (eg, 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 (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
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.
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 and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (eg, 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.

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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, 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, (eg, venipuncture)
7.2.2.
Assessment of Severity  
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 according to the 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, which can be found 
at http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. 
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 case report form (eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30 days after last administration of study IMP must be reported to the eCRF database as 
instructed. During the post-treatment follow-up period (through Week 24), AEs including SAEs 
related to protocol mandated procedures must be collected and reported to the eCRF database.
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.

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Serious Adverse Events
All SAEs including deaths, regardless of cause or relationship, that occurs after the subject first 
consents to participate in the study (ie, signing the informed consent) until 30days after the last 
dose of study IMP must be reported to the eCRF database and Gilead Drug Safety and Public 
Health (DSPH) as instructed. This also includes any SAEs resulting from protocol-associated 
procedures performed after informed consent is signed. During the post-treatment follow-up 
period (through Week 24) any SAEs deemed related to the use of study IMP 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 occured 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 DSPH.

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 DSPH 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, ie, 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 DSPH 
Fax:
+1 (650) 522-5477
E-mail: Safety_FC@gilead.com

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.

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
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 
suspected unexpected serious adverse reactions (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 IEC 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 or IEC 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
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 abnormal laboratory values have 
resolved or returned to baseline levels or they are considered irreversible, or until there is a 
satisfactory explanation for the changes observed.
Administration of all study drugs may be discontinued due to a clinical or laboratory adverse 
event. Subjects are allowed to take one study drug and not the other. 
Prednisolone may be dose-reduced or interrupted at the discretion of the investigator (e.g. due to 
new-onset, severe sepsis or diabetes mellitus that cannot adequately be controlled). Prednisolone 
should be discontinued in subjects with a Lille Score ≥ 0.56 at Day 7 (null responders); these 
subjects may continue GS-4997/placebo treatment. Except in Lille Score null responders, 
restarting prednisolone may be considered if the reason for interruption has resolved or become 
adequately controlled in the opinion of the investigator within 7 days of prednisolone 
interruption. Any decision to restart prednisolone must be reviewed with the Medical Monitor. 
There is no option for GS-4997/placebo dose reduction, but GS-4997/placebo may be interrupted 
due to drug-related toxicity (see below). If GS-4997/placebo is interrupted, it may be restarted on 

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a case by case basis if the reason for interruption has resolved or become adequately controlled 
in the opinion of the investigator within 7 days of GS-4997/placebo interruption. Any decision to 
discontinue or restart GS-4997/placebo must be reviewed with the Medical Monitor.
Subjects who meet any of the following criteria must stop GS-4997/placebo

Laboratory Criteria (based on central laboratory data):
Total bilirubin > 3x Baseline/Day 1 or nadir (confirmed by immediate repeat testing)
ALT and/or AST > 5x Baseline/Day 1 (confirmed by immediate repeat testing), unless 
the elevation is thought by the Principal Investigator to be secondary to an etiology other 
than GS-4997-related, drug-induced liver injury (e.g. infection). 
AST and/or ALT >500 U/L should trigger prompt (within 24Ǧ48 hours) evaluation of 
patients for consideration of GS-4997/placebo discontinuation. If patients with AST
and/or ALT >500 U/L are continued on study drug, they must be monitored closely with 
repeat PE and laboratory evaluation at least 3 times per week.

Lille score > 0.85 at any time point (eg, on/after first scheduled post-Baseline/Day 1 visit) 
while on study drug (base on central or local laboratory data)  

Any Grade 3 or higher AE assessed as possibly or likely related to GS-4997
Other than in the case of the liver enzymes noted above, Grade 3 or 4 clinically significant 
laboratory abnormalities should be confirmed by repeat testing as soon as practical to do so
(Medical Monitor needs to be notified), and preferably within 3 calendar days of receipt of the 
original test results.
Clinical events and clinically significant laboratory abnormalities will be graded according to the 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, which can be found 
at http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.
When restarting investigational medicinal product following resolution of the adverse event, the 
investigational medicinal product should be restarted at full dose following discussion with the 
Medical Monitor.
Any questions regarding toxicity management should be directed to the Medical Monitor.
7.5.1.
Assessment of Potential Drug-Induced Liver Injury by an Independent 
Adjudicator
Due to the challenge of recognizing and diagnosing drug-induced liver injury (DILI) in 
subjects with severe hepatic dysfunction (e.g. due to AH), a hepatologist with expertise in AH
and drug-related hepatotoxicity will review potential cases of DILI. Subjects will be categorized 
as those for whom DILI or worsening of hepatic function (treatment failure) attributable to study 

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drug could be excluded (e.g. a clear, alternative explanation exists); those for whom DILI or 
worsening of hepatic function (treatment failure) attributable to study drug could not be excluded 
(e.g. no clear, alternative explanation exists); and those with insufficient data to make a 
determination. 
The following events will be adjudicated:

Total bilirubin > 2 × Baseline/Day 1 or nadir and ALT and/or AST > 3 × Baseline/Day 1 or 
nadir (confirmed by immediate repeat testing)

Total bilirubin > 3 × Baseline/Day 1 or nadir (confirmed by immediate repeat testing)

ALT and/or AST > 5 × Baseline/Day 1 (confirmed by immediate repeat testing)

ALT and/or AST > 500 U/L (confirmed by immediate repeat testing)

Lille score >0.85 at any time point (eg, on/after first scheduled post-Baseline/Day 1 visit) 
while on study drug (base on central or local laboratory data)
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, and pregnancy reports regardless of an 
associated AE.  
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.  

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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 DSPH using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.
Refer to Section 7.4 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
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 (eg, 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 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH 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 DSPH. Gilead DSPH contact information is as follows: Email: 
Safety_FC@gilead.com and Fax: +1 (650) 522-5477. 
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 DSPH using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject 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 DSPH, fax number 
+1 650 522-5477 or email Safety_FC@gilead.com. 
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 DSPH 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. 

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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 7.4 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
The objectives of the study are described in Section 2 of the protocol, and endpoints for the study 
are described below.
8.1.1.
Primary Endpoint
The primary endpoint is the safety of GS-4997 in combination with prednisolone versus 
prednisolone alone in subjects with severe AH. Safety and tolerability will be evaluated by 
examining the incidence of treatment emergent adverse events, including serious adverse events, 
clinical laboratory tests, ECGs, and vital signs. The number and percentage of subjects who 
prematurely discontinue study drug due to adverse events will be provided. Adverse events that 
led to premature study drug discontinuation will be summarized by system organ class and 
preferred term.
8.2.
Secondary Endpoints
Clinical Outcomes:

Number (%) of subjects who die by Study Day 28, Week 8, Week 12, and Week 24

Number (%) of subjects receiving a liver transplant

Number (%) of subjects with HRS

Number (%) of subjects with infection

Length of hospital stay
Measures of Hepatic Synthetic Function:

Change from baseline in liver biochemistry tests (ALT, AST, GGT, alkaline phosphatase, 
bilirubin, albumin and INR) by visit

Lille response (score < 0.45) at Day 7, Lille null response (score ≥ 0.56) at Day 7, Lille score 
at Day 7 as a continuous variable, and combined score including  Lille score at Day 7 and 
baseline MELD score

Change from baseline in prognostic indices (MELD, CPT, and Maddrey’s DF scores) by visit

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variables will be descriptively summarized (n, mean, standard deviation, median, Q1, Q3, 
minimum and maximum).
8.8.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration page of the eCRF. Exposure data will be summarized by treatment group. 
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 
Version 4.03.
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 by 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 (using conventional units) will be summarized using only observed data. 
The value and change from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the grading scheme in the CTCAE 
Version 4.03.
Incidence of treatment-emergent grade 3 or higher laboratory abnormalities, defined as most 
severe grade 3 or higher post-baseline value that has increased by at least one toxicity grade from 
baseline at any time post baseline up to 30 days after the last dose of study drug, will be 
summarized by treatment group. If baseline data are missing, then any graded abnormality (ie, at 
least a Grade 1) will be considered treatment emergent.

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The DMC will also evaluate (based on an unblinded review of safety data) and recommend early 
termination of the trial if there is a > 20% higher percentage of subjects in the 
GS-4997/prednisolone group than in the prednisolone alone group with: 1) Grade 3 or higher, 
treatment-emergent, treatment-related  adverse event(s) of a specific type (excluding evaluation 
of liver function) where GS-4997/Placebo was prematurely withdrawn; 2) death on/prior to 
Study Day 28; 3) Lille score > 0.85 while on study drug; 4) any of the post-baseline 
GS-4997/placebo laboratory stopping criteria (ie, ALT or AST > 500 U/L that led to 
discontinuation of GS-4997/placebo, ALT or AST > 5x Baseline/Day 1 [confirmed on repeat 
testing]; or total bilirubin > 3 x Baseline/Day 1 or nadir [confirmed on repeat testing]).
The DMC will provide recommendations to Gilead on whether the nature, frequency, and 
severity of adverse effects associated with study treatment warrant the early termination of the 
study in the best interest of the participants, whether the study should continue as planned, or the 
study should continue with modifications. The DMC may also provide recommendations as 
needed regarding study design.
The DMC’s specific activities will be defined by a mutually agreed 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 Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 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 and regulatory agency, if required, 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 for any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial 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. 
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 for further details. 
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, ie, 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 (ie, 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. The eCRF should 
be completed in a timely manner to enable the sponsor to perform central monitoring of safety 
data. Subsequent to data entry, a study monitor will perform source data verification within the 
EDC system. Original entries as well as any changes to data fields will be stored in the audit

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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 capture 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 (eg, 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
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug.  This includes acknowledgment of receipt of each shipment of 
study product (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 lot number, date dispensed, subject identifier number, 
subject initials, and the initials of the person dispensing the medication.
At study initiation, the monitor will evaluate the site’s standard operating procedure of 
investigational medicinal product/destruction in order to ensure that it complies with 
Gilead Sciences requirements.  Drug may be returned or destroyed on an ongoing basis during 
the study, if appropriate.  At the end of the study, following final drug inventory reconciliation 
by the monitor, the study site will dispose of and/or destroy all unused investigational medicinal 
product supplies, including empty containers, according to these procedures. If the site cannot 
meet Gilead Science’s requirements for disposal, arrangements will be made between the site 
and Gilead Sciences or its representative for destruction or return of unused investigational 
medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
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 
IRBs/IECs/ECs, 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 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. 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.
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, eg, 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 (including 
electronic medical records, if applicable) 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.
Monitoring and Oversight of Biomarker Specimens
Biomarker research specimens will be tracked in a manner consistent with Good Clinical 
Practice by a quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as adherence to 
authorized use of specimens as specified in this protocol and in the Informed Consent Form.  
9.3.4.
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.
9.3.5.
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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10.
REFERENCES
Adachi E, Koibuchi T, Imai K, Kikuchi T, Shimizu S, Koga M, et al. Hemophagocytic syndrome 
in an acute human immunodeficiency virus infection. Internal medicine (Tokyo, 
Japan) 2013;52 (5):629-32.
Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, Shakil O. Pentoxifylline improves short-
term survival in severe acute alcoholic hepatitis: a double-blind, placebo-
controlled trial. Gastroenterology 2000;119 (6):1637-48.
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 4.
Child-Pugh-Turcotte (CPT) Classification of the severity of cirrhosis

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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. 
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 orchidectomy or has medical documentation of 
permanent male infertility.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
GS-4997 is contraindicated in pregnancy as a malformation effect is suspected, based on 
non-clinical data. In rats and rabbits, GS-4997 administration was associated with effects on 
embryo-fetal development at maternally toxic doses. This included total litter loss, increased 
resorptions and post implantation loss, reduced fetal weights, and visceral and skeletal 
malformations and variations. Embryofetal effects were observed in rats and rabbits at exposures 
(AUC24hr) that were 62- and 12-fold higher, respectively, than the GS-4997 steady state 
exposure in NASH subjects at the maximum human dose of 18 mg once daily. The NOELs for 
embryofetal development in rats and rabbits were 15 and 10 mg/kg/day, respectively. The 
exposure margins at these doses as compared to the maximum proposed human dose are 12 - and 
3-fold, respectively.
Preclinical data indicate that GS-4997 is unlikely to reduce the exposure of hormonal 
contraceptives through induction of human drug metabolizing enzymes or drug transporters. This 
is supported by clinical DDI data, which demonstrated multiple doses of GS-4997 did not result 
in increased activity of CYP3A4 or P-gp based on plasma exposures of sensitive probe substrates 
(midazolam and digoxin). Similarly, preclinical and clinical data indicate GS-4997 is unlikely to 
cause a clinically relevant increase in the exposure of hormonal contraceptives through inhibition 
of drug metabolizing enzymes or drug transporters. Please refer to the latest version of the 
investigator’s brochure for additional information.

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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 Baseline/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 90 days after the last dose of study drug.

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

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Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 90 days after the last dose of study drug.
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 90 days after the last 
dose of study drug. Female partners of male study subjects should consider using one of the 
above methods of contraception as well. 
Male subjects must also refrain from sperm donation during treatment and until at least 90 days 
after the last dose of study drug.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, 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 90 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 must report the information to 
the investigator.  Instructions for reporting pregnancy, partner pregnancy, and pregnancy 
outcome are outlined in Section 7.6.2.1.

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Appendix 4.
Child-Pugh-Turcotte (CPT) Classification of the severity of cirrhosis
POINTS
1
2
3
Encephalopathy
None
Grade 1-2
(medication-controlled)
Grade 3-4
(medication-refractory)
Ascites
None
Mild/Moderate
(diuretic-responsive)
Severe
(diuretic-refractory)
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
Note:  if the either ascites or encephalopathy is “none” because the patient is taking medication which has controlled the 
symptoms, the scoring should be 2 points (not 1 point).
CPT score is obtained by adding the points for each parameter
CPT class is scored as: 
A = 5-6 points
                  
B = 7-9 points
                  
C = 10-15 points