Clinical trial NCT02854631
Conditions: Alcoholic Hepatitis (AH)
Keywords: Cirrhosis Prednisone Jaundice
Sponsor: Gilead Sciences
Start date: 2016-09-01; Completion date: 2018-05-31
Enrollment: 104 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the safety and tolerability of selonsertib (GS-4997) in combination with prednisolone versus prednisolone alone in participants with severe alcoholic hepatitis (AH).

Detailed description:

Arms: arm 1: Selonsertib + prednisolone for 28 days arm 2: Selonsertib placebo + prednisolone for 28 days
Interventions: intervention 1: Selonsertib intervention 2: Prednisolone intervention 3: Placebo
Intervention descriptions: intervention 1: 18 mg tablet administered orally once daily intervention 2: 40 mg (4 x 10 mg tablets) administered orally once daily intervention 3: Selonsertib placebo tablet administered orally once daily

Protocol documents:
SAP_004.pdf: 
Study Title: 
Name of Test Drug: 
Study Number: 
Protocol Version (Date): 
Analysis Type: 
Analysis Plan Version: 
Analysis Plan Date: 
Analysis Plan Author(s): 
(r'J GILEAU 
STATISTICAL ANALYSIS PLAN 
A Phase 2, Double-Blind, Randomized Study Evaluating the 
Safety, Tolerability, and Efficacy ofGS-4997 in Combination 
with Prednisolone versus Prednisolone Alone in Subjects with 
Severe Alcoholic Hepatitis (AH) 
Selonserti.b (ASK1 Inhibitor, fonnerly GS-4997) 
GS-US-416-2124 
Original: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
Final Analysis 
Version 1 
21 May 2018 
PPD 
12 April 2016 
02 June 2016 
11 Januruy 2017 
04 August 2017 
CONFIDENTIAL AND PROPRIETARY INFORMATION 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF TABLES.........................................................................................................................................................4
LIST OF ABBREVIATIONS........................................................................................................................................5
PHARMACOKINETIC ABBREVIATIONS................................................................................................................7
1.
INTRODUCTION ................................................................................................................................................8
1.1.
Study Objectives ......................................................................................................................................8
1.2.
Study Design............................................................................................................................................9
1.3.
Sample Size and Power..........................................................................................................................10
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................11
2.1.
Data Monitoring Committee Analyses...................................................................................................11
2.2.
Internal Administrative Interim Analysis...............................................................................................11
2.3.
Primary Analysis....................................................................................................................................12
2.4.
Final Analysis ........................................................................................................................................12
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................13
3.1.
Analysis Sets..........................................................................................................................................13
3.1.1.
All Randomized Analysis Set...............................................................................................13
3.1.2.
Modified Intent to Treat Analysis Set ..................................................................................13
3.1.3.
Full Analysis Set ..................................................................................................................13
3.1.4.
Safety Analysis Set...............................................................................................................14
3.1.5.
Pharmacokinetic Analysis Set..............................................................................................14
3.1.6.
Pharmacokinetic Substudy Analysis Set ..............................................................................14
3.2.
Subject Grouping ...................................................................................................................................14
3.3.
Strata and Covariates..............................................................................................................................14
3.4.
Examination of Subject Subgroups........................................................................................................15
3.5.
Multiple Comparisons............................................................................................................................16
3.6.
Missing Data and Outliers......................................................................................................................16
3.6.1.
Missing Data ........................................................................................................................16
3.6.2.
Outliers.................................................................................................................................17
3.7.
Data Handling Conventions and Transformations .................................................................................17
3.8.
Analysis Visit Windows.........................................................................................................................18
3.8.1.
Definition of Study Day .......................................................................................................18
3.8.2.
Analysis Visit Windows.......................................................................................................19
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window................................................................................................................................20
4.
SUBJECT DISPOSITION ..................................................................................................................................22
4.1.
Subjects Randomized and Treated and Disposition ...............................................................................22
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................23
4.2.1.
Duration of Exposure to Study Drug....................................................................................23
4.2.2.
Adherence to Study Drug.....................................................................................................24
4.3.
Protocol Deviations................................................................................................................................25
5.
BASELINE CHARACTERISTICS....................................................................................................................26
5.1.
Demographics ........................................................................................................................................26
5.2.
Other Baseline Characteristics ...............................................................................................................26
5.3.
Prior Corticosteroids for Treatment of Alcoholic Hepatitis ...................................................................28
5.4.
Medical History and Baseline Infections ...............................................................................................29


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6.
EFFICACY ANALYSES ...................................................................................................................................30
6.1.
Secondary Efficacy Endpoints: ..............................................................................................................30
6.2.
Analysis Methods for Secondary Efficacy Endpoints............................................................................30
6.2.1.
Death ....................................................................................................................................30
6.2.2.
Liver Transplantation ...........................................................................................................31
6.2.3.
Transplantation-free survival ...............................................................................................31
6.2.4.
Lille score.............................................................................................................................32
6.2.5.
Mortality Risk using Baseline MELD score and Lille Score at Day 7.................................34
6.2.6.
Length of Initial Hospital Stay .............................................................................................35
6.2.7.
Events of Interest..................................................................................................................35
6.2.8.
Liver Biochemistry and Prognostic Indices..........................................................................36
6.3.
Exploratory Efficacy Endpoints.............................................................................................................38
6.4.
Analysis methods for Exploratory Efficacy Endpoints ..........................................................................38
6.5.
Changes to Efficacy Analysis ................................................................................................................39
7.
SAFETY ANALYSES........................................................................................................................................40
7.1.
Adverse Events and Deaths....................................................................................................................40
7.1.1.
Adverse Event Dictionary ....................................................................................................40
7.1.2.
Adverse Event Severity........................................................................................................40
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................40
7.1.4.
Serious Adverse Events........................................................................................................40
7.1.5.
Treatment-Emergent Adverse Events...................................................................................40
7.1.5.1.
Definition of Treatment-Emergent Adverse Events .......................................40
7.1.5.2.
Incomplete Dates ............................................................................................41
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................41
7.1.7.
Analysis of Adverse Events of Interest ................................................................................43
7.2.
Laboratory Evaluations ..........................................................................................................................44
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................45
7.2.2.
Graded Laboratory Values ...................................................................................................46
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities.............................................46
7.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities ...............................46
7.2.2.3.
Summaries of Laboratory Abnormalities........................................................46
7.3.
Body Weight, Height, BMI and Vital Signs...........................................................................................47
7.4.
Prior and Concomitant Medications.......................................................................................................47
7.4.1.
Concomitant Medications.....................................................................................................47
7.4.2.
Concomitant Enteral and Parenteral Nutrition Medications.................................................48
7.5.
Electrocardiogram Results .....................................................................................................................48
7.5.1.
Investigator Electrocardiogram Assessment ........................................................................48
7.6.
Other Safety Measures ...........................................................................................................................48
7.7.
Changes From Protocol-Specified Safety Analyses...............................................................................48
8.
PHARMACOKINETIC ANALYSES ................................................................................................................49
8.1.
PK Sample Collection............................................................................................................................49
8.2.
PK Analyses Related to Intensive PK Sampling....................................................................................49
8.2.1.
Estimation of Pharmacokinetic Parameters..........................................................................49
8.2.2.
Pharmacokinetic Parameters ................................................................................................50
8.3.
PK Analyses Related to Sparse PK Sampling........................................................................................51
9.
REFERENCES ...................................................................................................................................................52
10.
SOFTWARE.......................................................................................................................................................53
11.
SAP REVISION..................................................................................................................................................54
12.
APPENDICES ....................................................................................................................................................55


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Appendix 1.
Table of Contents for Statistical Tables, Figures, and Listings ..............................................56
Appendix 2.
GS-US-416-2124 Programming Specifications......................................................................68
LIST OF TABLES
Table 3-1.
Analysis Visit Windows.........................................................................................................20


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LIST OF ABBREVIATIONS
AE
adverse event
AH
alcoholic hepatitis
ALT
alanine aminotransferase
ASK1
Apoptosis Signal-regulating Kinase 1
AST
aspartate aminotransferase
AUDIT
Alcohol Use Disorders Identification Test
BAP
Biomarker Analysis Plan
bpm
beats per minute
BLQ
below the limit of quantitation
BMI
body mass index
CFR
Code of Federal Regulations
CI
confidence interval
CK-18
cytokeratin-18 fragment level
CPT
Child-Pugh-Turcotte
CSR
clinical study report
CTCAE
Common Toxicity Criteria for Adverse Events
DF
discriminant function
DMC
Data Monitoring Committee
eCRF
electronic case report form
ECG
Electrocardiogram
ELFTM
enhanced liver fibrosis test
ET
early termination
FAS
full analysis set
GGT
gamma-glutamyl transferase
HbA1c
glycated hemoglobin
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HDL
high-density lipoprotein
Hgb
Hemoglobin
HIV
human immunodeficiency virus
HLGT
high-level group term
HLT
high-level term
HRS
hepatorenal syndrome
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
INR
international normalized ratio
IWRS
interactive web response system
LDL
low-density lipoprotein
LLT
lower-level term


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LOCF
last observation carried forward
LOQ
limit of quantitation
LOXL2
serum lysyl-oxidase-like 2
LPS
Lipopolysaccharides
MedDRA
Medical Dictionary for Regulatory Activities
MELD
Model for End-Stage Liver Disease
mITT
modified Intent-to-Treat
mmHg
millimeters of mercury
PK
Pharmacokinetics
PKEX
pharmacokinetics study drug administration page
PLA
Placebo (to match selonsertib)
PRED
Prednisolone
PT
preferred term
Q1, Q3
first quartile, third quartile
QD
once daily
SADQ
Severity of Alcohol Dependence Questionnaire
SAP
statistical analysis plan
SBP
spontaneous bacterial peritonitis
SAE
serious adverse event
SD
standard deviation
SEL
Selonsertib (formerly GS-4997)
SOC
system organ class
SOW
statement of work
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
ULN
upper limit of normal
VLDL
very low-density lipoprotein
WBC
white blood cells
WHO
World Health Organization


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PHARMACOKINETIC ABBREVIATIONS
AUCtau
area under the concentration versus time curve over the dosing interval
Clast
last observed quantifiable concentration of the drug in plasma
Cmax
maximum observed concentration of the drug in plasma
Ctau
observed drug concentration at the end of the dosing interval
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination phase 
of the plasma concentration of drug versus time curve
t1/2
estimate of the terminal elimination half-life of the drug in plasma, calculated by dividing the 
natural log of 2 by the terminal elimination rate constant (λz)
CLss/F
Apparent oral clearance after administration of the drug at steady state:
CLss/F = Dose/AUCtau where “dose” is the dose of the drug (for selonsertib only)


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1. 
INTRODUCTION 
Version 1 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) for the fmal analysis for Study 
GS-US-416-2124 which will be conducted after all subjects complete their Week 24 study visit 
and/or Week 24 subject status fonn or prematurely discontinue from study. This SAP is based on 
Amendment 3 of the study protocol dated 04 August 2017 and the electronic case rep01i fonn 
(eCRF). The SAP will be fmalized before the database is fmalized. Any changes made after the 
finalization of the SAP will be documented in the clinical study rep01t (CSR). 
1.1. 
Study Objectives 
The primary objective of the study is: 
• 
To evaluate the safety and tolerability of selonsettib in combination with prednisolone versus 
prednisolone alone in subjects with severe alcoholic hepatitis (AH) 
The secondaty objectives of the study are: 
• 
To assess changes in hepatic synthetic function (liver biochemistry, Model for End-Stage 
Liver Disease [MELD] score, Child-Pugh-Turcotte [CPT] score, the Lille model, and 
Maddrey's Discriminant Flmction [DF]); 
• 
To assess m01tality at 28 days and at 8, 12, and 24 weeks; 
• 
To detennine the incidence of liver n·ansplantation; 
• 
To detennine the incidence of hepatorenal syndrome (HRS); 
• 
To determine the incidence of infection; 
• 
To assess length of initial hospital stay. 
The explorat01y objectives of the study are as follows: 
I 
I 
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1.2.
Study Design
This is a Phase 2, randomized, double-blind, proof-of-concept study evaluating the safety, 
tolerability, and biological activity of selonsertib in combination with prednisolone versus
prednisolone alone in subjects with severe, histologically-confirmed AH. Subjects are 18 to 
70 years of age, with a history of excessive alcohol consumption (average of > 40 g/day of 
alcohol for women and > 50 g/day of alcohol for men); AST ≥50 and ≤ 400 U/L; ALT 
≤300 U/L; AST/ALT ratio ≥1.5; onset of jaundice within the past 3 months; a screening 
Maddrey DF score ≥ 32 and ≤ 60; and a MELD score ≤ 30. Subjects consented under 
Amendment 1 of the study protocol will qualify for the study and be stratified based on the 
screening MELD score calculated using central laboratory results while all other subjects will 
qualify for the study and be stratified based on the screening MELD score calculated using local 
laboratory results. All analyses of laboratory values for efficacy and safety will be based on 
central laboratory (ie, Covance Laboratories, Inc.) results except for the specific cases for Lille 
and MELD scores described in Section 3.6.1.
Up to 120 subjects will be randomized to obtain 100 subjects with histologically-proven severe 
AH who are evaluable for the Full Analysis Set (FAS). Subjects meeting the study’s entry 
criteria will be randomly assigned within strata (screening MELD < 25 or ≥ 25) to one of the 
following 2 treatment groups in a 1:1 ratio:

Group A (n = 50-60): Selonsertib 18 mg QD + Prednisolone 40 mg QD for 28 days

Group B (n = 50-60): Selonsertib Placebo QD + Prednisolone 40 mg QD for 28 days
The screening and randomization phase will take approximately 2 weeks; and study drugs will 
be administered for a total of 28 days. Subjects will be followed for a total of 24 weeks (ie, 
20 weeks following last dose of study drug); with the exception of subjects who have a biopsy 
that is consistent with an alternative etiology for liver disease; and those with positive serologies 
for HBsAg, HIV, or hepatitis C virus (HCV)—these subjects will be followed to last dose date 
plus 30 days for safety evaluation. Laboratory results (serum chemistry, hematology, coagulation 
tests), calculation of MELD, CPT (includes clinical assessments of hepatic encephalopathy and 
ascites) and Maddrey DF scores, and collection of vital signs, alcohol consumption, and 
concomitant medications and assessment of HRS and infections will be performed at screening, 
Day 1, Weeks 1, 2, 3, 4, 6 and 8 and every 4 weeks thereafter through Week 24. Lille score will 
be calculated at Weeks 1, 2, 3, and 4. Adverse events will be collected through the last dose date 
of any study drug plus 30 days. Serious adverse events (SAEs) not related to study endpoints will 
be collected up to last dose date + 30 days. Adverse events and SAEs related to study endpoints 
(eg, deaths, infections, and HRS) will be collected throughout the study. Insulin, lipid profiles, 
and weight will be collected at screening, baseline, and at Weeks 4, 12, and 24. HbA1c will 
follow the lipid schedule, but will not be collected at screening or Week 4. Investigator 
assessment of 12-lead electrocardiograms (ECG) will be collected at screening, baseline and at 
Weeks 4 and 8. Pregnancy testing for women of childbearing potential will be performed at 
screening (serum), Day 1, and every 4 weeks throughout the study.


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ELF score will be collected at baseline, and at Weeks 4, 12 and 24; and the Alcohol Use 
Disorders Identification Test (AUDIT) and Severity of Alcohol Dependence Questionnaire 
(SADQ) will be administered at screening to detennine levels of alcohol use and dependence on 
alcohol. 
Single PK samples will be collected on Day 1 and at Weeks 1, 2, and 4. Subjects pruiicipating in 
the PK substudy will have a full profile collected between Weeks 1 and 3 of the study. 
1.3. 
Sample Size and Power 
The number of subjects was chosen based on clinical ex 
conce t studies. 
1 PO 
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2.
TYPE OF PLANNED ANALYSIS
2.1.
Data Monitoring Committee Analyses
An independent external Data Monitoring Committee (DMC) that included 2 hepatologists and a 
PhD statistician convened prior to study start, once 20 subjects had completed Study Day 28, and 
every 3 months thereafter to review the progress of the study and perform interim reviews of 
safety data in order to protect subject welfare and preserve study integrity. 
The DMC additionally evaluated trial stopping criteria, based on an unblinded review of safety 
data, and recommend early termination of the trial if there was a > 20% higher percentage of 
subjects in the SEL + PRED group than in the PLA + PRED group with: 1) Grade 3 or higher 
treatment-emergent, treatment-related adverse event(s) of a specified type, excluding evaluation 
of liver function, that led to premature discontinuation of selonsertib/placebo; 2) Death on/prior 
to Study Day 28; 3) Lille score > 0.85 while on study drug; or 4) post-baseline 
selonsertib/placebo laboratory stopping criteria (ie, ALT or AST > 500 U/L, ALT or AST > 5 x 
baseline [confirmed on repeat testing], and/or total bilirubin > 3 x baseline or nadir [confirmed 
on repeat testing]). See Section 7.1.7 of this SAP.
The DMC was to recommend to the sponsor whether the nature, frequency, and severity of 
adverse effects associated with study treatment warranted the early termination of the study in 
the best interests of the participants, whether the study should continue as planned, or whether 
the study should continue with modifications.
The DMC’s roles and responsibilities and the scope of analysis provided to the DMC were
provided in a mutually agreed upon charter, which defined the DMC membership, meeting 
logistics, and meeting frequency. 
2.2.
Internal Administrative Interim Analysis
An administrative interim analysis of efficacy and safety data was performed by the external 
statistician and reviewed by 2 individuals from Gilead. The purpose of this analysis was to assess 
the efficacy and safety of selonsertib + prednisolone in alcoholic hepatitis to support further 
planning and development of selonsertib for this indication. The 2 unblinded individuals from 
Gilead were independent of the GS-US-416-2124 study team and were not directly involved in 
routine study conduct. Individuals from Gilead who were unblinded were documented on an
unblinding form, and the rationale for performing the internal interim analysis was documented 
per Gilead standard operating procedures. The Study Team remained blinded to treatment
assignment until after the primary analysis (ie, all subjects had completed through the later of 
their Week 8 study visit, last dose date plus 30 days, or prematurely terminated from study) 
database had been finalized and the study was unblinded for the primary analysis.


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2.3.
Primary Analysis
The primary analysis was conducted once all subjects completed the later of their safety follow-
up visit 30 days following their last dose of study drug or Week 8 study visit; or they 
prematurely terminated from study. All data collected with onset/visit dates on/prior to
16 February 2018 (the date the last subject completed their Week 8 visit) were included in the 
database snapshot for the primary analysis. All outstanding data queries were resolved or 
adjudicated as unresolvable, and the data was cleaned and finalized. Treatment assignments were 
unblinded and TFLs were displayed by treatment group.
2.4.
Final Analysis
After all subjects complete the study, outstanding data queries will be resolved or adjudicated as 
unresolvable, and the final analysis of the data will be performed.


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GENERAL CONSIDERATIONS FOR DATA ANALYSES 
Version 1 
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD), median, first quartile (Q1), third 
quartile (Q3), minimum, and maximum will be presented. 
All statistical tests PPD 
) will be 
~~~~~~~~----~~~~--~--~----~~--~ 
2-sided and performed at the 5% significance level unless otherwise specified. 
By-subject listings will be presented for all subjects in the Safety Analysis Set unless otherwise 
specified. Listings will be sorted by subject ID number, visit date, and time (if applicable). Data 
collected on log forms, such as AEs, will be presented in chronological order within the subject. 
The treatment group to which subjects were randomized will be used in the listings. Age, sex at 
birth, race, and ethnicity will be included in the listings, as space permits. 
3.1. 
Analysis Sets 
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. Subjects included in each analysis set will be determined before the 
study blind is broken for the primary analysis. The analysis set will be identified and included as 
a subtitle of each table, figure, and listing. 
The number of subjects eligible for each analysis set will be provided by treatment group. 
Subjects who were excluded from the safety/miTT or F AS analysis sets will be summarized or 
provided in a by-subject listing. 
3.1.1. 
All Randomized Analysis Set 
All Randomized Analysis Set includes all subjects who were randomized into the study. 
3.1.2. 
Modified Intent to Treat Analysis Set 
The modified Intent to Treat (miTT) analysis set includes all subjects who were randomized and 
took at least 1 dose of study drug. The miTT analysis set is the same as the safety analysis set 
provided that all subjects receive their assigned treatment. This will be the secondary analysis set 
for efficacy analyses. 
3.1.3. 
Full Analysis Set 
The Full Analysis Set (F AS) includes all subjects who took at least 1 dose of study drug, and had 
histologically-confirmed severe AH. This is the primary analysis set for efficacy analyses. 
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3.1.4. 
Safety Analysis Set 
Version 1 
The Safety Analysis Set includes all subjects who were randomized and took at least 1 dose of 
study drug. This is the primary analysis set for safety analyses. 
3.1.5. 
Pharmacokinetic Analysis Set 
The Pharmacokinetic (PK) Analysis Set will include all randomized subjects who took at least 
1 dose of selonsertib and have at least 1 nonmissing postdose concentration value reported by the 
PK laboratory for selonsertib or the primary metabolite GS-607509. 
3.1.6. 
Pharmacokinetic Substudy Analysis Set 
The PK Substudy Analysis Set will include all randomized subjects who took at least 1 dose of 
selonsertib, participated in the PK substudy, and have at least 1 nonmissing steady state PK 
parameter for selonsertib or the primary metabolite GS-607509. This is the primary analysis set 
for detailed PK analysis that uses intensive PK sampling. 
3.2. 
Subject Grouping 
For analyses based on the miTT and F AS, subjects will be grouped according to the treatment to 
which they were randomized. For analyses based on the Safety Analysis Set, subjects will be 
grouped according to their randomized treatment except when their actual treatment differs from 
randomized treatment for the entire treatment duration. In this case, subjects will be grouped 
based on actual treatment received. 
For the PK Analysis Set, subjects will be grouped according to the actual treatment they 
received. 
3.3. 
Strata and Covariates 
Subjects will be randomly assigned to treatment groups via the interactive web response system 
(IWRS) in a 1:1 ratio using a stratified randomization schedule. Stratification will be based on 
the screening MELD score as follows: 
• 
Screening MELD score < 25 
• 
Screening MELD score 2 25 
Subjects enrolled under Amendment 1 ofthe protocol (eg, Subject IDs PP 
PPD 
and PPD 
will utilize Covance laboratory results £.-or- ca' l'c-uL'l-a-:-t-i_.on of 
screening MELD score; all other subjects will utilize local laboratory results for calculation of 
screening MELD score for the purposes of assignment to randomization stratum. 
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Death by Day 28 and by Week 8 will be summarized by randomization stratum as described in 
Section 3.4.  If there are discrepancies in stratum assignment between the IWRS and the 
calculated value, the stratum assigned based on the database-calculated screening MELD score
(as described above) will be used for analysis.
3.4.
Examination of Subject Subgroups
Death by Day 28 and by Week 8; and Lille score broken into 3 categories (< 0.16 [complete 
responder]; 0.16 to < 0.56 [partial responder]; and ≥ 0.56 [null responder]) at Week 1, Week 2, 
and Week 4 (LOCF) will be explored for the FAS by treatment group for the following baseline 
characteristics:

age (< 50 or ≥ 50 years)

sex (male, female)

race (White, Asian, other)

baseline total bilirubin (< 14 mg/dL, ≥ 14 mg/dL)

baseline prothrombin time (< 16.3 secs, ≥ 16.3 secs)

baseline Maddrey’s DF (< 38, ≥ 38)

baseline albumin (< 3.0 mg/dL, ≥ 3.0 mg/dL)

baseline creatinine (< 0.75 mg/dL, ≥ 0.75 mg/dL)

baseline CPT (scores < 10 [Class A and B], ≥ 10 [Class C])

baseline infection (yes or no)

baseline sodium (< 135 µmol/L, ≥ 135 µmol/L)

baseline MELD (< 21 or ≥ 21)

baseline platelets (≤ 100 ×103/µL, > 100 ×103/µL)

baseline ascites (none, any)

baseline hepatic encephalopathy (none, any)

baseline cirrhosis (no, yes, unknown)


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Cinhosis will be detennined from the liver biopsy eCRF, and will be defmed as a Meta vir score 
ofF4 or an Ishak score ofF5 or F6. If no fibrosis staging was perfmmed, cinhosis status will be 
unknown. 
Death by Study Day 28 and by Week 8 will also be explored by the following 2 postbaseline 
characteristics by treatment group: 
• 
randomization stratum (screening MELD < 25 and ;:: 25) 
• 
Lille score broken into 3 categories(< 0.16 [complete responder]; 0.16 to < 0.56 [partial 
responder]; and ~ 0.56 [null responder]) at Week 1. Subjects with missing Lille score values 
at Week 1 will be considered to be null responders. 
3.5. 
Multiple Comparisons 
PPD 
I 
3.6. 
Missing Data and Outliers 
3.6.1. 
Missing Data 
In general, missing data will not be imputed unless methods for handling missing data are 
specified, except for the cases described below. 
For subjects who are missing a baseline central laboratmy-calculated MELD score, the subject's 
screening locallaboratmy-calculated MELD score used to assess inclusion and exclusion criteria 
and to stratify the subject for randomization will be used in place of the missing central 
laboratmy-calculated baseline MELD score. 
For Lille scores, if the Week 1 Lille score for an individual subject cannot be calculated using 
centrallaboratmy data and a Week 1 Lille score using locallaboratmy data is available, then 
Lille scores for that subject will be calculated using local laboratmy data for all Lille score 
timepoints (eg, at Weeks 1, 2, 3, and 4). If both central and locallaboratmy Week 1 Lille scores 
are not calculable, then central laboratmy data will be used to calculate Lille scores for all visits. 
Individual subjects for whom the above imputationmles will be applied will be outlined in the 
Programming and Analysis Specifications (Appendix 2 of this SAP), along with the reason for 
their imputation. 
For subjects missing a last dose date of study dmg, imputation mles are described in 
Section 4.2.1. The handling of missing or incomplete dates for AE onset is described in 
Section 7.1.5.2, and for missing start dates for prior and concomitant medications in Section 7.4. 
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3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process. All data, 
including outliers, will be included in analyses.
3.7.
Data Handling Conventions and Transformations
In general, age (in years) on the date of the first dose of study drug will be used for analysis and 
presentation in listings. If a randomized subject was not dosed with any study drug, the baseline 
assessment date will be used for calculating age. For screen failures, date informed consent was 
signed will be used for calculating age. If only birth year is collected on the eCRF, “01 July” will 
be used for the unknown birth day and month for the purpose of age calculation, unless age is 
captured on the CRF. If only birth month and year are collected on the eCRF, “01” will be used 
for the unknown birth date for the purpose of age calculations unless age is captured on the 
eCRF.
Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ)
or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used for calculation of descriptive statistics if 
the datum is reported in the form of “x” (where x is considered the LOQ). For example, if 
the values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used for 
calculation of summary statistics. An exception to this rule is any value reported as < 1 or 
<0.1, etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used 
for calculation of summary statistics.

A value that is 1 unit above the LOQ will be used for calculation of descriptive statistics if 
the datum is reported in the form of “> x” (where x is considered the LOQ). Values with 
decimal points will follow the same logic as above.

The LOQ will be used for calculation of descriptive statistics if the datum is reported in the 
form of “≤ x” or “≥ x” (where x is considered the LOQ).
If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data or nonparametric analysis methods may be used, 
as appropriate.
Natural logarithm transformation will be used for plasma concentrations and analysis of PK 
parameters. Plasma concentration values that are below the limit of quantitation (BLQ) will be 
presented as “BLQ” in the concentration data listing. Values that are BLQ will be treated as 0 at 
predose time points, and one-half the value of the lower LOQ (LLOQ) at postbaseline time 
points, where LLOQ is corrected for the dilution factor (ie, reported LLOQ/dilution factor) for 
determination of summary and order statistics.


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The following conventions will be used for the presentation of summary and order statistics:

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as “BLQ.”

If more than 25% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ.”

If more than 50% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ.”

If more than 75% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.”

If all subjects have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”
3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day will be calculated from the date of first dose of selonsertib/placebo (SEL/PLA) study 
drug as follows:

For postdose study days: Assessment Date – First Dose Date SEL/PLA + 1

For days prior to the first dose: Assessment Date – First Dosing Date SEL/PLA
Therefore, study day 1 is the day of first dose of SEL/PLA study drug administration.
In the event that SEL/PLA and prednisolone (PRED) study drug were not started on the same 
date, the date of first dose of SEL/PLA will be used as the date of first dose of study drug since 
subjects are allowed (per protocol Amendment 2) to take “pre-doses” of commercial 
prednisolone for up to 3 days prior to starting study drug.
The last dosing date for an individual study drug (ie, SEL/PLA or PRED) will be the end date 
recorded for that study drug on the study drug administration eCRF where the “subject 
permanently discontinued” flag is marked ‘Yes’. The last dosing date for any study drug will be 
the maximum of the last dosing dates for SEL/PLA and PRED.


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Ifthe last dosing date of SELIPLA or PRED is missing or incomplete, the date of last dose will 
be estimated using the maximum ofnonmissing study drug start or stop dates (for the study drug 
of interest), visit dates, and laboratory collection dates (posttreatment visits and unscheduled 
visits are not included). 
3.8.2. 
Analysis Visit Windows 
Subject visits might not occur on protocol-specified days. Therefore, for purposes of analysis, 
observations will be assigned to visit windows. 
In general, the baseline value will be the last nonmissing value on or prior to the first dose date 
of SELIPLA study drug. When the Screening and Day 1 visits are conducted on the same date, 
the later time value for Covance laboratory values should be used for purposes of analysis since 
the date/time is prior to first dose date/time from the pharmacokinetic study drug administration 
(?KEX eCRF for all 4 subjects ( eg, Subject IDs PPO 
PO 
PPD 
and 
p 
Analysis windows for efficacy measures of hepatic synthetic function (ie, ALT, AST, GGT, 
alkaline phosphatase, total bilirubin, direct bilirubin, albumin, INR, MELD, CPT, and Maddrey's 
DF), Lille score and recidivism to alcohol are displayed in column 2 of Table 3-1. 
The analysis visit windows for liver fibrosis markers (ie, ELF score and its components) are 
displayed in the third column of Table 3-1. 
The analysis visit windows for safety laboratory tests and vital signs will include laboratory 
values collected up to last dose date of any study drug + 7 days for "on-treatment" visit windows. 
Values that are collected 2 8 days after the last dose date of study regimen will be assigned to 
follow up visits, where FU day is defined as: 
FU Day= Laboratory assessment date - Last Dose Date of Any Study Drug 
For analyses of laboratory parameters that are both efficacy and safety variables (eg, hepatic 
synthetic function tests, and HbA1c), absolute value and change from baseline visit windows 
will be calculated from Study Day 1; while toxicity grading summaries will utilize safety 
analysis visit windows. 
For all safety analyses related to laboratory toxicity grading, laboratory data collected up to 
30 days after the date of last dose of any study drug will be included. 
Visit windows for safety laboratory tests are displayed in the fourth column of Table 3-1. 
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Table 3-1.
Analysis Visit Windows
Analysis Visit
Visit Windows for
Hepatic Synthetic Function, 
Lille Scores, and 
Recidivism to Alcohol
Visit Windows 
for Liver 
Fibrosis Markers
Visit Windows for 
Vital Signs and Safety 
Laboratory tests 
(Hematology, Chemistry,
Coagulation, and Lipids)
Baseline
Study  Day ≤ 1
Study  Day ≤ 1
Study  Day ≤ 1
Week 1
2 ≤ Study Day ≤ 10
N/A
2 ≤ Study Day ≤ 10
Week 2
11 ≤ Study Day ≤ 17
N/A
11 ≤ Study Day ≤ 17
Week 3
18 ≤ Study Day ≤ 24
N/A
18 ≤ Study Day ≤ 24
Week 4
25 ≤ Study Day ≤ 34
2 ≤ Study Day ≤ 55
25 ≤ Study Day ≤ 38
Week 6
35 ≤ Study Day ≤ 48
N/A
N/A
Week 8
49 ≤ Study Day ≤ 69
N/A
N/A
Week 12
70 ≤ Study Day ≤ 97
56 ≤ Study Day ≤ 125
N/A
Week 16
98 ≤ Study Day ≤ 125
N/A
N/A
Week 20
126 ≤ Study Day ≤ 153
N/A
N/A
Week 24
Study Day ≥ 154
Study Day ≥ 126
N/A
FU Week 2
N/A
N/A
8 ≤ FU Day ≤ 20
FU Week 4
N/A
N/A
21 ≤ FU Day ≤ 30
Note: Hepatic Synthetic Function includes: ALT, AST, GGT, alkaline phosphatase, total bilirubin, direct bilirubin, albumin, INR, 
MELD score, CPT score, and Maddrey’s DF. Lille scores will only be calculated at Weeks 1, 2, 3 and 4.
Investigator assessment of 12-lead ECG, screening lab tests, and pregnancy tests (for women of 
child-bearing potential) will be listed using the nominal visit. For shift tables of investigator 
assessment of the 12-lead ECG, if the baseline/Day 1 visit is missing, the screening value may be 
used in place of the baseline value. If Week 4 visit is missing, the early study drug 
discontinuation visit may be used in place of Week 4.
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window.
If multiple, valid nonmissing, continuous measurements exist in an analysis window, records 
will be chosen based on the following rules if a single value is needed:

In general, the baseline value will be the last nonmissing value on or prior to the first dosing 
date of study drug, unless specified differently. If multiple measurements occur on the same 
day, the last nonmissing value prior to the time of first dosing of study drug will be 


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considered as the baseline value (ie, for Covance laboratory values). For measurements taken 
on the same date with visit names of screening and baseline (ie, for vital signs and ECGs), 
the baseline visit value will be utilized if available. If multiple measurements occur at the 
same time, the average of these measurements (for continuous data) will be considered the 
baseline value.

For postbaseline visits:
The record closest to the nominal day (nominal day for Week X = (X×7) day) for that 
visit will be selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken, unless 
otherwise specified.
If multiple, valid nonmissing, categorical measurements exist in an analysis window, records 
will be chosen based on the following rules if a single value is needed:

For baseline, the last available record on or prior to the date of the first dose of study drug
will be selected. If there are multiple records with the same time or no time recorded on the 
same day, the value with the lowest severity will be selected (eg, normal will be selected over 
abnormal for safety electrocardiogram [ECG] findings).

For postbaseline visits, if there are multiple records with the same time or no time recorded 
on the same day, the value with the worst severity within the window will be selected (eg, 
abnormal will be selected over normal for safety ECG findings).


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4. 
SUBJECT DISPOSITION 
4.1. 
Subjects Randomized and Treated and Disposition 
Version 1 
A summary of subjects randomized and treated will be provided by treatment group and overall 
for each investigator within a country. The summary will present the number and percentage of 
subjects in the Safety Analysis Set. 
A similar table will be provided by treatment group and randomization stratum. Subjects with a 
discrepancy in the MELD stratum ( < 25 and ~ 25) assignment in IWRS and the stratum assigned 
based on the screening clinical database-calculated MELD score will use the stratum assignment 
from the clinical database. Covance test results were used to calculate MELD scores at the 
screening visit for Subject IDs PPD 
and PPD 
(enrolled under protocol 
Amendment 1 ); and local laboratory tests results were used to calculate screening MELD scores 
for all other subjects. Subject ID PD 
enrolled under Amendment 1 but used local lab 
results to assess entry criteria (this was a protocol violation). A listing of subjects with 
discrepancies in stratification assignment between IWRS and the clinical database at the time of 
data finalization will be provided. 
The randomization schedule used for the study will be provided as a listing. 
A summary of subject disposition will be provided by treatment group and overall. Study drug 
completion will be summarized separately for each of the 2 study drugs in the regimen. This 
summary will present the number of subjects screened (overall), the number of subjects 
randomized, and the number of subjects in each of the categories listed below. 
• 
Safety Analysis Set I miTT (ie, randomized and treated) 
• 
F AS (ie, randomized and treated with biopsy-proven severe AH) 
• 
PK Analysis Set 
• 
PK Substudy Analysis Set 
• 
Completed Selonsertib/Placebo 
• 
Did not complete Selonsertib/Placebo with reasons for premature discontinuation of 
Selonsertib/Placebo 
• 
Completed Prednisolone 
• 
Did not complete Prednisolone with reasons for premature discontinuation of Prednisolone 
• 
Continuing study (if applicable) 
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• 
Completed study 
• 
Did not complete the study with reasons for premature discontinuation of study 
Version 1 
For the status of study drug completion (for each of the 2 drugs) and study completion and 
reasons for premature discontinuation, the number and percentage of subjects in each category 
will be provided. The denominator for the percentage calculation will be the total number of 
subjects in the Safety Analysis Set. 
The following by-subject listings will be provided by subject identification (ID) number in 
ascending order to support the above summary tables: 
• 
Subject disposition 
• 
Reasons for screen failure (will be provided by screening ID number in ascending order) for 
subjects screened but not randomized to study drug 
• 
Lot number and carton (prednisolone) or bottle (selonsertib/placebo) ID 
4.2. 
Extent of Study Drug Exposure and Adherence 
Extent of exposure to each of the individual study drugs will be examined by assessing the total 
duration and the level of adherence to each of the study drugs. The percentage of subjects with 
2:' 80% adherence to both drugs in the regimen will be presented. 
4.2.1. 
Duration of Exposure to Study Drug 
Total duration of exposure for each individual study drug will be defined as last dosing date of 
individual study drug minus first dosing date of individual study drug plus 1, regardless of any 
temporary interruptions in study drug administration, and will be expressed in days. Days on 
study regimen will be the number of days that the subject was on both drugs simultaneously (ie, 
minimum of end dates for each of the drugs minus the start date of selonsertib/placebo plus 1). If 
the last study drug dosing date is missing for an individual study drug, the latest of all study drug 
end dates for that study drug, clinical visit date, laboratory sample collection date, or vital signs 
assessment date that occurred during the on-treatment period will be used. For subjects with only 
the month and year of last dose date, the last dose date will be set to the last day of the month 
( eg, Subject ID PD 
....._ ____ _, 
The total duration of exposure to each individual study drug and for taking both study drugs in 
the regimen will be summarized using descriptive statistics and using the number (ie, cumulative 
counts) and percentage of subjects exposed through the following time periods: Baseline 
(Day 1 ), Week 1 (Day 7), Week 2 (Day 14 ), Week 3 (Day 21 ), and Week 4 (Day 28). A 3 day 
window (ie, ~ 25 days) will be used for the Week 4 category. Summaries will be provided by 
treatment group for the Safety Analysis Set. 
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4.2.2. 
Adherence to Study Drug 
Version 1 
The level of protocol defined adherence to each of the 2 study drugs will be determined by the 
total amount of study drug administered relative to the total amount of study drug expected to be 
administered based on what is specified in the protocol. 
The level of adherence will be expressed as a percentage using the following formula: 
\.At- reatment 1""\! erence 1o1 = 
x 
r>- T 
Adh 
(0 1 \ 
( 
Total Amount of Study Thug Administered 
J 100 
Study Thug Expected to be Administered on Treatment 
Total amount of study drug administered will be the total number of pills dispensed minus the 
total number of pills returned. If a bottle (selonsertib/placebo) or carton (prednisolone) of study 
drug is not returned, the subject will be assumed to have not taken the pills. 
Subjects are expected to take 28 tablets containing SEL (18 mg)/PLA and 112 tablets containing 
10 mg of PRED; unless the subject is prematurely terminated from study drug due to death, lack 
of efficacy (meeting Lille score criteria [ie, ?: 0.56 at Week 1 for prednisolone; or > 0.85 at 
Weeks 1, 2, 3, or 4 for both study drugs]), or does not have biopsy-proven severe AH on biopsy 
(ie, variable SDRGREAS_STD equal to 'PW', 'PV', 'LE, or 'DT' on the study drug completion 
eCRF for an individual study drug and subject). Subjects who were transplanted while on study 
drug ( eg, Subject ID PPD 
should also only have adherence calculated to their last dose 
date of study drug. Note that no subjects in the study had positive results for HBsAg, HCV RNA 
or HIV-1/HIV-2 per central laboratory assessment which was also a criteria for calculating 
adherence to last dose date. Subjects who do not complete individual study drug for the reasons 
for premature discontinuation mentioned above--as recorded on the study drug completion form, 
will have adherence for that study drug calculated to last dose date of individual study drug. 
In addition, subjects meeting individual SELIPLA subject stopping criteria for the study (eg, 
Grade 3 or higher treatment-emergent AE that is considered to be related to study drug and 
results in premature discontinuation ofSELIPLA, confirmed ALT or AST > 5 x baseline, 
confirmed total bilirubin > 3 x baseline or nadir, or ALT or AST > 500 U/L) who prematurely 
discontinued SELIPLA will have adherence for SELIPLA calculated to their last dose date of 
SELIPLA (ie, Subject ID PPD 
for confirmed ALT > 5 x baseline) . 
Descriptive statistics for the level of on-treatment adherence to each of the 2 study drugs will be 
provided by treatment group for the Safety Analysis Set. The number (%) of subjects who are 
?: 80% compliant to each of the 2 study drugs will be presented. 
A separate by-subject listing of study drug administration and study drug accountability will be 
provided by subject ID number (in ascending order) and visit (in chronological order). 
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4.3. 
Protocol Deviations 
Version 1 
Subjects who did not meet the eligibility criteria for study entry, but were randomized into the 
study will be summarized regardless of whether they were exempted by the sponsor or not. The 
summary will present the number and percentage of subjects who did not meet at least 
1 eligibility criterion and the number of subjects who did not meet specific criteria by treatment 
group based on the Safety Analysis Set. A by-subject listing will be provided for those subjects 
who did not meet at least 1 eligibility (inclusion or exclusion) criterion. The listing will present 
the eligibility criterion (or criteria if more than 1 deviation) that the subject did not meet. 
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. The number and percentage of subjects with important protocol deviations by 
deviation reason (eg, nonadherence to study drug, violation of select inclusion/exclusion criteria) 
will be summarized by treatment group for the Safety Analysis Set. A by-subject listing will be 
provided for those subjects with any protocol deviation. 
The last chronologie screening laboratory result from Covance and the screening value from 
the local laboratory for AST (U/L), ALT (U/L), AST/ALTratio, total bilirubin (mg/dL), 
serum creatinine (mg/dL), INR, prothrombin time (PT) in seconds, PT control (seconds), 
calculated MELD, calculated Maddrey DF, and serology testing (HbsAg, HCV Ab, HCV RNA, 
HIV -112 Ab) will be provided. Subject IDs PO 
and PPD 
used central 
laboratory values to determine eligibility (under 2rotocol Amendment 1) while all other subjects 
utilized local laboratory values. Subject ID PO 
enrolled under Amendment 1 and was 
assessed for eligibility using local labs (protocol violation). 
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5.
BASELINE CHARACTERISTICS
5.1.
Demographics
Subject demographic variables (ie, age, sex, race, and ethnicity) will be summarized by treatment 
group and overall using descriptive statistics for age, and using number and percentage of 
subjects for age (< 50, ≥50 years), sex, race, and ethnicity. Age at baseline is calculated in years 
at the first dosing date of study drug. If a subject did not receive study drug after randomization, 
the subject’s age will be calculated from the baseline assessment date. For screen failures, age 
will be calculated from the date of informed consent. The summary of demographic data will be 
provided for the Safety Analysis Set and for the Full Analysis Set.
A by-subject demographic listing, including the date of informed consent, will be provided by 
subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Prior alcohol consumption (g/day) before acute AH event, weight (kg), height (cm), and BMI 
(kg/m2) as a continuous and categorical (< 25, 25 to < 30 and ≥ 30 kg/m2) variable will be 
summarized separately by treatment group and sex and sex overall.
Baseline characteristics for the study will include the following:

Baseline height (cm)

Baseline weight (kg) 

Baseline BMI (kg/m2) 

Baseline BMI (< 25, 25 to < 30 and ≥ 30 kg/m2)

Prior alcohol consumption (g/day) before the acute AH event

Alcohol Use Disorders Identification Test (AUDIT) as a continuous variable

AUDIT as a categorical variable (< 8 [does not meet criteria]; ≥ 8 and <13 for women or 
<15 for men [harmful or hazardous drinking];  ≥ 13 for women, ≥ 15 for men [alcohol 
dependence])

Severity of Alcohol Dependence Questionnaire (SADQ) as a continuous variable

SADQ as a categorical variable (<16 [mild physical dependency]; 16-30 [moderate 
dependence]; ≥ 31 [severe alcohol dependence])

Method of liver biopsy (percutaneous, transjugular, missing)


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
Biopsy consistent with AH diagnosis (yes, no)

Fibrosis assessment method (Metavir-equivalent, Ishak, Not Available)

Fibrosis score as a subcategory to the fibrosis method (ie, Metavir-equivalent [F0, F1-F2, F3, 
F4] or Ishak [F0, F1-F2, F3-F4, and F5-F6]) 

Baseline ascites (none, mild/moderate [or diuretic responsive], severe [or diuretic refractory])

Baseline hepatic encephalopathy (none, grade 1-2 [medication controlled], grade 3-4 
[medication refractory])

Hospitalized at screening (yes, no) 

Days hospitalized prior to first dose date. Calculated as: (minimum of [date of first dose of 
study drug, date of release] – hospital admission date) +1 for subjects hospitalized at 
screening

Baseline pyrexia (baseline temperature ≥ 38° C, ≥ 100.4° F [yes] or < 38° C, < 100.4 ° F
[no])

Baseline infection (yes, no) as recorded on the medical history eCRF. 

Treatment for baseline infection (yes, no) as recorded on the medical history eCRF

Evidence of baseline infection on chest X-ray (yes, no)

Baseline MELD score (as a continuous variable)

Baseline CPT score (as a continuous variable)

Baseline CPT class (A [scores of 5-6], B [scores of 7-9], C [scores of 10-15])

Baseline Maddrey DF score (as a continuous variable)

Baseline AST (U/L)

Baseline ALT (U/L)

Baseline AST/ALT Ratio

Baseline total bilirubin (mg/dL)

Baseline direct bilirubin (mg/dL)

Baseline GGT (U/L)


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
Baseline albumin (g/dL)

Baseline alkaline phosphatase (U/L)

Baseline INR

Baseline serum creatinine (mg/dL)
Alcohol Consumption Level and Alcohol Dependence
The Alcohol Use Disorders Identification Test (AUDIT) is a screening tool developed by the 
World Health Organization (WHO) to assess alcohol consumption, drinking behaviors, and 
alcohol-related problems. AUDIT is comprised of 10 questions, with scores for each question 
ranging from 0 to 4. The total score (sum of a subject’s scores across each of the 10 individual 
questions) for AUDIT will be summarized as a continuous variable and for the categories: 
< 8 (does not meet criteria); ≥ 8 and <13 for women or <15 for men (harmful or hazardous 
drinking) or ≥ 13 for women, ≥ 15 for men (alcohol dependence).
The Severity of Alcohol Dependence Questionnaire (SADQ) is a short, self-administered, 
20-item questionnaire developed by the Addiction Research Unit at the Maudsley Hospital 
to measure severity of dependence on alcohol. Each question is assigned a score based on the 
subjects response (0 [almost never/not at all], 1 [sometimes/slightly], 2 [often/moderately], or 
3 [nearly always/quite a lot]). Total score (sum of scores for the subject across the 20 questions) 
for SADQ will be summarized as a continuous variable and for the categories: <16 (mild 
physical dependency); 16-30 (moderate dependence); ≥ 31 (severe alcohol dependence).
Formulas for MELD, CPT, and Maddrey’s DF
Clinical assessments for ascites and hepatic encephalopathy (to calculate CPT scores) and the 
Covance laboratory collection dates for each laboratory test required for MELD and CPT scores 
are recorded on the CPC_MELD eCRF. Formulas for calculation of MELD score, CPT score, 
and Maddrey’s DF are described in Section 6.2.8 of this SAP.
Baseline disease characteristics will be summarized by treatment group and overall using 
descriptive statistics for continuous variables and using number and percentage of subjects for 
categorical variables. Summaries of baseline characteristics will be provided for the Safety 
Analysis Set and Full Analysis Set. 
No formal statistical testing is planned.
A by-subject listing of baseline characteristics will be provided by subject ID in ascending order.
5.3.
Prior Corticosteroids for Treatment of Alcoholic Hepatitis
Corticosteroids could be administered for  ≤ 3 days prior to starting study drug per protocol. 
Medications with ATC class level 2 = “Corticosteroids for systemic use”  that started on Study 


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Days -3, -2, or -1 and stopped on Study Day -1 or 1 will be included. Subject ID P 
L...---,----' 
started Urbason on Study Day -7 (protocol violation) and is included in the listing and summary 
table. The indication for the drug entered on the CM eCRF will be checked to ensure that it is 
consistent with administration for an indication of alcoholic hepatitis. Corticosteroids used to 
treat alcoholic hepatitis prior to starting study drug will be summarized by preferred drug name. 
Prior corticosteroid medications used to treat AH will be provided in a by-subject listing sorted 
by subject ID number and administration date in chronological order. 
5.4. 
Medical History and Baseline Infections 
General medical history data will be collected at screening and listed only. General medical 
history data will not be coded. Subjects with baseline infections will have a checkbox 
marked on the MH eCRF to denote baseline infection events, and baseline infections will be 
listed separately. Results from cultures, x-rays, and ascitic fluid neutrophil cell counts (ie, 
> 250 cells/mm3) for spontaneous bacterial peritonitis (SBP) confirming reported infections 
during the screening period will be included on this listing. 
Prior medications that were used to treat baseline infections will be identified as drugs with a 
pull down indication of "infection" on the CM eCRF. Medications with an end date prior to 
screening date or a start date that is after the first dosing date of SEU PLA will be excluded. 
Listings will be provided for chest X-rays, and liver imaging performed at the screening visit. 
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6.
EFFICACY ANALYSES
The primary efficacy analysis will include subjects in the FAS. A secondary analysis of efficacy 
will include subjects in the mITT analysis set. Subjects who receive a liver transplantation while 
enrolled in the study will have measurements collected up to the time of liver transplantation 
included in efficacy analyses; data collected after transplantation will be excluded from efficacy 
analyses.
6.1.
Secondary Efficacy Endpoints:

Number (%) of subjects who die by Study Day 28 and by Weeks 8, 12, and 24

Number (%) of subjects receiving a liver transplant by Study Day 28 and by Weeks 8, 12, 
and 24

Summary of Lille score by visit through Week 4

Number (%) of subjects with Lille response (score < 0.45) at Day 7 (eg, Week 1)

Number (%) of subjects with Lille null response (score ≥ 0.56) at Day 7 (eg, Week 1)

Mortality Risk at Months 2 and 6 based on Lille score response at Day 7 (eg, Week 1) and 
the baseline MELD score (continuous)

Number (%) of subjects with infection while on study

Number (%) of subjects with HRS while on study 

Length of initial hospital stay

Change from baseline in liver biochemistry tests (ALT, AST, GGT, albumin, alkaline 
phosphatase, total bilirubin, direct bilirubin, and INR) by analysis visit through Week 24

Change from baseline in prognostic indices (MELD, CPT, and Maddrey’s DF) by analysis 
visit through Week 24
6.2.
Analysis Methods for Secondary Efficacy Endpoints
6.2.1.
Death
The number (%) of subjects with a death by Study Day 28, and by Weeks 8, 12, and 24 will be 
displayed by treatment group. For the endpoint death by Day 28, subjects who die on/prior to 
Study Day 28 or are known to be alive through Study Day 28 will be included in the 
denominator for calculation of percentage of subjects with death. Subjects not followed through 
Day 28 will be summarized by their reason for premature discontinuation from study. A 2-sided 


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Fisher’s exact test will be used to explore whether there are differences between treatment 
groups in percentage of subjects with death by Day 28. Deaths by Weeks 8, 12, and 24 will be 
summarized in the same manner as deaths by Study Day 28. Kaplan-Meier estimates of survival 
and the 95% CI (based on Greenwood’s formula and the log-log transformation of the survival 
function) will also be presented at each timepoint. A Kaplan-Meier figure for survival will be 
displayed. Deaths will be recorded on the Death and/or survival status eCRF and the date of last 
subject follow-up will be determined from the maximum of eCRF visit dates (including subject 
survival status visit dates), and Covance laboratory collection dates.
A listing of subject deaths while on study will be provided for the mITT analysis set; subjects 
included in the FAS will be flagged. Days from first dose of study drug (ie, Study Day) and days 
from last dose of study drug (ie, Follow-up Day) for subjects for whom death occurs after 
stopping study drug, will be provided in the listing.
6.2.2.
Liver Transplantation
The number (%) of subjects with liver transplantation by Study Day 28, and by Weeks 8, 12, and 
24 will be displayed by treatment group. For the endpoint liver transplantation by Day 28, 
subjects undergoing liver transplantation by Study Day 28 or who are known to still be on study
through Day 28 will be included in the denominator for calculation of percentage of subjects 
with liver transplantation. Subjects not followed through Day 28 will be summarized by their 
reason for premature discontinuation from study. Liver transplantation by Weeks 8, 12, and 24
will be summarized in a similar manner. Liver transplants will be recorded on the survival status 
eCRF.
A listing of liver transplants while on study will be provided for the mITT analysis set; subjects 
included in the FAS will be flagged. Days from first dose of study drug (ie, Study Day) and days 
from last dose of study drug (ie, Follow-up Day) for those transplanted after stopping study drug 
will be provided in the listing.
6.2.3.
Transplantation-free survival
Time up to the first liver transplant or death event (in days) will be calculated as:
(first of date of liver transplant/death – randomization date + 1)
Data from surviving subjects with no transplant will be censored at the last date that the subject 
is known to be alive and transplant-free (maximum of central laboratory dates and eCRF 
[including survival status] visit dates). 


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In the following SAS code, Days is the number of days from randomization date to the first 
death/liver transplant or to the date of last study visit if no death or liver transplant has been 
observed. Status is a binary variable with 1 representing no death and no transplant observed and 
0 representing that there is a death or transplant that has been observed.
proc lifetest data=txfs_2groups timelist= 28 56 84 168 conftype=loglog alpha=0.05 ;
      Time Days*Status(1);
      Strata = trtgrp;
run;
For each treatment group, the Kaplan-Meier (KM) estimates of transplant-free survival at Day 
28, and at Weeks 8, 12, and 24 and the 95% CI will be provided. The 95% CI will be calculated 
based on Greenwood’s formula and log-log transformation of the survival function.
A figure of the KM curve for transplant-free survival will be provided.
The median, Q1 and Q3 of the transplant-free survival will be provided for each treatment group. 
The 95% CI for median transplant-free survival is based on Brookmeyer-Crowley method of 
inverting a generalization of the sign test for censored data will also be provided for each 
treatment group.
6.2.4.
Lille score
The Lille score is a tool that has historically been used to predict which subjects with severe AH 
(eg, screening Maddrey DF score ≥ 32) are not responding to corticosteroid therapy; usually after
Study Day 7, and are potential candidates for alternative therapies {Louvet 2007}. The Lille 
score is calculated using baseline factors: age, albumin, total bilirubin, serum creatinine, 
prothrombin time; and the change in total bilirubin between baseline and Day 7 according to the 
following formula:
Lille score  = Exp(-R)/[1+exp(-R)], where
R = (3.19 – (0.101 × age [yrs]) + (1.47 × BL albumin [g/dL]) + 
       (0.28215 × (BL total bilirubin [mg/dL] – Day 7 total bilirubin [mg/dL]))  –
       (0.206 × RENAL INSUFFICIENCY) - (0.11115 × BL total bilirubin [mg/dL])  –
       (0.0096 × BL prothrombin time  [seconds])
Renal insufficiency is rated 0 if absent and 1 if present (serum creatinine ≤1.3 or > 1.3 mg/dL, 
respectively). The result will be rounded to the nearest 0.001. Covance central laboratory data 
will be used to calculate Lille scores for a subject for analysis purposes except when 1 or more of 
the central values required to calculate the Lille score at Week 1 are missing and local laboratory 
data is available to calculate a Week 1 score. For these cases, local labs will be used to calculate 
all Lille scores for the subject. See Section 3.6.1 of this SAP for a complete description of
imputations for Lille score for subjects in whom a Week 1 Lille score cannot be calculated based 
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Lille score will be summarized as a continuous variable by treatment group and visit at Weeks 1, 
2, 3, and 4 by selecting the total bilirubin value for the subject and visit using the analysis visit 
windows specified in Section 3.8.2 of this SAP. An additional timepoint will be displayed for 
“Week 4 or last observation carried forward (LOCF)”. For this additional timepoint, a subject 
will be included with their Week 4 analysis visit Lille score, or with the last chronologic Lille 
score collected between Study Days 2 and 24 for those subjects who have a missing Week 4 
Lille score. The total bilirubin for the visit window will be substituted in place of the Day 7 total 
bilirubin value in the Lille score formula above to calculate the Lille score for Weeks 2, 3, and 4.
The median (Q1, Q3) Lille score value at each on-treatment visit will be provided as a figure.
Lille score will additionally be summarized as a categorical variable at Week 1, Week 2, and at 
Week 4 (LOCF) by treatment group and visit for the following:
1) The number and percentage of subjects with a Lille response, defined as a Lille score < 0.45 
(yes or no) 
2) The number and percentage of subjects with a Lille null response, defined as a Lille score 
≥0.56, will be displayed by treatment group and visit. Null response is used as a criteria for 
premature discontinuation of prednisolone in clinical practice. Subjects with a complete or 
partial response (Lille score < 0.56) will be further subdivided into complete responders 
(Lille score < 0.16) and partial responders (Lille score 0.16 to < 0.56). 
The denominator for the percentage calculation will be the number of subjects in the treatment 
group for the FAS or mITT analysis set (as appropriate). Subjects missing a Lille score value 
within the visit window will be counted as failures. Subjects with a calculated Lille score 
meeting non-responder or null-responder criteria will be summarized as “observed” failures. 
Subjects missing a value within the visit window will be summarized as “missing value”. The 
reasons for subjects not having a Lille score will be summarized at each visit as follows:
1) Subjects who discontinue both study drugs in the regimen prior to the target day (ie, Study 
Days 7 [Week 1 and Week 4 LOCF] and Day 14 [Week 2] for the visit window will be 
summarized by the premature discontinuation reason for SEL/PLA from the study drug 
completion eCRF.
2) Subjects ongoing at the time of the visit will be summarize as “missing value at visit”
For the endpoints Lille response (yes, no) and Lille null response (vs. complete or partial 
response), p-values from a 2-sided Fisher’s exact test will be presented for the Week 1 visit to 
explore whether there are differences between treatment groups.
A listing of the Lille scores included in analysis will be provided. A footnote will provide 
Subject IDs for those subjects who had Lille scores calculated using local laboratory data.


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6.2.5.
Mortality Risk using Baseline MELD score and Lille Score at Day 7
A scoring system combining the Lille score at Day 7 and the baseline MELD score to calculate 
the 2- and 6-month overall mortality risk was created, and tested with a secondary derivation 
dataset (ie, validation dataset) {Louvet 2015}. The steps for calculating the mortality risk for an 
individual subject are described below:
Step 1: Calculate the mortality probability for an individual subject using the Lille score at 
Week 1 and baseline MELD scores from central laboratory data. Subjects with a missing 
centrally-assessed Lille score at Week 1 or baseline MELD score will utilize imputed values 
based on local laboratory data as specified in Section 3.6.1 of this SAP.
S = [2.4778 × (Week 1 Lille score - 0.4114) + 0.0695 × (Baseline MELD – 24.6812)] × 0.9836
where,
1) 0.4114 = mean value of Lille model in the secondary derivation dataset
2) 24.6812 = mean value of MELD score in the secondary derivation dataset
3) 0.9836 = the shrinkage factor estimated using bootstrap validation in the secondary 
derivation dataset
4) 2.4778 and 0.0695 = regression coefficients calculated from the multivariable prognostic 
model for the secondary derivation dataset
Step 2: Calculate mortality risk using S:
2-month mortality risk = [1-(0.8239 exp(S))]*100
6-month mortality risk = [1-(0.7285 exp(S))]*100
Where 0.8239 and 0.7285 were the survival rate at the mean values of predictors in secondary 
derivation dataset (calculated as the pooled survival estimates from cohorts included in 
secondary derivation dataset). 
Numerical Example: a subject with Week 1 Lille score = 0.45 and a baseline MELD = 21:
Step 1: Calculate S = [2.4778 × (0.45 - 0.4114) + 0.0695× (21– 24.6812)] × 0.9836 = -0.1576
Step 2: Calculate the mortality risk using S
2-month mortality risk = [1-(0.8239 exp(-0.1576))]*100 = 15.3%
6-month mortality risk = [1-(0.7285 exp(-0.1576))]*100 = 23.7%


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Mortality risk at Month 2 and at Month 6 will be provided as a continuous variable by treatment 
group. 
6.2.6.
Length of Initial Hospital Stay
The number and percentage of subjects who were hospitalized at the time they were screened for
the study will be presented by treatment group. The denominator for percentage will be the 
number of subjects in the FAS or modified ITT analysis set (as appropriate).
For those hospitalized at the time they were screened for the study, the following will be 
presented (denominator for percentage will be number hospitalized in appropriate analysis set):

Number and percentage of subjects who were transferred from another hospital to the current 
hospital where they are participating in this study

Number of subjects who were released from the hospital after the screening visit and prior to 
first dose of SEL/PLA study drug

Number and percentage of subjects still in the hospital on Study Day 1.
In addition, for those still in the hospital on Study Day 1, summary statistics of days
hospitalized from date of first dose of SEL/PLA by treatment group and death status (eg., 
alive or dead) will be presented where 
Days hospitalized from first dose of SEL/PLA =
(Date of release from hospital – date of first dose of SEL/PLA +1)
If the death date is the same as the release date or the subject has a nonmissing death date and 
there is no release date from hospitalization, the subject will be assumed to be “dead” upon 
release from the hospital. Date of death will be substituted for date of release in the formula for 
days hospitalized from first dose of SEL/PLA.
6.2.7.
Events of Interest
The number and percentage of subjects with the following 2 types of events will be summarized:

Infections of Interest (as described in Section 6.9.9 of the study protocol)

Hepatorenal Syndrome events (meeting International Ascites Club criteria as described in 
Section 6.9.8 of the study protocol) 
A postbaseline infection of interest will be considered to be “definite” in subjects with clinical 
evidence of infection (ie, AE with the infection field marked ‘yes’ on the AE eCRF) and a 
positive culture from a normally sterile source; infiltrate on chest x-ray and treatment with 
antibiotics; or ascitic fluid neutrophils ≥ 250 cells/mm3, regardless of culture positivity for SBP. 
All other infections will be considered to be “probable”. Results from laboratory investigations 


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will be used to enter the most specific AE verbatim term possible for coding purposes (ie, 
“E. Coli urinary tract infection” for a urinary tract infection where the pathogen “E. Coli” was 
present in a urine culture); and to serve as source documentation of the methods used to 
determine that the infection was “definite”.
A summary of postbaseline “infections” (ie, adverse events that have ‘yes’ marked for infection 
on the AE eCRF) will be presented by treatment group, high level group term (HLGT) and lower 
lever term (LLT) from the MedDRA dictionary separately for infections that are “definite” 
infections and for those that are “definite/probable” infections. Multiple events reported within a
HLGT, and LLT will be counted once only per subject in each summary. Infections will be 
summarized in alphabetic order of HLGT and then by LLT in descending total frequency within 
each HLGT. Infections with postbaseline onset dates or worsening on or after the first dose date 
of study drug through end of study will be summarized.
Culture and x-ray results collected for documenting definite infections will be presented 
alongside the reported infection in a listing sorted by start date for the infection and procedure 
date for the culture/x-ray. Cultures collected on/after Study Day 1 will be listed. 
Postbaseline medications used to treat infections (identified from an indication of “Infection” on 
the CM eCRF) will be summarized by treatment group and preferred name. Medications with 
stop dates prior to first dose date of SEL/PLA will be excluded.
A listing of subjects with HRS events entered on the AE eCRF that meet International Ascites
Club criteria as described in Section 6.9.8 of the study protocol will be provided. Subjects with 
an AE preferred term of “Hepatorenal syndrome” from the AE eCRF will be screened by the 
medical monitor to determine whether the event meets Ascites Club HRS criteria. New or 
worsening postbaseline HRS events reported during the study will be summarized. 
Medications used to treat HRS (ie, those with an indication of ‘HRS’ on the concomitant 
medication eCRF) will be summarized by treatment group and preferred name. Medications with 
stop dates prior to first dose date SEL/PLA will be excluded from analyses. Medications used to 
treat HRS will be listed.
6.2.8.
Liver Biochemistry and Prognostic Indices
Summary statistics for the absolute value and change and percentage change from baseline for 
liver biochemistry tests (ALT, AST, GGT, albumin, alkaline phosphatase, total bilirubin, direct 
bilirubin, and INR) and prognostic indices (MELD, CPT and Maddrey’s DF) will be presented 
by visit through Week 24 using central laboratory data except when noted otherwise (see 
Section 3.8.2 of the SAP for visit windows; and Section 3.6.1 for baseline MELD imputation 
rule when central laboratory data is not available).
Percentage change from baseline is calculated as:
([score at visit – score at baseline] ÷ score at baseline) × 100


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An additional timepoint will be added for “Week 4 (LOCF)”. For this additional timepoint, a 
subject will be included with their Week 4 value, or with the last chronologic value collected 
between Study Days 2 and 24 for subjects who are missing a Week 4 value. For all liver 
biochemistry tests and prognostic scores, subjects who receive a liver transplant while on study 
will have measurements collected up to the date of transplant included for summary tables. 
Median (Q1, Q3) absolute values by visit will be plotted for MELD score, ALT, AST, total 
bilirubin and INR throughWeek 24 for the final analysis. Median (Q1, Q3) change and 
percentage change from baseline by visit will be plotted for MELD score and for total bilirubin.
A listing of values included in efficacy analyses will be provided with subjects included in the 
FAS flagged in listings.
Formulas for calculating each of the prognostic indices are described below:
Maddrey DF score  =
[4.6 × (PT subject [sec] – PT control [sec])] + total bilirubin (mg/dL)
Note: PT control [sec] is only available at the screening visit for each subject. For calculations 
over time, the subject’s screening PT control [sec] will be used to calculate scores at each of the 
visits.
MELD score =
10 × {[0.957 × Ln(Scr)] + [0.378 × Ln(Tbil]) + [1.12 × Ln(INR)] + 0.643)}, 
where Scr = serum creatinine (in mg/dL), Tbil = Total Bilirubin (in mg/dL), INR = international 
normalized ratio, and Ln = natural log. If any lab value is less than 1.0, then it will be set to 
1.0 in the calculation. If the subject received dialysis at least twice in the past week, or if serum 
creatinine is > 4.0 mg/dL, then Scr will be set to 4.0 mg/dL in the above formula. The result will 
be rounded to the nearest whole number. Subjects missing a baseline MELD score using central
laboratory data will have their baseline MELD score imputed as described in Section 3.6.1 of 
this SAP. 
CPT score = Sum of the scores related to the 5 parameters below for a given subject and study 
visit (if any of the components are missing, the score will not be calculated for that subject and 
visit):


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Parameter 
1 
POINTS 
2 
Encephalopathy 
None 
Grade 1-2 (medication controlled) 
Ascites 
None 
Mild/Moderate (diuretic responsive) 
Bilirubin (mg/d.L) 
< 2 
2-3 
Albwnin (g/d.L) 
> 3.5 
2.8- 3.5 
INR 
< 1.7 
1.7- 2.3 
Version 1 
3 
Grade 3-4 (medication refractory) 
Severe (diw·etic refractmy) 
> 3 
< 2.8 
> 2.3 
Note: if either ascites or encephalopathy is "none" because the subject is taking medication which has controlled the symptoms, 
the scoring should be 2 points (not 1 point). 
The CPT score is obtained by adding the points for each parameter for a given subject at a visit. 
The CPT class is assigned based on the score: CPT A (5-6 points), CPT B (7-9 points), CPT C 
(10-15 points). 
For the MELD and CPT calculations, the dates for each of the individuallaboratmy tests utilized 
in the fmmula are collected on the CPC _MELD eCRF and merged with the Co vance laboratmy 
dataset by laboratmy test and laboratmy collection date prior to calculating the scores. The visit 
date for the CPC _MELD eCRF dete1mines the study day for pmposes of dete1mining the 
analysis visit windows as specified in Section 3.8.2 of this SAP. 
6.3. 
I 
I 
I 
6.4. 
Exploratory Efficacy Endpoints 
Analysis methods for Exploratory Efficacy Endpoints 
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Changes to Efficacy Analysis 
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Analyses of the endpoints change from baseline in LOXL2, CK18, serum cytokines and 
metabolic profiles, LPS, procalcitonin, and ASK-1 pathways will be described in a separate 
biomarker analysis plan (BAP). 
Fasting lipid tests (total cholesterol, HDL, LDL, VLDL), and triglycerides will not be 
summarized as explorat01y efficacy endpoints as the requirement for fasting was removed in 
Amendment 2 of the protocol. In addition, Co vance laboratories does not report results for 
cholesterol values when the sample is "icteric". As a high percentage of subjects have total 
bilimbin levels > 10 mg/dL for this subject population, these analyses would exclude the most 
severe AH subjects, and would not be representative of the entire set of subjects. The lipid 
profile will be summarized for safety only and insulin levels will be listed only using the same 
visit windows used for HbA1c. 
It should also be noted that many GGT and total protein values were cancelled by Covance due 
to icteric samples (ie, high total bilirubin). Summaries will be presented for completeness, but it 
should be noted that many values, especially those at early timepoints, will be missing. 
Analysis of the Chronic Liver Disease Questionnaire (CLDQ) will not be perfonned for the final 
analysis since there was no evidence of improved efficacy with treatment of SEL + PRED vs. 
PLA + PRED when the primmy analysis was performed. 
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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of 
MedDRA. System organ class (SOC), HLGT, high-level term (HLT), preferred term (PT), and 
lower-level term LLT will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, 4, or 5 according to Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The severity grade of events 
for which the investigator did not record severity will be categorized as “missing” for tabular 
summaries and data listings, and the most severe event will be considered in data presentations.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE eCRF to the 
question of “Related to Study Treatment.” Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs meet the 
definition of an SAE specified in the study protocol. SAEs captured and stored in the clinical 
database will be reconciled with the SAE database from the Gilead Pharmacovigilence and 
Epidemiology Department before data finalization.
7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) 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.


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7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met:

The AE onset is the same as or after the month and year (or year) of the first dosing date of 
study drug, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after the date of the last dose of any study drug 
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of study drug, will be considered to be treatment emergent. In 
addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of study drug will 
be considered treatment emergent.
7.1.6.
Summaries of Adverse Events and Deaths
Treatment-emergent AEs will be summarized based on the Safety Analysis Set.
A brief high-level summary of AEs will be provided by treatment group and will present the
number and percentage of subjects who had the following: any TEAE, any TEAE of Grade 2 or 
higher, any TEAE of Grade 3 or higher (further broken down by highest grade reported per 
subject [ie, Grade 3, 4, 5]), any TE treatment-related AE, any TE treatment-related AE of 
Grade 2 or higher, any TE treatment-related AE of Grade 3 or higher (further broken down by 
highest grade reported per subject [ie, Grade 3, 4, 5]), any TE SAE, any TE treatment-related 
SAE, any TEAE that led to premature discontinuation of both study drugs (defined as ≥ 1 AE 
with action taken on SEL/PLA=’study drug withdrawn’ and ≥ 1 AE with action taken on 
PRED=’study drug withdrawn’), any TEAE that led to premature discontinuation of 
Selonsertib/Placebo, any AE that led to premature discontinuation of Prednisolone, any TEAE 
that led to dose reduction or interruption of Prednisolone, any TEAE that led to interruption of 
Selonsertib/Placebo, any TEAE that led to interruption of Prednisolone, any TEAE that led to 
premature discontinuation from study, and all deaths reported during the study will also be 
summarized and included in this table.
The number and percentage of subjects will be provided and summarized by treatment group, 
SOC and PT for the following:

All TEAEs

TEAEs of Grade 3 or higher (by maximum severity)

TEAEs of Grade 2 or higher


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
All TE treatment-related AEs

TE Treatment-related AEs of Grade 3 or higher (by maximum severity)

TE Treatment-related AEs of Grade 2 or higher

All TE SAEs

All TE treatment-related SAEs 

All TEAEs leading to temporary interruption of Selonsertib/Placebo

All TEAEs leading to temporary interruption of Prednisolone

All TEAEs leading to dose modification or temporary interruption of Prednisolone

TEAEs leading to premature discontinuation of Selonsertib/Placebo

TEAEs leading to premature discontinuation of Prednisolone

TEAEs leading to discontinuation of both drugs in the study regimen (defined as AEs that led 
to discontinuation of either study drug for subjects with ≥1 AE with action taken on 
SEL/PLA=study drug withdrawn and ≥1 AE with action taken on PRED=study drug 
withdrawn)

All AEs recorded between screening and prior to first dose of study drug

All SAEs with an outcome of death
Multiple events reported within an SOC or PT will be counted once only per subject in each 
summary. Adverse events will be summarized by treatment group and will be listed first in 
alphabetic order of SOC and then by PT in descending total frequency within each SOC. In 
summaries by severity grade, the most severe grade will be used for those AEs that occurred 
more than once in an individual subject during the study.
In addition to the above summary tables, the following AEs will be summarized by treatment 
group and PT only: 

All TEAEs (occurring in ≥10% of subjects within any group)

TE treatment-related AEs (occurring in ≥5% of subjects within any group)

Grade 3 or Higher TE AEs

Grade 3 or Higher TE treatment-related AEs


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
Grade 3 or Higher TE treatment-related AEs Leading to Premature Discontinuation of 
Selonsertib/Placebo

TE SAEs 

TE treatment-related SAEs
The sort order for these tables will be in descending order of total frequency of PT events and 
alphabetic order of PT for events with the same total frequency.
At the request of the Pharmacovigilence and Epidemiology group, the following AE tables will 
be produced to summarize by treatment group, SOC, HLT and PT:

All TE AEs

TE SAEs
The sort order for these tables will be in descending order of total frequency of HLT and PT 
events and alphabetic order for SOC.
In addition, data listings will be provided for the following:

All AEs, indicating whether the event is treatment emergent

All AEs of Grade 3 or higher

All AEs of Grade 3 or higher related to study treatment

SAEs

SAEs related to study treatment

Deaths

All AEs leading to death

AEs leading to discontinuation of any of the study drugs

AEs leading to dose modification or interruption of any of the study drugs
7.1.7.
Analysis of Adverse Events of Interest
Post-baseline criteria (up to last dose date of SEL/PLA [confirmatory values may be collected 
after the last dose date]) will be used to screen for individual subjects who should stop dosing 
with SEL/PLA study drug. DMC members used these same criteria to determine whether there 
was a > 20% higher percentage of subjects in the SEL + PRED group than PLA + PRED group 
with events in any of the 4 categories (ie, DMC trial stopping criteria). 


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SEL/PLA study drug stopping criteria for an individual subject is as follows:
1) Grade 3 or higher, treatment-emergent, treatment-related adverse event(s) of a specific type 
(excluding evaluation of liver function) that leads to discontinuation of SEL/PLA
2) Death on/prior to Study Day 28
3) Lille Score > 0.85 while on study drug
4) Any of the post-baseline SEL/PLA laboratory stopping criteria:

ALT or AST > 500 U/L 

ALT or AST > 5 x Baseline/Day 1 (confirmed on repeat testing)

Total Bilirubin > 3 x Baseline/Day 1 or Nadir (confirmed on repeat testing)
The baseline/Day 1 value will be defined as the last available measurement on/prior to first dose 
of SEL/PLA, and the nadir value will be defined as the lowest postbaseline value prior to the 
current value being assessed. A listing will be provided that includes each individual subject who 
met any of the SEL/PLA stopping criteria.
Prednisolone study drug stopping criteria in an individual subject is as follows: Subjects with a 
Week 1 Lille score ≥0.56 will be prematurely discontinued from PRED. This criteria is the same 
as the secondary efficacy parameter Lille null response (Lille score ≥ 0.56 at Week 1) which is 
described in Section 6.2.4 of this SAP.
7.2.
Laboratory Evaluations
Summaries of laboratory data will be provided for the Safety Analysis Set and will include data 
collected up to the date of last dose of any study drug plus 30 days for subjects who have 
permanently discontinued study drug. The analysis will be based on values reported in 
conventional units. When values are below the LOQ, they will be listed as such, and the imputed 
value will be used for the purpose of calculating summary statistics as specified in Section 3.7.
A by-subject listing for laboratory test results will be provided by subject ID and analysis visit in 
chronological order for screening tests, hematology, serum chemistry, and coagulation, 
separately. Values falling outside of the relevant reference range and/or having a severity grade 
of 1 or higher according to CTCAE toxicity grading will be flagged in the data listings, as 
appropriate.
No formal statistical testing is planned.
Special handling of central laboratory serum creatinine data:
At initiation of the study, the Covance Statement of Work (SOW) specified that serum creatinine 
be analyzed using the Jaffe method with a reflex to serum enzymatic creatinine. Early in the 


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study, high bilirubin values prohibited resulting of creatinine, so the SOW was updated to use 
serum enzymatic creatinine with a reflex to LCMSMS methodology if serum enzymatic 
creatinine could not be resulted; Jaffe method was no longer used. At the same time, Gilead
asked Covance to perform regression analysis to determine if data from serum enzymatic 
creatinine and LCMSMS methods were combinable. Fourty samples (not from this study) 
measured creatinine using all 3 methods (Jaffe, enzymatic serum creatinine, and LCMSMS), and 
regression analysis using Deming and regular regression was performed.
Results of previous regression analyses comparing the Jaffe method and serum enzymatic 
creatinine met Covance’s criteria for combinability of data using the 2 methods (ie, 95% CI on 
slope contains 1; and 95% CI on intercept contains 0). Regression analysis of the 40 samples for 
LCMSMS and the Jaffe methods came close to meeting the combinability criteria, and only 
4 samples from Study GS-US-416-2124 were analyzed using the Jaffe method. LCMSMS and 
serum enzymatic creatinine failed to pass the combinability criteria (95% CI on the slope 
contained 1; but 95% CI on the intercept did not contain 0). Examination of individual data 
points as well as the reported bias (-0.055 mg/dL) show that serum LCMSMS was reading out 
approximately .055 mg/dL lower than serum enzymatic creatinine across the range of values.
In order to combine creatinine data from the 3 different test methods, Gilead will create a new 
lab test code called “GSI Serum Creatinine” that combines data from the 3 serum creatinine 
methods for analysis---adjusting for the LCMSMS negative bias (by adding 0.06 mg/dL [for 
2-decimal place reporting] to the reported result). Covance has recommended using Jaffe normal 
ranges for serum creatinine LCMSMS, and results from prior regression analysis suggest that 
serum enzymatic creatinine is combinable with the Jaffe method. Results of the “GSI serum 
creatinine” lab test code will be toxicity graded using CTCAE Version 4.03 and the Jaffe method 
normal ranges.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics will be provided by treatment group for hemoglobin, hematocrit, 
lymphocytes, neutrophils, platelet count, white blood cells (WBCs), bicarbonate, sodium, 
chloride, magnesium, phosphorus, potassium, albumin-corrected calcium, lactate dehydrogenase, 
blood urea nitrogen, serum creatinine, and serum glucose as follows:

Baseline values 

Values at each postbaseline analysis visit

Change from baseline at each postbaseline analysis visit
A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date of first dose of study drug. Change from baseline to a postbaseline visit will be defined as 
the value at the visit minus the baseline value. The mean, SD, median, Q1, Q3, minimum, and 
maximum values will be displayed to the reported number of digits; SD values will be displayed 
to the reported number of digits plus 1.


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Median (Q1, Q3) serum creatinine value over time will be plotted.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3.
7.2.2.
Graded Laboratory Values
The CTCAE Version 4.03 will be used for assigning toxicity grades (0 to 4) to laboratory results 
for analysis. Grade 0 includes all values that do not meet the criteria for an abnormality of at 
least Grade 1. For laboratory tests with criteria for both increased and decreased levels, analyses 
for each direction (ie, increased, decreased) will be presented separately. 
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last 
dose of study drug plus 30 days for subjects who permanently discontinued study drug. If the 
relevant baseline laboratory value is missing, any abnormality of at least Grade 1 observed 
within the time frame specified above will be considered treatment emergent.
7.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities
Treatment-emergent marked laboratory abnormalities are defined as values that increase from 
baseline by at least 3 toxicity grades at any postbaseline time point, up to and including the date 
of the last dose of study drug plus 30 days for subjects who permanently discontinued study 
drug. If the relevant baseline laboratory value is missing, any Grade 3 or 4 values observed 
within the timeframe specified above will be considered treatment-emergent marked 
abnormalities.
7.2.2.3.
Summaries of Laboratory Abnormalities
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by laboratory test (and direction of abnormality, when applicable)
and treatment group; subjects will be categorized according to the most severe postbaseline 
abnormality grade for a given lab test:

Grade 3 or 4 laboratory abnormalities

Marked laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 30 days after last dosing date.
A by-subject listing of treatment-emergent Grade 3 or 4 laboratory abnormalities will be 
provided by subject ID number and time point in chronological order. This listing will include all 
test results that were collected throughout the study for the lab test of interest, with all applicable 
toxicity grades displayed.


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7.3. 
Body Weight, Height, BMI and Vital Signs 
Descriptive statistics will be provided by treatment group for systolic and diastolic blood 
pressure, and pulse as follows: 
• 
Baseline value 
• 
Values at each postbaseline analysis visit 
• 
Change from baseline at each postbaseline analysis visit 
Version 1 
A baseline value will be defined as the last available value collected on or prior to the date of 
first dose of study drug. For subjects with screening and baseline visits conducted on the same 
date (ie, Subject ID PO 
the baseline record will be utilized as the baseline value. 
Change from baseline to a postbaseline visit will be defined as the postbaseline value minus the 
baseline value. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. No formal statistical testing is planned. 
A by-subject listing of height, body weight, BMI, and vital signs will be provided by subject ID 
number and time point in chronological order. 
7.4. 
Prior and Concomitant Medications 
Medications collected at screening and during the study will be coded using the current version 
ofthe World Health Organization (WHO) Drug dictionary. 
7.4.1. 
Concomitant Medications 
Concomitant medications are defined as medications taken while the subject is taking study drug. 
Use of concomitant medications will be summarized by preferred name using the number and 
percentage of subjects for each treatment group. A subject reporting the same medication more 
than once will be counted only once when calculating the number and percentage of subjects 
who received that medication. The summary will be ordered by descending overall frequency of 
preferred name. For drugs with the same frequency, sorting will be done alphabetically for 
preferred name. 
For the purposes of analysis, medications with a stop date that is on or prior to the date of first 
dosing date of study drug or a start date that is after the last dosing date of study drug will be 
excluded from the concomitant medication summary. If a partial stop date is entered, any 
medication with the month and year (if day is missing) or year (if day and month are missing) 
prior to the date of first study drug administration will be excluded from the concomitant 
medication summary. If a partial start date is entered, any medication with the month and year (if 
day is missing) or year (if day and month are missing) after the study drug stop date will be 
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excluded from the concomitant medication summary. Medications with completely missing start 
and stop dates will be included in the concomitant medication summary.
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned.
All prior and concomitant medications will be provided in a by-subject listing sorted by subject 
ID number and administration date in chronological order.
7.4.2.
Concomitant Enteral and Parenteral Nutrition Medications
Enteral and parenteral nutrition medications will be summarized separately using similar rules to 
those used for concomitant medications. Enteral and parenteral nutrition products are defined as 
medications recorded on the CM eCRF with a pull-down menu indication of “Parenteral or 
Enteral Nutrition”. A summary of concomitant enteral and parenteral nutrition medications will 
be based on the Safety Analysis Set.
All enteral and parenteral nutrition medications will be provided in a by-subject listing sorted by 
subject ID number and administration date in chronological order.
7.5.
Electrocardiogram Results
7.5.1.
Investigator Electrocardiogram Assessment
A shift table of the investigator assessment of a subject’s ECG results at Week 4/early study drug 
discontinuation visit and Week 8 compared with their baseline value will be presented by 
treatment group using the following categories: normal; abnormal, not clinically significant; 
abnormal, clinically significant; or missing. A subject with a missing ECG result at Baseline/Day 
1 will have the screening visit used for the baseline value. The number and percentage of 
subjects in each cross-classification group of the shift table will be presented. Subjects with a 
missing value at baseline or postbaseline will not be included in the denominator for percentage 
calculation. No formal statistical testing is planned.
A by-subject listing for ECG assessment results will be provided by subject ID number and 
nominal visit in chronological order.
7.6.
Other Safety Measures
A listing of pregnancies (or a listing stating that none were observed) will be provided.
7.7.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8. 
PHARMACOKINETIC ANALYSES 
8.1. 
PK Sample Collection 
Version 1 
A single PK sample will be collected on Day 1 (2 ± 1 hour postdose), at Week 1 (24 ± 4 hours 
postdose), Week 2 (2 ± 1 hour and 24 ± 4 hours postdose), and Week 4 (24 ± 4 hours postdose). 
PD 
A population PK model may be developed to characterize the PK of selonsertib and its 
metabolites (as applicable). Data from this study (single PK and PK substudy) may be combined 
with data from other studies in a meta-population analysis using nonlinear mixed-effects 
modeling techniques. Details of the population PK analysis will be provided in a separate 
population PK analysis plan. 
8.2. 
PK Analyses Related to Intensive PK Sampling 
Steady-state PK over a 24 hour dosing interval will be determined in subjects in the PK Substudy 
analysis set. Concentrations of selonse1tib and GS-607509 in plasma will be dete1mined using 
validated bioanalytical assays. 
8.2.1. 
Estimation of Pharmacokinetic Parameters 
Phrumacokinetic (PK) parameters will be estimated by application of a nonlinear model (using 
Phoenix WinNonlin® softwru·e version6.3) using standru·d noncompartmental methods. The 
linear up/log down trapezoidal mle will be used in conjlmction with the appropriate 
noncomprutmental model, with input values for dose level, dosing time, plasma concentration, 
a11d conesponding real-time values, based on dmg dosing times whenever possible. 
All predose sample times before time-zero will be conve1ted to 0. For ru·ea under the cmve 
(AUC), samples BLQ of the bioanalytical assays occUlTing prior to the achievement of the fust 
quantifiable concentration will be assigned a concentration value of 0 to prevent overestimation 
of the initial AUC. Samples that are BLQ at all other time points will be treated as missing data 
in WinNonlin. The nominal time point for a key event or dosing inte1val (t) may be used to 
pe1mit direct calculation of AUC over specific time inte1vals. The appropriateness of this 
approach will be assessed by the PK scientist on a profile-by-profile basis. 
Phrumacokinetic pru·ameters such as AUCtau, "Jvz and t112 are dependent on an accurate estimation 
of the te1minal elimination phase of dmg. The appropriateness of calculating these pru·ameters 
will be evaluated upon inspection ofPK data on a profile-by-profile basis by the PK scientist. 
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8.2.2.
Pharmacokinetic Parameters
The pharmacokinetic parameters for selonsertib and GS-607509 will be computed for all subjects 
with evaluable PK profiles who were in the selonsertib + prednisolone group. For each subject, 
the following PK parameters will be calculated for selonsertib and GS-607509 at the intensive 
PK visit, as appropriate:
Parameter
Description
AUCtau
area under the concentration versus time curve over the dosing interval
Clast
last observed quantifiable concentration of the drug in plasma
Cmax
maximum observed concentration of drug in plasma
Ctau
observed drug concentration at the end of the dosing interval
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
λz
terminal elimination rate constant; estimated by linear regression of the terminal 
elimination phase of the plasma concentration of drug versus time curve
t1/2
estimate of the terminal elimination half-life of the drug in plasma, calculated by dividing 
the natural log of 2 by the terminal elimination rate constant (λz)
CLss/F
Apparent oral clearance after administration of the drug, at steady state: CLss/F = 
Dose/AUCtau where “dose” is the dose of the drug 
(for selonsertib only)
Individual subject concentration data and individual subject PK parameters for selonsertib and its 
metabolite GS-607509 will be listed and summarized using descriptive statistics for the
selonsertib + prednisolone group for subjects participating in the PK substudy. Summary 
statistics (sample size, mean, SD, coefficient of variation [%CV], median, min, max, Q1, and 
Q3) will be presented for both individual subject concentration data by time point and individual 
subject PK parameters. Moreover, the geometric mean, 95% CI, and the mean and SD of the 
natural log-transformed values will be presented for individual subject PK parameter data. 
Individual concentration data listings and summaries will include all subjects with concentration 
data. The sample size for each time point will be based on the number of subjects with 
nonmissing concentration data at that time point. The number of subjects with concentration 
BLQ will be presented for each time point. For summary statistics, BLQ values will be treated as 
0 at predose and one-half of the lower limit of quantitation (LLOQ) for postdose time points, 
where LLOQ is corrected for the dilution factor (ie, reported dilution/dilution factor). 
Individual PK parameter data listings and summaries will include all subjects for whom PK 
parameter(s) can be derived. The sample size for each PK parameter will be based on the number 
of subjects with nonmissing data for that PK parameter.


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The following tables will be provided for each analyte for the Selonsertib+Prednisolone group:

Individual subject concentration data and summary statistics

Individual subject plasma PK parameters and summary statistics
The Mean (± SD) concentration data versus time (on linear and semilogarithmic scales) will be 
provided for each analyte for subjects in the Selonsertib + Prednisolone group. Individual, mean
postdose concentration values that are ≤LLOQ will not be displayed in the figures and 
remaining points connected.
The following listings will be provided:

PK sampling details by subject including actual dosing time and actual draw time, calculated 
time postdose of sample collection, differences in scheduled and actual draw time, sample
age and sample concentration.

Individual data on determination of plasma half-life and corresponding correlation coefficient 
by analyte
8.3.
PK Analyses Related to Sparse PK Sampling
Plasma concentrations of selonsertib and GS-607509 over time will be listed and summarized by 
nominal visit for subjects in the Selonsertib + Prednisolone group. Single PK concentration data 
along with the actual collection time and dosing time, and calculated time postdose of sample 
collection will be included in the PK sampling details listing as described above.


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9.
REFERENCES
Louvet A, Labreuche J, Artru F, Boursier J, Kim DJ, O'Grady J, et al. Combining Data From 
Liver Disease Scoring Systems Better Predicts Outcomes of Patients With 
Alcoholic Hepatitis. Gastroenterology 2015;149 (2):398-406 e8.
Louvet A, Naveau S, Abdelnour M, Ramond MJ, Diaz E, Fartoux L, et al. The Lille model: a 
new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated 
with steroids. Hepatology 2007;45 (6):1348-54.


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10.
SOFTWARE
SAS® Software Version 9.X. SAS Institute Inc., Cary, NC, USA.
nQuery Advisor(R) Version X.0. Statistical Solutions, Cork, Ireland.


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


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12.
APPENDICES
Appendix 1.
Table of Contents for Statistical Tables, Figures, and Listings
Appendix 2.
GS-US-416-2124 Programming Specifications


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Appendix 1.
Table of Contents for Statistical Tables, Figures, and Listings
Table 
Number
Description
Analysis Set
15.8.1.1
Subjects Randomized and Treated by Country and Investigator
Safety Analysis Set
15.8.1.2
Subjects Randomized and Treated by Randomization Stratum
Safety Analysis Set
15.8.1.3
Subject Disposition
All Screened Subjects
15.8.2.1
Eligibility Criteria Deviations
Randomized Analysis Set
15.8.2.2
Important Protocol Deviations
Randomized Analysis Set
15.8.2.3
Reasons for Screen Failure
Screened Subjects
15.8.3.1.1
Demographics
Safety Analysis Set
15.8.3.1.2
Demographics
Full Analysis Set
15.8.3.2.1
Baseline Characteristics
Safety Analysis Set
15.8.3.2.2
Baseline Characteristics
Full Analysis Set
15.8.3.2.3
Daily Alcohol Consumption (g/day), Baseline Height, Weight, and 
Body Mass Index by Sex
Safety Analysis Set
15.8.3.2.4
Daily Alcohol Consumption (g/day) and Baseline Height, Weight,
and Body Mass Index (kg/m2) by Sex
Full Analysis Set
15.8.3.2.5
Prior Medications Used to Treat Baseline Infections
Safety Analysis Set
15.8.3.2.6
Prior Corticosteroids Administered for Treatment of Alcoholic 
Hepatitis by Preferred Drug Name
Safety Analysis Set
15.8.4
Adherence to Study Drug Regimen
Safety Analysis Set
15.9.1.1
Number (%) of Subjects with Death On/Prior to Study Day 28 and 
Weeks 8, 12, and 24
Subjects with Death/Follow-
Up Through Timepoint of 
Interest
(Full Analysis Set)
15.9.1.2
Number (%) of Subjects with Death On/Prior to Study Day 28 and 
Weeks 8, 12, and 24
Subjects with Death/Follow-
Up Through Timepoint of 
Interest (Modified ITT 
Analysis Set)
15.9.1.3
Kaplan-Meier Estimate of Survival
Full Analysis Set
15.9.1.4
Support for Table 15.9.1.3: Listing of Days and Censoring Status 
of Survival
Full Analysis Set
15.9.1.5
Kaplan-Meier Estimate of Survival
Modified ITT Analysis Set
15.9.1.6
Support for Table 15.9.1.5: Listing of Days and Censoring Status 
of Survival
Modified ITT Analysis Set
15.9.1.7
Kaplan-Meier Estimate of Transplantation-Free Survival
Full Analysis Set
15.9.1.8
Support for Table 15.9.1.7: Listing of Days and Censoring Status 
of Transplantation-Free Survival
Full Analysis Set
15.9.1.9
Kaplan-Meier Estimate of Transplantation-Free Survival
Modified ITT Analysis Set


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Table 
Number
Description
Analysis Set
15.9.1.10
Support for Table 15.9.1.9: Listing of Days and Censoring Status 
of Transplantation-Free Survival
Modified ITT Analysis Set
15.9.2.1.1
Number (%) of Subjects with Liver Transplant On/Prior to Study 
Day 28 and Weeks 8, 12, and 24
Subjects with Liver 
Transplant/Follow-Up 
Through Timepoint of 
Interest (Full Analysis Set)
15.9.2.1.2
Number (%) of Subjects with Liver Transplant On/Prior to Study 
Day 28 and Weeks 8, 12, and 24
Subjects with Liver 
Transplant/Follow-Up 
Through Timepoint of 
Interest (Modified ITT
Analysis Set)
15.9.2.2.1
Lille Score by On-Treatment Visit (Covance Central Laboratory 
Results)
Full Analysis Set
15.9.2.2.2
Lille Score by On-Treatment Visit (Covance Central Laboratory 
Results)
Modified ITT Analysis Set
15.9.2.2.3
Lille Score at Week 1, Week 2, and Week 4 [LOCF] for 
Categorical Outcomes (Covance Central Laboratory Results)
Full Analysis Set
15.9.2.2.4
Lille Score at Week 1, Week 2, and Week 4 [LOCF] for 
Categorical Outcomes (Covance Central Laboratory Results)
Modified ITT Analysis Set
15.9.2.2.5
Mortality Risk at Months 2 and 6 Based on Lille Score at Week 1 
and Baseline MELD Score (Covance Central Laboratory Results)
Full Analysis Set
15.9.2.2.6
Mortality Risk at Months 2 and 6 Based on Lille Score at Week 1
and Baseline MELD Score (Covance Central Laboratory Results)
Modified ITT Analysis Set
15.9.2.3.1
Postbaseline Definite Infections Reported Through End of Study 
(by High Level Group Term and Low Level Term)
Full Analysis Set
15.9.2.3.2
Postbaseline Definite Infections Reported Through End of Study 
(by High Level Group Term and Low Level Term)
Modified ITT Set
15.9.2.3.3
Postbaseline Definite or Probable Infections Reported Through
End of Study (by High Level Group Term and Low Level Term)
Full Analysis Set
15.9.2.3.4
Postbaseline Definite or Probable Infections Reported Through 
End of Study (by High Level Group Term and Low Level Term)
Modified ITT Analysis Set
15.9.2.3.5
Postbaseline Medications Administered to Treat Infections
Through End of Study
Full Analysis Set
15.9.2.3.6
Postbaseline Medications Administered to Treat Infections 
Through End of Study
Modified ITT Analysis Set
15.9.2.4.1
Postbaseline Hepatorenal Syndrome Events Reported Through 
End of Study 
Full Analysis Set
15.9.2.4.2
Postbaseline Hepatorenal Syndrome Events Reported Through 
End of Study 
Modified ITT Analysis Set
15.9.2.4.3
Postbaseline Medications Administered to Treat Hepatorenal 
Syndrome Through End of Study
Full Analysis Set


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Table 
Number
Description
Analysis Set
15.9.2.4.4
Postbaseline Medications Administered to Treat Hepatorenal 
Syndrome Through End of Study
Modified ITT Analysis Set
15.9.2.5.1
Summary of Length of Initial Hospital Stay (Days) from First 
Dose Date of Study Drug
Full Analysis Set
15.9.2.5.2
Summary of Length of Initial Hospital Stay (Days) from First 
Dose Date of Study Drug
Modified ITT Analysis Set
15.9.2.6.1
ALT (U/L) and Change and Percentage Change from Baseline by 
Visit
Full Analysis Set
15.9.2.6.2
ALT (U/L) and Change and Percentage Change from Baseline by 
Visit
Modified ITT Analysis Set
15.9.2.6.3
AST (U/L) and Change and Percentage Change from Baseline by 
Visit
Full Analysis Set
15.9.2.6.4
AST (U/L) and Change and Percentage Change from Baseline by 
Visit
Modified ITT Analysis Set
15.9.2.6.5
GGT (U/L) and Change and Percentage Change from Baseline by 
Visit
Full Analysis Set
15.9.2.6.6
GGT (U/L) and Change and Percentage Change from Baseline by 
Visit
Modified ITT Analysis Set
15.9.2.6.7
Albumin (g/dL) and Change and Percentage Change from 
Baseline by Visit
Full Analysis Set
15.9.2.6.8
Albumin (g/dL) and Change and Percentage Change from 
Baseline by Visit
Modified ITT Analysis Set
15.9.2.6.9
Alkaline Phosphatase (U/L) and Change and Percentage Change 
from Baseline by Visit
Full Analysis Set
15.9.2.6.10
Alkaline Phosphatase (U/L) and Change and Percentage Change 
from Baseline by Visit
Modified ITT Analysis Set
15.9.2.6.11
Total Bilirubin (mg/dL) and Change and Percentage Change from 
Baseline by Visit
Full Analysis Set
15.9.2.6.12
Total Bilirubin (mg/dL) and Change and Percentage Change from 
Baseline by Visit
Modified ITT Analysis Set
15.9.2.6.13
Direct Bilirubin (mg/dL) and Change and Percentage Change from 
Baseline by Visit
Full Analysis Set
15.9.2.6.14
Direct Bilirubin (mg/dL) and Change and Percentage Change from 
Baseline by Visit
Modified ITT Analysis Set
15.9.2.6.15
INR and Change and Percentage Change from Baseline by Visit
Full Analysis Set
15.9.2.6.16
INR and Change and Percentage Change from Baseline by Visit
Modified ITT Analysis Set
15.9.2.7.1
MELD Score and Change and Percentage Change from Baseline 
by Visit
Full Analysis Set
15.9.2.7.2
MELD Score and Change and Percentage Change from Baseline 
by Visit
Modified ITT Analysis Set


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Table 
Number
Description
Analysis Set
15.9.2.7.3
CPT Score and Change and Percentage Change from Baseline by 
Visit
Full Analysis Set
15.9.2.7.4
CPT Score and Change and Percentage Change from Baseline by 
Visit
Modified ITT Analysis Set
15.9.2.7.5
Maddrey’s DF Score and Change and Percentage Change from 
Baseline by Visit
Full Analysis Set
15.9.2.7.6
Maddrey’s DF Score and Change and Percentage Change from 
Baseline by Visit
Modified ITT Analysis Set
15.9.3.1.1
ELF Test Score and Change and Percentage Change from Baseline 
by Visit (Subjects with Nonmissing Baseline and Week 4 Values)
Full Analysis Set
15.9.3.1.2
ELF Test Score and Change and Percentage Change from Baseline 
by Visit (Subjects with Nonmissing Baseline and Week 4 Values)
Modified ITT Analysis Set
15.9.3.1.3
Hyaluronic Acid and Change and Percentage Change from 
Baseline by Visit (Subjects with Nonmissing Baseline and Week 4 
Values)
Full Analysis Set
15.9.3.1.4
Hyaluronic Acid and Change and Percentage Change from 
Baseline by Visit (Subjects with Nonmissing Baseline and Week 4 
Values)
Modified ITT Analysis Set
15.9.3.1.5
PIIINP and Change and Percentage Change from Baseline by Visit 
(Subjects with Nonmissing Baseline and Week 4 Values)
Full Analysis Set
15.9.3.1.6
PIIINP and Change and Percentage Change from Baseline by Visit 
(Subjects with Nonmissing Baseline and Week 4 Values)
Modified ITT Analysis Set
15.9.3.1.7
TIMP-1 and Change and Percentage Change from Baseline by 
Visit (Subjects with Nonmissing Baseline and Week 4 Values)
Full Analysis Set
15.9.3.1.8
TIMP-1 and Change and Percentage Change from Baseline by 
Visit (Subjects with Nonmissing Baseline and Week 4 Values)
Modified ITT Analysis Set
15.9.3.2.1
Number (%) of Subjects with Recidivism to Alcohol by Visit
Full Analysis Set
15.9.3.2.2
Number (%) of Subjects with Recidivism to Alcohol by Visit
Modified ITT Analysis Set
15.9.3.3.1
HbA1c and Change and Percentage Change from Baseline
Full Analysis Set
15.9.3.3.2
HbA1c and Change and Percentage Change from Baseline
Modified ITT Analysis Set
15.9.4.1
Number (%) of Subjects with Death On/Prior to Study Day 28 by 
Subgroup (Subjects with Death/Follow-Up Through Day 28)
Full Analysis Set
15.9.4.2
Number (%) of Subjects with Death On/Prior to Week 8 by 
Subgroup (Subjects with Death/Follow-Up Through Week 8)
Full Analysis Set
15.9.4.3
Lille Score (Complete, Partial, and Null Response) at Week 1 by 
Subgroup (Missing Lille Score at Visit = Null Response)
Full Analysis Set
15.9.4.4
Lille Score (Complete, Partial, and Null Response) at Week 2 by 
Subgroup (Missing Lille Score at Visit = Null Response)
Full Analysis Set
15.9.4.5
Lille Score (Complete, Partial, and Null Response) at Week 4 
(LOCF) by Subgroup
(Missing Lille Score at Visit = Null Response)
Full Analysis Set


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Table 
Number
Description
Analysis Set
15.10.1.1
Plasma Selonsertib Concentrations (ng/mL) by Subject with 
Summary Statistics for Each Substudy Timepoint
PK Substudy Analysis Set
15.10.1.2
Plasma GS-607509 Concentrations (ng/mL) by Subject with 
Summary Statistics for Each Substudy Timepoint
PK Substudy Analysis Set
15.10.1.3
Plasma Selonsertib Pharmacokinetic Parameters by Subject with 
Summary Statistics for Each Parameter
PK Substudy Analysis Set
15.10.1.4
Plasma GS-607509 Pharmacokinetic Parameters by Subject with 
Summary Statistics for Each Parameter
PK Substudy Analysis Set
15.10.1.5
Plasma Selonsertib Concentrations (ng/mL) by Subject with 
Summary Statistics for Each Sparse Sampling Timepoint
PK Analysis Set
15.10.1.6
Plasma GS-607509 Concentrations (ng/mL) by Subject with 
Summary Statistics for Each Sparse Sampling Timepoint
PK Analysis Set
15.11.1
Extent of Exposure to Study Drug Regimen
Safety Analysis Set
15.11.2.1.1
Treatment-Emergent Adverse Events: Overall Summary
Safety Analysis Set
15.11.2.1.2
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term
Safety Analysis Set
15.11.2.1.3
Treatment-Emergent Adverse Events Occurring in At Least 10% 
of Subjects Within Any Treatment Group by Preferred Term
Safety Analysis Set
15.11.2.1.4
Treatment-Emergent Adverse Events by System Organ Class, 
High Level Term, and Preferred Term
Safety Analysis Set
15.11.2.2.1.1
Grade 3 or Higher Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and Severity
Safety Analysis Set
15.11.2.2.1.2
Grade 3 or Higher Treatment-Emergent Adverse Events by 
Preferred Term
Safety Analysis Set
15.11.2.2.2
Grade 2 or Higher Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term
Safety Analysis Set
15.11.2.3.1.1
Treatment-Emergent Treatment-Related Adverse Events by 
System Organ Class and Preferred Term
Safety Analysis Set
15.11.2.3.1.2
Treatment-Emergent Treatment-Related Adverse Events 
Occurring in at Least 5% of Subjects Within Any Treatment 
Group by Preferred Term
Safety Analysis Set
15.11.2.3.2.1
Grade 3 or Higher Treatment-Emergent Treatment-Related 
Adverse Events by System Organ Class, Preferred Term, and 
Severity
Safety Analysis Set
15.11.2.3.2.2
Grade 3 or Higher Treatment-Emergent Treatment-Related 
Adverse Events by Preferred Term
Safety Analysis Set
15.11.2.3.3
Grade 2 or Higher Treatment-Emergent Treatment-Related 
Adverse Events by System Organ Class and Preferred Term
Safety Analysis Set
15.11.2.4.1
Adverse Events Prior to First Dose of Study Drug by System 
Organ Class and Preferred Term
Safety Analysis Set


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Table 
Number
Description
Analysis Set
15.11.2.4.2
Summary of Subjects Meeting Any Selonsertib/Placebo Stopping 
Criteria
Safety Analysis Set
15.11.2.4.3
Grade 3 or Higher Treatment-Emergent Treatment-Related 
Adverse Event Leading to Premature Discontinuation of 
Selonsertib/Placebo by Preferred Term
Safety Analysis Set
15.11.2.4.4
Selonsertib/Placebo Laboratory Stopping Criteria
Safety Analysis Set
15.11.3
Treatment-Emergent Adverse Events with an Outcome of Death 
by System Organ Class and Preferred Term
Safety Analysis Set
15.11.4.1
Treatment-Emergent Serious Adverse Events by System Organ 
Class and Preferred Term
Safety Analysis Set
15.11.4.2
Treatment-Emergent Serious Adverse Events by Preferred Term
Safety Analysis Set
15.11.4.3
Treatment-Emergent Serious Adverse Events by System Organ 
Class, High Level Term, and Preferred Term
Safety Analysis Set
15.11.4.4
Treatment-Emergent Treatment-Related Serious Adverse Events 
by System Organ Class and Preferred Term
Safety Analysis Set
15.11.4.5
Treatment-Emergent Treatment-Related Serious Adverse Events 
by Preferred Term
Safety Analysis Set
15.11.5.1
Treatment-Emergent Adverse Events Leading to Premature 
Discontinuation of Selonsertib/Placebo
Safety Analysis Set
15.11.5.2
Treatment-Emergent Adverse Events Leading to Premature 
Discontinuation of Prednisolone
Safety Analysis Set
15.11.5.3
Treatment-Emergent Adverse Events Leading to Premature 
Discontinuation of Both Study Drugs in the Regimen
Safety Analysis Set
15.11.5.4
Treatment-Emergent Adverse Events Leading to Interruption of 
Selonsertib/Placebo
Safety Analysis Set
15.11.5.5
Treatment-Emergent Adverse Events Leading to Interruption of 
Prednisolone
Safety Analysis Set
15.11.5.6
Treatment-Emergent Adverse Events Leading to Dose 
Modification or Interruption of Prednisolone
Safety Analysis Set
15.11.6.1.1
Hemoglobin (g/dL) and Change from Baseline
Safety Analysis Set
15.11.6.1.2
Hematocrit (%) and Change from Baseline
Safety Analysis Set
15.11.6.1.3
Lymphocytes (x10^3/µL) and Change from Baseline
Safety Analysis Set
15.11.6.1.4
Neutrophils (x10^3/µL) and Change from Baseline
Safety Analysis Set
15.11.6.1.5
Platelet Count (x10^3/µL) and Change from Baseline
Safety Analysis Set
15.11.6.1.6
White Blood Cells (x10^3/µL) and Change from Baseline
Safety Analysis Set
15.11.6.1.7
Bicarbonate (mEq/L) and Change from Baseline
Safety Analysis Set
15.11.6.1.8
Sodium (mEq/L) and Change from Baseline
Safety Analysis Set
15.11.6.1.9
Chloride (mEq/L) and Change from Baseline
Safety Analysis Set
15.11.6.1.10
Magnesium (mg/dL) and Change from Baseline
Safety Analysis Set


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Table 
Number
Description
Analysis Set
15.11.6.1.11
Phosphorus (mg/dL) and Change from Baseline
Safety Analysis Set
15.11.6.1.12
Potassium (mEq/L) and Change from Baseline
Safety Analysis Set
15.11.6.1.13
Albumin Corrected Calcium (mg/dL) and Change from Baseline
Safety Analysis Set
15.11.6.1.14
Lactate Dehydrogenase (U/L) and Change from Baseline
Safety Analysis Set
15.11.6.1.15
Blood Urea Nitrogen (mg/dL) and Change from Baseline
Safety Analysis Set
15.11.6.1.16
Serum Creatinine (mg/dL) and Change from Baseline
Safety Analysis Set
15.11.6.1.17
Serum Glucose (mg/dL) and Change from Baseline
Safety Analysis Set
15.11.6.2
Treatment-Emergent Grade 3 or 4 Laboratory Abnormalities
Safety Analysis Set
15.11.6.3
Treatment-Emergent Marked Laboratory Abnormalities
Safety Analysis Set
15.11.7.1.1
Systolic Blood Pressure (mmHg) and Change from Baseline
Safety Analysis Set
15.11.7.1.2
Diastolic Blood Pressure (mmHg) and Change from Baseline
Safety Analysis Set
15.11.7.1.3
Pulse (beats/min) and Change from Baseline
Safety Analysis Set
15.11.7.2.1
Concomitant Medications by Preferred Drug Name
Safety Analysis Set
15.11.7.2.2
Concomitant Enteral and Parenteral Nutrition by Preferred Drug 
Name
Safety Analysis Set
15.11.8.1
Shift Table of Baseline vs. Postbaseline 12-Lead ECG 
Assessments
Safety Analysis Set


Selonsertib (ASK1 Inhibitor, formerly GS-4997)
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Figure 
Number
Description
Analysis Set
15.8.1
Disposition of Study Subjects
Safety Analysis Set
15.9.1.1
Kaplan-Meier Estimates of Survival
Full Analysis Set
15.9.1.2
Kaplan-Meier Estimates of Survival
Modified ITT Analysis Set
15.9.1.3
Kaplan-Meier Estimates of Transplantation-Free Survival
Full Analysis Set
15.9.1.4
Kaplan-Meier Estimates of Transplantation-Free Survival
Modified ITT Analysis Set
15.9.2.2.1
Median (Q1, Q3) Lille Score by On-Treatment Visit (Covance 
Central Laboratory Results)
Full Analysis Set
15.9.2.2.2
Median (Q1, Q3) Lille Score by On-Treatment Visit (Covance 
Central Laboratory Results)
Modified ITT Analysis Set
15.9.2.2.1
Median (Q1, Q3) MELD Score by Visit
Full Analysis Set
15.9.2.2.2
Median (Q1, Q3) MELD Score by Visit
Modified ITT Analysis Set
15.9.2.2.3
Median (Q1, Q3) Change from Baseline in MELD Score by Visit
Full Analysis Set
15.9.2.2.4
Median (Q1, Q3) Change from Baseline in MELD Score by Visit
Modified ITT Analysis Set
15.9.2.2.5
Median (Q1, Q3) Percentage Change from Baseline in MELD  
Score by Visit
Full Analysis Set
15.9.2.2.6
Median (Q1, Q3) Percentage Change from Baseline in MELD 
Score by Visit
Modified ITT Analysis Set
15.9.2.3.1
Median (Q1, Q3) Total Bilirubin (mg/dL) by Visit
Full Analysis Set
15.9.2.3.2
Median (Q1, Q3) Total Bilirubin (mg/dL) by Visit
Modified ITT Analysis Set
15.9.2.3.3
Median (Q1, Q3) Change from Baseline in Total Bilirubin
(mg/dL) by Visit
Full Analysis Set
15.9.2.3.4
Median (Q1, Q3) Change from Baseline in Total Bilirubin 
(mg/dL) by Visit
Modified ITT Analysis Set
15.9.2.3.5
Median (Q1, Q3) Percentage Change from Baseline in Total  
Bilirubin by Visit
Full Analysis Set
15.9.2.3.6
Median (Q1, Q3) Percentage Change from Baseline in Total 
Bilirubin by Visit
Modified ITT Analysis Set
15.9.2.4.1
Median (Q1, Q3) ALT (U/L) by Visit
Full Analysis Set
15.9.2.4.2
Median (Q1, Q3) ALT (U/L) by Visit
Modified ITT Analysis Set
15.9.2.5.1
Median (Q1, Q3) AST (U/L) by Visit
Full Analysis Set
15.9.2.5.2
Median (Q1, Q3) AST (U/L) by Visit
Modified ITT Analysis Set
15.9.2.6.1
Median (Q1, Q3) INR by Visit
Full Analysis Set
15.9.2.6.2
Median (Q1, Q3) INR by Visit
Modified ITT Analysis Set


Selonsertib (ASK1 Inhibitor, formerly GS-4997)
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Statistical Analysis Plan – Final Analysis
Version 1
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Figure 
Number
Description
Analysis Set
15.10.1
Mean (SD) Selonsertib Plasma Concentration vs Time (Linear and 
Semilogarithmic Scale)
PK Substudy Analysis Set
15.10.2
Mean (SD) GS-607509 Plasma Concentration vs Time (Linear and 
Semilogarithmic Scale)
PK Substudy Analysis Set
15.11.6.1.16
Median (Q1, Q3) Serum Creatinine (mg/dL) by Visit
Safety Analysis Set


Selonsertib (ASK1 Inhibitor, formerly GS-4997)
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Version 1
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Listing 
Number
Description
Analysis Set
16.1.6
Lot Numbers and Bottle/Carton IDs
Safety Analysis Set
16.1.7
Randomization Scheme and Codes
Randomized Subjects
16.2.1.1
Subject Disposition
Safety Analysis Set
16.2.1.2
Reasons for Screen Failure
Subjects Screened But Not 
Randomized
16.2.2.1
Important Protocol Deviations
Safety Analysis Set
16.2.2.2
Randomization Stratification Discrepancies between IWRS and 
Clinical Database
Safety Analysis Set
16.2.2.3
Subjects Who Received Incorrect Study Drug
Safety Analysis Set
16.2.3
Subjects Who Were Excluded From the Safety/mITT and/or Full 
Analysis Sets
Randomized Subjects
16.2.4.1
Demographics
Safety Analysis Set
16.2.4.2.1
Baseline Characteristics (I)
Safety Analysis Set
16.2.4.2.2
Baseline Characteristics (II)
Safety Analysis Set
16.2.4.2.3
Baseline Characteristics (III)
Safety Analysis Set
16.2.4.2.4
Baseline Characteristics (IV)
Safety Analysis Set
16.2.4.2.5
Baseline Characteristics (V)
Safety Analysis Set
16.2.4.2.6
Prior  Corticosteroids Administered for Treatment of Alcoholic 
Hepatitis 
Safety Analysis Set
16.2.4.3.1
Medical History
Safety Analysis Set
16.2.4.3.2
Chest X-Ray
Safety Analysis Set
16.2.4.3.3
Liver Imaging
Safety Analysis Set
16.2.4.3.4
Baseline Infections with Cultures and/or PMNC Counts from 
Ascitic Fluid
Safety Analysis Set
16.2.4.3.5
Prior Medications Used to Treat Baseline Infections
Safety Analysis Set
16.2.4.4.1
Prior and Concomitant Medications
Safety Analysis Set
16.2.4.4.2
Prior and Concomitant Enteral and Parenteral Nutrition
Safety Analysis Set
16.2.5.1
Study Drug Administration
Safety Analysis Set
16.2.5.2
Subjects Who Prematurely Discontinued Any of the Study Drugs
Safety Analysis Set
16.2.5.3
Study Drug Accountability and Adherence
Safety Analysis Set
16.2.5.4.1
Plasma Pharmacokinetic Sampling Details and Concentrations
PK Analysis Set
16.2.5.4.2
Terminal Elimination Rate Constant and Half Life of Drug
PK Substudy Analysis Set
16.2.6.1.1
Deaths
Modified ITT Analysis Set
16.2.6.1.2
Liver Transplants
Modified ITT Analysis Set
16.2.6.2.1
Lille Scores (Covance Central Laboratory Results)
Modified ITT Analysis Set


Selonsertib (ASK1 Inhibitor, formerly GS-4997)
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Statistical Analysis Plan – Final Analysis
Version 1
CONFIDENTIAL
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Listing 
Number
Description
Analysis Set
16.2.6.2.2
Categorical Efficacy Endpoints for Lille Score and Death
Modified ITT Analysis Set
16.2.6.3
MELD Score, Total Bilirubin, and Direct Bilirubin and Change 
and Percentage Change from Baseline (Efficacy Visit Windows 
Through Week 8)
Modified ITT Analysis Set
16.2.6.4
CPT Score and Maddrey's Discriminant Function and Change and 
Percentage Change from Baseline (Efficacy Visit Windows 
Through Week 8)
Modified ITT Analysis Set
16.2.6.5
AST, ALT, and Alkaline Phosphatase and Change and Percentage 
Change from Baseline (Efficacy Visit Windows Through Week 8)
Modified ITT Analysis Set
16.2.6.6
GGT, Albumin and INR and Change and Percentage Change from 
Baseline (Efficacy Visit Windows Through Week 8)
Modified ITT Analysis Set
16.2.6.7.1
Postbaseline Definite or Probable Infections Reported Through 
End of Study
Modified ITT Analysis Set
16.2.6.7.2
Postbaseline Cultures, X-Rays, and/or Polymorphonuclear Cell 
Counts from Ascitic Fluid for Infections
Modified ITT Analysis Set
16.2.6.7.3
Postbaseline Medications Administered to Treat Infections
Through End of Study
Modified ITT Analysis Set
16.2.6.8.1
Postbaseline Hepatorenal Syndrome (HRS)
Modified ITT Analysis Set
16.2.6.8.2
Postbaseline Medications Used to Treat Hepatorenal Syndrome
Modified ITT Analysis Set
16.2.6.9
Length of Initial Hospital Stay (Days) from First Study Drug Dose 
Date
Modified ITT Analysis Set
16.2.6.10.1
ELF Score and Hyaluronic Acid and Change and Percentage 
Change from Baseline (Efficacy Visit Windows Through Week 4)
Modified ITT Analysis Set
16.2.6.10.2
PIIINP and TIMP-1 and Change and Percentage Change from 
Baseline (Efficacy Visit Windows Through Week 4)
Modified ITT Analysis Set
16.2.7.1
Adverse Events
Safety Analysis Set
16.2.7.2
Adverse Events Leading to Death
Safety Analysis Set
16.2.7.3.1
Serious Adverse Events
Safety Analysis Set
16.2.7.3.2
Serious Adverse Events Related to Study Treatment
Safety Analysis Set
16.2.7.4.1
Adverse Events with Severity of Grade 3 or Higher
Safety Analysis Set
16.2.7.4.2
Adverse Events with Severity of Grade 3 or Higher Related to
Study Treatment
Safety Analysis Set
16.2.7.5.1
Adverse Events Leading to Premature Discontinuation of Any of 
the Study Drugs
Safety Analysis Set
16.2.7.5.2
Adverse Events Leading to Dose Modification or Interruption of 
Any of the Study Drugs
Safety Analysis Set


Selonsertib (ASK1 Inhibitor, formerly GS-4997)
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Version 1
CONFIDENTIAL
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21 May 2018
Listing 
Number
Description
Analysis Set
16.2.7.6.1
Selonsertib/Placebo Stopping Criteria 1: Grade 3 or Higher AEs 
Related to Study Drug that Led to Premature Discontinuation of 
Selonsertib/Placebo
Safety Analysis Set
16.2.7.6.2
Selonsertib/Placebo Stopping Criteria 2: Lille Score > 0.85 While 
on Study Drug
Safety Analysis Set
16.2.7.6.3
Selonsertib/Placebo Stopping Criteria 3: Death On/Prior to Study 
Day 28
Safety Analysis Set
16.2.7.6.4.1
Selonsertib/Placebo Stopping Criteria 4.1: Confirmed ALT or AST 
> 5 X Baseline While on Study Drug
Safety Analysis Set
16.2.7.6.4.2
Selonsertib/Placebo Stopping Criteria 4.2: ALT or AST > 500 U/L 
While on Study Drug
Safety Analysis Set
16.2.7.6.4.3
Selonsertib/Placebo Stopping Criteria 4.3: Confirmed Total 
Bilirubin > 3 X Baseline or Nadir While on Study Drug
Safety Analysis Set
16.2.8.1.1.1
Local and Covance Laboratory Screening Tests I 
Safety Analysis Set
16.2.8.1.1.2
Local and Covance Laboratory Screening Tests II
Safety Analysis Set
16.2.8.1.1.3
Covance Urine Drug Screen: Amphetamines/MDMA, Cocaine,
Opiates, and Cannabinoids
Safety Analysis Set
16.2.8.1.1.4
Central Laboratory (Covance) Reference Ranges
16.2.8.1.2.1
Hematology: Hematocrit, Hemoglobin, RBC, MCV, MCH, 
MCHC, and Platelets
Safety Analysis Set
16.2.8.1.2.2
Hematology: WBC, Neutrophils, and Lymphocytes
Safety Analysis Set
16.2.8.1.2.3
Hematology: Eosinophils, Basophils, and Monocytes
Safety Analysis Set
16.2.8.1.3.1
Chemistry: Sodium, Postassium, Bicarbonate, Chloride, 
Phosphorus, and Magnesium
Safety Analysis Set
16.2.8.1.3.2
Chemistry: Calcium, Calcium Corrected for Albumin, LDH, BUN, 
Uric Acid, Total Protein, and Serum Creatinine
Safety Analysis Set
16.2.8.1.3.3
Liver Related Chemistry: AST, ALT, Total Bilirubin, Direct 
Bilirubin, Alkaline Phosphatase, GGT, and Albumin
Safety Analysis Set
16.2.8.1.4
Coagulation: Prothrombin Time, Prothrombin Time Control, INR, 
and APTT
Safety Analysis Set
16.2.8.1.5.1
Lipids: Triglycerides, Total Cholesterol, HDL, and Calculated 
LDL and VLDL
Safety Analyis Set
16.2.8.1.5.2
Other: Insulin and HbA1c
Modified ITT Analysis Set
16.2.8.1.5.3
Other: Urine Pregnancy Test Results (Female Subjects)
Safety Analysis Set
16.2.8.1.6
Treatment-Emergent Grade 3 or Higher Laboratory Abnormalities
Safety Analysis Set
16.2.8.2.1
Body Height, Weight, BMI, and Vital Signs
Safety Analysis Set
16.2.8.2.2
12-Lead ECG Assessment
Safety Analysis Set
16.2.8.3
Pregnancy Report
Safety Analysis Set


Selonsertib (ASK1 Inhibitor, formerly GS-4997) 
GS-US-416-2124 
Statistical Analysis Plan- Final Analysis 
Version 1 
Appendix 2. 
GS-US-416-2124 Programming Specifications 
Lille Score Imputations 
Subjects missing a Covance-calculated Lille score at Week 1 who have a calculable value at 
Week 1 using local laboratory data (flagged with '*')will have local laboratory data used in 
place of Covance data for their entire duration of treatment. Subjects missing central laboratory 
data at Week 1 and the reason for the data being missing is outlined below: 
Subject ID 
Reason for Missing Data 
Both screening and Day 1 central laboratory samples were drawn, but were 
cancelled due to samples being out of stability when they arrived at Co vance. 
Day 1 Prothrombin time and INR were cancelled. No screening central labs were 
drawn for this subject. Subject stopped both drugs [local labs] at Week 1 for Lille 
score stopping criteria. 
Week 1 central laboratory total bilirubin was cancelled for "insufficient quantity" 
by Covance labs. Biomarker samples were not covered with a light resistant 
substance (total bilirubin requires covering) so could not be used to retest. Subject 
stopped prednisolone at Week 1 per local laboratory values. 
Week 1 central laboratory total bilirubin was not collected due to difficulties 
drawing blood. 
INR and PT were cancelled at both screening and baseline by Covance. Local 
laboratory values will be used. 
Covance labs were not collected by the site at the Week 1 visit. This subject was a 
"hard stick" and not enough blood could be drawn to run Covance labs. Local 
laboratory data will be used. 
NO IMPUTATION (Lille Score missing at Week 1); use Covance results for Lille scores: 
Subject was hospitalized at Week 1 for SAE hepatic encephalopathy. Subject 
enrolled under Amendment 1, so no local laboratory data was collected. Covance 
laboratory data will be used to calculate MELD score and Week 1 will be 
mtssmg. 
Week 1 central and local laboratory total bilirubin not collected until Study Day 
11 (outside the Week 1 visit window) due to Thanksgiving holiday. Covance 
laboratory data will be used to calculate MELD score; Week 1 will be missing. 
Protocol Violation reason for early d/c of drug; DIED before Week 1. 
DIED before reaching the Week 1 study visit 
CONFIDENTIAL 
Page 68 
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Selonsertib (ASK1 Inhibitor, formerly GS-4997) 
GS-US-416-2124 
Statistical Analysis Plan- Final Analysis 
Version 1 
Code to be used {or Lille scores: Subjects with non-missing values from Covance available to 
calculate Week 1 Lille score and subjects for whom a Week 1 Lille score is not calculable for 
both local laboratory and central laboratory data will use Covance laboratory results to calculate 
Lille scores for all on-treatment visits. 
MELD Score Imputations 
Subjects missing a baseline Covance MELD score will have their local laboratory screening 
MELD score (collected to assess inclusion/exclusion criteria and for stratification) used in place 
of the Covance baseline MELD score (subjects with ' #' below). Subjects missing baseline 
MELD scores from central laboratory data and the reason for their data being missing are 
outlined below: 
Subject ID 
Reason for Missing Data 
Serum enzymatic creatinine was not able to be resulted, and sample was not 
available for retesting using LCMSMS methodology (Covance test kit was 
Amendment 1 protocol test kit). The subject died in first week and has no 
postbaseline data. Use local lab screening MELD score. 
Both screening and Day 1 central laboratory samples were drawn, but were 
cancelled due to samples being out of stability when they arrived at Covance. Use 
local lab screening MELD score. 
Day 1 Prothrombin time and INR were cancelled by Covance. No screening 
central labs were drawn for this subject. Use local lab screening MELD score. 
INR and PT were cancelled by Covance at both the screening and baseline visits. 
Use local lab screening MELD score. 
CONFIDENTIAL 
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Prot_003.pdf: 


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Final
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Amendment 3
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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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Gilead Sciences, Inc. 
Amendment 3
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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 
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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.


GS-4997
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Gilead Sciences, Inc. 
Amendment 3
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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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Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 93
04 August 2017
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, 
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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.
Angeli P, Gines P, Wong F, Bernardi M, Boyer TD, Gerbes A, et al. Diagnosis and management 
of acute kidney injury in patients with cirrhosis: revised consensus 
recommendations of the International Club of Ascites. Gut 2015;64 (4):531-7.
Cederbaum AI, Yang L, Wang X, Wu D. CYP2E1 Sensitizes the Liver to LPS- and TNF alpha-
Induced Toxicity via Elevated Oxidative and Nitrosative Stress and Activation of 
ASK-1 and JNK Mitogen-Activated Kinases. International journal of hepatology 
2012;2012:582790.
Chayanupatkul M, Liangpunsakul S. Alcoholic hepatitis: a comprehensive review of 
pathogenesis and treatment. World J Gastroenterol 2014;20 (20):6279-86.
European Association for the Study of the Liver (EASL). EASL clinical practical guidelines: 
management of alcoholic liver disease. J Hepatol 2012;57 (2):399-420.
Fujino G, Noguchi T, Matsuzawa A, Yamauchi S, Saitoh M, Takeda K, et al. Thioredoxin and 
TRAF family proteins regulate reactive oxygen species-dependent activation of 
ASK1 through reciprocal modulation of the N-terminal homophilic interaction of 
ASK1. Mol Cell Biol 2007;27 (23):8152-63.
Fujisawa T, Takeda K, Ichijo H. ASK family proteins in stress response and disease. Molecular 
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Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. 
Gastroenterology 2011;141 (5):1572-85.
Gerczuk PZ, Breckenridge DG, Liles JT, Budas GR, Shryock JC, Belardinelli L, et al. An 
apoptosis signal-regulating kinase 1 inhibitor reduces cardiomyocyte apoptosis 
and infarct size in a rat ischemia-reperfusion model. J Cardiovasc Pharmacol 
2012;60 (3):276-82.
Hislop WS, Bouchier IA, Allan JG, Brunt PW, Eastwood M, Finlayson ND, et al. Alcoholic liver 
disease in Scotland and northeastern England: presenting features in 510 patients. 
Q J Med 1983;52 (206):232-43.


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Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 94
04 August 2017
Imoto K, Kukidome D, Nishikawa T, Matsuhisa T, Sonoda K, Fujisawa K, et al. Impact of 
mitochondrial reactive oxygen species and apoptosis signal-regulating kinase 1 on 
insulin signaling. Diabetes 2006;55 (5):1197-204.
Jinjuvadia R, Liangpunsakul S, Translational R, Evolving Alcoholic Hepatitis Treatment C. 
Trends in Alcoholic Hepatitis-related Hospitalizations, Financial Burden, and 
Mortality in the United States. J Clin Gastroenterol 2015;49 (6):506-11.
Louvet A, Labreuche J, Artru F, Boursier J, Kim DJ, O'Grady J, et al. Combining Data From 
Liver Disease Scoring Systems Better Predicts Outcomes of Patients With 
Alcoholic Hepatitis. Gastroenterology 2015;149 (2):398-406 e8.
Louvet A, Naveau S, Abdelnour M, Ramond MJ, Diaz E, Fartoux L, et al. The Lille model: a 
new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated 
with steroids. Hepatology 2007;45 (6):1348-54.
Louvet A, Wartel F, Castel H, Dharancy S, Hollebecque A, Canva-Delcambre V, et al. Infection 
in patients with severe alcoholic hepatitis treated with steroids: early response to 
therapy is the key factor. Gastroenterology 2009;137 (2):541-8.
Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med 2009;360 (26):2758-69.
Mathurin P, O'Grady J, Carithers RL, Phillips M, Louvet A, Mendenhall CL, et al. 
Corticosteroids improve short-term survival in patients with severe alcoholic 
hepatitis: meta-analysis of individual patient data. Gut 2011;60 (2):255-60.
Matsuzawa A, Saegusa K, Noguchi T, Sadamitsu C, Nishitoh H, Nagai S, et al. ROS-dependent 
activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-
mediated innate immunity. Nature immunology 2005;6 (6):587-92.
Meagher EA, Barry OP, Burke A, Lucey MR, Lawson JA, Rokach J, et al. Alcohol-induced 
generation of lipid peroxidation products in humans. J Clin Invest 1999;104 
(6):805-13.
Michelena J, Altamirano J, Abraldes JG, Affo S, Morales-Ibanez O, Sancho-Bru P, et al. 
Systemic inflammatory response and serum lipopolysaccharide levels predict 
multiple organ failure and death in alcoholic hepatitis. Hepatology 2015;62 
(3):762-72.
Mnich SJ, Blanner PM, Hu LG, Shaffer AF, Happa FA, O'Neil S, et al. Critical role for apoptosis 
signal-regulating kinase 1 in the development of inflammatory K/BxN serum-
induced arthritis. Int Immunopharmacol 2010;10 (10):1170-6.
Nagai H, Noguchi T, Takeda K, Ichijo H. Pathophysiological Roles of ASK1-MAP Kinase 
Signaling Pathways. Journal of Biochemistry and Molecular Biology 2007;40 
(1):1-6.


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Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 95
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Nakagawa H, Hirata Y, Takeda K, Hayakawa Y, Sato T, Kinoshita H, et al. Apoptosis signal-
regulating kinase 1 inhibits hepatocarcinogenesis by controlling the tumor-
suppressing function of stress-activated mitogen-activated protein kinase. 
Hepatology 2011;54 (1):185-95.
Nakagawa H, Maeda S, Hikiba Y, Ohmae T, Shibata W, Yanai A, et al. Deletion of apoptosis 
signal-regulating kinase 1 attenuates acetaminophen-induced liver injury by 
inhibiting c-Jun N-terminal kinase activation. Gastroenterology 2008;135 
(4):1311-21.
Nakamura T, Kataoka K, Fukuda M, Nako H, Tokutomi Y, Dong YF, et al. Critical role of 
apoptosis signal-regulating kinase 1 in aldosterone/salt-induced cardiac 
inflammation and fibrosis. Hypertension 2009;54 (3):544-51.
Nguyen-Khac E, Thevenot T, Piquet MA, Benferhat S, Goria O, Chatelain D, et al. 
Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J Med 
2011;365 (19):1781-9.
Noguchi H, Yamada S, Nabeshima A, Guo X, Tanimoto A, Wang KY, et al. Depletion of 
apoptosis signal-regulating kinase 1 prevents bile duct ligation-induced 
necroinflammation and subsequent peribiliary fibrosis. Am J Pathol 2014:1-18.
O'Shea RS, Dasarathy S, McCullough AJ, Practice Guideline Committee of the American 
Association for the Study of Liver D, Practice Parameters Committee of the 
American College of G. Alcoholic liver disease. Hepatology 2010;51 (1):307-28.
O'Shea RS, McCullough AJ. Treatment of alcoholic hepatitis. Clin Liver Dis 2005;9 (1):103-34.
Rudler M, Mouri S, Charlotte F, Lebray P, Capocci R, Benosman H, et al. Prognosis of treated 
severe alcoholic hepatitis in patients with gastrointestinal bleeding. J Hepatol 
2015;62 (4):816-21.
Singal AK, Guturu P, Hmoud B, Kuo YF, Salameh H, Wiesner RH. Evolving frequency and 
outcomes of liver transplantation based on etiology of liver disease. 
Transplantation 2013;95 (5):755-60.
Spahr L, Rubbia-Brandt L, Frossard JL, Giostra E, Rougemont AL, Pugin J, et al. Combination 
of steroids with infliximab or placebo in severe alcoholic hepatitis: a randomized 
controlled pilot study. J Hepatol 2002;37 (4):448-55.
Taieb J, Mathurin P, Elbim C, Cluzel P, Arce-Vicioso M, Bernard B, et al. Blood neutrophil 
functions and cytokine release in severe alcoholic hepatitis: effect of 
corticosteroids. J Hepatol 2000;32 (4):579-86.
Takeda K, Noguchi T, Naguro I, Ichijo H. Apoptosis signal-regulating kinase 1 in stress and 
immune response. Annu Rev Pharmacol Toxicol 2008;48:199-225.


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Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 96
04 August 2017
Terada Y, Inoshita S, Kuwana H, Kobayashi T, Okado T, Ichijo H, et al. Important role of 
apoptosis signal-regulating kinase 1 in ischemic acute kidney injury. Biochem 
Biophys Res Commun 2007;364 (4):1043-9.
Thursz MR, Richardson P, Allison M, Austin A, Bowers M, Day CP, et al. Prednisolone or 
pentoxifylline for alcoholic hepatitis. N Engl J Med 2015;372 (17):1619-28.
Tobiume K, Matsuzawa A, Takahashi T, Nishitoh H, Morita K, Takeda K, et al. ASK1 is 
required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO 
reports 2001;2 (3):222-8.
Tobiume K, Saitoh M, Ichijo H. Activation of apoptosis signal-regulating kinase 1 by the stress-
induced activating phosphorylation of pre-formed oligomer. Journal of cellular 
physiology 2002;191 (1):95-104.
Toldo S, Breckenridge DG, Mezzaroma E, Tassell BW, Shryock J, Kannan H, et al. Inhibition of 
apoptosis signal-regulating kinase 1 reduces myocardial ischemia-reperfusion 
injury in the mouse. Journal of the American Heart Association 2012;1 
(5):e002360.
Watanabe T, Otsu K, Takeda T, Yamaguchi O, Hikoso S, Kashiwase K, et al. Apoptosis signal-
regulating kinase 1 is involved not only in apoptosis but also in non-apoptotic 
cardiomyocyte death. Biochem Biophys Res Commun 2005;333 (2):562-7.
Xie Y, Ramachandran A, Breckenridge DG, Liles JT, Lebofsky M, Farhood A, et al. Inhibitor of 
apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver 
injury. Toxicol Appl Pharmacol 2015;286 (1):1-9.
Yokoi T, Fukuo K, Yasuda O, Hotta M, Miyazaki J, Takemura Y, et al. Apoptosis signal-
regulating kinase 1 mediates cellular senescence induced by high glucose in 
endothelial cells. Diabetes 2006;55 (6):1660-5.
Zhang R, Al-Lamki R, Bai L, Streb JW, Miano JM, Bradley J, et al. Thioredoxin-2 inhibits 
mitochondria-located ASK1-mediated apoptosis in a JNK-independent manner. 
Circ Res 2004;94 (11):1483-91.
Ziol M, Tepper M, Lohez M, Arcangeli G, Ganne N, Christidis C, et al. Clinical and biological 
relevance of hepatocyte apoptosis in alcoholic hepatitis. J Hepatol 2001;34 
(2):254-60.


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Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 97
04 August 2017
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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Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 103
04 August 2017
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.


GS-4997
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Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
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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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Amendment 3
CONFIDENTIAL
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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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Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 106
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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

Prot_002.pdf: 


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Prot_000.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
~ GILEAU 
CLINICAL STUDY PROTOCOL 
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) 
Gilead Sciences, Inc. 
129570 
2016-000821-3 7 
TBD 
Alcoholic Hepatitis (AH) 
GS-US-416-2124 
Gilead Medical Monitor: 
Name: 
Rob My_er_·s_., 
PPD 
Telephone: 
Fax: 
PPD 
Email: 
t-'t-'U 
Protocol Version/Date: 
Original: 
12 April2016 
CONFIDENTIALITY STATEMENT 
The infonnation contained in this document, particularly 1mpublished data, is the prope1ty or 
under contTol of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The infmmation is only to be used by you in 
collllection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the info1mation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessa1y to obtain infonned consent from those 
persons to whom the dmg may be administered. 


GS-4997
Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 2
12 April 2016
TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
LIST OF IN-TEXT FIGURES ......................................................................................................................................4
PROTOCOL SYNOPSIS ..............................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................17
1.
INTRODUCTION ..............................................................................................................................................21
1.1.
Background ............................................................................................................................................21
1.2.
GS-4997 .................................................................................................................................................22
1.2.1.
General Information .............................................................................................................22
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................23
1.2.3.
Preclinical Drug Metabolism and Pharmacokinetics............................................................24
1.2.4.
Preclinical Toxicology .........................................................................................................24
1.2.5.
Clinical Trials of GS-4997 ...................................................................................................25
1.3.
Rationale for This Study ........................................................................................................................30
1.4.
Rationale for Dose Selection..................................................................................................................31
1.5.
Risk/Benefit Assessment for the Study..................................................................................................31
1.6.
Compliance ............................................................................................................................................32
2.
OBJECTIVES.....................................................................................................................................................33
3.
STUDY DESIGN................................................................................................................................................35
3.1.
Study Design..........................................................................................................................................35
3.2.
Treatment Plan and Regimen .................................................................................................................35
3.3.
Biomarker Testing..................................................................................................................................37
3.3.1.
Biomarker Samples to Address the Study Objectives ..........................................................37
3.3.2.
Biomarker Samples for Optional Future Research...............................................................38
3.3.3.
Biomarker Samples for Optional Genomic Research...........................................................39
4.
SUBJECT POPULATION..................................................................................................................................41
4.1.
Number of Subjects and Subject Selection ............................................................................................41
4.2.
Inclusion Criteria....................................................................................................................................41
4.3.
Exclusion Criteria...................................................................................................................................42
5.
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
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.....................................................................................................................47
5.6.1.
Investigational Medicinal Product Return or Disposal.........................................................47
6.
STUDY PROCEDURES ....................................................................................................................................49


GS-4997 
Protocol GS-US-416-2124 
Gilead Sciences, Inc. 
6.1. 
6.2. 
6.3. 
6.4. 
6.5. 
6.6. 
6.7. 
6.8. 
6.9. 
6.1 0. 
Subject Emollment and Treatment Assignment . 
Pretreatment Assessments 
............... .............. . 
6.2.1. 
Screening Visit 
............... ............... .............. . 
6.2.2. 
Baseline I Day 1 Assessments and Randomization 
Treatment Assessments 
............... ............... .............. . 
6.3.1. 
Week 1 Visit (±3 Days) 
6.3.2. 
Week 2 Visit (±3 Days) 
6.3.3. 
Week 3 Visit (±3 Days) 
............... .............. . 
6.3.4. 
Week 4 I End of Treatment Visit (EoT) (±3 days) 
6.3.5. 
Follow Up Visit (±5 Days) ... ............... .............. . 
Pharmacokinetic Assessments .............. . 
6.4.1. 
Sparse PK 
.............. . 
6.4.2. 
Intensive PK Substudy 
6.4.3. 
PPD 
Post-Treatm'-e-n-:-t'A:-s-se-s-sm 
.. ._
en~ts~ 
.. _ _. 
6.5.1. 
Week 6 (± 3 Days) ... 
6.5.2. 
Weeks 8, 16, and 20 / Post Treatment Visits(± 5 Days) ..... 
6.5.3. 
Weeks 12 and 24 I Post Treatment Visits(± 5 Days) .. 
Unscheduled Visits ....... . 
Assessments for Premature Discontinuation from Study ..... . 
Criteria for Discontinuation of Study Treatment. .. 
Description of Assessments .. 
6.9.1. 
Liver Biopsy 
6.9.2. 
Electrocardiogram 
6.9.3. 
AUDIT I SADQ Questionnaires .. 
6.9.4. 
Quality of Life (QoL) Measures .. 
6.9.5. 
Hepatic Encephalopathy ..... . 
6.9.6. 
Ascites . 
6.9.7. 
Hepatorenal Syndrome (HRS) .. 
6.9. 8. 
Infection ..... . 
End of Study Definition 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ..... . 
8. 
7.1. 
7.2. 
7.3. 
7.4. 
7.5. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events . 
7.1.1. 
Adverse Events 
............... ............... ............... ............... .............. . 
7.1.2. 
Serious Adverse Events 
............... ............... ............... .............. . 
7.1.3. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events 
............... .............. . 
Assessment of Adverse Events and Serious Adverse Events ............... . 
7.2.1. 
Assessment of Causality for Study Drugs and Procedures .. 
7.2.2. 
Assessment of Severity 
Gilead Reporting Requirements . 
Toxicity Management ... 
Special Situations Reports ..... 
7.5.1. 
Definitions of Special Situations 
7.5.2. 
Instructions for Reporting Special Situations ..... . 
STATISTICAL CONSIDERATIONS .............. . 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Primary Endpoint . .............. . 
8.2. 
Secondary Endpoints ............. .............. . 
8.2.1. 
Exploratory Endpoints 
8.3. 
Analysis Conventions.. 
. ............. . 
8.3.1. 
Analysis Sets ............. . 
CONFIDENTIAL 
Page 3 
Final 
Original 
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........ 68 
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.... 74 
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.... 75 
. ... 75 
. ... 75 
12 April 2016 


GS-4997
Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 4
12 April 2016
8.4.
Data Handling Conventions ...................................................................................................................76
8.5.
Demographic Data and Baseline Characteristics ...................................................................................77
8.6.
Interim Analysis.....................................................................................................................................77
8.7.
Efficacy Analysis ...................................................................................................................................77
8.7.1.
Exploratory Analysis............................................................................................................77
8.8.
Safety Analysis.......................................................................................................................................77
8.8.1.
Extent of Exposure...............................................................................................................78
8.8.2.
Adverse Events.....................................................................................................................78
8.8.3.
Laboratory Evaluations ........................................................................................................78
8.8.4.
Other Safety Evaluations......................................................................................................79
8.9.
Pharmacokinetic Analysis......................................................................................................................79
8.9.1.
Other Exploratory Analyses .................................................................................................79
8.10.
Sample Size............................................................................................................................................79
8.11.
Data Monitoring Committee ..................................................................................................................79
9.
RESPONSIBILITIES..........................................................................................................................................81
9.1.
Investigator Responsibilities ..................................................................................................................81
9.1.1.
Good Clinical Practice..........................................................................................................81
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Ethics Committee (EC) Review and Approval ..........................................................81
9.1.3.
Informed Consent.................................................................................................................81
9.1.4.
Confidentiality......................................................................................................................82
9.1.5.
Study Files and Retention of Records ..................................................................................82
9.1.6.
Electronic Case Report Forms..............................................................................................83
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................84
9.1.8.
Inspections............................................................................................................................84
9.1.9.
Protocol Compliance............................................................................................................84
9.2.
Sponsor Responsibilities ........................................................................................................................85
9.2.1.
Protocol Modifications.........................................................................................................85
9.2.2.
Study Report and Publications .............................................................................................85
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................85
9.3.1.
Payment Reporting...............................................................................................................85
9.3.2.
Access to Information for Monitoring..................................................................................86
9.3.3.
Monitoring and Oversight of Biomarker Specimens............................................................86
9.3.4.
Access to Information for Auditing or Inspections ..............................................................86
9.3.5.
Study Discontinuation..........................................................................................................86
10.
REFERENCES ...................................................................................................................................................87
11.
APPENDICES ....................................................................................................................................................91
Appendix 1.
Investigator Signature Page....................................................................................................92
Appendix 2.
Study Procedures Table..........................................................................................................93
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................97
LIST OF IN-TEXT TABLES
Table 3-1.
Biomarkers .............................................................................................................................37
LIST OF IN-TEXT FIGURES
Figure 3-1.
Overall Study Design .............................................................................................................35


GS-4997 
Protocol GS-US-416-2124 
Gilead Sciences, Inc. 
Study Title: 
INDNumber: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Study Centers Planned: 
Number of Subjects 
Planned: 
Target Population: 
Duration of Study: 
Objectives: 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
Final 
Original 
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) 
129570 
2016-000821-37 
TBD 
Approximately 50 centers in the United States, Canada, France, 
Austria and United Kingdom 
Up to 120 subjects will be randomized in order to obtain 
100 subjects with severe AH 
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) 
Participation in the study can last up to 26 weeks, which includes a 
2-week screening period, a 4-week treatment period, and 20 week 
post treatment period. 
The primary objective ofthis study is as follows: 
To evaluate the safety and tolerability ofGS-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, MaddrF.
e ~'~s:-----. 
Discriminant Function (Maddrey's DF), andii._P_P_0 __ 
___, 
Page 5 
12 April 2016 


GS-4997 
Protocol GS-US-416-2124 
Final 
Gilead Sciences, Inc. 
Original 
Study Design: 
CONFIDENTIAL 
• 
To assess mortality at 28 days, 12 weeks and 24 weeks; 
• 
To detetmine the incidence of liver transplantation; 
• 
To detetmine the incidence ofhepatorenal syndrome (HRS); 
• 
To detetmine the incidence of infection; 
• 
To assess length ofhospital stay. 
The exploratmy objectives of this study are: 
~ 
I 
I 
I 
I 
I 
I 
I 
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-confumed AH. 
Page 6 
12 April2016 


GS-4997
Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 7
12 April 2016
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.
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:
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) Onset of jaundice within the past 3 months;
c) Maddrey’s DF ≥32 at screening;


GS-4997
Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 8
12 April 2016
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 
1 month 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 (subjects with fatty liver due to coexistent metabolic 
syndrome will not be excluded);
3) Serum aspartate aminotransferase (AST) >400 U/L or alanine 
aminotransferase (ALT) >300 U/L;
4) MELD >30 at screening;


GS-4997
Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 9
12 April 2016
5) Grade 4 Hepatic Encephalopathy (HE) by West Haven criteria;
6) Concomitant or previous history of hepatocellular carcinoma;
7) History of liver transplantation;
8) HIV Ab positive;
9) Uncontrolled sepsis;
10) 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;
11) Type 1 hepatorenal syndrome (HRS) or renal failure defined as 
a serum creatinine >250 μmol/L (>2.8 mg/dL) or the 
requirement for renal replacement therapy;
12) Subjects dependent on inotropic (eg, epinephrine or 
norepinephrine) or ventilatory support (ie, endotracheal
intubation or positive-pressure ventilation);
13) Portal vein thrombosis;
14) Acute pancreatitis;
15) Cessation of alcohol consumption for more than 2 months 
before baseline/Day1;
16) 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;
17) 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;
18) 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 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;


GS-4997
Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 10
12 April 2016
19) Treatment with immunosuppressive drugs (eg, systemic 
corticosteroids, budesonide, tacrolimus, sirolimus, 
cyclosporine, azathioprine, mycophenolate mofetil, and 
methotrexate), pentoxifylline, or N-acetylcysteine (NAC) 
within 6 months of screening;
20) Use of the following CYP3A4 inhibitors (clarithromycin, 
conivaptan, grapefruit juice, itraconazole, ketoconazole, 
nefazodone, posaconazole, buprenorphine/naloxone, 
telithromycin, voriconazole) or CYP3A4 inducers 
(carbamazepine, phenytoin, rifampin, St. John’s wort) within 
2 weeks of baseline/Day 1;
21) Active ocular herpes simplex;
22) 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;
23) 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;
24) Concurrent participation in another therapeutic clinical study;
25) Known hypersensitivity to the study drugs (GS-4997 and 
prednisolone), the metabolites, or formulation excipients;
26) 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;
27) Unavailable for follow-up assessment or concern for subject’s 
compliance with the protocol procedures.


GS-4997 
Protocol GS-US-416-2124 
Gilead Sciences, Inc. 
Study Procedures/ 
Frequency: 
CONFIDENTIAL 
Final 
Original 
Screening assessments should be completed within 14 days of 
Baseline/Day 1 visit. 
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), Hepatic Encephalopathy (HE) and ascites assessment, safety 
laborat01y tests, and review of adverse events, alcohol 
consumption, and concomitant medications will be done at evety 
visit. 
PO 
Screening assessments will include complete medical hist01y, PE 
including vital signs, HE, ascites, Hepatorenal Syndrome (HRS) 
and infection assessment, laborat01y assessments (hematology, 
chemistiy, coagulation tests, HIV and hepatitis Band C serology; 
and urinalysis), pregnancy tests (for females of child-bearing 
potential), liver biopsy, liver ulti·asound, standard 12-lead ECG, 
chest x-ray, AUDIT I SADQ questionnaires, adverse events and 
concomitant medication assessment. 
Recent gastrointestinal bleeding: 
Gastrointestinal bleeding will be ti·eated and the subject stabilized 
dm'ing the screening period for at least 48 hours prior to 
randomization. 
Sepsis: 
All subjects will be screened for infection with chest radiography, 
m'inalysis, urine culture, paracentesis with ascetic fluid (if 
clinically-detectable ascites is present) cell count, differential, and 
culture, and blood cultures. Sepsis will be defmed as the presence 
of any positive culture or the requirement for initiation of 
antibiotics due to clinical or radiological signs of infection. 
Culture-negative pyrexia and leukocytosis on their own will not be 
regarded as signs of active sepsis, since these findings are often 
seen in subjects with AH without infection. Subjects with evidence 
of sepsis must be ti·eated for a minimum of 2 days with appropriate 
antibiotics, and once sepsis is deemed m1der control by the 
investigator, the subject may continue screening and be 
randomized if eligible within the screening period. 
Page 11 
12 April2016 


GS-4997 
Protocol GS-US-416-2124 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Final 
Original 
Eligible subjects will be randomized to one of the two treatment 
groups. Prior to initial dosing, required baseline/Day 1 assessments 
will be perfmmed and will include vital signs, PE, HE, ascites, 
HRS and infection assessment, laboratmy assessments, pregnancy 
tests (for females of child-bearing potential), and review of 
adverse events, concomitant medication, CLDQ questionnaire and 
alcohol consumption. 
PO 
While on study, subjects will undergo the following procedmes 
and laboratmy assessments: 
• 
CLDQ questionnaire at baseline/Day 1, Weeks 4 and 24 
• 
Sparse PK Sampling at baseline/Day 1 and at Weeks 1, 2 and 4 
• 
Blood for Biomarkers at screening, baseline/Day 1, and at 
Weeks 1, 2, 4, 8, 12 and 24 
• 
ELF™ Test and LOXL-2 at baseline/Day 1 and at Weeks 4, 
12 and 24 
• 
12-lead ECGs at screening, baseline/Day I, and at Weeks 4 
and 8 
• 
Fasting blood glucose, insulin and lipid profile at screening, 
baseline/Day I and at Weeks 4, 12 and 24 
• 
Hemoglobin Ale at baseline/Day 1 and at Weeks 12, and 24 
• 
Urine collection at screening 
• 
Stool collection at baseline/Day 1 and at Weeks 4 and 24. 
Intensive PK Sub-study 
PPD 
I 
L-, 
I 
!! 
I 
PPD 
Page 12 
12 April2016 


GS-4997 
Protocol GS-US-416-2124 
Gilead Sciences, Inc. 
Test Product, Dose, and 
Mode of Administration: 
Reference Therapy: 
Criteria for Evaluation: 
Safety: 
Efficacy: 
CONFIDENTIAL 
pp 
Final 
Original 
• 
Treatment Group A: GS-4997 I8 mg (I x I8 mg tablet) AND 
prednisolone 40 mg (4 x IO mg tablets) both administered 
orally once daily; n=50-60 subjects 
• 
Treatment Group B: GS-4997 placebo (I tablet) AND 
prednisolone 40 mg (4 x IO mg tablets) administered orally 
once daily; n=50-60 subjects 
Up to 60 subjects per atm will be randmnized in order to obtain 
50 subjects in each rum for the full analysis set (ie, subjects 
randomized with histologically-proven severe AH who took at 
least one dose of study dmg) 
Treatment will be administered for 28 days inclusive of inpatient, 
and if applicable, outpatient periods. 
Prednisolone 10 mg tablets will be used. 
Safety will be evaluated by examining the incidence of treatment 
emergent adverse events, including serious adverse events, clinical 
laboratory tests, ECGs, and vital signs. An independent, external 
Data Monitoring Committee (DMC) that consists of two 
hepatologists and a PhD statistician will convene prior to the 
study, once 10 subjects have been treated for 28 days and eve1y 
3 months thereafter to monitor the study for safety events 
including SAEs, deaths, grade 3 and 4 AEs, and grade 3 and above 
laboratmy abnmmalities. 
The biological activity of prednisolone, and the combination of 
GS-4997 and prednisolone will be evaluated using clinical 
outcomes and biomarker variables. 
Page 13 
12 April2016 


GS-4997 
Protocol GS-US-416-2124 
Gilead Sciences, Inc. 
Phatmacokinetics: 
Statistical Methods: 
CONFIDENTIAL 
Final 
Original 
The plasma concentration of GS-4997 and its metabolite, 
GS-607509, will be detennined. The plasma concentration of other 
GS-4997 metabolites and/or prednisolone may be explored. PK 
samples may also be used to measure protein-binding of GS-4997 
and/or its metabolites. PO 
Primary Endpoint: 
The primaty endpoint is the safety of GS-4997 in combination 
with prednisolone versus prednisolone alone in subjects with 
severe AH. 
Secondary Endpoints: 
• 
Clinical outcomes 
-
Mmtality at 28 days, 12 weeks, and 24 weeks 
-HRS 
-Infection 
-
Length of hospital stay 
-
Liver transplantation 
-
Measures ofhepatic synthetic ftmction: 
• 
Change from baseline in liver biochemistty: AL T, 
AST, GGT, albmnin, alkaline phosphatase, bilimbin, 
andiNR 
• 
Lille response (score <0.45) 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, 
Child-Pugh score, Maddrey's DF 
PPD 
-
.._ _ __, 
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GS-4997 
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CONFIDENTIAL 
Exploratory Endpoints: 
~ 
D 
I 
Efficacy Analysis: 
Final 
Original 
The biological activity of prednisolone, and the combination of 
GS-4997 and prednisolone will be evaluated using clinical 
outcomes and measmes of he atic s 
thetic ftmction. PO 
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GS-4997 
Protocol GS-US-416-2124 
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Exploratory Analysis: 
PPD 
Safety Analysis: 
Final 
Original 
All safety data collected will be listed and be summarized, as 
appropriate, by treatment group. Safety endpoints will be analyzed 
by the number and percent of subjects with events or abnonnalities 
for categorical variables or 8-number summaty (n, mean, standard 
deviation, median, Ql, Q3, minimum, maximum) for continuous 
vm·iables by treatment group. 
Pharmacokinetic Analysis: 
GS-4997 and GS-607509 plasma concentrations will be listed and 
smnmarized for all subjects. PO 
Sample Size: 
The number of subjects was chosen based on clinical "'v'""''''"'"'""' 
with other similar 
studies. 
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents. 
CONFIDENTIAL 
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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
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
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 et al 2011, Singal et al 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}. 
Alcoholic hepatitis 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 et al 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 et al 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 alcoholic hepatitis 
(typically defined by a Maddrey’s Discriminant Function (DF) ≥32, short-term mortality rates 
are high (approximately 25% to 45%) {Akriviadis et al 2000, Mathurin et al 2011}. 
Alcoholic hepatitis 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 et al 2014, Lucey et al 2009, Meagher et al 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 et al 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 et al 2010}. Indeed, 6-month mortality remains 
high despite prednisolone therapy {Mathurin et al 2011, Thursz et al 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 et al 2009}. In a cohort of 162 patients with AH 
(established by biopsy), 20% of patients had infections at hospital admission and 52% of those 


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treated with corticosteroids developed infections, including some patients with invasive 
aspergillosis {Michelena et al 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 et al 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 et al 2011, Nguyen-Khac et al 2011, O'Shea et al 2005, Spahr 
et al 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 et al 2007, Takeda et al 2008, Tobiume et al 2001, Watanabe et al 2005}.  The ASK1 protein 
is ubiquitously expressed and is normally bound and repressed by thiol-containing antioxidant
proteins in the cytosol and mitochondria {Fujino et al 2007, Takeda et al 2008, Zhang et al 2004}. In 
settings of elevated oxidative stress, ASK1 is autophosphorylated {Tobiume et al 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 et al 2007, Takeda et al 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 et al 2005, Mnich et al 2010, Nakamura et al 2009, 
Takeda et al 2008, Terada et al 2007, Tobiume et al 2001, Yokoi et al 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 et al 2013, 
Gerczuk et al 2012, Imoto et al 2006, Nakagawa et al 2008, Takeda et al 2008, Toldo et al 2012, 
Watanabe et al 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 et al 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 et al 2011, Nakagawa et al 2008, Noguchi et al 2014}. Moreover, pharmacological 
inhibition of ASK1 in mice reduces hepatocellular injury and necrosis induced by acetaminophen 


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overdose, as well as cardiac and renal apoptosis and necrosis induced by acute 
ischemia/reperfusion injury {Toldo et al 2012, Xie et al 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 is a potent and selective ATP competitive inhibitor of the kinase ASK1 with an IC50 of 
1.76 ± 0.85 nM. In an in vitro kinase selectivity screen (KINOMEscan, DiscoverRx) that
evaluated the affinity of GS-4997 for the active sites of 451 kinases, GS-4997 had the highest
affinity for ASK1 (Kd = 0.3 nM) followed by DYRK1A (Kd = 4.2 nM), and the N-terminal
kinase domain of RSK4 (Kd = 8.6 nM). The Kd value of GS-4997 for ASK1 was 14-fold lower
than that for DYRK1A, 29-fold lower than that for RSK4, and 50-fold lower than the Kd value
determined for all other kinases.
The potency of GS-4997 to inhibit ASK1 activation and signaling was characterized in cellular
assays and in vivo models of oxidative stress. In HK2 human renal proximal tubular epithelial
cells, GS-4997 inhibited auranofin-induced ASK1 autophosphorylation and inhibited the
downstream phosphorylations of p38 and JNK. GS-4997 efficacy was similar to results obtained
when ASK1 expression was reduced by siRNA. The potency of GS-4997 to inhibit
auranofin-induced p38 activation in human HK2 cells (EC50 10.5 ± 1.3 nM) and human PBMCs
(EC50 10.8 ± 1.3 nM) were in-congruent with the potency of GS-4997 to inhibit ASK1 kinase in
a biochemical assay (1.76 ± 0.85 nM). GS-4997 inhibited auranofin-induced production of the
proinflammatory chemokine CXCL1 in human whole blood and in isolated human PBMCs with
mean EC50 values of 131 ± 70 nM and 32 ± 13 nM, respectively. The approximate 4-fold
difference in potency observed between whole blood and isolated PBMCs is likely due to plasma 
protein binding; the free fraction of GS-4997 in human plasma is 12%.
In safety pharmacology studies, GS-4997 had no effect on the central nervous and respiratory
systems in male rats at doses up to 100 mg/kg, the highest dose tested. Mild to moderate
prolongation of the QT interval corrected for heart rate (QTc; up to +17 msec) for up to 20 hours
post dose and decreased systolic, diastolic and mean arterial pressure (up to -14%) were
observed in cynomolgus monkeys after single dose of 75 and 10 mg/kg, respectively. The no
observed effect level (NOEL) for cardiovascular effects was 3 mg/kg (human equivalent dose
[HED] of 58 mg).
GS-607509, a major metabolite of GS-4997, has low potency to bind and inhibit ASK1 
(approximately 100-fold less than GS-4997), low affinity for other off target kinases, and no 
significant binding to a broad panel of ion channels, transporters and receptors.  In addition, the 
metabolite is > 99% protein bound in human blood.  Therefore, GS-607509 is an inactive 
metabolite, which is not expected to have pharmacological activity at clinically relevant 
exposures.   


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1.2.3.
Preclinical Drug Metabolism and Pharmacokinetics
Consistent with the moderate to high bioavailability seen in nonclinical species, GS-4997 shows
high, concentration-independent forward permeability across Caco-2 monolayers, with low
efflux. GS-4997 has a moderate volume of distribution, close to that of total body water. 
Systemic clearance in nonclinical species is well predicted from the rates of metabolism by 
hepatic microsomal fractions and hepatocytes. GS-4997 has good metabolic stability with human 
hepatic material in vitro and low clearance in vivo.  In vitro, the main route of metabolism of 
GS-4997 involves N-dealkylation, resulting in loss of the isopropyl group (metabolite M33, 
GS-607509.  In rat, other routes of metabolism were detected, including oxidation (with 
subsequent glucuronidation) and hydrolysis of the amide.  GS-4997 is unlikely to cause clinical
interactions through inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or 
CYP2D6. Substrate dependent inhibition was observed for CYP3A (IC50 2.69 μM). The potential 
for the metabolite GS-607509 to cause inhibition was also investigated, and it had no inhibitory 
effect on the activities of human hepatic microsomal CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6 or CYP3A (IC50 > 25 μM); thus, it is unlikely to affect the PK of drugs 
metabolized by these enzymes.
The effects of GS-4997 and GS-607509 on the activity of the conjugating enzyme, uridine
diphosphate glucuronosyltransferase 1A1 (UGT1A1), were also determined. GS-4997 inhibited
this enzyme with an IC50 of 1.9 μM, while GS-607509 inhibited this enzyme to a lesser extent
(IC50 19.4 μM). No clinically relevant or dose-dependent increases in bilirubin levels were noted
in the first-in-human Phase 1 study with GS-4997 (GS-US-223-0102). As such, GS-4997 and
GS-607509 are unlikely to cause clinically relevant inhibition of UGT1A1.
GS-4997 was a weak inhibitor of the breast cancer resistance protein (BCRP), the organic anion
transporter proteins (OATP)1B1, and OATP1B3 (IC50 for each ≥ 9.9 μM). GS-4997 is a more
potent inhibitor of P-gp, organic cation transporters (OCT1 and OCT2), and multidrug and toxin
extrusion 1 (MATE1) transporter (IC50 3.4, 2.8, 5.5, and 2.4 μM, respectively). GS-607509 was a
weak inhibitor of all transporters (IC50 > 10 μM) except MATE1 (IC50 6.4 μM). As such, the
overall potential for interactions for GS-4997/metabolite is low for most transporters. GS-4997
and GS-607509 are not expected to be a clinically relevant inducer through activation of either
AhR or PXR.
Elimination of GS-4997 and its metabolites is likely to occur through a mixture of urinary,
biliary and intestinal excretion.
1.2.4.
Preclinical Toxicology
The toxicity profile of GS-4997 has been assessed in rats and cynomolgus monkeys administered
GS-4997 orally for up to 26 weeks in rats or 39 weeks in monkeys.  Additionally, studies were 
conducted to assess the effect of GS-4997 on embryofetal development as well as the potential 
for genotoxicity and phototoxicity.  Target organs/tissues identified in the repeat-dose toxicity 
studies with GS-4997 were the GI (monkey only; profuse diarrhea), kidney (monkey - tubule 
degeneration/necrosis/regeneration; rat - tubular basophilia, eosinophilic droplets and pigment 
deposition), hematopoietic tissue (mild decrease red blood cell parameters), lymphoid tissue 


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(monkey only; decreased lymphocytes), adrenal (rat only; cortical hypertrophy), and lung 
(monkey only; phospholipidosis). In general, findings were reversible, monitorable, and only 
occurred at doses that exceeded the projected exposure (AUC24h) at the proposed maximum 
human dose by at least 5-fold. In addition, embryo-fetal effects were observed in association 
with maternal toxicity in rats and rabbits at exposures (AUC24h) that were 67- and 12-fold higher, 
respectively.  The no-observed-adverse-effect level (NOAEL) from the long term repeat dose 
toxicity studies in rat and monkey were 15 and 5 mg/kg/day, respectively.  These respective 
doses were associated with exposures (AUC24h) that were 19- and 1-fold the projected steady 
state exposure in humans at the maximum proposed human dose of 18 mg once daily.  
Furthermore, GS-4997 was nongenotoxic and nonphototoxic. 
For further information on GS-4997, refer to the investigator’s brochure (IB) for GS-4997,
3rd edition, dated 13 May 2015.
1.2.5.
Clinical Trials of GS-4997
As of 08 February 2016, four Phase 1 studies with GS-4997 have completed and two Phase 1
studies with GS-4997 are ongoing. In the completed and ongoing Phase 1 studies, 253 healthy 
subjects have been dosed with GS-4997.
Three Phase 2 studies of GS-4997 in subjects with diabetic kidney disease (DKD)
(GS-US-223-1015), pulmonary arterial hypertension ( PAH) (GS-US-357-1394), and 
nonalcoholic steatohepatitis (NASH) (GS-US-384-1497) are ongoing.
1.2.5.1.
An Adaptive, Single and Multiple Dose Phase 1 Study of GS 4997 in Healthy 
Volunteers to Evaluate the Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics, and its Drug-Drug Interaction Potential Using a Probe 
CYP3A Substrate (Study GS-US-223-0102)
Single- and multiple-dose oral administration of GS-4997 once daily over 14 days was well 
tolerated in healthy adult subjects. GS-4997 exposure increased in an approximately 
dose-proportional manner over the dose-range tested (1 to 100 mg) following single and multiple 
oral administrations (once daily for 14 days) under fasted conditions. GS-4997 terminal t1/2 
values ranged from 15 to 23 hours and Tmax ranged from 2 to 4 hours following single and 
multiple dosing. GS-607509 is a major, inactive metabolite of GS-4997 that, upon once daily 
dosing of GS-4997, accumulated to approximately 6-fold of GS-4997 AUC. Urinary excretion 
appears to be a minor pathway of elimination of GS-4997 and GS-607509. No food effect on the 
PK of GS-4997 was demonstrated. As such, GS-4997 may be administered with or without food. 
Changes in midazolam PK upon co-administration with GS-4997 were minimal and, therefore, 
GS-4997 is not considered a clinically relevant CYP3A inhibitor. No clinically significant vital
signs changes, ECG changes, or laboratory changes were noted on study. These results provide 
adequate characterization of the PK and safety of GS-4997 to enable further clinical 
investigation with this molecule. Further information on this study is available in the 
Investigator’s Brochure for GS-4997.


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After completion of this study, a concentration-QT (C-QT) analysis of intensive, time-matched 
ECG data collected in this Phase 1 study was conducted as an alternative to a dedicated thorough 
QT (TQT) study to evaluate changes in QT interval with GS-4997. The primary C-QTc analysis 
evaluated the effect of GS-4997 and its metabolite (GS-607509) on time-matched, 
baseline-adjusted, placebo-corrected QTcF (ΔΔQTcF) intervals. Categorical analysis and C-QTc 
modeling demonstrated that there were no clinically relevant relationships between ΔΔQTcF and 
GS-4997 dose or plasma concentrations of GS-4997 and its metabolite (GS-607509). Thus, at 
exposures achieved at the proposed dose range (up to 18 mg), this analysis provided adequate 
evidence to exclude a clinically relevant effect on QTc interval. Based on these results, a waiver 
for conducting a TQT study was granted by the Division of Cardiovascular and Renal Products
at the Food and Drug Administration.
1.2.5.2.
A Phase 1 Study to Evaluate the Effect of Acid Reducing Agents on GS-4997 
Pharmacokinetics (GS-US-223-1432)
This Phase 1, open-label, single-center 2-cohort study was designed to evaluate the safety,
tolerability, and PK of GS-4997 when administered alone and in combination with gastric acid
reducing agents (famotidine, omeprazole) in healthy adult males and females of nonchildbearing
potential. Cohort 1 investigated the potential interaction of a H2-receptor antagonist (famotidine
[Pepcid®]) when coadministered with GS-4997 (20 mg). Cohort 2 investigated the potential
interaction of a proton pump inhibitor (omeprazole [Prilosec®]) when coadministered with
GS-4997 (20 mg).
No clinically relevant drug-drug interactions occurred between GS-4997 and famotidine or
omeprazole. As such, GS-4997 may be administered with gastric acid reducing agents. No new
safety concerns for GS-4997 in healthy subjects were identified, either when administered alone
as a single 20-mg oral dose or when coadministered with famotidine (40 mg) orally twice daily
or omeprazole (20 mg) orally once daily.
1.2.5.3.
A Phase 1 Study to Evaluate the Effect of GS-4997 on a Probe Substrate of Drug 
Transporter P-glycoprotein (P-gp) and the Effect of Inhibitors/Inducers of 
Cytochrome P450 3A (CYP3A) and Inhibitors of Organic Anion Transporting 
Polypeptide (OATP) 1B1 and 1B3 on GS-4997 Pharmacokinetics
(GS-US-223-1434)
This Phase 1 open-label, single-center, multiple-cohort study was designed to evaluate the safety
of GS-4997 and the effect of GS-4997 on the drug transporter P-gp and the effect of
inhibitors/inducers of CYP3A and inhibitors of OATP1B1/1B3 on the PK of GS-4997 in healthy
adult males and females of nonchildbearing potential administered GS-4997 alone or in
combination with various probe drugs.
GS-4997 is a very weak P-gp inhibitor and may increase exposures of sensitive P-gp substrates
such as digoxin. GS-4997 is not a sensitive substrate of hepatic uptake transporters
OATP1B1/1B3 and may be coadministered with OATP1B1/1B3 inhibitors. Because rifampin
significantly decreased GS-4997 plasma exposure, exclusion of strong CYP3A4 inducers in
combination with GS-4997 in long-term clinical studies should be considered. While multiple


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doses of ritonavir, a strong CYP3A4 inhibitor, significantly increased GS-4997 plasma exposure,
and bosentan, a moderate CYP3A4 inducer, decreased GS-4997 plasma exposure, the clinical
relevance of these findings has not been established. A 2-fold increase in bosentan plasma
concentrations has been observed with bosentan and ketoconazole coadministration, which did
not warrant dose adjustment {Actelion Pharmaceuticals LTD 2012}. Thus, the lower increase in
bosentan exposure observed with GS-4997 does not warrant dose adjustment in long-term
clinical studies. Single or multiple oral doses of GS-4997 (20 mg) administered alone or in 
combination with oral doses of digoxin (0.5 mg, once daily), rifampin (600 mg, once daily),
ritonavir (100 mg, twice daily), or bosentan (125 mg, twice daily) were well tolerated in healthy
adult subjects and no significant safety concerns were observed in the study.
1.2.5.4.
A Phase 1, Open-Label, Mass-Balance Study of Radiolabeled [14C]-GS-4997 in
Healthy Subjects (Study GS-US-223-1573)
Study GS-US-223-1573 was designed as an open-label, single center, single dose Phase 1 
study to evaluate the metabolism, route of elimination, and PK characteristics of radiolabeled
[14C]-GS-4997 (18 mg) in 8 healthy male subjects.
The mean overall recovery of radioactivity was 95%, with recovery primarily in feces (~58%)
versus urine (~37%). Radioactivity was eliminated as a combination of metabolites and
unchanged parent drug. GS-4997 metabolism involved oxidation, hydrolysis, N-dealkylation,
methylation, and glucuronidation with N-dealkylation as a major pathway. No new safety
concerns for GS-4997 18-mg in healthy subjects were identified.
1.2.5.5.
A Phase 1, Open-Label, Parallel-Group, Single Dose Study to Evaluate the
Pharmacokinetics of GS-4997 in Subjects with Normal and Impaired Hepatic
Function (Study GS-US-223-1018)
Study GS-US-223-1018 was a Phase 1, open-label, parallel-group, single-dose study evaluating
the safety, tolerability, and PK of GS-4997 in subjects with normal hepatic function and mild, 
moderate, or severe hepatic impairment. Up to 60 subjects were planned for enrollment in 1 of 
3 hepatic impairment cohorts: Cohort 1 (moderate hepatic impairment), Cohort 2 (severe hepatic 
impairment), or Cohort 3 (mild hepatic impairment). Within each cohort, each subject with
impaired hepatic function was matched for age (± 10 years), sex, and body mass index (BMI; 
± 20%) with a control subject with normal hepatic function. Data from healthy controls could be 
used in > 1 cohort if a subject was an appropriate match for a subject with hepatic impairment in 
> 1 cohort. All subjects received a single oral dose of GS-4997 6 mg in a fed state on Day 1. The 
study conduct is completed and final data analysis is ongoing. Preliminary results are presented 
below.
Preliminary pharmacokinetic results from this study are available. There were no significant 
changes in GS-4997 exposure (Cmax, AUCinf) in subjects with mild or moderate hepatic 
impairment (CPT class A and B, respectively) as compared to healthy matched control subjects 
as indicated by geometric least squares mean ratios (GLSMRs) near 100% and 90% confidence 
intervals (CIs) between 70% and 143%. There was a slight increase in GS-4997 AUCinf
(42.65%) in subjects with severe hepatic impairment (CPT class C) as compared to the healthy 


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matched control subjects for that group (N=10). An ad hoc analysis was performed to compare 
GS-4997 exposures in subjects with severe hepatic impairment to pooled healthy volunteers from 
all cohorts (N=22) and the increase in AUCinf was less (21.4% increase). The mean plasma 
protein binding of GS-4997 at 3 hours postdose was similar in subjects with normal hepatic 
function and mild and moderate hepatic impairment (5.3% unbound in each group) with slightly 
higher unbound fraction in subjects with severe hepatic impairment (7.0%). Plasma exposures 
(Cmax and AUC) of the primary metabolite GS-607509 were decreased (up to 53%) in subjects 
with moderate and severe hepatic impairment. GS-607509 is an inactive metabolite, thus, 
decreases in GS-607509 exposure are not clinically relevant. 
The slight increase in GS-4997 exposure (AUC) in subjects with severe hepatic impairment is 
less than what was observed with a strong CYP3A4 inhibitor (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 CYP3A4 inhibitors are currently allowed in all 
ongoing Phase 2 studies evaluating doses of GS-4997 of up to 18 mg once daily. GS-4997 has 
been evaluated at doses up to 100 mg in Phase 1 studies for up to 2 weeks and up to 18 mg in 
Phase 2 studies for up to 48 weeks and appears to be well tolerated. Based on the current 
safety/tolerability profile for GS-4997 over a wide dose/exposure range, the increase in GS-4997 
exposure in subjects with severe hepatic impairment is unlikely to be clinically relevant at the 
doses currently being evaluated in Phase 2 studies (up to 18 mg once daily). Therefore, dose 
adjustments are not considered necessary in subjects with mild, moderate, or severe hepatic 
impairment.
1.2.5.6.
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 DKD.
Approximately 300 subjects with type 2 diabetes mellitus and Stage 3 or Stage 4 renal
impairment and albuminuria receiving standard of care for DKD are planned to be 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 estimated glomerular filtration rate (eGFR) decline in subjects with DKD.
1.2.5.6.1.
Preliminary Safety Analyses
Based on the database used for the DMC meeting on 11 November 2015 which included 
unblinded safety data from 332 subjects (data cut-off date of 6 October  2015), 207 subjects 
(62.3%) had at least 1 treatment-emergent AE during the study; 36 events in 29 subjects were 
considered by the investigator to be related to study drug; 79 events in 43 subjects were serious 
adverse events. The most frequently reported AEs were hyperkalemia (15 of 332 subjects 
[4.5%]), diarrhea, nausea (14 of 332 subjects each [4.2%]), back pain, hyperuricemia 
[13 subjects each [3.9%]), upper respiratory tract infection (12 subjects [3.6%]), acute kidney 
injury, hypertension (11 subjects each [3.3%]), constipation, edema peripheral, and 


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hypoglycemia (10 subjects each [3.0%]). Counting each subject once using the highest toxicity 
grade, Grade 3 and 4 AEs were reported for 31 and 6 subjects, respectively, and 1 death 
(grade 5) occurred (unobserved death, likely myocardial infarction in a patient with pre-existing 
coronary artery disease). Thirteen subjects had AEs leading to study drug discontinuation. Since 
the study is ongoing, treatment assignment for the AEs is not known.
1.2.5.7.
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. Approximately 120 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 are planned to be randomized 1:1:1:1 to 
receive either GS-4997 2, 6, or 18 mg or placebo, orally, once daily, for 24 weeks. Subjects also 
will continue receiving 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.
As of 15 February 2016, 151 subjects had been randomized and 150 subjects have been treated 
with study drug or placebo for a median (min, max) of 16.1 (3.9, 48.1) weeks. A total of 
101 subjects (67.3%) remain on treatment and 14 subjects (9.3%) have discontinued study drug. 
The most frequent reason for discontinuation of study drug was due to an AE (5 subjects, 3.3%), 
followed by investigator’s discretion (4 subjects, 2.7%), and protocol violation, withdrawal of 
consent, and increase in dose of PAH medication or new PAH medication added (1 subject each, 
0.7% each). Because the study is still ongoing and blinded, the treatment received by these 
subjects is unknown. The external DMC review of the unblinded safety data from 150 subjects 
resulted in no safety concerns.
1.2.5.8.
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)
Study GS-US-384-1497 is an ongoing, randomized, open-label, multicenter, Phase 2 study of 
GS-4997 evaluating the safety, tolerability, and biological activity of GS-4997 alone or 
in combination with simtuzumab (SIM) in subjects with NASH and liver fibrosis (stages F2-F3). 
Approximately 70 subjects are planned to be randomized 2:2:1:1:1 into 5 groups (Group A to 
Group E) to receive 1 of the following study drug regimens for 24 weeks: GS-4997 6 mg, orally, 
once daily (Group A), GS-4997 18 mg, orally, once daily (Group B), GS-4997 6 mg, orally, once 
daily + SIM 125 mg, SC, weekly (Group C), GS-4997 18 mg, orally, once daily + SIM 125 mg, 
SC, weekly (Group D) and SIM 125 mg, SC, weekly (Group E). The primary objective of this 


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study is to evaluate the safety and tolerability of GS-4997 alone or in combination with SIM in 
subjects with NASH and fibrosis stages F2-F3.
As of 31 March 2016, 72 subjects out of a planned 72 subjects with NASH and liver fibrosis 
have been randomized 2:2:1:1:1 to 1 of 5 treatment groups to receive GS-4997 alone or GS-4997 
in combination with simtuzumab for 24 weeks. Open-label long term dosing will be considered 
with a regimen to be determined after all data are analyzed.
Preliminary Safety Analyses
Based on the database used for the DMC meeting on 26 January 2016 which included unblinded 
safety data from 20 subjects (data cut-off date of 22 Dec 2015), 4 subjects (20%) had at least 1 
treatment-emergent AE during the study; none were considered by the investigator to be related
to study drug; none were serious adverse events. The most frequently reported AEs were nausea 
(2 of 20 subjects [10%]), and amnesia (2 of 20 subjects [10%]). No AE of ≥Grade 3 severity 
was reported and no adverse events led to the discontinuation of study drug.
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 et al 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 et al 2001} is hypothesized to improve efficacy and safety 
compared with corticosteroid treatment in patients with AH.
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 et al 2015, Louvet et al 
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 et al 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 


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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.
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 
(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 CYP3A4 
inhibitors are currently allowed in all ongoing Phase 2 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 alcoholic hepatitis. The rationale for this 
approach is two-fold. First, in many centers, performance of liver biopsy in subjects with 
suspected severe alcoholic hepatitis 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 alcoholic hepatitis. Importantly, a 
clinical diagnosis of alcoholic hepatitis (as per standard of care) and contraindications to 
prednisolone (e.g. infection) will be excluded in all subjects prior to starting treatment.


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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 1.2.5), 
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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2. 
OBJECTIVES 
The primaty objective of this study is: 
Final 
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• 
To evaluate the safety and tolerability of GS-4997 in combination with prednisolone versus 
prednisolone alone in subjects with severe AH 
The secondaty objectives of this study are as follows: 
• 
To assess changes in hepatic synthetic function [liver biochemistry, Model for End-Stage 
Liver Disease [ME~~ scorea....Child-Puoh score, the Lille model, Maddrey's Discriminant 
Flmction (DF), and 
PPD 
,___ ___ _. 
• 
To assess mmtality at 28 days, Weeks 12 and Week 24 
• 
To detemline the incidence of liver transplantation; 
• 
To determine the incidence ofhepatorenal syndrome (HRS); 
• 
To detennine the incidence of infection; 
• 
To assess length ofhospital stay; 
The exploratmy objectives of this study are: 
~ 
c 
I 
I 
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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 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.


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The full analysis set will comprise 100 subjects but up to 120 subjects will be randomized to 
account for subjects in whom AH is not confnmed on liver biopsy. Full analysis set includes 
those randomized and dosed with histologically-proven severe AH. Safety data will be reported 
for all subjects who take study dmg. 
All subjects with severe AH should complete screening, on-treatment, and post-treatment 
assessments as outlined in Appendix 2. If the subject meets criteria for discontinuation of 
treatment (see Section 6.8 of this protocol), the subject should complete an End of Treatment 
(EoT) visit as soon as possible after all study dmgs ru·e discontinued and attend post-treatment 
visits as outlined in Appendix 2. If biopsy results are not consistent with AH, the subject must 
stop study chugs within 3 days of receipt of liver biopsy result, attend an Eo T visit as soon as 
possible and have a Follow Up visit 30 days after stopping ch11g, and be withch·awn from the 
study. 
Intensive PK Sub-study 
~PD 
Stopping Rules for Individual Subjects 
Administration of all study ch11gs may be discontinued due to a clinical or laboratory adverse 
event. There is no option for GS-4997 /placebo dose reduction, but GS-4997 /placebo may be 
intenupted due to chug-related toxicity following discussion with the Medical Monitor. If 
GS-4997 /placebo is intem1pted, it may be restmied on a case by case basis after discussion with 
the Medical Monitor. GS-4997/placebo should be stopped if AST/ALT increase to 
>5x baseline/Day 1/nadir (if confitmed on repeat testing) or ifbilimbin increases to 
>3x baseline/Day 1/nadir (if confi1med on repeat testing). Prednisolone can be dose 
reducedlintenupted at the discretion of the investigator but this should also be discussed with the 
Medical Monitor. Subjects are allowed to take one study chug and not the other. 
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3.3. 
3.3.1. 
PPD 
Biomarker Testing 
Biomar ker Samples to Address the Study Objectives 
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~~-----~~-~-~~ . Stool samples may be used for microbiome analysis. The specific 
analyses will include, but will not be limited to, the biomarkers and assays listed below in 
Table 3-1. Because biomarker science is a rapidly evolving area of investigation, and adverse 
events in particular are difficult to predict, it is not possible to specify prospectively all tests that 
will be done on the specimens provided. The testing outlined is based upon the cunent state of 
scientific knowledge. It may be modified during or after the end of the study to remove tests no 
longer indicated and/or to add new tests based upon the growing state of the rut knowledge. If a 
test will no longer be perfotmed 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 
IRBIIEC/EC-approved Infonned Consent Fotm (ICF) and applicable laws ( eg, health 
requirements). 
Table 3-1. 
Biomar kers 
Bioma1·ker Focus 
Planned Biomarkers 
Rational 
Specimen Collected 
Liver tissue smrogate 
ELF Test 
Assess potential changes 
Blood 
marker panel 
in liver fibrosis due to 
treatment 
Liver tissue damage 
Senun LOXL2 
Assess potential changes 
Blood 
marker 
in liver tissue damage due 
to treatment 
Apoptosis and Necrosis 
Circulating Cytokeratin 18 
Detemline changes in liver 
Blood 
markers 
(CK18) fragments, M30 
cell death due to 
for apoptosis and M65 for 
treatment 
all dying cells) 
Inflammatmy involvement 
Senllll cytokines 
Detennine changes in the 
Blood 
inflanunatory status due 
to treatment 
Infection 
Lipopolysaccharide 
Assess changes in gut 
Blood 
(LPS)/ endotoxin 
batTier function due to 
treatment 
Infection 
Procakitonin 
Assess changes in gut 
Blood 
barrier function due to 
treatment 
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Biomarker Focus 
Metabolome 
ASKl pathway activity 
Intestinal microbial 
composition 
ASKl pathway activity 
ASKl pathway activity 
FXR Pathway Activity 
Circulating Micro RNA 
Planned Biomarket·s 
Circulating metabolite 
profiles (open platform) 
phospho-p38 . 
Stoolmicrobiome 
detennined by 16S 
ribosomal DNA 
sequencing 
Focused panel gene 
expression (Nanostring) 
phospho-p38 IHC 
FGF19 
Senun miRNA 
R ational 
Assess changes in the 
metabolome due to 
treatment 
blood marker of ASK1 
pathway activity to 
monitor PD effects 
Assess changes in 
microbial populations due 
to treatment 
Assess gene expression in 
disease at baseline 
Assess ASKl pathway 
activation at baseline 
Assess FXR pathway 
activity to info1m potential 
combinations 
Assess changes in 
circulating miRNA 
associated with liver 
disease due to treatment 
* 
Biomarker blood sample phospho-p38 will only oc.cm· at select US study sites. 
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Specimen Collected 
Blood 
Blood 
Stool 
Liver 
Liver 
Blood 
Blood 
For sampling procedures, storage conditions, and shipment instructions, see the Centr·al 
Laborat01y Services Manual. 
3.3.2. 
Biomarker Samples for Optional Future Research 
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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 alcoholic hepatitis (Maddrey’s  
DF ≥ 32). Up to 20 additional subjects will be randomized to account for subjects in whom
alcoholic hepatitis 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 hepatic encephalopathy (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:
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) Onset of jaundice within the past 3 months;
c) Maddrey’s DF ≥32 at screening;
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 
1 month 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;
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;


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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 (subjects with fatty liver due to coexistent 
metabolic syndrome will not be excluded);
3) Serum aspartate aminotransferase (AST) >400 U/L or alanine aminotransferase (ALT) 
>300 U/L;
4) MELD >30 at screening;
5) Grade 4 Hepatic Encephalopathy (HE) by West Haven criteria;
6) Concomitant or previous history of hepatocellular carcinoma;
7) History of liver transplantation;
8) HIV Ab positive;
9) Uncontrolled sepsis;
10) 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;
11) Type 1 hepatorenal syndrome (HRS) or renal failure defined as a serum creatinine 
>250 μmol/L (> 2.8 mg/dL) or the requirement for renal replacement therapy;
12) Subjects dependent on inotropic (eg, epinephrine or norepinephrine) or ventilatory support 
(ie, endotracheal intubation or positive-pressure ventilation);
13) Portal vein thrombosis;
14) Acute pancreatitis;
15) Cessation of alcohol consumption for more than 2 months before baseline/Day 1;


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16) 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;
17) 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.
18) 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 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;
19) Treatment with immunosuppressive drugs (eg, systemic corticosteroids, budesonide, 
tacrolimus, sirolimus, cyclosporine, azathioprine, mycophenolate mofetil, and methotrexate), 
pentoxifylline, or N-acetylcysteine (NAC) within 6 month of screening;
20) Use of the following CYP3A4 inhibitors (clarithromycin, conivaptan, grapefruit juice, 
itraconazole, ketoconazole, nefazodone, posaconazole, bupenorphine/naloxone, 
telithromycin, voriconazole) or CYP3A4 inducers (carbamazepine, phenytoin, rifampin, St. 
John’s Wort) within 2 weeks of baseline;
21) Active ocular herpes simplex;
22) 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;
23) 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;
24) Concurrent participation in another therapeutic clinical study;
25) Known hypersensitivity to the study drugs (GS-4997 and prednisolone), the metabolites, or 
formulation excipient;
26) 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;
27) Unavailable for follow-up assessment or concern for subject’s compliance with the protocol 
procedures


GS-4997 
Protocol GS-US-416-2124 
Gilead Sciences, Inc. 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
5.1. 
Randomization, Blinding and Treatment Codes 
Final 
Original 
This is a randomized, double blind study. An Interactive Web Response System (IWRS) will be 
used for centralized randomization and treatment assignment. Randomization will be stratified 
by MELD < or~ 25 at screening. Within each of the strata, subjects will be randomized in a 
1:1 ratio to receive GS-4997 +prednisolone or GS-4997 placebo +prednisolone . 
Investigative site personnel will obtain the subject's identification number and study dmg 
assignment from the IWRS. 
Study dmg will be dispensed by the study phrumacist, or designee. 
5.1.1. 
Procedures for Breaking Treatment Codes 
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IWRS system 
for that subject. Gilead recommends but does not require that the investigator contacts the Gilead 
medical monitor before breaking the blind. Treatment assignment should remain blinded unless 
that knowledge is necessary to dete1mine subject emergency medical care. The rationale for 
unblinding must be clearly explained in somce documentation and on the electronic case rep01t 
f01m ( eCRF), along with the date on which the treatment assignment was obtained. The 
investigator is requested to contact the Gilead medical monitor promptly in case of any treatment 
unblinding. 
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject's treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject. 
Gilead Thug Safety and Public Health (DSPH) may independently unblind cases for expedited 
rep01ting of suspected unexpected serious adverse reactions (SUSARs). 
5.2. 
Description and Handling of Study Drugs 
5.2.1. 
Formulation 
5.2.1.1. 
GS-4997 18 mg and GS-4997 Placebo to Match (PTM) 
GS-4997 will be supplied as 18 mg strength round, plain-faced, white film-coated tablets. In 
addition to the active · 
GS-4997 tablets contain the 
used inactive 
CONFIDENTIAL 
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12 April2016 


GS-4997
Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 45
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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.


GS-4997
Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 46
12 April 2016
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. 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. If a subject misses a dose, the subject should take their next dose at the 
regular dosing time.
5.4.
Prior and Concomitant Medications
In vitro data suggests 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 
the follow-up period. Enteral and parenteral nutritional products administered during the study 
will be recorded on eCRFs.


GS-4997
Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Original
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5.5.
Prohibited Medications
The use of any investigational medication or device in the 30 days prior to screening and through 
the study is prohibited. Administration of pentoxifylline or NAC during the study period is also 
prohibited. 
Co-administration of strong CYP3A4 inhibitors may increase GS-4997 exposure. In a drug-drug 
interaction study of GS-4997 co-administered with ritonavir (strong CYP3A4 inhibitor), 
GS-4997 exposures were significantly increased. Therefore, co-administration of the following 
CYP3A4 inhibitors with study drug is prohibited: clarithromycin, conivaptan, grapefruit juice, 
itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole.
Co-administration of strong CYP3A4 inducers may decrease GS-4997 exposures. In a drug-drug 
interaction study of GS-4997 co-administered with repeat dose rifampin (strong CYP3A4 
inducer), GS-4997 exposures were significantly reduced. Therefore, co-administration of the 
following CYP3A4 inducers with study drug is prohibited: carbamazepine, phenytoin, rifampin, 
St. John’s wort.
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 


GS-4997
Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 48
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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.


GS-4997
Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Original
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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 Hepatic 
Encephalopathy (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
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 specials 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. This will be done at the 
discretion of the investigator with prior approval of the Medical Monitor.
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the screening visit to ensure an 
approximate 8-hour fast prior to the blood sample collection under fasting condition the next 
morning.


GS-4997 
Protocol GS-US-416-2124 
Gilead Sciences, Inc. 
Day -14 to Day 0 
The following will be performed and documented at screening: 
• 
Obtain written informed consent 
• 
PPD 
• 
• 
Obtain medical history 
• 
Review and record whether the subject has met inclusion/exclusion criteria 
• 
AUDIT I SADQ questionnaire 
• 
Assess alcohol consumption 
• 
Complete physical examination including, vital signs, body weight, and height 
• 
Record all concomitant medications that the subject has taken within 30 days prior to 
screenmg 
• 
Perform standard 12-lead ECG 
• 
Collect urine samples for urine drug screen and culture 
• 
Assessments for hepatic encephalopathy, ascites, Hepatorenal Syndrome (HRS), and 
infection 
• 
Obtain blood samples for: 
-
Hematology 
Final 
Original 
-
Chemistry: alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, 
alkaline phosphatase, bicarbonate, blood urea nitrogen (BUN), calcium, chloride, 
creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphorus, potassium, 
sodium, total and direct bilirubin, total protein, uric acid, gamma-glutamyl transferase 
(GGT) 
-
Coagulation Tests: PT, PTT, and INR 
-
Serum Pregnancy Test (only for females subjects of childbearing potential) 
-
Blood for Biomarkers 
CONFIDENTIAL 
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12 April 2016 


GS-4997
Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Original
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HBV, HCV, and HIV serology
Blood cultures
Blood glucose and insulin (fasting)
Lipid Profile (fasting)

Perform chest x-ray

Perform liver ultrasound (it is acceptable to use a liver ultrasound previously performed
during the current hospitalization)

Perform paracentesis (ascitic fluid tap) with ascitic fluid cell count, differential, and culture if 
clinically-detectable ascites is present

Perform liver biopsy
Note: Can be performed up to 7 days post Baseline/Day 1. Liver biopsy obtained during the 
current hospital admission 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 liver biopsy 
result, attend an End of Treatment (EoT) visit soon as possible, have a 30-day safety 
follow-up visit , and be withdrawn from the study.

Record any serious adverse events and all adverse events occurring after signing of the 
consent form
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events 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
Subjects eligible for randomization at Day 1 should be instructed to fast (no food or drink, except 
water), starting from midnight (00:00) or earlier, as appropriate, on the evening prior to the 
baseline/Day 1 visit to ensure an approximate 8-hour fast prior to the blood sample collection 
under fasting condition the next morning.  


GS-4997
Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Original
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After review of inclusion and exclusion criteria to confirm continued eligibility, subjects will be 
randomized to study drug assignment and receive their Subject Identification Number via the 
IWRS prior to their first dose of study drug.
Randomization will be stratified by MELD < or ≥ 25 at screening.
The following will be performed and documented at the randomization visit prior to dosing:

Review inclusion/exclusion criteria and confirm continued eligibility

QoL Questionnaire (CLDQ)

Assess alcohol consumption

Complete physical examination including, vital signs, and body weight

Perform standard 12-lead ECG

Assessments for hepatic encephalopathy, ascites, HRS and infection

Obtain blood samples for:
Hematology
Chemistry: alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, 
alkaline phosphatase, bicarbonate, blood urea nitrogen (BUN), calcium, chloride, 
creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphorus, potassium, 
sodium, total and direct bilirubin, total protein, uric acid, gamma-glutamyl transferase 
(GGT)
Coagulation Tests: PT, PTT, and INR
Blood for Biomarkers
ELFTM Test and LOXL2
Blood glucose and insulin (fasting)
Hemoglobin A1c
Lipid Profile (fasting)
Sparse PK Sample


GS-4997 
Protocol GS-US-416-2124 
Gilead Sciences, Inc. 
_ 
PD 
• 
Urine pregnancy test (for females of childbearing potential) 
• 
Collect stool for microbiome testing 
Final 
Original 
• 
Record all concomitant medications that the subject has taken since the previous visit 
• 
Record any serious adverse events and all adverse events occmTing after signing of the 
consent fonn 
• 
Randomization via IWRS 
• 
Administer or dispense GS-4997 and prednisolone, and provide subject with dosing 
instmction on appropriate dosing and administration 
6.3. 
Treatment Assessments 
6.3.1. 
Week 1 Visit (±3 Days) 
Dming the Week 1 safety visit the following will be perf01med and documented: 
• 
Review of liver biopsy results if unavailable dming the screening period and reassess study 
entty criteria. 
• 
Assess alcohol consumption 
• 
Complete physical examination including, vital signs 
• 
Assessments for hepatic encephalopathy, ascites, HRS, and infection 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistly: alanine aminott·ansferase (AL T), aspruiate aminott·ansferase (AST), albumin, 
alkaline phosphatase, bicru·bonate, blood mea nitt·ogen (BUN), calcimn, chloride, 
creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphoms, potassium, 
sodium, total and direct bilimbin, total protein, mic acid, gamma-glutrunyl transferase 
(GGT) 
-
Coagulation Tests: PT, PTT, and INR 
CONFIDENTIAL 
Page 53 
12 April2016 


GS-4997 
Protocol GS-US-416-2124 
Gilead Sciences, Inc. 
-
Blood for biomarkers 
-
Sparse PK Sample 
• 
Record all concomitant medications that the subject has taken since the previous visit 
Final 
Original 
• 
Record any serious adverse events and all adverse events occuning since the previous visit 
• 
Administer or dispense prednisolone, and provide subject with dosing instmction on 
appropriate dosing and administration. 
• 
PPD 
• 
Assess for Study Dmg adherence 
• 
Perfmm study dmg accountability 
6.3.2. 
Week 2 Visit (±3 Days) 
During the Week 2 safety visit, the following will be perfonned and documented: 
• 
Assess alcohol consumption 
• 
Complete physical examination including vital signs 
• 
Assessments for hepatic encephalopathy, ascites, HRS and infection 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistty: alanine aminotransferase (AL T), aspa.t1ate aminott·ansferase (AST), albumin, 
alkaline phosphatase, bicru·bonate, blood urea nitrogen (BUN), calcimn, chloride, 
creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphoms, potassium, 
sodium, total and direct bilimbin, total protein, uric acid, gamma-gluta.tnyl transferase 
(GGT) 
-
Coagulation Tests: PT, PTT, and INR 
-
Blood for biomru·kers 
CONFIDENTIAL 
Page 54 
12 April2016 


GS-4997 
Protocol GS-US-416-2124 
Gilead Sciences, Inc. 
-
Sparse PK Sample 
• 
Record all concomitant medications that the subject has taken since the previous visit 
Final 
Original 
• 
Record any serious adverse events and all adverse events occutTing since the previous visit 
• 
PPD 
• 
Assess for Study Dmg adherence 
• 
Perfmm study dmg accountability 
6.3.3. 
Week 3 Visit (:1:3 Days) 
During the Week 3 safety visit, the following will be perfmmed and documented: 
• 
Assess alcohol consumption 
• 
Complete physical examination including vital signs 
• 
Assessments for hepatic encephalopathy, ascites, HRS and infection 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemist:Iy: alanine aminon·ansferase (AL T), aspartate aminot:I·ar1sferase (AST), albumin, 
alkaline phosphatase, bicar·bonate, blood urea nitrogen (BUN), calcium, chloride, 
creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphorus, potassium, 
sodium, total and direct bilirubin, total protein, uric acid, garmna-glutamyl transferase 
(GGT) 
-
Coagulation Tests: PT, PTT, and INR 
• 
Record all concomitant medications that the subject has taken since the previous visit 
• 
Record any serious adverse events and all adverse events occutTing since the previous visit 
• 
Administer or dispense prednisolone, and provide subject with dosing inst:Iuction on 
appropriate dosing and administration 
CONFIDENTIAL 
Page 55 
12 April2016 


GS-4997 
Protocol GS-US-416-2124 
Gilead Sciences, Inc. 
• 
PPD 
• 
Assess for Study Dmg adherence 
• 
Perfmm study dmg accountability 
6.3.4. 
Week 4 I End of Treatment Visit (EoT) (±3 days) 
Final 
Original 
If the subject meets criteria for discontinuation of treatment (see Sectiou 6.8 of this protocol), the 
subject should complete au End of Treatment visit as soon as possible after all study dmgs are 
discontinued and attend post-treatment visits as outlined in Appendix 2. Subjects that have their 
scheduled Week 4 visit prior to Day 28 will require a phone contact between Study Days 28-35 
to assess moliality and liver transplantation. 
Subjects should be iustmcted to fast (no food or drink, except water), statting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Week 4 visit to ensure an 
approximate 8-hour fast prior to the fasted blood sample collection the next momiug. 
Subjects should be instructed not to take study dmg in the moming 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 perfmmed and documented at this visit: 
• 
QoL Questiollllaire (CLDQ) 
• 
Assess alcohol consumption 
• 
Complete physical examination including, vital signs, and body weight 
• 
Perfmm standard 12-lead ECG 
• 
Assessments for hepatic encephalopathy, ascites, HRS, and infection. 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistry: alanine aminotr·ausferase (AL T), asprutate aminotransferase (AST), albumin, 
alkaline phosphatase, bicarbonate, blood urea uitr·ogeu (BUN), calcium, chloride, 
creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphoms, potassium, 
sodium, total and direct bilimbin, total protein, uric acid, gamma-glutatnyl transferase 
(GGT) 
-
Coagulation Tests: PT, PTT, and INR 
CONFIDENTIAL 
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12 April2016 


GS-4997 
Protocol GS-US-416-2124 
Gilead Sciences, Inc. 
-
Blood for Biomarkers 
-
ELF™ Test and LOXL2 
-
Blood glucose and insulin (fasting) 
-
Lipid Profile (fasting) 
-
Sparse PK Sample 
• 
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 
Final 
Original 
• 
Record any serious adverse events and all adverse events occurring since the previous visit 
• 
Assess for Study Drug adherence 
• 
Perform study drug accountability 
6.3.5. 
Follow Up Visit (±5 Days) 
Subjects whose liver biopsy results are not consistent with AH, must stop study drugs within 3 
days of receipt of 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, and be withdrawn from the study. 
• 
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 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistry: alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, 
alkaline phosphatase, bicarbonate, blood urea nitrogen (BUN), calcium, chloride, 
creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphorus, potassium, 
sodium, total and direct bilirubin, total protein, uric acid, gamma-glutamyl transferase 
(GGT) 
CONFIDENTIAL 
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GS-4997 
Protocol GS-US-416-2124 
Gilead Sciences, Inc. 
6.4. 
Pharmacokinetic Assessments 
6.4.1. 
Sparse PK 
Final 
Original 
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). 
• 
Week 2 - samples should be collected at 24 (±4) lus after prior dose (prior to dosing on visit 
day) AND at 2 (±1) hrs postdose. 
If a subject requires hemodialysis or hemoperfusion therapy, a PK sample should be collected 
prior to initiation of the procedme (within 30 minutes), upon completion of the procedme (within 
15 minutes), and approximately 1 hr after completion of the procedme. For subjects who initiate 
dialysis, GS-4997/PTM should be administered following dialysis on days of the procedme and 
at the usual time on non-dialysis days. The timing of prednisolone dosing should remain 
unchanged in subjects on dialysis. Additionally, a sample of dialysate should be collected at the 
end of the procedme and total volume of dialysate recorded. PK sampling only needs to be 
performed on one occasion ofhemodialysis/hemoperfusion. 
Note: If a subject discontinues treatment, but remains on study, PK samples do not need to be 
collected after the end of treatment visit. 
6.4.2. 
Intensive PK Substudy 
PPD 
CONFIDENTIAL 
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GS-4997 
Protocol GS-US-416-2124 
Gilead Sciences, Inc. 
p 
6.5. 
Post-Treatment Assessments 
6.5.1. 
Week 6 (± 3 Days) 
Final 
Original 
Subjects will retum for Follow-Up Visits struting at Week 6 after the Week 4 I End of Treatment 
Visit or the last dose of study drug to undergo the following: 
During the Week 6 post treatment visit, the following will be perf01med and documented: 
• 
Assess alcohol consumption 
• 
Complete physical examination including vital signs 
• 
Assessments for hepatic encephalopathy, ascites, HRS and infection 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistly: alanine aminofl·ansferase (AL T), aspruiate aminofl·ansferase (AST), albumin, 
alkaline phosphatase, bicru·bonate, blood urea nitrogen (BUN), calcimn, chloride, 
creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphoms, potassium, 
sodium, total and direct bilimbin, total protein, uric acid, gamma-glutamyl transferase 
(GGT) 
-
Coagulation Tests: PT, PTT, and INR 
• 
Record all concomitant medications that the subject has taken since the previous visit 
• 
Record any serious adverse events and all adverse events occmTing since the previous visit 
6.5.2. 
Weeks 8, 16, and 20 I Post Treatment Visits (± 5 Days) 
During the Week 8, 16, and 20 post treatment visits, the following will be perf01med and 
documented: 
• 
Assess alcohol consumption 
• 
Complete physical examination including, vital signs 
• 
Perf01m standru·d 12-lead ECG (Week 8 only) 
• 
Assessments for hepatic encephalopathy, ascites, HRS and infection 
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
Obtain blood samples for:
Hematology
Chemistry: alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, 
alkaline phosphatase, bicarbonate, blood urea nitrogen (BUN), calcium, chloride, 
creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphorus, potassium, 
sodium, total and direct bilirubin, total protein, uric acid, gamma-glutamyl transferase 
(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
6.5.3.
Weeks 12 and 24 / Post Treatment Visits (± 5 Days)
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Week 12 and Week 24 visits to 
ensure an approximate 8-hour fast prior to the fasted blood sample collection the next morning.
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

Complete physical examination including, vital signs, and body weight

Assessments for hepatic encephalopathy, ascites, HRS and infection


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• 
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-
Hematology 
Final 
Original 
-
Chemistry: alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, 
alkaline phosphatase, bicarbonate, blood urea nitrogen (BUN), calcium, chloride, 
creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphorus, potassium, 
sodium, total and direct bilirubin, total protein, uric acid, gamma-glutamyl transferase 
(GGT) 
-
Coagulation Tests: PT, PTT, and INR 
-
Blood for Biomarkers 
-
ELF™ Test and LOXL2 
-
Blood glucose and insulin (fasting) 
-
Hemoglobin Ale 
-
Lipid Profile (fasting) 
PD 
• 
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 any serious adverse events and all adverse events occurring since the previous visit 
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. 
• 
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 
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
Obtain blood samples for:
Hematology
Chemistry: alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, 
alkaline phosphatase, bicarbonate, blood urea nitrogen (BUN), calcium, chloride, 
creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphorus, potassium, 
sodium, total and direct bilirubin, total protein, uric acid, gamma-glutamyl transferase 
(GGT)
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 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 and 
all required follow-up study visits.  
If biopsy results are not consistent with AH, the subject must stop study drugs within 3 days of 
receipt of 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, and be withdrawn from the study.
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.
6.8.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

Liver biopsy inconsistent with diagnosis of alcoholic hepatitis

Subject who develops a serious adverse event consisting of a serious allergic reaction to the 
study drug

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator after discussion with the 
Medical Monitor

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


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
Subject noncompliance

Pregnancy during the study; refer to Appendix 3

Sponsor discretion

Discontinuation of the study at the request of Gilead, a regulatory agency or an institutional 
review board or independent ethics committee (IRB/IEC/EC)
6.9.
Description of Assessments
6.9.1.
Liver Biopsy
A core liver biopsy will be performed at Screening. Liver biopsy can be performed up to 7 days 
post Baseline/Day 1 visit and either via the percutaneous or transjugular route. Subjects may start 
treatment prior to receipt of liver biopsy result if subject has met all other eligibility assessments. 
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 liver biopsy result, attend an EoT visit as soon 
as possible, have a Follow Up visit 30 days later, and be withdrawn from the study.
Liver biopsy obtained during the current hospital admission prior to screening is acceptable.
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.
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. 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 


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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.
6.9.5.
Hepatic Encephalopathy
The severity of hepatic encephalopathy 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)
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
6.9.7.
Hepatorenal Syndrome (HRS)
The occurrence of HRS should be confirmed based on the following diagnostic criteria of the 
International Ascites Club. The date of diagnosis/resolution and specific therapies for HRS 
should be recorded.

Cirrhosis with ascites

Serum creatinine >133 μmol/L (1.5 mg/dL)

No improvement of serum creatinine (decrease to a level of ≤133 μmol/L) 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


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
No current or recent treatment with nephrotoxic drugs

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.
6.9.8.
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.
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.
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.
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, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
eCRF database and 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.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period
however; if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead 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.
7.3.
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. 
7.4.
Toxicity Management 
Subjects who meet any of the following laboratory criteria must stop GS-4997/placebo

Total bilirubin > 3x Baseline/Day 1 (confirmed by on repeat testing)

ALT and/or AST > 5x Baseline/Day1 or nadir (confirmed by on repeat testing)

Any Grade 4 AE assessed as related to GS-4997
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.

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.


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
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.
Special Situations Reports
7.5.1.
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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7.5.2.
Instructions for Reporting Special Situations
7.5.2.1.
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 7.3 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.
7.5.2.2.
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 7.3 and the eCRF completion guidelines for full instructions on the mechanism
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
Final 
Original 
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 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 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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8.2.1. 
I 
I 
I 
I 
I 
I 
I 
I 
I 
PD 
8.3. 
8.3.1. 
8.3.1.1. 
Exploratory Endpoints 
Analysis Conventions 
Analysis Sets 
Efficacy 
Final 
Original 
The prima1y analysis set for efficacy analyses will be the Full Analysis Set (F AS) which includes 
all subjects with severe alcoholic hepatitis who were randomized into the study and received at 
least one dose of study drug. 
Subjects who receive study dmg other than that to which they were assigned will be analyzed 
according to the treatment group to which they were randomized. 
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8.3.1.2. 
Safety 
Final 
Original 
The primaty analysis set for safety analyses will be the Safety Analysis set which includes all 
subjects who received at least one dose of study dmg. Treatment-emergent data will be analyzed 
and defmed as data collected from the first dose of study dm g through the date of last dose of 
study dmg plus 30 days. Subjects who received study dmg other than that to which they were 
assigned will be analyzed according to the study dmg received. 
8.3.1.3. 
Phrumacokinetics 
The Phrumacokinetic (PK) Analysis Set includes all subjects who have been administered at 
least one dose of active study dmg (GS-4997) and have at least one non-missing postdose 
concentration value for the conesponding analyte in plasma or sennn. 
PD 
8.3.1.4. 
Explorat01y Biomarkers 
8.4. 
Data Handling Conventions 
Missing data can have an impact on the inte1pretation of the trial data. In general, values for 
missing data will not be imputed. 
Where appropriate, safety data for subjects who received study dmg but did not complete the 
study will be included in summruy statistics. For example, if a subject received study medication, 
the subject will be included in a summruy of adverse events according to the treatment received; 
however, if the subject is not dosed then they will be excluded from the stnnmruy. If safety 
laborat01y results for a subject are missing for any reason at a time point, the subject will be 
excluded from the calculation of summruy statistics for that time point. If the subject is missing a 
predose value, then the subject will be excluded from the calculation of stnnmruy statistics for 
the predose value and the change from predose values. 
Values for missing safety laborat01y data, ECGs, and vital signs will not be imputed; however, a 
missing baseline result will be replaced with a screening result, if available. If no pre-treatment 
laborat01y value is available, the baseline value will be assumed to be n01mal (ie, no grade 
[Grade 0]) for the summaty of graded laboratory abnormalities. 
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8.5. 
Demographic Data and Baseline Characteristics 
Final 
Original 
Demographic and baseline measurements will be summarized using standard descriptive 
methods by treatment group. Demographic summa1·ies will include age, sex, race, and ethnicity. 
Baseline characteristics summa1y will include body weight, height, body mass index, baseline 
MELD, CPT, Maddrey DF, and other baseline disease characteristic variables of interest. 
8.6. 
Interim Analysis 
An interim analysis will be conducted after all subjects have been followed through the Day 28 
visit for pmposes of intemal decision making. The senior and executive VPs, and project lead 
from Clinical Research and the statistician responsible for overseeing the Liver Disease 
Therapeutic area will be unblinded for this interim. None of the persons 1mblinded will be 
responsible for the conduct of the study. 
8.7. 
Efficacy Analysis 
The biological activity of the combination of GS-4997 and prednisolone and prednisolone alone 
will be evaluated using clinical outcomes (mmtality, hepatorenal synru·ome [HRS], infection, 
liver transplantation, and length of hospital stay) and measures of hepatic function (Lille 
re_~oonse at Day 7, and change from baseline in MELD, CPT, and Maddrey's DF scores, 
PPD 
The percentage of subjects with Lille score response (defined 
as a Lille score <0.45 at Day 7), and percentage of subjects who have died by Day 28 will be 
compared between treatment groups using a 2-sided Fisher's exact test. Time to death/liver 
transplantation up to Day 28, Week 12 and Week 24 will be analyzed using Kaplan-Meier 
methods. For continuous variables, an 8-nmnber summaiy will be provided by treatment group. 
For categorical variables, descriptive statistics ( cmmt and percentage of subjects in each 
categmy) will be presented by treatment group. Point estimates (and when appropriate 95% CI) 
will be calculated for each parameter. 
8.7.1. 
Exploratory Analysis 
PPD 
8.8. 
Safety Analysis 
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, ECGs, 
and vital signs measmements at va1·ious time points during the study, and by the documentation 
ofAEs. 
All safety data collected while "on treatment" (ie, on or after the first dose of study dmg 
a&ninistration up to 30 days after the last dose of study drug) will be summarized by treatment 
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group according to the study drug received. Safety endpoints will be analyzed as the number and 
percentage of subjects with events or abnormalities for categorical variables. Continuous 
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 postbaseline 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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8.8.4. 
Other Safety Evaluations 
Sunnnruy statistics for the 12-lead ECGs perfmmed will be generated by analysis visit. 
8.9. 
Pharmacokinetic Analysis 
GS-4997 and GS-607509 plasma/setum concentrations in all subjects will be listed and 
summarized. PPO 
8.9.1. 
Other Exploratory Analyses 
PO 
8.10. 
Sample Size 
The number of subjects was chosen based on clinical ex 
conce t studies. PO 
8.11. 
Data Monitoring Committee 
Final 
Original 
An independent, extemal Data Monitoring Committee (DMC) that includes two hepatologists 
and a PhD statistician will convene once 20 subjects have been treated for 28 days and eve1y 
3 months thereafter to monitor the study for safety events including SAEs, death, grade 3 and 
higher AEs and grade 3 and higher treatment-emergent laboratoty abnotmalities. 
The DMC will provide recommendations to Gilead on whether the nature, frequency, and 
severity of adverse effects associated with study treatment wruTant the eru'ly tetmiuation of the 
study in the best interest of the pruticipants, whether the study should continue as planned, or the 
study should continue with modifications. The DMC may also provide recommendations as 
needed regru·ding study design. 
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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, physical examination, 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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Nakagawa H, Maeda S, Hikiba Y, Ohmae T, Shibata W, Yanai A, et al. Deletion of apoptosis 
signal-regulating kinase 1 attenuates acetaminophen-induced liver injury by 
inhibiting c-Jun N-terminal kinase activation. Gastroenterology 2008;135 
(4):1311-21.
Nakamura T, Kataoka K, Fukuda M, Nako H, Tokutomi Y, Dong YF, et al. Critical role of 
apoptosis signal-regulating kinase 1 in aldosterone/salt-induced cardiac 
inflammation and fibrosis. Hypertension 2009;54 (3):544-51.
Nguyen-Khac E, Thevenot T, Piquet MA, Benferhat S, Goria O, Chatelain D, et al. 
Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J Med 
2011;365 (19):1781-9.
Noguchi H, Yamada S, Nabeshima A, Guo X, Tanimoto A, Wang KY, et al. Depletion of 
apoptosis signal-regulating kinase 1 prevents bile duct ligation-induced 
necroinflammation and subsequent peribiliary fibrosis. Am J Pathol 2014:1-18.
O'Shea RS, Dasarathy S, McCullough AJ, Practice Guideline Committee of the American 
Association for the Study of Liver D, Practice Parameters Committee of the 
American College of G. Alcoholic liver disease. Hepatology 2010;51 (1):307-28.
O'Shea RS, McCullough AJ. Treatment of alcoholic hepatitis. Clin Liver Dis 2005;9 (1):103-34.
Rudler M, Mouri S, Charlotte F, Lebray P, Capocci R, Benosman H, et al. Prognosis of treated 
severe alcoholic hepatitis in patients with gastrointestinal bleeding. J Hepatol 
2015;62 (4):816-21.
Singal AK, Guturu P, Hmoud B, Kuo YF, Salameh H, Wiesner RH. Evolving frequency and 
outcomes of liver transplantation based on etiology of liver disease. 
Transplantation 2013;95 (5):755-60.
Spahr L, Rubbia-Brandt L, Frossard JL, Giostra E, Rougemont AL, Pugin J, et al. Combination 
of steroids with infliximab or placebo in severe alcoholic hepatitis: a randomized 
controlled pilot study. J Hepatol 2002;37 (4):448-55.
Taieb J, Mathurin P, Elbim C, Cluzel P, Arce-Vicioso M, Bernard B, et al. Blood neutrophil 
functions and cytokine release in severe alcoholic hepatitis: effect of 
corticosteroids. J Hepatol 2000;32 (4):579-86.
Takeda K, Noguchi T, Naguro I, Ichijo H. Apoptosis signal-regulating kinase 1 in stress and 
immune response. Annu Rev Pharmacol Toxicol 2008;48:199-225.


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Gilead Sciences, Inc. 
Original
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Terada Y, Inoshita S, Kuwana H, Kobayashi T, Okado T, Ichijo H, et al. Important role of 
apoptosis signal-regulating kinase 1 in ischemic acute kidney injury. Biochem 
Biophys Res Commun 2007;364 (4):1043-9.
Thursz MR, Richardson P, Allison M, Austin A, Bowers M, Day CP, et al. Prednisolone or 
pentoxifylline for alcoholic hepatitis. N Engl J Med 2015;372 (17):1619-28.
Tobiume K, Matsuzawa A, Takahashi T, Nishitoh H, Morita K, Takeda K, et al. ASK1 is 
required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO 
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Tobiume K, Saitoh M, Ichijo H. Activation of apoptosis signal-regulating kinase 1 by the stress-
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Zhang R, Al-Lamki R, Bai L, Streb JW, Miano JM, Bradley J, et al. Thioredoxin-2 inhibits 
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relevance of hepatocyte apoptosis in alcoholic hepatitis. J Hepatol 2001;34 
(2):254-60.


GS-4997
Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 91
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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


GS-4997 
Protocol GS-US-416-2124 
Final 
Gilead Sciences, Inc. 
Original 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
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) 
GS-US-416-2124, O•·iginal, 12 April2016 
Tbis protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approvaL 
--=-
Ro-:--
b f-:--
yer-s, ~---Jvl 1f'(j 
PPD 
Medical Monitor 
Date 
~STIGATORSTATEMENT 
1 have read the protocol, including all appendices, and J agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Sire Number 
CONFIDENTIAL 
Page 92 
12 April2016 


GS-4997
Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 93
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Appendix 2.
Study Procedures Table
Screeninga
Treatment
Post-Treatment
Unscheduled 
Visit
-14 days
Baseline/
Day 1
Week 1
Week 2
Week 3
Week 
4/EoTr
Week 6
Week 8
Week 12s Week 16
Week 20
Week 24s
Follow Up 
visit t
±3 days
±5 days
Informed Consent
X
Review Inclusion/Exclusion 
Criteria
X
X
X
Medical History
X
AUDIT / SADQb
X
QoL (CLDQ) b
X
X
X
Alcohol Consumption
X
X
X
X
X
X
X
X
X
X
X
X
Complete Physical Examc
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGd
X
X
X
X
Urine Drug Screene
X
Urine Collection
X
Hepatic Encephalopathyc
X
X
X
X
X
X
X
X
X
X
X
X
Ascitesc
Xf
X
X
X
X
X
X
X
X
X
X
X
HRSd
X
X
X
X
X
X
X
X
X
X
X
X
Infectiond
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistryg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation Testsh
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Testi
X
X
X
X
X
X
X
X
ELF test, LOXL2
X
X
X
X


GS-4997 
Protocol GS-US-416-2124 
Gilead Sciences, Inc. 
Hepatitis B and C HIV serology 
Chest X-ray 
Liver Ultrasound 
Blood Cultures 
Ascitic Fluid Tapi 
Liver Biopsy 
Blood Glucose (fasting)1 
Insulin (fastingY 
Hemoglobin Ale 
Lipid Profile (fastingi 
Review Concomitant Medications 
Adverse Events 
FPD 
Sparse PK Samplen 
Stool Collection 
Blood Sample for Biomarkers" 
Randomization 
CONFIDENTIAL 
Screenln~:" 
-14 days 
X 
X 
X 
X 
X 
xk 
X 
X 
X 
X 
X 
X 
Treatment 
Weeki 
Week2 
Week3 
Baseline/ 
Day 1 
±3 days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Post-Treatment 
Week 
4/EoT' 
Week 6 
WeekS Week 12' Week 16 
Week20 
±5 days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xn 
X 
X 
X 
X 
Page 94 
Week24' 
X 
X 
X 
X 
X 
X 
X 
X 
Follow Up 
visit' 
X 
X 
Final 
Original 
Unscheduled 
Visit 
X 
X 
12 April 2016 
J 


GS-4997 
Protocol GS-US-416-2124 
Gilead Sciences, Inc. 
GS-4997 Dispensing 
Prednisolone Dispensing 
f PD 
Genomic Sampleq 
Study Drug Adherence 
Scr~~nine:• 
Bas~ 
lin~/ 
-14 days 
Day 1 
X 
X 
X 
Tr~atm~nt 
w~~k l 
We~k2 Week3 
±3 days 
X 
X 
X 
X 
X 
Post-Tr~atm~nt 
Week 
4/EoT' 
w~~k 6 
We~k8 Week 12' Week 16 
Week20 
±5 days 
X 
Follow Up 
Week24' 
vi~it' 
Final 
Original 
IUnschedul~d 
Visit 
I 
a 
The visit window may be extended lmder special cu·cmustances with explicit approval of the Medical Monitor. Subjects who fail to meet eligibility criteria due to an abnotmal 
laboratory result may undergo re,-testu1g of the abnormal analyte once dm·ing the scre.enulg window. This will be done at the discretion of the u1vestigator and also with prior 
approval of the Medical Monitor. 
b 
A Legally Authorized Representative may assist the subject in completing the questionnaires. If the subject is lmable or refuses to complete a questiollllaire, this should be 
doctuuented on the relevant eCRF. 
c 
Petfonu a complete Physical Exam with a focus on ascites and encephalopathy. 
d 
Please see section 6.9 for description of assessments and rec.ord diagnosis/abnotmal fmdings as an AE. 
e 
Dmg screen for amphetanunes, cocaine and opiates (ie heroin, morphine). 
f 
Subjects with evidence of sepsis or gastrou1testinal bleeding may be treated for a nlitumtuU of 2 days with appropriate antibiotics. Once deemed stable, subject may continue 
sct·eenulg and randomized if eligible. 
g 
Chenustry will include: alanine anlinotransferase (ALT), aspartate anlinotransferase (AST), albumin, alkalu1e phosphatase, bicarbonate, blood mea tutl·ogen (BUN), calcium, 
chloride, creatinine, glucose, lactate dehydrogenase (LDH), magnesimn, phosphoms, potassituu, sodium, total and direct bilirubin, total protein, mic acid, ganm1a-glutamyl 
transferase (GGT). 
h 
Coagulation Panelu1cludes: PT, PTI and INR. 
Females of childbearing potential only. Semm pregnancy test at Screeni11g. Urine pregnancy test for other visits. 
J 
Paracentesis with ascitic fluid cell count, differential, and cultlU'e will be petfonned if clilllcally-detectable ascites is present. 
k 
Liver biopsy obtained dlll'ing the cmrent hospital admission prior to screening is acceptable. Liver biopsy can be petfotmed up to 7 days post Baseline/Day 1. However, if 
biopsy results are not consistent with AH, the subject will discontinue study dmg witlun 3 days of receipt of liver biopsy result, attend an EoT visit as soon as possible and 
attend a 30-day FU visits and be wiilidrawn from the study. 
Subjects must be in a fasted state for at least 8 homs rior to blood collection. 
m l 
.._P_D 
_ ___. 
n 
~lease refer to Section 6.4.1 for sample collection instructions. If subject's last dose of study drug is prior to ilie Week 4 visit, PK sample can still be collected at Week 4 as 
long as last dose date and tune is prior to sample collection. 
o 
Biomarker phospho-p38 blood sample will be collected prior to the fu·st dose of study dmg. This collection will only occm· at select US study sites. 
CONFIDENTIAL 
Page 95 
12 April2016 


GS-4997 
Protocol GS-US-416-2124 
Gilead Sciences, Inc. 
Final 
Original 
p 
q 
r 
s 
PD 
PPD 
Sub.1'-
e.c-.t-
s -d
'""ts-
·c_o_n~
tu_m_u
,_l_g"~'th·e study at any tune tor any reason sliOUid complete the procedures requu·ed tOrilie Week 4fEiid of Treatment Vtstt . .Addii'ionallY,s1tbjects that 
discontinue treatment prior to week 4 will require a phone contact between study days 28-35 to assess for mottality and liver transplantation. 
Subjects \,.-jth a Week 12 or Week 24 visit prior to Day 84 or Day 168 respectively will be required to have a telephone contact between Days 84-89 or 168-173 to assess for 
mortality and liver transplantation. 
Subjects whose liver biopsy results are not consistent with AH, must stop study dmgs within 3 days of receipt ofliver biopsy result, attend an EoT visit as soon as possible 
and have a Follow Up visit 30 days after their last dose of study dmg, and be withdrawn from the study. 
CONFIDENTIAL 
Page 96 
12 April2016 


GS-4997
Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 97
12 April 2016
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause. In 
addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
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 67- and 12-fold higher, respectively, than the projected exposure at the 
proposed human dose of 18 mg/day. 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 13- 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.


GS-4997
Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Original
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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 following the end of relevant systemic exposure.

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


GS-4997
Protocol GS-US-416-2124
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 99
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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 end of relevant systemic exposure.
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 the end of relevant 
systemic exposure. Female partners of male study subjects are asked to select one of the above 
methods.
Male subjects must also refrain from sperm donation during treatment and until at least 90 days 
after the end of relevant systemic exposure.
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 7.5.2.1.