Clinical trial NCT02854605
Conditions: Nonalcoholic Steatohepatitis (NASH)
Keywords: Non-alcoholic fatty liver disease (NAFLD) Fibrosis GS-9674
Sponsor: Gilead Sciences
Start date: 2016-10-26; Completion date: 2018-01-09
Enrollment: 140 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the safety and tolerability of GS-9674 in participants with nonalcoholic steatohepatitis (NASH).

Detailed description:

Arms: arm 1: GS-9674 30 mg + placebo to match GS-9674 100 mg for 24 weeks arm 2: GS-9674 100 mg + placebo to match GS-9674 30 mg for 24 weeks arm 3: Placebo to match GS-9674 30 mg + placebo to match GS-9674 100 mg for 24 weeks
Interventions: intervention 1: GS-9674 intervention 2: Placebo to match GS-9674
Intervention descriptions: intervention 1: Tablet administered orally once daily intervention 2: Tablet(s) administered orally once daily

Protocol documents:
Prot_002.pdf: 
Study Title: 
Sponsor: 
INDNumber: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Medical 
Monitor: 
Protocol Version/Date: 
~ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Randomized, Double-Blind, Placebo-Contmlled Study 
Evaluating the Safety, Tolerability, and Efficacy ofGS-9674 in 
Subjects with Nonalcoholic Steatohepatitis (NASH) 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
U.S.A. 
127960 
2016-0024 96-10 
NCT02854605 
Nonalcoholic steatohepatitis (NASH) 
GS-US-402-1852 
Name: 
Telephone: 
Fax: 
Email: 
Original: 
Amendment 1: 
Amendment 2: 
C. ~hen Djedjos, M.D. 
PPD 
~PD 
PD 
28 Jtme 2016 
03 October 2016 
24 Januaty 2017 
CONFIDENTIALITY STATEMENT 
The infonnation contained in this document~ particulm·ly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The infotmation is only to be used by you in 
com1ection with authorized clinical studies of the investigational drug described in the protocol. 
You will not disclose any of the information to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessaty to obtain informed consent from those 
persons to whom the dmg may be administered. 


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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....................................................................12
1.
INTRODUCTION ..............................................................................................................................................16
1.1.
Background ............................................................................................................................................16
1.1.1.
GS-9674 General Information..............................................................................................17
1.1.2.
Nonclinical Toxicology........................................................................................................17
1.1.3.
Nonclinical Pharmacology ...................................................................................................18
1.1.4.
Nonclinical Pharmacokinetics..............................................................................................19
1.1.5.
Clinical Trials of GS-9674 ...................................................................................................20
1.2.
Rationale for This Study ........................................................................................................................23
1.3.
Risk/Benefit Assessment for the Study..................................................................................................25
1.4.
Compliance ............................................................................................................................................26
2.
OBJECTIVES.....................................................................................................................................................27
3.
STUDY DESIGN................................................................................................................................................28
3.1.
Study Design..........................................................................................................................................28
3.2.
Treatment Plan and Regimen .................................................................................................................29
3.3.
Biomarker Testing..................................................................................................................................29
3.3.1.
Biomarker Samples to Address the Study Objectives ..........................................................29
3.3.2.
Biomarker Samples for Optional Future Research...............................................................29
3.3.3.
Biomarker Samples for Optional Genomic Research...........................................................30
4.
SUBJECT POPULATION..................................................................................................................................31
4.1.
Number of Subjects and Subject Selection ............................................................................................31
4.2.
Inclusion Criteria....................................................................................................................................31
4.3.
Exclusion Criteria...................................................................................................................................32
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................35
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................35
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................35
5.2.
Description and Handling of GS-9674 and PTM GS-9674....................................................................36
5.2.1.
Formulation..........................................................................................................................36
5.2.2.
Packaging and Labeling .......................................................................................................36
5.2.3.
Storage and Handling...........................................................................................................36
5.3.
Dosage and Administration of GS-9674/ PTM GS-9674.......................................................................37
5.4.
Prior and Concomitant Medications.......................................................................................................37
5.5.
Prohibited Medications ..........................................................................................................................38
5.6.
Accountability for GS-9674/ PTM GS-9674 .........................................................................................39
5.6.1.
Investigational Medicinal Product Return or Disposal.........................................................39
6.
STUDY PROCEDURES ....................................................................................................................................40
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................40
6.2.
Pretreatment Assessments – Screening Visit .........................................................................................40
6.3.
Baseline/Day 1 Randomization and Assessments..................................................................................42
6.4.
Treatment Assessments..........................................................................................................................44


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6.4.1.
Week 1 .................................................................................................................................44
6.4.2.
Week 4 Visit.........................................................................................................................45
6.4.3.
Week 8, 16, and 20 Visits.....................................................................................................46
6.4.4.
Week 12 Visit.......................................................................................................................47
6.4.5.
Week 24 Visit.......................................................................................................................48
6.4.6.
Unscheduled Visits...............................................................................................................49
6.5.
Follow-Up Visit .....................................................................................................................................50
6.6.
Assessments for Premature Discontinuation from Study.......................................................................50
6.7.
Criteria for Discontinuation of Study Treatment....................................................................................51
6.8.
PK and PD Substudy Visits....................................................................................................................51
6.9.
Description of Assessments ...................................................................................................................52
6.9.1.
Clinical Laboratory Analytes ...............................................................................................52
6.9.2.
Medical History....................................................................................................................53
6.9.3.
Physical Examination...........................................................................................................53
6.9.4.
Vital Signs............................................................................................................................53
6.9.5.
Quality of Life (QoL) Assessments......................................................................................53
6.9.6.
Electrocardiogram................................................................................................................54
6.9.7.
FibroScan® ...........................................................................................................................54
6.9.8.
MRE and MRI-PDFF...........................................................................................................54
6.10.
End of Study Definition .........................................................................................................................54
6.11.
Post Study Care......................................................................................................................................54
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................55
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................55
7.1.1.
Adverse Events.....................................................................................................................55
7.1.2.
Serious Adverse Events........................................................................................................55
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................56
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................56
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................56
7.2.2.
Assessment of Severity ........................................................................................................57
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................57
7.4.
Gilead Reporting Requirements.............................................................................................................59
7.5.
Toxicity Management ............................................................................................................................59
7.6.
Special Situations Reports......................................................................................................................62
7.6.1.
Definitions of Special Situations..........................................................................................62
7.6.2.
Instructions for Reporting Special Situations.......................................................................63
8.
STATISTICAL CONSIDERATIONS................................................................................................................65
8.1.
Analysis Objectives and Endpoints........................................................................................................65
8.1.1.
Analysis Objectives..............................................................................................................65
8.1.2.
Primary Endpoint .................................................................................................................65
8.1.3.
Exploratory Efficacy Endpoints ...........................................................................................66
8.2.
Analysis Conventions.............................................................................................................................66
8.2.1.
Analysis Sets ........................................................................................................................66
8.2.2.
Interim Analysis ...................................................................................................................68
8.3.
Data Handling Conventions ...................................................................................................................68
8.4.
Demographic Data and Baseline Characteristics ...................................................................................68
8.5.
Efficacy Analysis ...................................................................................................................................68
8.6.
Safety Analysis.......................................................................................................................................69
8.6.1.
Extent of Exposure...............................................................................................................69
8.6.2.
Adverse Events.....................................................................................................................69
8.6.3.
Laboratory Evaluations ........................................................................................................69


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8.6.4.
Other Safety Evaluations......................................................................................................70
8.7.
Pharmacokinetic Analysis......................................................................................................................70
8.8.
Pharmacodynamic Analysis ...................................................................................................................70
8.9.
Biomarker Analysis................................................................................................................................70
8.10.
Sample Size............................................................................................................................................70
8.11.
Data Monitoring Committee ..................................................................................................................71
9.
RESPONSIBILITIES..........................................................................................................................................72
9.1.
Investigator Responsibilities ..................................................................................................................72
9.1.1.
Good Clinical Practice..........................................................................................................72
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)/ 
Ethics Committee (EC) Review and Approval ....................................................................72
9.1.3.
Informed Consent.................................................................................................................72
9.1.4.
Confidentiality......................................................................................................................73
9.1.5.
Study Files and Retention of Records ..................................................................................73
9.1.6.
Case Report Forms...............................................................................................................74
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................75
9.1.8.
Inspections............................................................................................................................75
9.1.9.
Protocol Compliance............................................................................................................76
9.2.
Sponsor Responsibilities ........................................................................................................................76
9.2.1.
Protocol Modifications.........................................................................................................76
9.2.2.
Study Report and Publications .............................................................................................76
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................77
9.3.1.
Payment Reporting...............................................................................................................77
9.3.2.
Access to Information for Monitoring..................................................................................77
9.3.3.
Monitoring and Oversight of Biomarker Specimens............................................................77
9.3.4.
Access to Information for Auditing or Inspections ..............................................................77
9.3.5.
Study Discontinuation..........................................................................................................77
10.
REFERENCES ...................................................................................................................................................78
11.
APPENDICES ....................................................................................................................................................81
Appendix 1.
Investigator Signature Page....................................................................................................82
Appendix 2.
Study Procedures Table for GS-US-402-1852 .......................................................................83
Appendix 3.
CTCAE Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities .........................................................................................................................87
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................88


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LIST OF IN-TEXT TABLES
Table 1-1.
Exposure Margins for GS-9674 Based on Observed GS-9674 Exposure After 
Administration of 100 mg GS-9674 Under Fed Conditions in Cohort 5 Compared to 
Exposures Observed at NOAEL Doses in Mouse and Cynomolgus Monkey........................18
Table 1-2.
Preliminary Pharmacokinetic Results from Study GS-US-402-2102 Evaluating the 
Effect of DDIs on Administration of 100 mg GS-9674 with Food (Cohorts 1-3)..................22
Table 1-3.
Preliminary Pharmacokinetic Results from Study GS-US-402-2102 Evaluating the 
Effect of GS-9674 100 mg with Food on CYP3A, OATP/CYP3A, P-gp, OATP, or 
OATP/BCRP (Cohorts 5-6)....................................................................................................23
Table 5-1.
List of Medications Prohibited and to be used with Caution..................................................38
LIST OF IN-TEXT FIGURES
Figure 3-1.
Overall Study Design .............................................................................................................28


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Dr.
Foster City, CA 94404, U.S.A.
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Subjects 
with Nonalcoholic Steatohepatitis (NASH)
IND Number:
EudraCT Number: 
Clinical Trials.gov 
Identifier:
127960
2016-002496-10
NCT02854605
Study Centers 
Planned:
Approximately 50 centers in North America, Europe, and Asia Pacific
Objectives:
The primary objective of this study is to evaluate the safety and 
tolerability of GS-9674 in subjects with NASH as assessed by magnetic 
resonance imaging-proton density fat fraction (MRI-PDFF) and magnetic 
resonance elastography (MRE) or a historical liver biopsy consistent with 
NASH and non-cirrhotic fibrosis.
The exploratory objectives of this study are listed in Section 2.
Study Design:
This is a Phase 2, randomized, double-blind, placebo-controlled study 
evaluating the safety, tolerability, and efficacy of GS-9674 in subjects 
with NASH as assessed by MRI-PDFF and MRE or a historical liver 
biopsy consistent with NASH and non-cirrhotic fibrosis.
Participation in the study can last up to 34 weeks, which includes a 
6-week screening period, a 24-week treatment period during which study 
drug will be administered, and a 4-week follow-up period. The screening 
period may be extended under special circumstances with the explicit 
approval of the Medical Monitor.
Subjects meeting the study’s entry criteria will be randomly assigned in a 
2:2:1 ratio to 1 of 3 treatment groups as shown in the figure below:


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Randomization will be stratified by the presence or absence of diabetes 
mellitus as determined by medical history, use of medication for 
indication of diabetes mellitus, or based on screening lab values if 
previously undiagnosed (ie, hemoglobin A1c ≥ 6.5% OR fasting plasma 
glucose ≥126 mg/dL).
Number of Subjects 
Planned:
Approximately 125 Subjects
Target Population:
Males and non-pregnant females between 18-75 years of age without 
cirrhosis and with NASH as assessed by magnetic resonance imaging 
(MRI) and magnetic resonance elastography (MRE) or a historical liver 
biopsy consistent with NASH and non-cirrhotic fibrosis.
Duration of 
Treatment:
24 Weeks
Diagnosis and Main 
Eligibility Criteria:
Key inclusion and exclusion criteria are as follows:
Inclusion Criteria:

Meets the following conditions:
a.
A clinical diagnosis of nonalcoholic fatty liver disease (NAFLD) 
with histological or imaging evidence of fatty liver within the 
past two years. If necessary an ultrasound may be performed 
during screening to confirm NAFLD, and
b. Screening MRI-PDFF with ≥8% steatosis and
c.
Screening MRE with liver stiffness ≥ 2.5 kPa
Note: criterion a. must be met before evaluating criteria b. and c.
OR


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d. A historical liver biopsy within 12 months of Screening consistent 
with NASH (defined as the presence of steatosis, lobular 
inflammation, and hepatocellular ballooning) with fibrosis, but 
not cirrhosis, and
e.
No documented weight loss > 5% between the date of the liver 
biopsy and Screening.
Note: Screening MRI-PDFF and MRE will be performed prior to 
the baseline visit for all subjects including those with historical 
liver biopsies meeting criteria 3d.

Platelet count ≥ 150,000/mm3;

Albumin ≥ 3.3 g/dL;

Serum creatinine ≤ ULN;
Exclusion Criteria:

Pregnant or lactating females;

ALT > 5X ULN;

Other causes of liver disease including autoimmune, viral, and 
alcoholic liver disease;

Cirrhosis of the liver as defined by any of the following:
a.
Cirrhosis on historical liver biopsy (eg, NASH Clinical Research 
Network [CRN] classification stage 4 or equivalent)
b. Evidence of cirrhosis on liver imaging (eg, ultrasound, CT, or 
MRI) including a nodular liver surface, splenomegaly, or portal 
venous collaterals
c.
Screening FibroSURE/FibroTest® ≥ 0.75, unless a historical liver 
biopsy within 12 months of Screening does not reveal cirrhosis. 
In patients with Gilbert’s syndrome or hemolysis, 
FibroSURE/FibroTest® will be calculated using direct bilirubin 
instead of total bilirubin.
d. Prior history of decompensated liver disease, including ascites, 
hepatic encephalopathy, or variceal bleeding;

BMI < 18 kg/m2;

Uncontrolled diabetes mellitus (hemoglobin A1c > 9% at screening);

INR > 1.2 unless on anticoagulant therapy;

Total bilirubin > 1x ULN, except with diagnosis of Gilbert’s 
syndrome.
Refer to Sections 4.2 and 4.3 for complete listing of inclusion and 
exclusion criteria.


GS-9674 
Protocol GS-US-402-1852 
Gilead Sciences, Inc. 
Study 
Procedures/ 
Frequency: 
CONFIDENTIAL 
Final 
Amendment 2 
After signing the informed consent f01m, subjects will complete a 
screening visit which will include the following assessments: complete 
medical history, physical examination (PE), vital signs, laborat01y 
assessments (blood chemistry, hematology, coagulation panel, 
hemoglobin Ale, biomarkers), viral serology, pregnancy test (for females 
of child-bearing potential), standard 12-lead ECG, MRI-PDFF and MRE 
examinations, urine drug test, review of concomitant medications and 
adverse events. 
After the screening period and a randomization visit at Baseline/Day 1, 
study visits will occur on Weeks 1, 4, 8, 12, 16, 20 and 24 with a 
Follow-Up visit 4 weeks after the last dose of study dmg. At minimum, 
vital signs, symptom driven PE, safety laboratory tests (blood chemistty, 
hematology, and coagulation panel), review of concomitant medications 
and adverse events will be done at every visit. 
Eligible subjects will be randomized to one of 3 treatment groups. Prior 
to initial dosing, required Baseline/Day 1 assessments will be perf01med 
and will include Quality of Life (QoL) assessments (general and 
pmritus), symptom driven PE, vital signs, laborat01y assessments, 
pregnancy tests (for females of child-bearing potential), urine, blood, and 
stool collection for biomarker assessment, single PD sampling, standard 
12-lead ECG, FibroScan®, review of concomitant medications and 
adverse events. 
PPD 
Subjects will retum to clinic for a safety visit at Week 1. Week 1 
assessments include QoL: pmritus assessments, symptom driven PE, 
vital signs, and laborat01y tests (blood chemistry, hematology, 
coagulation panel, lipid profile, biomarkers, PK and PD sampling). 
While on study, subjects will undergo the following procedmes and 
laborat01y assessments: 
• 
MRE and MRI-PDFF at Weeks 12 and 24 
• 
FibroScan® at Baseline/Day 1 and Weeks 12 and 24 
• 
Single PK and PD sampling at Baseline/Day 1 (PD only) and at 
Weeks 1, 4, 8, 12, 16, 20, and 24 
• 
Blood for Biomarkers at Baseline/Day 1, and Weeks 1, 4, 12, and 24 
• 
12-lead ECGs at Baseline/Day 1, and Weeks 12 and 24 
• 
Blood chemistty, hematology, coagulation panel, and fasting lipid 
profile at Baseline/Day 1 and at Weeks 1, 4, 8, 12, 16, 20, and 24 
• 
Hemoglobin Ale (HbA1c) at Baseline/Day 1, Weeks 12 and 24 
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Test Product: 
• 
Stool collection at Baseline/Day 1 and Week 24 
• 
Urine collection at Baseline/Day 1 and Weeks 1, 4, 12, and 24 
• 
Urine pregnancy test (females of childbearing potential only) at 
Baseline/Day 1 and Weeks 4, 8, 12, 16, 20, and 24 
• 
QoL: general assessments [SF-36 health survey, Chronic Liver 
Disease Questionnaire (CLDQ), and Work Productivity and Activity 
Impai1ment (WPAI)] at Baseline/Day 1 and Weeks 12 and 24 
• 
QoL: pmritus assessments (VAS-itch and 5D-itch) at Baseline/Day 1 
and Weeks 1, 4, 8, 12, 16, 20, and 24 
Subjects will retum for their final visit, the Follow-Up visit, 4 Weeks 
after the last dose of study dmg. At this visit assessments include a 
symptom driven PE, vital signs, safety laboratory tests, and review of 
concomitant medications and adverse events. A urine pregnancy test will 
be perfonned for females of child bearing potential only. 
PPD 
GS-9674 30 mg tablet administered orally once daily with food. 
GS-9674 100 mg tablet administered orally once daily with food. 
Reference Product: 
Placebo-to-match (PTM) GS-9674 30 mg tablet administered orally once 
daily with food. 
Placebo-to-match (PTM) GS-9674 100 mg tablet administered orally 
once daily with food. 
Dose and Mode of 
• 
Treatment Group A: GS-9674 30 mg (1 x 30 mg tablet)+ PTM 
Administration: 
GS-9674 100 mg (1 x PTM 100 mg tablet) administered orally once 
daily with food 
CONFIDENTIAL 
• 
Treatment Group B: GS-9674 100 mg (1 x 100 mg tablet) + PTM 
GS-9674 30 mg (1 x PTM 30 mg tablet) administered orally once 
daily with food 
• 
Treatment Group C: PTM GS-9674 30 mg (1 x PTM 30 mg tablet) 
+ PTM GS-9674 100 mg (1 x PTM 100 mg tablet) administered 
orally once daily with food 
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GS-9674 
Protocol GS-US-402-1852 
Gilead Sciences, Inc. 
Criteria for 
Evaluation: 
Safety: 
Final 
Amendment 2 
The primaty endpoint is the safety of GS-9674 in subjects with NASH. 
Safety will be assessed during the study through the repotiing of AEs, 
and by clinicallaborat01y tests and vital sign assessments at various time 
points during the study. Concomitant medication usage will also be 
assessed throughout the study. 
An independent, extemal Data Monitoring Committee (DMC) that 
consists of two hepatologists and a PhD statistician will convene once 
20 subjects have been emolled and evety 3 to 4 months thereafter to 
monitor the study for safety events. The DMC will meet on an ad hoc 
basis if there are at least 3 Grade ~ 3 serious, treatment-related 
Common Terminology Criteria for Adverse Events (CTCAE) obsetved in 
the study. In the event of two similar Grade 4-CTCAE treatment-related 
adverse events or one Grade 5-CTCAE treatment-related adverse event, 
the DMC will review the data and advise the sponsor regarding stopping 
or continuing the study. 
Efficacy: 
Efficacy will be assessed through a number of explorat01y endpoints. 
These explorat01y endpoints are described in Section 8.1.3. 
Phatmacokinetic and Plasma concentrations of GS-9674, GS-716070 (metabolite of GS-9674), 
Phatmacodynamic: 
and other metabolites as appropriate, will be determined for PK analyses 
as applicable. Plasma or serum concentrations ofFGF19, Cl4, and bile 
acids will be detetmined as applicable for PD analyses. 
Statistical Methods: 
Safety Analysis: 
Efficacy 
Analysis: 
Explorat01y 
Analysis: 
Sample Size: 
All safety data collected will be listed and summarized, as appropriate, 
by treatment group. 
The biological activity of GS-9674 will be evaluated using biomarker 
variables. f PD 
~ 
I 
PPD 
I 
Due to the explorat01y nature of this study, no f01mal power calculations 
were used to detennine sample size. The number of subjects was chosen 
based on clinical experience with other similru· proof of concept studies. 
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including ru·chiving of essential documents. 
CONFIDENTIAL 
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
Ab
antibody
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
Apo B
apolipoprotein B
aPTT
activated partial thromboplastine time
AST
aspartate aminotransferase
ATP
adenosine triphosphate
ATV
atorvastatin
AUC
area under the plasma/serum concentration versus time curve
AUCtau
area under the plasma/serum concentration versus time curve over the dosing 
interval
AUCinf
area under the plasma/serum concentration versus time curve extrapolated to 
infinite time, calculated as AUC0-last + (Clast/z)
AUCpartial
partial area under the plasma/serum concentration versus time curve
BAP
Biomarker Analysis Plan
BCRP
breast cancer resistance protein
BMI
body mass index
BUN
blood urea nitrogen
BW
body weight
C4
7-alpha-hydroxy-4-cholesten-3-one
CBC
complete blood count
cc
cubic centimeter
CFR
code of federal regulations
CI
confidence interval
CK-18
cytokeratin 18
CL
systemic clearance
CLDQ
Chronic Liver Disease Questionnaire
Clast
last observed quantifiable plasma/serum concentration of the drug
Cmax
maximum observed plasma/serum concentration of drug
Cmin
minimum observed plasma/serum concentration of drug
Ctau
observed drug concentration at the end of the dosing interval
CRO
contract (or clinical) research organization 
CRN
NASH Clinical Research Network
CsA
cyclosporine
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CV
cardiovascular
CYP
cytochrome P450


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CYP2C8
cytochrome P4502C8
CYP3A
cytochrome P4503A
DAB
metabolite of dabigatran etexilate
DDI
drug-drug interaction
DE
dabigatran etexilate
DILI
drug induced liver injury
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health
EC
ethics committee
EC50
concentration of drug that gives half-maximal response
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
ELF™Test
enhanced liver fibrosis test
ET
early termination
EU
European Union
ESA
erythropoiesis-stimulating agent
FAS
Full Analysis Set
FDA
(United States) Food and Drug Administration
FGF19
fibroblast growth factor 19
FSH
follicle-stimulating hormone
FXR
farnesoid X receptor
GCP
good clinical practice
GCSF
granulocyte colony stimulating factor
GFZ
gemfibrozil
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
Hb
hemoglobin
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
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HIV-1
human immunodeficiency virus type 1
HLT
high-level term


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HLGT
high-level group term
HMG-CoA
3-hydroxy-3-methylglutaryl-coenzyme A
HOMA-IR
homeostatic assessment of insulin resistance
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ID
identification
IEC
independent ethics committee/ institutional ethics committee
IND
Investigational New Drug (Application)
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
LDH
lactate dehydrogenase
LLT
lower-level term
MedDRA
Medical Dictionary for Regulatory Activities
MCV
mean corpuscular volume
MDZ
midazolam
miRNA
micro ribonucleic acid
mm Hg
millimeters of mercury
MRE
magnetic resonance elastography
MRI
magnetic resonance imaging
MRI-PDFF
magnetic resonance imaging – proton density fat fraction
NAFLD
nonalcoholic fatty liver disease
NAS
NAFLD Activity Score
NASH
nonalcoholic steatohepatitis
NMR
nuclear magnetic resonance spectroscopy
NOAEL
no observed adverse event level
OATP
organic anion-transporting polypeptide
oz
ounce 
PBC
primary biliary cholangitis
PD
pharmacodynamic
PE
physical exam
PK
pharmacokinetic
P-gp
P-glycoprotein
pH
measure of acidity 
PRA
pravastatin
PSC
primary sclerosing cholangitis
PT
preferred term


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PT
prothrombin time
PTM
placebo-to-match
PTT
partial prothrombin time
QA
quality assurance
QD
once a day
QoL
quality of life
RBC
red blood cell count
RIF
rifampin
RNA
ribonucleic acid
ROS
reactive oxygen species, or
rosuvastatin
SADR
serious adverse drug reaction
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SF-36
Short Form (36) Health Survey
SOC
system organ class
SOP
standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
t1/2
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)
TEAE
treatment-emergent adverse event
Tlast
last measured concentration
Tmax
time (observed time point) of Cmax
TGR5
bile acid receptor
TPO
thrombopoietin
TR-FRET
time-resolved fluorescence resonance energy transfer
UGT1A1
uridine diphosphate glucuronosyltransferase 1A1
ULN
upper limit of the normal range
US
United States
USPI
United States product insert
Vss
volume of distribution
VAS
visual analog scale
VORI
voriconazole
WBC
white blood cell count
WPAI
work productivity and activity impairment questionnaire


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1.
INTRODUCTION
1.1.
Background
Chronic liver disease and the consequences of end-stage liver disease are increasing globally 
despite improved prevention and treatment of viral hepatitis. This is due to the emerging 
epidemics of obesity, metabolic syndrome, and diabetes mellitus that are leading to an increased 
incidence of nonalcoholic fatty liver disease (NAFLD). Nonalcoholic fatty liver disease is 
characterized by the excess accumulation of lipid droplets within the liver, also known as hepatic 
steatosis. Prevalence rates of NAFLD range from 6% to 37% worldwide {Vernon 2011}, {Ong 
2007}. Nonalcoholic steatohepatitis (NASH), an aggressive form of NAFLD characterized by the 
presence of inflammation and hepatocellular ballooning, with or without fibrosis, is present in 
approximately 25% of patients with NAFLD. Nonalcoholic steatohepatitis is associated with 
increased liver-related mortality {Williams 2011}, {Ong 2007}. In the United States (US), it has 
been estimated that 3% to 6% of the population {Vernon 2011}, {Wanless 1990}, or the equivalent 
of up to 15 million adults, have NASH. NASH represents a significant and growing unmet 
medical need for which there are no currently approved therapies. Furthermore, as NASH is a 
manifestation of the metabolic syndrome, risk factors for cardiovascular disease (eg, 
atherosclerotic disease, cardiac arrhythmogenicity) frequently coexist in these patients {Faramawi 
2008}, {Voulgari 2010}, {Dietrich 2014}. A treatment that targets the underlying metabolic 
disorder could potentially ameliorate these cardiovascular risks and associated morbidity and 
mortality.
Nonalcoholic steatohepatitis is primarily thought to occur as the result of the metabolic 
syndrome, the impact of obesity, insulin resistance, and dyslipidemia in the liver. Simple 
steatosis is not sufficient to cause liver injury; it is the presence of inflammation and 
hepatocellular injury on the background of steatosis that defines NASH and results in the 
progression to end-stage liver disease and its complications. The “2-hit” hypothesis of NASH 
suggests that in the setting of steatosis and metabolic dysfunction, increased oxidative stress and 
the generation of reactive oxygen species (ROS) likely mediate the inflammatory changes in the 
liver (steatohepatitis) that may lead to progressive fibrosis {Dowman 2010}, {Kannel 1982}, {Koek 
2011}, {Sumida 2013}. The major pathways in NASH disease progression include those involved 
in metabolic dysfunction in the hepatocyte, and activation of hepatic stellate cells and 
macrophages leading to progressive inflammation and liver fibrosis. Advanced fibrosis and 
cirrhosis are characterized by extensive collagen deposition and remodeling of the extracellular 
matrix. In addition, evidence suggests that lipotoxic intermediates of fatty acids likely contribute 
to the etiology of NASH {Neuschwander-Tetri 2010}.
Over time, NASH may result in progressive liver fibrosis, ultimately leading to cirrhosis in 
10-20% of affected patients. Advanced fibrosis (bridging fibrosis or cirrhosis) is associated with 
increased morbidity and mortality {Ekstedt 2014}, {Yeh 2014}. Patients with cirrhosis may 
develop hepatocellular carcinoma (HCC) and other complications of end-stage liver disease, 
including jaundice, fluid retention (edema and ascites), portal hypertension and variceal 
bleeding, impaired coagulation and hepatic encephalopathy. Decompensated liver disease, as 


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defined by the development of one of the above complications, has a high mortality and the only 
known effective treatment is liver transplantation. With the increasing prevalence of obesity and 
obesity-related diseases, NASH is expected to become the leading indication for liver
transplantation, and the leading etiology of HCC among liver transplant recipients in the US 
{Wong 2014}, {Afzali 2012}.
1.1.1.
GS-9674 General Information
GS-9674 is a potent agonist of Farnesoid X Receptor (FXR) whose activity in intestinal 
epithelial cells results in the release of fibroblast growth factor 19 (FGF19). FGF19 is an 
endocrine peptide which drives a signaling cascade to decrease lipogenesis, gluconeogenesis, 
hepatic triglyceride accumulation, and bile acid synthesis. Please refer to the Investigator’s 
Brochure (IB) for additional information on GS-9674, including:

In vitro FXR agonism

Nonclinical pharmacokinetics and in vitro metabolism

Nonclinical pharmacology and toxicology
1.1.2.
Nonclinical Toxicology
The nonclinical toxicity profile of GS-9674 has been assessed in mice and cynomolgus monkeys 
administered GS-9674 orally for up to 26 and 39 weeks, respectively. GS-9674-related effects 
were primarily limited to non-adverse findings in the liver for both species that are likely related 
to the pharmacology of the compound. Mild increases in alkaline phosphatase (ALP) activity and 
liver weights were observed in the 4 week and chronic (26 or 39 weeks) studies.  In the 4-week 
studies and 26-week mouse study, these findings were associated with hepatocellular 
hypertrophy (both species) and minimal oval cell hyperplasia (monkeys). In the chronic monkey 
study, there were no correlating histological changes in the liver. The above findings were 
observed at ≥100 mg/kg/day after 4 weeks of dosing and at all doses (≥20 mg/kg/day) after 26 
weeks of dosing in mice. In monkeys, the above findings were observed at doses of 300 
mg/kg/day after both 4 and 39 weeks of dosing. The decreases in cholesterol (≥60 mg/kg/day) 
and triglycerides (≥100 mg/kg/day) as well as increased albumin (≥60 mg/kg/day) observed in 
mice after 4 and/or 26 weeks of dosing as well as the decrease in serum bile acids (300 
mg/kg/day) in monkeys after 39 weeks of dosing are also likely to be related to the 
pharmacology of GS-9674. Other minimal to mild, non-adverse findings observed after 26 or 39
weeks of dosing in mice or monkeys, respectively, that were considered GS-9674-related 
included decreased red blood cell parameters (mouse; ≥20 mg/kg/day), increased platelets 
(mouse; 600/300 mg/kg/day), shortened activated partial thromboplastin time (monkey; 300 
mg/kg/day), and increased phosphorus (mouse; 600/300 mg/kg/day). All findings showed 
evidence of reversibility after a 4-week recovery period. The no-observed-adverse effect levels 
(NOAEL) in mice after 26 weeks of dosing and in monkeys after 39 weeks of dosing were 60 
and 300 mg/kg/day, respectively. 


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Preliminary PK data from Cohort 5 (administration of GS-9674 100 mg with food) in the 
ongoing Phase 1 study of GS-9674 (GS-US-402-1851, included in IB) indicate adequate safety 
margins based on GS-9674 exposures at the nonclinical NOAEL doses in mouse and 
cynomolgus monkey (Table 1-1).
Table 1-1.
Exposure Margins for GS-9674 Based on Observed GS-9674 
Exposure After Administration of 100 mg GS-9674 Under Fed 
Conditions in Cohort 5 Compared to Exposures Observed at NOAEL 
Doses in Mouse and Cynomolgus Monkey 
Species
NOAEL
Exposure Margina
Dose 
mg/kg/day
AUCtau
µg*hr/mL
Mouse
60
Male: 66
Female: 110
   Male: 13
Female: 22
Cynomolgus Monkey
300
163
32
a
Calculated using observed human AUCinf of 5.02 µg*hr/mL at 100 mg QD dose administered fed from Cohort 5 in 
Study GS-US-402-1851.
1.1.3.
Nonclinical Pharmacology
GS-9674 is a potent and selective agonist of FXR. This conclusion is supported by the following 
data: 1) modeling demonstrated an interaction of GS-9674 with the binding domain of FXR 
consistent with agonist activity, 2) GS-9674 induced an agonist response in a time-resolved 
fluorescence resonance energy transfer (TR-FRET) biochemical assay with an EC50 of 16 nM, 
which was comparable to that of other known FXR agonists, and 3) GS-9674 did not activate the 
structurally similar bile acid receptor TGR5, did not activate other nuclear hormone receptors, 
and did not bind to a panel of other off-target receptors and enzymes.
The cellular potency of GS-9674 to activate FXR-mediated transcription was characterized using 
a firefly luciferase reporter gene engineered under the control of a FXR/RXR response element 
(PC-402-2012). GS-9674 caused complete FXR activation with an EC50 value of 43 nM, which 
was more potent than chenodeoxycholic acid (EC50 of 1770 nM).
Oral dose-ranging experiments in male cynomolgus monkeys demonstrated maximal increases in 
plasma FGF19 at a dose of 5 mg/kg (PC-402-2016). In addition, the oral administration of 
GS-9674 (30 mg/kg) to cynomolgus monkeys directly activated intestinal FXR, as measured by 
the expression of FXR-target genes in the ileum (15-fold increase in FGF19 mRNA, and a 2-fold 
increase in organic solute transporter (OST)α and (OST)β mRNA) (PC-402-2005).
The effects of GS-9674 on FGF19 levels were compared in cynomolgus monkeys following both 
oral and intravenous (IV) administration (PC-402-2016). Despite greater exposures following IV 
administration, only the oral administration of GS-9674 increased circulating FGF19 levels. 
These data suggest that intestinal FXR agonism by GS-9674 causes FGF19 production, whereas 
low systemic free drug concentrations limit effects following IV administration of GS-9674.


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GS-9674 was evaluated in a choline-deficient high fat diet /NaN02 rat model of liver fibrosis 
(PC-402-2015). This in vivo model utilized "2 hits" to mimic the metabolic and oxidative stress 
components of NASH disease in humans {Nakamoto 2009}, {Murakami 2013 }. Treatment with 
GS-9674 dose-dependently reduced both biochemical and histological measures of liver fibrosis 
in this model. 
Safety pharmacology studies have been conducted to examine the potential effects ofGS-9674 
on the cardiovascular (CV), respiratory, and central nervous system (CNS) systems. There were 
no GS-9674-related effects on the CNS or respiratory system in mice administered up to 
600 mg/kg. In addition, there was no significant human ether-a-go-go-related gene inhibition at 
concentrations up to 100 J.lM or GS-9674-related effects on the CV system in monkeys 
administered up to 300 mg/kg. 
Overall, the results from these pharmacology studies demonstrate that GS-9674 is a potent and 
selective agonist of intestinal FXR with the potential to benefit NASH patients by inducing 
FGF19 production. 
1.1.4. 
Non clinical Phannacokinetics 
GS-9674 has shown low oral bioavailability in nonclinical species (am~roximately 10% and 20% 
when dosed PO 
). Low, 
pH-dependent solubility and efflux transport have been identified as factors likely limiting 
GS-9674 absorption. 
The low systemic clearance (CL) of GS-9674 in rats, dogs and monkeys was considerably lower 
than the predicted hepatic clearance based on in vitro studies with hepatocytes. This discrepancy 
is most likely a result of protein-restricted clearance in vivo due to the very high plasma protein 
binding(> 99.6%) across species. The volume of distribution (V ss) ofGS-9674 was consistent 
with extracellular fluid (ranging from 0.16-0.21 Llkg) in rats, dogs, and monkeys. 
After oral dosing to albino and pigmented mice, C4C]GS-9674-derived radioactivity was 
distributed to most of the tissues, with the highest maximum concentrations of radioactivity 
determined in organs of absorption and excretion. Generally similar distribution patterns and 
tissue concentrations of C4C]GS-9674-derived radioactivity were observed in albino and 
pigmented mice with no observed binding to melanin. In both strains, no quantifiable 
radioactivity was detected in brain, suggesting C4C]GS-9674-derived radioactivity did not cross 
the blood: brain barrier. Fecal elimination was a predominant route of elimination of 
C4C]GS-9674-derived radioactivity in both mice (85. 7% and 5.45% recovered in feces and urine, 
respectively) and monkeys (78.2% and 69.7% recovered in feces in intact and bile duct 
cannulated animals) likely representing drug not absorbed from the gastrointestinal tract. 
Approximately 6% of the administered radioactivity was excreted in bile and urine in monkeys. 
Radiolabeled material was primarily excreted within the first 48 hours. 
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GS-9674 undergoes oxidative metabolism in human hepatocytes. Comparison of metabolism in 
hepatocytes from mice, rats, dogs, monkeys, and humans did not identify any metabolites unique 
to humans, supporting the selection of mice and monkeys for the assessment of the toxicology of 
GS-9674. Of the recombinant human CYP isozymes tested, CYP2C8, CYP3A4, and CYP2C19 
were shown to metabolize GS-9674. Potent inhibitors of these CYPs therefore may affect 
metabolism of GS-9674. GS-9674 had little inhibitory effect on the activities of CYP1A2, 
CYP2B6, CYP2C19 or CYP2D6 (IC50 > 25 μM). For CYP2C8, CYP2C9, and CYP3A, IC50
values of 2.4 to 13.6 μM were obtained but GS-9674 was not a mechanism-based inhibitor of 
these enzymes. GS-9674 showed moderate inhibition of human UGT1A1, sodium-taurocholate 
cotransporting polypeptide (NTCP), and bile salt export pump (IC50 2.8-7.7 μM). GS-9674 
inhibited human OATP1B1, OATP1B3, and OATP2B1 with IC50 values of 0.68, 0.41, and 
0.21 μM, respectively. GS-9674 therefore has the potential to affect hepatic/intestinal uptake of 
OATP substrates or metabolism of CYP2C8, CYP2C9, or CYP3A4 substrates when its 
concentrations are sufficiently high. However, low solubility, high protein binding (> 99.98%) 
and low systemic levels reduce the potential for GS-9674 to cause drug-drug interactions via 
inhibition of metabolic enzymes and transporters.
GS-9674 is a substrate for efflux transporters P-glycoprotein and breast cancer resistance protein, 
as well as the uptake transporters OATP1B1, 1B3, and 2B1, and NTCP. Inhibitors or genetic 
polymorphisms affecting the activity of these transporters may affect GS-9674 intestinal 
absorption and hepatic uptake. This was illustrated in an in vivo study in monkeys where 
pretreatment with cyclosporin A, a known inhibitor of efflux transporters, increased the 
bioavailability of GS-9674 approximately 5-fold.
GS-9674 is highly selective for FXR over other nuclear hormone receptors in cell-based reporter 
assays, including those associated with potential for induction of human drug metabolizing 
enzymes and transporters (eg, pregnane X receptor, constitutive androstane receptor). Thus the 
liability of GS-9674 to cause drug-drug interactions through proteins regulated by these nuclear 
receptors is low.
1.1.5.
Clinical Trials of GS-9674
As of 03 January 2017, 1 Phase 1 clinical study has been completed (GS-US-402-1851), 3 Phase 
1 clinical studies are ongoing (GS-US-402-3885, GS-US-402-2102, and GS-US-402-2101), and 
4 Phase 2 studies in subjects with NASH, PBC, and PSC are ongoing (GS-US-384-3914, GS-
US-402-1852, GS-US-427-4024, and GS-US-428-4025).
A brief summary of preliminary ongoing study GS-US-402-2102 is presented below.


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1.1.5.1.
GS-US-402-2102
Study GS-US-402-2102 is an ongoing Phase 1, open-label, multicenter, multiple-cohort study 
designed to evaluate transporter and CYP-mediated drug-drug interactions (DDIs) between 
GS-9674 100 mg and various probe drugs in healthy subjects. A total of approximately 
180 subjects are planned to be enrolled.
Preliminary PK results from the following cohorts are presented below and in Table 1-2 and 
Table 1-3:

Cohort 1: Impact of OATP/MRP2/P-gp inhibition (single dose cyclosporine 600 mg: CsA) or 
OATP1B1/1B3 inhibition (single dose rifampin 600 mg: RIF) on single dose administration 
of GS-9674 100 mg with food (N=24).  Single doses of CsA or RIF significantly increased 
GS-9674 exposure (6.5- and 8.0-fold respectively), with more modest increases in 
GS-716070 exposure (3.3- and 4.9-fold respectively). These data indicate the GS-9674 is a 
sensitive substrate of hepatic OATP with intestinal P-gp playing a minimal to no role in 
GS-9674 absorption as seen by a smaller increase in GS-9674 by CsA compared to single 
dose RIF.  Based on these data, coadministration of GS-9674 with potent inhibitors of OATP 
is not recommended and moderate inhibitors of OATP should be used with caution, whereas 
GS-9674 may be coadministered with P-gp inhibitors.

Cohort 2: Impact of CYP3A inhibition (multiple dose voriconazole 200 mg BID 4 days: 
VORI) and CYP2C8 inhibition (multiple dose gemfibrozil 600 mg BID 4 days: GFZ) on 
single dose administration of GS-9674 100 mg with food (N=18). Coadministration of 
GS-9674 with VORI did not result in clinically meaningful changes in GS-9674 or 
GS-716070 exposures indicating that CYP3A plays a minimal role in the disposition of 
GS-9674 and GS-716070.  As such, GS-9674 may be coadministered with CYP3A 
inhibitors.  Coadministration of GS-9674 with GFZ increased GS-9674 exposure 75% with 
reduction of GS-716070 exposure by 55% indicating that biotransformation of GS-9674 to 
GS-716070 is predominantly mediated by CYP2C8.  Based on the less than 2-fold increase 
in GS-9674 exposure, GS-9674 may be coadministered with inhibitors of CYP2C8.

Cohort 3: Impact of CYP3A/2C8/OATP/P-gp induction (multiple dose rifampin 600 mg QD 
7 days in the evening: RIF) on single dose AM administration of GS-9674 100 mg with food
(N=18).  Plasma exposure of GS-9674 and GS-716070 were substantially reduced after 
multiple dose administration of RIF indicating that GS-9674 and GS-716070 are sensitive to 
induction of OATP and CYP2C8.  As such, coadministration of GS-9674 with potent or 
moderate inducers of OATP or CYP2C8 is not recommended.


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
Cohort 5: Impact of single dose administration of GS-9674 100 mg with food on CYP3A 
activity (single dose midazolam: MDZ) or OATP/CYP3A activity (single dose atorvastatin: 
ATV) (N=24).  GS-9674 did not alter MDZ exposure (90%CIs of the %GMR for AUC and 
Cmax were contained within the predetermined lack of effect bounds of 70-143%) indicating 
the GS-9674 is not an inhibitor of CYP3A. As such, GS-9674 may be coadministered with 
CYP3A substrates.  GS-9674 modestly increased ATV exposure (39%).  Similar increases in 
ATV exposure do not necessitate a priori dose modification as per the LIPITOR® United 
States product insert (USPI).  As such, ATV may be coadministered with GS-9674 

Cohort 6: Impact of single dose administration of GS-9674 100 mg with food on P-gp (single 
dose dabigatran etexilate 75 mg: DE), OATP (single dose pravastatin 40 mg: PRA) or 
OATP/BCRP (single dose rosuvastatin 10 mg: ROS) (N=24). GS-9674 did not alter DE (free 
or total dabigatran: DAB metabolite of DE), PRA, or ROS exposures (90%CIs of the %GMR 
for AUC and Cmax were contained within the predetermined lack of effect bounds of 
70-143%) indicating the GS-9674 is not an inhibitor of P-gp, OATP, or BCRP.  As such,
GS-9674 may be coadministered with P-gp, OATP, or BCRP substrates.
Table 1-2.
Preliminary Pharmacokinetic Results from Study GS-US-402-2102 
Evaluating the Effect of DDIs on Administration of 100 mg GS-9674 
with Food (Cohorts 1-3)
%GMR (90%CI) Test/Reference
Cohort 1 (N=24)
Cohort 2 (N=18)
Cohort 3 (N=18)
Analyte
PK 
Parameter
CsA
RIFa
VORI
GFZ
RIFb
GS-9674
AUCinf
655 
(577, 743)
796
(719, 880)
95.9
(81.0, 114)
175
(149, 206)
32.8
(27.9, 38.4)
Cmax
512
(448, 584)
547
(497, 603)
76.8
(60.2, 97.9)
139
(115, 168)
35.5
(29.1, 43.3)
GS-716070
AUCinf
331
(297, 369)
493
(442, 551)
129
(109, 154)
44.5
(38.7, 51.1)
12.6
(10.5, 15.0)
Cmax
211
(191, 232)
301
(274, 331)
99.2
(81.1, 121)
31.2
(26.1, 37.4)
17.0
(13.7, 21.2)
Data are presented to 3 significant digits
a
Single Dose
b
Multiple Dose


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Table 1-3.
Preliminary Pharmacokinetic Results from Study GS-US-402-2102 
Evaluating the Effect of GS-9674 100 mg with Food on CYP3A, 
OATP/CYP3A, P-gp, OATP, or OATP/BCRP (Cohorts 5-6)
Cohort
Enzyme/ 
Transporter
Analyte
PK Parameter
Test
Reference
% GMR 
(90%CI) 
Test/Reference
5 
(N=24)
CYP3A
MDZ
AUCinf 
37.3 (27.5)
63.9 (29.1)
102 (95.8, 108)
Cmax 
7.79 (27.6)
7.92 (35.6)
100 (94.8, 106)
OATP/
CYP3A
ATV
AUCinf 
15.5 (33.5)
10.8 (39.0)
139 (124, 156)
Cmax 
1.06 (35.6)
0.98 (35.9)
107 (94.6, 120)
6
(N=24)
P-gp
Total 
DAB
AUCinf 
624 (32.0)
535 (34.3)
118 (109, 128)
Cmax 
84.4 (40.0)
68.0 (37.8)
125 (112, 139)
Free 
DAB
AUCinf 
543 (32.0)
477 (37.3)
116 (108, 124)
Cmax 
75.0 (39.6)
60.8 (42.5)
125 (114, 138)
OATP
PRA
AUCinf 
109 (55.6)
99.6 (66.7)
115 (104, 126)
Cmax 
41.7 (58.8)
42.4 (66.5)
104 (91.5, 117)
OATP/ 
BCRP
ROS
AUCinf 
38.3 (40.3)
34.9 (39.5)
111 (101, 121)
Cmax
3.06 (40.4)
2.86 (43.4)
108 (98.3, 119)
Data are presented as mean (%CV) to three significant digits
1.2.
Rationale for This Study
Current evidence suggests that NASH is a consequence of the metabolic syndrome with resulting 
lipotoxicity and oxidative stress in the steatotic liver, setting off an inflammatory response with 
subsequent activation of hepatic stellate cells and fibrogenesis. FXR agonism has been shown to 
reduce hepatic lipid synthesis and circulating triglycerides due to down regulation of SREBP-1c, 
as well as reduce insulin resistance and hepatic gluconeogenesis. Thus GS-9674 is postulated to 
halt the instigating triggers for NASH. Animal models have demonstrated the ability for 
GS-9674 to reverse the metabolic dysfunction and NASH-like liver injury in a choline-deficient 
high fat diet /NaNO2 rat model of liver fibrosis. This Phase 2 study has been designed as a 
multicenter, randomized, double-blind, placebo-controlled study evaluating the safety and 
efficacy of GS-9674 for 24 weeks in subjects with NASH. Approximately 125 NASH subjects 
without cirrhosis will be randomized in a 2:2:1 ratio to receive GS-9674 at a dose of 30 mg or 
100 mg orally QD, or placebo. Randomization will be stratified by the presence or absence of 
diabetes mellitus, a common comorbidity in patients with this condition. 
Inclusion criteria for the study were developed in order to noninvasively identify subjects with 
NASH. Specifically, all subjects will have a clinical diagnosis of NAFLD and evidence of 
NASH histologically or based on magnetic resonance imaging; specifically ≥ 8% hepatic 
steatosis on MRI-PDFF {Bannas 2015}, and increased liver stiffness on MRE (≥2.5 kPa) {Park 
2016}. Previous studies have shown that patients with NAFLD and increased liver stiffness by 


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MRE have a high probability of NASH on liver biopsy {Loomba 2014}, {Chen 2011}. For 
example, Park et al. reported that an MRE liver stiffness cut-off of ≥ 2.53 kPa was 64% 
sensitive, 68% specific, and had an area under the receiver operating characteristic curve 
(AUROC) of 0.70 and positive predictive value of 87% for the differentiation of simple 
steatosis from NASH on biopsy. Moreover, in this cohort of 104 patients, Park et al 
demonstrated that a liver stiffness by MRE of ≥ 2.65 kPa optimally identified the presence of at 
least stage 1 fibrosis (AUROC 0.82). Based on these criteria, subjects enrolled in this study have 
a high probability of NASH with fibrosis, a population with a large unmet medical need. Since 
the safety and PK of GS-9674 have not yet been explored in subjects with cirrhosis, criteria have 
been developed in order to exclude cirrhotic subjects based on a validated serum marker for 
fibrosis (FibroSURE/FibroTest®) and historical clinical, histological, and imaging data {Ratziu 
2006}.
The primary endpoint of this study will be the safety and tolerability of GS-9674. In addition, the 
biological activity of GS-9674 will be determined based on endpoints including routine liver 
biochemistry (eg, ALT and GGT); noninvasive serum markers of liver injury (eg, serum CK-18, 
FibroSURE/FibroTest® and ELF™ Test); and imaging-based methods for quantifying hepatic 
steatosis (MRI-PDFF) and fibrosis (MRE and FibroScan®). An important endpoint of interest is 
the proportion of subjects achieving ≥ 30% reduction in steatosis as assessed by MRI-PDFF. 
This level of reduction has been associated with a significant improvement in NASH histology 
(≥ 2-point reduction in NAFLD Activity Score) {Patel 2015}. Based on preclinical and clinical 
data, a treatment duration of 24 weeks with GS-9674 is expected to be sufficient to lead to 
meaningful improvements in hepatic steatosis on MRI-PDFF and liver biochemistry.  In addition 
to these liver-related endpoints, the effects of GS-9674 on carbohydrate and lipid metabolism 
(eg, glucose, insulin, free fatty acids, apolipoproteins, lipid profiles, and metabolites) will be 
closely monitored in light of the mechanism of action of GS-9674 and the importance of 
metabolic dysfunction in contributing to the morbidity and mortality (eg, cardiovascular) of 
subjects with NASH.
This study will evaluate the safety, tolerability, and efficacy of 30 mg and 100 mg GS-9674 
administered with food for 24 weeks in subjects with NASH. The doses were selected based on 
short-term safety, PK and PD results from Study GS-US-402-1851 in healthy subjects. 
Across the range of GS-9674 doses evaluated (10-300 mg QD), doses ≥30 mg provide 
comparable intestinal FXR activation assessed as increases in FGF19 exposure. Food, by 
slowing oral absorption of GS-9674, results in prolonged elevation of plasma FGF19 
concentrations. Exposure-response relationships show that changes in C4 exposure are 
negatively correlated with changes in FGF19 exposure as well as GS-9674 exposure. Based on 
these results, GS-9674 doses of 30 and 100 mg with food are selected for further study as they 
are expected to 1) provide enteral FXR agonism and improvements in subjects with NASH and 
2) inform on the impact of increasing systemic GS-9674 exposure on safety and efficacy.
In the Phase 1 study, GS-US-402-1851, GS-9674 was tested at doses up to 300 mg once daily for 
up to 14 days and was well tolerated. Taken together, these data support the evaluation of 
GS-9674 30 and 100 mg in subjects with NASH.


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1.3.
Risk/Benefit Assessment for the Study 
This study will provide information on the safety and efficacy of GS-9674 for the treatment of
patients with NASH. As there are currently no approved therapies for NASH, there is a large
unmet medical need for this growing population of patients.
Subjects with NASH randomized to the placebo control arm in the study may benefit from 
frequent medical monitoring and close assessment of their NASH during the duration of placebo 
treatment. Subjects randomized to GS-9674 may benefit from an improvement in their 
underlying NASH which may manifest as improvements in liver biochemistry, measures of 
hepatic steatosis or fibrosis, or improvements in quality of life. Importantly, this study will 
provide further data to inform the clinical development of the investigational medicinal product 
GS-9674 for use in an area of unmet medical need. 
In the Phase 1 study, 94 subjects have received GS-9674 in single or multiple doses (14 days) up 
to 300 mg. All treatment emergent adverse events (TEAEs) were mild to moderate (Grade 1 or 
2), and overall, the rate of any adverse events (AEs) was similar between subjects treated with 
GS-9674 or placebo. The predominant toxicities were anemia, back pain, diarrhea, and headache. 
Grade 2 or 3 elevations in serum ALT were seen in five (5%) GS-9674 treated subjects and one 
(4%) placebo treated subject. Grade 2 or 3 ALT elevations that occurred on-treatment were 
observed in 2/23 (9%) BID treated subjects, but none of the 71 subjects who received once daily 
(QD) GS-9674 dosing. In these cases, elevations in serum bilirubin or prolongation of INR were 
not observed, serum ALT levels normalized upon treatment cessation, and no evidence of drug 
hypersensitivity syndrome (eg, fever, rash, eosinophilia) was noted. In nonclinical studies, 
effects on the liver have been limited to non-adverse mild increases in alkaline phosphatase and 
liver weights and minimal hepatocellular hypertrophy that are likely a pharmacological response 
to FXR agonism. There were no elevations in liver transaminases or changes in liver pathology 
(degeneration/necrosis) in the nonclinical studies to suggest direct cellular damage. In order to 
mitigate the potential risk of hepatotoxicity with GS-9674, QD dosing of GS-9674 has been 
chosen for this study. Moreover, close monitoring of liver biochemistry values will be performed 
and parameters for discontinuation of the study drugs due to liver test abnormalities have been 
defined (see Section 7.5, Toxicity Management: Observation for Drug-Induced Liver Injury) and 
will be closely followed.
Additional risks to study subjects include those attributable to study participation in general, 
including risks associated with frequent clinic visits and laboratory blood draws, and the 
associated pain and discomfort of phlebotomy. Strategies to mitigate these risks include close 
monitoring of lab values as well as AEs. Parameters for discontinuation of the study drugs due to 
AEs and non-hepatic laboratory abnormalities are also defined and will be closely followed.
Overall, the nonclinical and limited preliminary clinical data show a positive benefit/risk ratio in 
support of the study in subjects with NASH. Appropriate safety monitoring will be conducted 
throughout the study to further characterize the safety profile of GS-9674 in NASH subjects 
without cirrhosis.


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In summary, there are no approved treatment options available for patients with NASH. Based
on past clinical experience with GS-9674, the risk/benefit is positive and supports the continued
evaluation of GS-9674 in this patient population. Data from this study will support the
development of GS-9674 for the treatment of this condition.
1.4.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2. 
OBJECTIVES 
The primary objective of this study is as follows: 
• 
To evaluate the safety and tolerability of GS-9674 in subjects with NASH. 
The exploratory objectives ofthis study are as follows: 
~ 
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3.
STUDY DESIGN
3.1.
Study Design
This is a Phase 2, randomized, double-blind, placebo-controlled study designed to evaluate the 
safety, tolerability, and efficacy of GS-9674 in subjects with NASH. To be eligible to participate, 
subjects must have evidence of hepatic steatosis and increased liver stiffness as assessed by 
MRI-PDFF and MRE respectively, or a historical liver biopsy consistent with NASH and non-
cirrhotic fibrosis. Any subject with a history of decompensated liver disease, including ascites, 
hepatic encephalopathy, or variceal bleeding will be ineligible.
The overall study design is presented graphically in Figure 3-1.
Figure 3-1.
Overall Study Design


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3.2. 
Treatment Plan and Regimen 
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Subjects meeting the study's enhy criteria will be randomly assigned in a 2:2: 1 ratio to 1 of 
3 different ti·eatinent groups (A, B, and C) as shown in Figure 3-1. Randomization will be 
stratified by the presence or absence of diabetes mellitus as determined by medical hist01y, use 
of medication for indication of diabetes mellitus, or based on screening lab values if previously 
undiagnosed (ie, hemoglobin Ale ~ 6.5% OR fasting plasma glucose ~ 126 mg/dL). 
Study dmg will be administered for a total of 24 weeks from the Baseline/Day I visit up to and 
including the Week 24 visit. Dosage and administi·ation of the study dmg and reference product 
are described in Section 5.3. 
3.3. 
Biomarker Testing 
3.3.1. 
Biomarker Samples to Address the Study Objectives 
Biological specimens will be collected in this study as per the studu rocedures table 
~ppendix 2) PPD 
Because biomarker science is a 
~--~~----~--~--------~~ 
rapidly evolving area of investigation, and adverse events in paliicular are difficult to predict, it 
is not possible to specify prospectively all tests that will be done on the specimens provided. The 
biomarker tests 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 a1t knowledge. Samples will be 
stored for up to 15 years after the end of the study. 
Biomarkers testing can include circulating markers ofFXR activity such as FGF19, bile acids, 
and C4. Circulating protein markers of liver damage and inflammation, lipids, and other 
biochemicals associated with liver metabolic activity will also be measured. Stool samples may 
be analyzed for the presence of bile acids and a survey of potential changes in the intestinal 
microbiome during the study. 
3.3.2. 
Biomarker Samples for Optional Future Research 
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3.3.3. 
Biomarker Samples for Optional Genomic Research 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
This study will enroll approximately 125 subjects with nonalcoholic steatohepatitis (NASH).
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1)
Males and females between 18-75 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;
3)
Meets the following conditions:
a.
A clinical diagnosis of NAFLD, with histological or imaging evidence of fatty liver 
within the past two years. If necessary an ultrasound may be performed during
screening to confirm NAFLD, and
b. Screening MRI-PDFF with ≥8% steatosis and
c.
Screening MRE with liver stiffness ≥ 2.5 kPa;
Note: criterion a. must be met before evaluating criteria b. and c.
OR
d. A historical liver biopsy within 12 months of Screening consistent with NASH 
(defined as the presence of steatosis, lobular inflammation, and hepatocellular 
ballooning) with fibrosis, but not cirrhosis, and
e.
No documented weight loss > 5% between the date of the liver biopsy and Screening.
Note: Screening MRI-PDFF and MRE will be performed prior to the baseline visit for 
all subjects including those with historical liver biopsies meeting criteria 3d.
4)
Platelet count ≥ 150,000/mm3;
5)
Albumin ≥ 3.3 g/dL;
6)
Serum creatinine ≤ ULN;
7)
Female subjects of childbearing potential (see definition in Appendix 4) must have a 
negative serum pregnancy test prior to starting study treatment;


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8)
All female subjects of childbearing potential who engage in heterosexual intercourse must 
agree to use a highly effective method of contraception during intercourse from the 
screening visit throughout the study period and for 30 days following the last dose of study 
drug (see Appendix 4 for details);
9)
Female subjects must refrain from egg donation or harvest during treatment and for at least
30 days after last dose of study drug;
10)
Male subjects are required to use barrier contraception (condom plus spermicide) during 
heterosexual intercourse from the screening through the study completion and for 90 days 
following the last dose of study drug (see Appendix 4 for details);
11)
Male subjects must refrain from sperm donation from screening through at least 90 days 
following the last dose of study drug;
12)
Willing and able to comply with scheduled visits, drug administration plan, laboratory 
tests, other study procedures, and study restrictions;
13)
Must be able to read and complete Quality of Life questionnaires independently.
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; lactating females must agree to discontinue nursing before 
the study drug is administered;
2)
ALT > 5X ULN;
3)
Other causes of liver disease including autoimmune, viral, and alcoholic liver disease;
4)
Cirrhosis of the liver as defined by any of the following:
a.
Cirrhosis on historical liver biopsy (eg, NASH Clinical Research Network [CRN]
classification stage 4 or equivalent)
b. Evidence of cirrhosis on liver imaging (eg, ultrasound, CT, or MRI) including a nodular 
liver surface, splenomegaly, or portal venous collaterals
c.
Screening FibroSURE/FibroTest® ≥ 0.75, unless a historical liver biopsy within 
12 months of Screening does not reveal cirrhosis. In patients with Gilbert’s syndrome 
or hemolysis, FibroSURE/FibroTest® will be calculated using direct bilirubin instead of 
total bilirubin;
d. Prior history of decompensated liver disease, including ascites, hepatic encephalopathy,
or variceal bleeding;
5)
History of liver transplantation;
6)
Weight reduction surgery in the 2 years prior to Screening or planned during the study;


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7)
History of intestinal resection or malabsorptive condition that may limit the absorption of 
GS-9674. Prior cholecystectomy and appendectomy are permitted.
8)
BMI < 18 kg/m2;
9)
Uncontrolled diabetes mellitus (hemoglobin A1c > 9% at screening);
10)
INR > 1.2 unless on anticoagulant therapy;
11)
Total bilirubin > 1x ULN, except with diagnosis of Gilbert’s syndrome;
12)
Chronic hepatitis B (HBsAg positive);
13)
Chronic hepatitis C (HCV RNA positive); subjects cured of HCV infection less than 
2 years prior to the Screening visit are not eligible.
14)
HIV Ab positive;
15)
Alcohol consumption greater than 21 oz/week for males or 14 oz/week for females 
(1oz/30mL of alcohol is present in 1 12oz/360mL beer, 1 4oz/120mL glass of wine, and a 
1 oz/30 mL measure of 40% proof alcohol);
16)
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;
17)
Unstable cardiovascular disease as defined by any of the following:
a.
Unstable angina within 6 months prior to screening
b. Myocardial infarction, coronary artery bypass graft surgery or coronary angioplasty 
within 6 months prior to screening
c.
Transient ischemic attack or cerebrovascular accident within 6 months prior to 
screening
d. Obstructive valvular heart disease or hypertrophic cardiomyopathy
e.
Congestive heart failure;
18)
History of known hypercoagulable condition or prior arterial or venous thromboembolic 
disease;
19)
Use of any prohibited concomitant medications as described in Section 5.5;


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20)
History of a malignancy within 5 years of screening with the following exceptions:
a.
Adequately treated carcinoma in situ of the cervix
b.
Adequately treated basal or squamous cell cancer or other localized non-melanoma skin 
cancer;
21)
Any laboratory abnormality or condition that could, in the opinion of the investigator, 
adversely affect the safety of the subject or impair the assessment of study results;
22)
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;
23)
Concurrent participation in another therapeutic clinical study;
24)
Known hypersensitivity to GS-9674, the metabolites, or formulation excipient;
25)
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 or a 
psychiatric (including any subjects with a psychiatric hospital admission or emergency 
room visit in the 2 years prior to screening) or medical condition;
26)
Unavailable for follow-up assessment or concern for subject’s compliance with the 
protocol procedures;
27)
Contraindications or inability to complete MRI scanning (eg, presence of permanent 
pacemakers, implanted cardiac devices, weight restrictions, etc.).


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
An Interactive Web Response System (IWRS) will be used for centralized randomization and 
treatment assignment. Randomization will be stratified by the presence or absence of diabetes 
mellitus as determined by medical history, use of medication for indication of diabetes mellitus, 
or based on screening lab values if previously undiagnosed (ie, hemoglobin A1c ≥ 6.5% OR 
fasting plasma glucose ≥126 mg/dL).
Investigative site personnel will obtain the subject’s identification number and study drug 
assignment from the IWRS. Subjects and all personnel directly involved in the conduct of the 
study will be blinded to treatment assignment.
Study drug will be dispensed by the study pharmacist, or designee, in a blinded fashion to the 
subjects.
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator (or designee) may obtain treatment assignment directly from the 
IWRS system for that subject (refer to the Study Reference Binder for IWRS unblinding 
instructions). Gilead recommends but does not require that the investigator contact the Gilead
Medical Monitor before breaking the blind. Treatment assignment should remain blinded unless 
that knowledge is necessary to determine subject emergency medical care. The rationale for 
unblinding must be clearly explained in source documentation and on the electronic case report 
form (eCRF), along with the date on which the treatment assignment was obtained. The 
investigator is requested to contact the Gilead Medical Monitor promptly in case of any 
treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical study 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 Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).


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5.2. 
Description and Handling of GS-9674 and PTl\11 GS-9674 
5.2.1. 
Formulation 
Final 
Amendment 2 
tablets. The tablets 
GS-9674 30 mg tablets are ronnd, plain-faced, film-coated orange tablets and 
'"'"G""S:--9
"'"'67>7..-;4~100 mg tablets ru·e capsule-shaped, plain-faced, film-coated orange tablets. 
Placebo-to-match (PTM) GS-9674 tablets are identical in size, shape, color, and appearance to 
their con esponding strengths of active GS-9674 tablets. PTM GS-9674 tablets contain the 
following ingredients: IPP 
5.2.2. 
Packaging and Labeling 
GS-9674 tablets and PTM GS-9674 tablets are packaged in white, high-density polyethylene 
(HDPE) bottles. Each bottle contains 30 tablets, a 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, aluminum-faced liner. 
Study dmg to be distJ:ibuted to centers in the US and other patiicipating conntries shall be labeled 
to meet applicable requirements of the United States Food and Dmg Administration (FDA), EU 
Guideline to Good Manufacturing Practice- Annex 13 (Investigational Medicinal Products), 
ru1d/or other local regulations. 
5.2.3. 
Storage and Handling 
GS-9674 tablets and PTM GS-9674 tablets should be stored at controlled room temperature lmtil 
required for administration. Controlled room temperature is defmed as 25°C (77°F); temperature 
excursions ru·e petmitted between l5°C and 30°C (59°F and 86°F). Storage conditions ru·e 
specified on the label. 
Until study drug tablets ru·e dispensed to the subjects, all bottles of study mugs should be stored 
in a securely locked area, accessible only to authorized site personnel. To ensure the stability and 
proper identification, the mug products should not be stored in a container other than the 
container in which they were supplied. Consideration should be given to handling, preparation, 
and disposal through measures that minimize m·ug contact with the body. Appropriate 
precautions should be followed to avoid direct eye contact or exposure when handling GS-967 4 
tablets and PTM GS-9674 tablets. 
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5.3.
Dosage and Administration of GS-9674/ PTM GS-9674 
GS-9674 and GS-9674 PTM tablets will be provided by Gilead Sciences, Inc. In order to 
maintain the blind, each subject will be supplied with 2 bottles of tablets. One bottle will contain
GS-9674 30 mg or PTM GS-9674 30 mg, the second bottle will contain GS-9674 100 mg or 
PTM GS-9674 100 mg. Dosing for each treatment group will be as follows:

Treatment Group A: GS-9674 30 mg (1 x 30 mg tablet) + PTM GS-9674 100 mg (1 x PTM 
100 mg tablet) administered orally once daily with food

Treatment Group B: GS-9674 100 mg (1 x 100 mg tablet) + PTM GS-9674 30 mg 
(1 x PTM 30 mg tablet) administered orally once daily with food

Treatment Group C: PTM GS-9674 30 mg (1 x PTM 30 mg tablet) + PTM GS-9674 
100 mg (1 x PTM 100 mg tablet) administered orally once daily with food
The study drug dose should be taken at approximately the same time each day with food.
A dose will be considered missed if the subject cannot take the dose within 12 hours of their 
regular dosing time. If a subject misses a dose, the subject should take their next dose at the 
regular dosing time.
5.4.
Prior and Concomitant Medications
Concomitant use of certain medications or herbal/natural supplements with study drug may result 
in PK and/or PD interactions resulting in increases or decreases in exposure of study drug or 
these medications. 
Concomitant medications taken within 30 days of screening through the follow-up visit need to 
be recorded in the source documents and electronic Case Report Forms (eCRFs).
Subjects with co-morbid diseases requiring medication(s) must be taking the medication(s) 
without a change in dose within 28 days of Baseline/Day 1.
GS-9674 increased atorvastatin exposure (39%) which does not necessitate a priori dose 
modification based on the LIPITOR® USPI.  Subjects taking atorvastatin with GS-9674 should 
be monitored as per label recommendations.


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5.5.
Prohibited Medications
The following medications are prohibited from 28 days prior to Baseline/Day 1 up to and 
including the day of the last dose of study drug:

Vitamin E

Hematologic stimulating agents (eg, erythropoiesis-stimulating agents (ESAs); granulocyte 
colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics)

Chronic systemic immunosuppressants including, but not limited to, corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal 
antibodies (eg, infliximab). Use for < 2 weeks total is allowed.

Investigational agents or devices for any indication

Concomitant use of certain medications or herbal/natural supplements (potent inhibitors of 
OATP or potent or moderate inducers of OATP, CYP2C8, P-gp, or CYP3A) with study 
drug(s) may result in PK interactions resulting in increases or decreases in exposure of study 
drug(s) or concomitant medications. Examples of representative medications which are 
prohibited from 28 days prior to Baseline/Day 1 up to and including the day of the last dose 
of study drug, are listed below in Table 5-1:
Table 5-1.
List of Medications Prohibited and to be used with Caution
Drug Class
Agents Disallowed
Use with Caution
Antibiotics
Clarithromycin, Erythromycin
Acid Reducing Agents
H2-Receptor Antagonistsa
Antacidsb
Anticonvulsantsc
Carbamazepine, Oxcarbazepine, Phenobarbital, 
Phenytoin
Antimycobacterialsc
Rifabutin, Rifapentine, Rifampin
Endothelin Receptor 
Antagonists
Bosentan
Herbal/Natural 
Supplementsc
St. John’s Wort, Echinaccea. Milk thistle (ie, 
silymarin), Chinese herb sho-saiko-to (or Xiao-
Shai-Hu-Tang)
Bile Acid Sequestrantsd
Cholestyramine, Colesevelam, 
Colestipol
Otherc
Modafinil
a
H2-Receptor Antagonists can be taken up to 3 days prior to study drug dosing.
b
Antacids that directly neutralize stomach pH (ie, Tums, Maalox) are permitted but may not be taken within 4 hours (before 
or after) study drug administration.
c
May result in a decrease in the concentrations of study drug.
d 
Bile acid sequestrants are permitted but may not be taken within 4 hours (before or after) study drug administration.


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Medications for disease conditions excluded from the protocol (eg, HIV-1, HBV, or HCV
infection, active cancer, transplantation) are not listed under this prohibited medications section 
and are disallowed in the study.
5.6.
Accountability for GS-9674/ PTM GS-9674 
The investigator or designee (eg, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug bottles. This includes acknowledgement of receipt of each 
shipment of study drug (quantity and condition), subject dispensing records, and returned or 
destroyed study product. All used and unused study drug bottles dispensed to subjects must be 
returned to the site.
Study drug accountability records will be provided to each study site to:

Record the date received and quantity of study drug bottles

Record the date, subject number, subject initials, and the study drug bottle number dispensed

Record the date, quantity of used and unused study drug returned, along with the initials of 
the person recording the information.
5.6.1.
Investigational Medicinal Product Return or Disposal
Refer to Section 9.1.7 for instructions regarding study drug return or disposal.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. Additional information is 
provided in the Study Reference Binder.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the investigator to ensure that subjects are eligible to participate in the 
study prior to enrollment and throughout the study. 
Documentation of the personally signed and dated informed consent of each subject, using the 
study-specific informed consent form (ICF), is required before initiating the screening process.
After written informed consent has been obtained and eligibility to participate established, 
investigative site personnel will obtain the subject’s identification number and study drug 
assignment from the interactive web response system (IWRS).
6.2.
Pretreatment Assessments – Screening Visit
Subjects will be screened within 6 weeks prior to randomization to determine eligibility for 
participation in the study. The screening period may be extended under special circumstances 
with the explicit approval of the Medical Monitor.
A historical MRE and MRI-PDFF within 6 months of screening from this study or another 
Gilead study (i.e. GS-US-426-3989) may be used to determine eligibility for this study. 
Retesting of an exclusionary laboratory value during the Screening period is permitted only if in 
the Principle Investigator’s opinion, the retest value will be within acceptable parameters; if the 
initial value was deemed to be inaccurate, inconsistent with the subject’s previous result(s); in 
error (e.g. mishandled sample) or due to an extenuating circumstance. 
Subjects who fail to meet eligibility criteria may be re-screened once if there is a reasonable 
expectation that the subject will meet eligibility criteria after repeat screening or in the following 
situations:

Previously screen failed for this study or another Gilead study due to a low MRE or MRI-
PDFF measurement using an MR scanner previously qualified for this or another Gilead 
study, but have an MRE ≥2.5 kPa and MRI-PDFF ≥ 8% within 6 months of prior 
Screening/Re-screening.  


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
Previously screen failed for this study or another Gilead study due to a low MRE or MRI-
PDFF measurement using an MR scanner previously qualified for this or another Gilead 
study and have a historical liver biopsy within 12 months of Screening/Re-screening that is 
consistent with NASH (defined as the presence of steatosis, hepatocellular ballooning, and 
lobular inflammation) with fibrosis, but not cirrhosis. 

Previously screen failed for this study or another Gilead study due to a 
FibroSURE/FibroTest® ≥ 0.75 in whom Gilbert’s syndrome or hemolysis is present; a repeat 
FibroSURE/FibroTest® calculated using direct bilirubin instead of total bilirubin will be used 
to determine eligibility. 

Previously screen failed for this study or another Gilead study due to a 
FibroSURE/FibroTest® ≥ 0.75 and with a historical liver biopsy within 12 months of 
Screening that does not reveal cirrhosis; FibroSure/Fibrotest score will not be used to 
determine eligibility.
If MRE and MRI-PDFF were performed within 6 months of re-screening using an MR scanner 
previously qualified for this or another Gilead study, MRE and MRI-PDFF do not need to be 
repeated. All other screening procedures must be repeated and meet eligibility criteria. If prior 
imaging was performed greater than 6 months prior to re-screening, MRE and MRI-PDFF must 
be repeated. Refer to the Study Reference Binder for re-screening guidelines.
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 fasted blood sample collection the next morning.
The following will be performed and documented at Screening:

Obtain written informed consent before initiation of any screening procedures

Review and record whether the subject meets inclusion and exclusion criteria

Obtain screening number from IWRS

Obtain medical history

Complete physical examination

Record vital signs, body weight, and height

Obtain blood samples for:
— Chemistry
— Hematology 
— Coagulation Panel 


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— Hemoglobin A1c
— Biomarkers
— HIV-1, HBV, and HCV Serology
— Serum pregnancy test (only for female subjects of child bearing potential)
— Serum FSH (only for some female subjects - see Appendix 4) 

Conduct standard 12-Lead ECG

Perform Ultrasound (if necessary) for confirmation of NAFLD

Perform MRE and MRI-PDFF

Review any historical liver biopsy results, if available

Urine drug screen for amphetamines, cocaine and opiates (ie, heroin, morphine)

Record all concomitant medications that the subject has taken within 30 days prior to 
screening

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 4 weeks of the start of screening for randomization into the study.
From the time of obtaining informed consent through the first administration of the study drug, 
record all serious adverse events (SAEs), as well as any adverse events related to protocol-
mandated procedures on the adverse events electronic case report form (eCRF). If a condition 
starts during or after informed consent but prior to the first dose of study drug, the event should
be captured in medical history eCRF.  If a pre-existing condition worsens in frequency or 
severity following the start of the screening visit, it must be recorded on the adverse events eCRF
with a start date of the worsening or exacerbation. See Section 7 Adverse Events and Toxicity 
Management for additional details.
6.3.
Baseline/Day 1 Randomization and Assessments
Subjects returning to the clinic for randomization at Baseline/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 visit to ensure an approximate 8-hour fast prior to the blood sample 
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After review of inclusion and exclusion criteria to confi1m continued eligibility, subjects will be 
randomized to study dmg assignment and receive their Subject Identification Number via the 
IWRS prior to their fn·st dose of study mug. 
The following will be peif01med and documented at the Baseline/Day I visit prior to dosing: 
• 
QoL: general assessments (CLDQ, SF-36, and WPAI) 
• 
QoL: pmritus assessments (VAS-itch and 5D-itch) 
Note: It is recommended that QoL assessments be completed prior to any study procedures being 
perf01med and prior to the subject seeing a health care provider. Refer to the Study Reference 
Binder for guidance on QoL assessment aillninistration. 
• 
Symptom ffi·iven physical examination 
• 
Record vital signs, waist circumference, and body weight 
• 
Obtain blood samples for: 
-
Chemistiy 
-
Hematology 
-
Coagulation Panel 
-
Lipid Profile 
-
Hemoglobin Al e 
-
Biomarkers 
-
Single PD Sampling 
PD 
• 
Conduct standard 12-Lead ECG 
• 
Perf01m FibroScan® (if available) 
• 
Collect urine samples for: 
-
Urine pregnancy test for females of child bearing potential only 
-
Bioma1·ker testing 
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
Collect stool sample for biomarker testing

Dispense study drug and provide subject with instruction on appropriate dosing and 
administration; 

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 screening visit
Once all visit procedures have been completed, subjects will take their Baseline/Day 1 dose of 
study drug with food while at the investigative site.
Subjects will return to the investigative site at Week 1 (±3 days) for a mandatory safety visit. 
Then, starting at the Week 4 visit, subjects will have visits every 4 weeks up to the Week 24 
visit.
6.4.
Treatment Assessments
6.4.1.
Week 1
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Week 1 visit to ensure an 
approximate 8-hour fast prior to the fasted blood sample collection the next morning.
Subjects should also be instructed to HOLD their dose of study drug on the day of their Week 1 
visit until all visit procedures have been completed. The study drug dose should be taken with 
food after the visit.
During the Week 1 safety visit the following will be performed and documented (±3 days):

QoL: pruritus assessments (VAS-itch and 5D-itch)

Symptom driven physical examination

Record vital signs and body weight

Obtain blood samples for:
— Chemistry
— Hematology
— Coagulation Panel
— Lipid Profile
— Biomarkers


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— Single PK and PD sampling

Collect urine sample for biomarker testing

Assess for study drug adherence

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
6.4.2.
Week 4 Visit
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Week 4 visit to ensure an 
approximate 8-hour fast prior to the fasted blood sample collection the next morning.
Subjects should also be instructed to HOLD their dose of study drug on the day of their Week 4 
visit until all visit procedures have been completed. The study drug dose should be taken with 
food after the visit.
The following will be performed and documented at this visit (±3 days):

QoL: pruritus assessments (VAS-itch and 5D-itch)

Symptom driven physical examination

Record vital signs and body weight

Obtain blood samples for:
— Chemistry
— Hematology
— Coagulation Panel
— Lipid Profile
— Biomarkers
— Single PK and PD sampling

Collect urine samples for:
Urine pregnancy test for females of child bearing potential only
Biomarker testing


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
Assess for study drug adherence

Dispense study drug

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
6.4.3.
Week 8, 16, and 20 Visits
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Weeks 8, 16, and 20 visits to ensure 
an approximate 8-hour fast prior to the fasted blood sample collection the next morning.
Subjects should also be instructed to HOLD their dose of study drug on the day of their Weeks 8, 
16, and 20 visits until all visit procedures have been completed. The study drug dose should be 
taken with food after the visit.
The following will be performed and documented at these visits (±3 days):

QoL: pruritus assessments (VAS-itch and 5D-itch)

Symptom driven physical examination

Record vital signs and body weight

Obtain blood samples for:
— Chemistry
— Hematology
— Coagulation Panel
— Lipid Profile
— Single PK and PD sampling

Urine pregnancy test for females of child bearing potential only

Assess for study drug adherence

Dispense study drug

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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6.4.4.
Week 12 Visit 
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Week 12 visit to ensure an 
approximate 8-hour fast prior to the fasted blood sample collection the next morning.
Subjects should also be instructed to HOLD their dose of study drug on the day of their Week 12 
visit until all visit procedures have been completed. The study drug dose should be taken with 
food after the visit.
The following will be performed and documented at this visit (±7 days):

QoL: general assessments (CLDQ, SF-36, and WPAI)

QoL: pruritus assessments (VAS-itch and 5D-itch) 

Symptom driven physical examination

Record vital signs and body weight

Obtain blood samples for:
— Chemistry
— Hematology
— Coagulation Panel
— Lipid Profile
— Hemoglobin A1c
— Biomarkers
— Single PK and PD sampling

Collect urine samples for:
Urine pregnancy test for females of child bearing potential only
Biomarker testing

Conduct standard 12-Lead ECG

Perform FibroScan® (if available)

Perform MRE and MRI-PDFF


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
Assess for study drug adherence

Dispense study drug

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
6.4.5.
Week 24 Visit
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Week 24 visit to ensure an 
approximate 8-hour fast prior to the fasted blood sample collection the next morning.
Subjects should also be instructed to HOLD their dose of study drug on the day of their Week 24 
visit until all visit procedures have been completed. 
The following will be performed and documented at this visit (±7 days):

QoL: general assessments (CLDQ, SF-36, and WPAI)

QoL: pruritus assessments (VAS-itch and 5D-itch) 

Symptom driven physical examination

Record vital signs, waist circumference, and body weight

Obtain blood samples for:
— Chemistry
— Hematology
— Coagulation Panel
— Lipid Profile
— Hemoglobin A1c
— Biomarkers
— Single PK and PD sampling

Collect urine samples for:
Urine pregnancy test for females of child bearing potential only
Biomarker testing

Conduct standard 12-Lead ECG


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Perf01m FibroScan® (if available) 
• 
Perf01m MRE and MRI-PDFF 
• 
Assess for study dmg adherence 
• 
Collect stool sample for biomarkers 
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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 occmTing since the previous visit 
Once all visit procedmes have been completed, subjects will take their fmal dose of study dmg 
while at the investigative site. 
PD 
6.4.6. 
Unscheduled Visits 
Additional unscheduled assessments may be perf01med at the discretion of the investigator. 
Subjects retmning to the clinic for an unscheduled visit should be instmcted to fast (no food or 
drink, except water), starting from midnight (00:00) or earlier, as appropriate, on the evening 
prior to the visit to ensme an approximate 8-hom fast prior to the blood sample collection lmder 
fasting condition the next moming. 
Subjects should also be instmcted to HOLD their dose of study dmg on the day of an 
unscheduled visit lmtil all visit procedmes have been completed. The study drug dose should be 
taken with food after the visit. 
At a miuimmn, the following will be perf01med and documented. 
• 
Symptom driven physical examination 
• 
Record body weight 
• 
Obtain blood samples for: 
-
Chemistly 
-
Hematology 
• 
Record all concomitant mediations that the subject has taken since the previous visit 
• 
Record any serious adverse events and all adverse events occmTing since the previous visit 
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If the Unscheduled visit is performed for the sole purpose of distribution of study drug, the 
assessments noted above do not need to be performed.
6.5.
Follow-Up Visit
Subjects will return for a Follow-Up Visit four weeks after their last dose of study drug.
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Follow-Up visit to ensure an 
approximate 8-hour fast prior to the blood sample collection under fasting condition the next 
morning.
The following will be performed and documented at this visit (±5 days):

Symptom driven physical examination

Record vital signs and body weight

Obtain blood samples for:
— Chemistry
— Hematology
— Coagulation Panel

Urine pregnancy test for female subjects of child bearing potential only

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse occurring since the previous visit
6.6.
Assessments for Premature Discontinuation from Study
Subjects prematurely discontinuing from the study (for example, as a result of an AE), should 
have an Early Termination (ET) visit, if possible, and a Follow-Up visit 4 weeks after their last 
dose of study drug. The study assessments to be performed at the ET visit are the same as those 
performed at the Week 24 visit (refer to Section 6.4.5). The study assessments to be performed at 
the Follow-Up visit are listed in Section 6.5. The subject will then be withdrawn from the study.
If these visits are not possible or acceptable to the subject or investigator, the subject may be 
withdrawn from the study. 


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6.7. 
Criteria for Discontinuation of Study Treatment 
Study medication may be discontinued in the following instances: 
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• 
Intercunent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercunent illness, the subject 
may resume study dosing at the discretion of the investigator. 
• 
Unacceptable toxicity, or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedmes or is considered to not be in the subject's best 
interest 
• 
Subject request to discontinue for any reason 
• 
Subject noncompliance 
• 
Pregnancy dming the study (refer to Appendix 4) 
• 
Sponsor discretion 
• 
Discontinuation of the study at the request of Gilead, a regulatoty agency or an institutional 
review board, independent ethics committee, or ethics committee (IRBIIEC/EC) 
6.8. 
PK and PD Substudy Visits 
·po 
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6.9. 
Description of Assessments 
6.9.1. 
Clinical Laboratory Analytes 
Chemistry: 
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alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, alkaline 
phosphatase (ALP), 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). Also includes C-
Peptide and Insulin for the Baseline/Day!, Weeks 4, 12, and 24 visits. 
Hematology: 
Hematocrit (Hct), Hemoglobin (Hb), Platelet count, Red blood cell count (RBC), White blood 
cell count (WBC) with differential (absolute and percentage) including Lymphocytes, 
Monocytes, Neutrophils, Eosinophils, and Basophils and, Reticulocyte count and mean 
corpuscular volume (MCV). 
Coagulation Panel: 
Prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio 
(INR) 
Pregnancy Tests: 
Serum ~-hCG or urine ~-hCG (if positive, requires immediate confirmation with Serum ~-hCG) 
Additional Tests: 
Lipid Profile, Hemoglobin Ale, HIV-1, HBV & HCV Serology, urine drug screen (for 
amphetamines, cocaine, opiates), creatine phosphokinase, and genomic sample collection. 
Biomarker Tests: 
CK18 (M30 and M65), FGF-19, C4, Apolipoprotein B (Apo B), metabolite profile, bile acids, 
stool microbiome, blood miRN A, NMR lipoprofile, free fatty acids, ELF™ Test, and 
FibroSURE/Fibro Test®. 
PPD 
Pharmacokinetic (PK) and Pharmacodynamic (PD) Assessments 
Single PK and PD Sampling 
Single PK and PD plasma samples will be collected and archived for 1) PK analysis of GS-9674, 
GS-716070 (metabolite of GS-9674 ), and other metabolites as applicable, 2) to measure the 
concentration ofthe PD biomarkers FGF19 and C4. 
PK and PD Substudy 
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6.9.2. 
Medical History 
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Medical hist01y, including details of illnesses and allergies, date(s) of onset, whether condition(s) 
is cunently ongoing, and medication histoty, including nicotine and alcohol use, will be 
collected for all subjects dming screening. 
6.9.3. 
Physical Examination 
A complete physical examination should include somce documentation of general appearance, 
and the following body systems: head, neck, and thyroid; eyes, ears, nose, throat, mouth, and 
tongue; chest (excluding breasts); respirat01y; cardiovascular; lymph nodes; abdomen; skin, hair, 
nails; musculoskeletal; nemological. 
The focus of a symptom driven physical examination will be dete1mined by the investigator 
based on subject complaint. For eg, if a subject complains of a cough, a lung exam should be 
perf01med. If consistent with pneumonia (rales/crackles on exam) then an AE would be 
documented. 
Height, body weight, and hip circumference will be collected at specified time points. 
6.9.4. 
Vital Signs 
Vital signs measmements should include blood pressme, hea1t rate, respiration rate, and body 
temperature. 
6.9.5. 
Quality of Life (QoL) Assessments 
It is recommended that these questiollllaires be completed prior to the clinical and laborat01y 
assessments. The subject should read the questiollllaires by himself/herself and record the 
answers by himself/herself. 
6.9.5.1. 
Chronic Liver Disease Questi01maire (CLDQ) 
The CLDQ asks questions related to liver disease to measme health related quality of life in 
subjects with chronic liver disease. 
6.9.5.2. 
SF-36 Health Survey 
The SF-36 Health Survey asks questions to measme ftmctional health and well-being from the 
subject's point of view and consists of eight health domains (physical ftmctioning, role-physical, 
bodily pain, general health, vitality, social ftmctioning, role-emotional, and mental health). These 
health domain scales contribute to the physical health and mental health summaty measmes. 
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6.9.5.3.
Work Productivity and Activity Impairment (WPAI) 
The Work Productivity and Activity Impairment (WPAI) questionnaire asks questions regarding 
the effect of NASH on a person’s ability to work and perform regular activities.
6.9.5.4.
VAS-itch
The visual analogue scale (VAS)-itch is a tool for measuring the intensity of pruritus.
6.9.5.5.
5-D itch
The 5-D itch is multidimensional measure of itching that allows changes in chronic pruritus to be 
detected over time. The questionnaire measures the degree, duration, direction, disability, and 
distribution of pruritus.
6.9.6.
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 in the AE eCRF page.
6.9.7.
FibroScan®
Liver stiffness will be assessed by FibroScan®. It is required that each subject’s FibroScan®
assessments be done with the same type of probe at each study visit. If FibroScan® is not 
available at a site the test may be omitted.
Please refer to the Study Reference Binder for instructions on FibroScan® measurements.
6.9.8.
MRE and MRI-PDFF
Liver stiffness will be assessed by MRE and the degree of steatosis will be measured by 
Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF). These assessments can 
occur sequentially.
The MRE and MRI-PDFF images will be analyzed by a central reader. 
Please refer to the Study Reference Binder for MRE and MRI-PDFF imaging guidelines.
6.10.
End of Study Definition
End of study is defined as when the last patient last visit (LPLV) for the Follow-Up visit (four 
weeks after their last dose of study drug) occurs, or the ET visit, whichever occurs later.
6.11.
Post Study Care 
No post study ongoing care will be provided.


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


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; 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 study drug 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 
GS-9674 therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the GS-9674. 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 study drug.


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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, 4, or 5 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
(Appendix 3).
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 electronic 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 GS-9674; AEs 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 
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Serious Adverse Events
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signs 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 GS-9674, 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 study drug, 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 (see Study Reference Binder) and submit within 24 hours to:
Gilead DSPH:
Fax: +1 (650) 522-5477
Email: 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.

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.


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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 drug. 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. 
To minimize the possibility of exposing study subjects to unusual risk, the safety information 
from this study will also be reviewed periodically by an independent Data Monitoring 
Committee (DMC). The DMC may have access to partially blinded or unblinded data and will 
make recommendations regarding the study according to the DMC charter. See Section 8.11 for 
additional details regarding the DMC.
7.5.
Toxicity Management 
Observation for Drug Induced Liver Injury (DILI):
Although subjects enrolled in this study will have baseline liver disease, their hepatic function 
should not be significantly impaired. However, at baseline, some may have liver biochemistry 
levels above the upper limit of normal (ULN).  Baseline values for liver tests (ALT, AST, total 
bilirubin, and ALP) will be determined by averaging the values obtained at screening and 
baseline/Day1.
For subjects with ALT and AST below ULN at study start, close observation for DILI (as 
described below) will be performed in subjects with any of the following criteria (all labs 
confirmed by repeat testing):

ALT or AST > 3 x ULN at any time

Total bilirubin > 2 x ULN

ALP > 3 x ULN

INR >1.5 (except for subjects on anticoagulant therapy)  


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Clinical signs or symptoms that are, in the opinion of the investigator, consistent with 
hepatitis (such as right upper quadrant discomfort, fever, nausea, vomiting, jaundice, rash, or 
eosinophilia > 5%)
For subjects with ALT or AST between 1 and 5 x ULN at study start, close observation for DILI 
(as described below) will be performed in subjects with any of the following criteria (all labs 
confirmed by repeat testing):

ALT or AST > 2 x baseline at any time

Total bilirubin > 2 x ULN  

Alkaline phosphatase > 3 x ULN

INR >1.5 (except for subjects on anticoagulant therapy)  

Clinical signs or symptoms that are, in the opinion of the investigator, consistent with 
hepatitis (such as right upper quadrant discomfort, fever, nausea, vomiting, jaundice, rash, or 
eosinophilia > 5%).  
Close observation includes:

Repeating liver biochemistries (ALT, AST, ALP, total bilirubin, INR) and obtaining creatine
phosphokinase (CPK) levels within 48 hours

Obtaining a more detailed history of symptoms and prior or concurrent disease

Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and special 
diets

Obtaining a history of exposure to environmental chemical agents

Ruling out other causes of liver disease as needed (obtain viral hepatitis panel, imaging for 
evaluation of biliary tract disease, etc. if required in the opinion of the primary investigator)

Continue to monitor liver biochemistries twice weekly. Frequency can decrease to once a 
week or less if abnormalities stabilize or study drug has been discontinued and subject is 
asymptomatic
During a period of close observation, study drug can be continued, if desired, at the discretion of 
the Gilead Medical Monitor and the principal investigator during the DILI evaluation. 


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However, for all subjects, study drug should be withheld if any of the following criteria are met:

ALT or AST > 5 x baseline

ALT or AST >10 x ULN 

ALT or AST >3 x baseline with 1 or more of the following:
Total bilirubin > 2 x ULN or 1.5 x baseline
INR >1.5 (except for subjects on anticoagulant therapy)
Appearance of clinical signs or symptoms that are, in the opinion of the investigator, 
consistent with drug-induced hepatotoxicity

ALT or AST > baseline with any 2 or more of the following:
Total bilirubin > 2 x ULN or 1.5 x baseline
INR >1.5 (except for subjects on anticoagulant therapy)
Appearance of clinical signs or symptoms that are, in the opinion of the investigator, 
consistent with drug-induced hepatotoxicity
AND

No other cause for the combination of laboratory abnormalities is immediately apparent (eg,
prolonged INR with warfarin use) important potential causes or contributors to abnormal 
AST/ALT or total bilirubin values include, but are not limited to:
Obstructive gall bladder or bile duct disease
Viral or alcoholic hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus, 
cytomegalovirus, herpes simplex virus, varicella)
Autoimmune hepatitis
Concomitant administration of other hepatotoxins, including excessive doses of 
acetaminophen, drugs that inhibit bilirubin glucuronidation (eg, indinavir, atazanavir, 
irinotecan), or herbal or dietary supplements
Hypoxic or ischemic hepatopathy or congestive hepatopathy in association with 
significant right-sided heart failure
Wilson disease
Progression of malignancy involving the liver (note that metastatic disease to the liver, by 
itself, should not be used as an explanation for significant AST/ALT elevations)


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If study drugs are withheld, they may be reintroduced with approval from the Medical Monitor if 
another etiology for elevated liver tests is present. Study drug must be discontinued if close 
monitoring of a patient for DILI is not possible, or if total bilirubin, ALT or AST elevation 
recurs following re-challenge with study drug.
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 AEs should be confirmed by repeat testing as soon as practical to do so, and 
preferably within 3 calendar days of receipt of the original test results.

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.

Any questions regarding toxicity management should be directed to the Medical Monitor.
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of AEs associated with product complaints, occupational exposure with an AE, pregnancy 
reports regardless of an associated AE, and AE in an infant following exposure from 
breastfeeding.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labeling (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).


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Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product. 
Occupational exposure is defined as exposure to a medicinal product as a result of one’s 
professional or non-professional occupation.
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to Gilead 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 4 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.


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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 drug and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does 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 
Details will be provided in the statistical analysis plan (SAP). 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The primary objective of this study is as follows: 
• 
To evaluate the safety and tolerability of GS-967 4 in subjects with NASH. 
The exploratory objectives of this study are as follows: 
~ 
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Primary Endpoint 
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The primaty endpoint is the safety of GS-9674 in subjects with NASH. Safety endpoints include 
adverse events and laborat01y evaluations. 
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8.1.3. 
Exploratory Efficacy Endpoints 
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Analysis Conventions 
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All individual subject data will be listed as measured. All statistical summruies and analyses will 
be perfonned using SAS® software (SAS Institute, Cmy, N01ih Cm·olina, USA). 
8.2.1. 
Analysis Sets 
8.2.1.1. 
Efficacy 
The prima1y analysis set for efficacy analysis is defmed as the Full Analysis Set (F AS), which 
includes all subjects who were randomized into the study and received at least 1 dose of study 
dmg. 
Subjects who receive study dmg other than that to which they were assigned for the entire 
duration of treatment, will be analyzed according to the treatment group they were randomized 
to. 
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8.2.1.2. 
Safety 
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The primaty analysis set for safety analyses is defmed as all subjects who received at least 
one dose of study drug. Subjects who receive study dmg other than that to which they were 
assigned for the entire dmation of treatment, will be analyzed according to the study drug 
received. 
All data collected dming treatment plus 30 days after last dose of study drug will be included in 
the safety summaries. 
8.2.1.3. 
Phrumacokinetics 
There are two phrumacokinetic analysis sets: 1) The PK 
· Set which includes 
concentration data from the · 
drawn at each 
The PK Analysis Set will include all emolled or randomized subjects who took at least one dose 
of study dmg and for whom concentration data of analytes GS-9674 (and its metabolites as 
applicable) ru·e available. The PK Analysis Set will be used for analyses of population PK. 
pp 
8.2.1.4. 
Phatmacodynamics 
There are two phru·macodynamic analysis sets: 1) The PD 
· Set which includes 
concentration data from the · 
drawn at each visit 
The PD Analysis Set will include all emolled or randomized subjects who took at least one dose 
of study dmg and for whom concentration data ofFGF19, C4, and bile acids are available. The 
PD Analysis Set may be used for descriptive and/or population based PD analyses as applicable. 
PD 
8.2.1.5. 
Bioma1·kers 
The Biomru·ker Analysis Set will include data from subjects in the Safety Analysis Set who have 
the necessa1y baseline and on-study measmements to provide interpretable results for the 
specific parameters of interest. 
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8.2.2. 
Interim Analysis 
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An administrative interim analysis will be perfmmed after all subjects finish 12 weeks of 
treatment. 
8.3. 
Data Handling Conventions 
Missing data can have an impact on the inte1pretation of the study data. In general, values for 
Inissing data will not be imputed. 
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example, if a subject received study medication, the subject will be 
included in a summmy of adverse events according to the treatment received; othe1wise, if the 
subject is not dosed then they will be excluded from the summa1y. If safety laboratmy results for 
a subject are Inissing for any reason at a time point, the subject will be excluded from the 
calculation of sUllllnmy statistics for that time point. If the subject is missing a pre-dose value, 
then the subject will be excluded from the calculation of summmy statistics for the pre-dose 
value and the change from pre-dose values. 
Values for Inissing safety laboratmy data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. If no pre-treatment laboratmy value is 
available, the baseline value will be assmned to be nmmal (ie, no grade [Grade OJ) for the 
summary of graded laboratmy abnmmalities. 
Values for Inissing vital signs data will not be imputed; however, a Inissing baseline result will 
be replaced with a screening result, if available. 
8.4. 
Demographic Data and Baseline Characteristics 
Demographic and baseline measurements will be summarized using standard descriptive 
methods. 
Demographic summaries will include sex, race/ethnicity, and age. 
Baseline data will include a sUllllnmy of body weight, height, body mass index, and 
randmnization stratification group (presence or absence of diabetes) and other disease 
characteristic vm·iables. 
8.5. 
Efficacy Analysis 
The biological activity ofGS-9674 will be evaluated using radiolo 
variables. PPD 
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8.6.
Safety Analysis
All safety data collected on or after the date that GS-9674 was first dispensed up to the date of 
last dose of GS-9674 plus 30 days will be summarized by treatment group. Data for the 
pretreatment and follow-up periods will be included in data listings. 
8.6.1.
Extent of Exposure
Data for a subject’s extent of exposure to GS-9674 will be generated from the study drug
administration eCRF. Exposure data will be summarized by treatment group. 
8.6.2.
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. A treatment-emergent 
adverse event (TEAE) will be defined as 1 or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug.

Any AEs leading to premature discontinuation of study drug.
Summaries (number and percentage of subjects) of TEAEs by SOC and PT will be provided. 
Treatment-emergent AEs will also be summarized by relationship to study drug and severity. In 
addition, TEAEs leading to premature discontinuation of study drug and study will be 
summarized and listed.
All AEs collected during the course of the study will be presented in data listings with a field for 
treatment-emergent event (yes/no). 
8.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, Median, Q1, Q3, minimum, and 
maximum) by treatment group and study visit along with the corresponding change from 
baseline values. 
Graded laboratory abnormalities will be defined using the grading scheme in the CTCAE 
Version 4.03 (Appendix 3). Grading of laboratory abnormalities for analysis purposes will be 
performed by the central laboratory.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
1 toxicity grade from baseline at any time post baseline up to and including the date of last dose 


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of study dmg plus 30 days will be summarized by treatment group. If baseline data are missing, 
then any graded abnmmality (ie, at least a Grade 1) will be considered treatment emergent. 
8.6.4. 
Other Safety Evaluations 
Summmy statistics for the 12-lead ECGs petfmmed at Baseline/Day 1, Week 12, and Week 24, 
will be generated. 
8.7. 
Pharmacokinetic Analysis 
Plasma concentl'ations and PK parameters (eg, AUCu.u, Cmax and Ctau) will be listed and 
summarized as appropriate for GS-9674 (and its metabolites as applicable) using descriptive 
statistics. 
Details of the analysis plan will be provided in the Phatmacokinetic Repmting a11d Analysis 
Plan. 
8.8. 
Pharmacodynamic Analysis 
Primary PD parameters (AUCpartiaJ, Cmax, Cmin as applicable) ofFGF19 and C4 will be listed and 
summarized as appropriate for GS-9674 using descriptive statistics. 
Details of the analysis plan will be provided in the Phmmacodynamics Repmting and Analysis 
Plan. 
8.9. 
Biomarker Analysis 
Descriptive statistics ofbiomm·ker expression and change from baseline will be provided at each 
sampling time by treatment. Point estimates and 95% confidence intervals may be calculated. 
PD 
8.10. 
Sample Size 
Due to the exploratmy nature of this study, no fotmal power calculations were used to detennine 
sample size. The number of subjects was chosen based on clinical experience with other similm· 
proof of concept studies. However, assuming that 4% of subjects in the placebo atm (N=25) and 
32% in the GS-9674 100 mg mm (N=50) have a ~ 30% reduction in MRI-PDFF at 
Week 24, this sample size will provide 80% power to detect the difference based on a two-sided 
Fisher's exact test at a significance level of 0.05. 
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8.11.
Data Monitoring Committee
An independent, external data monitoring committee (DMC) that consists of two hepatologists
and a PhD statistician will review the progress of the study and perform reviews of safety data. 
The DMC will convene once 20 subjects have been enrolled and will meet every 3 to 4 months 
thereafter to monitor the study for safety events. The DMC will meet on an ad hoc basis if there 
are at least 3 Grade ≥ 3 serious, treatment-related Common Terminology Criteria for Adverse 
Events (CTCAE) observed in the study. In the event of two similar Grade 4-CTCAE treatment-
related adverse events or one Grade 5-CTCAE treatment-related adverse event, the DMC will 
review the data and advise the sponsor regarding stopping or continuing the study. The DMC 
will provide recommendation to Gilead whether the nature, frequency, and severity of adverse 
effects associated with study treatment warrant the early termination of the study in the best 
interests of the participants, whether the study should continue as planned, or the study should 
continue with modifications. The 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 has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC/EC approval, with the exception of those necessary 
to reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB/IEC/EC-approved consent form for documenting 


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written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by the 
IRB/IEC/EC or local requirements. The consent form will inform subjects about genomic testing 
and sample retention.
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 the Central Laboratory Services Manual for specific 
laboratory instructions. NOTE: The investigator must keep a screening log showing codes, 
names, and addresses for all subjects screened and for all subjects enrolled in the study. 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 study drug, 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 GS-9674, 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.
Case Report Forms
For each subject consented, an electronic case report form (eCRF) will be completed by an 
authorized study staff member whose training for this function is documented according to study 
procedures. eCRF should be completed on the day of the subject visit to enable the sponsor to 
perform central monitoring of safety data. The Eligibility Criteria eCRF should be completed 


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only after all data related to eligibility have been received. Subsequent to data entry, a study 
monitor will perform source data verification within the electronic data capture (EDC) system. 
Original entries as well as any changes to data fields will be stored in the audit trail of the 
system. Prior to database lock (or any interim time points as described in the clinical data 
management plan), the investigator will use his/her log in credentials to confirm that the forms 
have been reviewed, and that the entries accurately reflect the information in the source 
documents. The eCRF 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 study, 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
Where possible, study drug should be destroyed at the site. 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.
The study monitor will provide instructions for return.
The study monitor will evaluate each study center’s study drug disposal procedures and provide 
appropriate instruction for destruction of unused study drug supplies. If the site has an 
appropriate standard operating procedure (SOP) for drug destruction as determined by Gilead 
QA, the site may destroy used (empty or partially empty) and unused study drug supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If study drug is destroyed on site, the investigator must maintain accurate records for all study 
drug destroyed. Records must show the identification and quantity of each unit destroyed, the 
method of destruction, and the person who disposed of the study drug. Upon study completion, 
copies of the study drug accountability records must be filed at the site. Another copy will be 
returned to Gilead. Refer to the Pharmacy Binder for study drug disposal/return instructions.
The study monitor will review study drug supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this study to 
Gilead’s appointed study monitors, the IRB/IEC/EC, or to regulatory authority or health 
authority inspectors.


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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.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/IEC/EC
in accordance with local requirements and receive documented IRB/IEC/EC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agencies. 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.
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. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
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.


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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 study payments, meal, 
travel expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
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/ECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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10.
REFERENCES
Afzali A, Berry K, Ioannou GN. Excellent posttransplant survival for patients with nonalcoholic
steatohepatitis in the United States. Liver Transpl 2012;18 (1):29-37.
Bannas P, Kramer H, Hernando D, Agni R, Cunningham AM, Mandal R, et al. Quantitative 
magnetic resonance imaging of hepatic steatosis: Validation in ex vivo human 
livers. Hepatology 2015;62 (5):1444-55.
Chen J, Talwalkar JA, Yin M, Glaser KJ, Sanderson SO, Ehman RL. Early detection of 
nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease by 
using MR elastography. Radiology 2011;259 (3):749-56.
Dietrich P, Hellerbrand C. Non-alcoholic fatty liver disease, obesity and the metabolic syndrome. 
Best practice & research 2014;28 (4):637-53.
Dowman JK, Tomlinson JW, Newsome PN. Pathogenesis of non-alcoholic fatty liver disease. 
QJM 2010;103 (2):71-83.
Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal P, Kechagias S, et al. Fibrosis stage is the 
strongest predictor for disease-specific mortality in NAFLD after up to 33 years 
of follow-up [Accepted Article]. Hepatology 2014.
Faramawi MF, Wildman RP, Gustat J, Rice J, Abdul Kareem MY. The association of the 
metabolic syndrome with QTc interval in NHANES III. Eur J Epidemiol 2008;23 
(7):459-65.
Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial 
fibrillation: the Framingham study. N Engl J Med 1982;306 (17):1018-22.
Koek GH, Liedorp PR, Bast A. The role of oxidative stress in non-alcoholic steatohepatitis. Clin 
Chim Acta 2011;412 (15-16):1297-305.
Loomba R, Wolfson T, Ang B, Hooker J, Behling C, Peterson M, et al. Magnetic resonance 
elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver 
disease: a prospective study. Hepatology 2014;60 (6):1920-8.
Murakami S, Takayama F, Egashira T, Imao M, Mori A. Fermented papaya preparation halts the 
progression of non-alcoholic steatohepatitis in rats. Journal of Biophysical 
Chemisty 2013;4 (2):84-90.
Nakamoto K, Takayama F, Mankura M, Hidaka Y, Egashira T, Ogino T, et al. Beneficial Effects 
of Fermented Green Tea Extract in a Rat Model of Non-alcoholic Steatohepatitis. 
Journal of clinical biochemistry and nutrition 2009;44 (3):239-46.


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Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic 
steatohepatitis: the central role of nontriglyceride fatty acid metabolites. 
Hepatology 2010;52 (2):774-88.
Ong JP, Younossi ZM. Epidemiology and natural history of NAFLD and NASH. Clin Liver Dis 
2007;11 (1):1-16, vii.
Park CC, Nguyen P, Hernandez C, Bettencourt R, Ramirez K, Fortney L, et al. Magnetic 
Resonance Elastography vs Transient Elastography in Detection of Fibrosis and 
Noninvasive Measurement of Steatosis in Patients with Biopsy-proven 
Nonalcoholic Fatty Liver Disease [Accepted Manuscript]. Gastroenterology 2016.
Patel JR, Bettencourt R, Cui JY, Salotti J, Hooker J, Bhatt A, et al. Non-invasive quantitative 
decline in liver fat content on MRI and histologic response in nonalcoholic 
steatohepatitis: A secondary analysis of MOZART trial [Abstract 913]. American 
Association for the Study of Liver Diseases (AASLD); 2015 13-17 November; 
San Francisco, CA. pp. 659A-60A.
Ratziu V, Thibault V, Benhamou Y, Poynard T. Successful rescue therapy with tenofovir in a 
patient with hepatic decompensation and adefovir resistant HBV mutant. Comp 
Hepatol 2006;5:1.
Sumida Y, Niki E, Naito Y, Yoshikawa T. Involvement of free radicals and oxidative stress in 
NAFLD/NASH. Free radical research 2013;47 (11):869-80.
Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history 
of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. 
Aliment Pharmacol Ther 2011;34 (3):274-85.
Voulgari C, Tentolouris N, Papadogiannis D, Moyssakis I, Perrea D, Kyriaki D, et al. Increased 
left ventricular arrhythmogenicity in metabolic syndrome and relationship with 
myocardial performance, risk factors for atherosclerosis, and low-grade 
inflammation. Metabolism: clinical and experimental 2010;59 (2):159-65.
Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with 
analysis of risk factors. Hepatology 1990;12 (5):1106-10.
Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, et al. Prevalence of 
nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely 
middle-aged population utilizing ultrasound and liver biopsy: a prospective study. 
Gastroenterology 2011;140 (1):124-31.
Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing 
indication for liver transplantation in patients with hepatocellular carcinoma in the 
U.S. Hepatology 2014;59 (6):2188-95.


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Yeh MM, Brunt EM. Pathological features of fatty liver disease. Gastroenterology 2014;147 
(4):754-64.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table for GS-US-402-1852
Appendix 3.
CTCAE Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


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Gilead Sciences, Inc. 
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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
U.S.A. 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, 
Tolerability, and Efficacy of GS-9674 in Subjects with Nonalcoholic Steatohepatitis 
(NASH) 
GS-US-402-1852 Amendment 2, 24 January 2017 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PD 
a~ fvl~ /if) 9~ 
Name (Printed) f:h~&--
1\: e ()( o) 
Author 
v 
~ 
---=--' ) J-tj_/ w '~--
Date 
~ ( 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 82 
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Appendix 2.
Study Procedures Table for GS-US-402-1852
Screeningb
Treatment
Follow-Up
Unscheduled 
Visitaa
Week -6 to 
Day 0a
Baseline
/Day 1
Week 1
± 3 days
Week 4
± 3 days
Week 8
± 3 days
Week 12
± 7 days
Week 16
± 3 days
Week 20
± 3 days
Week 24/ETc
± 7 days
Follow-Upc
± 5 days
Subject Fastingd
X
X
X
X
X
X
X
X
X
X
X
Written Informed 
Consente
X
Review 
Inclusion/Exclusion 
Criteria
X
X
Medical History 
X
QoL: General 
Assessments (CLDQ, 
SF-36, and WPAI)f
X
X
X
QoL: Pruritus 
Assessments (VAS-
itch and 5D-itch)f
X
X
X
X
X
X
X
X
Complete Physical 
Examination
X
Symptom Driven 
Physical Examinationg
X
X
X
X
X
X
X
X
X
X
Vital Signsh
X
X
X
X
X
X
X
X
X
X
Weighti
X
Xi
X
X
X
X
X
X
Xj
X
X
Height
X


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Screeningb
Treatment
Follow-Up
Unscheduled 
Visitaa
Week -6 to 
Day 0a
Baseline
/Day 1
Week 1
± 3 days
Week 4
± 3 days
Week 8
± 3 days
Week 12
± 7 days
Week 16
± 3 days
Week 20
± 3 days
Week 24/ETc
± 7 days
Follow-Upc
± 5 days
Chemistryk
X
X
X
X
X
X
X
X
X
X
X
Hematologyl
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panelm
X
X
X
X
X
X
X
X
X
X
Lipid Profile
X
X
X
X
X
X
X
X
Hemoglobin A1c
X
X
X
X
Blood for 
Biomarkersn
X
X
X
X
X
X
Single PK and PD
Sampling
Xo
X
X
X
X
X
X
X
HIV-1, HBV and
HCV Serology
X
Pregnancy Testp
X
X
X
X
X
X
X
X
X
Serum FSHq
X
Genomic Sampler
X
12-lead ECG
X
X
X
X
Ultrasounds
Xr
FibroScan®t
X
X
X
MREu,v
X
X
X
MRI-PDFFu,v
X
X
X
Urine Drug Screenw
X


GS-9674 
Protocol GS-US-402-1852 
Gilead Sciences, Inc. 
Screeningb 
Week-6 to 
DayOa 
Urine Collection for 
(Biomarker) 
Stool Collection for 
(Biomarker) 
fPD 
Study Drug 
Adherence 
Dispense GS-9674 
and PTM GS-9674Y 
Concomitant 
X 
Medications 
Adverse Events 
X 
Take GS-9674/ PTM 
GS-9674 Tabletsz 
Baseline 
Weekl 
/Day 1 
± 3 days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment 
Week4 
WeekS Week12 Week16 
± 3 days 
± 3 days 
± 7 days 
± 3 days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X -Daily (Baseline/ Day 1 to Week 24) 
Week20 Week24/ET' 
± 3 days 
± 7 days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Follow-Up 
Follow-Upc 
± 5 days 
X 
X 
Final 
Amendment 2 
Unscheduled 
Visiea 
X 
X 
a. 
The screening visit window may be extended under special circumstances with explicit approval of the Medical Monitor. Subjects who fail to meet eligibility criteria due to 
an abnormal laboratory result may undergo re-testing of the abnormal analyte during the screening window. This will be done at the discretion of the investigator and with 
prior approval of the Medical Monitor. 
b. 
Subjects who failed screening may be re-screened under certain circumstances and at the discretion of the investigator. See Section 6.2 and the Study Reference Binder for 
re-screening guidelines. 
c. 
Subjects discontinuing the study at any time for any reason (Early Termination- ET) should complete the procedures listed for the Week 24/ET Visit AND the Follow-Up 
visit. 
d. 
Subjects must be in a fasted state for at least 8 hours prior to blood collection. 
e. 
Obtain written informed consent before initiation of any screening procedure. 
f. 
It is recommended that QoL assessments be completed prior to any study procedures being performed and prior to the subject seeing a health care provider. Refer to the Study 
Reference Binder for guidance on QoL assessment administration. 
g. 
The focus of a symptom driven physical examination will be determined by the investigator based on subject complaint. 
h. 
Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
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I 


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Gilead Sciences, Inc. 
1. 
Refer to the Study Reference Binder for specific instructions on how weight should be measured. 
Final 
Amendment 2 
J. 
During the Baseline/Day 1 and Week 24 visits, measurements of waist circumference should be performed. Refer to the Study Reference Binder for specific instructions on 
how these measurements are to be done. 
k. 
Blood chemistry will include: alanine aminotransferase (AL T), 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). Also includes C-Peptide and Insulin for the Baseline/Day 1, Week 4, 12, and 24 visits. 
1. 
Hematology will include: complete blood cell count with differential (red blood cells, white blood cells, platelets, and hematocrit). 
m. 
Coagulation Panel includes: PT, PTT, and INR. 
n. PPD 
o. 
OruyPD samphng at Baseiille?Day 1. 
p. 
Females of childbearing potential only (see Appendix 4). Serum pregnancy test at Screening and Urine pregnancy test at all other visits, except Week 1. 
q. 
Only required for some female subjects- see App;.;e..;.n..;.di.;.;.x..;.4..;..;.._ ______________________________ ___, 
r. 
PPD 
Ultrasound may be performed if necessary to confirm NAFLD. 
S. 
t. 
Subject should be in fasted state for Fibroscan collection. Refer to the Study Reference Binder for further details. If FibroScan®is not available at a site the test may be 
U. 
v. 
w. 
X. 
y. 
z. 
omitted. 
Subjects should be in fasted state for MRE/MRI-PDFF exams. Refer to the Study Reference Binder for further details. Subject must have confirmed NAFLD (from prior 
imaging) OR a historical biopsy consistent with NASH and non-cirrhotic fibrosis before MRE/MRI-PDFF exams are done. A historical MRE and MRI-PDFF performed 
using a Gilead qualified MR scanner within 6 months of screening may be used to determine eligibility for this study. 
For re-screen subjects: ifMRE/MRI-PDFF were performed on a Gilead qualified MR scanner within 6 months of re-screening, MRE and MRI-PDFF do not need to be 
repeated. If prior imaging was performed greater than 6 months prior to re-screening, MRE and MRI-PDFF must be repeated. 
Drug screen for am hetamines, cocaine, and opiates (ie, heroin, m.£..~ne). 
f.EP 
_J 
StudyclTug Wifl be ass1gneCivia1l'ie""IWRS system every 4 weekSfiom Baseline/Day 1 through Week 20. 
Subjects will self-administer the study drug at the investigative site at the conclusion of the Baseline/Day 1 and Week 24 visits. 
aa. If the Unscheduled visit is performed for the sole purpose of distribution of study drug, the assessments noted for this visit do not need to be performed. 
CONFIDENTIAL 
Page 86 
24 January 201 7 


GS-9674
Protocol GS-US-402-1852
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 87
24 January 2017
Appendix 3.
CTCAE Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf


GS-9674
Protocol GS-US-402-1852
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 88
24 January 2017
Appendix 4.
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-9674 has not yet been studied in pregnant women. In initial dose range-finding studies in 
pregnant mice and rabbits, there were no effects on embryofetal development other than a 
decrease in fetal body weights in the pregnant rabbits administered 1000 mg/kg/day. The 
decrease in fetal body weights are likely secondary to maternal toxicity rather than a direct effect 
of GS-9674. The NOEL for embryo/fetal development is 300 mg/kg/day in mice and 
200 mg/kg/day in rabbits. These doses were associated with exposures that are > 50-fold higher 
than the anticipated human exposure at the maximum proposed human dose of 100 mg once 
daily.
Drug-drug interaction (DDI) data do not suggest a potential for interaction with hormones used 
for contraception.
Please refer to the latest version of the Investigator’s Brochure for additional information. 


GS-9674
Protocol GS-US-402-1852
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 89
24 January 2017
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 30 days following the last dose of the study drug, GS-9674:

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)
Or 

Consistent and correct use of one hormonal method and one barrier method.
Barrier methods
■
Diaphragm with spermicide
■
Cervical cap with spermicide
■
Male condom (with or without spermicide)
Hormonal methods
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone
■
Implants of levonorgestrel
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring


GS-9674
Protocol GS-US-402-1852
Final
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 90
24 January 2017
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the last dose of the study drug, GS-9674.
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 (plus spermicide) during treatment and until 
90 days after the last dose of GS-9674. Additional contraception recommendations should also 
be considered if the female partner is not pregnant.
Male subjects must also refrain from sperm donation during treatment and until at least 90 days 
after the last dose of the study drug, GS-9674.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM). Female condom and male condom should not be used 
together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days (or 90 days for the partner of male subjects)
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.

SAP_003.pdf: 


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Prot_001.pdf: 
Study Title: 
Sponsor: 
INDNumber: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Medical 
Monitor: 
Protocol Version/Date: 
~ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Randomized, Double-Blind, Placebo-Contmlled Study 
Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in 
Subjects with Nonalcoholic Steatohepatitis (NASH) 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
U.S.A. 
127960 
20 16-0024 96-10 
NCT02854605 
Nonalcoholic steatohepatitis (NASH) 
GS-US-402-1852 
Name: 
Telephone: 
Fax: 
Email: 
Original: 
Amendment 1: 
C. ~hen Djedjos, M.D. 
PPD 
~PD 
I"'U 
28 Jtme 2016 
03-0ctober-2016 
CONFIDENTIALITY STATEMENT 
The infonnation contained in this document, particularly unpublished data, is the property or 
tmder control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The 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 infmmation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessaty to obtain infmmed consent from those 
persons to whom the dmg may be administered. 


GS-9674
Protocol GS-US-402-1852
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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03 October 2016
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....................................................................12
1.
INTRODUCTION ..............................................................................................................................................16
1.1.
Background ............................................................................................................................................16
1.1.1.
GS-9674 General Information..............................................................................................17
1.1.2.
Nonclinical Toxicology........................................................................................................17
1.1.3.
Nonclinical Pharmacology ...................................................................................................18
1.1.4.
Nonclinical Pharmacokinetics..............................................................................................19
1.1.5.
Clinical Trials of GS-9674 ...................................................................................................20
1.2.
Rationale for This Study ........................................................................................................................23
1.3.
Risk/Benefit Assessment for the Study..................................................................................................25
1.4.
Compliance ............................................................................................................................................26
2.
OBJECTIVES.....................................................................................................................................................27
3.
STUDY DESIGN................................................................................................................................................28
3.1.
Study Design..........................................................................................................................................28
3.2.
Treatment Plan and Regimen .................................................................................................................28
3.3.
Biomarker Testing..................................................................................................................................29
3.3.1.
Biomarker Samples to Address the Study Objectives ..........................................................29
3.3.2.
Biomarker Samples for Optional Future Research...............................................................29
3.3.3.
Biomarker Samples for Optional Genomic Research...........................................................29
4.
SUBJECT POPULATION..................................................................................................................................31
4.1.
Number of Subjects and Subject Selection ............................................................................................31
4.2.
Inclusion Criteria....................................................................................................................................31
4.3.
Exclusion Criteria...................................................................................................................................32
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................35
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................35
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................35
5.2.
Description and Handling of GS-9674 and PTM GS-9674....................................................................36
5.2.1.
Formulation..........................................................................................................................36
5.2.2.
Packaging and Labeling .......................................................................................................36
5.2.3.
Storage and Handling...........................................................................................................36
5.3.
Dosage and Administration of GS-9674/ PTM GS-9674.......................................................................37
5.4.
Prior and Concomitant Medications.......................................................................................................37
5.5.
Prohibited Medications ..........................................................................................................................37
5.6.
Accountability for GS-9674/ PTM GS-9674 .........................................................................................38
5.6.1.
Investigational Medicinal Product Return or Disposal.........................................................39
6.
STUDY PROCEDURES ....................................................................................................................................40
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................40
6.2.
Pretreatment Assessments – Screening Visit .........................................................................................40
6.3.
Baseline/Day 1 Randomization and Assessments..................................................................................42
6.4.
Treatment Assessments..........................................................................................................................43


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Protocol GS-US-402-1852
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Gilead Sciences, Inc. 
Amendment 1
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6.4.1.
Week 1 .................................................................................................................................43
6.4.2.
Week 4 Visit.........................................................................................................................44
6.4.3.
Week 8, 16, and 20 Visits.....................................................................................................45
6.4.4.
Week 12 Visit.......................................................................................................................46
6.4.5.
Week 24 Visit.......................................................................................................................47
6.4.6.
Unscheduled Visits...............................................................................................................48
6.5.
Follow-Up Visit .....................................................................................................................................49
6.6.
Assessments for Premature Discontinuation from Study.......................................................................49
6.7.
Criteria for Discontinuation of Study Treatment....................................................................................50
6.8.
PK and PD Substudy Visits....................................................................................................................50
6.9.
Description of Assessments ...................................................................................................................51
6.9.1.
Clinical Laboratory Analytes ...............................................................................................51
6.9.2.
Medical History....................................................................................................................52
6.9.3.
Physical Examination...........................................................................................................52
6.9.4.
Quality of Life (QoL) Assessments......................................................................................52
6.9.5.
Electrocardiogram................................................................................................................53
6.9.6.
FibroScan® ...........................................................................................................................53
6.9.7.
MRE and MRI-PDFF...........................................................................................................53
6.10.
End of Study Definition .........................................................................................................................54
6.11.
Post Study Care......................................................................................................................................54
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................55
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................55
7.1.1.
Adverse Events.....................................................................................................................55
7.1.2.
Serious Adverse Events........................................................................................................55
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................56
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................56
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................56
7.2.2.
Assessment of Severity ........................................................................................................57
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................57
7.4.
Gilead Reporting Requirements.............................................................................................................59
7.5.
Toxicity Management ............................................................................................................................59
7.6.
Special Situations Reports......................................................................................................................62
7.6.1.
Definitions of Special Situations..........................................................................................62
7.6.2.
Instructions for Reporting Special Situations.......................................................................63
8.
STATISTICAL CONSIDERATIONS................................................................................................................65
8.1.
Analysis Objectives and Endpoints........................................................................................................65
8.1.1.
Analysis Objectives..............................................................................................................65
8.1.2.
Primary Endpoint .................................................................................................................65
8.1.3.
Exploratory Efficacy Endpoints ...........................................................................................66
8.2.
Analysis Conventions.............................................................................................................................66
8.2.1.
Analysis Sets ........................................................................................................................66
8.2.2.
Interim Analysis ...................................................................................................................68
8.3.
Data Handling Conventions ...................................................................................................................68
8.4.
Demographic Data and Baseline Characteristics ...................................................................................68
8.5.
Efficacy Analysis ...................................................................................................................................68
8.6.
Safety Analysis.......................................................................................................................................69
8.6.1.
Extent of Exposure...............................................................................................................69
8.6.2.
Adverse Events.....................................................................................................................69
8.6.3.
Laboratory Evaluations ........................................................................................................69
8.6.4.
Other Safety Evaluations......................................................................................................70


GS-9674
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Final
Gilead Sciences, Inc. 
Amendment 1
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8.7.
Pharmacokinetic Analysis......................................................................................................................70
8.8.
Pharmacodynamic Analysis ...................................................................................................................70
8.9.
Biomarker Analysis................................................................................................................................70
8.10.
Sample Size............................................................................................................................................70
8.11.
Data Monitoring Committee ..................................................................................................................71
9.
RESPONSIBILITIES..........................................................................................................................................72
9.1.
Investigator Responsibilities ..................................................................................................................72
9.1.1.
Good Clinical Practice..........................................................................................................72
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)/ 
Ethics Committee (EC) Review and Approval ....................................................................72
9.1.3.
Informed Consent.................................................................................................................72
9.1.4.
Confidentiality......................................................................................................................73
9.1.5.
Study Files and Retention of Records ..................................................................................73
9.1.6.
Case Report Forms...............................................................................................................74
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................75
9.1.8.
Inspections............................................................................................................................75
9.1.9.
Protocol Compliance............................................................................................................76
9.2.
Sponsor Responsibilities ........................................................................................................................76
9.2.1.
Protocol Modifications.........................................................................................................76
9.2.2.
Study Report and Publications .............................................................................................76
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................76
9.3.1.
Payment Reporting...............................................................................................................76
9.3.2.
Access to Information for Monitoring..................................................................................77
9.3.3.
Monitoring and Oversight of Biomarker Specimens............................................................77
9.3.4.
Access to Information for Auditing or Inspections ..............................................................77
9.3.5.
Study Discontinuation..........................................................................................................77
10.
REFERENCES ...................................................................................................................................................78
11.
APPENDICES ....................................................................................................................................................81
Appendix 1.
Investigator Signature Page....................................................................................................82
Appendix 2.
Study Procedures Table for GS-US-402-1852 .......................................................................83
Appendix 3.
CTCAE Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities .........................................................................................................................87
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................88


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Protocol GS-US-402-1852
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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LIST OF IN-TEXT TABLES
Table 1-1.
Exposure Margins for GS-9674 Based on Observed GS-9674 Exposure After 
Administration of 100 mg GS-9674 Under Fed Conditions in Cohort 5 Compared to 
Exposures Observed at NOAEL Doses in Mouse and Cynomolgus Monkey........................18
Table 1-2.
Preliminary Pharmacokinetic Results from Study GS-US-402-2102 Evaluating the 
Effect of DDIs on Administration of 100 mg GS-9674 with Food (Cohorts 1-3)..................22
Table 1-3.
Preliminary Pharmacokinetic Results from Study GS-US-402-2102 Evaluating the 
Effect of GS-9674 100 mg with Food on CYP3A, OATP/CYP3A, P-gp, OATP, or 
OATP/BCRP (Cohorts 5-6)....................................................................................................23
Table 5-1.
List of Medications Prohibited and to be used with Caution..................................................38
LIST OF IN-TEXT FIGURES
Figure 3-1.
Overall Study Design .............................................................................................................28


GS-9674
Protocol GS-US-402-1852
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 6
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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Dr.
Foster City, CA 94404, U.S.A.
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Subjects 
with Nonalcoholic Steatohepatitis (NASH)
IND Number:
EudraCT Number: 
Clinical Trials.gov 
Identifier:
127960
2016-002496-10
NCT02854605
Study Centers 
Planned:
Approximately 50 centers in North America, Europe, and Asia Pacific
Objectives:
The primary objective of this study is to evaluate the safety and 
tolerability of GS-9674 in subjects with NASH as assessed by magnetic 
resonance imaging-proton density fat fraction (MRI-PDFF) and magnetic 
resonance elastography (MRE).
The exploratory objectives of this study are listed in Section 2.
Study Design:
This is a Phase 2, randomized, double-blind, placebo-controlled study 
evaluating the safety, tolerability, and efficacy of GS-9674 in subjects 
with NASH as assessed by MRI-PDFF and MRE.
Participation in the study can last up to 32 weeks, which includes a 
4-week screening period, a 24-week treatment period during which study 
drug will be administered, and a 4-week follow-up period. The screening 
period may be extended under special circumstances with the explicit 
approval of the Medical Monitor.
Subjects meeting the study’s entry criteria will be randomly assigned in a 
2:2:1 ratio to 1 of 3 treatment groups as shown in the figure below:


GS-9674
Protocol GS-US-402-1852
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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03 October 2016
Randomization will be stratified by the presence or absence of diabetes 
mellitus as determined by medical history, use of medication for 
indication of diabetes mellitus, or based on screening lab values if 
previously undiagnosed (ie, hemoglobin A1c ≥ 6.5% OR fasting plasma 
glucose ≥126 mg/dL).
Number of Subjects 
Planned:
Approximately 125 Subjects
Target Population:
Males and non-pregnant females between 18-75 years of age without 
cirrhosis and with NASH as assessed by magnetic resonance imaging 
(MRI) and magnetic resonance elastography (MRE).
Duration of 
Treatment:
24 Weeks
Diagnosis and Main 
Eligibility Criteria:
Key inclusion and exclusion criteria are as follows:
Inclusion Criteria:

Meets all of the following conditions:
a.
A clinical diagnosis of nonalcoholic fatty liver disease (NAFLD) 
with histological or imaging evidence of fatty liver within the 
past two years. If necessary an ultrasound may be performed 
during screening to confirm NAFLD. Note: criterion a. must be 
met before evaluating criteria b. and c.
b. Screening MRI-PDFF with ≥10% steatosis
c.
Screening MRE with liver stiffness ≥ 2.90 kPa

Platelet count ≥ 150,000/mm3;

Albumin ≥ 3.3 g/dL;

Creatinine Clearance (CLcr) as calculated by the Cockcroft-Gault 
equation ≥90 ml/min;


GS-9674
Protocol GS-US-402-1852
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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Exclusion Criteria:

Pregnant or lactating females;

ALT > 5X ULN;

Other causes of liver disease including autoimmune, viral, and 
alcoholic liver disease;

Cirrhosis of the liver as defined by any of the following:
a.
Cirrhosis on historical liver biopsy (eg, Brunt/Kleiner stage 4 or 
equivalent)
b. Evidence of cirrhosis on liver imaging (eg, ultrasound, CT, or 
MRI) including a nodular liver surface, splenomegaly, or portal 
venous collaterals
c.
Screening FibroSURE/FibroTest® ≥ 0.75, as determined by the 
central laboratory
d. Prior history of decompensated liver disease, including ascites, 
hepatic encephalopathy, or variceal bleeding;

BMI < 18 kg/m2;

Uncontrolled diabetes mellitus (hemoglobin A1c > 9% at screening);

INR > 1.2 unless on anticoagulant therapy;

Total bilirubin > 1x ULN, except with diagnosis of Gilbert’s 
syndrome.
Refer to Sections 4.2 and 4.3 for complete listing of inclusion and 
exclusion criteria.
Study 
Procedures/
Frequency:
After signing the informed consent form, subjects will complete a 
screening visit which will include the following assessments: complete 
medical history, physical examination (PE), vital signs, laboratory 
assessments (blood chemistry, hematology, coagulation panel, 
hemoglobin A1c, biomarkers), viral serology, pregnancy test (for females 
of child-bearing potential), standard 12-lead ECG, MRI-PDFF and MRE 
examinations, urine drug test, review of concomitant medications and 
adverse events.
After the screening period and a randomization visit at Baseline/Day 1, 
study visits will occur on Weeks 1, 4, 8, 12, 16, 20 and 24 with a 
Follow-Up visit 4 weeks after the last dose of study drug. At minimum, 
vital signs, symptom driven PE, safety laboratory tests (blood chemistry, 
hematology, and coagulation panel), review of concomitant medications 
and adverse events will be done at every visit.
Eligible subjects will be randomized to one of 3 treatment groups. Prior 
to initial dosing, required Baseline/Day 1 assessments will be performed 


GS-9674 
Protocol GS-US-402-1852 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Final 
Amendment 1 
and will include Quality of Life (QoL) assessments (general and 
pruritus), symptom driven PE, vital signs, laborat01y assessments, 
pregnancy tests (for females of child-bearing potential), urine, blood, and 
stool collection for biomarker assessment, single PD sampling, standru·d 
12-lead ECG, FibroScan®, review of concomitant medications and 
adverse events. 
PPD 
Subjects will rehm1 to clinic for a safety visit at Week 1. Week 1 
assessments include QoL: pruritus assessments, symptom driven PE, 
vital signs, ru1d laborat01y tests (blood chemis1ly, hematology, 
coagulation panel, lipid profile, biomarkers, PK and PD srunpling). 
While on study, subjects will undergo the following procedures and 
laboratory assessments: 
• 
MRE and MRI-PDFF at Weeks 12 and 24 
• 
FibroScan® at Baseline/Day 1 and Weeks 12 and 24 
• 
Single PK and PD sampling at Baseline/Day 1 (PD only) and at 
Weeks 1, 4, 8, 12, 16, 20, and 24 
• 
Blood for Biomarkers at Baseline/Day 1, and Weeks 1, 4, 12, and 24 
• 
12-lead ECGs at Baseline/Day 1, and Weeks 12 and 24 
• 
Blood chemis1ly, hematology, coagulation panel, and fasting lipid 
profile at Baseline/Day 1 and at Weeks 1, 4, 8, 12, 16, 20, and 24 
• 
Hemoglobin Ale (HbAl c) at Baseline/Day 1, Weeks 12 and 24 
• 
Stool collection at Baseline/Day 1 and Week 24 
• 
Urine collection at Baseline/Day I and Weeks I, 4, I2, and 24 
• 
Urine pregnancy test (females of childbearing potential only) at 
Baseline/Day 1 and Weeks 4, 8, 12, 16, 20, and 24 
• 
QoL: general assessments [SF-36 health survey, Chronic Liver 
Disease Questionnaire (CLDQ), and Work Productivity and Activity 
Impai1ment (WP AI)] at Baseline/Day I and Weeks I2 ru1d 24 
• 
QoL: pruritus assessments (VAS-itch and 5D-itch) at Baseline/Day 1 
and Weeks 1, 4, 8, 12, 16, 20, and 24 
Subjects will retum for their final visit, the Follow-Up visit, 4 Weeks 
after the last dose of study drug. At this visit assessments include a 
symptom driven PE, vital signs, safety laboratory tests, and review of 
concomitant medications and adverse events. A urine pregnancy test will 
be perfonned for females of child beru·ing potential only. 
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Test Product: 
PPD 
Final 
Amendment 1 
GS-9674 30 mg tablet administered orally once daily with food. 
GS-967 4 100 mg tablet administered orally once daily with food. 
Reference Product: 
Placebo-to-match (PTM) GS-9674 30 mg tablet administered orally once 
daily with food. 
Dose and Mode of 
Administration: 
Criteria for 
Evaluation: 
Safety: 
CONFIDENTIAL 
Placebo-to-match (PTM) GS-9674 100 mg tablet administered orally 
once daily with food. 
• 
Treatment Group A: GS-9674 30 mg (1 x 30 mg tablet)+ PTM 
GS-9674 100 mg (1 x PTM 100 mg tablet) administered orally once 
daily with food 
• 
Treatment Group B: GS-9674 100 mg (1 x 100 mg tablet) + PTM 
GS-9674 30 mg (1 x PTM 30 mg tablet) administered orally once 
daily with food 
• 
Treatment Group C: PTM GS-9674 30 mg (1 x PTM 30 mg tablet) 
+ PTM GS-9674 100 mg (1 x PTM 100 mg tablet) administered 
orally once daily with food 
The prima1y endpoint is the safety ofGS-9674 in subjects with NASH. 
Safety will be assessed during the study through the reporting of AEs, 
and by clinical laboratory tests and vital sign assessments at vm·ious time 
points during the study. Concomitant medication usage will also be 
assessed throughout the study. 
An independent, extemal Data Monitoring Committee (DMC) that 
consists of two hepatologists and a PhD statistician will convene once 
20 subjects have been enrolled and every 3 to 4 months thereafter to 
monitor the study for safety events. The DMC will meet on an ad hoc 
basis if there m·e at least 3 Grade~ 3 serious, treatment-related 
Common Terminology Criteria for Adverse Events (CTCAE) obsetved in 
the study. In the event of two similar Grade 4-CTCAE treatment-related 
adverse events or one Grade 5-CTCAE treatment-related adverse event, 
the DMC will review the data and advise the sponsor regm·ding stopping 
or continuing the study. 
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Gilead Sciences, Inc. 
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Efficacy: 
Efficacy will be assessed through a number of explorat01y endpoints. 
These explorat01y endpoints are described in Section 8.1.3. 
Pha1macokinetic and Plasma concentrations ofGS-9674, GS-716070 (metabolite ofGS-9674), 
Phmmacodynamic: 
and other metabolites as appropriate, will be dete1mined for PK analyses 
as applicable. Plasma or serum concentrations ofFGF19, Cl4, and bile 
acids will be dete1mined as applicable for PD analyses. 
Statistical Methods: 
Safety Analysis: 
Efficacy 
Analysis: 
Explorat01y 
Analysis: 
Sample Size: 
All safety data collected will be listed and summarized, as appropriate, 
by treatment group. 
The biological activi!Y of GS-9674 will be evaluated usina biomarker 
variables. PO 
PPD 
I 
I 
Due to the explorat01y nature of this study, no f01mal power calculations 
were used to detennine sample size. The number of subjects was chosen 
based on clinical experience with other similar proof of concept 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
Ab
antibody
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
Apo B
apolipoprotein B
aPTT
activated partial thromboplastine time
AST
aspartate aminotransferase
ATP
adenosine triphosphate
ATV
atorvastatin
AUC
area under the plasma/serum concentration versus time curve
AUCtau
area under the plasma/serum concentration versus time curve over the dosing 
interval
AUCinf
area under the plasma/serum concentration versus time curve extrapolated to 
infinite time, calculated as AUC0-last + (Clast/z)
AUCpartial
partial area under the plasma/serum concentration versus time curve
BAP
Biomarker Analysis Plan
BCRP
breast cancer resistance protein
BMI
body mass index
BUN
blood urea nitrogen
BW
body weight
C4
7-alpha-hydroxy-4-cholesten-3-one
CBC
complete blood count
cc
cubic centimeter
CFR
code of federal regulations
CI
confidence interval
CK-18
cytokeratin 18
CL
systemic clearance
CLcr
creatinine clearance
CLDQ
Chronic Liver Disease Questionnaire
Clast
last observed quantifiable plasma/serum concentration of the drug
Cmax
maximum observed plasma/serum concentration of drug
Cmin
minimum observed plasma/serum concentration of drug
Ctau
observed drug concentration at the end of the dosing interval
CRO
contract (or clinical) research organization 
CsA
cyclosporine
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CV
cardiovascular
CYP
cytochrome P450


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CYP2C8
cytochrome P4502C8
CYP3A
cytochrome P4503A
DAB
metabolite of dabigatran etexilate
DDI
drug-drug interaction
DE
dabigatran etexilate
DILI
drug induced liver injury
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health
EC
ethics committee
EC50
concentration of drug that gives half-maximal response
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
ELF™Test
enhanced liver fibrosis test
ET
early termination
EU
European Union
ESA
erythropoiesis-stimulating agent
FAS
Full Analysis Set
FDA
(United States) Food and Drug Administration
FGF19
fibroblast growth factor 19
FSH
follicle-stimulating hormone
FXR
farnesoid X receptor
GCP
good clinical practice
GCSF
granulocyte colony stimulating factor
GFZ
gemfibrozil
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
Hb
hemoglobin
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
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HIV-1
human immunodeficiency virus type 1
HLT
high-level term


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HLGT
high-level group term
HMG-CoA
3-hydroxy-3-methylglutaryl-coenzyme A
HOMA-IR
homeostatic assessment of insulin resistance
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ID
identification
IEC
independent ethics committee/ institutional ethics committee
IND
Investigational New Drug (Application)
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
LDH
lactate dehydrogenase
LLT
lower-level term
MedDRA
Medical Dictionary for Regulatory Activities
MCV
mean corpuscular volume
MDZ
midazolam
miRNA
micro ribonucleic acid
mm Hg
millimeters of mercury
MRE
magnetic resonance elastography
MRI
magnetic resonance imaging
MRI-PDFF
magnetic resonance imaging – proton density fat fraction
NAFLD
nonalcoholic fatty liver disease
NAS
NAFLD Activity Score
NASH
nonalcoholic steatohepatitis
NMR
nuclear magnetic resonance spectroscopy
NOAEL
no observed adverse event level
OATP
organic anion-transporting polypeptide
oz
ounce 
PBC
primary biliary cholangitis
PD
pharmacodynamic
PE
physical exam
PK
pharmacokinetic
P-gp
P-glycoprotein
pH
measure of acidity 
PRA
pravastatin
PSC
primary sclerosing cholangitis
PT
preferred term


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PT
prothrombin time
PTM
placebo-to-match
PTT
partial prothrombin time
QA
quality assurance
QD
once a day
QoL
quality of life
RBC
red blood cell count
RIF
rifampin
RNA
ribonucleic acid
ROS
reactive oxygen species, or
rosuvastatin
SADR
serious adverse drug reaction
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SF-36
Short Form (36) Health Survey
SOC
system organ class
SOP
standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
t1/2
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)
TEAE
treatment-emergent adverse event
Tlast
last measured concentration
Tmax
time (observed time point) of Cmax
TGR5
bile acid receptor
TPO
thrombopoietin
TR-FRET
time-resolved fluorescence resonance energy transfer
UGT1A1
uridine diphosphate glucuronosyltransferase 1A1
ULN
upper limit of the normal range
US
United States
USPI
United States product insert
Vss
volume of distribution
VAS
visual analog scale
VORI
voriconazole
WBC
white blood cell count
WPAI
work productivity and activity impairment questionnaire


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1.
INTRODUCTION
1.1.
Background
Chronic liver disease and the consequences of end-stage liver disease are increasing globally 
despite improved prevention and treatment of viral hepatitis. This is due to the emerging 
epidemics of obesity, metabolic syndrome, and diabetes mellitus that are leading to an increased 
incidence of nonalcoholic fatty liver disease (NAFLD). Nonalcoholic fatty liver disease is 
characterized by the excess accumulation of lipid droplets within the liver, also known as hepatic 
steatosis. Prevalence rates of NAFLD range from 6% to 37% worldwide {Vernon et al 2011}, 
{Ong et al 2007}. Nonalcoholic steatohepatitis (NASH), an aggressive form of NAFLD 
characterized by the presence of inflammation and hepatocellular ballooning, with or without 
fibrosis, is present in approximately 25% of patients with NAFLD. Nonalcoholic steatohepatitis 
is associated with increased liver-related mortality {Williams et al 2011}, {Ong et al 2007}. In the 
United States (US), it has been estimated that 3% to 6% of the population {Vernon et al 2011}, 
{Wanless et al 1990}, or the equivalent of up to 15 million adults, have NASH. NASH represents 
a significant and growing unmet medical need for which there are no currently approved 
therapies. Furthermore, as NASH is a manifestation of the metabolic syndrome, risk factors for 
cardiovascular disease (eg, atherosclerotic disease, cardiac arrhythmogenicity) frequently coexist 
in these patients {Faramawi et al 2008}, {Voulgari et al 2010}, {Dietrich et al 2014}. A treatment that 
targets the underlying metabolic disorder could potentially ameliorate these cardiovascular risks 
and associated morbidity and mortality.
Nonalcoholic steatohepatitis is primarily thought to occur as the result of the metabolic 
syndrome, the impact of obesity, insulin resistance, and dyslipidemia in the liver. Simple 
steatosis is not sufficient to cause liver injury; it is the presence of inflammation and 
hepatocellular injury on the background of steatosis that defines NASH and results in the 
progression to end-stage liver disease and its complications. The “2-hit” hypothesis of NASH 
suggests that in the setting of steatosis and metabolic dysfunction, increased oxidative stress and 
the generation of reactive oxygen species (ROS) likely mediate the inflammatory changes in the 
liver (steatohepatitis) that may lead to progressive fibrosis {Dowman et al 2010}, {Kannel et al 
1982}, {Koek et al 2011}, {Sumida et al 2013}. The major pathways in NASH disease progression 
include those involved in metabolic dysfunction in the hepatocyte, and activation of hepatic 
stellate cells and macrophages leading to progressive inflammation and liver fibrosis. Advanced 
fibrosis and cirrhosis are characterized by extensive collagen deposition and remodeling of the 
extracellular matrix. In addition, evidence suggests that lipotoxic intermediates of fatty acids 
likely contribute to the etiology of NASH {Neuschwander-Tetri 2010}.
Over time, NASH may result in progressive liver fibrosis, ultimately leading to cirrhosis in 
10-20% of affected patients. Advanced fibrosis (bridging fibrosis or cirrhosis) is associated with 
increased morbidity and mortality {Ekstedt et al 2014}, {Yeh et al 2014}. Patients with cirrhosis 
may develop hepatocellular carcinoma (HCC) and other complications of end-stage liver disease, 
including jaundice, fluid retention (edema and ascites), portal hypertension and variceal 
bleeding, impaired coagulation and hepatic encephalopathy. Decompensated liver disease, as 


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defined by the development of one of the above complications, has a high mortality and the only 
known effective treatment is liver transplantation. With the increasing prevalence of obesity and 
obesity-related diseases, NASH is expected to become the leading indication for liver
transplantation, and the leading etiology of HCC among liver transplant recipients in the US 
{Wong et al 2014}, {Afzali et al 2012}.
1.1.1.
GS-9674 General Information
GS-9674 is a potent agonist of Farnesoid X Receptor (FXR) whose activity in intestinal 
epithelial cells results in the release of fibroblast growth factor 19 (FGF19). FGF19 is an 
endocrine peptide which drives a signaling cascade to decrease lipogenesis, gluconeogenesis, 
hepatic triglyceride accumulation, and bile acid synthesis. Please refer to the Investigator’s 
Brochure (IB) for additional information on GS-9674, including:

In vitro FXR agonism

Nonclinical pharmacokinetics and in vitro metabolism

Nonclinical pharmacology and toxicology
1.1.2.
Nonclinical Toxicology
The nonclinical toxicity profile of GS-9674 has been assessed in mice and cynomolgus monkeys 
administered GS-9674 orally for up to 26 and 13 weeks, respectively. GS-9674-related effects 
were primarily limited to non-adverse findings in the liver for both species that are likely related 
to the pharmacology of the compound. Mild increases in alkaline phosphatase (ALP) activity and 
liver weights were observed in the 4 week and chronic (26 or 13 weeks) studies.  In the 4-week 
studies and 26-week mouse study, these findings were associated with hepatocellular 
hypertrophy (both species) and minimal oval cell hyperplasia (monkeys). In the chronic monkey 
study, there were no correlating histological changes in the liver after 13 weeks of dosing. The 
above findings were observed at ≥100 mg/kg/day after 4 weeks of dosing and at all doses 
(≥20 mg/kg/day) after 26 weeks of dosing in mice. In monkeys, the above findings were 
observed at doses of 300 mg/kg/day after both 4 and 13 weeks of dosing. The decreases in 
cholesterol (≥60 mg/kg/day) and triglycerides (≥100 mg/kg/day) as well as increased albumin 
(≥60 mg/kg/day) observed in mice after 4 and/or 26 weeks of dosing as well as the decrease in 
serum bile acids (300 mg/kg/day) in monkeys after 13 weeks of dosing are also likely to be 
related to the pharmacology of GS-9674. Other minimal to mild, non-adverse findings observed 
after 13 or 26 weeks of dosing in monkeys or mice, respectively, that were considered GS-9674-
related included decreased red blood cell parameters (mouse; ≥20 mg/kg/day), increased 
platelets (mouse; 600/300 mg/kg/day), shortened activated partial thromboplastin time (monkey; 
300 mg/kg/day), and increased phosphorus (mouse; 600/300 mg/kg/day). All findings observed 
in monkeys after 13 weeks of dosing had resolved at the end of the 4-week recovery period. The 
no-observed-adverse effect levels (NOAEL) in mice after 26 weeks of dosing and in monkeys 
after 13 weeks of dosing were 60 and 300 mg/kg/day, respectively. 


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Preliminary PK data from Cohort 5 (administration of GS-9674 100 mg with food) in the 
ongoing Phase 1 study of GS-9674 (GS-US-402-1851, included in IB, Ed 02) indicate adequate 
safety margins based on GS-9674 exposures at the nonclinical NOAEL doses in mouse and 
cynomolgus monkey (Table 1-1).
Table 1-1.
Exposure Margins for GS-9674 Based on Observed GS-9674 
Exposure After Administration of 100 mg GS-9674 Under Fed 
Conditions in Cohort 5 Compared to Exposures Observed at NOAEL 
Doses in Mouse and Cynomolgus Monkey 
Species
NOAEL
Exposure Margina
Dose 
mg/kg/day
AUCtau
µg*hr/mL
Mouse
60
Male: 66
Female: 110
   Male: 13
Female: 22
Cynomolgus Monkey
300
110
22
a
Calculated using observed human AUCinf of 5.02 µg*hr/mL at 100 mg QD dose administered fed from Cohort 5 in 
Study GS-US-402-1851.
1.1.3.
Nonclinical Pharmacology
GS-9674 is a potent and selective agonist of FXR. This conclusion is supported by the following 
data: 1) modeling demonstrated an interaction of GS-9674 with the binding domain of FXR 
consistent with agonist activity, 2) GS-9674 induced an agonist response in a time-resolved 
fluorescence resonance energy transfer (TR-FRET) biochemical assay with an EC50 of 16 nM, 
which was comparable to that of other known FXR agonists, and 3) GS-9674 did not activate the 
structurally similar bile acid receptor TGR5, did not activate other nuclear hormone receptors, 
and did not bind to a panel of other off-target receptors and enzymes.
The cellular potency of GS-9674 to activate FXR-mediated transcription was characterized using 
a firefly luciferase reporter gene engineered under the control of a FXR/RXR response element 
(PC-402-2012). GS-9674 caused complete FXR activation with an EC50 value of 43 nM, which 
was more potent than chenodeoxycholic acid (EC50 of 1770 nM).
Oral dose-ranging experiments in male cynomolgus monkeys demonstrated maximal increases in 
plasma FGF19 at a dose of 5 mg/kg (PC-402-2016). In addition, the oral administration of 
GS-9674 (30 mg/kg) to cynomolgus monkeys directly activated intestinal FXR, as measured by 
the expression of FXR-target genes in the ileum (15-fold increase in FGF19 mRNA, and a 2-fold 
increase in organic solute transporter (OST)α and (OST)β mRNA) (PC-402-2005).
The effects of GS-9674 on FGF19 levels were compared in cynomolgus monkeys following both 
oral and intravenous (IV) administration (PC-402-2016). Despite greater exposures following IV 
administration, only the oral administration of GS-9674 increased circulating FGF19 levels. 
These data suggest that intestinal FXR agonism by GS-9674 causes FGF19 production, whereas 
low systemic free drug concentrations limit effects following IV administration of GS-9674.


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GS-9674 was evaluated in a choline-deficient high fat diet /NaN02 rat model of liver fibrosis 
(PC-402-2015). This in vivo model utilized "2 hits" to mimic the metabolic and oxidative stress 
components ofNASH disease in humans {Nakamoto et al2009}, {Murakami et al2013}. Treatment 
with GS-9674 dose-dependently reduced both biochemical and histological measures of liver 
fibrosis in this model. 
Safety pharmacology studies have been conducted to examine the potential effects ofGS-9674 
on the cardiovascular (CV), respiratory, and central nervous system (CNS) systems. There were 
no GS-9674-related effects on the CNS or respiratory system in mice administered up to 
600 mg/kg. In addition, there was no significant human ether-a-go-go-related gene inhibition at 
concentrations up to 100 J.lM or GS-9674-related effects on the CV system in monkeys 
administered up to 300 mg/kg. 
Overall, the results from these pharmacology studies demonstrate that GS-9674 is a potent and 
selective agonist of intestinal FXR with the potential to benefit NASH patients by inducing 
FGF19 production. 
1.1.4. 
Non clinical Phannacokinetics 
GS-9674 has shown low oral bioavailability in nonclinical species (am~roximately 10% and 20% 
when dosed as PPD 
). Low, 
pH-dependent solubility and efflux transport have been identified as factors likely limiting 
GS-9674 absorption. 
The low systemic clearance (CL) of GS-9674 in rats, dogs and monkeys was considerably lower 
than the predicted hepatic clearance based on in vitro studies with hepatocytes. This discrepancy 
is most likely a result of protein-restricted clearance in vivo due to the very high plasma protein 
binding(> 99.6%) across species. The volume of distribution (V ss) ofGS-9674 was consistent 
with extracellular fluid (ranging from 0.16-0.21 Llkg) in rats, dogs, and monkeys. 
After oral dosing to albino and pigmented mice, C4C]GS-9674-derived radioactivity was 
distributed to most of the tissues, with the highest maximum concentrations of radioactivity 
determined in organs of absorption and excretion. Generally similar distribution patterns and 
tissue concentrations of C4C]GS-9674-derived radioactivity were observed in albino and 
pigmented mice with no observed binding to melanin. In both strains, no quantifiable 
radioactivity was detected in brain, suggesting C4C]GS-9674-derived radioactivity did not cross 
the blood: brain barrier. Fecal elimination was a predominant route of elimination of 
C4C]GS-9674-derived radioactivity in both mice (85. 7% and 5.45% recovered in feces and urine, 
respectively) and monkeys (78.2% and 69.7% recovered in feces in intact and bile duct 
cannulated animals) likely representing drug not absorbed from the gastrointestinal tract. 
Approximately 6% of the administered radioactivity was excreted in bile and urine in monkeys. 
Radiolabeled material was primarily excreted within the first 48 hours. 
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GS-9674 undergoes oxidative metabolism in human hepatocytes. Comparison of metabolism in 
hepatocytes from mice, rats, dogs, monkeys, and humans did not identify any metabolites unique 
to humans, supporting the selection of mice and monkeys for the assessment of the toxicology of 
GS-9674. Of the recombinant human CYP isozymes tested, CYP2C8, CYP3A4, and CYP2C19 
were shown to metabolize GS-9674. Potent inhibitors of these CYPs therefore may affect 
metabolism of GS-9674. GS-9674 had little inhibitory effect on the activities of CYP1A2, 
CYP2B6, CYP2C19 or CYP2D6 (IC50 > 25 μM). For CYP2C8, CYP2C9, and CYP3A, IC50
values of 2.4 to 13.6 μM were obtained but GS-9674 was not a mechanism-based inhibitor of 
these enzymes. GS-9674 showed moderate inhibition of human UGT1A1, sodium-taurocholate 
cotransporting polypeptide (NTCP), and bile salt export pump (IC50 2.8-7.7 μM). GS-9674 
inhibited human OATP1B1, OATP1B3, and OATP2B1 with IC50 values of 0.68, 0.41, and 
0.21 μM, respectively. GS-9674 therefore has the potential to affect hepatic/intestinal uptake of 
OATP substrates or metabolism of CYP2C8, CYP2C9, or CYP3A4 substrates when its 
concentrations are sufficiently high. However, low solubility, high protein binding (> 99.98%) 
and low systemic levels reduce the potential for GS-9674 to cause drug-drug interactions via 
inhibition of metabolic enzymes and transporters.
GS-9674 is a substrate for efflux transporters P-glycoprotein and breast cancer resistance protein, 
as well as the uptake transporters OATP1B1, 1B3, and 2B1, and NTCP. Inhibitors or genetic 
polymorphisms affecting the activity of these transporters may affect GS-9674 intestinal 
absorption and hepatic uptake. This was illustrated in an in vivo study in monkeys where 
pretreatment with cyclosporin A, a known inhibitor of efflux transporters, increased the 
bioavailability of GS-9674 approximately 5-fold.
GS-9674 is highly selective for FXR over other nuclear hormone receptors in cell-based reporter 
assays, including those associated with potential for induction of human drug metabolizing 
enzymes and transporters (eg, pregnane X receptor, constitutive androstane receptor). Thus the 
liability of GS-9674 to cause drug-drug interactions through proteins regulated by these nuclear 
receptors is low.
1.1.5.
Clinical Trials of GS-9674
As of 23 September 2016, 4 Phase 1 clinical studies are ongoing (GS-US-402-1851, 
GS-US-402-3885, GS-US-402-2102, and GS-US-402-2101), and 4 Phase 2 studies in subjects 
with NAFLD, NASH, PBC, and PSC are ongoing or planned (GS-US-384-3914, 
GS-US-402-1852, GS-US-427-4024, and GS-US-428-4025, respectively). These Phase 1 and 2 
studies are described in the IB.
A brief summary of preliminary results not included in the IB from ongoing study 
GS-US-402-2102 is presented below.


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1.1.5.1.
GS-US-402-2102
Study GS-US-402-2102 is an ongoing Phase 1, open-label, multicenter, multiple-cohort study 
designed to evaluate transporter and CYP-mediated drug-drug interactions (DDIs) between 
GS-9674 100 mg and various probe drugs in healthy subjects. A total of approximately 
180 subjects are planned to be enrolled.
Preliminary PK results from the following cohorts are presented below and in Table 1-2 and 
Table 1-3:

Cohort 1: Impact of OATP/MRP2/P-gp inhibition (single dose cyclosporine 600 mg: CsA) or 
OATP1B1/1B3 inhibition (single dose rifampin 600 mg: RIF) on single dose administration 
of GS-9674 100 mg with food (N=24).  Single doses of CsA or RIF significantly increased 
GS-9674 exposure (6.5- and 8.0-fold respectively), with more modest increases in 
GS-716070 exposure (3.3- and 4.9-fold respectively). These data indicate the GS-9674 is a 
sensitive substrate of hepatic OATP with intestinal P-gp playing a minimal to no role in 
GS-9674 absorption as seen by a smaller increase in GS-9674 by CsA compared to single 
dose RIF.  Based on these data, coadministration of GS-9674 with potent inhibitors of OATP 
is not recommended and moderate inhibitors of OATP should be used with caution, whereas 
GS-9674 may be coadministered with P-gp inhibitors.

Cohort 2: Impact of CYP3A inhibition (multiple dose voriconazole 200 mg BID 4 days: 
VORI) and CYP2C8 inhibition (multiple dose gemfibrozil 600 mg BID 4 days: GFZ) on 
single dose administration of GS-9674 100 mg with food (N=18). Coadministration of 
GS-9674 with VORI did not result in clinically meaningful changes in GS-9674 or 
GS-716070 exposures indicating that CYP3A plays a minimal role in the disposition of 
GS-9674 and GS-716070.  As such, GS-9674 may be coadministered with CYP3A 
inhibitors.  Coadministration of GS-9674 with GFZ increased GS-9674 exposure 75% with 
reduction of GS-716070 exposure by 55% indicating that biotransformation of GS-9674 to 
GS-716070 is predominantly mediated by CYP2C8.  Based on the less than 2-fold increase 
in GS-9674 exposure, GS-9674 may be coadministered with inhibitors of CYP2C8.

Cohort 3: Impact of CYP3A/2C8/OATP/P-gp induction (multiple dose rifampin 600 mg QD 
7 days in the evening: RIF) on single dose AM administration of GS-9674 100 mg with food
(N=18).  Plasma exposure of GS-9674 and GS-716070 were substantially reduced after 
multiple dose administration of RIF indicating that GS-9674 and GS-716070 are sensitive to 
induction of OATP and CYP2C8.  As such, coadministration of GS-9674 with potent or 
moderate inducers of OATP or CYP2C8 is not recommended.

Cohort 5: Impact of single dose administration of GS-9674 100 mg with food on CYP3A 
activity (single dose midazolam: MDZ) or OATP/CYP3A activity (single dose atorvastatin: 
ATV) (N=24).  GS-9674 did not alter MDZ exposure (90%CIs of the %GMR for AUC and 
Cmax were contained within the predetermined lack of effect bounds of 70-143%) indicating 
the GS-9674 is not an inhibitor of CYP3A. As such, GS-9674 may be coadministered with 
CYP3A substrates.  GS-9674 modestly increased ATV exposure (39%).  Similar increases in 


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ATV exposure do not necessitate a priori dose modification as per the LIPITOR® United 
States product insert (USPI).  As such, ATV may be coadministered with GS-9674 

Cohort 6: Impact of single dose administration of GS-9674 100 mg with food on P-gp (single 
dose dabigatran etexilate 75 mg: DE), OATP (single dose pravastatin 40 mg: PRA) or 
OATP/BCRP (single dose rosuvastatin 10 mg: ROS) (N=24). GS-9674 did not alter DE (free 
or total dabigatran: DAB metabolite of DE), PRA, or ROS exposures (90%CIs of the %GMR 
for AUC and Cmax were contained within the predetermined lack of effect bounds of 
70-143%) indicating the GS-9674 is not an inhibitor of P-gp, OATP, or BCRP.  As such,
GS-9674 may be coadministered with P-gp, OATP, or BCRP substrates.
Table 1-2.
Preliminary Pharmacokinetic Results from Study GS-US-402-2102 
Evaluating the Effect of DDIs on Administration of 100 mg GS-9674 
with Food (Cohorts 1-3)
%GMR (90%CI) Test/Reference
Cohort 1 (N=24)
Cohort 2 (N=18)
Cohort 3 (N=18)
Analyte
PK 
Parameter
CsA
RIFa
VORI
GFZ
RIFb
GS-9674
AUCinf
655 
(577, 743)
796
(719, 880)
95.9
(81.0, 114)
175
(149, 206)
32.8
(27.9, 38.4)
Cmax
512
(448, 584)
547
(497, 603)
76.8
(60.2, 97.9)
139
(115, 168)
35.5
(29.1, 43.3)
GS-716070
AUCinf
331
(297, 369)
493
(442, 551)
129
(109, 154)
44.5
(38.7, 51.1)
12.6
(10.5, 15.0)
Cmax
211
(191, 232)
301
(274, 331)
99.2
(81.1, 121)
31.2
(26.1, 37.4)
17.0
(13.7, 21.2)
Data are presented to 3 significant digits
a
Single Dose
b
Multiple Dose


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Table 1-3.
Preliminary Pharmacokinetic Results from Study GS-US-402-2102 
Evaluating the Effect of GS-9674 100 mg with Food on CYP3A, 
OATP/CYP3A, P-gp, OATP, or OATP/BCRP (Cohorts 5-6)
Cohort
Enzyme/ 
Transporter
Analyte
PK Parameter
Test
Reference
% GMR 
(90%CI) 
Test/Reference
5 
(N=24)
CYP3A
MDZ
AUCinf 
37.3 (27.5)
63.9 (29.1)
102 (95.8, 108)
Cmax 
7.79 (27.6)
7.92 (35.6)
100 (94.8, 106)
OATP/
CYP3A
ATV
AUCinf 
15.5 (33.5)
10.8 (39.0)
139 (124, 156)
Cmax 
1.06 (35.6)
0.98 (35.9)
107 (94.6, 120)
6
(N=24)
P-gp
Total 
DAB
AUCinf 
624 (32.0)
535 (34.3)
118 (109, 128)
Cmax 
84.4 (40.0)
68.0 (37.8)
125 (112, 139)
Free 
DAB
AUCinf 
543 (32.0)
477 (37.3)
116 (108, 124)
Cmax 
75.0 (39.6)
60.8 (42.5)
125 (114, 138)
OATP
PRA
AUCinf 
109 (55.6)
99.6 (66.7)
115 (104, 126)
Cmax 
41.7 (58.8)
42.4 (66.5)
104 (91.5, 117)
OATP/ 
BCRP
ROS
AUCinf 
38.3 (40.3)
34.9 (39.5)
111 (101, 121)
Cmax
3.06 (40.4)
2.86 (43.4)
108 (98.3, 119)
Data are presented as mean (%CV) to three significant digits
1.2.
Rationale for This Study
Current evidence suggests that NASH is a consequence of the metabolic syndrome with resulting 
lipotoxicity and oxidative stress in the steatotic liver, setting off an inflammatory response with 
subsequent activation of hepatic stellate cells and fibrogenesis. FXR agonism has been shown to 
reduce hepatic lipid synthesis and circulating triglycerides due to down regulation of SREBP-1c, 
as well as reduce insulin resistance and hepatic gluconeogenesis. Thus GS-9674 is postulated to 
halt the instigating triggers for NASH. Animal models have demonstrated the ability for 
GS-9674 to reverse the metabolic dysfunction and NASH-like liver injury in a choline-deficient 
high fat diet /NaNO2 rat model of liver fibrosis. This Phase 2 study has been designed as a 
multicenter, randomized, double-blind, placebo-controlled study evaluating the safety and 
efficacy of GS-9674 for 24 weeks in subjects with NASH. Approximately 125 NASH subjects 
without cirrhosis will be randomized in a 2:2:1 ratio to receive GS-9674 at a dose of 30 mg or 
100 mg orally QD, or placebo. Randomization will be stratified by the presence or absence of 
diabetes mellitus, a common comorbidity in patients with this condition. 
Inclusion criteria for the study were developed in order to noninvasively identify subjects with 
NASH. Specifically, all subjects will have a clinical diagnosis of NAFLD, evidence of ≥ 10% 
hepatic steatosis on MRI-PDFF {Bannas et al 2015}, and increased liver stiffness on MRE 
(≥2.90 kPa). Previous studies have shown that patients with NAFLD and increased liver 
stiffness by MRE have a high probability of NASH on liver biopsy {Loomba et al 2014}, {Chen et 


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al 2011}. For example, Chen et al. reported that an MRE liver stiffness cut-off of ≥ 2.90 kPa was 
83% sensitive, 82% specific, and had an area under the receiver operating characteristic curve 
(AUROC) of 0.93 and positive predictive value of 88% for the differentiation of simple 
steatosis from NASH on biopsy. Moreover, in a meta-analysis of MRE for the diagnosis of 
NAFLD-related fibrosis {Singh et al 2016}, a liver stiffness ≥ 2.88 kPa optimally identified the 
presence of at least stage 1 fibrosis (AUROC 0.86). Based on these criteria, subjects enrolled in 
this study have a high probability of NASH with fibrosis, a population with a large unmet 
medical need. Since the safety and PK of GS-9674 have not yet been explored in subjects with 
cirrhosis, criteria have been developed in order to exclude cirrhotic subjects based on a validated 
serum marker for fibrosis (FibroSURE/FibroTest®) and historical clinical, histological, and 
imaging data {Ratziu et al 2006}.
The primary endpoint of this study will be the safety and tolerability of GS-9674. In addition, the 
biological activity of GS-9674 will be determined based on endpoints including routine liver 
biochemistry (eg, ALT and GGT); noninvasive serum markers of liver injury (eg, serum CK-18, 
FibroSURE/FibroTest® and ELF™ Test); and imaging-based methods for quantifying hepatic 
steatosis (MRI-PDFF) and fibrosis (MRE and FibroScan®). An important endpoint of interest is 
the proportion of subjects achieving ≥ 30% reduction in steatosis as assessed by MRI-PDFF. 
This level of reduction has been associated with a significant improvement in NASH histology 
(≥ 2-point reduction in NAFLD Activity Score) {Patel et al 2015}. Based on preclinical and 
clinical data, a treatment duration of 24 weeks with GS-9674 is expected to be sufficient to lead 
to meaningful improvements in hepatic steatosis on MRI-PDFF and liver biochemistry.  In 
addition to these liver-related endpoints, the effects of GS-9674 on carbohydrate and lipid 
metabolism (eg, glucose, insulin, free fatty acids, apolipoproteins, lipid profiles, and metabolites) 
will be closely monitored in light of the mechanism of action of GS-9674 and the importance of 
metabolic dysfunction in contributing to the morbidity and mortality (eg, cardiovascular) of 
subjects with NASH.
This study will evaluate the safety, tolerability, and efficacy of 30 mg and 100 mg GS-9674 
administered with food for 24 weeks in subjects with NASH. The doses were selected based on 
short-term safety, PK and PD results from Study GS-US-402-1851 in healthy subjects. 
Across the range of GS-9674 doses evaluated (10-300 mg QD), doses ≥30 mg provide 
comparable intestinal FXR activation assessed as increases in FGF19 exposure. Food, by 
slowing oral absorption of GS-9674, results in prolonged elevation of plasma FGF19 
concentrations. Exposure-response relationships show that changes in C4 exposure are 
negatively correlated with changes in FGF19 exposure as well as GS-9674 exposure. Based on 
these results, GS-9674 doses of 30 and 100 mg with food are selected for further study as they 
are expected to 1) provide enteral FXR agonism and improvements in subjects with NASH and 
2) inform on the impact of increasing systemic GS-9674 exposure on safety and efficacy.
In the Phase 1 study, GS-US-402-1851, GS-9674 was tested at doses up to 300 mg once daily for 
up to 14 days and was well tolerated. Taken together, these data support the evaluation of 
GS-9674 30 and 100 mg in subjects with NASH.


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1.3.
Risk/Benefit Assessment for the Study 
This study will provide information on the safety and efficacy of GS-9674 for the treatment of
patients with NASH. As there are currently no approved therapies for NASH, there is a large
unmet medical need for this growing population of patients.
Subjects with NASH randomized to the placebo control arm in the study may benefit from 
frequent medical monitoring and close assessment of their NASH during the duration of placebo 
treatment. Subjects randomized to GS-9674 may benefit from an improvement in their 
underlying NASH which may manifest as improvements in liver biochemistry, measures of 
hepatic steatosis or fibrosis, or improvements in quality of life. Importantly, this study will 
provide further data to inform the clinical development of the investigational medicinal product 
GS-9674 for use in an area of unmet medical need. 
In the Phase 1 study, 94 subjects have received GS-9674 in single or multiple doses (14 days) up 
to 300 mg. All treatment emergent adverse events (TEAEs) were mild to moderate (Grade 1 or 
2), and overall, the rate of any adverse events (AEs) was similar between subjects treated with 
GS-9674 or placebo. The predominant toxicities were anemia, back pain, diarrhea, and headache. 
Grade 2 or 3 elevations in serum ALT were seen in five (5%) GS-9674 treated subjects and one 
(4%) placebo treated subject. Grade 2 or 3 ALT elevations that occurred on-treatment were 
observed in 2/23 (9%) BID treated subjects, but none of the 71 subjects who received once daily 
(QD) GS-9674 dosing. In these cases, elevations in serum bilirubin or prolongation of INR were 
not observed, serum ALT levels normalized upon treatment cessation, and no evidence of drug 
hypersensitivity syndrome (eg, fever, rash, eosinophilia) was noted. In nonclinical studies, 
effects on the liver have been limited to non-adverse mild increases in alkaline phosphatase and 
liver weights and minimal hepatocellular hypertrophy that are likely a pharmacological response 
to FXR agonism. There were no elevations in liver transaminases or changes in liver pathology 
(degeneration/necrosis) in the nonclinical studies to suggest direct cellular damage. In order to 
mitigate the potential risk of hepatotoxicity with GS-9674, QD dosing of GS-9674 has been 
chosen for this study. Moreover, close monitoring of liver biochemistry values will be performed 
and parameters for discontinuation of the study drugs due to liver test abnormalities have been 
defined (see Section 7.5, Toxicity Management: Observation for Drug-Induced Liver Injury) and 
will be closely followed.
Additional risks to study subjects include those attributable to study participation in general, 
including risks associated with frequent clinic visits and laboratory blood draws, and the 
associated pain and discomfort of phlebotomy. Strategies to mitigate these risks include close 
monitoring of lab values as well as AEs. Parameters for discontinuation of the study drugs due to 
AEs and non-hepatic laboratory abnormalities are also defined and will be closely followed.
Overall, the nonclinical and limited preliminary clinical data show a positive benefit/risk ratio in 
support of the study in subjects with NASH. Appropriate safety monitoring will be conducted 
throughout the study to further characterize the safety profile of GS-9674 in NASH subjects 
without cirrhosis.


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In summary, there are no approved treatment options available for patients with NASH. Based
on past clinical experience with GS-9674, the risk/benefit is positive and supports the continued
evaluation of GS-9674 in this patient population. Data from this study will support the
development of GS-9674 for the treatment of this condition.
1.4.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


GS-9674 
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2. 
OBJECTIVES 
The primary objective of this study is as follows: 
• 
To evaluate the safety and tolerability of GS-9674 in subjects with NASH. 
The exploratory objectives of this study are as follows: 
~ 
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3.
STUDY DESIGN
3.1.
Study Design
This is a Phase 2, randomized, double-blind, placebo-controlled study designed to evaluate the 
safety, tolerability, and efficacy of GS-9674 in subjects with NASH. To be eligible to participate, 
subjects must have evidence of hepatic steatosis and increased liver stiffness as assessed by 
MRI-PDFF and MRE respectively. Any subject with a history of decompensated liver disease, 
including ascites, hepatic encephalopathy, or variceal bleeding will be ineligible.
The overall study design is presented graphically in Figure 3-1.
Figure 3-1.
Overall Study Design
3.2.
Treatment Plan and Regimen
Subjects meeting the study’s entry criteria will be randomly assigned in a 2:2:1 ratio to 1 of 
3 different treatment groups (A, B, and C) as shown in Figure 3-1. Randomization will be 
stratified by the presence or absence of diabetes mellitus as determined by medical history, use 
of medication for indication of diabetes mellitus, or based on screening lab values if previously 
undiagnosed (ie, hemoglobin A1c ≥ 6.5% OR fasting plasma glucose ≥126 mg/dL).
Study drug will be administered for a total of 24 weeks from the Baseline/Day 1 visit up to and 
including the Week 24 visit. Dosage and administration of the study drug and reference product 
are described in Section 5.3.


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Gilead Sciences, Inc. 
3.3. 
Biomarker Testing 
3.3.1. 
Biomarker Samples to Address the Study Objectives 
Final 
Amendment 1 
Biological specimens will be collected in this study as per the studurocedures table 
L
endix 2) PPD 
Because biomarker science is a 
.----~-~-----r~---~~----~-~------~~~ 
rapidly evolving area of investigation, and adverse events in pa1ticular are difficult to predict, it 
is not possible to specify prospectively all tests that will be done on the specimens provided. The 
biomarker tests 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 a1t knowledge. Samples will be 
stored for up to 15 years after the end of the study. 
Bioma1·kers testing can include circulating markers ofFXR activity such as FGF19, bile acids, 
and C4. Circulating protein markers of liver damage and inflammation, lipids, and other 
biochemicals associated with liver metabolic activity will also be measured. Stool samples may 
be analyzed for the presence of bile acids and a survey of potential changes in the intestinal 
microbiome during the study. 
3.3.2. 
Biomarker Samples for Optional Future Research 
PD 
3.3.3. 
Biomarker Samples for Optional Genomic Research 
PD 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
This study will enroll approximately 125 subjects with nonalcoholic steatohepatitis (NASH).
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1)
Males and females between 18-75 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;
3)
Meets all of the following conditions:
a.
A clinical diagnosis of nonalcoholic fatty liver disease (NAFLD) with histological or
imaging evidence of fatty liver within the past two years. If necessary an ultrasound 
may be performed during screening to confirm NAFLD. Note: criterion a. must be met 
before evaluating criteria b. and c.
b. Screening MRI-PDFF with ≥10% steatosis
c.
Screening MRE with liver stiffness ≥ 2.90 kPa;
4)
Platelet count ≥ 150,000/mm3;
5)
Albumin ≥ 3.3 g/dL;
6)
Creatinine Clearance (CLcr) as calculated by the Cockcroft-Gault equation ≥ 90 ml/min;
7)
Female subjects of childbearing potential (see definition in Appendix 4) must have a 
negative serum pregnancy test prior to starting study treatment;
8)
All female subjects of childbearing potential who engage in heterosexual intercourse must 
agree to use a highly effective method of contraception during intercourse from the 
screening visit throughout the study period and for 30 days following the last dose of study 
drug (see Appendix 4 for details);
9)
Female subjects must refrain from egg donation or harvest during treatment and for at least
30 days after last dose of study drug;


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10)
Male subjects are required to use barrier contraception (condom plus spermicide) during 
heterosexual intercourse from the screening through the study completion and for 90 days 
following the last dose of study drug (see Appendix 4 for details);
11)
Male subjects must refrain from sperm donation from screening through at least 90 days 
following the last dose of study drug;
12)
Willing and able to comply with scheduled visits, drug administration plan, laboratory 
tests, other study procedures, and study restrictions;
13)
Must be able to read and complete Quality of Life questionnaires independently.
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; lactating females must agree to discontinue nursing before 
the study drug is administered;
2)
ALT > 5X ULN;
3)
Other causes of liver disease including autoimmune, viral, and alcoholic liver disease;
4)
Cirrhosis of the liver as defined by any of the following:
a.
Cirrhosis on historical liver biopsy (eg, Brunt/Kleiner stage 4 or equivalent)
b. Evidence of cirrhosis on liver imaging (eg, ultrasound, CT, or MRI) including a nodular 
liver surface, splenomegaly, or portal venous collaterals
c.
Screening FibroSURE/FibroTest® ≥ 0.75, as determined by the central laboratory
d. Prior history of decompensated liver disease, including ascites, hepatic encephalopathy,
or variceal bleeding;
5)
History of liver transplantation;
6)
Weight reduction surgery in the past or planned during the study;
7)
History of intestinal resection or malabsorptive condition that may limit the absorption of 
GS-9674. Prior cholecystectomy and appendectomy are permitted.
8)
BMI < 18 kg/m2;
9)
Uncontrolled diabetes mellitus (hemoglobin A1c > 9% at screening);
10)
INR > 1.2 unless on anticoagulant therapy;
11)
Total bilirubin > 1x ULN, except with diagnosis of Gilbert’s syndrome;


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12)
Chronic hepatitis B (HBsAg positive);
13)
Chronic hepatitis C (HCV RNA positive);
14)
HIV Ab positive;
15)
Alcohol consumption greater than 21 oz/week for males or 14 oz/week for females 
(1oz/30mL of alcohol is present in 1 12oz/360mL beer, 1 4oz/120mL glass of wine, and a 1 
oz/30 mL measure of 40% proof alcohol);
16)
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;
17)
Unstable cardiovascular disease as defined by any of the following:
a.
Unstable angina within 6 months prior to screening
b. Myocardial infarction, coronary artery bypass graft surgery or coronary angioplasty 
within 6 months prior to screening
c.
Transient ischemic attack or cerebrovascular accident within 6 months prior to 
screening
d. Obstructive valvular heart disease or hypertrophic cardiomyopathy
e.
Congestive heart failure;
18)
History of known hypercoagulable condition or prior arterial or venous thromboembolic 
disease;
19)
Use of any prohibited concomitant medications as described in Section 5.5;
20)
History of a malignancy within 5 years of screening with the following exceptions:
a.
Adequately treated carcinoma in situ of the cervix
b.
Adequately treated basal or squamous cell cancer or other localized non-melanoma skin 
cancer;
21)
Any laboratory abnormality or condition that could, in the opinion of the investigator, 
adversely affect the safety of the subject or impair the assessment of study results;


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22)
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;
23)
Concurrent participation in another therapeutic clinical study;
24)
Known hypersensitivity to GS-9674, the metabolites, or formulation excipient;
25)
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 or a 
psychiatric (including any subjects with a psychiatric hospital admission or emergency 
room visit in the 2 years prior to screening) or medical condition;
26)
Unavailable for follow-up assessment or concern for subject’s compliance with the 
protocol procedures;
27)
Contraindications or inability to complete MRI scanning (eg, presence of permanent 
pacemakers, implanted cardiac devices, weight restrictions, etc.).


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
An Interactive Web Response System (IWRS) will be used for centralized randomization and 
treatment assignment. Randomization will be stratified by the presence or absence of diabetes 
mellitus as determined by medical history, use of medication for indication of diabetes mellitus, 
or based on screening lab values if previously undiagnosed (ie, hemoglobin A1c ≥ 6.5% OR 
fasting plasma glucose ≥126 mg/dL).
Investigative site personnel will obtain the subject’s identification number and study drug 
assignment from the IWRS. Subjects and all personnel directly involved in the conduct of the 
study will be blinded to treatment assignment.
Study drug will be dispensed by the study pharmacist, or designee, in a blinded fashion to the 
subjects.
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator (or designee) may obtain treatment assignment directly from the 
IWRS system for that subject (refer to the Study Reference Binder for IWRS unblinding 
instructions). Gilead recommends but does not require that the investigator contact the Gilead
Medical Monitor before breaking the blind. Treatment assignment should remain blinded unless 
that knowledge is necessary to determine subject emergency medical care. The rationale for 
unblinding must be clearly explained in source documentation and on the electronic case report 
form (eCRF), along with the date on which the treatment assignment was obtained. The 
investigator is requested to contact the Gilead Medical Monitor promptly in case of any 
treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical study 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 Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).


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5.2. 
Description and Handling of GS-9674 and PTl\11 GS-9674 
5.2.1. 
Formulation 
Final 
Amendment 1 
GS-9674 is supplied as 30m~ and 100 mg strength Cas free fmm e uivalent tablets. The tablets 
contain GS-9674-02 PD 
GS-9674 30 mg tablets are round, plain-faced, film-coated orange tablets and 
'"'"G""S~-9~6=7i""14-:100 mg tablets ru·e capsule-shaped, plain-faced, film-coated orange tablets. 
Placebo-to-match (PTM) GS-9674 tablets are identical in size, shape, color, and appearance to 
their conesponding stren ths of active GS-9674 tablets. PTM GS-9674 tablets PD 
5.2.2. 
Packaging and Labeling 
GS-9674 tablets and PTM GS-9674 tablets are packaged in white, high-density polyethylene 
(HDPE) bottles. Each bottle contains 30 tablets, a 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, aluminum-faced liner. 
Study dmg 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 Dmg Administration (FDA), EU 
Guideline to Good Manufacturing Practice- Annex 13 (Investigational Medicinal Products), 
ru1d/or other local regulations. 
5.2.3. 
Storage and Handling 
GS-9674 tablets and PTM GS-9674 tablets should be stored at controlled room temperatme lmtil 
required for administration. Controlled room temperature is defmed as 25°C (77°F); temperature 
excursions ru·e petmitted between l5°C and 30°C (59°F and 86°F). Storage conditions ru·e 
specified on the label. 
Until study dmg tablets ru·e dispensed to the subjects, all bottles of study mugs should be stored 
in a securely locked area, accessible only to authorized site personnel. To ensure the stability and 
proper identification, the mug products should not be stored in a container other than the 
container in which they were supplied. Consideration should be given to handling, preparation, 
and disposal through measures that minimize m·ug contact with the body. Appropriate 
precautions should be followed to avoid direct eye contact or exposure when handling GS-9674 
tablets and PTM GS-9674 tablets. 
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5.3.
Dosage and Administration of GS-9674/ PTM GS-9674 
GS-9674 and GS-9674 PTM tablets will be provided by Gilead Sciences, Inc. In order to 
maintain the blind, each subject will be supplied with 2 bottles of tablets. One bottle will contain
GS-9674 30 mg or PTM GS-9674 30 mg, the second bottle will contain GS-9674 100 mg or 
PTM GS-9674 100 mg. Dosing for each treatment group will be as follows:

Treatment Group A: GS-9674 30 mg (1 x 30 mg tablet) + PTM GS-9674 100 mg (1 x PTM 
100 mg tablet) administered orally once daily with food

Treatment Group B: GS-9674 100 mg (1 x 100 mg tablet) + PTM GS-9674 30 mg 
(1 x PTM 30 mg tablet) administered orally once daily with food

Treatment Group C: PTM GS-9674 30 mg (1 x PTM 30 mg tablet) + PTM GS-9674 
100 mg (1 x PTM 100 mg tablet) administered orally once daily with food
The study drug dose should be taken at approximately the same time each day with food.
A dose will be considered missed if the subject cannot take the dose within 12 hours of their 
regular dosing time. If a subject misses a dose, the subject should take their next dose at the 
regular dosing time.
5.4.
Prior and Concomitant Medications
Concomitant use of certain medications or herbal/natural supplements with study drug may result 
in PK and/or PD interactions resulting in increases or decreases in exposure of study drug or 
these medications. 
Concomitant medications taken within 30 days of screening through the follow-up visit need to 
be recorded in the source documents and electronic Case Report Forms (eCRFs).
Subjects with co-morbid diseases requiring medication(s) must be taking the medication(s) 
without a change in dose within 28 days of Baseline/Day 1.
GS-9674 increased atorvastatin exposure (39%) which does not necessitate a priori dose 
modification based on the LIPITOR® USPI.  Subjects taking atorvastatin with GS-9674 should 
be monitored as per label recommendations.
5.5.
Prohibited Medications
The following medications are prohibited from 28 days prior to Baseline/Day 1 up to and 
including the day of the last dose of study drug:

Vitamin E

Hematologic stimulating agents (eg, erythropoiesis-stimulating agents (ESAs); granulocyte 
colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics)


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
Chronic systemic immunosuppressants including, but not limited to, corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal 
antibodies (eg, infliximab). Use for <2 weeks total is allowed.

Investigational agents or devices for any indication

Concomitant use of certain medications or herbal/natural supplements (potent inhibitors of 
OATP or potent or moderate inducers of OATP, CYP2C8, P-gp, or CYP3A) with study 
drug(s) may result in PK interactions resulting in increases or decreases in exposure of study 
drug(s) or concomitant medications. Examples of representative medications which are 
prohibited from 28 days prior to Baseline/Day 1 up to and including the day of the last dose 
of study drug, are listed below in Table 5-1:
Table 5-1.
List of Medications Prohibited and to be used with Caution
Drug Class
Agents Disallowed
Use with Caution
Antibiotics
Clarithromycin, Erythromycin
Acid Reducing Agents
H2-Receptor Antagonistsa
Antacidsb
Anticonvulsantsc
Carbamazepine, Oxcarbazepine, Phenobarbital, 
Phenytoin
Antimycobacterialsc
Rifabutin, Rifapentine, Rifampin
Endothelin Receptor 
Antagonists
Bosentan
Herbal/Natural 
Supplementsc
St. John’s Wort, Echinaccea. Milk thistle (ie, 
silymarin), Chinese herb sho-saiko-to (or Xiao-
Shai-Hu-Tang)
Otherc
Modafinil
a
H2-Receptor Antagonists can be taken up to 3 days prior to study drug dosing.
b
Antacids that directly neutralize stomach pH (ie, Tums, Maalox) are permitted but may not be taken within 4 hours (before 
or after) study drug administration.
c
May result in a decrease in the concentrations of study drug.
Medications for disease conditions excluded from the protocol (eg, HIV-1, HBV, or HCV
infection, active cancer, transplantation) are not listed under this prohibited medications section 
and are disallowed in the study.
5.6.
Accountability for GS-9674/ PTM GS-9674 
The investigator or designee (eg, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug bottles. This includes acknowledgement of receipt of each 
shipment of study drug (quantity and condition), subject dispensing records, and returned or 
destroyed study product. All used and unused study drug bottles dispensed to subjects must be 
returned to the site.


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Study drug accountability records will be provided to each study site to:

Record the date received and quantity of study drug bottles

Record the date, subject number, subject initials, and the study drug bottle number dispensed

Record the date, quantity of used and unused study drug returned, along with the initials of 
the person recording the information.
5.6.1.
Investigational Medicinal Product Return or Disposal
Refer to Section 9.1.7 for instructions regarding study drug return or disposal.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. Additional information is 
provided in the Study Reference Binder.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the investigator to ensure that subjects are eligible to participate in the 
study prior to enrollment and throughout the study. 
Documentation of the personally signed and dated informed consent of each subject, using the 
study-specific informed consent form (ICF), is required before initiating the screening process.
After written informed consent has been obtained and eligibility to participate established, 
investigative site personnel will obtain the subject’s identification number and study drug 
assignment from the interactive web response system (IWRS).
6.2.
Pretreatment Assessments – Screening Visit
Subjects will be screened within 4 weeks prior to randomization to determine eligibility for 
participation in the study. The screening period may be extended under special circumstances 
with the explicit approval of the Medical Monitor.
Screening labs may be repeated once within the screening period, prior to administration of study 
drug to rule out laboratory error, if any. This will be done at the discretion of the investigator and 
with prior approval of the Medical Monitor.
Subjects who fail to meet eligibility criteria may be rescreened once if there is a reasonable 
expectation that the subject will meet eligibility criteria after repeat screening.
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 fasted blood sample collection the next morning.
The following will be performed and documented at Screening:

Obtain written informed consent before initiation of any screening procedures

Review and record whether the subject meets inclusion and exclusion criteria

Obtain screening number from IWRS


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
Obtain medical history

Complete physical examination

Record vital signs, body weight, and height

Obtain blood samples for:
— Chemistry
— Hematology 
— Coagulation Panel 
— Hemoglobin A1c
— Biomarkers
— HIV-1, HBV, and HCV Serology
— Serum pregnancy test (only for female subjects of child bearing potential)
— Serum FSH (only for some female subjects - see Appendix 4) 

Conduct standard 12-Lead ECG

Perform Ultrasound (if necessary) for confirmation of NAFLD

Perform MRE and MRI-PDFF

Urine drug screen for amphetamines, cocaine and opiates (ie, heroin, morphine)

Record all concomitant medications that the subject has taken within 30 days prior to 
screening

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 4 weeks of the start of screening for randomization into the study.
From the time of obtaining informed consent through the first administration of the study drug, 
record all serious adverse events (SAEs), as well as any adverse events related to protocol-
mandated procedures on the adverse events electronic 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.


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6.3. 
Baseline/Day 1 Randomization and Assessments 
Final 
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Subjects retuming to the clinic for randomization at Baseline/Day I should be instructed to fast 
(no food or drink, except water), statting from midnight (00:00) or earlier, as appropriate, on the 
evening prior to the visit to ensure an approximate 8-hom· fast prior to the blood sample 
collection under fasting condition the next moming. 
After review of inclusion and exclusion criteria to confilm continued eligibility, subjects will be 
randomized to study dmg assignment and receive their Subject Identification Number via the 
IWRS prior to their first dose of study dmg. 
The following will be perfmmed and documented at the Baseline/Day I visit prior to dosing: 
• 
QoL: general assessments (CLDQ, SF-36, and WPAI) 
• 
QoL: pmritus assessments 01 AS-itch and 5D-itch) 
Note: It is recommended that QoL assessments be completed prior to any study procedures being 
performed and prior to the subject seeing a health care provider. Refer to the Study Reference 
Binder for guidance on QoL assessment administration. 
• 
Symptom driven physical examination 
• 
Record vital signs, waist circtm1ference, and body weight 
• 
Obtain blood samples for: 
-
Chemistly 
-
Hematology 
-
Coagulation Panel 
-
Lipid Profile 
-
Hemoglobin A I c 
-
Biomat·kers 
Single PD Sampling 
PD 
• 
Conduct standard I2-Lead ECG 
• 
Perfmm FibroScan® (if available) 
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
Collect urine samples for:
— Urine pregnancy test for females of child bearing potential only
— Biomarker testing

Collect stool sample for biomarker testing

Dispense study drug and provide subject with instruction on appropriate dosing and 
administration; 

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 screening visit
Once all visit procedures have been completed, subjects will take their Baseline/Day 1 dose of 
study drug with food while at the investigative site.
Subjects will return to the investigative site at Week 1 (±3 days) for a mandatory safety visit. 
Then, starting at the Week 4 visit, subjects will have visits every 4 weeks up to the Week 24 
visit.
6.4.
Treatment Assessments
6.4.1.
Week 1
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Week 1 visit to ensure an 
approximate 8-hour fast prior to the fasted blood sample collection the next morning.
Subjects should also be instructed to HOLD their dose of study drug on the day of their Week 1 
visit until all visit procedures have been completed. The study drug dose should be taken with 
food after the visit.
During the Week 1 safety visit the following will be performed and documented (±3 days):

QoL: pruritus assessments (VAS-itch and 5D-itch)

Symptom driven physical examination

Record vital signs and body weight

Obtain blood samples for:
— Chemistry
— Hematology


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— Coagulation Panel
— Lipid Profile
— Biomarkers
— Single PK and PD sampling

Collect urine sample for biomarker testing

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
6.4.2.
Week 4 Visit
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Week 4 visit to ensure an 
approximate 8-hour fast prior to the fasted blood sample collection the next morning.
Subjects should also be instructed to HOLD their dose of study drug on the day of their Week 4 
visit until all visit procedures have been completed. The study drug dose should be taken with 
food after the visit.
The following will be performed and documented at this visit (±3 days):

QoL: pruritus assessments (VAS-itch and 5D-itch)

Symptom driven physical examination

Record vital signs and body weight

Obtain blood samples for:
— Chemistry
— Hematology
— Coagulation Panel
— Lipid Profile
— Biomarkers
— Single PK and PD sampling


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
Collect urine samples for:
Urine pregnancy test for females of child bearing potential only
Biomarker testing

Dispense study drug

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
6.4.3.
Week 8, 16, and 20 Visits
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Weeks 8, 16, and 20 visits to ensure
an approximate 8-hour fast prior to the fasted blood sample collection the next morning.
Subjects should also be instructed to HOLD their dose of study drug on the day of their Weeks 8, 
16, and 20 visits until all visit procedures have been completed. The study drug dose should be 
taken with food after the visit.
The following will be performed and documented at these visits (±3 days):

QoL: pruritus assessments (VAS-itch and 5D-itch)

Symptom driven physical examination

Record vital signs and body weight

Obtain blood samples for:
— Chemistry
— Hematology
— Coagulation Panel
— Lipid Profile
— Single PK and PD sampling

Urine pregnancy test for females of child bearing potential only

Dispense study drug

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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6.4.4.
Week 12 Visit 
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Week 12 visit to ensure an 
approximate 8-hour fast prior to the fasted blood sample collection the next morning.
Subjects should also be instructed to HOLD their dose of study drug on the day of their Week 12 
visit until all visit procedures have been completed. The study drug dose should be taken with 
food after the visit.
The following will be performed and documented at this visit (±7 days):

QoL: general assessments (CLDQ, SF-36, and WPAI)

QoL: pruritus assessments (VAS-itch and 5D-itch) 

Symptom driven physical examination

Record vital signs and body weight

Obtain blood samples for:
— Chemistry
— Hematology
— Coagulation Panel
— Lipid Profile
— Hemoglobin A1c
— Biomarkers
— Single PK and PD sampling

Collect urine samples for:
Urine pregnancy test for females of child bearing potential only
Biomarker testing

Conduct standard 12-Lead ECG

Perform FibroScan® (if available)

Perform MRE and MRI-PDFF


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
Dispense study drug

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
6.4.5.
Week 24 Visit
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Week 24 visit to ensure an 
approximate 8-hour fast prior to the fasted blood sample collection the next morning.
Subjects should also be instructed to HOLD their dose of study drug on the day of their Week 24 
visit until all visit procedures have been completed. 
The following will be performed and documented at this visit (±7 days):

QoL: general assessments (CLDQ, SF-36, and WPAI)

QoL: pruritus assessments (VAS-itch and 5D-itch) 

Symptom driven physical examination

Record vital signs, waist circumference, and body weight

Obtain blood samples for:
— Chemistry
— Hematology
— Coagulation Panel
— Lipid Profile
— Hemoglobin A1c
— Biomarkers
— Single PK and PD sampling

Collect urine samples for:
Urine pregnancy test for females of child bearing potential only
Biomarker testing

Conduct standard 12-Lead ECG

Perform FibroScan® (if available)


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• 
Perf01m MRE and MRI-PDFF 
• 
Collect stool sample for biomarkers 
Final 
Amendment 1 
• 
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 
Once all visit procedmes have been completed, subjects will take their fmal dose of study dmg 
while at the investigative site. 
PD 
6.4.6. 
Unscheduled Visits 
Additional unscheduled assessments may be perf01med at the discretion of the investigator. 
Subjects retmning to the clinic for an unscheduled visit should be instructed to fast (no food or 
drink, except water), struiing from midnight (00:00) or earlier, as appropriate, on the evening 
prior to the visit to ensme an approximate 8-hom fast prior to the blood sample collection under 
fasting condition the next moming. 
Subjects should also be instmcted to HOLD their dose of study drug on the day of an 
unscheduled visit lmtil all visit procedmes have been completed. The study dmg dose should be 
taken with food after the visit. 
At a minimum, the following will be perf01med and documented. 
• 
Symptom driven physical exrunination 
• 
Record body weight 
• 
Obtain blood samples for: 
-
Chemistly 
-
Hematology 
• 
Record all concomitant mediations that the subject has taken since the previous visit 
• 
Record any serious adverse events and all adverse events occmTing since the previous visit 
If the Unscheduled visit is pe1f01med for the sole pmpose of distt·ibution of study dmg, the 
assessments noted above do not need to be performed. 
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6.5.
Follow-Up Visit
Subjects will return for a Follow-Up Visit four weeks after their last dose of study drug.
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Follow-Up visit to ensure an 
approximate 8-hour fast prior to the blood sample collection under fasting condition the next 
morning.
The following will be performed and documented at this visit (±5 days):

Symptom driven physical examination

Record vital signs and body weight

Obtain blood samples for:
— Chemistry
— Hematology
— Coagulation Panel

Urine pregnancy test for female subjects of child bearing potential only

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse occurring since the previous visit
6.6.
Assessments for Premature Discontinuation from Study
Subjects prematurely discontinuing from the study (for example, as a result of an AE), should 
have an Early Termination (ET) visit, if possible, and a Follow-Up visit 4 weeks after their last 
dose of study drug. The study assessments to be performed at the ET visit are the same as those 
performed at the Week 24 visit (refer to Section 6.4.5). The study assessments to be performed at 
the Follow-Up visit are listed in Section 6.5. The subject will then be withdrawn from the study.
If these visits are not possible or acceptable to the subject or investigator, the subject may be 
withdrawn from the study. 


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6.7. 
Criteria for Discontinuation of Study Treatment 
Study medication may be discontinued in the following instances: 
Final 
Amendment 1 
• 
Intercunent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercunent illness, the subject 
may resume study dosing at the discretion of the investigator. 
• 
Unacceptable toxicity, or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedmes or is considered to not be in the subject's best 
interest 
• 
Subject request to discontinue for any reason 
• 
Subject noncompliance 
• 
Pregnancy dming the study (refer to Appendix 4) 
• 
Sponsor discretion 
• 
Discontinuation of the study at the request of Gilead, a regulatoty agency or an institutional 
review board, independent ethics committee, or ethics committee (IRBIIEC/EC) 
6.8. 
PK and PD Substudy Visits 
PD 
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6.9. 
Description of Assessments 
6.9.1. 
Clinical Laboratory Analytes 
Chemistry: 
Final 
Amendment 1 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, alkaline 
phosphatase (ALP), 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). Also includes C-
Peptide and Insulin for the Baseline/Day!, Weeks 4, 12, and 24 visits. 
Creatinine clearance is calculated by the Cockcroft-Gault equation {Cockcroft et al1976} using 
actual body weight (BW). The calculation will be performed by the central laboratory. 
Hematology: 
Hematocrit (Hct), Hemoglobin (Hb ), Platelet count, Red blood cell count (RBC), White blood 
cell count (WBC) with differential (absolute and percentage) including Lymphocytes, 
Monocytes, Neutrophils, Eosinophils, and Basophils and, Reticulocyte count and mean 
corpuscular volume (MCV). 
Coagulation Panel: 
Prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio 
(INR) 
Pregnancy Tests: 
Serum ~-hCG or urine ~-hCG (if positive, requires immediate confirmation with Serum ~-hCG) 
Additional Tests: 
Lipid Profile, Hemoglobin Ale, HIV-1, HBV & HCV Serology, urine drug screen (for 
amphetamines, cocaine, opiates), creatine phosphokinase, and genomic sample collection. 
Biomarker Tests: 
CK18 (M30 and M65), FGF-19, C4, Apolipoprotein B (Apo B), metabolite profile, bile acids, 
stool microbiome, blood miRN A, NMR lipoprofile, free fatty acids, ELF™ Test, and 
FibroSURE/Fibro Test®. 
PPD 
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Phrumacokinetic CPK) and Phatmacodvnamic CPD) Assessments 
Single PK and PD Sampling 
Final 
Amendment 1 
Single PK ru1d PD plasma samples will be collected and ru·chived for 1) PK analysis of GS-9674, 
GS-716070 (metabolite of GS-9674), and other metabolites as applicable, 2) to measure the 
concentration of the PD biomru·kers FGF19 and C4. 
PK and PD Substudy 
pp 
6.9.2. 
Medical History 
Medical histoty, induding details of illnesses and allergies, date(s) of onset, whether condition(s) 
is cunently ongoing, and medication histoty, including nicotine and alcohol use, will be 
collected for all subjects during screening. 
6.9.3. 
Physical Examination 
A complete physical examination should include source documentation of general appearance, 
and the following body systems: head, neck, and thyroid; eyes, ears, nose, throat, mouth, and 
tongue; chest (excluding breasts); respiratoty; cru·diovasculru·; lymph nodes; abdomen; skin, hair, 
nails; musculoskeletal; neurological. 
The focus of a symptom driven physical examination will be dete1mined by the investigator 
based on subject complaint. For eg, if a subject complains of a cough, a lung exam should be 
perfotmed. If consistent with pneumonia (rales/crackles on exam) then an AE would be 
documented. 
Height~ body weight, and hip circumference will be collected at specified time points. 
6.9.4. 
Quality of Life (QoL) Assessments 
It is recommended that these questionnaires be completed prior to the clinical and laboratoty 
assessments. The subject should read the questionnaires by himself/herself and record the 
answers by himself/herself. 
6.9.4.1. 
Chronic Liver Disease Questionnaire (CLDQ) 
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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6.9.4.2.
SF-36 Health Survey
The SF-36 Health Survey asks 36 questions to measure functional health and well-being from the 
subject’s point of view and consists of eight health domains (physical functioning, role-physical, 
bodily pain, general health, vitality, social functioning, role-emotional, and mental health). These 
health domain scales contribute to the physical health and mental health summary measures.
6.9.4.3.
Work Productivity and Activity Impairment (WPAI) 
The Work Productivity and Activity Impairment (WPAI) questionnaire asks 6 questions 
regarding the effect of NASH on a person’s ability to work and perform regular activities.
6.9.4.4.
VAS-itch
The visual analogue scale (VAS)-itch is a tool for measuring the intensity of pruritus.
6.9.4.5.
5-D itch
The 5-D itch is multidimensional measure of itching that allows changes in chronic pruritus to be 
detected over time. The questionnaire measures the degree, duration, direction, disability, and 
distribution of pruritus.
6.9.5.
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 in the AE eCRF page.
6.9.6.
FibroScan®
Liver stiffness will be assessed by FibroScan®. It is required that each subject’s FibroScan®
assessments be done with the same type of probe at each study visit. If FibroScan® is not 
available at a site the test may be omitted.
Please refer to the Study Reference Binder for instructions on FibroScan® measurements.
6.9.7.
MRE and MRI-PDFF
Liver stiffness will be assessed by MRE and the degree of steatosis will be measured by 
Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF). These assessments can 
occur sequentially.
The MRE and MRI-PDFF images will be analyzed by a central reader. 
Please refer to the Study Reference Binder for MRE and MRI-PDFF imaging guidelines.


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6.10.
End of Study Definition
End of study is defined as when the last patient last visit (LPLV) for the Follow-Up visit (four 
weeks after their last dose of study drug) occurs, or the ET visit, whichever occurs later.
6.11.
Post Study Care 
No post study ongoing care will be provided.


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


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; 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 study drug 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 
GS-9674 therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the GS-9674. 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 study drug.


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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, 4, or 5 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
(Appendix 3).
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 electronic 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 GS-9674; AEs 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 
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Serious Adverse Events
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signs 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 GS-9674, 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 study drug, 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 (see Study Reference Binder) and submit within 24 hours to:
Gilead DSPH:
Fax: +1 (650) 522-5477
Email: 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.

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.


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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 drug. 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. 
To minimize the possibility of exposing study subjects to unusual risk, the safety information 
from this study will also be reviewed periodically by an independent Data Monitoring 
Committee (DMC). The DMC may have access to partially blinded or unblinded data and will 
make recommendations regarding the study according to the DMC charter. See Section 8.11 for 
additional details regarding the DMC.
7.5.
Toxicity Management 
Observation for Drug Induced Liver Injury (DILI):
Although subjects enrolled in this study will have baseline liver disease, their hepatic function 
should not be significantly impaired. However, at baseline, some may have liver biochemistry 
levels above the upper limit of normal (ULN).  Baseline values for liver tests (ALT, AST, total 
bilirubin, and ALP) will be determined by averaging the values obtained at screening and 
baseline/Day1.
For subjects with ALT and AST below ULN at study start, close observation for DILI (as 
described below) will be performed in subjects with any of the following criteria (all labs 
confirmed by repeat testing):

ALT or AST > 3 x ULN at any time

Total bilirubin > 2 x ULN

ALP > 3 x ULN

INR >1.5 (except for subjects on anticoagulant therapy)  


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
Clinical signs or symptoms that are, in the opinion of the investigator, consistent with 
hepatitis (such as right upper quadrant discomfort, fever, nausea, vomiting, jaundice, rash, or 
eosinophilia > 5%)
For subjects with ALT or AST between 1 and 5 x ULN at study start, close observation for DILI 
(as described below) will be performed in subjects with any of the following criteria (all labs 
confirmed by repeat testing):

ALT or AST > 2 x baseline at any time

Total bilirubin > 2 x ULN  

Alkaline phosphatase > 3 x ULN

INR >1.5 (except for subjects on anticoagulant therapy)  

Clinical signs or symptoms that are, in the opinion of the investigator, consistent with 
hepatitis (such as right upper quadrant discomfort, fever, nausea, vomiting, jaundice, rash, or 
eosinophilia > 5%).  
Close observation includes:

Repeating liver biochemistries (ALT, AST, ALP, total bilirubin, INR) and obtaining creatine
phosphokinase (CPK) levels within 48 hours

Obtaining a more detailed history of symptoms and prior or concurrent disease

Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and special 
diets

Obtaining a history of exposure to environmental chemical agents

Ruling out other causes of liver disease as needed (obtain viral hepatitis panel, imaging for 
evaluation of biliary tract disease, etc. if required in the opinion of the primary investigator)

Continue to monitor liver biochemistries twice weekly. Frequency can decrease to once a 
week or less if abnormalities stabilize or study drug has been discontinued and subject is 
asymptomatic
During a period of close observation, study drug can be continued, if desired, at the discretion of 
the Gilead Medical Monitor and the principal investigator during the DILI evaluation. 


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However, for all subjects, study drug should be withheld if any of the following criteria are met:

ALT or AST > 5 x baseline

ALT or AST >10 x ULN 

ALT or AST >3 x baseline with 1 or more of the following:
Total bilirubin > 2 x ULN or 1.5 x baseline
INR >1.5 (except for subjects on anticoagulant therapy)
Appearance of clinical signs or symptoms that are, in the opinion of the investigator, 
consistent with drug-induced hepatotoxicity

ALT or AST > baseline with any 2 or more of the following:
Total bilirubin > 2 x ULN or 1.5 x baseline
INR >1.5 (except for subjects on anticoagulant therapy)
Appearance of clinical signs or symptoms that are, in the opinion of the investigator, 
consistent with drug-induced hepatotoxicity
AND

No other cause for the combination of laboratory abnormalities is immediately apparent (eg,
prolonged INR with warfarin use) important potential causes or contributors to abnormal 
AST/ALT or total bilirubin values include, but are not limited to:
Obstructive gall bladder or bile duct disease
Viral or alcoholic hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus, 
cytomegalovirus, herpes simplex virus, varicella)
Autoimmune hepatitis
Concomitant administration of other hepatotoxins, including excessive doses of 
acetaminophen, drugs that inhibit bilirubin glucuronidation (eg, indinavir, atazanavir, 
irinotecan), or herbal or dietary supplements
Hypoxic or ischemic hepatopathy or congestive hepatopathy in association with 
significant right-sided heart failure
Wilson disease
Progression of malignancy involving the liver (note that metastatic disease to the liver, by 
itself, should not be used as an explanation for significant AST/ALT elevations)


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If study drugs are withheld, they may be reintroduced with approval from the Medical Monitor if 
another etiology for elevated liver tests is present. Study drug must be discontinued if close 
monitoring of a patient for DILI is not possible, or if total bilirubin, ALT or AST elevation 
recurs following re-challenge with study drug.
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 AEs should be confirmed by repeat testing as soon as practical to do so, and 
preferably within 3 calendar days of receipt of the original test results.

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.

Any questions regarding toxicity management should be directed to the Medical Monitor.
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of AEs associated with product complaints, occupational exposure with an AE, pregnancy 
reports regardless of an associated AE, and AE in an infant following exposure from 
breastfeeding.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labeling (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).


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Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product. 
Occupational exposure is defined as exposure to a medicinal product as a result of one’s 
professional or non-professional occupation.
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to Gilead 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 4 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.


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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 drug and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does 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 
Details will be provided in the statistical analysis plan (SAP). 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The primary objective of this study is as follows: 
• 
To evaluate the safety and tolerability of GS-967 4 in subjects with NASH. 
The exploratory objectives of this study are as follows: 
~ 
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8.1.2. 
Primary Endpoint 
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The primaty endpoint is the safety of GS-9674 in subjects with NASH. Safety endpoints include 
adverse events and laborat01y evaluations. 
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8.1.3. 
Exploratory Efficacy Endpoints 
PD 
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8.2. 
Analysis Conventions 
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All individual subject data will be listed as measured. All statistical summruies and analyses will 
be perfonned using SAS® software (SAS Institute, Cmy, N01ih Cm·olina, USA). 
8.2.1. 
Analysis Sets 
8.2.1.1. 
Efficacy 
The prima1y analysis set for efficacy analysis is defined as the Full Analysis Set (F AS), which 
includes all subjects who were randomized into the study and received at least 1 dose of study 
dmg. 
Subjects who receive study dmg other than that to which they were assigned for the entire 
duration of treatment, will be analyzed according to the treatment group they were randomized 
to. 
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8.2.1.2. 
Safety 
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The primaty analysis set for safety analyses is defmed as all subjects who received at least 
one dose of study drug. Subjects who receive study dmg other than that to which they were 
assigned for the entire dmation of treatment, will be analyzed according to the study drug 
received. 
All data collected dming treatment plus 30 days after last dose of study drug will be included in 
the safety sUllllilaries. 
8.2.1.3. 
Phrumacokinetics 
There are two phrumacokinetic analysis sets: 1) The PK 
· Set which includes 
concentration data from the · 
drawn at each 
The PK Analysis Set will include all enrolled or randomized subjects who took at least one dose 
of study dmg and for whom concentration data of analytes GS-9674 (and its metabolites as 
applicable) ru·e available. The PK Analysis Set will be used for analyses of population PK. 
pp 
8.2.1.4. 
Phrumacodynamics 
There are two phrumacodynamic analysis sets: 1) The PD 
· Set which includes 
concentration data from the · 
drawn at each visit 
The PD Analysis Set will include all enrolled or randomized subjects who took at least one dose 
of study dmg and for whom concentration data ofFGF19, C4, and bile acids are available. The 
PD Analysis Set may be used for descriptive and/or population based PD analyses as applicable. 
PD 
8.2.1.5. 
Bioma1·kers 
The Biomru·ker Analysis Set will include data from subjects in the Safety Analysis Set who have 
the necessaty baseline and on-study measmements to provide interpretable results for the 
specific parruneters of interest. 
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8.2.2. 
Interim Analysis 
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An administrative interim analysis will be perfmmed after all subjects finish 12 weeks of 
treatment. 
8.3. 
Data Handling Conventions 
Missing data can have an impact on the inte1pretation of the study data. In general, values for 
Inissing data will not be imputed. 
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example, if a subject received study medication, the subject will be 
included in a summary of adverse events according to the treatment received; othe1wise, if the 
subject is not dosed then they will be excluded from the summa1y. If safety laboratmy results for 
a subject are Inissing for any reason at a time point, the subject will be excluded from the 
calculation of sUllllnaty statistics for that time point. If the subject is missing a pre-dose value, 
then the subject will be excluded from the calculation of summmy statistics for the pre-dose 
value and the change from pre-dose values. 
Values for Inissing safety laboratmy data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. If no pre-treatment laboratmy value is 
available, the baseline value will be assmned to be nmmal (ie, no grade [Grade OJ) for the 
summary of graded laboratmy abnmmalities. 
Values for Inissing vital signs data will not be imputed; however, a Inissing baseline result will 
be replaced with a screening result, if available. 
8.4. 
Demographic Data and Baseline Characteristics 
Demographic and baseline measurements will be summarized using standard descriptive 
methods. 
Demographic summaries will include sex, race/ethnicity, and age. 
Baseline data will include a sUllllnaty of body weight, height, body mass index, and 
randmnization stratification group (presence or absence of diabetes) and other disease 
characteristic vm·iables. 
8.5. 
Efficacy Analysis 
The biological activity ofGS-9674 will be evaluated usina radiologic endpoints and biomarker 
variables. PPD 
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8.6.
Safety Analysis
All safety data collected on or after the date that GS-9674 was first dispensed up to the date of 
last dose of GS-9674 plus 30 days will be summarized by treatment group. Data for the 
pretreatment and follow-up periods will be included in data listings. 
8.6.1.
Extent of Exposure
Data for a subject’s extent of exposure to GS-9674 will be generated from the study drug
administration eCRF. Exposure data will be summarized by treatment group. 
8.6.2.
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. A treatment-emergent 
adverse event (TEAE) will be defined as 1 or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug.

Any AEs leading to premature discontinuation of study drug.
Summaries (number and percentage of subjects) of TEAEs by SOC and PT will be provided. 
Treatment-emergent AEs will also be summarized by relationship to study drug and severity. In 
addition, TEAEs leading to premature discontinuation of study drug and study will be 
summarized and listed.
All AEs collected during the course of the study will be presented in data listings with a field for 
treatment-emergent event (yes/no). 
8.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, Median, Q1, Q3, minimum, and 
maximum) by treatment group and study visit along with the corresponding change from 
baseline values. 
Graded laboratory abnormalities will be defined using the grading scheme in the CTCAE 
Version 4.03 (Appendix 3). Grading of laboratory abnormalities for analysis purposes will be 
performed by the central laboratory.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
1 toxicity grade from baseline at any time post baseline up to and including the date of last dose 


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of study dmg plus 30 days will be smnmarized by treatment group. If baseline data are missing, 
then any graded abnmmality (ie, at least a Grade 1) will be considered treatment emergent. 
8.6.4. 
Other Safety Evaluations 
Summaty statistics for the 12-lead ECGs petfmmed at Baseline/Day 1, Week 12, and Week 24, 
will be generated. 
8.7. 
Pharmacokinetic Analysis 
Plasma concentl'ations and PK parameters (eg, AUCu.u, Cmax and Ctau) will be listed and 
smnmarized as appropriate for GS-9674 (and its metabolites as applicable) using descriptive 
statistics. 
Details of the analysis plan will be provided in the Phatmacokinetic Reporting atld Analysis 
Plan. 
8.8. 
Pharmacodynamic Analysis 
Primary PD parameters (AUCpartiaJ, Cmax, Cmin as applicable) ofFGF19 and C4 will be listed and 
summarized as appropriate for GS-9674 using descriptive statistics. 
Details of the analysis plan will be provided in the Phatmacodynamics Reporting and Analysis 
Plan. 
8.9. 
Biomarker Analysis 
Descriptive statistics ofbiomm·ker expression and change from baseline will be provided at each 
sampling time by treatment. Point estimates and 95% confidence intervals may be calculated. 
PD 
8.10. 
Sample Size 
Due to the exploratmy nature of this study, no fotmal power calculations were used to detetmine 
sample size. The number of subjects was chosen based on clinical experience with other similm· 
proof of concept studies. However, assuming that 4% of subjects in the placebo atm (N=25) and 
32% in the GS-9674 100 mg atm (N=50) have a ~ 30% reduction in MRI-PDFF at 
Week 24, this sample size will provide 80% power to detect the difference based on a two-sided 
Fisher's exact test at a significance level of 0.05. 
CONFIDENTIAL 
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8.11.
Data Monitoring Committee
An independent, external data monitoring committee (DMC) that consists of two hepatologists
and a PhD statistician will review the progress of the study and perform reviews of safety data. 
The DMC will convene once 20 subjects have been enrolled and will meet every 3 to 4 months 
thereafter to monitor the study for safety events. The DMC will meet on an ad hoc basis if there 
are at least 3 Grade ≥ 3 serious, treatment-related Common Terminology Criteria for Adverse 
Events (CTCAE) observed in the study. In the event of two similar Grade 4-CTCAE treatment-
related adverse events or one Grade 5-CTCAE treatment-related adverse event, the DMC will 
review the data and advise the sponsor regarding stopping or continuing the study. The DMC 
will provide recommendation to Gilead whether the nature, frequency, and severity of adverse 
effects associated with study treatment warrant the early termination of the study in the best 
interests of the participants, whether the study should continue as planned, or the study should 
continue with modifications. The 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 has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC/EC approval, with the exception of those necessary 
to reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB/IEC/EC-approved consent form for documenting 


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written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by the 
IRB/IEC/EC or local requirements. The consent form will inform subjects about genomic testing 
and sample retention.
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 the Central Laboratory Services Manual for specific 
laboratory instructions. NOTE: The investigator must keep a screening log showing codes, 
names, and addresses for all subjects screened and for all subjects enrolled in the study. 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 study drug, 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 GS-9674, 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.
Case Report Forms
For each subject consented, an electronic case report form (eCRF) will be completed by an 
authorized study staff member whose training for this function is documented according to study 
procedures. eCRF should be completed on the day of the subject visit to enable the sponsor to 
perform central monitoring of safety data. The Eligibility Criteria eCRF should be completed 


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only after all data related to eligibility have been received. Subsequent to data entry, a study 
monitor will perform source data verification within the electronic data capture (EDC) system. 
Original entries as well as any changes to data fields will be stored in the audit trail of the 
system. Prior to database lock (or any interim time points as described in the clinical data 
management plan), the investigator will use his/her log in credentials to confirm that the forms 
have been reviewed, and that the entries accurately reflect the information in the source 
documents. The eCRF 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 study, 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
Where possible, study drug should be destroyed at the site. 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.
The study monitor will provide instructions for return.
The study monitor will evaluate each study center’s study drug disposal procedures and provide 
appropriate instruction for destruction of unused study drug supplies. If the site has an 
appropriate standard operating procedure (SOP) for drug destruction as determined by Gilead 
QA, the site may destroy used (empty or partially empty) and unused study drug supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If study drug is destroyed on site, the investigator must maintain accurate records for all study 
drug destroyed. Records must show the identification and quantity of each unit destroyed, the 
method of destruction, and the person who disposed of the study drug. Upon study completion, 
copies of the study drug accountability records must be filed at the site. Another copy will be 
returned to Gilead. Refer to the Pharmacy Binder for study drug disposal/return instructions.
The study monitor will review study drug supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this study to 
Gilead’s appointed study monitors, the IRB/IEC/EC, or to regulatory authority or health 
authority inspectors.


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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.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/IEC/EC
in accordance with local requirements and receive documented IRB/IEC/EC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agencies. 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.
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. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
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 


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expenses paid or reimbursed for such services, including any clinical study payments, meal, 
travel expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
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/ECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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10.
REFERENCES
Afzali A, Berry K, Ioannou GN. Excellent posttransplant survival for patients with nonalcoholic 
steatohepatitis in the United States. Liver Transpl 2012;18 (1):29-37.
Bannas P, Kramer H, Hernando D, Agni R, Cunningham AM, Mandal R, et al. Quantitative 
magnetic resonance imaging of hepatic steatosis: Validation in ex vivo human 
livers. Hepatology 2015;62 (5):1444-55.
Chen J, Talwalkar JA, Yin M, Glaser KJ, Sanderson SO, Ehman RL. Early detection of 
nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease by 
using MR elastography. Radiology 2011;259 (3):749-56.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Dietrich P, Hellerbrand C. Non-alcoholic fatty liver disease, obesity and the metabolic syndrome. 
Best practice & research 2014;28 (4):637-53.
Dowman JK, Tomlinson JW, Newsome PN. Pathogenesis of non-alcoholic fatty liver disease. 
QJM 2010;103 (2):71-83.
Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal P, Kechagias S, et al. Fibrosis stage is the 
strongest predictor for disease-specific mortality in NAFLD after up to 33 years 
of follow-up [Accepted Article]. Hepatology 2014.
Faramawi MF, Wildman RP, Gustat J, Rice J, Abdul Kareem MY. The association of the 
metabolic syndrome with QTc interval in NHANES III. Eur J Epidemiol 2008;23 
(7):459-65.
Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial 
fibrillation: the Framingham study. N Engl J Med 1982;306 (17):1018-22.
Koek GH, Liedorp PR, Bast A. The role of oxidative stress in non-alcoholic steatohepatitis. Clin 
Chim Acta 2011;412 (15-16):1297-305.
Loomba R, Wolfson T, Ang B, Hooker J, Behling C, Peterson M, et al. Magnetic resonance 
elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver 
disease: a prospective study. Hepatology 2014;60 (6):1920-8.
Murakami S, Takayama F, Egashira T, Imao M, Mori A. Fermented papaya preparation halts the 
progression of non-alcoholic steatohepatitis in rats. Journal of Biophysical 
Chemisty 2013;4 (2):84-90.


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Nakamoto K, Takayama F, Mankura M, Hidaka Y, Egashira T, Ogino T, et al. Beneficial Effects 
of Fermented Green Tea Extract in a Rat Model of Non-alcoholic Steatohepatitis. 
Journal of clinical biochemistry and nutrition 2009;44 (3):239-46.
Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic 
steatohepatitis: the central role of nontriglyceride fatty acid metabolites. 
Hepatology 2010;52 (2):774-88.
Ong JP, Younossi ZM. Epidemiology and natural history of NAFLD and NASH. Clin Liver Dis 
2007;11 (1):1-16, vii.
Patel JR, Bettencourt R, Cui JY, Salotti J, Hooker J, Bhatt A, et al. Non-invasive quantitative 
decline in liver fat content on MRI and histologic response in nonalcoholic 
steatohepatitis: A secondary analysis of MOZART trial [Abstract 913]. American 
Assoication for the Study of Liver Diseases (AASLD); 2015 13-17 November; 
San Francisco, CA. pp. 659A-60A.
Ratziu V, Thibault V, Benhamou Y, Poynard T. Successful rescue therapy with tenofovir in a 
patient with hepatic decompensation and adefovir resistant HBV mutant. Comp 
Hepatol 2006;5:1.
Singh S, Venkatesh SK, Loomba R, Wang Z, Sirlin C, Chen J, et al. Magnetic resonance 
elastography for staging liver fibrosis in non-alcoholic fatty liver disease: a 
diagnostic accuracy systematic review and individual participant data pooled 
analysis. European radiology 2016;26 (5):1431-40.
Sumida Y, Niki E, Naito Y, Yoshikawa T. Involvement of free radicals and oxidative stress in 
NAFLD/NASH. Free radical research 2013;47 (11):869-80.
Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history 
of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. 
Aliment Pharmacol Ther 2011;34 (3):274-85.
Voulgari C, Tentolouris N, Papadogiannis D, Moyssakis I, Perrea D, Kyriaki D, et al. Increased 
left ventricular arrhythmogenicity in metabolic syndrome and relationship with 
myocardial performance, risk factors for atherosclerosis, and low-grade 
inflammation. Metabolism: clinical and experimental 2010;59 (2):159-65.
Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with 
analysis of risk factors. Hepatology 1990;12 (5):1106-10.
Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, et al. Prevalence of 
nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely 
middle-aged population utilizing ultrasound and liver biopsy: a prospective study. 
Gastroenterology 2011;140 (1):124-31.


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Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing 
indication for liver transplantation in patients with hepatocellular carcinoma in the 
U.S. Hepatology 2014;59 (6):2188-95.
Yeh MM, Brunt EM. Pathological features of fatty liver disease. Gastroenterology 2014;147 
(4):754-64.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table for GS-US-402-1852
Appendix 3.
CTCAE Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


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Appendix l. 
Investig11tor Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
U.S.A. 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, 
Tolerability, and Efficacy of GS-9674 in Subjects with Nonalcoholic Steatohepatitis 
(NASH) 
GS-US-402-1852 Amendment 1, 03 October 2016 
This protocol has been approved by Gilead Sciences, Inc. The foUowing signature documents 
this approval. 
PPD 
Name (Printed) 
Author 
Date 
lNVESTIGATOR STATEMENT 
l have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staiT to conduct this study as described. 1 will conduct this study as 
outlined herein and will make a reasonable eilort to complete the study within the time 
designated. 
I wiJ 1 provide all study personnel under my supervision copies of the protocoJ and access to all 
information provided by Gilead Sciences, Tnc. l 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 
Site Number 
CONFIDENTlAL 
Page 82 
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Appendix 2.
Study Procedures Table for GS-US-402-1852
Screening
Treatment
Follow-Up
Unscheduled 
Visity
Week -4
to Day 0a
Baseline/
Day 1
Week 1
± 3 days
Week 4
± 3 days
Week 8
± 3 days
Week 12
± 7 days
Week 16
± 3 days
Week 20
± 3 days
Week 24/ETb
± 7 days
Follow-Upb
± 5 days
Subject Fastingc
X
X
X
X
X
X
X
X
X
X
X
Written Informed 
Consentd
X
Review 
Inclusion/Exclusion 
Criteria
X
X
Medical History 
X
QoL: General 
Assessments (CLDQ, 
SF-36, and WPAI)e
X
X
X
QoL: Pruritus 
Assessments (VAS-
itch and 5D-itch)e
X
X
X
X
X
X
X
X
Complete Physical 
Examination
X
Symptom Driven 
Physical Examinationf
X
X
X
X
X
X
X
X
X
X
Vital Signsg
X
X
X
X
X
X
X
X
X
X
Weighth
X
Xi
X
X
X
X
X
X
Xi
X
X
Height
X


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Screening
Treatment
Follow-Up
Unscheduled 
Visity
Week -4
to Day 0a
Baseline/
Day 1
Week 1
± 3 days
Week 4
± 3 days
Week 8
± 3 days
Week 12
± 7 days
Week 16
± 3 days
Week 20
± 3 days
Week 24/ETb
± 7 days
Follow-Upb
± 5 days
Chemistryj
X
X
X
X
X
X
X
X
X
X
X
Hematologyk
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panell
X
X
X
X
X
X
X
X
X
X
Lipid Profile
X
X
X
X
X
X
X
X
Hemoglobin A1c
X
X
X
X
Blood for 
Biomarkersm
X
X
X
X
X
X
Single PK and PD
Sampling
Xn
X
X
X
X
X
X
X
HIV-1, HBV and
HCV Serology
X
Pregnancy Testo
X
X
X
X
X
X
X
X
X
Serum FSHp
X
Genomic Sampleq
X
12-lead ECG
X
X
X
X
Ultrasoundr
Xr
FibroScan®s
X
X
X
MREt
X
X
X
MRI-PDFFt
X
X
X
Urine Drug Screenu
X


GS-9674 
Protocol GS-US-402-1852 
Gilead Sciences, Inc. 
Screening 
Week -4 
toDay Oa 
Urine Collection for 
(Biomarker) 
Stool Collection for 
(Biomarker) 
fPD 
Dispense GS-9674 
and PTM GS-9674w 
Concomitant 
X 
Medications 
Adverse Events 
X 
Take GS-9674/ PTM 
GS-9674 Tabletsx 
Baseline/ 
Weekl 
Day 1 
± 3 days 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment 
Week4 
WeekS Week12 Week16 
± 3 days 
± 3 days 
± 7 days 
± 3 days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X- Daily (Baseline/ Day 1 to Week 24) 
Week20 Week24/ETb 
± 3 days 
± 7 days 
X 
X 
X 
X 
X 
X 
X 
Follow-Up 
Follow-Uph 
± 5 days 
X 
X 
Final 
Amendment 1 
Unscheduled 
VisifY 
X 
X 
a. 
The screening visit window may be extended nnder special circumstances with explicit approval of the Medical Monitor. Subjects who fail to meet eligibility criteria due to 
an abnormal laboratory result may nndergo re-testing of the abnormal analyte during the screening window. This will be done at the discretion of the investigator and with 
prior approval of the Medical Monitor. 
b. 
Subjects discontinuing the study at any time for any reason (Early Termination- ET) should complete the procedures listed for the Week 24/ET Visit AND the Follow-Up 
visit. 
c. 
Subjects must be in a fasted state for at least 8 hours prior to blood collection. 
d. 
Obtain written informed consent before initiation of any screening procedure. 
e. 
It is recommended that QoL assessments be completed prior to any study procedures being performed and prior to the subject seeing a health care provider. Refer to the Study 
Reference Binder for guidance on QoL assessment administration. 
f. 
The focus of a symptom driven physical examination will be determined by the investigator based on subject complaint. 
g. 
Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
h. 
Refer to the Study Reference Binder for specific instructions on how weight should be measured. 
1. 
During the Baseline/Day 1 and Week 24 visits, measurements of waist circumference should be performed. Refer to the Study Reference Binder for specific instructions on 
how these measurements are to be done. 
CONFIDENTIAL 
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03 October 2016 
I 


GS-9674 
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J. 
Blood chemistry will include: 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, gamrna-
glutamyl transferase ( GGT). Also includes C-Peptide and Insulin for the Baseline/Day 1, Week 4, 12, and 24 visits. 
k. 
l. 
Hematology will include: complete blood cell count with differential (red blood cells, white blood cells, platelets, and hematocrit). 
Coagulation Panel includes: PT, PTT, and INR. 
m. PPD 
n. 
0. 
p. 
q. 
r. 
PD samplmg oi1ly at BaselllielDay . 
Females of childbearing potential only (see Appendix 4). Serum pregnancy test at Screening and Urine pregnancy test at all other visits, except Week 1. 
Only required for some female subjects- see Appendix 4. 
P~D 
~----~----------------------------------------------~ 
~Itrasouna may be pertormedl.f necessary to conim n1\J"XFLD-. -----------------------------' 
S. 
Subject should be in fasted state for Fibroscan collection. Refer to the Study Reference Binder for further details. If FibroScan'~"'is not available at a site the test may be 
omitted. 
t. 
Subjects should be in fasted state for MRE/MRI-PDFF exams. Refer to the Study Reference Binder for further details. Subject must have confirmed NAFLD before 
MRE/MRI-PDFF exams are done. 
u. 
Drug screen for amphetamines, cocaine, and opiates (ie, heroin, morphine). 
v. 
PPD 
w. 
StudychUg wiffbe assignedvia fueiWRS system every 4 weeKs from Baseline/Day 1 through Week 20. 
x. 
Subjects will self-administer the study drug at the investigative site at the conclusion of the Baseline/Day 1 and Week 24 visits. 
y. 
If the Unscheduled visit is performed for the sole purpose of distribution of study drug, the assessments noted for this visit do not need to be performed. 
CONFIDENTIAL 
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03 October 2016 


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Appendix 3.
CTCAE Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf


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Appendix 4.
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-9674 has not yet been studied in pregnant women. In initial dose range-finding studies in 
pregnant mice and rabbits, there were no effects on embryofetal development other than a 
decrease in fetal body weights in the pregnant rabbits administered 1000 mg/kg/day. The 
decrease in fetal body weights are likely secondary to maternal toxicity rather than a direct effect 
of GS-9674. The NOEL for embryo/fetal development is 300 mg/kg/day in mice and 
200 mg/kg/day in rabbits. These doses were associated with exposures that are > 50-fold higher 
than the anticipated human exposure at the maximum proposed human dose of 100 mg once 
daily.
Drug-drug interaction (DDI) data do not suggest a potential for interaction with hormones used 
for contraception.
Please refer to the latest version of the Investigator’s Brochure for additional information. 


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Amendment 1
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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 30 days following the last dose of the study drug, GS-9674:

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)
Or 

Consistent and correct use of one hormonal method and one barrier method.
Barrier methods
■
Diaphragm with spermicide
■
Cervical cap with spermicide
■
Male condom (with or without spermicide)
Hormonal methods
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone
■
Implants of levonorgestrel
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring


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Amendment 1
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Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the last dose of the study drug, GS-9674.
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 (plus spermicide) during treatment and until 
90 days after the last dose of GS-9674. Additional contraception recommendations should also 
be considered if the female partner is not pregnant.
Male subjects must also refrain from sperm donation during treatment and until at least 90 days 
after the last dose of the study drug, GS-9674.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM). Female condom and male condom should not be used 
together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days (or 90 days for the partner of male subjects)
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.

Prot_000.pdf: 
Study Title: 
Sponsor: 
INDNumber: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Medical 
Monitor: 
Protocol Version/Date: 
~ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Randomized, Double-Blind, Placebo-Contmlled Study 
Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in 
Subjects with Nonalcoholic Steatohepatitis (NASH) 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
U.S.A. 
127960 
20 16-0024 96-10 
TBD 
Nonalcoholic steatohepatitis (NASH) 
GS-US-402-1852 
Name: 
Telephone: 
Fax: 
Email: 
Original: 
G-~ ~hen Djedjos, M.D. 
PPD 
PPD 
t"'t"'U 
28 June 2016 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The inf01mation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the inf01mation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessaty to obtain inf01med consent from those 
persons to whom the dmg may be administered. 


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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....................................................................12
1.
INTRODUCTION ..............................................................................................................................................16
1.1.
Background ............................................................................................................................................16
1.1.1.
GS-9674 General Information..............................................................................................17
1.1.2.
Nonclinical Toxicology........................................................................................................17
1.1.3.
Nonclinical Pharmacology ...................................................................................................18
1.1.4.
Nonclinical Pharmacokinetics..............................................................................................19
1.1.5.
Clinical Trials of GS-9674 ...................................................................................................20
1.2.
Rationale for This Study ........................................................................................................................24
1.3.
Risk/Benefit Assessment for the Study..................................................................................................26
1.4.
Compliance ............................................................................................................................................26
2.
OBJECTIVES.....................................................................................................................................................27
3.
STUDY DESIGN................................................................................................................................................28
3.1.
Study Design..........................................................................................................................................28
3.2.
Treatment Plan and Regimen .................................................................................................................28
3.3.
Biomarker Testing..................................................................................................................................29
3.3.1.
Biomarker Samples to Address the Study Objectives ..........................................................29
3.3.2.
Biomarker Samples for Optional Future Research...............................................................29
3.3.3.
Biomarker Samples for Optional Genomic Research...........................................................29
4.
SUBJECT POPULATION..................................................................................................................................31
4.1.
Number of Subjects and Subject Selection ............................................................................................31
4.2.
Inclusion Criteria....................................................................................................................................31
4.3.
Exclusion Criteria...................................................................................................................................32
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................35
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................35
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................35
5.2.
Description and Handling of GS-9674 and PTM GS-9674....................................................................35
5.2.1.
Formulation..........................................................................................................................35
5.2.2.
Packaging and Labeling .......................................................................................................36
5.2.3.
Storage and Handling...........................................................................................................36
5.3.
Dosage and Administration of GS-9674/ PTM GS-9674.......................................................................36
5.4.
Prior and Concomitant Medications.......................................................................................................37
5.5.
Prohibited Medications ..........................................................................................................................37
5.6.
Accountability for GS-9674/ PTM GS-9674 .........................................................................................39
5.6.1.
Investigational Medicinal Product Return or Disposal.........................................................39
6.
STUDY PROCEDURES ....................................................................................................................................40
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................40
6.2.
Pretreatment Assessments – Screening Visit .........................................................................................40
6.3.
Baseline/Day 1 Randomization and Assessments..................................................................................42
6.4.
Treatment Assessments..........................................................................................................................43


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6.4.1.
Week 1 .................................................................................................................................43
6.4.2.
Week 4 Visit.........................................................................................................................44
6.4.3.
Week 8, 16, and 20 Visits.....................................................................................................45
6.4.4.
Week 12 Visit.......................................................................................................................46
6.4.5.
Week 24 Visit.......................................................................................................................47
6.4.6.
Unscheduled Visits...............................................................................................................48
6.5.
Follow-Up Visit .....................................................................................................................................49
6.6.
Assessments for Premature Discontinuation from Study.......................................................................49
6.7.
Criteria for Discontinuation of Study Treatment....................................................................................50
6.8.
PK and PD Substudy Visits....................................................................................................................50
6.9.
Description of Assessments ...................................................................................................................51
6.9.1.
Clinical Laboratory Analytes ...............................................................................................51
6.9.2.
Medical History....................................................................................................................52
6.9.3.
Physical Examination...........................................................................................................52
6.9.4.
Quality of Life (QoL) Assessments......................................................................................52
6.9.5.
Electrocardiogram................................................................................................................53
6.9.6.
FibroScan® ...........................................................................................................................53
6.9.7.
MRE and MRI-PDFF...........................................................................................................53
6.10.
End of Study Definition .........................................................................................................................54
6.11.
Post Study Care......................................................................................................................................54
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................55
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................55
7.1.1.
Adverse Events.....................................................................................................................55
7.1.2.
Serious Adverse Events........................................................................................................55
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................56
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................56
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................56
7.2.2.
Assessment of Severity ........................................................................................................57
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................57
7.4.
Gilead Reporting Requirements.............................................................................................................59
7.5.
Toxicity Management ............................................................................................................................59
7.6.
Special Situations Reports......................................................................................................................62
7.6.1.
Definitions of Special Situations..........................................................................................62
7.6.2.
Instructions for Reporting Special Situations.......................................................................62
8.
STATISTICAL CONSIDERATIONS................................................................................................................64
8.1.
Analysis Objectives and Endpoints........................................................................................................64
8.1.1.
Analysis Objectives..............................................................................................................64
8.1.2.
Primary Endpoint .................................................................................................................64
8.1.3.
Exploratory Efficacy Endpoints ...........................................................................................65
8.2.
Analysis Conventions.............................................................................................................................65
8.2.1.
Analysis Sets ........................................................................................................................65
8.2.2.
Interim Analysis ...................................................................................................................67
8.3.
Data Handling Conventions ...................................................................................................................67
8.4.
Demographic Data and Baseline Characteristics ...................................................................................67
8.5.
Efficacy Analysis ...................................................................................................................................67
8.6.
Safety Analysis.......................................................................................................................................68
8.6.1.
Extent of Exposure...............................................................................................................68
8.6.2.
Adverse Events.....................................................................................................................68
8.6.3.
Laboratory Evaluations ........................................................................................................68
8.6.4.
Other Safety Evaluations......................................................................................................69


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8.7.
Pharmacokinetic Analysis......................................................................................................................69
8.8.
Pharmacodynamic Analysis ...................................................................................................................69
8.9.
Biomarker Analysis................................................................................................................................69
8.10.
Sample Size............................................................................................................................................69
8.11.
Data Monitoring Committee ..................................................................................................................70
9.
RESPONSIBILITIES..........................................................................................................................................71
9.1.
Investigator Responsibilities ..................................................................................................................71
9.1.1.
Good Clinical Practice..........................................................................................................71
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)/ 
Ethics Committee (EC) Review and Approval ....................................................................71
9.1.3.
Informed Consent.................................................................................................................71
9.1.4.
Confidentiality......................................................................................................................72
9.1.5.
Study Files and Retention of Records ..................................................................................72
9.1.6.
Case Report Forms...............................................................................................................73
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................74
9.1.8.
Inspections............................................................................................................................74
9.1.9.
Protocol Compliance............................................................................................................75
9.2.
Sponsor Responsibilities ........................................................................................................................75
9.2.1.
Protocol Modifications.........................................................................................................75
9.2.2.
Study Report and Publications .............................................................................................75
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................75
9.3.1.
Payment Reporting...............................................................................................................75
9.3.2.
Access to Information for Monitoring..................................................................................76
9.3.3.
Monitoring and Oversight of Biomarker Specimens............................................................76
9.3.4.
Access to Information for Auditing or Inspections ..............................................................76
9.3.5.
Study Discontinuation..........................................................................................................76
10.
REFERENCES ...................................................................................................................................................77
11.
APPENDICES ....................................................................................................................................................80
Appendix 1.
Investigator Signature Page....................................................................................................81
Appendix 2.
Study Procedures Table for GS-US-402-1852 .......................................................................82
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............86
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................87


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LIST OF IN-TEXT TABLES
Table 1-1.
Exposure Margins for GS-9674 Based on Observed GS-9674 Exposure After 
Administration of 100 mg GS-9674 QD Under Fed Conditions at Steady-State in 
Cohort 5 Compared to Exposures Observed at NOAEL Doses in Mouse and 
Cynomolgus Monkey .............................................................................................................18
Table 1-2.
Preliminary Safety Summary of Subjects Following Single- and Multiple-Dose 
Administration of GS-9674 Under Fasting or Fed Conditions in Healthy Volunteers 
(GS-US-402-1851) .................................................................................................................21
Table 1-3.
Preliminary Plasma Pharmacokinetic Parameters of GS-9674 Following Single- and 
Multiple-Dose Administration of GS-9674 Under Fasting or Fed Conditions in 
Healthy Volunteers (GS-US-402-1851) .................................................................................23
Table 1-4.
Preliminary Pharmacodynamic Parameters (FGF19 and C4) Following Multiple-
Dose Administration of Placebo, or GS-9674 Under Fasting or Fed Conditions in 
Healthy Volunteers (GS-US-402-1851) .................................................................................24
Table 5-1.
List of Prohibited Medications ...............................................................................................38
LIST OF IN-TEXT FIGURES
Figure 3-1.
Overall Study Design .............................................................................................................28


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Dr.
Foster City, CA 94404, U.S.A.
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Subjects 
with Nonalcoholic Steatohepatitis (NASH)
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
127960
2016-002496-10
TBD
Study Centers 
Planned:
Approximately 50 centers in North America, Europe, and Asia Pacific
Objectives:
The primary objective of this study is to evaluate the safety and 
tolerability of GS-9674 in subjects with NASH as assessed by magnetic 
resonance imaging-proton density fat fraction (MRI-PDFF) and magnetic 
resonance elastography (MRE).
The exploratory objectives of this study are listed in Section 2.
Study Design:
This is a Phase 2, randomized, double-blind, placebo-controlled study 
evaluating the safety, tolerability, and efficacy of GS-9674 in subjects 
with NASH as assessed by MRI-PDFF and MRE.
Participation in the study can last up to 32 weeks, which includes a 
4-week screening period, a 24-week treatment period during which study 
drug will be administered, and a 4-week follow-up period. The screening 
period may be extended under special circumstances with the explicit 
approval of the Medical Monitor.
Subjects meeting the study’s entry criteria will be randomly assigned in a 
2:2:1 ratio to 1 of 3 treatment groups as shown in the figure below:


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Randomization will be stratified by the presence or absence of diabetes 
mellitus as determined by medical history, use of medication for 
indication of diabetes mellitus, or based on screening lab values if 
previously undiagnosed (ie, hemoglobin A1c ≥ 6.5% OR fasting plasma 
glucose ≥126 mg/dL).
Number of Subjects 
Planned:
Approximately 125 Subjects
Target Population:
Males and non-pregnant females between 18-75 years of age without 
cirrhosis and with NASH as assessed by magnetic resonance imaging 
(MRI) and magnetic resonance elastography (MRE).
Duration of 
Treatment:
24 Weeks
Diagnosis and Main 
Eligibility Criteria:
Key inclusion and exclusion criteria are as follows:
Inclusion Criteria:

Meets all of the following conditions:
a.
A clinical diagnosis of nonalcoholic fatty liver disease (NAFLD) 
with imaging documenting fatty liver within the past two years. 
If necessary an ultrasound may be performed during screening to 
confirm NAFLD. Note: criterion a. must be met before 
evaluating criteria b. and c.
b. Screening MRI-PDFF with ≥10% steatosis
c.
Screening MRE with liver stiffness ≥ 2.90 kPa

Platelet count ≥ 100,000/mm3;

Creatinine Clearance (CLcr) as calculated by the Cockcroft-Gault 
equation ≥60 ml/min;


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Exclusion Criteria:

Pregnant or lactating females;

ALT > 5X ULN;

Other causes of liver disease including autoimmune, viral, and 
alcoholic liver disease;

Cirrhosis of the liver as defined by any of the following:
a.
Cirrhosis on historical liver biopsy (eg, Brunt/Kleiner stage 4 or 
equivalent)
b. Evidence of cirrhosis on liver imaging (eg, ultrasound, CT, or 
MRI) including a nodular liver surface, splenomegaly, or portal 
venous collaterals
c.
Screening FibroSURE/FibroTest® ≥ 0.75, as determined by the 
central laboratory
d. Prior history of decompensated liver disease, including ascites, 
hepatic encephalopathy, or variceal bleeding;

BMI < 18 kg/m2;

INR > 1.2 unless on anticoagulant therapy;

Total bilirubin > 1x ULN, except with diagnosis of Gilbert’s 
syndrome.
Refer to Sections 4.2 and 4.3 for complete listing of inclusion and 
exclusion criteria.
Study 
Procedures/
Frequency:
After signing the informed consent form, subjects will complete a 
screening visit which will include the following assessments: complete 
medical history, physical examination (PE), vital signs, laboratory 
assessments (blood chemistry, hematology, coagulation panel, 
hemoglobin A1c, biomarkers), viral serology, pregnancy test (for females 
of child-bearing potential), standard 12-lead ECG, MRI-PDFF and MRE 
examinations, urine drug test, review of concomitant medications and 
adverse events.
After the screening period and a randomization visit at Baseline/Day 1, 
study visits will occur on Weeks 1, 4, 8, 12, 16, 20 and 24 with a 
Follow-Up visit 4 weeks after the last dose of study drug. At minimum, 
vital signs, symptom driven PE, safety laboratory tests (blood chemistry, 
hematology, and coagulation panel), review of concomitant medications 
and adverse events will be done at every visit.
Eligible subjects will be randomized to one of 3 treatment groups. Prior 
to initial dosing, required Baseline/Day 1 assessments will be performed 
and will include Quality of Life (QoL) assessments (general and 
pruritus), symptom driven PE, vital signs, laboratory assessments, 
pregnancy tests (for females of child-bearing potential), urine, blood, and 


GS-9674 
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stool collection for biomarker assessment, single PD sampling, standru·d 
12-lead ECG, FibroScan®, review of concomitant medications ru1d 
adverse events. 
PPD 
Subjects will return to clinic for a safety visit at Week 1. Week 1 
assessments include QoL: pmritus assessments, symptom driven PE, 
vital signs, and laboratory tests (blood chemistly, hematology, 
coagulation panel, lipid profile, biomarkers, PK and PD sampling). 
While on study, subjects will undergo the following procedmes and 
laboratmy assessments: 
• 
MRE and MRI-PDFF at Weeks 12 and 24 
• 
FibroScan® at Baseline/Day 1 and Weeks 12 and 24 
• 
Single PK and PD sampling at Baseline/Day 1 (PD only) and at 
Weeks 1, 4, 8, 12, 16, 20, and 24 
• 
Blood for Biomarkers at Baseline/Day 1, and Weeks 1, 4, 12, and 24 
• 
12-lead ECGs at Baseline/Day 1, and Weeks 12 and 24 
• 
Blood chemistiy, hematology, coagulation panel, and fasting lipid 
profile at Baseline/Day 1 and at Weeks 1, 4, 8, 12, 16, 20, and 24 
• 
Hemoglobin Ale (HbA1c) at Baseline/Day 1, Weeks 12 and 24 
• 
Stool collection at Baseline/Day 1 and Week 24 
• 
Urine collection at Baseline/Day 1 and Weeks 1, 4, 12, and 24 
• 
Urine pregnancy test (females of childbearing potential only) at 
Baseline/Day 1 and Weeks 4, 8, 12, 16, 20, and 24 
• 
QoL: general assessments [SF-36 health smvey, Chronic Liver 
Disease Questionnaire (CLDQ), and Work Productivity and Activity 
Impaitment (WPAI)] at Baseline/Day 1 and Weeks 12 and 24 
• 
QoL: pmritus assessments (VAS-itch and 5D-itch) at Baseline/Day 1 
and Weeks 1, 4, 8, 12, 16, 20, and 24 
Subjects will return for their final visit, the Follow-Up visit, 4 Weeks 
after the last dose of study dmg. At this visit assessments include a 
symptom driven PE, vital signs, safety laboratory tests, and review of 
concomitant medications and adverse events. A urine pregnancy test will 
be perf01med for females of child bearing potential only. 
PO 
Page 9 
28 June 2016 


GS-9674 
Protocol GS-US-402-1852 
Gilead Sciences, Inc. 
Test Product: 
PPD 
GS-9674 30 mg tablet administered orally once daily with food. 
GS-9674 100 mg tablet administered orally once daily with food. 
Final 
Original 
Reference Product: 
Placebo-to-match (PTM) GS-9674 30 mg tablet administered orally once 
daily with food. 
Dose and Mode of 
Administration: 
Criteria for 
Evaluation: 
Safety: 
Efficacy: 
CONFIDENTIAL 
Placebo-to-match (PTM) GS-9674 100 mg tablet administered orally 
once daily with food. 
• 
Treatment Group A: GS-9674 30 mg (1 x 30 mg tablet)+ PTM 
GS-9674 100 mg (1 x PTM 100 mg tablet) administered orally once 
daily with food 
• 
Treatment Group B: GS-9674 100 mg (1 x 100 mg tablet) + PTM 
GS-9674 30 mg (1 x PTM 30 mg tablet) administered orally once 
daily with food 
• 
Treatment Group C: PTM GS-9674 30 mg (1 x PTM 30 mg tablet) 
+ PTM GS-9674 100 mg (1 x PTM 100 mg tablet) administered 
orally once daily with food 
The primaty endpoint is the safety of GS-9674 in subjects with NASH. 
Safety will be assessed during the study through the repmiing of AEs, 
and by clinicallaboratmy tests and vital sign assessments at various time 
points during the study. Concomitant medication usage will also be 
assessed throughout the study. 
An independent, extemal Data Monitoring Committee (DMC) that 
consists of two hepatologists and a PhD statistician will convene once 
20 subjects have been enrolled and eve1y 3 to 4 months thereafter to 
monitor the study for safety events. The DMC will meet on an ad hoc 
basis if there are at least 3 Grade ~ 3 serious, treatment-related 
Common Terminology Criteria for Adverse Events (CTCAE) observed in 
the study. In the event of two similar Grade 4-CTCAE treatment-related 
adverse events or one Grade 5-CTCAE treatment-related adverse event, 
the DMC will review the data and advise the sponsor regm·ding stopping 
or continuing the study. 
Efficacy will be assessed through a number of exploratmy endpoints. 
These exploratmy endpoints are described in Section 8.1.3. 
Page 10 
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Phrumacokinetic and A single predose PK and PD blood srunple will be collected at each on-
Pha~macodynamic : 
treatment visit for all subjects. Plasma concentrations ofGS-9674, 
GS-716070 (metabolite ofGS-9674), and other metabolites as 
appropriate, will be determined for PK analyses as applicable. Plasma or 
semm concentrations ofFGF19, C14, and bile acids will be detetmined 
as applicable for PD analyses. 
Statistical Methods: 
Safety Analysis: 
Efficacy 
Analysis: 
Exploratmy 
Analysis: 
Srunple Size: 
All safety data collected will be listed and be smnmarized, as appropriate, 
by treatment group. 
The biological activi!Y of GS-9674 will be evaluated usina biomarker 
variables. PO 
PPD 
Due to the exploratmy natme of this study, no fmmal power calculations 
were used to detetmine sample size. The number of subjects was chosen 
based on clinical experience with other simila~· proof of concept studies. 
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents. 
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
Ab
antibody
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
Apo B
apolipoprotein B
aPTT
activated partial thromboplastine time
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the plasma/serum concentration versus time curve
AUCtau
area under the plasma/serum concentration versus time curve over the dosing 
interval
AUCinf
area under the plasma/serum concentration versus time curve extrapolated to 
infinite time, calculated as AUC0-last + (Clast/z)
AUCpartial
partial area under the plasma/serum concentration versus time curve
BAP
Biomarker Analysis Plan
BCRP
breast cancer resistance protein
BMI
body mass index
BUN
blood urea nitrogen
BW
body weight
C4
7-alpha-hydroxy-4-cholesten-3-one
CBC
complete blood count
cc
cubic centimeter
CFR
code of federal regulations
CI
confidence interval
CK-18
cytokeratin 18
CL
systemic clearance
CLcr
creatinine clearance
CLDQ
Chronic Liver Disease Questionnaire
Clast
last observed quantifiable plasma/serum concentration of the drug
Cmax
maximum observed plasma/serum concentration of drug
Cmin
minimum observed plasma/serum concentration of drug
Ctau
observed drug concentration at the end of the dosing interval
CRO
contract (or clinical) research organization 
CTCAE
Common Terminology Criteria for Adverse Events
CSR
Clinical Study Report
CV
cardiovascular
CYP
cytochrome P450
CYP3A
cytochrome P4503A
DILI
drug induced liver injury


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DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health
EC
ethics committee
EC50
concentration of drug that gives half-maximal response
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
ELF™Test
enhanced liver fibrosis test
ET
early termination
EU
European Union
ESA
erythropoiesis-stimulating agent
FAS
Full Analysis Set
FDA
(United States) Food and Drug Administration
FGF19
fibroblast growth factor 19
FSH
follicle-stimulating hormone
FXR
farnesoid X receptor
GCP
good clinical practice
GCSF
granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
Hb
hemoglobin
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
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HIV-1
human immunodeficiency virus type 1
HLT
high-level term
HLGT
high-level group term
HMG-CoA
3-hydroxy-3-methylglutaryl-coenzyme A
HOMA-IR
homeostatic assessment of insulin resistance
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use


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ID
identification
IEC
independent ethics committee/ institutional ethics committee
IND
Investigational New Drug (Application)
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
LDH
lactate dehydrogenase
LLT
lower-level term
MedDRA
Medical Dictionary for Regulatory Activities
MCV
mean corpuscular volume
miRNA
micro ribonucleic acid
mm Hg
millimeters of mercury
MRE
magnetic resonance elastography
MRI
magnetic resonance imaging
MRI-PDFF
magnetic resonance imaging – proton density fat fraction
NAFLD
nonalcoholic fatty liver disease
NAS
NAFLD Activity Score
NASH
nonalcoholic steatohepatitis
NMR
nuclear magnetic resonance spectroscopy
NOAEL
no observed adverse event level
OATP
organic anion-transporting polypeptide
oz
ounce 
PD
pharmacodynamic
PE
physical exam
PK
pharmacokinetic
P-gp
P-glycoprotein
pH
measure of acidity 
PT
preferred term
PT
prothrombin time
PTM
placebo-to-match
PTT
partial prothrombin time
QA
quality assurance
QD
once a day
QoL
quality of life
RBC
red blood cell count
RNA
ribonucleic acid
ROS
reactive oxygen species
SADR
serious adverse drug reaction
SAE
serious adverse event


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SAP
statistical analysis plan
SF-36
Short Form (36) Health Survey
SOC
system organ class
SOP
standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
t1/2
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)
TEAE
treatment-emergent adverse event
Tlast
last measured concentration
Tmax
time (observed time point) of Cmax
TGR5
bile acid receptor
TPO
thrombopoietin
TR-FRET
time-resolved fluorescence resonance energy transfer
UGT1A1
uridine diphosphate glucuronosyltransferase 1A1
ULN
upper limit of the normal range
US
United States
Vss
volume of distribution
VAS
visual analog scale
WBC
white blood cell count
WPAI
work productivity and activity impairment questionnaire


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1.
INTRODUCTION
1.1.
Background
Chronic liver disease and the consequences of end-stage liver disease are increasing globally 
despite improved prevention and treatment of viral hepatitis. This is due to the emerging 
epidemics of obesity, metabolic syndrome, and diabetes mellitus that are leading to an increased 
incidence of nonalcoholic fatty liver disease (NAFLD). Nonalcoholic fatty liver disease is 
characterized by the excess accumulation of lipid droplets within the liver, also known as hepatic 
steatosis. Prevalence rates of NAFLD range from 6% to 37% worldwide {Vernon et al 2011}, 
{Ong et al 2007}. Nonalcoholic steatohepatitis (NASH), an aggressive form of NAFLD 
characterized by the presence of inflammation and hepatocellular ballooning, with or without 
fibrosis, is present in approximately 25% of patients with NAFLD. Nonalcoholic steatohepatitis 
is associated with increased liver-related mortality {Williams et al 2011}, {Ong et al 2007}. In the 
United States (US), it has been estimated that 3% to 6% of the population {Vernon et al 2011}, 
{Wanless et al 1990}, or the equivalent of up to 15 million adults, have NASH. NASH represents 
a significant and growing unmet medical need for which there are no currently approved 
therapies. Furthermore, as NASH is a manifestation of the metabolic syndrome, risk factors for 
cardiovascular disease (eg, atherosclerotic disease, cardiac arrhythmogenicity) frequently coexist 
in these patients {Faramawi et al 2008}, {Voulgari et al 2010}, {Dietrich et al 2014}. A treatment that 
targets the underlying metabolic disorder could potentially ameliorate these cardiovascular risks 
and associated morbidity and mortality.
Nonalcoholic steatohepatitis is primarily thought to occur as the result of the metabolic 
syndrome, the impact of obesity, insulin resistance, and dyslipidemia in the liver. Simple 
steatosis is not sufficient to cause liver injury; it is the presence of inflammation and 
hepatocellular injury on the background of steatosis that defines NASH and results in the 
progression to end-stage liver disease and its complications. The “2-hit” hypothesis of NASH 
suggests that in the setting of steatosis and metabolic dysfunction, increased oxidative stress and 
the generation of reactive oxygen species (ROS) likely mediate the inflammatory changes in the 
liver (steatohepatitis) that may lead to progressive fibrosis {Dowman et al 2010}, {Kannel et al 
1982}, {Koek et al 2011}, {Sumida et al 2013}. The major pathways in NASH disease progression 
include those involved in metabolic dysfunction in the hepatocyte, and activation of hepatic 
stellate cells and macrophages leading to progressive inflammation and liver fibrosis. Advanced 
fibrosis and cirrhosis are characterized by extensive collagen deposition and remodeling of the 
extracellular matrix. In addition, evidence suggests that lipotoxic intermediates of fatty acids 
likely contribute to the etiology of NASH {Neuschwander-Tetri 2010}.
Over time, NASH may result in progressive liver fibrosis, ultimately leading to cirrhosis in 
10-20% of affected patients. Advanced fibrosis (bridging fibrosis or cirrhosis) is associated with 
increased morbidity and mortality {Ekstedt et al 2014}, {Yeh et al 2014}. Patients with cirrhosis 
may develop hepatocellular carcinoma (HCC) and other complications of end-stage liver disease, 
including jaundice, fluid retention (edema and ascites), portal hypertension and variceal 
bleeding, impaired coagulation and hepatic encephalopathy. Decompensated liver disease, as 


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defined by the development of one of the above complications, has a high mortality and the only 
known effective treatment is liver transplantation. With the increasing prevalence of obesity and 
obesity-related diseases, NASH is expected to become the leading indication for liver
transplantation, and the leading etiology of HCC among liver transplant recipients in the US 
{Wong et al 2014}, {Afzali et al 2012}.
1.1.1.
GS-9674 General Information
GS-9674 is a potent agonist of Farnesoid X Receptor (FXR) whose activity in intestinal 
epithelial cells results in the release of fibroblast growth factor 19 (FGF19). FGF19 is an 
endocrine peptide which drives a signaling cascade to decrease lipogenesis, gluconeogenesis, 
hepatic triglyceride accumulation, and bile acid synthesis. Please refer to the Investigator’s 
Brochure (IB) for additional information on GS-9674, including:

In vitro FXR agonism

Nonclinical pharmacokinetics and in vitro metabolism

Nonclinical pharmacology and toxicology
1.1.2.
Nonclinical Toxicology
The nonclinical toxicity profile of GS-9674 has been assessed in mice and cynomolgus monkeys 
administered GS-9674 orally for 4 weeks in both species and for 13 weeks in monkeys and 26 
weeks (in-life phase only) in mice. GS-9674-related effects included non-adverse findings in the 
liver for both species that are likely related to the pharmacology of the compound. In both mice 
and cynomolgus monkeys, mild increases in alkaline phosphatase (ALP) activity, liver weight, 
and hepatocellular hypertrophy were observed after 4 weeks of dosing. Minimal oval cell 
hyperplasia was also observed in the liver of cynomolgus monkeys after 4 weeks of dosing. The 
increases in ALP activity and liver weights persisted but did not progress with longer term 
dosing in monkeys (13 weeks) but the histopathological changes were no longer evident. In 
mice, the ALP activity and liver weights were still present and were modestly more pronounced 
with longer term dosing (26 weeks). In mice, the above findings were observed at 
≥100 mg/kg/day after 4 weeks of dosing and at all doses (≥ 20 mg/kg/day) after 26 weeks of 
dosing.  In monkeys, the above findings were observed at doses of 300 mg/kg/day after both 
4 and 13 weeks of dosing. Decreases in cholesterol (≥60 mg/kg/day) and triglycerides 
(≥100 mg/kg/day) as well as increased albumin (≥60 mg/kg/day) observed in mice after 
4 and/or 26 weeks of dosing as well as the decrease in serum bile acids (300 mg/kg/day) in 
monkey after 13 weeks of dosing are also likely to be related to the pharmacology of GS-9674.
Other minimal to mild, non-adverse findings observed after 13 or 26 weeks of dosing in 
monkeys or mice, respectively, that were considered GS-9674-related included decreased red 
blood cell parameters (mouse; ≥20 mg/kg/day), increased platelets (mouse; 600/300 mg/kg/day), 
shortened activated partial thromboplastin time (monkey; 300 mg/kg/day), and increased 
phosphorus (mouse; 600/300 mg/kg/day). Findings present in monkeys after 13 weeks of dosing 
were reversible after a 4 week nondosing recovery period. In the 26 week mouse study, there 


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were no adverse findings based on the in-life data at 60 mg/kg/day, and the no-observed-adverse 
effect level (NOAEL) in monkeys after 13 weeks of dosing was 300 mg/kg/day. 
Preliminary steady-state PK data from Cohort 5 (administration of GS-9674 100 mg with food) 
in the ongoing Phase 1 study of GS-9674 (GS-US-402-1851: Section 1.1.5.1) indicate adequate 
safety margins based on GS-9674 exposures at the nonclinical NOAEL doses in mouse and 
cynomolgus monkey (Table 1-1).
Table 1-1.
Exposure Margins for GS-9674 Based on Observed GS-9674 
Exposure After Administration of 100 mg GS-9674 Once Daily Under 
Fed Conditions at Steady-State in Cohort 5 Compared to Exposures 
Observed at NOAEL Doses in Mouse and Cynomolgus Monkey 
Species
NOAEL
Exposure Margina
Dose 
mg/kg/day
AUCtau
µg*hr/mL
Mouse
60b
110
22
Cynomolgus Monkey
300
110
22
a
Calculated using observed human AUCtau of 5.02 µg*hr/mL at 100 mg QD dose administered fed from cohort 5 in 
Study GS-US-402-1851.
1.1.3.
Nonclinical Pharmacology
GS-9674 is a potent and selective agonist of FXR. This conclusion is supported by the following 
data: 1) modeling demonstrated an interaction of GS-9674 with the binding domain of FXR 
consistent with agonist activity, 2) GS-9674 induced an agonist response in a time-resolved 
fluorescence resonance energy transfer (TR-FRET) biochemical assay with an EC50 of 16 nM, 
which was comparable to that of other known FXR agonists, and 3) GS-9674 did not activate the 
structurally similar bile acid receptor TGR5, did not activate other nuclear hormone receptors, 
and did not bind to a panel of other off-target receptors and enzymes.
The cellular potency of GS-9674 to activate FXR-mediated transcription was characterized using 
a firefly luciferase reporter gene engineered under the control of a FXR/RXR response element 
(PC-402-2012). GS-9674 caused complete FXR activation with an EC50 value of 43 nM, which 
was more potent than chenodeoxycholic acid (EC50 of 1770 nM).
Oral dose-ranging experiments in male cynomolgus monkeys demonstrated maximal increases in 
plasma FGF19 at a dose of 5 mg/kg (PC-402-2016). In addition, the oral administration of 
GS-9674 (30 mg/kg) to cynomolgus monkeys directly activated intestinal FXR, as measured by 
the expression of FXR-target genes in the ileum (15-fold increase in FGF19 mRNA, and a 2-fold 
increase in organic solute transporter (OST)α and (OST)β mRNA) (PC-402-2005).
The effects of GS-9674 on FGF19 levels were compared in cynomolgus monkeys following both 
oral and intravenous (IV) administration (PC-402-2016). Despite greater exposures following IV 
administration, only the oral administration of GS-9674 increased circulating FGF19 levels. 


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These data suggest that intestinal FXR agonism by GS-9674 causes FGF19 production, whereas 
low systemic free drug concentrations limit effects following IV administration ofGS-9674. 
GS-9674 was evaluated in a choline-deficient high fat diet /NaN02 rat model of liver fibrosis 
(PC-402-2015). This in vivo model utilized "2 hits" to mimic the metabolic and oxidative stress 
components ofNASH disease in humans {Nakamoto et al2009}, {Murakami et a12013}. Treatment 
with GS-9674 dose-dependently reduced both biochemical and histological measures of liver 
fibrosis in this model. 
Safety pharmacology studies have been conducted to examine the potential effects ofGS-9674 
on the cardiovascular (CV), respiratory, and central nervous system (CNS) systems. There were 
no GS-9674-related effects on the CNS or respiratory system in mice administered up to 
600 mg/kg. In addition, there was no significant human ether-a-go-go-related gene inhibition at 
concentrations up to 100 J.lM or GS-9674-related effects on the CV system in monkeys 
administered up to 300 mg/kg. 
Overall, the results from these pharmacology studies demonstrate that GS-9674 is a potent and 
selective agonist of intestinal FXR with the potential to benefit NASH patients by inducing 
FGF19 production. 
1.1.4. 
Non clinical Phannacokinetics 
GS-9674 has shQwn low oral bioavailability in nonclinical species (al?proximately 10% and 20% 
when dosed as PPD 
j ). Low, 
pH-dependent solUbility and effiux transport have been id entified as factors liKely limiting 
GS-9674 absorption. 
The low systemic clearance (CL) of GS-9674 in rats, dogs and monkeys was considerably lower 
than the predicted hepatic clearance based on in vitro studies with hepatocytes. This discrepancy 
is most likely a result of protein-restricted clearance in vivo due to the very high plasma protein 
binding(> 99.6%) across species. The volume of distribution (V ss) ofGS-9674 was consistent 
with extracellular fluid (ranging from 0.16-0.21 Llkg) in rats, dogs, and monkeys. 
After oral dosing to albino and pigmented mice, C4C]GS-9674-derived radioactivity was 
distributed to most of the tissues, with the highest maximum concentrations of radioactivity 
determined in organs of absorption and excretion. Generally similar distribution patterns and 
tissue concentrations of C4C]GS-9674-derived radioactivity were observed in albino and 
pigmented mice with no observed binding to melanin. In both strains, no quantifiable 
radioactivity was detected in brain, suggesting C4C]GS-9674-derived radioactivity did not cross 
the blood: brain barrier. Fecal elimination was a predominant route of elimination of 
C4C]GS-9674-derived radioactivity in both mice (85. 7% and 5.45% recovered in feces and urine, 
respectively) and monkeys (78.2% and 69.7% recovered in feces in intact and bile duct 
cannulated animals) likely representing drug not absorbed from the gastrointestinal tract. 
Approximately 6% of the administered radioactivity was excreted in bile and urine in monkeys. 
Radiolabeled material was primarily excreted within the first 48 hours. 
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GS-9674 undergoes oxidative metabolism in human hepatocytes. Comparison of metabolism in 
hepatocytes from mice, rats, dogs, monkeys, and humans did not identify any metabolites unique 
to humans, supporting the selection of mice and monkeys for the assessment of the toxicology of 
GS-9674. Of the recombinant human CYP isozymes tested, CYP2C8, CYP3A4, and CYP2C19 
were shown to metabolize GS-9674. Potent inhibitors of these CYPs therefore may affect 
metabolism of GS-9674. GS-9674 had little inhibitory effect on the activities of CYP1A2, 
CYP2B6, CYP2C19 or CYP2D6 (IC50 > 25 μM). For CYP2C8, CYP2C9, and CYP3A, IC50
values of 2.4 to 13.6 μM were obtained but GS-9674 was not a mechanism-based inhibitor of 
these enzymes. GS-9674 showed moderate inhibition of human UGT1A1, sodium-taurocholate 
cotransporting polypeptide (NTCP), and bile salt export pump (IC50 2.8-7.7 μM). GS-9674 
inhibited human OATP1B1, OATP1B3, and OATP2B1 with IC50 values of 0.68, 0.41, and 
0.21 μM, respectively. GS-9674 therefore has the potential to affect hepatic/intestinal uptake of 
OATP substrates or metabolism of CYP2C8, CYP2C9, or CYP3A4 substrates when its 
concentrations are sufficiently high. However, low solubility, high protein binding (> 99.98%) 
and low systemic levels reduce the potential for GS-9674 to cause drug-drug interactions via 
inhibition of metabolic enzymes and transporters.
GS-9674 is a substrate for efflux transporters P-glycoprotein and breast cancer resistance protein, 
as well as the uptake transporters OATP1B1, 1B3, and 2B1, and NTCP. Inhibitors or genetic 
polymorphisms affecting the activity of these transporters may affect GS-9674 intestinal 
absorption and hepatic uptake. This was illustrated in an in vivo study in monkeys where 
pretreatment with cyclosporin A, a known inhibitor of efflux transporters, increased the 
bioavailability of GS-9674 approximately 5-fold.
GS-9674 is highly selective for FXR over other nuclear hormone receptors in cell-based reporter 
assays, including those associated with potential for induction of human drug metabolizing 
enzymes and transporters (eg, pregnane X receptor, constitutive androstane receptor). Thus the 
liability of GS-9674 to cause drug-drug interactions through proteins regulated by these nuclear 
receptors is low.
1.1.5.
Clinical Trials of GS-9674
Ongoing clinical experience with GS-9674 includes a Phase 1 clinical study (GS-US-402-1851). 
A brief summary of results from this ongoing study is presented below.
1.1.5.1.
GS-US-402-1851
Study GS-US-402-1851 is an ongoing Phase 1, randomized, placebo-controlled, single- and 
multiple-dose study with 4 prespecified, staggered dose-escalation cohorts and 4 randomized, 
placebo-controlled, single- and multiple-dose cohorts with adaptive dose selection and dose 
frequency.
Preliminary data based on an interim safety analysis as of 22 June 2016 are provided in the 
following sections. A total of 105 subjects have been randomized into 7 cohorts. One subject 
withdrew consent after randomization but prior to dosing and was not replaced. Therefore, safety 
data described below includes 104 dosed subjects.


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Subjects received single and multiple doses of GS-9674 at a dose of 10 mg QD (Cohort 1), 
30 mg QD (Cohort 2), 100 mg QD (Cohort 3), or 300 mg QD (Cohort 4) administered in a 
fasting state, or GS-9674 100 mg QD administered in a fed state (Cohort 5), GS-9674 50 mg 
BID (Cohort 6), or 15 mg BID (Cohort 7). A summary of treatment-emergent adverse events 
(AEs) is provided in Table 1-2. Overall, the rate of any AEs was similar between subjects treated 
with GS-9674 or placebo. All AEs were Grade 1 or 2 in severity; AEs occurring in greater than 
two GS-9674 treated subjects were back pain (n = 5), diarrhea (n=3), and headache (n = 6).
Table 1-2.
Preliminary Safety Summary of Subjects Following Single- and 
Multiple-Dose Administration of GS-9674 Under Fasting or Fed 
Conditions in Healthy Volunteers (GS-US-402-1851)
Cohort 1: 
10 mg 
QD 
Fasted
(N = 12)
Cohort 2: 
30 mg 
QD 
Fasted
(N = 12)
Cohort 3: 
100 mg 
QD 
Fasted
(N = 12)
Cohort 4: 
300 mg 
QD 
Fasted
(N = 12)
Cohort 5: 
100 mg   
QD    
Fed       
(N = 12)
Cohort 6: 
50 mg 
BID
(N = 11a)
Cohort 7: 
15 mg 
BID
(N = 12)
Pooled 
Placebo
(N = 21)
Treatment-
Emergent 
Adverse 
Event
4 (33%)
3 (25%)
4 (33%)
3 (25%)
5 (42%)
3 (27%)
4 (33%)
5 (24%)
Treatment-
Emergent 
Adverse 
Event 
Related to 
Study 
Drug
0 (0%)
  0 (0%)
0 (0%)
0 (0%)
1 (8%)
0 (0%)
1 (8%)
0 (0%)
Grade 3 or 
4 
Treatment-
Emergent 
Adverse 
Event
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
Grade 2, 3, 
or 4 
Treatment-
Emergent 
Adverse 
Event
0 (0%)
1 (8%)
1 (8%)
0 (0%)
1 (8%)
0 (0%)
0 (0%)
0 (0%)
a
1 subject withdrew consent after randomization prior to dosing and was not replaced.


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Grade 2 or 3 elevations in serum alanine aminotransferase (ALT) were seen in five (6%) 
GS-9674 treated subjects and one (5%) placebo treated subject. Of these, two GS-9674 treated 
subjects were noted to have grade 2 or 3 elevations of ALT during active treatment; one each in 
Cohort 6 (GS-9674 50 mg BID) and Cohort 7 (GS-9674 15 mg BID). The remaining subjects 
with elevated ALT were identified at the follow-up visit 4 days after completing study drug. In 
two of these subjects, elevated ALT was associated with very high serum creatine kinase levels, 
consistent with elevation due to strenuous exercise. All ALT elevations returned to baseline and 
were not associated with changes in bilirubin or coagulation parameters. There were no clinically 
important treatment- or dose-related trends in vital signs, ECG, or physical examination findings
in this study.
Preliminary PK parameters for GS-9674 after single- and multiple-dose administration of 10, 30, 
100 or 300 mg under fasting conditions and 100 mg under fed conditions in healthy volunteers 
are presented in Table 1-3. GS-9674 was rapidly absorbed with a median Tmax occurring between 
1.25 and 3.25 hours under fasting conditions. Across the dose levels tested, plasma 
concentrations declined in a bi-phasic manner with a median t1/2 of 5.56 to 12.8 hours. The lower 
observed median t1/2 of 5 to 6 hours in the 10 mg and 30 mg cohorts, respectively, may be a 
result of plasma concentrations falling below the limit of quantitation during the distributional 
phase of the profile. In general, GS-9674 AUC and Cmax increased less than dose proportionally 
above 10 mg upon single and multiple dosing. As expected based on the short GS-9674 t1/2 and 
once daily dosing, minimal to no accumulation was observed for GS-9674 AUC, Cmax or C24
from single to multiple dose administration. Administration of GS-9674 with food resulted in 
prolonged absorption of GS-9674 with an approximately 60% reduction in mean Cmax and 
approximately 35% reduction in mean AUC.  Plasma concentrations of GS-716070 (a metabolite 
of GS-9674 with ~40-fold less potency than GS-9674 against FXR) were analyzed in Cohort 5 
(GS-9674 100 mg administered fed).  The t1/2 of GS-716070 was similar to that of GS-9647 with 
AUC and Cmax ~60% and 35%, respectively of that observed for GS-9674.  Similar to GS-9674,
GS-716070 did not accumulate upon multiple dosing.  


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Table 1-3.
Preliminary Plasma Pharmacokinetic Parameters of GS-9674
Following Single- and Multiple-Dose Administration of GS-9674 
Under Fasting or Fed Conditions in Healthy Volunteers 
(GS-US-402-1851)
Parameter 
Mean (%CV)
Cohort 1: 
10 mg Fasted
(N = 12)
Cohort 2: 
30 mg Fasted
(N = 12)
Cohort 3: 
100 mg Fasted
(N = 12)
Cohort 4: 
300 mg Fasted
(N = 12)
Cohort 5: 
100 mg Fed
(N = 12)
Single 
Dose
AUCinf 
(ng*h/ml)
1260 (30.3)
2480 (37.2)
7740 (93.9)
12,500 (33.9)
5020 (40.4)
Cmax (ng/ml)
304 (41.6)
580 (48.9)
2590 (118)
3060 (66.2)
928 (58.3)
C24 (ng/ml)
2.61 (49.9)b
6.04 (35.7)
23.5 (40.0)
76.0 (67.4)
26.8 (42.3)
Tmax (h)a
3.00
(2.38, 4.00)
3.00
(2.38, 3.63)
1.75
(1.38, 2.63)
1.25
(1.00, 3.13)
3.75
(2.88, 4.25)
T1/2 (h)a
5.56
(5.46, 6.41)
8.10
(5.74, 9.58)
11.2
(8.30, 11.9)
12.4
(11.4, 13.9)
10.9
(8.87, 11.6)
Multiple 
Dose
AUCtau 
(ng*h/ml)
1280 (35.8)
2890 (23.5)
6720 (59.2)
8490 (48.8)
4180 (46.8)
Cmax (ng/ml)
322 (42.4)
718 (32.8)
2230 (75.9)
2330 (81.5)
819 (53.4)
Ctau (ng/ml)
2.75 (55.5)
7.90 (50.3)
36.3 (42.5)
70.1 (56.3)
22.6 (37.4)
Tmax (h)a
2.50
(1.50, 3.50)
3.00
(1.88, 3.13)
1.50
(1.00, 2.63)
3.25
(1.00, 5.00)
3.50
(3.00, 4.25)
T1/2 (h)a
6.75
(5.64, 8.45)
5.95
(5.54, 6.55)
8.99
(6.84, 11.49)
12.8
(10.0, 14.7)
13.1
(10.3, 15.0)
Pharmacokinetic parameters are presented as Mean (%CV), and shown to 3 significant digits 
a
Tmax and T1/2 are presented as median (Q1, Q3)
b
N=11
Preliminary changes in primary PD parameters (AUC2-8, Cmax, and Cmin) determined to be the 
most sensitive measures of changes in FGF19 and C4 after multiple dose administration of 
placebo, 10, 30, 100 or 300 mg GS-9674 under fasting conditions and 100 mg under fed 
conditions in healthy volunteers are presented in Table 1-4. In general, similar changes in PD 
parameters were observed after single or multiple dose administration (single dose data not 
shown). GS-9674 doses > 30 mg significantly increased FGF19 AUC2-8 and Cmax and reduced 
C4 AUC2-8 and Cmax. Administration of 100 mg GS-9674 with food resulted in prolonged 
elevation of FGF19 plasma concentrations compared to administration of GS-9674 100 mg under 
fasting conditions. Across the dose range of 10 to 300 mg GS-9674 administered fasted, 
GS-9674 exposure was weakly correlated with changes in FGF19 and moderately correlated with 
changes in C4 (Spearman correlation r = 0.45, p=0.002). Additionally, FGF19 and C4 AUC2-8
changes were inversely correlated (r = -0.335, p=0.02).


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Table 1-4.
Preliminary Pharmacodynamic Parameters (FGF19 and C4)
Following Multiple-Dose Administration of Placebo, or GS-9674 
Under Fasting or Fed Conditions in Healthy Volunteers 
(GS-US-402-1851)
PD Parameter Ratio 
Compared to Day -1
GeoMean (%CV)
Placebo
GS-9674
Fasted
(N=12)
Fed
(N=3)
10 mg 
Fasted
(N=12)
30 mg 
Fasted
(N=12)
100 mg 
Fasted
(N=12)
100 mg 
Fed
(N=12)
300 mg 
Fasted
(N=12)
FGF19
Day 
20
AUC2-8
1.35
(53.9)
0.77 
(32.7)
3.07
(71.9)*
3.99
(42.0)*
3.61
(26.9)*
2.30 
(40.1)*
3.94
(62.0)*
Cmax
1.21
(48.0)
0.73 
(45.2)
2.05
(94.6)*
2.39
(45.9)*
2.32
(44.9)*
2.24 
(31.1)*
3.08
(57.0)*
C4
Day 
20
AUC2-8
1.24
(93.8)
0.98 
(41.9)
0.67
(86.8)*
0.39
(57.1)*
0.50
(101)*
0.69 
(71.3)
0.33
(97.8)*
Cmin
1.29
(78.7)
1.08 
(42.6)
0.78
(59.3)
0.37
(59.6)*
0.71
(72.6)*
0.45 
(80.5)*
0.44
(76.3)*
Pharmacodynamic parameters are presented as geometric mean ratio (arithmetic %CV), and shown to 3 significant digits
* p<0.05 compared to placebo
1.2.
Rationale for This Study
Current evidence suggests that NASH is a consequence of the metabolic syndrome with resulting 
lipotoxicity and oxidative stress in the steatotic liver, setting off an inflammatory response with 
subsequent activation of hepatic stellate cells and fibrogenesis. FXR agonism has been shown to 
reduce hepatic lipid synthesis and circulating triglycerides due to down regulation of SREBP-1c, 
as well as reduce insulin resistance and hepatic gluconeogenesis. Thus GS-9674 is postulated to 
halt the instigating triggers for NASH. Animal models have demonstrated the ability for 
GS-9674 to reverse the metabolic dysfunction and NASH-like liver injury in a choline-deficient 
high fat diet /NaNO2 rat model of liver fibrosis. This Phase 2 study has been designed as a 
multicenter, randomized, double-blind, placebo-controlled study evaluating the safety and 
efficacy of GS-9674 for 24 weeks in subjects with NASH. Approximately 125 NASH subjects 
without cirrhosis will be randomized in a 2:2:1 ratio to receive GS-9674 at a dose of 30 mg or 
100 mg orally QD, or placebo. Randomization will be stratified by the presence or absence of 
diabetes mellitus, a common comorbidity in patients with this condition.
Inclusion criteria for the study were developed in order to noninvasively identify subjects with 
NASH. Specifically, all subjects will have a clinical diagnosis of NAFLD, evidence of ≥ 10% 
hepatic steatosis on MRI-PDFF {Bannas et al 2015}, and increased liver stiffness on MRE 
(≥2.90 kPa). Previous studies have shown that patients with NAFLD and increased liver 
stiffness by MRE have a high probability of NASH on liver biopsy {Loomba et al 2014}, {Chen et 
al 2011}. For example, Chen et al. reported that an MRE liver stiffness cut-off of ≥ 2.90 kPa was 
83% sensitive, 82% specific, and had an area under the receiver operating characteristic curve 
(AUROC) of 0.93 and positive predictive value of 88% for the differentiation of simple steatosis 
from NASH on biopsy. Moreover, in a meta-analysis of MRE for the diagnosis of NAFLD-


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related fibrosis {Singh et al 2016}, a liver stiffness ≥ 2.88 kPa optimally identified the presence of 
at least stage 1 fibrosis (AUROC 0.86). Based on these criteria, subjects enrolled in this study 
have a high probability of NASH with fibrosis, a population with a large unmet medical need.
Since the safety and PK of GS-9674 have not yet been explored in subjects with cirrhosis, 
criteria have been developed in order to exclude cirrhotic subjects based on a validated serum 
marker for fibrosis (FibroSURE/FibroTest®) and historical clinical, histological, and imaging 
data {Ratziu et al 2006}.
The primary endpoint of this study will be the safety and tolerability of GS-9674. In addition, the 
biological activity of GS-9674 will be determined based on endpoints including routine liver 
biochemistry (eg, ALT and GGT); noninvasive serum markers of liver injury (eg, serum CK-18, 
FibroSURE/FibroTest® and ELF™ Test); and imaging-based methods for quantifying hepatic 
steatosis (MRI-PDFF) and fibrosis (MRE and FibroScan®). An important endpoint of interest is 
the proportion of subjects achieving ≥ 30% reduction in steatosis as assessed by MRI-PDFF. 
This level of reduction has been associated with a significant improvement in NASH histology 
(≥ 2-point reduction in NAFLD Activity Score) {Patel et al 2015}. Based on preclinical and 
clinical data, a treatment duration of 24 weeks with GS-9674 is expected to be sufficient to lead 
to meaningful improvements in hepatic steatosis on MRI-PDFF and liver biochemistry.  In 
addition to these liver-related endpoints, the effects of GS-9674 on carbohydrate and lipid 
metabolism (eg, glucose, insulin, free fatty acids, apolipoproteins, lipid profiles, and metabolites) 
will be closely monitored in light of the mechanism of action of GS-9674 and the importance of 
metabolic dysfunction in contributing to the morbidity and mortality (eg, cardiovascular) of 
subjects with NASH.
This study will evaluate the safety, tolerability, and efficacy of 30 mg and 100 mg GS-9674 
administered with food for 24 weeks in subjects with NASH. The doses were selected based on 
short-term safety, PK and PD results from Study GS-US-402-1851 in healthy subjects. 
Across the range of GS-9674 doses evaluated (10-300 mg QD), doses ≥30 mg provide 
comparable intestinal FXR activation assessed as increases in FGF19 exposure. Food, by 
slowing oral absorption of GS-9674, results in prolonged elevation of plasma FGF19 
concentrations. Exposure-response relationships show that changes in C4 exposure are 
negatively correlated with changes in FGF19 exposure as well as GS-9674 exposure. Based on 
these results, GS-9674 doses of 30 and 100 mg with food are selected for further study as they 
are expected to 1) provide enteral FXR agonism and improvements in subjects with NASH and 
2) inform on the impact of increasing systemic GS-9674 exposure on safety and efficacy.
In the Phase 1 study, GS-US-402-1851, GS-9674 was tested at doses up to 300 mg once daily for 
up to 14 days and was well tolerated. Taken together, these data support the evaluation of 
GS-9674 30 and 100 mg in subjects with NASH.


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1.3.
Risk/Benefit Assessment for the Study 
This study will provide information on the safety and efficacy of GS-9674 for the treatment of
patients with NASH. As there are currently no approved therapies for NASH, there is a large
unmet medical need for this growing population of patients.
Potential risks of a participant’s study involvement include unknown AEs, general risks 
associated with frequent clinic visits and laboratory blood draws, and the associated pain and 
discomfort of phlebotomy. Strategies to mitigate these risks include close monitoring of lab 
values as well as AEs. 
Subjects with NASH randomized to the placebo control arm in the study may benefit from 
frequent medical monitoring and close assessment of their NASH during the duration of placebo 
treatment. Subjects randomized to GS-9674 may benefit from an improvement in their 
underlying NASH which may manifest as improvements in liver biochemistry, measures of 
hepatic steatosis or fibrosis, or improvements in quality of life. Importantly, this study will 
provide further data to inform the clinical development of the investigational medicinal product 
GS-9674 for use in an area of unmet medical need. 
Overall, the nonclinical and limited preliminary clinical data show a positive benefit/risk ratio in 
support of the study in subjects with NASH. Appropriate safety monitoring will be conducted 
throughout the study to further characterize the safety profile of GS-9674 in NASH subjects 
without cirrhosis.
In summary, there are no approved treatment options available for patients with NASH. Based
on past clinical experience with GS-9674, the risk/benefit is positive and supports the continued
evaluation of GS-9674 in this patient population. Data from this study will support the
development of GS-9674 for the treatment of this condition.
1.4.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


GS-9674 
Protocol GS-US-402-1852 
Gilead Sciences, Inc. 
2. 
OBJECTIVES 
The primary objective of this study is as follows: 
• 
To evaluate the safety and tolerability of GS-9674 in subjects with NASH. 
The exploratory objectives of this study are as follows: 
~ 
D 
I 
I 
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3.
STUDY DESIGN
3.1.
Study Design
This is a Phase 2, randomized, double-blind, placebo-controlled study designed to evaluate the 
safety, tolerability, and efficacy of GS-9674 in subjects with NASH. To be eligible to participate, 
subjects must have evidence of hepatic steatosis and increased liver stiffness as assessed by 
MRI-PDFF and MRE respectively. Any subject with a history of decompensated liver disease, 
including ascites, hepatic encephalopathy, or variceal bleeding will be ineligible.
The overall study design is presented graphically in Figure 3-1.
Figure 3-1.
Overall Study Design
3.2.
Treatment Plan and Regimen
Subjects meeting the study’s entry criteria will be randomly assigned in a 2:2:1 ratio to 1 of 
3 different treatment groups (A, B, and C) as shown in Figure 3-1. Randomization will be 
stratified by the presence or absence of diabetes mellitus as determined by medical history, use 
of medication for indication of diabetes mellitus, or based on screening lab values if previously 
undiagnosed (ie, hemoglobin A1c ≥ 6.5% OR fasting plasma glucose ≥126 mg/dL).
Study drug will be administered for a total of 24 weeks from the Baseline/Day 1 visit up to and 
including the Week 24 visit. Dosage and administration of the study drug and reference product 
are described in Section 5.3.


GS-9674 
Protocol GS-US-402-1852 
Gilead Sciences, Inc. 
3.3. 
Biomarker Testing 
3.3.1. 
Biomarker Samples to Address the Study Objectives 
Biological specimens will be collected in this stud~er the study rocedmes table 
Final 
Original 
L
endix 2) PPD 
Because biomarker science is a 
.----~-~-----r~---~~----~-~------~~~ 
rapidly evolving area of investigation, and adverse events in pmiicular are difficult to predict, it 
is not possible to specify prospectively all tests that will be done on the specimens provided. The 
biomarker tests 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 a1t knowledge. Samples will be 
stored for up to 15 years after the end of the study. 
Bioma1·kers testing can include circulating markers ofFXR activity such as FGF19, bile acids, 
and C4. Circulating protein markers of liver damage and inflammation, lipids, and other 
biochemicals associated with liver metabolic activity will also be measmed. Stool samples may 
be analyzed for the presence of bile acids and a smvey of potential changes in the intestinal 
microbiome dming the study. 
3.3.2. 
Biomarker Samples for Optional Future Research 
PD 
3.3.3. 
Biomarker Samples for Optional Genomic Research 
PD 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
This study will enroll approximately 125 subjects with nonalcoholic steatohepatitis (NASH).
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1)
Males and females between 18-75 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;
3)
Meets all of the following conditions:
a.
A clinical diagnosis of nonalcoholic fatty liver disease (NAFLD) with imaging 
documenting fatty liver within the past two years. If necessary an ultrasound may be 
performed during screening to confirm NAFLD. Note: criterion a. must be met before 
evaluating criteria b. and c.
b. Screening MRI-PDFF with ≥10% steatosis
c.
Screening MRE with liver stiffness ≥ 2.90 kPa;
4)
Platelet count ≥ 100,000/mm3;
5)
Creatinine Clearance (CLcr) as calculated by the Cockcroft-Gault equation ≥ 60 ml/min;
6)
Female subjects of childbearing potential (see definition in Appendix 4) must have a 
negative serum pregnancy test prior to starting study treatment;
7)
All female subjects of childbearing potential who engage in heterosexual intercourse must 
agree to use a highly effective method of contraception during intercourse from the 
screening visit throughout the study period and for 30 days following the last dose of study 
drug (see Appendix 4 for details);
8)
Female subjects must refrain from egg donation or harvest during treatment and for at least
30 days after last dose of study drug;
9)
Male subjects are required to use barrier contraception (condom plus spermicide) during 
heterosexual intercourse from the screening through the study completion and for 90 days 
following the last dose of study drug (see Appendix 4 for details);


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10)
Male subjects must refrain from sperm donation from screening through at least 90 days 
following the last dose of study drug;
11)
Willing and able to comply with scheduled visits, drug administration plan, laboratory 
tests, other study procedures, and study restrictions;
12)
Must be able to read and complete Quality of Life questionnaires independently.
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; lactating females must agree to discontinue nursing before 
the study drug is administered;
2)
ALT > 5X ULN;
3)
Other causes of liver disease including autoimmune, viral, and alcoholic liver disease;
4)
Cirrhosis of the liver as defined by any of the following:
a.
Cirrhosis on historical liver biopsy (eg, Brunt/Kleiner stage 4 or equivalent)
b. Evidence of cirrhosis on liver imaging (eg, ultrasound, CT, or MRI) including a nodular 
liver surface, splenomegaly, or portal venous collaterals
c.
Screening FibroSURE/FibroTest® ≥ 0.75, as determined by the central laboratory
d. Prior history of decompensated liver disease, including ascites, hepatic encephalopathy,
or variceal bleeding;
5)
History of liver transplantation;
6)
Weight reduction surgery in the past or planned during the study;
7)
History of intestinal resection or malabsorptive condition that may limit the absorption of 
GS-9674. Prior cholecystectomy and appendectomy are permitted.
8)
BMI < 18 kg/m2;
9)
INR > 1.2 unless on anticoagulant therapy;
10)
Total bilirubin > 1x ULN, except with diagnosis of Gilbert’s syndrome;
11)
Chronic hepatitis B (HBsAg positive);
12)
Chronic hepatitis C (HCV RNA positive);
13)
HIV Ab positive;


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14)
Alcohol consumption greater than 21 oz/week for males or 14 oz/week for females 
(1oz/30mL of alcohol is present in 1 12oz/360mL beer, 1 4oz/120mL glass of wine, and a 1 
oz/30 mL measure of 40% proof alcohol);
15)
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;
16)
Unstable cardiovascular disease as defined by any of the following:
a.
Unstable angina within 6 months prior to screening
b. Myocardial infarction, coronary artery bypass graft surgery or coronary angioplasty 
within 6 months prior to screening
c.
Transient ischemic attack or cerebrovascular accident within 6 months prior to 
screening
d. Obstructive valvular heart disease or hypertrophic cardiomyopathy
e.
Congestive heart failure;
17)
History of known hypercoagulable condition or prior arterial or venous thromboembolic 
disease;
18)
Use of any prohibited concomitant medications as described in Section 5.5;
19)
History of a malignancy within 5 years of screening with the following exceptions:
a.
Adequately treated carcinoma in situ of the cervix
b.
Adequately treated basal or squamous cell cancer or other localized non-melanoma skin 
cancer;
20)
Any laboratory abnormality or condition that could, in the opinion of the investigator, 
adversely affect the safety of the subject or impair the assessment of study results;
21)
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;
22)
Concurrent participation in another therapeutic clinical study;
23)
Known hypersensitivity to GS-9674, the metabolites, or formulation excipient;


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24)
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 or a 
psychiatric (including any subjects with a psychiatric hospital admission or emergency 
room visit in the 2 years prior to screening) or medical condition;
25)
Unavailable for follow-up assessment or concern for subject’s compliance with the 
protocol procedures;
26)
Contraindications or inability to complete MRI scanning (eg, presence of permanent 
pacemakers, implanted cardiac devices, weight restrictions, etc.).


GS-9674 
Protocol GS-US-402-1852 
Gilead Sciences, Inc. 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
5.1. 
Randomization, Blinding and Treatment Codes 
Final 
Original 
An Interactive Web Response System (IWRS) will be used for centralized randomization and 
treatment assignment. Randomization will be stratified by the presence or absence of diabetes 
mellitus as dete1mined by medical hist01y, use of medication for indication of diabetes mellitus, 
or based on screening lab values if previously lmdiagnosed (ie, hemoglobin Ale :::: 6.5% OR 
fasting plasma glucose :::: 126 mg/d.L). 
Investigative site personnel will obtain the subject's identification number and study dmg 
assignment from the IWRS. Subjects and all personnel directly involved in the conduct of the 
study will be blinded to treatment assignment. 
Study dmg will be dispensed by the study pha1macist, or designee, in a blinded fashion to the 
subjects. 
5.1.1. 
Procedures for Breaking Treatment Codes 
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator (or designee) may obtain treatment assignment directly from the 
IWRS system for that subject (refer to the Study Reference Binder for IWRS unblinding 
instmctions). Gilead recommends but does not require that the investigator contact the Gilead 
Medical Monitor before breaking the blind. Treatment assignment should remain blinded unless 
that knowledge is necessmy to dete1mine subject emergency medical care. The rationale for 
unblinding must be clem·ly explained in somce docmnentation and on the electronic case report 
f01m ( eCRF), along with the date on which the treatment assignn1ent was obtained. The 
investigator is requested to contact the Gilead Medical Monitor promptly in case of ailY 
treatment unblinding. 
Blinding of study treatment is critical to the integrity of this clinical study 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 Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected lmexpected serious adverse reactions (SUSARs). 
5.2. 
Description and Handling of GS-9674 and PTM GS-9674 
5.2.1. 
Formulation 
GS-9674 is supplied as 30 mg a11d 100 mg strength (as free f01m equivalent) tablets. The tablets 
contain GS-967 4-02 
PD 
D and inactive in ·edients PD 
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GS-9674 
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Gilead Sciences, Inc. 
p 
GS-9674 30 mg tablets are round, plain-faced, film-coated orange tablets and 
~~~~ 
GS-9674 100 mg tablets are capsule-shaped, plain-faced, fihn-coated orange tablets. 
Final 
Original 
Placebo-to-match (PTM) GS-9674 tablets are identical in size, shape, color, and appearance to 
their conesponding strengths of active GS-9674 tablets. PTM GS-9674 tablets contain the 
followin~ 
·edients: PD 
5.2.2. 
Packaging and Labeling 
GS-9674 tablets and PTM GS-9674 tablets are packaged in white, high-density polyethylene 
(HDPE) bottles. Each bottle contains 30 tablets, a silica gel desiccant, and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant screw cap with 
an induction-sealed, ahuninum-faced liner. 
Study drug to be distributed to centers in the US and other pruiicipating 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 (hiVestigational Medicinal Products), 
and/or other local regulations. 
5.2.3. 
Storage and Handling 
GS-9674 tablets and PTM GS-9674 tablets should be stored at controlled room temperature 1mtil 
required for administration. Controlled room temperature is defined as 25°C (77°F); temperature 
excursions ru·e petmitted between 15°C and 30°C (59°F and 86°F). Storage conditions are 
specified on the label. 
Until study drug tablets are dispensed to the subjects, all bottles of study drugs should be stored 
in a securely locked area, accessible only to authorized site persollllel. To ensure the stability and 
proper identification, the drug products should not be stored in a container other than the 
container in which they were supplied. Consideration should be given to handling, preparation, 
and disposal tln·ough measures that minitnize drug contact with the body. Appropriate 
precautions should be followed to avoid direct eye contact or exposure when handling GS-9674 
tablets and PTM GS-9674 tablets. 
5.3. 
Dosage and Administration of GS-9674/ PTM GS-9674 
GS-9674 and GS-9674 PTM tablets will be provided by Gilead Sciences, Inc. In order to 
maintain the blind, each subject will be supplied with 2 bottles of tablets. One bottle will contain 
GS-9674 30 mg or PTM GS-9674 30 mg, the second bottle will contain GS-9674 100 mg or 
PTM GS-9674 100 mg. Dosing for each treatment group will be as follows: 
• 
Treatment Group A: GS-9674 30 mg (1 x 30 mg tablet)+ PTM GS-9674 100 mg (1 x PTM 
100 mg tablet) administered orally once daily with food 
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
Treatment Group B: GS-9674 100 mg (1 x 100 mg tablet) + PTM GS-9674 30 mg 
(1 x PTM 30 mg tablet) administered orally once daily with food

Treatment Group C: PTM GS-9674 30 mg (1 x PTM 30 mg tablet) + PTM GS-9674 
100 mg (1 x PTM 100 mg tablet) administered orally once daily with food
The study drug dose should be taken at approximately the same time each day with food.
A dose will be considered missed if the subject cannot take the dose within 12 hours of their 
regular dosing time. If a subject misses a dose, the subject should take their next dose at the 
regular dosing time.
5.4.
Prior and Concomitant Medications
Concomitant use of certain medications or herbal/natural supplements with study drug may result 
in PK and/or PD interactions resulting in increases or decreases in exposure of study drug or 
these medications. 
Concomitant medications taken within 30 days of screening through the follow-up visit need to 
be recorded in the source documents and electronic Case Report Forms (eCRFs).
Subjects with co-morbid diseases requiring medication(s) must be taking the medication(s) 
without a change in dose within 28 days of Baseline/Day 1.
5.5.
Prohibited Medications
The following medications are prohibited from 28 days prior to Baseline/Day 1 up to and 
including the day of the last dose of study drug:

Hematologic stimulating agents (eg, erythropoiesis-stimulating agents (ESAs); granulocyte 
colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics)

Chronic systemic immunosuppressants including, but not limited to, corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal 
antibodies (eg, infliximab). Use for <2 weeks total is allowed.

Investigational agents or devices for any indication

Concomitant use of certain medications or herbal/natural supplements (sensitive substrates, 
inhibitors or inducers of drug transporters P-gp, BCRP, or OATP, or the drug metabolizing 
enzyme CYP3A or inhibitors or inducers of CYP2C8) with study drug(s) may result in PK 
interactions resulting in increases or decreases in exposure of study drug(s) or concomitant 
medications. Examples of representative medications which are prohibited from 28 days 
prior to Baseline/Day 1 up to and including the day of the last dose of study drug, are listed 
below in Table 5-1:


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Table 5-1.
List of Prohibited Medications
Drug Class
Agents Disallowed
Antibiotics
Azithromycin, Clarithromycin, Erythromycin
Acid Reducing Agents
Proton-Pump Inhibitors, H2-Receptor Antagonists, Antacidsa
Alpha 1-Adrenoceptor Antagonists
Alfuzosin
Anticonvulsantsb
Carbamazepine, Clonazepam, Ethosuximide, Oxcarbazepine,
Phenobarbital, Phenytoin
Antidiabetics
Glyburide, Repaglinide
Antidepressants
Trazodone
Antifungals
Itraconazole, Ketoconazole, Voriconazole
Antigout
Colchicine
Antimycobacterialsb
Rifamycins, Isoniazid
Cardiac Medications
Amiodarone, Amlodipine, Bepridil, Digoxin, Diltiazem, 
Disopyramide, Dronedarone, Felodipine, Nicardipine, Nifedipine, 
Olmesartan, Ranolazine, Systemic Lidocaine, Telmisartan, 
Valsartan, Verapamil, Quinidine
Corticosteroids
Dexamethasone, Fluticasone
Endothelin Receptor Antagonists
Bosentan
Ergot Derivatives
Dihydroergotamine, Ergonovine, Ergotamine, Methylergonovine
GI Motility Agents
Cisapride
Herbal/Natural Supplementsb
St. John’s Wort, Echinaccea. Milk thistle (ie, silymarin), Chinese 
herb sho-saiko-to (or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase Inhibitorsc
Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin , Pravastatin, 
Rosuvastatin, Simvastatin
Inhaled Beta Agonists
Salmeterol
Phosphodiesterase Type 5 (PDE5) inhibitors
Sildenafil, Tadalafil, Vardenifil
Sedatives/Hypnotics
Buspirone, Clorazepate, Diazepam, Estazolam, Flurazepam, 
Midazolam, Triazolam, Zolpidem
Selective Serotonin Reuptake Inhibitors
Fluvoxamine
Other
Gemfibrozil, Modafinil, Sulfasalazine, Methotrexate
a
Antacids that directly neutralize stomach pH (ie, Tums, Maalox) are permitted but may not be taken within 4 hours (before 
or after) study drug administration.
b
May result in a decrease in the concentrations of study drug.
c
Use with study drug may result in an increase in the concentration of the HMG-CoA reductase inhibitors. The 28 day 
washout period does not apply to HMG-CoA reductase inhibitors, which can be taken up to the day before Baseline/Day 1.
Medications for disease conditions excluded from the protocol (eg, HIV-1, HBV, or HCV
infection, active cancer, transplantation) are not listed under this prohibited medications section 
and are disallowed in the study.


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5.6.
Accountability for GS-9674/ PTM GS-9674 
The investigator or designee (eg, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug bottles. This includes acknowledgement of receipt of each 
shipment of study drug (quantity and condition), subject dispensing records, and returned or 
destroyed study product. All used and unused study drug bottles dispensed to subjects must be 
returned to the site.
Study drug accountability records will be provided to each study site to:

Record the date received and quantity of study drug bottles

Record the date, subject number, subject initials, and the study drug bottle number dispensed

Record the date, quantity of used and unused study drug returned, along with the initials of 
the person recording the information.
5.6.1.
Investigational Medicinal Product Return or Disposal
Refer to Section 9.1.7 for instructions regarding study drug return or disposal.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. Additional information is 
provided in the Study Reference Binder.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the investigator to ensure that subjects are eligible to participate in the 
study prior to enrollment and throughout the study. 
Documentation of the personally signed and dated informed consent of each subject, using the 
study-specific informed consent form (ICF), is required before initiating the screening process.
After written informed consent has been obtained and eligibility to participate established, 
investigative site personnel will obtain the subject’s identification number and study drug 
assignment from the interactive web response system (IWRS).
6.2.
Pretreatment Assessments – Screening Visit
Subjects will be screened within 4 weeks prior to randomization to determine eligibility for 
participation in the study. The screening period may be extended under special circumstances 
with the explicit approval of the Medical Monitor.
Screening labs may be repeated once within the screening period, prior to administration of study 
drug to rule out laboratory error, if any. This will be done at the discretion of the investigator and 
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 fasted blood sample collection the next morning.
The following will be performed and documented at Screening:

Obtain written informed consent before initiation of any screening procedures

Review and record whether the subject meets inclusion and exclusion criteria

Obtain screening number from IWRS

Obtain medical history

Complete physical examination


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
Record vital signs, body weight, and height

Obtain blood samples for:
— Chemistry
— Hematology 
— Coagulation Panel 
— Hemoglobin A1c
— Biomarkers
— HIV-1, HBV, and HCV Serology
— Serum pregnancy test (only for female subjects of child bearing potential)
— Serum FSH (only for some female subjects - see Appendix 4) 

Conduct standard 12-Lead ECG

Perform Ultrasound (if necessary) for confirmation of NAFLD

Perform MRE and MRI-PDFF

Urine drug screen for amphetamines, cocaine and opiates (ie, heroin, morphine)

Record all concomitant medications that the subject has taken within 30 days prior to 
screening

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 4 weeks of the start of screening for randomization into the study.
From the time of obtaining informed consent through the first administration of the study drug, 
record all serious adverse events (SAEs), as well as any adverse events related to protocol-
mandated procedures on the adverse events electronic 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.


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6.3. 
Baseline/Day 1 Randomization and Assessments 
Final 
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Subjects retuming to the clinic for randomization at Baseline/Day I should be instructed to fast 
(no food or drink, except water), statting from midnight (00:00) or earlier, as appropriate, on the 
evening prior to the visit to ensure an approximate 8-hour fast prior to the blood sample 
collection under fasting condition the next moming. 
After review of inclusion and exclusion criteria to confilm continued eligibility, subjects will be 
randomized to study dmg assignment and receive their Subject Identification Number via the 
IWRS prior to their first dose of study drug. 
The following will be perfmmed and documented at the Baseline/Day I visit prior to dosing: 
• 
QoL: general assessments (CLDQ, SF-36, and WPAI) 
• 
QoL: pmritus assessments 01 AS-itch and 5D-itch) 
Note: It is recommended that QoL assessments be completed prior to any study procedures being 
performed and prior to the subject seeing a health care provider. Refer to the Study Reference 
Binder for guidance on QoL assessment administration. 
• 
Symptom driven physical examination 
• 
Record vital signs, waist circtm1ference, and body weight 
• 
Obtain blood samples for: 
-
Chemistly 
-
Hematology 
-
Coagulation Panel 
-
Lipid Profile 
-
Hemoglobin A I c 
-
Biomat·kers 
Single PD Sampling 
PD 
• 
Conduct standard I2-Lead ECG 
• 
Perfmm FibroScan® (if available) 
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
Collect urine samples for:
— Urine pregnancy test for females of child bearing potential only
— Biomarker testing

Collect stool sample for biomarker testing

Dispense study drug and provide subject with instruction on appropriate dosing and 
administration; 

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 screening visit
Once all visit procedures have been completed, subjects will take their Baseline/Day 1 dose of 
study drug with food while at the investigative site.
Subjects will return to the investigative site at Week 1 (±3 days) for a mandatory safety visit. 
Then, starting at the Week 4 visit, subjects will have visits every 4 weeks up to the Week 24 
visit.
6.4.
Treatment Assessments
6.4.1.
Week 1
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Week 1 visit to ensure an 
approximate 8-hour fast prior to the fasted blood sample collection the next morning.
Subjects should also be instructed to HOLD their dose of study drug on the day of their Week 1 
visit until all visit procedures have been completed. The study drug dose should be taken with 
food after the visit.
During the Week 1 safety visit the following will be performed and documented (±3 days):

QoL: pruritus assessments (VAS-itch and 5D-itch)

Symptom driven physical examination

Record vital signs and body weight

Obtain blood samples for:
— Chemistry
— Hematology


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— Coagulation Panel
— Lipid Profile
— Biomarkers
— Single PK and PD sampling

Collect urine sample for biomarker testing

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
6.4.2.
Week 4 Visit
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Week 4 visit to ensure an 
approximate 8-hour fast prior to the fasted blood sample collection the next morning.
Subjects should also be instructed to HOLD their dose of study drug on the day of their Week 4 
visit until all visit procedures have been completed. The study drug dose should be taken with 
food after the visit.
The following will be performed and documented at this visit (±3 days):

QoL: pruritus assessments (VAS-itch and 5D-itch)

Symptom driven physical examination

Record vital signs and body weight

Obtain blood samples for:
— Chemistry
— Hematology
— Coagulation Panel
— Lipid Profile
— Biomarkers
— Single PK and PD sampling


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
Collect urine samples for:
Urine pregnancy test for females of child bearing potential only
Biomarker testing

Dispense study drug

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
6.4.3.
Week 8, 16, and 20 Visits
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Weeks 8, 16, and 20 visits to ensure 
an approximate 8-hour fast prior to the fasted blood sample collection the next morning.
Subjects should also be instructed to HOLD their dose of study drug on the day of their Weeks 8, 
16, and 20 visits until all visit procedures have been completed. The study drug dose should be 
taken with food after the visit.
The following will be performed and documented at these visits (±3 days):

QoL: pruritus assessments (VAS-itch and 5D-itch)

Symptom driven physical examination

Record vital signs and body weight

Obtain blood samples for:
— Chemistry
— Hematology
— Coagulation Panel
— Lipid Profile
— Single PK and PD sampling

Urine pregnancy test for females of child bearing potential only

Dispense study drug

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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6.4.4.
Week 12 Visit 
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Week 12 visit to ensure an 
approximate 8-hour fast prior to the fasted blood sample collection the next morning.
Subjects should also be instructed to HOLD their dose of study drug on the day of their Week 12 
visit until all visit procedures have been completed. The study drug dose should be taken with 
food after the visit.
The following will be performed and documented at this visit (±7 days):

QoL: general assessments (CLDQ, SF-36, and WAPI)

QoL: pruritus assessments (VAS-itch and 5D-itch) 

Symptom driven physical examination

Record vital signs and body weight

Obtain blood samples for:
— Chemistry
— Hematology
— Coagulation Panel
— Lipid Profile
— Hemoglobin A1c
— Biomarkers
— Single PK and PD sampling

Collect urine samples for:
Urine pregnancy test for females of child bearing potential only
Biomarker testing

Conduct standard 12-Lead ECG

Perform FibroScan® (if available)

Perform MRE and MRI-PDFF


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
Dispense study drug

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
6.4.5.
Week 24 Visit
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Week 24 visit to ensure an 
approximate 8-hour fast prior to the fasted blood sample collection the next morning.
Subjects should also be instructed to HOLD their dose of study drug on the day of their Week 24 
visit until all visit procedures have been completed. 
The following will be performed and documented at this visit (±7 days):

QoL: general assessments (CLDQ, SF-36, and WAPI)

QoL: pruritus assessments (VAS-itch and 5D-itch) 

Symptom driven physical examination

Record vital signs, waist circumference, and body weight

Obtain blood samples for:
— Chemistry
— Hematology
— Coagulation Panel
— Lipid Profile
— Hemoglobin A1c
— Biomarkers
— Single PK and PD sampling

Collect urine samples for:
Urine pregnancy test for females of child bearing potential only
Biomarker testing

Conduct standard 12-Lead ECG

Perform FibroScan® (if available)


GS-9674 
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• 
Perf01m MRE and MRI-PDFF 
• 
Collect stool sample for biomarkers 
• 
Record all concomitant medications that the subject has taken since the previous visit 
Final 
Original 
• 
Record any serious adverse events and all adverse events occmTing since the previous visit 
Once all visit procedmes have been completed, subjects will take their fmal dose of study dmg 
while at the investigative site. 
PD 
6.4.6. 
Unscheduled Visits 
Additional unscheduled assessments may be perf01med at the discretion of the investigator. 
Subjects retmning to the clinic for an unscheduled visit should be instructed to fast (no food or 
drink, except water), struiing from midnight (00:00) or earlier, as appropriate, on the evening 
prior to the visit to ensme an approximate 8-hom fast prior to the blood sample collection under 
fasting condition the next moming. 
Subjects should also be instmcted to HOLD their dose of study drug on the day of an 
unscheduled visit lmtil all visit procedmes have been completed. The study dmg dose should be 
taken with food after the visit. 
At a minimum, the following will be perf01med and documented. 
• 
Symptom driven physical exrunination 
• 
Record body weight 
• 
Obtain blood samples for: 
-
Chemistly 
-
Hematology 
• 
Record all concomitant mediations that the subject has taken since the previous visit 
• 
Record any serious adverse events and all adverse events occmTing since the previous visit 
If the Unscheduled visit is perf01med for the sole purpose of distt·ibution of study dmg, the 
assessments noted above do not need to be performed. 
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6.5.
Follow-Up Visit
Subjects will return for a Follow-Up Visit four weeks after their last dose of study drug.
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Follow-Up visit to ensure an 
approximate 8-hour fast prior to the blood sample collection under fasting condition the next 
morning.
The following will be performed and documented at this visit (±5 days):

Symptom driven physical examination

Record vital signs and body weight

Obtain blood samples for:
— Chemistry
— Hematology
— Coagulation Panel

Urine pregnancy test for female subjects of child bearing potential only

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse occurring since the previous visit
6.6.
Assessments for Premature Discontinuation from Study
Subjects prematurely discontinuing from the study (for example, as a result of an AE), should 
have an Early Termination (ET) visit, if possible, and a Follow-Up visit 4 weeks after their last 
dose of study drug. The study assessments to be performed at the ET visit are the same as those 
performed at the Week 24 visit (refer to Section 6.4.5). The study assessments to be performed at 
the Follow-Up visit are listed in Section 6.5. The subject will then be withdrawn from the study.
If these visits are not possible or acceptable to the subject or investigator, the subject may be 
withdrawn from the study. 


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6.7. 
Criteria for Discontinuation of Study Treatment 
Study medication may be discontinued in the following instances: 
Final 
Original 
• 
Intercunent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercunent illness, the subject 
may resume study dosing at the discretion of the investigator. 
• 
Unacceptable toxicity, or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedmes or is considered to not be in the subject's best 
interest 
• 
Subject request to discontinue for any reason 
• 
Subject noncompliance 
• 
Pregnancy dming the study (refer to Appendix 4) 
• 
Sponsor discretion 
• 
Discontinuation of the study at the request of Gilead, a regulatoty agency or an institutional 
review board, independent ethics committee, or ethics committee (IRBIIEC/EC) 
6.8. 
PK and PD Substudy Visits 
PD 
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6.9. 
Description of Assessments 
6.9.1. 
Clinical Laboratory Analytes 
Chemistry: 
Final 
Original 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, alkaline 
phosphatase (ALP), 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). Also includes C-
Peptide and Insulin for the Baseline/Day!, Weeks 4, 12, and 24 visits. 
Creatinine clearance is calculated by the Cockcroft-Gault equation {Cockcroft et al1976} using 
actual body weight (BW). The calculation will be performed by the central laboratory. 
Hematology: 
Hematocrit (Hct), Hemoglobin (Hb ), Platelet count, Red blood cell count (RBC), White blood 
cell count (WBC) with differential (absolute and percentage) including Lymphocytes, 
Monocytes, Neutrophils, Eosinophils, and Basophils and, Reticulocyte count and mean 
corpuscular volume (MCV). 
Coagulation Panel: 
Prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio 
(INR) 
Pregnancy Tests: 
Serum ~-hCG or urine ~-hCG (if positive, requires immediate confirmation with Serum ~-hCG) 
Additional Tests: 
Lipid Profile, Hemoglobin Ale, HIV-1, HBV & HCV Serology, urine drug screen (for 
amphetamines, cocaine, opiates), and genomic sample collection. 
Biomarker Tests: 
CK18 (M30 and M65), FGF-19, C4, Apolipoprotein B (Apo B), metabolite profile, bile acids, 
stool microbiome, blood miRN A, NMR lipoprofile, free fatty acids, ELF™ Test, and 
FibroSURE/Fibro Test®. 
PPD 
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Phrumacokinetic CPK) and Phrumacodvnrunic CPD) Assessments 
Single PK and PD Sampling 
Final 
Original 
Single PK ru1d PD plasma samples will be collected and ru·chived for 1) PK analysis of GS-9674, 
GS-716070 (metabolite of GS-9674), and other metabolites as applicable, 2) to measure the 
concentration of the PD biomru·kers FGF19 and C4. 
PK and PD Substudy 
pp 
6.9.2. 
Medical History 
Medical histoty, induding details of illnesses and allergies, date(s) of onset, whether condition(s) 
is cunently ongoing, and medication histoty, including nicotine and alcohol use, will be 
collected for all subjects during screening. 
6.9.3. 
Physical Examination 
A complete physical examination should include source documentation of general appearance, 
and the following body systems: head, neck, and thyroid; eyes, ears, nose, throat, mouth, and 
tongue; chest (excluding breasts); respiratoty; cru·diovasculru·; lymph nodes; abdomen; skin, hair, 
nails; musculoskeletal; neurological. 
The focus of a symptom driven physical examination will be dete1mined by the investigator 
based on subject complaint. For eg, if a subject complains of a cough, a lung exam should be 
perfotmed. If consistent with pneumonia (rales/crackles on exam) then an AE would be 
documented. 
Height~ body weight, and hip circumference will be collected at specified time points. 
6.9.4. 
Quality of Life (QoL) Assessments 
It is recommended that these questioilllaires be completed prior to the clinical and laboratoty 
assessments. The subject should read the questioilllaires by himself/herself and record the 
answers by himself/herself. 
6.9.4.1. 
Chronic Liver Disease Questioilllaire (CLDQ) 
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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6.9.4.2.
SF-36 Health Survey
The SF-36 Health Survey asks 36 questions to measure functional health and well-being from the 
subject’s point of view and consists of eight health domains (physical functioning, role-physical, 
bodily pain, general health, vitality, social functioning, role-emotional, and mental health). These 
health domain scales contribute to the physical health and mental health summary measures.
6.9.4.3.
Work Productivity and Activity Impairment (WPAI) 
The Work Productivity and Activity Impairment (WPAI) questionnaire asks 6 questions 
regarding the effect of NASH on a person’s ability to work and perform regular activities.
6.9.4.4.
VAS-itch
The visual analogue scale (VAS)-itch is a tool for measuring the intensity of pruritus.
6.9.4.5.
5-D itch
The 5-D itch is multidimensional measure of itching that allows changes in chronic pruritus to be 
detected over time. The questionnaire measures the degree, duration, direction, disability, and 
distribution of pruritus.
6.9.5.
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 in the AE eCRF page.
6.9.6.
FibroScan®
Liver stiffness will be assessed by FibroScan®. It is required that each subject’s FibroScan®
assessments be done with the same type of probe at each study visit. If FibroScan® is not 
available at a site the test may be omitted.
Please refer to the Study Reference Binder for instructions on FibroScan® measurements.
6.9.7.
MRE and MRI-PDFF
Liver stiffness will be assessed by MRE and the degree of steatosis will be measured by 
Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF). These assessments can 
occur sequentially.
The MRE and MRI-PDFF images will be analyzed by a central reader. 
Please refer to the Study Reference Binder for MRE and MRI-PDFF imaging guidelines.


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6.10.
End of Study Definition
End of study is defined as when the last patient last visit (LPLV) for the Follow-Up visit (four 
weeks after their last dose of study drug) occurs, or the ET visit, whichever occurs later.
6.11.
Post Study Care 
No post study ongoing care will be provided.


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


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; 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 study drug 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 
GS-9674 therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the GS-9674. 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 study drug.


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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, 4, or 5 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
(Appendix 3).
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 electronic 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 GS-9674; AEs 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 occur after the subject first consents to 
participate in the study (ie, signs 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 GS-9674, 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 study drug, 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 (see Study Reference Binder) and submit within 24 hours to:
Gilead DSPH:
Fax: +1 (650) 522-5477
Email: 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.

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.


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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 drug. 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. 
To minimize the possibility of exposing study subjects to unusual risk, the safety information 
from this study will also be reviewed periodically by an independent Data Monitoring 
Committee (DMC). The DMC may have access to partially blinded or unblinded data and will
make recommendations regarding the study according to the DMC charter. See Section 8.11 for 
additional details regarding the DMC.
7.5.
Toxicity Management 
Observation for Drug Induced Liver Injury (DILI):
Although subjects enrolled in this study will have baseline liver disease, their hepatic function 
should not be significantly impaired. However, at baseline, some may have liver biochemistry 
levels above the upper limit of normal (ULN). 
For subjects with ALT and AST below ULN at study start, close observation for DILI (as 
described below) should be considered in subjects with any of the following criteria (all labs 
confirmed by repeat testing):

ALT or AST > 3 x ULN at any time

Total bilirubin > 2 x ULN

Alkaline phosphatase > 3 x ULN

INR >1.5 x ULN (except for subjects on anticoagulant therapy)  


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
Clinical signs or symptoms that are, in the opinion of the investigator, consistent with 
hepatitis (such as right upper quadrant discomfort, fever, nausea, vomiting, jaundice, rash, or 
eosinophilia > 5%)
For subjects with ALT or AST between 1 and 5 x ULN at study start, close observation for DILI 
(as described below) should be considered in subjects with any of the following criteria (all labs 
confirmed by repeat testing):

ALT or AST > 2 x baseline at any time

Total bilirubin > 2 x ULN  

Alkaline phosphatase > 3 x ULN

INR >1.5 x ULN (except for subjects on anticoagulant therapy)  

Clinical signs or symptoms that are, in the opinion of the investigator, consistent with 
hepatitis (such as right upper quadrant discomfort, fever, nausea, vomiting, jaundice, rash, or 
eosinophilia > 5%).  
Close observation includes:

Repeating liver biochemistries (ALT, AST, ALP, total bilirubin, INR) within 48 hours

Obtaining a more detailed history of symptoms and prior or concurrent disease

Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and special 
diets

Obtaining a history of exposure to environmental chemical agents

Ruling out other causes of liver disease as needed (obtain viral hepatitis panel, imaging for 
evaluation of biliary tract disease, etc. if required in the opinion of the primary investigator)

Continue to monitor liver biochemistries twice weekly. Frequency can decrease to once a 
week or less if abnormalities stabilize or study drug has been discontinued and subject is 
asymptomatic
During a period of close observation, study drug can be continued, if desired, at the discretion of 
the Gilead Medical Monitor and the principal investigator during the DILI evaluation. 
However, for all subjects, study drug should be withheld if any of the following criteria are met:

ALT or AST > 3 x ULN AND either Total bilirubin > 2 x ULN or INR > 1.5 (in subjects not 
on anticoagulation)


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
ALT or AST > 3 x ULN AND the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

ALT or AST > 8 x ULN 

ALT or AST >5 x ULN for more than 2 weeks
AND

No other cause for the combination of laboratory abnormalities is immediately apparent (eg,
prolonged INR with warfarin use) important potential causes or contributors to abnormal 
AST/ALT or total bilirubin values include, but are not limited to:
Obstructive gall bladder or bile duct disease
Viral or alcoholic hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus, 
cytomegalovirus, herpes simplex virus, varicella)
Autoimmune hepatitis
Concomitant administration of other hepatotoxins, including excessive doses of 
acetaminophen, drugs that inhibit bilirubin glucuronidation (eg, indinavir, atazanavir, 
irinotecan), or herbal or dietary supplements
Hypoxic or ischemic hepatopathy or congestive hepatopathy in association with 
significant right-sided heart failure
Wilson disease
Progression of malignancy involving the liver (note that metastatic disease to the liver, by 
itself, should not be used as an explanation for significant AST/ALT elevations)
If study drugs are withheld, they may be reintroduced with approval from the Medical Monitor.
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 AEs should be confirmed by repeat testing as soon as practical to do so, and 
preferably within 3 calendar days of receipt of the original test results.

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.


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
Any questions regarding toxicity management should be directed to the Medical Monitor.
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of AEs associated with product complaints, occupational exposure with an AE, pregnancy 
reports regardless of an associated AE, and AE in an infant following exposure from 
breastfeeding.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labeling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product. 
Occupational exposure is defined as exposure to a medicinal product as a result of one’s 
professional or non-professional occupation.
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to Gilead 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.


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The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (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 4 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 drug and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications.
Special situations involving non-Gilead concomitant medications does 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 
Details will be provided in the statistical analysis plan (SAP). 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The primary objective of this study is as follows: 
• 
To evaluate the safety and tolerability of GS-967 4 in subjects with NASH. 
The exploratory objectives of this study are as follows: 
~ 
0 
I 
I 
I 
I 
I 
I 
I 
I 
8.1.2. 
Primary Endpoint 
-
Final 
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The primaty endpoint is the safety of GS-9674 in subjects with NASH. Safety endpoints include 
extent of exposure, adverse events, and laboratmy evaluations. 
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8.1.3. 
Exploratory Efficacy Endpoints 
PD 
I 
I 
I 
I 
I 
I 
I 
I 
I 
8.2. 
Analysis Conventions 
Final 
Original 
All individual subject data will be listed as measured. All statistical summruies and analyses will 
be perfonned using SAS® software (SAS Institute, Cmy, N01ih Cm·olina, USA). 
8.2.1. 
Analysis Sets 
8.2.1.1. 
Efficacy 
The prima1y analysis set for efficacy analysis is defined as the Full Analysis Set (F AS), which 
includes all subjects who were randomized into the study and received at least 1 dose of study 
dmg. 
Subjects who receive study dmg other than that to which they were assigned for the entire 
duration of treatment, will be analyzed according to the treatment group they were randomized 
to. 
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8.2.1.2. 
Safety 
Final 
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The primaty analysis set for safety analyses is defmed as all subjects who received at least 
one dose of study drug. Subjects who receive study dmg other than that to which they were 
assigned for the entire dmation of treatment, will be analyzed according to the study drug 
received. 
All data collected dming treatment plus 30 days after last dose of study drug will be included in 
the safety sUllllilaries. 
8.2.1.3. 
Phrumacokinetics 
There are two phrumacokinetic analysis sets: 1) The PK 
· Set which includes 
concentration data from the · 
drawn at each 
The PK Analysis Set will include all enrolled or randomized subjects who took at least one dose 
of study dmg and for whom concentration data of analytes GS-9674 (and its metabolites as 
applicable) ru·e available. The PK Analysis Set will be used for analyses of population PK. 
pp 
8.2.1.4. 
Phrumacodynamics 
There are two phru·macodynamic analysis sets: 1) The PD Analysis Set which includes 
concentration data from the · 
drawn at each visit as well 
The PD Analysis Set will include all enrolled or randomized subjects who took at least one dose 
of study dmg and for whom concentration data ofFGF19, C4, and bile acids are available. The 
PD Analysis Set may be used for descriptive and/or population based PD analyses as applicable. 
PD 
8.2.1.5. 
Bioma1·kers 
The Biomru·ker Analysis Set will include data from subjects in the Safety Analysis Set who have 
the necessaty baseline and on-study measmements to provide interpretable results for the 
specific paratneters of interest. 
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8.2.2. 
Interim Analysis 
An administrative interim analysis will be perfmmed after all subjects fmish 12 weeks of 
treatment. 
8.3. 
Data Handling Conventions 
Final 
Original 
Missing data can have an impact on the inte1pretation of the study data. In general, values for 
missing data will not be imputed. 
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example, if a subject received study medication, the subject will be 
included in a summary of adverse events according to the treatment received; othe1wise, if the 
subject is not dosed then they will be excluded from the summa1y. If safety laboratmy results for 
a subject are missing for any reason at a time point, the subject will be excluded from the 
calculation of sUllllnaty statistics for that time point. If the subject is missing a pre-dose value, 
then the subject will be excluded from the calculation of summmy statistics for the pre-dose 
value and the change from pre-dose values. 
Values for missing safety laboratmy data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. If no pre-treatment laboratmy value is 
available, the baseline value will be assmned to be nmmal (ie, no grade [Grade OJ) for the 
summary of graded laboratmy abnmmalities. 
Values for missing vital signs data will not be imputed; however, a missing baseline result will 
be replaced with a screening result, if available. 
8.4. 
Demographic Data and Baseline Characteristics 
Demographic and baseline measurements will be summarized using standard descriptive 
methods. 
Demographic summaries will include sex, race/ethnicity, and age. 
Baseline data will include a sUllllnaty of body weight, height, body mass index, and 
randomization stratification group (presence or absence of diabetes) and other disease 
characteristic vm·iables. 
8.5. 
Efficacy Analysis 
The biological activity ofGS-9674 will be evaluated usina radiologic endpoints and biomarker 
variables. PPD 
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8.6.
Safety Analysis
All safety data collected on or after the date that GS-9674 was first dispensed up to the date of 
last dose of GS-9674 plus 30 days will be summarized by treatment group. Data for the 
pretreatment and follow-up periods will be included in data listings. 
8.6.1.
Extent of Exposure
Data for a subject’s extent of exposure to GS-9674 will be generated from the study drug
administration eCRF. Exposure data will be summarized by treatment group.
8.6.2.
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. A treatment-emergent 
adverse event (TEAE) will be defined as 1 or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug.

Any AEs leading to premature discontinuation of study drug.
Summaries (number and percentage of subjects) of TEAEs by SOC and PT will be provided. 
Treatment-emergent AEs will also be summarized by relationship to study drug and severity. In 
addition, TEAEs leading to premature discontinuation of study drug and study will be 
summarized and listed.
All AEs collected during the course of the study will be presented in data listings with a field for 
treatment-emergent event (yes/no). 
8.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, Median, Q1, Q3, minimum, and 
maximum) by treatment group and study visit along with the corresponding change from 
baseline values. 
Graded laboratory abnormalities will be defined using the grading scheme in the CTCAE 
Version 4.03 (Appendix 3). Grading of laboratory abnormalities for analysis purposes will be 
performed by the central laboratory.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
1 toxicity grade from baseline at any time post baseline up to and including the date of last dose 


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of study dmg plus 30 days will be smnmarized by treatment group. If baseline data are missing, 
then any graded abnmmality (ie, at least a Grade 1) will be considered treatment emergent. 
8.6.4. 
Other Safety Evaluations 
Summaty statistics for the 12-lead ECGs petfmmed at Baseline/Day 1, Week 12, and Week 24, 
will be generated. 
8.7. 
Pharmacokinetic Analysis 
Plasma concentl'ations and PK parameters (eg, AUCu.u, Cmax and Ctau) will be listed and 
smnmarized as appropriate for GS-9674 (and its metabolites as applicable) using descriptive 
statistics. 
Details of the analysis plan will be provided in the Phatmacokinetic Reporting atld Analysis 
Plan. 
8.8. 
Pharmacodynamic Analysis 
Primary PD parameters (AUCpartiaJ, Cmax, Cmin as applicable) ofFGF19 and C4 will be listed and 
summarized as appropriate for GS-9674 using descriptive statistics. 
Details of the analysis plan will be provided in the Phatmacodynamics Reporting and Analysis 
Plan. 
8.9. 
Biomarker Analysis 
Descriptive statistics of biomm·ker expression and change from baseline will be provided at each 
sampling time by treatment. Point estimates and 95% confidence intervals may be calculated. 
PD 
8.10. 
Sample Size 
Due to the exploratmy nature of this study, no fotmal power calculations were used to detetmine 
sample size. The number of subjects was chosen based on clinical experience with other similm· 
proof of concept studies. However, assmning that 4% of subjects in the placebo atm (N=25) and 
32% in the GS-9674 100 mg atm (N=50) have a ~ 30% reduction in MRI-PDFF at 
Week 24, this sample size will provide 80% power to detect the difference based on a two-sided 
Fisher's exact test at a significance level of 0.05. 
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8.11.
Data Monitoring Committee
An independent, external data monitoring committee (DMC) that consists of two hepatologists 
and a PhD statistician will review the progress of the study and perform reviews of safety data. 
The DMC will convene once 20 subjects have been enrolled and will meet every 3 to 4 months 
thereafter to monitor the study for safety events. The DMC will meet on an ad hoc basis if there 
are at least 3 Grade ≥ 3 serious, treatment-related Common Terminology Criteria for Adverse 
Events (CTCAE) observed in the study. In the event of two similar Grade 4-CTCAE treatment-
related adverse events or one Grade 5-CTCAE treatment-related adverse event, the DMC will 
review the data and advise the sponsor regarding stopping or continuing the study. The DMC 
will provide recommendation to Gilead whether the nature, frequency, and severity of adverse 
effects associated with study treatment warrant the early termination of the study in the best 
interests of the participants, whether the study should continue as planned, or the study should 
continue with modifications. The 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 has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC/EC approval, with the exception of those necessary 
to reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB/IEC/EC-approved consent form for documenting 


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written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by the 
IRB/IEC/EC or local requirements. The consent form will inform subjects about genomic testing 
and sample retention.
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 the Central Laboratory Services Manual for specific 
laboratory instructions. NOTE: The investigator must keep a screening log showing codes, 
names, and addresses for all subjects screened and for all subjects enrolled in the study. 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 study drug, 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 GS-9674, 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.
Case Report Forms
For each subject consented, an electronic case report form (eCRF) will be completed by an 
authorized study staff member whose training for this function is documented according to study 
procedures. eCRF should be completed on the day of the subject visit to enable the sponsor to 
perform central monitoring of safety data. The Eligibility Criteria eCRF should be completed 


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only after all data related to eligibility have been received. Subsequent to data entry, a study 
monitor will perform source data verification within the electronic data capture (EDC) system. 
Original entries as well as any changes to data fields will be stored in the audit trail of the 
system. Prior to database lock (or any interim time points as described in the clinical data 
management plan), the investigator will use his/her log in credentials to confirm that the forms 
have been reviewed, and that the entries accurately reflect the information in the source 
documents. The eCRF 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 study, 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
Where possible, study drug should be destroyed at the site. 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.
The study monitor will provide instructions for return.
The study monitor will evaluate each study center’s study drug disposal procedures and provide 
appropriate instruction for destruction of unused study drug supplies. If the site has an 
appropriate standard operating procedure (SOP) for drug destruction as determined by Gilead 
QA, the site may destroy used (empty or partially empty) and unused study drug supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If study drug is destroyed on site, the investigator must maintain accurate records for all study 
drug destroyed. Records must show the identification and quantity of each unit destroyed, the 
method of destruction, and the person who disposed of the study drug. Upon study completion, 
copies of the study drug accountability records must be filed at the site. Another copy will be 
returned to Gilead. Refer to the Pharmacy Binder for study drug disposal/return instructions.
The study monitor will review study drug supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this study to 
Gilead’s appointed study monitors, the IRB/IEC/EC, or to regulatory authority or health 
authority inspectors.


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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.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/IEC/EC
in accordance with local requirements and receive documented IRB/IEC/EC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agencies. 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.
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. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
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 


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expenses paid or reimbursed for such services, including any clinical study payments, meal, 
travel expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
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/ECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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10.
REFERENCES
Afzali A, Berry K, Ioannou GN. Excellent posttransplant survival for patients with nonalcoholic 
steatohepatitis in the United States. Liver Transpl 2012;18 (1):29-37.
Bannas P, Kramer H, Hernando D, Agni R, Cunningham AM, Mandal R, et al. Quantitative 
magnetic resonance imaging of hepatic steatosis: Validation in ex vivo human 
livers. Hepatology 2015;62 (5):1444-55.
Chen J, Talwalkar JA, Yin M, Glaser KJ, Sanderson SO, Ehman RL. Early detection of 
nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease by 
using MR elastography. Radiology 2011;259 (3):749-56.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Dietrich P, Hellerbrand C. Non-alcoholic fatty liver disease, obesity and the metabolic syndrome. 
Best practice & research 2014;28 (4):637-53.
Dowman JK, Tomlinson JW, Newsome PN. Pathogenesis of non-alcoholic fatty liver disease. 
QJM 2010;103 (2):71-83.
Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal P, Kechagias S, et al. Fibrosis stage is the 
strongest predictor for disease-specific mortality in NAFLD after up to 33 years 
of follow-up [Accepted Article]. Hepatology 2014.
Faramawi MF, Wildman RP, Gustat J, Rice J, Abdul Kareem MY. The association of the 
metabolic syndrome with QTc interval in NHANES III. Eur J Epidemiol 2008;23 
(7):459-65.
Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial 
fibrillation: the Framingham study. N Engl J Med 1982;306 (17):1018-22.
Koek GH, Liedorp PR, Bast A. The role of oxidative stress in non-alcoholic steatohepatitis. Clin 
Chim Acta 2011;412 (15-16):1297-305.
Loomba R, Wolfson T, Ang B, Hooker J, Behling C, Peterson M, et al. Magnetic resonance 
elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver 
disease: a prospective study. Hepatology 2014;60 (6):1920-8.
Murakami S, Takayama F, Egashira T, Imao M, Mori A. Fermented papaya preparation halts the 
progression of non-alcoholic steatohepatitis in rats. Journal of Biophysical 
Chemisty 2013;4 (2):84-90.


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Nakamoto K, Takayama F, Mankura M, Hidaka Y, Egashira T, Ogino T, et al. Beneficial Effects 
of Fermented Green Tea Extract in a Rat Model of Non-alcoholic Steatohepatitis. 
Journal of clinical biochemistry and nutrition 2009;44 (3):239-46.
Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic 
steatohepatitis: the central role of nontriglyceride fatty acid metabolites. 
Hepatology 2010;52 (2):774-88.
Ong JP, Younossi ZM. Epidemiology and natural history of NAFLD and NASH. Clin Liver Dis 
2007;11 (1):1-16, vii.
Patel JR, Bettencourt R, Cui JY, Salotti J, Hooker J, Bhatt A, et al. Non-invasive quantitative 
decline in liver fat content on MRI and histologic response in nonalcoholic 
steatohepatitis: A secondary analysis of MOZART trial [Abstract 913]. American 
Assoication for the Study of Liver Diseases (AASLD); 2015 13-17 November; 
San Francisco, CA. pp. 659A-60A.
Ratziu V, Thibault V, Benhamou Y, Poynard T. Successful rescue therapy with tenofovir in a 
patient with hepatic decompensation and adefovir resistant HBV mutant. Comp 
Hepatol 2006;5:1.
Singh S, Venkatesh SK, Loomba R, Wang Z, Sirlin C, Chen J, et al. Magnetic resonance 
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diagnostic accuracy systematic review and individual participant data pooled 
analysis. European radiology 2016;26 (5):1431-40.
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of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. 
Aliment Pharmacol Ther 2011;34 (3):274-85.
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Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing 
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(4):754-64.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table for GS-US-402-1852
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
U.S.A. 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, 
Tolerability, and Efficacy of GS-9674 in Subjects with Nonalcoholic Steatohepatitis 
(NASH) 
GS-US-402-1852 Original Protocol, 28 June 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PPD 
INVESTIGATOR STATEMENT 
1 have read the protocol, including all appendices, and I agree that it contains all necessary 
details tor 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. 
1 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 marerial with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
S1te Number 
CONFIDENTIAL 
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Appendix 2.
Study Procedures Table for GS-US-402-1852
Screening
Treatment
Follow-Up
Unscheduled 
Visity
Week -4
to Day 0a
Baseline/
Day 1
Week 1
± 3 days
Week 4
± 3 days
Week 8
± 3 days
Week 12
± 7 days
Week 16
± 3 days
Week 20
± 3 days
Week 24/ETb
± 7 days
Follow-Upb
± 5 days
Subject Fastingc
X
X
X
X
X
X
X
X
X
X
X
Written Informed 
Consentd
X
Review 
Inclusion/Exclusion 
Criteria
X
X
Medical History 
X
QoL: General 
Assessments (CLDQ, 
SF-36, and WPAI)e
X
X
X
QoL: Pruritus 
Assessments (VAS-
itch and 5D-itch)e
X
X
X
X
X
X
X
X
Complete Physical 
Examination
X
Symptom Driven 
Physical Examinationf
X
X
X
X
X
X
X
X
X
X
Vital Signsg
X
X
X
X
X
X
X
X
X
X
Weighth
X
Xi
X
X
X
X
X
X
Xi
X
X
Height
X


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Screening
Treatment
Follow-Up
Unscheduled 
Visity
Week -4
to Day 0a
Baseline/
Day 1
Week 1
± 3 days
Week 4
± 3 days
Week 8
± 3 days
Week 12
± 7 days
Week 16
± 3 days
Week 20
± 3 days
Week 24/ETb
± 7 days
Follow-Upb
± 5 days
Chemistryj
X
X
X
X
X
X
X
X
X
X
X
Hematologyk
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panell
X
X
X
X
X
X
X
X
X
X
Lipid Profile
X
X
X
X
X
X
X
X
Hemoglobin A1c
X
X
X
X
Blood for 
Biomarkersm
X
X
X
X
X
X
Single PK and PD
Sampling
Xn
X
X
X
X
X
X
X
HIV-1, HBV and
HCV Serology
X
Pregnancy Testo
X
X
X
X
X
X
X
X
X
Serum FSHp
X
Genomic Sampleq
X
12-lead ECG
X
X
X
X
Ultrasoundr
Xr
FibroScan®s
X
X
X
MREt
X
X
X
MRI-PDFFt
X
X
X
Urine Drug Screenu
X


GS-9674 
Protocol GS-US-402-1852 
Gilead Sciences, Inc. 
Screening 
Week -4 
toDay Oa 
Urine Collection for 
(Biomarker) 
Stool Collection for 
(Biomarker) 
Fp-o 
Dispense GS-9674 
and PTM GS-9674w 
Concomitant 
X 
Medications 
Adverse Events 
X 
Take GS-9674/ PTM 
GS-9674 Tabletsx 
Baseline/ 
Weekl 
Day 1 
± 3 days 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment 
Week4 
WeekS Week12 Week16 
± 3 days 
± 3 days 
± 7 days 
± 3 days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X- Daily (Baseline/ Day 1 to Week 24) 
Week20 Week24/ETb 
± 3 days 
± 7 days 
X 
X 
X 
X 
X 
X 
X 
Follow-Up 
Follow-Uph 
± 5 days 
X 
X 
Final 
Original 
Unscheduled 
VisifY 
X 
X 
a. 
The screening visit window may be extended nnder special circumstances with explicit approval of the Medical Monitor. Subjects who fail to meet eligibility criteria due to 
an abnormal laboratory result may nndergo re-testing of the abnormal analyte during the screening window. This will be done at the discretion of the investigator and with 
prior approval of the Medical Monitor. 
b. 
Subjects discontinuing the study at any time for any reason (Early Termination- ET) should complete the procedures listed for the Week 24/ET Visit AND the Follow-Up 
visit. 
c. 
Subjects must be in a fasted state for at least 8 hours prior to blood collection. 
d. 
Obtain written informed consent before initiation of any screening procedure. 
e. 
It is recommended that QoL assessments be completed prior to any study procedures being performed and prior to the subject seeing a health care provider. Refer to the Study 
Reference Binder for guidance on QoL assessment administration. 
f. 
The focus of a symptom driven physical examination will be determined by the investigator based on subject complaint. 
g. 
Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
h. 
Refer to the Study Reference Binder for specific instructions on how weight should be measured. 
1. 
During the Baseline/Day 1 and Week 24 visits, measurements of waist circumference should be performed. Refer to the Study Reference Binder for specific instructions on 
how these measurements are to be done. 
CONFIDENTIAL 
Page 84 
28 June 2016 
I 


GS-9674 
Protocol GS-US-402-1852 
Gilead Sciences, Inc. 
Final 
Original 
J. 
Blood chemistry will include: 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, gamrna-
glutamyl transferase ( GGT). Also includes C-Peptide and Insulin for the Baseline/Day 1, Week 4, 12, and 24 visits. 
k. 
l. 
Hematology will include: complete blood cell count with differential (red blood cells, white blood cells, platelets, and hematocrit). 
Coagulation Panel includes: PT, PTT, and INR. 
m. PPD 
n. 
0. 
p. 
q. 
r. 
PD samplmg oi1ly at BaselllielDay . 
Females of childbearing potential only (see Appendix 4). Serum pregnancy test at Screening and Urine pregnancy test at all other visits, except Week 1. 
Only required for some female subjects- see Appendix 4. 
P~D 
~----~----------------------------------------------~ 
~Itrasouna may be pertormedl.f necessary to conim n1\J"XFLD-. ------------------------------' 
S. 
Subject should be in fasted state for Fibroscan collection. Refer to the Study Reference Binder for further details. If FibroScan'~"'is not available at a site the test may be 
omitted. 
t. 
Subjects should be in fasted state for MRE/MRI-PDFF exams. Refer to the Study Reference Binder for further details. Subject must have confirmed NAFLD before 
MRE/MRI-PDFF exams are done. 
u. 
Drug screen for amphetamines, cocaine, and opiates (ie, heroin, morphine). 
v. 
PPD 
w. 
StudychUg wiffbe assignedvia fueiWRS system every 4 weeKs from Baseline/Day 1 through Week 20. 
x. 
Subjects will self-administer the study drug at the investigative site at the conclusion of the Baseline/Day 1 and Week 24 visits. 
y. 
If the Unscheduled visit is performed for the sole purpose of distribution of study drug, the assessments noted for this visit do not need to be performed. 
CONFIDENTIAL 
Page 85 
28 June 2016 


GS-9674
Protocol GS-US-402-1852
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 86
28 June 2016
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf


GS-9674
Protocol GS-US-402-1852
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 87
28 June 2016
Appendix 4.
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
The risks of treatment with GS-9674 during pregnancy have not been evaluated. There are no 
pre-clinical data available to determine whether GS-9674 is teratogenic or fetotoxic in early 
human pregnancy. Pregnancy must therefore be excluded before the start of treatment with study 
drug and prevented thereafter by reliable, highly effective contraceptive methods. Pregnancy 
tests will be performed regularly throughout this study. Please refer to the latest version of the 
investigator’s brochure for additional information.
Drug-drug interaction (DDI) with hormones used for contraception is not available. There are 
insufficient data to exclude the possibility of a clinically relevant interaction between GS-9674 
and hormonal contraceptives that result in reduced contraception efficacy. Therefore, the use of 
hormonal contraception with GS-9674 is not recommended.
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 also not rely on hormone-containing contraceptives as a form 
of birth control during the study. 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 


GS-9674
Protocol GS-US-402-1852
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 88
28 June 2016
will be performed at monthly intervals thereafter. Female subjects must agree to one of the 
following from Screening until 30 days following the last dose of the study drug, GS-9674.

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)
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the last dose of the study drug, GS-9674.
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 (plus spermicide) during treatment and until 
90 days after the last dose of GS-9674. Additional contraception recommendations should also 
be considered if the female partner is not pregnant.
Male subjects must also refrain from sperm donation during treatment and until at least 90 days 
after the last dose of the study drug, GS-9674.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM). Female condom and male condom should not be used 
together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days (or 90 days for the partner of male subjects)
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.