Conditions: Nonalcoholic Steatohepatitis (NASH)
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 127
Healthy volunteers: no

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

Detailed description:

Arms:
arm 1: Participants will receive firsocostat 1 x 5 mg + 1 x placebo matched to firsocostat 5 mg + 2 x placebo matched to firsocostat 10 mg for 12 weeks. arm 2: Participants will receive firsocostat 2 X 10 mg + 2 x placebo matched to firsocostat 5 mg for 12 weeks. arm 3: Participants will receive 2 x placebo matched to firsocostat 5 mg + 2 x placebo matched to firsocostat 10 mg for 12 weeks.

Interventions: intervention 1: Firsocostat intervention 2: Placebo
Intervention descriptions: intervention 1: Capsules orally once daily. intervention 2: Placebo matched to firsocostat orally once daily.

Protocol document:
Prot_000.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Sciences Medical 
Monitor 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Safety, Tolerability, and Efficacy of GS-0976 in 
Subjects with Nonalcoholic Steatohepatitis 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
124915 
Not Applicable 
Not Available 
Nonalcoholic steatohepatitis (NASH) 
GS-US-426-3989 
Name: 
Telephone: 
Fax: 
Email: 
Original: 
Amendment 1: 
IPIPD 
IPIPD 
IPIPD 
PPU 
20 June 2016 
15 December 2016 
CONFIDENTIALITY STATEMENT 
The info1mation contained in this document, paiiicularly unpublished data, is the prope1iy or 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 infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational diug described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessaiy to obtain infonned consent from those 
persons to whom the di11g may be adininistered. 


GS-0976
Protocol GS-US-426-3989
Final
Gilead Sciences, Inc.
Amendment 1
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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
1.2.
GS-0976 .................................................................................................................................................17
1.2.1.
General Information .............................................................................................................17
1.2.2.
Nonclinical Pharmacology ...................................................................................................17
1.2.3.
Nonclinical Toxicology........................................................................................................17
1.2.4.
Nonclinical Pharmacokinetics..............................................................................................18
1.2.5.
Clinical Trials of GS-0976 ...................................................................................................19
1.3.
Rationale for the Current Study .............................................................................................................24
1.3.1.
Rationale for this Study........................................................................................................25
1.4.
Risk/Benefit Assessment for the Study..................................................................................................26
1.5.
Compliance ............................................................................................................................................27
2.
OBJECTIVES.....................................................................................................................................................28
3.
STUDY DESIGN................................................................................................................................................29
3.1.
Study Design..........................................................................................................................................29
3.2.
Treatment Plan and Regimen .................................................................................................................29
3.3.
Biomarker Testing..................................................................................................................................30
3.3.1.
Biomarker Samples to Address the Study Objectives ..........................................................30
3.3.2.
Biomarker Samples for Optional Future Research...............................................................30
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 Study Drugs .............................................................................................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-0976/PTM GS-0976........................................................................36
5.4.
Prior and Concomitant Medications.......................................................................................................37
5.5.
Accountability for GS-0976/PTM GS-0976 ..........................................................................................38
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................38
6.
STUDY PROCEDURES ....................................................................................................................................39
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................39
6.2.
Pretreatment Assessments......................................................................................................................39


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6.2.1.
Screening Visit .....................................................................................................................39
6.3.
Baseline/Day 1 Randomization and Assessments..................................................................................41
6.4.
Treatment Assessments..........................................................................................................................43
6.4.1.
Week 1 Visit (±3 days).........................................................................................................43
6.4.2.
Week 4 Visit (±3 days).........................................................................................................44
6.4.3.
Week 8 Visit (±3 days).........................................................................................................44
6.4.4.
Week 12 Visit (±7 days).......................................................................................................45
6.4.5.
Unscheduled Visit ................................................................................................................46
6.4.6.
Follow-Up Visit (±5 days) ...................................................................................................47
6.5.
Assessments for Premature Discontinuation from Study.......................................................................48
6.6.
Criteria for Discontinuation of Study Treatment....................................................................................48
6.7.
.48
6.8.
Description of Assessments ...................................................................................................................49
6.8.1.
Clinical Laboratory Analytes ...............................................................................................49
6.8.2.
Physical Examination...........................................................................................................50
6.8.3.
Vital Signs............................................................................................................................50
6.8.4.
Medical History....................................................................................................................51
6.8.5.
Pharmacogenomic Testing ...................................................................................................51
6.8.6.
Health Related Quality of Life (HRQoL).............................................................................51
6.8.7.
Electrocardiogram................................................................................................................51
6.8.8.
FibroScan® ...........................................................................................................................51
6.8.9.
MRE and MRI-PDFF...........................................................................................................52
6.9.
End of Study Definition .........................................................................................................................52
6.10.
Poststudy Care........................................................................................................................................52
6.11.
Sample Storage.......................................................................................................................................52
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................53
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................53
7.1.1.
Adverse Events.....................................................................................................................53
7.1.2.
Serious Adverse Events........................................................................................................53
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................54
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................54
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................54
7.2.2.
Assessment of Severity ........................................................................................................55
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................55
7.4.
Gilead Reporting Requirements.............................................................................................................56
7.5.
Toxicity Management ............................................................................................................................57
7.6.
Special Situations Reports......................................................................................................................59
7.6.1.
Definitions of Special Situations..........................................................................................59
7.6.2.
Instructions for Reporting Special Situations.......................................................................60
8.
STATISTICAL CONSIDERATIONS................................................................................................................62
8.1.
Analysis Objectives and Endpoints........................................................................................................62
8.1.1.
Analysis Objectives..............................................................................................................62
8.1.2.
Primary Endpoint .................................................................................................................62
8.1.3.
Exploratory Efficacy Endpoints ...........................................................................................62
8.2.
Analysis Conventions.............................................................................................................................63
8.2.1.
Analysis Sets ........................................................................................................................63
8.3.
Data Handling Conventions ...................................................................................................................64
8.4.
Demographic Data and Baseline Characteristics ...................................................................................65
8.5.
Efficacy Analysis ...................................................................................................................................65
8.6.
Safety Analysis.......................................................................................................................................65
CCI


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8.6.1.
Extent of Exposure...............................................................................................................65
8.6.2.
Adverse Events.....................................................................................................................65
8.6.3.
Laboratory Evaluations ........................................................................................................66
8.6.4.
Other Safety Evaluations......................................................................................................66
8.7.
Pharmacokinetic Analysis......................................................................................................................66
8.8.
Biomarker Analysis................................................................................................................................66
8.9.
Sample Size............................................................................................................................................66
8.10.
Data Monitoring Committee ..................................................................................................................67
9.
RESPONSIBILITIES..........................................................................................................................................68
9.1.
Investigator Responsibilities ..................................................................................................................68
9.1.1.
Good Clinical Practice..........................................................................................................68
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (EC) 
Review and Approval...........................................................................................................68
9.1.3.
Informed Consent.................................................................................................................68
9.1.4.
Confidentiality......................................................................................................................69
9.1.5.
Study Files and Retention of Records ..................................................................................69
9.1.6.
Case Report Forms...............................................................................................................70
9.1.7.
Study Drug Accountability and Return ................................................................................71
9.1.8.
Inspections............................................................................................................................71
9.1.9.
Protocol Compliance............................................................................................................71
9.2.
Sponsor Responsibilities ........................................................................................................................72
9.2.1.
Protocol Modifications.........................................................................................................72
9.2.2.
Study Report.........................................................................................................................72
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................72
9.3.1.
Payment Reporting...............................................................................................................72
9.3.2.
Access to Information for Monitoring..................................................................................72
9.3.3.
Monitoring and Oversight of Biomarker Specimens............................................................72
9.3.4.
Access to Information for Auditing or Inspections ..............................................................73
9.3.5.
Study Discontinuation..........................................................................................................73
10.
REFERENCES ...................................................................................................................................................74
11.
APPENDICES ....................................................................................................................................................77
Appendix 1.
Investigator Signature Page....................................................................................................78
Appendix 2.
Study Procedures Table for GS-US-426-3989 .......................................................................79
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................81
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 ..........................83


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Gilead Sciences, Inc.
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LIST OF IN-TEXT TABLES
Table 1-1.
Summary of Single Dose Pharmacokinetic Parameters of GS-0976 Following 
Administration of 30 mg to 1000 mg GS-0976 Under Fasting Conditions and 200 
mg GS-0976 Under Fed Conditions .......................................................................................20
Table 1-2.
Summary of Single and Multiple Dose Pharmacokinetic Parameters of GS-0976 
Following Administration of 50 mg BID, 100 mg QD, 100 mg BID, or 200 mg QD 
GS-0976 Under Fed Conditions .............................................................................................22
Table 1-3.
Summary of Single and Multiple Dose Pharmacokinetic Parameters of ND-011535 
Following Administration of 50 mg BID, 100 mg QD, 100 mg BID, or 200 mg QD 
GS-0976 Under Fed Conditions .............................................................................................23
Table 5-1.
List of Prohibited Medications ...............................................................................................38
LIST OF IN-TEXT FIGURES
Figure 3-1.
Overall Study Design .............................................................................................................29


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Final
Gilead Sciences, Inc.
Amendment 1
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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Safety, Tolerability, and Efficacy of GS-0976 in Subjects 
with Nonalcoholic Steatohepatitis
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
124915
Not Applicable
Not Available
Study Centers 
Planned:
Approximately 50 centers in the United States
Objectives:
The primary objective of this study is to evaluate the safety and 
tolerability of GS-0976 in subjects with nonalcoholic steatohepatitis 
(NASH) as assessed by magnetic resonance imaging-proton density fat 
fraction (MRI-PDFF) and magnetic resonance elastrography (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 biological activity of GS-0976 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 approximately 22 weeks, which 
includes a 6-week Screening period, a 12-week treatment period during 
which study drugs 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-0976
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Study drugs will be administered for a total of 12 weeks. 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 (i.e., hemoglobin A1c ≥ 6.5% OR fasting plasma 
glucose ≥126 mg/dL).
Number of 
Subjects 
Planned:
Approximately 125 subjects
Target 
Population:
Males and non-pregnant, non-lactating females between 18-75 years of 
age without cirrhosis and with NASH as assessed by MRI-PDFF and 
MRE or a historical liver biopsy consistent with NASH and non-cirrhotic 
fibrosis.
Duration of 
Treatment:
Subjects will be treated for 12 weeks.
Diagnosis and 
Main Eligibility 
Criteria:
Key inclusion and exclusion criteria are as follows:
Key Inclusion Criteria:

Meets the following conditions:
a) A clinical diagnosis of nonalcoholic fatty liver disease (NAFLD) with 
imaging or a liver biopsy documenting fatty liver within two years 
prior to Screening (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
tlQ 
C: ·c 
a, 
u 
Vl 
6 Weeks 
Group A (n=S0) 
GS-0976 5 mg+ 5 mg-PTM + 2 x 10 mg-PTM 
orally once daily 
Group B (n=S0) 
2 x GS-097610 mg+ 2 x 5 mg-PTM 
orally once daily 
Group C (n=25) 
2 x 5 mg-PTM + 2 x 10 mg-PTM 
orally once daily 
12 Weeks 
> 
"'C 
:::, 
ai 
0 
"'C 
C: 
I.LI 
--.... 
C. 
:::> 
15 
u.. 
4 
Weeks 


GS-0976
Protocol GS-US-426-3989
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Gilead Sciences, Inc.
Amendment 1
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
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

No documented weight loss > 5% between the date of the liver biopsy 
and Screening.

Platelet count ≥ 100,000/mm3

Creatinine Clearance (CLcr ) as calculated by the Cockcroft-Gault 
equation ≥ 60 ml/min
Key Exclusion Criteria:

Pregnant or lactating females;

ALT > 5 x 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 (e.g. NASH CRN classification
stage 4 or equivalent);
b) Evidence of cirrhosis on liver imaging (e.g. ultrasound, CT, or MRI) 
including a nodular liver surface, splenomegaly, or portal venous 
collaterals;
c) Prior history of decompensated liver disease, including ascites, 
hepatic encephalopathy or variceal bleeding;
d) 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. 

BMI < 18 kg/m2;

INR > 1.2, unless on anticoagulant therapy;

Total bilirubin > 1 x ULN, except with diagnosis of Gilbert’s 
syndrome;
Refer to Sections 4.2 and 4.3 for complete listing of inclusion and 
exclusion criteria.
Subjects with laboratory abnormalities outside of the above parameters 
may be approved for inclusion in the trial with approval from the Medical 
Monitor.


GS-0976 
Protocol GS-US-426-3989 
Gilead Sciences, Inc. 
Study 
Procedures/ 
Frequency: 
CONFIDENTIAL 
Final 
Amendment 1 
After signing the info1med consent fo1m, subjects will complete a 
Screening visit which will include the following assessments: complete 
medical histo1y, physical examination (PE), vital signs, laborato1y 
assessments (blood chemistiy, hematology, coagulation panel, 
hemoglobin Ale, and HIV-1, HBV, and HCV serology), sernm 
pregnancy test (for females of child-bearing potential), urine drng test, 
standard 12-lead ECG, ulti·asound (if necessa1y), review of adverse 
events, concomitant medications, and MRI-PDFF and MRE 
examinations. 
After the Screening period and a randomization visit at Baseline/Day 1, 
study visits will occur on Weeks 1, 4, 8, 12, and a Follow-Up visit 4 
weeks after the last dose of study diugs. At minimum, vital signs, 
symptom di·iven PE, safety laborato1y tests (blood chemistiy, 
hematology, coagulation panel, and lipid profile), review of adverse 
events and concomitant medications will be done at eve1y visit. 
Eligible subjects will be randomized to one of 3 ti·eatment groups. Prior 
to initial dosing, required Baseline/Day 1 assessments will be perfo1med 
and will include symptom di·iven PE, vital signs (including waist 
circumference), laborato1y assessments, pregnancy tests (for females of 
child-bearing potential), urine, blood, and stool collection for biomarker 
assessment, Quality of Life (QoL) questionnaires, standard 12-lead ECG, 
FibroScan® (if available), review of adverse events and concomitant 
medications. 
While on study, subjects will undergo the following procedures and 
laborato1y assessments: 
• 
MRE and MRI-PDFF at Week 12 
• 
FibroScan® at Baseline/Day 1 and Week 12 (if available) 
• 
Single PK sampling at Weeks 1, 4, 8, and 12 
• 
Blood collection for Biomarkers at Baseline/Day 1, and at Weeks 1, 
4, and 12 
• 
Urine collection for Biomarkers at Baseline/Day 1, and at Weeks 1, 4, 
and 12 
• 
12-lead ECGs at Baseline/Day 1 and Week 12 
• 
Hematology, blood chemistiy, fasting lipid profile, PT, PTT, and INR 
at Baseline/Day 1, and at Weeks 1, 4, 8, 12, and Follow-Up visit 
• 
Hemoglobin Ale (HbAle) at Baseline/Day 1 and Week 12 
• 
Stool collection for Biomarkers at Baseline/Day 1 and Week 12 
Page9 
15 December 2016 


GS-0976 
Protocol GS-US-426-3989 
Gilead Sciences, Inc. 
Test Product, Dose, 
and Mode of 
Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Criteria for 
Evaluation: 
Safety: 
CONFIDENTIAL 
Final 
Amendment 1 
• 
Urine pregnancy test (females of childbearing potential only) at 
Baseline/Day 1, and at Weeks 4, 8, 12, and Follow-Up visit 
• 
SF-36, WPAI, and CLDQ at Baseline/Day 1 and Week 12 
Subjects will return for their final visit, the Follow-Up visit, 4 weeks after 
the last dose of study chu gs. At this visit assessments include a symptom 
driven PE, vital signs, review of concomitant medications and AEs, and 
safety laborato1y tests. A urine pregnancy test will be perfonned for 
females of child bearing potential only. 
• 
Treatment Group A: GS-0976 5 mg (1 x 5 mg capsule, 1 x 5 mg-PTM 
capsule, 2 x 10 mg-PTM capsules) administered orally once daily; 
n=50 subjects 
• 
Treatment Group B: GS-0976 20 mg (2 x 10 mg capsule, 
2 x 5 mg-PTM capsules) administered orally once daily; 
n=50 subjects 
• 
Treatment Group C: GS-0976 Placebo (2 x 5 mg-PTM capsules, 
2 x 10 mg-PTM capsules) achninistered orally once daily; 
n=25 subjects 
Placebo-to-match 5 mg (5 mg-PTM) GS-0976 capsules and 
placebo-to-match 10 mg capsules (10 mg-PTM) are identical in size, 
shape, color and appearance to their conesponding strengths of active 
GS-0976 capsules. 
The primaiy endpoint is the safety of GS-0976 in subjects with NASH. 
Safety will be assessed during the study through the repo1t ing of AEs, 
and by clinical laborato1y tests and vital sign assessments at various time 
points during the study. Concoinitant medication usage will also be 
assessed throughout the study. 
An independent, external Data Monitoring Cominittee (DMC) that 
consists of two hepatologists and a PhD statistician will convene once 
20 subjects have been randoinized 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 siinilar Grade 
3 serious, treatment related 
Common Tenninology Criteria for Adverse Events (CTCAE) observed in 
the trial. In the event of two siinilar Grade 4-CTCAE treatment related 
Page 10 
15 December 2016 


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events or one Grade 5-CTCAE treatment related event, the DMC will 
review the data and advise the sponsor regarding stopping or continuing 
the trial.
Efficacy:
Efficacy will be assessed through a number of exploratory endpoints. 
These exploratory endpoints are described in Section 8.1.3.
Pharmacokinetics:
A single PK blood sample will be collected at each on-treatment visit for 
all subjects. Plasma concentrations of GS-0976, and other metabolites as 
appropriate, will be determined for PK analyses as applicable.
Statistical 
Methods:
Safety Analysis:
All safety data collected will be listed and summarized, as appropriate, by 
treatment group.
Efficacy 
Analysis:
The biological activity of GS-0976 will be evaluated using biomarker 
variables. Because efficacy endpoints will be evaluated for exploratory 
purpose, formal statistical comparisons will not be made for these 
endpoints. Ninety-five percent confidence intervals (95% CI) will be 
provided if applicable.
Exploratory 
Analysis:
Point estimates and 95% CI will be calculated for all continuous 
exploratory parameters (e.g. MRI-PDFF, MRE, FibroScan®). For 
categorical variables, descriptive statistics will be calculated with count 
and percentage of subjects in each category by treatment group.
Sample Size:
Due to the exploratory nature of this study, no formal power calculations 
were used to determine 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 Practices 
(GCPs) including archiving of essential documents.


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Amendment 1
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C
degrees Celsius
F
degrees Fahrenheit
ACC
acetyl-CoA carboxylases
AE
adverse event
ALP
alkaline phosphatase 
ALT
alanine aminotransferase
Apo B
apolipoprotein B
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC0-last
area under the plasma concentration-time curve from time 0 to the last 
measurable concentration
AUCinf
area under the plasma/serum/PBMC concentration versus time curve 
extrapolated to infinite time, calculated as AUC0-last + (Clast/λz)
AUCpartial
partial area under the plasma/serum concentration versus time curve
AUCtau
area under the plasma/serum/PBMC concentration versus time curve over the 
dosing interval
AUROC
area under the receiver operating characteristic curve
BAP
Biomarker Analysis Plan
BID
twice a day
BMI
body mass index
BUN
blood urea nitrogen
BW
body weight
C4
7-alpha-hydroxy-4-cholesten-3-one
CFR
Code of Federal Regulations
CI
confidence interval
CK-18
cytokeratin 18
CLDQ
Chronic Liver Disease questionnaire
CL/F
apparent oral clearance
CLcr
creatinine clearance
CLrenal
Renal clearance 
Clast
last observed quantifiable serum/plasma/PBMC concentration of the drug
Cmax
maximum observed concentration of drug
Cmin
minimum observed plasma/serum concentration of drug
CRO
contract (or clinical) research organization
CSR
clinical study report
CT
computed tomography
Ctau
observed drug concentration at the end of the dosing interval
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450


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Gilead Sciences, Inc.
Amendment 1
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CYP3A
cytochrome P4503A
DILI
drug induced liver injury
dL
deciliter
DMC
Data Monitoring Committee
DNL
de novo lipogenesis
DSPH
Drug Safety and Public Health
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form(s)
EDC
electronic data capture
ELF™Test
enhanced liver fibrosis test
ESA
erythropoiesis-stimulating agent
eSAE
electronic serious adverse event
eSSR
electronic special situations report
ET
early termination
EU
European Union
FAS
Full Analysis Set
FDA
(United States) Food and Drug Administration
FGF19
fibroblast growth factor 19
FSH
follicle stimulating hormone
GCP
Good Clinical Practice (Guidelines)
GCSF
granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
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
HCV Ab
hepatitis C antibody
HDPE
high density polyethylene
HIV
human immunodeficiency virus
HIV-1
human immunodeficiency virus type 1
HLGT
high-level group term
HLT
high-level term
HOMA-IR
homeostatic assessment of insulin resistance
HRQoL
health related quality of life
IB
Investigator Brochure


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ICF
Informed Consent Form
ICH
International Conference on Harmonisation
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
kg
kilogram
LDH
lactate dehydrogenase
LLT
lower-level term
MAD
multiple ascending dose
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
miRNA
micro ribonucleic acid
mmHg
millimeters of mercury
MPR
metabolite-to-parent
MRE
magnetic resonance elastography
MRI
magnetic resonance imaging
MRI-PDFF
magnetic resonance imaging – proton density fat fraction
NAFLD
nonalcoholic fatty liver disease
NASH
nonalcoholic steatohepatitis
NMR
nuclear magnetic resonance spectroscopy
NOEL
no-observed--effect-level
NOAEL
no observed adverse event level
N/C
not calculated
OATP
organic anion-transporting polypeptide
oz
ounce
PE
physical exam
PG
pharmacogenomics(s)
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PT
preferred term
PT
prothrombin time
PTM
placebo-to-match
PTT
partial prothrombin time
QD
once daily
QoL
quality of life


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QT
electrocardiographic interval between the beginning of the Q wave and 
termination of the T wave representing the time for both ventricular 
depolarization and repolarization to occur
RAUC
Ratio of Day 10 AUC0-tau / Day 1AUC0-t
RBC
red blood cell count
RNA
ribonucleic acid
ROS
reactive oxygen species
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
SSR
special situations report
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAE
treatment-emergent adverse event
Tmax
the time (observed time point) of Cmax
T1/2
an estimate of the terminal elimination half-life of the drug in, calculated by 
dividing the natural log of 2 by the terminal elimination rate constant (λz)
TPO
Thrombopoietin
ULN
Upper limit of the normal range
US
United States
Vz/F
apparent volume of distribution of the drug
WBC
White blood cell count
WHO
World Health Organization
WPAI
Work Productivity and Activity Impairment


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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 {Ong 2007, Vernon 
2011}. 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 {Ong 2007, Williams 2011}. 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 
{Dietrich 2014, Faramawi 2008, Voulgari 2010}. 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 2015, 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 
{Afzali 2012, Wong 2014}.
1.2.
GS-0976
GS-0976 is a small molecule allosteric inhibitor that acts at the protein-protein homodimer 
interface of acetyl coenzyme A (acetyl-CoA) carboxylases (ACC) ACC1 and ACC2, to prevent 
dimerization. ACC1 and ACC2 are important regulators of fatty acid metabolism. ACC1 
catalyzes the first step of de novo lipogenesis (DNL) by converting acetyl-CoA to malonyl-CoA 
while ACC2 regulates the entry of fatty acids into the mitochondria where beta oxidation can 
occur. Therefore, inhibition of ACC1 and ACC2 will reduce DNL and increase fatty acid beta 
oxidation. GS-0976 is being developed for the treatment of NASH.
1.2.1.
General Information
For further information on GS-0976, refer to the current Investigator Brochure (IB) for GS-0976.
1.2.2.
Nonclinical Pharmacology
GS-0976 has been characterized in several biochemical and cellular assays to enhance the 
understanding of the mechanism of action and has been well characterized in vivo in several 
mechanistic models to demonstrate target engagement and in animal disease models to 
demonstrate specific activity on endpoints relevant to metabolic disease. Moreover, extensive 
safety pharmacology and receptor screening studies have been conducted.
The results of these pharmacodynamic (PD) studies indicate that GS-0976 can favorably affect 
the DNL, hepatic steatosis, insulin resistance, and body weight/body fat elevations produced in 
nonclinical models of metabolic disease without affecting food consumption or markers of liver 
function. In total, these studies confirm the potential for GS-0976 to impact important metabolic 
endpoints associated with NASH.
1.2.3.
Nonclinical Toxicology
The toxicity of GS-0976 was evaluated in rats and dogs in acute and repeated dose nonclinical 
studies up to 13 weeks in duration. Selection of the test species was based on the in vitro and in 
vivo assessment of metabolism. In in vitro experiments using human hepatocytes, 
no human-specific metabolites were identified and all metabolites detected were also present in 
rat and/or dog hepatocytes.
There were no adverse findings in safety pharmacology studies (central nervous system, 
respiratory and cardiovascular studies) at exposures ~ 50 fold above the predicted steady-state 
clinical exposure (Cmax ~110 ng/mL) after administration of 20 mg GS-0976 once daily (QD) 
fasted. The genotoxicity potential of GS-0976 was considered low as the compound is negative 
in the in vitro Ames, chromosome aberration studies and the in vivo mouse micronucleus study.


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Single doses of GS-0976 up to 1000 mg/kg were tolerated in rats and dogs. In the 28-day studies, 
the no-observed-adverse-effects levels (NOAELs) for the rat and dog were 60 and 
100 mg/kg/day respectively, the highest doses tested in the studies, affording exposure margins 
of at least 23 (rat) and 63 (dog) times above the predicted steady-state clinical exposure after 
administration of 20 mg GS-0976 QD fasted (240 ng•h/mL). In the 13-week rat study, no dose 
limiting toxicity was observed and the NOAEL was 60 mg/kg/day, the highest dose tested, 
providing an exposure margin of 23-fold above predicted steady-state clinical exposure. In the 
13-week dog study, bilateral posterior cortical cataracts and histological evidence of cataracts
were observed at 90 mg/kg/day, with progression in severity after a 28-day recovery period. 
There was no evidence of cataracts at doses ≤30 mg/kg/day. In the 13-week dog study, the 
presence of cataracts was found at exposures approximately 82 times above the predicted 
steady-state clinical exposure. No evidence of cataracts was observed at doses ≤ 30 mg/kg/day. 
The NOAEL for the 13-week dog study was 30 mg/kg/day, providing an exposure margin of 
approximately 15 fold above the predicted steady-state clinical exposure at 20 mg.
In the rat embryo-fetal development dose-range finding study, maternal toxicity and fetal 
abnormalities (external and soft tissue malformations, and developmental variations) were 
observed at doses ≥ 50 mg/kg/day in a dose-dependent manner. The no-observed-effect level 
(NOEL) for the embryo-fetal rat study was 25 mg/kg/day at an approximate exposure margin of
5.8 times above the predicted steady-state clinical exposure. In the rabbit study, 100 mg/kg/day 
was not tolerated and maternal toxicity (decreased body weight gain and food consumption) was 
observed at doses ≥ 25 mg/kg/day. While decreases in fetal weights were observed at doses 
≥10 mg/kg/day, no external malformations and developmental variations were observed at all 
doses.  The NOEL for the embryo-fetal rabbit study was less than 10 mg/kg/day. At this dose, 
the predicted steady-state clinical exposure margin is approximately 53. The observed 
embryo-fetal effects were not unexpected as the deletion of ACC1 in mice is embryonically 
lethal.
1.2.4.
Nonclinical Pharmacokinetics
GS-0976 is highly protein bound in plasma, and the volume of distribution of GS-0976 across 
nonclinical species is greater than total body water (0.7 L/kg), suggesting that GS-0976 is well 
distributed. A significant fraction of the absorbed parent compound is extracted by the liver 
indicating that GS-0976 is available to the target site (ie, the liver).
The metabolism of GS-0976 has been evaluated in in vitro incubations of rat, dog, Cynomolgus 
monkey, and human hepatocytes. No metabolites unique to the human were detected. In vivo 
metabolite identification studies in Sprague-Dawley rat and Beagle dog have demonstrated that 
the primary metabolite of GS-0976 is the glucuronide conjugate.
Neither GS-0976 nor the metabolite, NDI-011535, inhibits the cytochrome P450 (CYP) enzymes 
involved in drug metabolism. GS-0976 is not an inducer of CYP1A2 or CYP2B6 isozymes and 
is a mild inducer of CYP 3A4 in human hepatocytes in vitro.


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A single nonclinical study to evaluate elimination of GS-0976 and the metabolite NDI-011535 
was performed in bile duct cannulated Sprague-Dawley rats to profile concentrations over time 
in plasma, urine, and bile. Overall, the pharmacokinetic (PK) profile in plasma and bile indicate 
that GS-0976 is rapidly cleared from the plasma compartment, and the primary route of 
elimination is via the bile.
1.2.5.
Clinical Trials of GS-0976 
1.2.5.1.
Study 0976-101: Single Ascending Dose (SAD) Study
The first-in-human single ascending dose (SAD) study (Protocol Number 0976-101) was a 
randomized, placebo-controlled, double-blind study performed in normal, healthy adult subjects 
at one study center in the United States with a starting dose of 30 mg. The dosing in this study is 
completed with PK and tolerability data obtained following dosing of 30, 80, 200, 500, 800, and 
1000 mg in the fasted state and 200 mg following a high fat meal (fed state) to cohorts of 
8 subjects (6 active and 2 placebo control per group). Final data from the SAD study indicated 
that single doses of GS-0976 were tolerated across the dose range of 30 to 1000 mg. There were 
no deaths, serious adverse events (SAEs), or subject discontinuations due to adverse events 
(AEs) in this study. There were no clinically important treatment related or dose related trends in 
the incidence or severity of treatment emergent adverse events (TEAEs), clinical laboratory, vital 
sign, ECG, or physical examination assessments in this study. Abdominal discomfort, vessel 
puncture site pain, dizziness, and presyncope, reported by 2 subjects each (6% overall for fasted 
GS-0976), were the most frequently reported events in this study. Of the 27 TEAEs reported in 
the study, all were of Grade 1 severity. The principal investigator considered 2 TEAEs to be 
probably related (1 episode each of nausea and dyspepsia in placebo fasted subjects), 4 possibly 
related (1 episode of cough in the 30 mg GS-0976 fasted group and 1 episode each of discolored 
feces, abdominal discomfort, and diarrhea in the 500 mg GS-0976 fasted group), and 
21 unrelated to study treatment. 
Pharmacokinetic parameters of GS-0976 are presented in Table 1-1. Plasma GS-0976 maximum
plasma concentration (Cmax) and overall exposure (AUCinf) generally increased in a dose 
proportional manner across the range of 30 to 500 mg, under fasted conditions, with greater than 
dose-proportional increases above 500 mg. Similar results were observed for plasma 
NDI-011535 (glucuronide metabolite of GS-0976). The apparent total body clearance (CL/F) and 
apparent volume of distribution (Vz/F) of GS-0976 decreased with increasing GS-0976 doses of 
800 mg and 1000 mg. Urinary excretion of unchanged GS-0976 was negligible. GS-0976 Cmax
was approximately 68% lower under fed compared to fasted conditions; however, overall plasma 
GS-0976 exposure (based on AUC0-t and AUC0-inf) was only approximately 9% to 14% lower 
under fed compared to fasted conditions, which may not be a clinically significant difference. 
The median Tmax and mean T1/2 values were similar under fed and fasted conditions, although
there was a delay in the first quantifiable concentration and a prolonged absorption/distribution 
phase observed under fed compared to fasted conditions. Similar results were observed for 
plasma NDI-011535. Mean plasma NDI-011535 exposure was < 10% of GS-0976 plasma 
exposure, based on metabolite-to-parent (MPR) Cmax and MPR AUCinf.


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Table 1-1.
Summary of Single Dose Pharmacokinetic Parameters of GS-0976 
Following Administration of 30 mg to 1000 mg GS-0976 Under
Fasting Conditions and 200 mg GS-0976 Under Fed Conditions
PK 
Parameter
Mean + SD
GS-0976 Dose (mg)
30 mg
Fasted
(N=6)a
80 mg
Fasted
(N=6)a
200 mg
Fasted
(N=6)a
200 mg
Fed
(N=6)a
500 mg
Fasted
(N=6)b
800 mg
Fasted
(N=6)b
1000 mg
Fasted
(N=6)
Plasma
AUC0-t
(ng*h/mL)
176 + 104
363 + 215
1210 + 537
1160 + 613
2930 +
2440
6420 + 3180
17,400 +
8400
AUC0-inf
(ng*h/mL)
179 + 115
402 + 225
1250 + 616
1260 + 683
2960 +
2460
6460 + 3190
17,500 +
8410
Cmax
(ng/mL)
79.7 + 65.9
101 + 47.8
416 + 211
134 + 70.1
1110 +
1150
2570 + 1880
8380 + 3210
Tmax (h)c
1.26 
(0.23, 2.00)
2.00 
(1.50, 2.00)
1.50 
(1.01, 4.00)
2.00 
(1.50, 24.0)
1.75 
(1.01, 3.00)
2.01 
(1.01, 3.00)
2.50 
(1.02, 4.01)
T1/2 (h)
4.47 + 1.56
6.98 + 2.81
11.7 + 1.35
8.70 + 2.10
10.2 + 2.13
8.24 + 3.26
9.46 + 2.60
CL/F (L/h)
250 + 178
251 + 124
189 + 76.5
212 + 131
290 + 188
146 + 57.4
65.2 + 21.3
Vz/F (L)
1730 +
1510
2360 +
1390
3150 +
1270
2500 +
1290
4190 +
2570
1620 + 561
904 + 469
Urine
Ae0-48 (µg)
9.72 + 8.73
25.8 + 11.7
48.8 + 21.3
N/C
135 + 106
1030 + 924
636 + 600
Fe (%)
0.032 +
0.029
0.032 +
0.015
0.024 +
0.011
N/C
0.027 +
0.021
0.129 +
0.115
0.064 +
0.060
CLRenal
(mL/h)
50.0 + 45.1
109 + 96.2
46.2 + 15.5
N/C
77.5 + 65.7
135 + 62.2
42.6 + 36.5
PK parameters are presented to 3 significant digits, N/C = Not Calculated
a
N=5 for AUC0-inf, T1/2, CL/F, and Vz/F
b
N=5 for Ae0-48, Fe, and CLrenal
c
Tmax is presented as median (minimum, maximum)
The Ae0-48, Fe, and Clrenal for subject 
 (500 mg GS-0976) were missing, because this subject was unable to provide urine 
samples during the 12-24 hour, 24-36 hour, and 36-48 hour intervals, due to an AE.
The Ae0-48, Fe, CLrenal for subject 
 (800 mg GS-0976) were excluded from the summary statistics, because the urine sample 
for the 24-36 hour collection interval was partially spilled prior to volume measurement (ie, calculations were based off an 
approximate urine volume)
1.2.5.2.
Study 0976-102: Multiple Ascending Dose (MAD) Study
The multiple ascending dose (MAD) study (Protocol Number 0976-102) was a randomized, 
double-blind, placebo-controlled, clinical study conducted in healthy adult subjects at one study 
center in the United States. Five (5) cohorts of 8 subjects (6 active and 2 placebo) were evaluated 
at the following GS-0976 doses: 50 mg BID (100 mg daily) or placebo, 100 mg QD (100 mg 
daily) or placebo, 100 mg BID (200 mg daily) or placebo, 200 mg QD (200 mg daily) or 
placebo, or 150 mg QD (150 mg daily) or placebo. In each cohort, subjects received multiple 
PPD
PPD--


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oral doses of GS-0976 or placebo BID (every 12 hours) or once daily (QD) for 9 consecutive 
days (Days 1 through 9), with a single oral dose of GS-0976 or placebo on the morning of 
Day 10. Doses were administered approximately 30 minutes after meals. Preliminary safety and 
PK data are available for the first 4 dose groups. 
Each of the first 4 dose groups was fully enrolled and, overall, 24 subjects received GS-0976 and 
8 subjects received placebo. The majority of these 32 subjects who received GS-0976 (19/24, 
79%) and placebo (4/8, 50%) had at least 1 treatment-related AE as assessed by the principal 
investigator. The incidence of treatment-related AEs appeared to increase with higher doses and 
BID dosing of GS-0976: 50% of subjects at 50 mg BID, 62.5% at 100 mg QD, 75% at 200 mg 
QD, and 100% at 100 mg BID. One subject in the 200 mg QD cohort discontinued due to an AE 
on study Day 7 for Grade 4 elevated triglycerides (TG). No deaths or SAEs were reported. 
The most frequently reported TEAEs were gastrointestinal disorders and involved nausea 
(33% of all subjects who received GS-0976 vs. 0% of all subjects who received placebo), 
abdominal distension (25% GS-0976 vs. 13% placebo), constipation 
(21% GS-0976 vs. 13% placebo), diarrhea (21% GS-0976 vs. 0% placebo), and vomiting 
(13% GS-0976 vs. 0% placebo). In addition, TEAEs of increased blood triglycerides were 
reported (25% GS-0976 vs. 0% placebo) and involved Grade 3 events in 5 subjects (3 subjects in 
the 100 mg BID cohort and 2 subjects in the 50 mg BID cohort), and a Grade 4 event in 1 subject 
in the 200 mg QD cohort (discontinued treatment).
There were no clinically important treatment-related or dose-related trends in vital signs, ECG, 
or physical examination assessments in this study.
Preliminary single (Day 1) and (Day 10) multiple dose PK parameters for GS-0976 and 
ND-011535 after administration of 50 mg BID, 100 mg QD, 100 mg QD, and 200 mg QD 
GS-0976 under fed conditions are presented Tables 1-2 and 1-3, respectively. In general, 
GS-0976 AUC and Cmax increased in a dose proportional manner across the doses evaluated.  
GS-0976 AUC accumulated approximately 2-fold on Day 10 compared to Day 1 with minimal 
accumulation of Cmax.  Median GS-0976 Tmax occurred between 3 and 6 hours, in agreement with 
the food effect observed in study 0976-101.  The mean T1/2 of GS-0976 ranged from 
3.5-10.3 hours with higher variability contributing to the higher mean estimates from Day 10 in 
the 50 mg BID and 100 mg QD cohorts.  Mean plasma NDI-011535 exposure was < 10% of 
GS-0976 plasma exposure, based on MPR for AUC and Cmax.  The PK profile of NDI-011535 
was consistent with the PK profile of GS-0976, as seen by the consistent MPR for AUCinf and 
Cmax on Day 1 and Day 10 as well as across the doses evaluated. NDI-011535 exhibits formation 
rate limited kinetics as the mean T1/2 of NDI-011535 was consistent with that observed for 
GS-0976.


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Table 1-2.
Summary of Single and Multiple Dose Pharmacokinetic Parameters 
of GS-0976 Following Administration of 50 mg BID, 100 mg QD, 
100 mg BID, or 200 mg QD GS-0976 Under Fed Conditions
Plasma PK Parameter
Mean + SD
GS-0976 Dose
50 mg BID Fed 
(N=6)
100 mg QD Fed 
(N=6)
100 mg BID Fed 
(N=6)
200 mg QD Fed 
(N=6)
Day 1
AUC0-12or24 (ng*h/mL)
143 + 29.1
268 + 95.7
345 + 77.0
868 + 221
AUC0-inf (ng*h/mL)
178 + 40.7a
278 + 110a
671b
979 + 286a
Cmax (ng/mL)
41.3 + 14.3
64.9 + 31.7
61.6 + 14.7
152 + 68.4
Tmax (h)c
2.50 (1.50, 3.02)
3.50 (1.00, 6.00)
5.02 (3.00, 8.00)
5.00 (2.00, 6.00)
T1/2 (h)
3.50 + 1.63a
4.33 + 0.741a
5.58b
5.86 + 3.59a
CL/F (L/h)
292 + 61.6a
403 + 139a
149b
219 + 64.0a
Vz/F (L)
1350 + 333a
2560 + 1180a
1120b
1710 + 720a
Day 10
AUC0-tau (ng*h/mL)
305 + 77.0
369 + 160
742 + 217
1770 + 573a
RAUC
2.13 + 0.279
1.37 + 0.323
2.23 + 0.766
2.10 + 0.636a
Cmax (ng/mL)
49.4 + 15.2
53.5 + 22.4
121 + 56.3
198 + 86.6a
Cave (ng/mL)
25.4 + 6.42
15.4 + 6.68
61.8 + 18.1
73.7 + 23.9a
Ctrough (ng/mL)
12.4 + 5.04
3.16 + 2.24
56.1 + 22.7
33.9 + 42.9a
Tmax (h)c
4.01 (2.05, 8.00)
3.01 (2.00, 12.0)
6.00 (2.00, 6.00)
4.00 (1.50, 6.00)a
T1/2 (h)
10.3 + 6.66
7.92 + 4.52
6.83 + 1.62
5.91 + 0.987a
CLss/F (L/h)
173 + 41.5
312 + 116
145 + 43.5
125 + 46.4a
PK parameters are presented to 3 significant digits
RAUC = Ratio of Day 10 AUC0-tau / Day 1 AUC0-t
a
N=5
b
N=1
c
Tmax is presented as median (minimum, maximum)


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Table 1-3.
Summary of Single and Multiple Dose Pharmacokinetic Parameters 
of ND-011535 Following Administration of 50 mg BID, 100 mg QD, 
100 mg BID, or 200 mg QD GS-0976 Under Fed Conditions
Plasma PK Parameter 
Mean + SD
GS-0976 Dose
50 mg BID Fed 
(N=6)
100 mg QD Fed 
(N=6)
100 mg BID Fed 
(N=6)
200 mg QD Fed 
(N=6)
Day 1
AUC0-12or24 (ng*h/mL)
11.6 + 3.57a
23.7 + 0.891b
29.9 + 15.1a
78.8 + 43.3c
MPR AUC
0.064 + 0.022c
0.042d
0.063 + 0.027a
0.0636 + 0.027c
Cmax (ng/mL)
3.14 + 1.39
3.98 + 2.29
4.36 + 2.63
9.54 + 6.66
MPR Cmax
0.057 + 0.013
0.051 + 0.023
0.054 + 0.028
0.048 + 0.020
Tmax (h)e
2.50 (1.50, 302)
3.50 (1.50, 6.00)
6.00 (4.00, 11.9)
6.00 (4.00, 6.00)
T1/2 (h)
5.13 + 2.93a
3.59 + 0.895b
N/C
7.55 + 2.06c
Day 10
AUC0-tau (ng*h/mL)
28.5 + 8.89
46.0 + 22.6f
67.0 + 31.6
129 + 74.3a
RAUC
2.49 + 0.32a
2.50 + 0.150b
1.93 + 0.752a
2.41 + 1.03f
MPR AUC
0.072 + 0.013
0.073 + 0.015 N=3
0.050 + 0.020
0.052 + 0.016a
Cmax (ng/mL)
4.92 + 1.90
4.52 + 3.82
6.62 + 2.84
12.2 + 5.33a
Cave (ng/mL)
2.37 + 0.741
1.92 + 0.943f
3.95 + 1.64
5.38 + 3.09a
MPR Cmax
0.075 + 0.014
0.057 + 0.028
0.046 + 0.019
0.051 + 0.02a
Ctrough (ng/mL)
1.20 + 0.383
0.575 + 0.078b
3.76 + 1.45
3.21 + 3.18c
Tmax (h)e
3.50 (2.05, 6.00)
4.51 (2.00, 6.02)
6.00 (1.50, 6.04)
6.00 (3.00, 6.00)a
T1/2 (h)
4.61 + 1.30a
6.00 + 0.225b
5.67 + 0.40b
5.14 + 2.14f
PK parameters are presented to 3 significant digits
RAUC = Ratio of Day 10 AUC0-tau / Day 1 AUC0-t
MPR = Metabolite to Parent Ratio corrected for molecular weight
N/C = Not Calculated
a
N=5
b
N=2
c
N=4
d
N=1
e
Tmax and T1/2 are presented as median (minimum, maximum)
f
N=3
1.2.5.3.
Study 0976-103: Single Ascending Dose Pharmacodynamic Study
The single ascending dose PD study (Study 0976-103) was a two-period, two-treatment, 
crossover, randomized, double-blind, study to determine the PD activity on fractional DNL of a 
single oral dose of 20, 50, or 200 mg of GS-0976 compared to placebo in 3 cohorts of 10 adult 
male subjects who were overweight and/or obese, but otherwise healthy, at each dose level (total 
30 subjects). Subjects were randomized in Period 1 to receive a single oral dose of either 


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GS-0976 or matched placebo followed by a washout and administration of the opposite study 
medication in Period 2. 
The objectives of the study were to assess the following after a single oral dose of GS-0976 in 
overweight and/or obese, but otherwise healthy, adult male subjects: PD effects of GS-0976 on 
fractional DNL, safety and tolerability of GS-0976, correlation of PK and PD effects, and PK 
parameters. 
Fractional DNL was evaluated by utilizing a qualified method that measured the appearance of 
de novo synthesis of palmitate in very-low density lipoproteins (VLDL) in response to oral 
fructose using [13C] acetate incorporation into palmitate and mass isotopomer distribution 
analysis (MIDA). Review of the data demonstrated mean inhibition of fractional DNL (71%, 
87%, and 98% by AUC) by GS-0976 at 20, 50, and 200 mg, respectively, compared to matched 
placebo.
A total of 41 TEAEs were experienced by 15 (52%) subjects following administration of 
GS-0976 (28 considered possibly related); 22 TEAEs were experienced by 12 (40%) pooled 
placebo subjects (17 considered possibly related), and 4 TEAEs were experienced by 4 (13%) 
subjects following the [13C] acetate infusion. Gastrointestinal events including diarrhea (11/29, 
38% GS-0976 vs. 9/30, 30% placebo) and flatulence (5/29, 17% GS-0976 vs. 3/30, 
10% placebo) were the most common TEAEs following both active and placebo treatments. The 
incidence of treatment emergent AEs did not increase with rising GS-0976 dose levels. 
Most TEAEs in the study were of Grade 1 severity (39/41, 95 %) and were resolved by study 
completion. Three subjects experienced 4 TEAEs of Grade 2 severity including headache and 
nausea (placebo), arthralgia (GS-0976 20 mg), and dyspepsia (GS-0976 20 mg). No deaths or 
SAEs were reported. 
Overall, no clinically important trends in changes over time were noted in the laboratory results 
for GS-0976 active groups compared to placebo. 
1.3.
Rationale for the Current Study
Current evidence suggests that NASH is a consequence of the metabolic syndrome and 
lipotoxicity in the steatotic liver, which sets off an inflammatory response with subsequent 
activation of hepatic stellate cells and fibrogenesis. A key finding in patients with NASH is 
upregulation of the hepatic synthesis of fatty acids and triglycerides, referred to as de novo 
lipogenesis (DNL). Enhanced DNL in NASH occurs despite the excessive delivery of fatty acids 
to the liver from the diet as chylomicrons and from adipose tissue via lipolysis {Lambert 2014}.
DNL-derived fatty acids and their byproducts (e.g. diacylglycerol, lysophosphatidic acid, and 
eicosanoids) represent important signaling mediators that drive the lipotoxicity and inflammation 
characteristic of NASH {Neuschwander-Tetri 2010}. The first and rate-limiting step in DNL is 
the conversion of acetyl-coA to malonyl-coA by acetyl-coA carboxylase (ACC). ACC exists as 
two isoforms (ACC1 and ACC2). Whereas ACC1 is a cytosolic enzyme present in lipogenic 
tissues (e.g. liver and adipose), ACC2 is a mitochondria-associated enzyme present in oxidative 
tissues (e.g. liver, heart, and skeletal muscle) {Bianchi 1990, Kim 1997}. Inhibition of ACC1 
reduces DNL in lipogenic tissues while inhibition of ACC2 in oxidative tissues enhances 


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mitochondrial fatty acid oxidation {Harwood 2005}. Due to this unique position in intermediary 
metabolism {Harwood 2005, Tong 2006}, pharmacologic inhibition of ACC is an attractive 
strategy for limiting fatty acid synthesis while simultaneously stimulating fatty acid oxidation.
GS-0976 is a highly potent and selective allosteric inhibitor of ACC1 and ACC2. 
Pharmacodynamic studies indicate that GS-0976 reduces DNL, hepatic steatosis, inflammatory 
mediators, and fibrosis in preclinical models of liver disease {Harriman 2016}. In addition,
GS-0976 improves metabolic parameters (e.g. plasma triglycerides and free fatty acids, insulin, 
and leptin sensitivity) in high fat and high sucrose diet-induced obesity models. In total, these 
studies confirm the potential for GS-0976 to impact important histologic endpoints in NASH and 
also ameliorate the metabolic dysfunction frequently observed in these patients. Moreover, the 
liver-directed biodistribution of GS-0976 ensures that pharmacological effects are focused on the 
key target tissue for NASH and is anticipated to minimize effects outside of the liver.
In summary, the totality of the preclinical and clinical evidence, in addition to the large unmet 
medical need and the lack of existing therapies, suggests that the evaluation of GS-0976 in 
subjects with NASH, as proposed in the current study, is of merit.
1.3.1.
Rationale for this Study
This Phase 2 study has been designed as a multicenter, randomized, double-blind, 
placebo-controlled study evaluating the safety and efficacy of GS-0976 for 12 weeks in subjects 
with NASH. Approximately 125 NASH subjects without cirrhosis will be randomized in a 
2:2:1 ratio to receive GS-0976 at a dose of 5 mg or 20 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 
MRE have a high probability of NASH on liver biopsy. 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 ≥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 {Loomba 2014}. Since the safety and PK of GS-0976 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 (FibroTest®) and historical 
clinical, histological, and imaging data {Ratziu 2006}.
The primary endpoint of this study will be the safety and tolerability of GS-0976. In addition, the 
biological activity of GS-0976 will be determined based on endpoints including routine liver 


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biochemistry (e.g. ALT and GGT); noninvasive serum markers of liver injury (e.g. serum 
CK-18, 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 12 weeks with GS-0976 is expected to be sufficient to lead to 
meaningful improvements in hepatic steatosis on MRI-PDFF and liver biochemistry. Liver 
histology has not been included as an endpoint because it is not feasible to repeat this invasive 
procedure over a 12-week study. In addition to these liver-related endpoints, the effects of 
GS-0976 on carbohydrate and lipid metabolism (e.g. with glucose, insulin, free fatty acids, 
apolipoproteins, lipid profiles, and metabolites) will be closely monitored in light of the 
mechanism of action of GS-0976 and the importance of metabolic dysfunction in contributing to 
the morbidity and mortality (e.g. cardiovascular) of subjects with NASH.
The doses of GS-0976 chosen for evaluation in this study, 5 and 20 mg QD for 12 weeks, are 
supported by the safety, tolerability and effects of GS-0976 on DNL from studies 0976-101, 
0976-102, and 0976-103. As described in Section 1.2.5, single doses of GS-0976 up to 1000 mg 
or multiple daily doses (10 days) up to 200 mg were administered safely to healthy subjects in 
these studies. Moreover, a single dose of 20 mg resulted in a mean inhibition of fractional DNL 
of 71%. This level of DNL is postulated to be sufficient to achieve meaningful reductions in 
hepatic steatosis and lipid-derived inflammatory mediators that contribute to the pathogenesis of 
NASH. The four-fold GS-0976 dose range in this study will assess the impact of a range of 
GS-0976 systemic exposure on safety and effect of GS-0976 in subjects with NASH. 
Additionally, nonclinical toxicology studies up to 13 weeks in duration have been conducted in 
rats and dogs at exposure margins multiple folds above the expected clinical exposure. Based on 
preliminary data from studies 0976-101 (Section 1.2.5.1) and 0976-102 (Section 1.2.5.2), 
GS-0976 exposures in this study are expected to remain > 15 to 23-fold lower than the GS-0976 
exposures observed at the NOAELs in the 13-week rat and dog studies, respectively.
1.4.
Risk/Benefit Assessment for the Study
This study will provide information on the safety and efficacy of GS-0976 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. 
The potential benefits of GS-0976 for the treatment of NASH in the current study population 
include hypothesized improvements in hepatic steatosis and inflammation due to reduced DNL 
and increased beta oxidation that have been observed in pre-clinical and/or clinical studies of 
ACC inhibition. Improvements in liver biochemistry and hepatic fibrogenesis would be expected 
to ensue based on these effects.
To date, 96 subjects have received GS-0976 in Phase 1 studies in single doses up to 1000 mg or 
multiple daily doses (10 days) up to 200 mg. In general, treatment emergent adverse events 
(TEAEs) were mild to moderate with the predominant toxicities being gastrointestinal 


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(e.g. nausea, flatulence, diarrhea, constipation) in nature (see Section 1.2.5). Asymptomatic, 
Grade 3 or 4 elevations in blood triglycerides have been noted in 6 subjects treated for 10 days 
with GS-0976 at daily doses of 100 mg or higher. There is a potential risk to study participants of 
experiencing these and previously undetected side effects with longer term GS-0976 dosing. 
However, lower doses of 5 mg and 20 mg daily have been chosen for this study in order to 
mitigate this potential risk. 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 laboratory abnormalities will be well-defined and closely followed.
In summary, there are no approved treatment options available for patients with NASH. Based 
on past clinical experience with GS-0976, the risk/benefit is positive and supports the continued 
evaluation of GS-0976 in this patient population. Data from this study will support the 
development of GS-0976 for the treatment of this condition.
1.5.
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-0976 in subjects with NASH.
The exploratory objectives of this study are as follows: 
CCI


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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-0976 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 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 (i.e., hemoglobin A1c ≥ 6.5% OR fasting plasma glucose ≥126 mg/dL).
Study drugs will be administered for a total of 12 weeks from the Baseline/Day 1 visit. Dosage 
and administration of the study drugs and reference product are described in Section 5.3.
Group A (n=S0) 
GS-0976 5 mg+ 5 mg-PTM + 2 x 10 mg-PTM 
orally once daily 
C 
0 
bO 
C 
1ii 
Group B (n=S0) 
C 
N 
... 
a, 
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2 x GS-0976 10 mg+ 2 x 5 mg-PTM 
a, 
.,,. 
0 
... 
orally once daily 
u 
"'C 
VI 
C 
(0 
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Group C (n=25) 
2 x 5 mg-PTM + 2 x 10 mg-PTM 
orally once daily 
6Weeks 
12Weeks 
.... 
C 
QI 
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1ii 
QI 
r+ 
... 
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Weeks 


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3.3. 
3.3.1. 
Bio marker Testing 
Biomarker Samples to Address the Study Objectives 
Final 
Amendment 1 
Biological specimens will be collected in this study as per the study procedures table to evaluate 
the association of explorato1y systemic and/or tissue specific biomarkers with study drugs 
response, pathway markers, including efficacy and/or adverse events and to increase knowledge 
and understanding of the biology of NASH or related diseases such as liver fibrosis, and 
inflammato1y diseases and/or the validation of a companion diagnostic for GS-0976 based upon 
the cunent state of scientific knowledge. Because biomarker science is a rapidly evolving area of 
investigation, it is not possible to specify prospectively all tests that will be done on the 
specimens provided. It may be modified during or after the end of the study to remove tests no 
longer indicated and/or to add new tests based upon the growing state of aii knowledge. Samples 
will be will be stored for up to 15 years after the end of study. 
3.3.2. 
Biomarker Samples for Optional Future Research 
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 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 imaging or a liver biopsy documenting fatty liver 
within two years prior to Screening (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 3a. must be met before evaluating criteria 3b. and 3c.
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.
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 3) 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 
drugs (see Appendix 3 for details);


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8) Male subjects are required to use barrier contraception (condom plus spermicide) during 
intercourse from the Screening through the study completion and for 90 days following the 
last dose of study drugs (see Appendix 3 for details); 
9) Male subjects must refrain from sperm donation from Screening through at least 90 days 
following the last dose of study drugs.
10) Female subjects must refrain from egg donation or harvest for 30 days after last dose of study 
drugs.
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 will not be randomized in this study.
1) Pregnant or lactating females; lactating females must agree to discontinue nursing before the 
study drugs are administered;
2) ALT > 5 x 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 (e.g. NASH CRN classification stage 4 or equivalent);
b) Evidence of cirrhosis on liver imaging (e.g. ultrasound, CT, or MRI) including a nodular 
liver surface, splenomegaly, or portal venous collaterals;
c) Prior history of decompensated liver disease, including ascites, hepatic encephalopathy or 
variceal bleeding;
d) 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.
5) History of liver transplantation;
6) Weight reduction surgery in the 2 years prior to Screening or planned during the study 
(weight reduction surgery is disallowed during the study);
7) History of intestinal resection or malabsorptive condition that may limit the absorption of 
GS-0976. Prior cholecystectomy and appendectomy are permitted


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8) BMI < 18 kg/m2;
9) INR > 1.2, unless on anticoagulant therapy;
10) Total bilirubin > 1 x ULN, except with diagnosis of Gilbert’s syndrome;
11) Chronic hepatitis B (HBsAg positive);
12) Chronic hepatitis C (HCV Ab and HCV RNA positive). Subjects cured of HCV infection less 
than 2 years prior to the Screening visit are not eligible.
13) HIV Ab positive;
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 (i.e. heroin, morphine) at 
Screening. Subjects on stable methadone or buprenorphine maintenance treatment for at least 
6 months prior to Screening may be included in the study. Subjects with a positive urine drug 
screen due to prescription opioid-based medication are eligible if the prescription and 
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) Use of prohibited concomitant medications as described in Section 5.4
18) History of a malignancy within 5 years prior to 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;
19) Any laboratory abnormality or condition that, in the investigator’s opinion, could adversely 
affect the safety of the subject or impair the assessment of study results;
20) Participation in another investigational study of a drug or device within 28 days prior or 
within 5 half-lives of the prior investigational agent (whichever is longer) prior to Screening;
21) Concurrent participation in another therapeutic clinical study;


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22) Known hypersensitivity to GS-0976, the metabolites, or formulation excipient;
23) 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;
24) Unavailable for follow-up assessment or concern for subject’s compliance with the protocol 
procedures;
25) Contraindications or inability to complete MRI scanning (e.g. presence of permanent 
pacemakers, implanted cardiac devices, weight restrictions, etc.).
Subjects with laboratory abnormalities outside of the above parameters may be approved for 
inclusion in the trial with approval from the Medical Monitor.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
This is a randomized, double-blind, placebo-controlled study. Subjects meeting the study entry 
criteria will be randomly assigned in a 2:2:1 ratio to 1 of 3 different treatment group as described 
in Section 5.3.
5.1.
Randomization, Blinding and Treatment Codes
An Interactive Web Response System (IWRS) will be used for centralized randomization and 
treatment assignment. Randomization will be stratified by the presence or absence of diabetes 
mellitus as determined by medical history, 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 drugs 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 Study Reference Binder for IWRS unblinding
instructions). Gilead recommends but does not require that the investigator contact the Gilead 
medical monitor before breaking the blind. Treatment assignment should remain blinded unless 
that knowledge is necessary to determine subject emergency medical care. The rationale for 
unblinding must be clearly explained in source documentation and on the electronic case report 
form (eCRF), along with the date on which the treatment assignment was obtained. The 
investigator is requested to contact the Gilead medical monitor promptly in case of any treatment 
unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead 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 Study Drugs
5.2.1.
Formulation
GS-0976 will be supplied as white opaque size 0 hard gelatin capsules containing 10 mg of 
GS-0976, and as white opaque size 2 hard gelatin capsules containing 5 mg of GS-0976. In 
addition to the active ingredient, GS-0976 capsules contain the following inactive ingredients: 
lactose monohydrate, stearoyl polyoxylglycerides and croscarmellose sodium, which are 
common pharmaceutical excipients.
Placebo-to-match (10 mg-PTM and 5 mg-PTM) GS-0976 capsules are identical in size, shape, 
color and appearance to their corresponding strengths of active GS-0976 capsules. PTM 
GS-0976 capsules contain lactose monohydrate.
5.2.2.
Packaging and Labeling
GS-0976 capsules and PTM GS-0976 are packaged in white, high density polyethylene (HDPE) 
bottles. Each bottle contains 30 capsules.  Each bottle is enclosed with a white, continuous 
thread, child-resistant polypropylene screw cap with an induction-sealed and aluminum-faced 
liner.
Study drugs to be distributed to centers in the US shall be labeled to meet applicable 
requirements of the United States Food and Drug Administration (FDA) and/or other local 
regulations.
5.2.3.
Storage and Handling
GS-0976 and PTM GS-0976 should be stored at controlled room temperature of 25 °C (77 °F); 
excursions are permitted between 15°C and 30°C (59°F and 86°F).  Storage conditions are 
specified on the label.  Until dispensed to the subjects, all bottles of study drugs should be stored 
in a securely locked area, accessible only to authorized site personnel. 
To ensure the stability and proper identification, study drugs should not be stored in a container 
other than the container in which they were supplied. 
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling.
5.3.
Dosage and Administration of GS-0976/PTM GS-0976 
GS-0976 capsules will be provided by Gilead Sciences.  Subjects will take 4 capsules of 
GS-0976 (5 mg, 5 mg-PTM, 10 mg, or 10 mg-PTM) once daily at approximately the same time 
each morning.  Study drugs should be swallowed whole with water and may be taken with or 
without food.  A dose will be considered missed if the subject cannot take the dose within 
12 hours of their regular dosing time.  If a subject misses a dose, the subject should take their 


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next dose at the regular dosing time. Study drug dosing and administration will occur as follows, 
based on treatment group randomization:

Treatment Group A: GS-0976 5 mg (1 x 5 mg capsule + 1 x 5 mg-PTM 
capsule + 2 x 10 mg-PTM capsules) administered orally once daily;

Treatment Group B: GS-0976 20 mg (2 x 10 mg capsules + 2 x 5 mg-PTM capsules) 
administered orally once daily;

Treatment Group C: GS-0976 Placebo (2 x 5 mg-PTM capsules + 2 x 10 mg-PTM capsules) 
administered orally once daily.
5.4.
Prior and Concomitant Medications
All concomitant medication will be recorded in the source documents and eCRFs.  This includes 
concomitant medications taken within 30 days prior to Screening and any taken during the study 
to the end of the follow-up period.
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 drugs:

Hematologic stimulating agents (e.g. 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 (inhibitors or inducers 
of drug transporters P-gp, or OATP1B3 or 1B3, or substrates of CYP3A which are sensitive 
to induction) with GS-0976 may result in PK interactions resulting in increases or decreases 
in exposure of GS-0976 or concomitant medications. Examples of representative medications 
which are prohibited from 28 days prior to Baseline/Day 1 through the treatment period 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
Anticonvulsantsa
Phenobarbital, Phenytoin, Carbamazepine, Oxcarbazepine
Antifungals
Itraconazole, Ketoconazole
Antimycobacterialsa
Rifamycins, Isoniazid
Cardiac Medications
Amiodarone, Digoxin, Dronedarone, Felodipine, Verapamil, 
Quinidine, Ranolazine, Bosentan, Olmesartan, Telmisartan, 
Valsartan
Herbal/Natural Supplementsa
St. John’s Wort, Echinaccea. Milk thistle (i.e. silymarin), Chinese 
herb sho-saiko-to (or Xiao-Shai-Hu-Tang)
Selective Serotonin Reuptake Inhibitors
Fluvoxamine
Other
Gemfibrozil, Modafinil
a
May result in a decrease in the concentrations of study drugs.
Medications for disease conditions excluded from the protocol (e.g., HIV-1, HBV, or HCV
infection, active cancer, transplantation) are not listed under this Concomitant Medication 
section and are disallowed in the study.
5.5.
Accountability for GS-0976/PTM GS-0976
The investigator or designee (e.g., pharmacist) is responsible for ensuring adequate 
accountability of all used and unused study drug bottles. This includes acknowledgement of 
receipt of each shipment of study drug (quantity and condition), subject dispensing records, and 
returned or destroyed study product. 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.
5.5.1.
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 randomized 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 the Contract Research Organization (CRO).  
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the investigator to ensure that subjects are eligible to participate in the 
study prior to enrollment and throughout the study. 
Documentation of the personally signed and dated informed consent of each subject, using the 
study-specific ICF, is required before initiating the Screening process.
After written informed consent has been obtained and eligibility to participate established, 
investigative site personnel will obtain the subject’s identification number and study drug 
assignment from the interactive web response system (IWRS).
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 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 Gilead Medical Monitor.
Subjects who previously failed screening in GS-US-426-3989 can be re-screened in the 
following situations:

Previously screen failed due to a low MRE or MRI-PDFF measurement, but have an 
MRE ≥2.5 kPa and MRI-PDFF ≥8% within 6 months of prior Screening/Re-screening.

Previously screen failed due to a low MRE or MRI-PDFF measurement 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 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. 


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
Previously screen failed 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, MRE and MRI-PDFF 
does 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. A historical MRE and MRI-PDFF within 
6 months of screening in another Gilead study (i.e. GS-US-384-3914, GS-US-402-1852) may be 
used to determine eligibility into this study. All other screening procedures must be repeated and 
meet eligibility criteria.
Screening labs may be repeated within the Screening period, prior to administration of study 
drugs to rule out laboratory error, if any. This will be done at the discretion of the investigator.
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 
Hemoglobin A1c
HIV-1, HBV and HCV serology (if HCV Ab positive, reflex to HCV RNA.)
Serum pregnancy test (only for female subjects of child bearing potential - see
Appendix 3.)


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• 
Conduct standard 12-Lead ECG 
• 
Perfo1m ultrasound (if necessaiy) for confnmation of NAFLD 
• 
Perfo1m MRE and MRI-PDFF 
• 
Review any historical liver biopsy results, if available. 
Final 
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• 
Urine diug screen for amphetamines, cocaine and opiates (i.e., 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 occuning after signing of the consent fo1m . 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 6 weeks of the staii of Screening for randomization into the study. The screening 
period may be extended under special circumstances with the explicit approval of the Medical 
Monitor. 
From the time of obtaining infonned consent through the first adininistration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events electronic case repo1i fonn 
(eCRF). All other untoward medical occmTences observed during the Screening period, 
including exacerbation or changes in medical histo1y are to be captured on the medical histo1y 
eCRF. See Section 7 Adverse Events and Toxicity Management for additional details. 
6.3. 
Baseline/Day 1 Randomization and Assessments 
Subjects retmning to the clinic for randomization at Baseline/Day 1 should be instructed to fast 
(no food or di·ink, except water), staiiing from midnight (00:00) or eai·lier, as appropriate, on the 
evening prior to the Baseline/Day 1 visit to ensure an approximate 8-hour fast prior to the blood 
sainple collection under fasting conditions the next morning. 
After review of inclusion and exclusion criteria to confnm continued eligibility, subjects will be 
randomized to study diug assignment and receive their Subject Identification Number via the 
IWRS prior to their first dose of study mugs. 
Randomization will be sti·atified by the presence or absence of diabetes mellitus as detennined 
by medical histo1y, 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). 
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The following will be perfonned and documented at the Baseline/Day 1 visit prior to dosing: 
• 
QoL Questionnaires (SF-36, WPAI, and CLDQ) 
Note: It is recommended that QoL questionnaires be completed prior to any study procedures 
being perfo1med and prior to the subject seeing a health care provider. 
• 
Symptom driven physical examination 
• 
Record vital signs, waist circmnf erence, and body weight 
• 
Obtain blood samples for: 
-
Chemistiy 
-
Hematology 
-
Coagulation Panel 
-
Lipid Profile 
-
Hemoglobin Ale 
-
Biomarkers 
• 
Conduct standard 12-Lead ECG 
• 
Perfo1m FibroScan® (if available) 
• 
Collect urine samples for: 
-
Urine pregnancy test for females of child bearing potential only 
-
Biomarkers 
• 
Collect stool sample for Biomarkers (see Study Reference Binder for instiuctions) 
• 
Dispense study mugs, and provide subject with insti11ction on appropriate dosing and 
adininisti·ation; subject will take the Baseline/Day 1 dose of study di11gs on-site 
• 
Record all concomitant medications that the subject has taken since the previous visit 
• 
Record any serious adverse events and all adverse events occuning since the Screening visit 
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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 12
visit.
6.4.
Treatment Assessments
6.4.1.
Week 1 Visit (±3 days)
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Week 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 drugs on the day of their Week 1 
visit until all visit procedures have been completed. The study drugs should be taken after the 
visit.
During the Week 1 safety visit (±3 days), the subject will return to the investigative site and the 
following will be performed and documented:

Symptom driven physical examination

Record vital signs, and body weight

Obtain blood samples for:
Chemistry
Hematology
Coagulation Panel
Lipid Profile
Biomarkers
Single PK sampling

Collect urine sample for biomarkers

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events occurring since the previous visit

Review of study drug dosing compliance (pill count)


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6.4.2.
Week 4 Visit (±3 days)
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Week 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 drugs on the day of their Week 4 
visit until all visit procedures have been completed. The study drugs should be taken after the 
visit.
The following will be performed and documented at this visit (±3 days):

Symptom driven physical examination

Record vital signs, and body weight

Obtain blood samples for:
Chemistry
Hematology
Coagulation Panel
Lipid Profile
Biomarkers
Single PK sampling

Collect urine samples for:
Urine pregnancy test for females of child bearing potential only
Biomarkers

Dispense study drugs

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events occurring since the previous visit

Review of study drug dosing compliance (pill count)
6.4.3.
Week 8 Visit (±3 days)
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Week 8 visit to ensure an 
approximate 8-hour fast prior to the fasted blood sample collection the next morning.


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Subjects should also be instructed to HOLD their dose of study drugs on the day of their Week 8 
visit until all visit procedures have been completed. The study drugs should be taken after the 
visit.
The following will be performed and documented at these visits (±3 days):

Symptom driven physical examination

Record vital signs, and body weight

Obtain blood samples for:
Chemistry
Hematology
Coagulation Panel
Lipid Profile
Single PK sampling

Urine pregnancy test for females of child bearing potential only

Dispense study drugs

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events occurring since the previous visit

Review of study drug dosing compliance (pill count)
6.4.4.
Week 12 Visit (±7 days)
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the Week 12 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 drugs on the day of their 
Week 12 visit until all visit procedures have been completed. The study drugs should be taken 
after the visit.
The following will be performed and documented at this visit (±7 days):

QoL Questionnaires (SF-36, WPAI, and CLDQ)

Symptom driven physical examination


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
Record vital signs, waist circumference, and body weight

Obtain blood samples for:
Chemistry
Hematology
Coagulation Panel
Lipid Profile
Hemoglobin A1c
Biomarker
Single PK sampling

Collect urine samples for:
Urine pregnancy test for females of child bearing potential only
Biomarkers

Conduct standard 12-Lead ECG

Perform FibroScan® (if available)

Perform MRE and MRI-PDFF

Collect stool sample for Biomarkers (see Study Reference Binder for instructions)

Record all concomitant medications that the subject has taken since the previous visit

Record any serious adverse events and all adverse events occurring since the previous visit

Review of study drug dosing compliance (pill count)
6.4.5.
Unscheduled Visit
Additional unscheduled assessments may be performed at the discretion of the investigator.
Subjects returning to the clinic for an unscheduled visit should be instructed to fast (no food or 
drink, except water), starting from midnight (00:00) or earlier, as appropriate, on the evening 
prior to the visit to ensure an approximate 8-hour fast prior to the blood sample collection under 
fasting condition the next morning.


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Subjects should also be instructed to HOLD their dose of study drugs on the day of an 
unscheduled visit until all visit procedures have been completed. The study drugs should be 
taken after the visit.
At a minimum, the following will be performed and documented.

Symptom driven physical examination

Obtain blood samples for:
Chemistry
Hematology

Record body weight

Record all concomitant mediations that the subject has taken since the previous visit

Record any serious adverse events and all adverse events occurring since the previous visit
If the Unscheduled visit is performed for the sole purpose of distribution of study drug, the 
assessments noted above do not need to be performed.
6.4.6.
Follow-Up Visit (±5 days)
Subjects will return for a Follow-Up visit, four weeks after the date of last dose of study drugs.
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
Lipid Profile


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Urine pregnancy test for female subjects of child bearing potential only 
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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 occmTing since the previous visit 
6.5. 
Assessments for Premature Discontinuation from Study 
Subjects prematmely discontinuing from the study (for example, as a result of an AE), should 
have an Early Tennination (ET) visit, if possible, and a Follow-Up visit 4 weeks after the date of 
last dose of study dmgs. The study assessments to be perfo1med at the ET visit are the same as 
those perfonned at the Week 12 visit (refer to Section 6.4.4). The study assessments to be 
perfo1med at the Follow-Up visit are listed in Section 6.4.6. 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. 
6.6. 
Criteria for Discontinuation of Study Treatment 
Study medication may be discontinued in the following instances: 
• 
IntercmTent 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 3. 
• 
Sponsor discretion 
• 
Discontinuation of the study at the request of Gilead, a regulato1y agency or an institutional 
review board or independent ethics committee (IRB/IEC) 
6.7. 
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6.8. 
Description of Assessments 
6.8.1. 
Clinical Laboratory Analytes 
Final 
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Fasting is required prior to all study visits. All study procedures will be perfo1med before dosing 
while the subject is in a fasted state. Subjects will take their dose of study diugs after the study 
visit has concluded. 
Chemistiy: 
Alanine aininoti·ansferase (ALT), aspartate aminotl'ansferase (AST), albumin, alkaline 
phosphatase (ALP), bicarbonate, blood urea niti·ogen (BUN), calcium, chloride, creatinine, 
glucose, lactate dehydi·ogenase (LDH), magnesium, phosphorns, potassium, sodium, total and 
direct bilirnbin, total protein, uric acid, gamma-glutamyl ti·ansferase (GGT). Also includes 
C-Peptide and Insulin for the Baseline/Day!, Week 4, and 12 visits. 
Creatinine clearance is calculated by the Cockcroft-Gault equation {Cockcroft 1976} using actual 
body weight (BW). The calculation will be perfonned by the centi·al laborato1y. 
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, Neutl'ophils, Eosinophils, and Basophils and, Reticulocyte count and mean 
corpuscular volume (MCV). 
Coagulation Panel: 
INR, Prothrombin time (PT), paiiial thromboplastin time (PTT) 
Pregnancy Tests: 
Sernm P-hCG or urine P-hCG (if positive, requires immediate confomation with Sernm P-hCG) 
Additional Tests: 
Lipid Profile, Hemoglobin Ale, HIV-I, HBV & HCV Serology (ifHCV A~ 
s), sern1~ 
and genomic sample 
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Biomarkers: 
Final 
Amendment 1 
fucluding but not limited to: CK18 (M30 and M65), FGF19, C4, Apolipoprotein B (Apo B), 
metabolite profile, bile acids, stool microbiome, blood miRNA, NMR lipoprofile, free fatty 
acids, ELF™ Test, and FibroSURE/FibroTest®. 
Phaimacokinetic (PK) Assessments: 
Single PK Sampling 
Single PK samples will be collected and ai·chived for PK analysis of GS-0976 and other 
metabolites as applicable 
6.8.2. 
Physical Examination 
A complete physical examination should include source documentation of general appearance, 
and the following body systems: head, neck, and thyroid; eyes, eai·s, nose, throat, mouth, and 
tongue; chest ( excluding breasts); respirato1y; cai·diovasculai·; lymph nodes; abdomen; skin, hair, 
nails; musculoskeletal; neurological. 
The focus of a symptom driven physical examination will be detennined by the investigator 
based on subject complaint. For example, if a subject complains of a cough, a lung exam should 
be perfonned. 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. 
6.8.3. 
Vital Signs 
Assessment of vital signs will include measurement of resting blood pressure, pulse, respirato1y 
rate and temperature. 
Blood pressure will be measured using the following standardized process: 
• 
Subject should sit for 
5 minutes with feet flat on the floor and measurement aim suppo1ied 
so that the midpoint of the manometer cuff is at heaii level; 
• 
Use a mercmy sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachia! a1ie1y; 
Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to the 
nearest whole number on an automatic device. 
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6.8.4.
Medical History
Medical history, including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing, and medication history will be collected on all subjects during 
Screening. If available, historical liver biopsy information will also be collected.
6.8.5.
Pharmacogenomic Testing
From subjects who agree to participate and provide consent, one blood sample will be obtained. 
This sample should be collected at the Day 1 visit, but may be collected at any time during the 
study or at a separate poststudy visit, if necessary. 
6.8.6.
Health Related Quality of Life (HRQoL)
It is recommended that these questionnaires be completed prior to the clinical and laboratory 
assessments. The subject should read the questionnaires by himself/herself and record the 
answers by himself/herself.
6.8.6.1.
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.
6.8.6.2.
CLDQ
The CLDQ asks 29 questions related to liver disease to measure health related quality of life in 
subjects with chronic liver disease.
6.8.6.3.
WPAI
The Work Productivity and Activity Impairment (WPAI) questionnaire asks 6 questions 
regarding the effect of NASH on a person’s ability to work and perform regular activities. 
6.8.7.
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.
6.8.8.
FibroScan®
The sites will perform liver stiffness assessments by FibroScan®. It is required that each subject 
have the FibroScan® assessments done with the same type of probe at Baseline Day 1 and 
Week 12 visits (if available).


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6.8.9.
MRE and MRI-PDFF
Liver stiffness will be assessed by MRE (shear wave 60 Hz) 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. 
6.9.
End of Study Definition
Subjects are considered to have completed the study after the completion of the Week 16 
Follow-Up visit, regardless of treatment duration or early termination of study drugs.
6.10.
Poststudy Care
No poststudy ongoing care will be provided.
6.11.
Sample Storage
Residual biological samples from all visits will be frozen and stored if specific consent is 
obtained. These stored samples may be used by Gilead or research partners of Gilead to help 
answer questions about the study drugs, NASH, and its associated conditions, or clinical 
laboratory testing to provide additional safety data. No human genetic testing will be performed 
without express consent of the study subjects. At the conclusion of this study, these samples may 
be retained in storage for Gilead for a period of up to 15 years.


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An 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 posttreatment 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 AE and must be reported.

Preexisting 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 preexisting 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

Persistent or significant disability/incapacity

A congenital anomaly/birth defect


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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 respectively.. 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 study 
drugs using clinical judgment and the following considerations:

No: Evidence exists that the AE has an etiology other than the study drugs. For SAEs, an 
alternative causality must be provided (eg, preexisting condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the study drugs.
It should be emphasized that ineffective treatment should not be considered as causally related in 
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The relationship to study procedures (eg, invasive procedures such as venipuncture) should be 
assessed using the following considerations:

No: Evidence exists that the AE has an etiology other than the study procedure.

Yes: The AE 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
(see Appendix 4).
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.
The distinction between the seriousness and the severity of an adverse event should be noted. 
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For 
example, a headache may be severe in intensity, but would not be classified as serious unless it 
met one of the criteria for serious events listed above.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (eCRF): all SAEs and AE related to 
protocol-mandated procedures.
7.3.1.1.
Adverse Events
Following initiation of study medication until 30 days after last administration of study drugs, all 
AEs, regardless of cause or relationship must be reported to the eCRF database as instructed.
All AEs should be followed up until resolution or until the AE is stable, if possible. 
Gilead Sciences, Inc. may request that certain AEs be followed beyond the protocol defined 
follow-up period.
7.3.1.2.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required posttreatment 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 ICF is signed.


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Any SAEs and deaths that occur after the posttr·eatment follow-up visit but within 30 days of the 
last dose of study diugs, regardless of causality, should also be repo1ied. 
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 di11gs, he/she should promptly document and 
repo1i 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. 
7.3.1.3. 
Elech'onic Serious Adverse Event ( eSAE) Repo1i ing Process 
• 
Site personnel record all SAE data in the eCRF database and from there tr·ansmit the SAE 
infonnation 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 infonnation elech'onically, i.e., the 
eCRF database is not functioning, record the SAE on the paper serious adverse event 
repo1i ing fo1m and submit within 24 hours to: 
Gilead DSPH Fax: IPIPD 
Email: IPIPD 
• 
As soon as it is possible to do so, any SAE reported via paper must be tr·anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been repo1ied via a paper fonn because the eCRF database has been locked, no 
fuither action is necessaiy. 
• 
For fatal or life-threatening events, copies of hospital case repo1is, autopsy repo1is, 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 tr·aceability of a document to the subject identifiers. 
• 
Additional infonnation may be requested to ensure the timely completion of accurate safety 
repo1is. 
• 
Any medications necessaiy for tr·eatment of the SAE must be recorded onto the concomitant 
medication section of the subject's eCRF and the event description section of the SAE fonn. 
7.4. 
Gilead Reporting Requirements 
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the European Union (EU) Clinical Trials Directive (2001/20/EC) and 
relevant updates, and other country-specific legislation or regulations, Gilead may be required to 
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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 IB or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study drugs. The investigator should notify the IRB or IEC of SUSAR reports as soon 
as is practical, where this is required by local regulatory agencies, and in accordance with the 
local institutional policy. 
7.5.
Toxicity Management 
Observation for Drug Induced Liver Injury (DILI):
Although subjects randomized 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

ALP > 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%)
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  


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
ALP > 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 drugs have been discontinued and subject is 
asymptomatic
During a period of close observation, study drugs can be continued, if desired, at the discretion 
of the principal investigator. 
However, for all subjects, study drugs 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)

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 
(e.g. 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


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Viral or alcoholic hepatitis (e.g. 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 (e.g. 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 Gilead 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. 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 an 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.


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Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
Occupational exposure 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 by transmitting electronically and also by sending paper 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 
Section 7.3. 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: 
 and Fax: 
PPD
PPD


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Pregnancies of female paiiners of male study subjects exposed to Gilead or other study diugs 
must also be repo1ied and relevant infonnation should be submitted to. Gilead DSPH using the 
pregnancy and pregnancy outcome fonns 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 comJ)leted, the outcome should be reJ)orted directly to Gilead DSPH, fax number 
IPIPD 
or email IPD 
Refer to Appendix 3 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements. 
7.6.2.2. 
Repo1iing Other Special Situations 
All special situations repo1is (SSRs) will be recorded in the eCRF database within the timelines 
outlined in the eCRF completion guideline. 
Electronic Special Situations Repo1i ( eSSR) Repo1iing Process 
• 
Site personnel record all SSR data in the eCRF database and from there transmit the SSR 
infonnation 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 SSR infonnation electr·onically, i.e., the eCRF 
database is not functioning, record the SSR on the paper serious adverse event repo1iing fonn 
and subinit within 24 hours to: 
Gilead DSPH: Email: IPIPD 
Fax: IPD 
As soon as it is possible to do so, any SSR repo1ied via paper must be tr·anscribed into the eCRF 
Database according to instructions in the eCRF completion guidelines. 
If an SSR has been reported via a paper fo1m because the eCRF database has been locked, no 
fuither action is necessaiy. 
These repo1is must consist of situations that involve study diugs and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concoinitant medications does not need to be repo1ied on 
the special situations repo1i fonn; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be repo1ied on the AE fonn. 
Any inappropriate use of concoinitant medications prohibited by this protocol should not be 
repo1ied as "Inisuse," but may be more appropriately documented as a protocol deviation. 
Refer to Section 7.3 and the eCRF completion guidelines for full instmctions on the mechanism 
of special situations repo1iing. 
All clinical sequelae in relation to these special situation repo1is will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE repo1i fo1m. Details of the symptolilS and 
signs, clinical management, and outcome will be repo1ied, when available. 
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8. 
STATISTICAL CONSIDERATIONS 
Details will be provided in the statistical analysis plan (SAP). 
8.1. 
8.1.1. 
Analysis Objectives and Endpoints 
Analysis Objectives 
The primary objective of this study is as follows: 
• 
To evaluate the safety and tolerability of GS-097 6 in subjects with NASH. 
The explorato1y objectives of this study are as follows: 
8.1.2. 
Primary Endpoint 
The prima1y endpoint is the safety of GS-0976 in subjects with NASH. 
8.1.3. 
Exploratory Efficacy Endpoints 
I 
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8.2.
Analysis Conventions
All individual subject data will be listed as measured.  All statistical summaries and analyses will 
be performed using SAS® software (SAS Institute, Cary, North Carolina, USA).
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The primary analysis set for efficacy analysis is defined as the Full Analysis Set (FAS), which 
includes all subjects who were randomized into the study and received at least 1 dose of study 
drugs.
Subjects who receive study drugs 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.
8.2.1.2.
Safety
The primary analysis set for safety analyses is defined as all subjects who received at least 
one dose of study drugs. Subjects who receive study drugs other than that to which they were 
assigned for the entire duration of treatment, will be analyzed according to the study drugs
received.
All data collected during treatment plus 30 days after last dose of study drugs will be included in 
the safety summaries.
CCI


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8.2.1.3. 
Phaimacokinetics 
Final 
Amendment 1 
There are two phaimacokinetic analysis sets: 1) The PK analysis set which includes 
concentration data from the sin le sam les drawn at each visit 
The PK analysis set will include all randomized subjects who took at least one dose of study 
diugs and for whom concentration data of analytes GS-0976 (and its metabolites as applicable) 
are available. The PK analysis set will be used for analyses of population PK. 
8.2.1.4. 
Biomai·kers 
The Biomarker Analysis Set will include data from subjects in the Safety Analysis Set who have 
the necessaiy baseline and on-study measurements to provide interpretable results for the 
specific parameters of interest. 
8.3. 
Data Handling Conventions 
Missing data can have an impact on the inte1p retation of the trial data. In general, values for 
missing data will not be imputed. 
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example, if a subject received study medication, the subject will be 
included in a summaiy 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 laborato1y results for 
a subject ai·e missing for any reason at a time point, the subject will be excluded from the 
calculation of summaiy statistics for that time point. If the subject is missing a pre-dose value, 
then the subject will be excluded from the calculation of summaiy statistics for the pre-dose 
value and the change from pre-dose values. 
Values for missing safety laborato1y data will not be imputed; however, a missing baseline result 
will be replaced with a Screening result, if available. If no pre-treatment laborato1y value is 
available, the baseline value will be assumed to be n01mal (ie, no grade [Grade O]) for the 
summary of graded laborato1y abno1malities. 
Values for missing vital signs data will not be imputed; however, a missing baseline result will 
be replaced with a Screening result, if available. 
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8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods. 
Demographic summaries will include sex, race/ethnicity, and age.
Baseline data will include a summary of body weight, height, body mass index, and 
randomization stratification group (presence or absence of diabetes), and other disease 
characteristic variables.
8.5.
Efficacy Analysis
The biological activity of GS-0976 will be evaluated using radiologic and biochemical endpoints 
and biomarker variables. Because efficacy endpoints will be evaluated for exploratory purpose, 
formal statistical comparisons will not be made for these endpoints. Point estimates and 
ninety-five percent confidence intervals (95% CI) will be provided if applicable.
8.6.
Safety Analysis
All safety data collected on or after the date that GS-0976 was first dispensed up to the date of 
last dose of GS-0976 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-0976 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 start date of study drugs and no later than 30 days 
after permanent discontinuation of study drug.

Any AEs leading to premature discontinuation of study drugs.
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 
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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 laborato1y data will be summarized (n, mean, SD, Median, Ql , Q3, minimum, and 
maximum) by treatment group and study visit along with the coITesponding change from 
baseline values. 
Graded laborato1y abnonnalities will be defined using the grading scheme in the CTCAE 
Version 4.03 (refer to Appendix 4). Grading oflaborato1y abnonnalities for analysis purposes 
will be perfonned by the central laborato1y. 
fucidence of treatment-emergent laborato1y abnonnalities, 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 
of study diu gs plus 30 days will be summarized by treatment group. If baseline data are missing, 
then any graded abnonnality (ie, at least a Grade 1) will be considered treatment emergent. 
8.6.4. 
Other Safety Evaluations 
The number and percentage of subjects developing antibodies to GS-0976 will be summarized 
by treatment aim. Summary statistics for the 12-lead ECGs perfo1med at Baseline and Week 12 
will be generated. 
8.7. 
Pharmacokinetic Analysis 
Plasma concentrations and phan nacokinetic paraineters (eg, AUCtau, Cmax and Ctau) will be listed 
and summai·ized as appropriate for GS-0976 (and its metabolites as applicable) using descriptive 
statistics. 
Details of the analysis plan will be provided in the phaim acokinetic repo1i ing and analysis plan. 
8.8. 
Biomarker Analysis 
Descriptive statistics of biomarker expression and change from baseline will be provided at each 
sainpling time by treatment. Point estimates and 95% confidence intervals may be calculated. 
8.9. 
Sample Size 
Due to the explorato1y nature of this study, no fo1m al power calculations were used to dete1mine 
sainple size. The number of subjects was chosen based on clinical experience with other similar 
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proof of concept studies. However, assuming that 4% of subjects in the placebo arm (N=25) and 
32% in the GS-0976 20 mg arm (N=50) have a ≥ 30% reduction in MRI-PDFF at Week 12, 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.
8.10.
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 randomized 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 similar Grade ≥ 3 serious, treatment related Common Terminology 
Criteria for Adverse Events (CTCAE) observed in the trial. In the event of two similar Grade 
4-CTCAE treatment related events or one Grade 5-CTCAE treatment related event, the DMC 
will review the data and advise the sponsor regarding stopping or continuing the trial. 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 (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), 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. 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, "Protection of Human Subjects", and 21 CFR, part 56, 
"Institutional Review Boards".
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 
"Financial Disclosure by Clinical Investigators", providing documentation of their financial 
interest or arrangements with Gilead, or proprietary interests in the study drugs 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 (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. The investigator will not begin any study subject activities until 
approval from the IRB 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 any modifications made to the protocol or any accompanying material to be provided to 
the subject after initial IRB 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-approved consent form for documenting written 
informed consent. Each informed consent (or assent as applicable) will be appropriately signed 


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and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB local 
requirements. The consent form will inform subjects about 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, or laboratory. Laboratory specimens 
must be labeled in such a way as to protect subject identity while allowing the results to be 
recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The investigator 
must keep a Screening log showing codes, names, and addresses for all subjects screened and for 
all subjects randomized in the trial. Subject data will be processed in accordance with all 
applicable regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, eCRF, the study drugs, 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, eCRF and query forms, IRB
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);

Documentation of the reason(s) a consented subject is not randomized


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
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 study drugs, including dates of dispensing and 
return;

Record of all AEs 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 randomized, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received and the subject has been randomized. Subsequent to data entry, a 
study monitor will perform source data verification within the EDC system. Original entries as 


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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 (e.g., data entry error). At the conclusion of the trial, Gilead 
will provide the site with a read-only archive copy of the data entered by that site. This archive 
must be stored in accordance with the records retention requirements outlined in Section 9.1.5.
9.1.7.
Study Drug Accountability and Return
Gilead recommends that used and unused study drug supplies be returned to the shipping facility 
from which it came for eventual destruction. The study monitor will provide instructions for 
return. If return is not possible, the study monitor will evaluate each study center’s 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 drugs are destroyed on site, the investigator must maintain accurate records for all study 
drugs destroyed. Records must show the identification and quantity of each unit destroyed, the 
method of destruction, and the person who disposed of the study drugs. Upon study completion, 
copies of the study drug accountability records must be filed at the site. Another copy will be 
returned to Gilead.
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 trial to 
Gilead’s appointed study monitors, to IRB, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.


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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB in 
accordance with local requirements and receive documented IRB approval before modifications 
can be implemented.
9.2.2.
Study Report 
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases. 
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, eg, attendance at Investigator's Meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
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.  


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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, and ECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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10.
REFERENCES
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.
Bianchi A, Evans JL, Iverson AJ, Nordlund AC, Watts TD, Witters LA. Identification of an 
isozymic form of acetyl-CoA carboxylase. J Biol Chem 1990;265 (3):1502-9.
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. Hepatology 2015;61 (5):1547-54.
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.
Harriman G, Greenwood J, Bhat S, Huang X, Wang R, Paul D, et al. Acetyl-CoA carboxylase 
inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and 
modulates dyslipidemia in rats. Proc Natl Acad Sci U S A 2016;113 (13):E1796-
805.
Harwood HJ, Jr. Treating the metabolic syndrome: acetyl-CoA carboxylase inhibition. Expert 
opinion on therapeutic targets 2005;9 (2):267-81.
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.
Kim KH. Regulation of mammalian acetyl-coenzyme A carboxylase. Annu Rev Nutr 
1997;17:77-99.
Koek GH, Liedorp PR, Bast A. The role of oxidative stress in non-alcoholic steatohepatitis. Clin 
Chim Acta 2011;412 (15-16):1297-305.


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Lambert D, Rouger C, Diebold MD, Ramaholimihaso F, Boulagnon C, Nguyen Y, et al. 
[Gastritis due to Helicobacter pylori, an unusual cause of chronic diarrhoea in 
HIV infected patients] [French]. Medecine et maladies infectieuses 2014;44 
(2014):334-8.
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.
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 
Assoication for the Study of Liver Diseases (AASLD); 2015 13-17 November; 
San Francisco, CA. pp. 659A-60A.
Ratziu V, Massard J, Charlotte F, Messous D, Imbert-Bismut F, Bonyhay L, et al. Diagnostic 
value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver 
fibrosis in patients with non-alcoholic fatty liver disease. BMC gastroenterology 
2006;6:6.
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.
Tong L, Harwood HJ, Jr. Acetyl-coenzyme A carboxylases: versatile targets for drug discovery. 
J Cell Biochem 2006;99 (6).
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.


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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.
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-426-3989
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0


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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, 
Tolerability, and Efficacy of GS-0976 in Subjects with Nonalcoholic Steatohepatitis 
GS-US-426-3989, Amendment 1, 15 December 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PPD 
PPD 
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 N axne (Printed) 
Signature 
Date 
Site Number 
CONFIDEN'ITAL 
Page 78 
15 December 2016 


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Appendix 2.
Study Procedures Table for GS-US-426-3989
Assessments
Screeninga
Baseline / 
Day 1
On-treatment Visits
Follow Up 
Visitb
(± 5 Days)
Week 1
± 3 days
Week 4
± 3 days
Week 8
± 3 days
Week 12/ETb
± 7 days
Clinical Assessments
Written Informed Consentc
X
Determine Eligibility 
X
X
Medical History
X
Historical Liver Biopsy (If 
Available)
X
Physical Examination
X
Xd
Xd
Xd
Xd
Xd
Xd
Vital Signse including Weight
X
X
X
X
X
X
X
Height
X
Waist Circumference 
X
X
12- lead ECG
X
X
X
Ultrasoundf
X
MRE, MRI-PDFF
X
X
FibroScan®g
X
X
SF-36, WPAI, and CLDQ
Questionnairesh
X
X
Adverse Events
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
Dispense Study Drugs
X
X
X
Review of Study Drug Dosing 
Compliance (Pill Count)
X
X
X
X
Laboratory Assessments
Subject Fastingi
X
X
X
X
X
X
X


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Assessments
Screeninga
Baseline / 
Day 1
On-treatment Visits
Follow Up 
Visitb
(± 5 Days)
Week 1
± 3 days
Week 4
± 3 days
Week 8
± 3 days
Week 12/ETb
± 7 days
Chemistry, Hematology, 
Coagulation Panel
X
X
X
X
X
X
X
Lipid Profile
X
X
X
X
X
X
Pregnancy Testj
X
X
X
X
X
X
Serum FSHk
X
Single PK Sampling
X
X
X
X
Hemoglobin A1c
X
X
X
Blood and Urine Collection 
(Biomarker)
X
X
X
X
Stool Collection (Biomarker)
X
X
Urine Drug Screeningl
X
HIV-1, HBV & HCVm Serology
X
Genomic Samplen
X
a.
Screening assessments to be completed within 6 weeks prior to Day 1.  The Screening period also may be extended longer under special circumstances with the explicit 
approval of the Gilead Medical Monitor.
b.
Subjects discontinuing treatment at any time for any reason (Early Termination – ET) should complete the procedures listed for the Week 12/ET visit AND the Follow-Up 
visit.
c.
Obtain written informed consent before initiation of any screening procedure.
d.
Symptom-driven physical examination
e.
Vital signs include blood pressure, heart rate, respiration rate, and body temperature.
f.
Ultrasound may be performed if necessary to confirm NAFLD.
g.
Perform FibroScan® if available.
h.
It is recommended that QoL questionnaires 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 questionnaire administration for subjects with QoL questionnaires available at Baseline/Day 1.
i.
Subjects must be in a fasted state at least 8 hours prior to blood collection.
j.
Females of childbearing potential only (See Appendix 3). Serum pregnancy test at Screening and urine pregnancy test at all other visits, except Week 1.
k.
l.
Drug screen for amphetamines, cocaine, and opiates (i.e., heroin, morphine).
m.
HCV Ab positive, reflex to HCV RNA. 
n.
CCI
CCI
CCI


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Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a. Definitions 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. Definitions of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchiectomy or medical documentation.
2) Contraceptive Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
The data of GS-0976 on pregnant women is not available now.  Relevant non-clinical 
reproductive toxicity studies for human pregnancy have not been conducted yet. There are 
insufficient data to exclude the possibility of a clinically relevant interaction between GS-0976 
and hormonal contraception that results in reduced contraception efficacy. Therefore, 
contraceptive steroids are not recommended as a contraceptive method either solely or as a part 
of a contraceptive regimen. Please refer to the latest version of the investigator’s brochure for 
GS-0976 for additional information.
b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures. They must 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 check-in visit prior to enrollment. At minimum, a pregnancy test 
will be performed at the end of relevant system exposure. In the event of a delayed menstrual 
period (over one month between menstruations), a pregnancy test must be performed to rule out 
pregnancy.  This is even true for women of childbearing potential with infrequent or irregular 


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periods. Female subjects must agree to one of the following from Screening until 30 days 
following the last dose of the study drugs.

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 drugs.
3) Contraceptive Requirements for Male Subjects
It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure of the male subject’s seminal fluid.  Therefore, male subjects with female 
partners of childbearing potential must use condoms during treatment until 90 days after the last 
dose of the study drugs.
Male subjects must refrain from sperm donation from clinic admission, throughout the study 
period, and continuing for at least 90 days following the last dose of study drugs.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicide 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 (90 days of partner of male subject) 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 drugs 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.


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Final
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Amendment 1
CONFIDENTIAL
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15 December 2016
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) Version 
4.0 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2, Randomized, Double-Blind, Placebo-Controlled 
Study Evaluating the Safety, Tolerability, and Efficacy of 
GS-0976 in Subjects with Nonalcoholic Steatohepatitis
Name of Test Drug:
GS-0976
Study Number:
GS-US-426-3989
Protocol Version (Date):
Amendment 1.1: 19 December 2016
Analysis Type:
Final Analysis
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
21 July, 2017
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(r) GILEAU 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF TABLES ........................................................................................................................................................4
LIST OF ABBREVIATIONS .......................................................................................................................................5
PHARMACOKINETIC ABBREVIATIONS ...............................................................................................................7
1.
INTRODUCTION ................................................................................................................................................8
1.1.
Study Objectives ......................................................................................................................................8
1.2.
Study Design............................................................................................................................................8
1.2.1.
Design Configuration, Subject Population and Treatment Groups ........................................8
1.2.2.
Study Duration .......................................................................................................................9
1.2.3.
Schedule of Assessments .......................................................................................................9
1.3.
Sample Size and Power............................................................................................................................9
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................10
2.1.
Interim Analyses ....................................................................................................................................10
2.1.1.
Data Monitoring Committee Analyses.................................................................................10
2.1.2.
Interim Analysis...................................................................................................................10
2.2.
Final Analysis ........................................................................................................................................10
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................11
3.1.
Analysis Sets..........................................................................................................................................11
3.1.1.
All Randomized Analysis Set ..............................................................................................11
3.1.2.
Full Analysis Set ..................................................................................................................11
3.1.3.
Safety Analysis Set ..............................................................................................................11
3.1.4.
Pharmacokinetic Analysis Set..............................................................................................11
3.1.5.
12
3.2.
Subject Grouping ...................................................................................................................................12
3.3.
Strata and Covariates .............................................................................................................................12
3.4.
Examination of Subject Subgroups........................................................................................................12
3.5.
Multiple Comparisons............................................................................................................................12
3.6.
Missing Data and Outliers......................................................................................................................13
3.6.1.
Missing Data ........................................................................................................................13
3.6.2.
Outliers.................................................................................................................................13
3.7.
Data Handling Conventions and Transformations .................................................................................13
3.8.
Analysis Visit Windows.........................................................................................................................14
3.8.1.
Definition of Study Day.......................................................................................................14
3.8.2.
Definition Analysis Visit Windows .....................................................................................14
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis 
Visit Window.......................................................................................................................16
4.
SUBJECT DISPOSITION..................................................................................................................................18
4.1.
Subject Enrollment and Disposition.......................................................................................................18
4.2.
Extent of Study Drug Exposure and Adherence ....................................................................................19
4.2.1.
Duration of Exposure to Study Drug....................................................................................19
4.2.2.
Adherence to Study Drug.....................................................................................................19
4.3.
Protocol Deviations................................................................................................................................20
5.
BASELINE CHARACTERISTICS....................................................................................................................21
5.1.
Demographics ........................................................................................................................................21
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5.2.
Other Baseline Characteristics ...............................................................................................................21
5.3.
Medical History .....................................................................................................................................22
6.
EFFICACY ANALYSES ...................................................................................................................................23
6.1.
Exploratory Efficacy Endpoints.............................................................................................................23
6.1.1.
Calculation and Remarks for Some Efficacy Endpoints ......................................................24
6.2.
Analysis Methods for Exploratory Efficacy Endpoints..........................................................................25
6.2.1.
Statistical Analysis Models ..................................................................................................25
6.2.2.
Statistical Analysis Methods ................................................................................................26
6.2.3.
Missing MRI-PDFF Data Handling .....................................................................................27
6.2.4.
Imaging Data Repeat Scan and Re-read...............................................................................27
6.3.
Subgroup Analysis of the Efficacy Endpoints .......................................................................................27
6.4.
Changes From Protocol-Specified Efficacy Analyses ...........................................................................28
7.
SAFETY ANALYSES........................................................................................................................................29
7.1.
Adverse Events and Deaths....................................................................................................................29
7.1.1.
Adverse Event Dictionary....................................................................................................29
7.1.2.
Adverse Event Severity........................................................................................................29
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................29
7.1.4.
Serious Adverse Events........................................................................................................29
7.1.5.
Treatment-Emergent Adverse Events ..................................................................................29
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................30
7.2.
Laboratory Evaluations..........................................................................................................................32
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................32
7.2.2.
Graded Laboratory Values ...................................................................................................33
7.2.3.
Liver-related Laboratory Evaluations ..................................................................................34
7.3.
Body Weight, Waist Circumference and Vital Signs.............................................................................35
7.4.
Prior and Concomitant Medications.......................................................................................................36
7.4.1.
Prior Medications.................................................................................................................36
7.4.2.
Concomitant Medications ....................................................................................................37
7.5.
Electrocardiogram Results .....................................................................................................................37
7.6.
Other Safety Measures...........................................................................................................................37
7.7.
Changes From Protocol-Specified Safety Analyses...............................................................................37
8.
PHARMACOKINETIC ANALYSES ................................................................................................................38
8.1.
PK Sample Collection............................................................................................................................38
8.2.
PK Analyses Related to Intensive PK Sampling....................................................................................38
8.2.1.
Estimation of PK Parameters ...............................................................................................38
8.2.2.
PK Parameters......................................................................................................................39
9.
REFERENCES ...................................................................................................................................................41
10.
SOFTWARE.......................................................................................................................................................42
11.
SAP REVISION .................................................................................................................................................43
12.
APPENDIX.........................................................................................................................................................44
Appendix 1.
Procedures Table for Study GS-US-426-3989 .......................................................................44
Appendix 2.
Pooled Cohort Risk Score and Pooled Cohort Risk Calculation............................................46
Appendix 3.
Health Related QoL Score Calculation: .................................................................................47
Appendix 4.
CTCAE Grade for Laboratory Parameters .............................................................................49


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LIST OF TABLES
Table 3-1.
Analysis Visit Windows for Vital Signs Including Weight, Chemistry, 
Hematology, Coagulation Labs, Lipid Profile, and Pooled Cohort Score and 
Risk ........................................................................................................................................15
Table 3-2.
Analysis Visit Windows for FibroSure/FibroTest, CK-18, ELF (and its 
components), Free Fatty Acid, C-Reactive Protein, ApoA1, ApoB, and Bile 
Acids ......................................................................................................................................15
Table 3-3.
Analysis Visit Windows for Insulin and HOMA-IR ..............................................................15
Table 3-4.
Analysis Visit Windows for Waist Circumference, ECG, HbA1c, and QoL-
Questionnaire .........................................................................................................................16
Table 3-5.
Analysis Visit Windows for FibroScan, MRE, and MRI-PDFF ............................................16
Table 8-1.
Study Treatments and Associated Analytes ...........................................................................39
Table 8-2.
PK Parameters for Each Analyte............................................................................................39


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LIST OF ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate transaminase
ATC
anatomical therapeutic chemical
AUC
area under the concentration
BLQ
below the limit of quantitation
BMI
body mass index
CI
confidence interval
CK18 
cytokeratin (C18)
CLDQ
chronic liver disease questionnaire
CRF
case report form
CRP
C reactive protein
CSR
clinical study report
CTCAE
common terminology criteria for adverse events
DBP
diastolic blood pressure
DILI
drug induced liver injury
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate 
ELF
enhanced liver fibrosis
ET
early termination
EOT
end of treatment
FAS
Full Analysis Set
FU
follow-up
GGT
uric acid Gamma-glutamyl transferase
GSI
Gilead Sciences, Inc.
HbA1c
hemoglobin A1c 
HCV
hepatitis C virus
HDL
high-density lipoprotein
HDL-C
HDL-cholesterol
HLT
high level term
HLGT
high level group term
HOMA-IR
homeostasis model assessment of insulin resistance
ID
identification
IND
Investigational New Drug (Application)


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INR
international normalized ratio
IXRS
interactive voice/web response system
LDH
lactate dehydrogenase
LDL-C
low-density lipoprotein cholesterol
LLT
lower level term
LLOQ
lower limit of quantitation
MedDRA
medical dictionary for regulatory activities
MRE
magnetic resonance elastography 
MRI-PDFF
magnetic resonance imaging – proton density fat fraction
NASH
nonalcoholic steatohepatitis
PE
physical examination
PK
pharmacokinetic
PT
preferred term
Q1
first quartile
Q3
third quartile
QoL
quality of life
RBC
red blood cell
RNA
Ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation 
SOC
system organ class
TE
treatment-emergent
TFLs
tables, figures, and listings
ULN
upper limit of normal
ULOQ
upper limit of quantitation 
VLDL-C
very low density lipoprotein-cholesterol
WBC
white blood cell
WHO
World Health Organization
WPAI
work productivity and activity impairment questionnaire


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PHARMACOKINETIC ABBREVIATIONS
AUClast
area under the concentration versus time curve from time zero to the last quantifiable 
concentration
AUCtau
area under the concentration versus time curve over the dosing interval
Clast
last observed quantifiable concentration of the drug 
Cmax
maximum observed concentration of drug 
Ctau
observed drug concentration at the end of the dosing interval
CLss/F
apparent oral clearance after administration of the drug:
at steady state: CLss/F = Dose/AUCtau , where “Dose” is the dose of the drug
t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the natural log 
of 2 by the terminal elimination rate constant (z)
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination 
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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report 
(CSR) for Study GS-US-426-3989. This SAP is based on the study protocol Amendment 1.1
dated 19 December 2016 and the electronic case report form (eCRF). The SAP will be
finalized before database finalization. Any changes made after the finalization of the SAP 
will be documented in the CSR.
1.1.
Study Objectives
The primary objective of this study is as follows:

To evaluate the safety and tolerability of GS-0976 in subjects with nonalcoholic 
steatohepatitis (NASH).
The exploratory objectives of this study are as follows:
1.2.
Study Design
1.2.1.
Design Configuration, Subject Population and Treatment Groups
This is a Phase 2, randomized, double-blind, placebo-controlled study designed to evaluate 
the safety, tolerability, and efficacy of GS-0976 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 noncirrhotic fibrosis. Any subject with history of decompensated liver disease,
including ascites, hepatic encephalopathy, or variceal bleeding, will be ineligible.
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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, respectively:

Group A (n = 50): GS-0976 5 mg (1 5 mg + PTM 5 mg + 2 × PTM 10 mg), orally 
once daily; 

Group B (n = 50): GS-0976 20 mg (2 × 10 mg + 2 × PTM 5 mg), orally once daily; 

Group C (n = 25): GS-0976 Placebo (2 × PTM 5 mg + 2 × PTM 10 mg), orally once 
daily.
Randomization will be stratified by the presence or absence of diabetes mellitus as 
determined by medical history, or based on Screening or Baseline/Day 1 lab values prior to 
first dosing if previously undiagnosed (ie, hemoglobin A1c ≥ 6.5% or fasting 
glucose ≥126 mg/dL).
1.2.2.
Study Duration
The total time to complete all study visits is up to approximately 22 weeks including the 
following periods:

6-week screening period

12-week treatment period

4-week follow-up period
1.2.3.
Schedule of Assessments
The schedule of assessments is provided as an appendix to the SAP (Appendix 1). After the 
Screening period and a randomization visit at Baseline/Day 1, study visits will occur at 
Weeks 1, 4, 8, 12, and a Follow-Up visit 4 weeks after the last dose of study drug. At 
minimum, vital sign measurements, symptom-driven physical examinations (PEs), safety 
laboratory tests (blood chemistry, hematology, coagulation panel, and lipid profile), and 
review of adverse events (AEs) and concomitant medications (CMs) will be done at every 
visit. Refer to Appendix 1 for details.
1.3.
Sample Size and Power
Due to the exploratory nature of this study, no formal power calculations were used to 
determine sample size. The number of subjects was chosen based on clinical experience 
with other similar proof-of-concept studies. However, assuming that 4% of subjects in the 
Placebo arm (N = 25) and 32% in the GS-0976 20 mg arm (N = 50) have a ≥ 30% reduction 
in MRI-PDFF at Week 12, this sample size will provide 80% power to detect the difference 
between GS-0976 and Placebo based on a 2-sided Fisher’s exact test at a significance level 
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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analyses
2.1.1.
Data Monitoring Committee Analyses
An external multidisciplinary Data Monitoring Committee (DMC) will review the progress 
of the study and perform interim reviews of safety data in order to protect subject welfare 
and preserve study integrity. The DMC is to recommend 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 whether the study should continue with modifications.
The first DMC review will be conducted after approximately 20 subjects have been enrolled 
and every 3 to 4 months thereafter to monitor the study for safety events until all 
randomized subjects complete or discontinue the study. The DMC will meet on an ad hoc 
basis if there are at least 3 Grade 3 or higher serious, treatment-related adverse events (AEs) 
observed in the study, based on the Common Terminology Criteria for Adverse Events 
(CTCAE). 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 regarding stopping or continuing the study.
The DMC’s role and responsibilities and the scope of analysis to be provided to the DMC 
are provided in a mutually agreed upon charter, which defines the DMC membership, 
meeting logistics, and meeting frequency.
2.1.2.
Interim Analysis
There is no interim analysis planned for this study.
2.2.
Final Analysis
After all subjects have completed the study, outstanding data queries have been resolved or 
adjudicated as unresolvable, and the data have been cleaned and finalized, the study blind 
will be broken and the final analysis of the data will be performed.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous 
variables, the number of subjects (n), mean, standard deviation (SD), median, first quartile 
(Q1), third quartile (Q3), minimum, and maximum will be presented.
Data collected in the study will be presented in by subject listings for all subjects in the 
specified analysis set and will be sorted by subject ID number, visit date, and time (if 
applicable), unless otherwise specified. Data collected on log forms, such as AEs, will be 
presented in chronological order for each subject.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their 
definitions are provided in this section. The analysis set will be identified and included as a 
subtitle of each table, figure, and listing.
For each analysis set, the number and percentage of subjects eligible for inclusion, as well 
as the number and percentage of subjects who were excluded and the reasons for their 
exclusion, will be summarized. Percentage will be calculated in proportion to the number of 
subjects in the all randomized analysis set by treatment group.
A listing of reasons for exclusion from analysis sets will be provided by subject.
3.1.1.
All Randomized Analysis Set
The All Randomized Analysis Set includes all subjects who were randomized into the study.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all subjects who were randomized into the study and
took at least 1 dose of study drug. This is the primary analysis set for efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least 1 dose of study drug. This is 
the primary analysis set for safety analyses.
3.1.4.
Pharmacokinetic Analysis Set
The Pharmacokinetic (PK) Analysis Set will include all randomized subjects who took at 
least 1 dose of study drug and have at least 1 nonmissing postdose concentration value 
reported by the PK laboratory.
This is the primary analysis set for all PK analyses. 


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3.2. 
Subject Grouping 
Version 1.0 
For analyses based on the All Randomized Analysis Set or FAS, subjects will be grouped 
according to the ti·eatment to which they were randomized. For analyses based on the Safety 
Analysis Set, subjects will be grouped according to actual ti·eatment received. The actual 
ti·eatment received will differ from the randomized ti·eatment only when their actual 
ti·eatment differs from randomized ti·eatment for the entire ti·eatment dmation. 
Treatment groups GS-0976 20 mg and GS-0976 5 mg will be combined together as group 
GS-097 6 pooled for analysis based on Safety Analysis Set. The sUIIllnaiy will be prepai·ed 
by ti·eatment groups in the order of GS-0976 20 mg, GS-0976 5 mg, GS-0976 pooled, and 
Placebo. 
3.3. 
Strata and Covariates 
Subjects will be randomly assigned to ti·eatment groups via the interactive web response 
system (IXRS) in a 2:2:1 ratio using a sti·atified randomization schedule. Sti·atification will 
be based on the presence or absence of diabetes mellitus. 
If there ai·e discrepancies in sti·atification factor values between the IWRS and the clinical 
database, the baseline values recorded in the clinical database will be used for analyses, 
which is determined by medical histo1y , or based on lab values ( either Screening or 
Baseline/Day 1 value prior to first dosing) if previously undiagnosed (ie, hemoglobin 
Ale :::: 6.5% or fasting glucose:::: 126 mg/dL). 
3.4. 
Examination of Subject Subgroups 
Subgrouping of subjects based on randomization sh'atification factor will be explored for 
subgroup analyses. The subgroups are as follows: 
• 
presence of diabetes mellitus 
• 
absence of diabetes mellitus 
3.5. 
Multiple Comparisons 
Adjustments for multiplicity will not be made because no fonnal statistical testing will be 
perfo1med in this study. Any p-values displayed are for explorato1y pm-poses only. 
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3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.
For missing MRI-PDFF, imputation rules are specified in Section 6.2.3. For missing last 
dosing date of study drug, imputation rules are described in Section 4.2.1. The handling of 
missing or incomplete dates for AE onset is described in Section 7.1.5.2, and for prior and 
concomitant medications in Section 7.4.
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis.
3.7.
Data Handling Conventions and Transformations
In general, age (in years) on the date of the first dose of study drug will be used for analyses 
and presentation in listings. If an enrolled subject was not dosed with any study drug, the 
randomization date will be used instead of the first dosing date of study drug. For screen 
failures, the date the informed consent was signed will be used for age calculation. If only 
birth year is collected on the case report form (CRF), “01 July” will be used for the 
unknown birth day and month for the purpose of age calculation. If only birth year and
month are collected, “01” will be used for the unknown birth day.
Non-PK data that are continuous in nature but are less than the lower limit of quantitation
(LOQ) or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used for calculation of descriptive 
statistics if the datum is reported in the form of “x” (where x is considered the LOQ).
For example, if the values are reported as < 50 and < 5.0, values of 49 and 4.9, 
respectively, will be used for calculation of summary statistics. An exception to this rule 
is any value reported as < 1 or < 0.1, etc. For values reported as < 1 or < 0.1, a value of 
0.9 or 0.09, respectively, will be used for calculation of summary statistics.

A value that is 1 unit above the LOQ will be used for calculation of descriptive statistics 
if the datum is reported in the form of “> x” (where x is considered the LOQ). Values 
with decimal points will follow the same logic as above.

The LOQ will be used for calculation of descriptive statistics if the datum is reported in 
the form of “≤ x” or “≥ x” (where x is considered the LOQ).


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If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data or nonparametric analysis methods may be 
used, as appropriate.
Natural logarithm-transformation will be used for blood concentrations and analysis of PK 
parameters. Plasma concentration values that are below the limit of quantitation (BLQ) will 
be presented as “BLQ” in the concentration data listing. Values that are BLQ will be treated 
as 0 at predose time points, and one-half the value of the LLOQ at postbaseline time points.
The following conventions will be used for the presentation of summary and order statistics:

If at least 1 subject has a concentration value of BLQ for the time point, the minimum 
value will be displayed as “BLQ.”

If more than 25% of the subjects have a concentration data value of BLQ for a given 
time point, the minimum and Q1 values will be displayed as “BLQ.”

If more than 50% of the subjects have a concentration data value of BLQ for a given 
time point, the minimum, Q1, and median values will be displayed as “BLQ.”

If more than 75% of the subjects have a concentration data value of BLQ for a given 
time point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.”

If all subjects have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”
3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day is the day relative to the date of the first dose of study drug. Study Day 1 will be 
defined as the day of first dose of study drug administration.
Study day will be calculated from the date of first dose of study drug administration and 
derived as follows:

For postdose study days: Assessment Date – First Dosing Date + 1

For days prior to the first dose: Assessment Date – First Dosing Date
If the last dosing date of study drug is missing or incomplete, the date of last dose will be 
estimated using the maximum of nonmissing study drug start or stop dates, visit dates, and 
laboratory collection dates (posttreatment visits and unscheduled visits are not included).
3.8.2.
Definition Analysis Visit Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of 
analysis, observations will be assigned to analysis windows.


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In general, the baseline value will be the last nonmissing value on or prior to the first dosing 
date of study drug. For imaging the data, baseline will be the first nonmissing value from 
screening up to first dosing date plus 4 weeks.
Selected safety and efficacy data collected up to and including the last dosing date plus 
30 days (or 42 days for imaging data) will be mapped according to the following analysis 
windows. Early termination (ET) or follow-up (FU) will use the nominal visit name. 
Table 3-1.
Analysis Visit Windows for Vital Signs Including Weight,
Chemistry, Hematology, Coagulation Labs, Lipid Profile, and 
Pooled Cohort Score and Risk 
Analysis Visit
Study Day
Lower Limit
Upper Limit
Baseline/Day
1
NA
1
Week 1
8
2
18
Week 4
29
19
42
Week 8
57
43
70
Week 12
85
71
> 85
NA = not applicable
Table 3-2.
Analysis Visit Windows for FibroSure/FibroTest, CK-18, ELF 
(and its components), Free Fatty Acid, C-Reactive Protein, 
ApoA1, ApoB, and Bile Acids  
Analysis Visit
Study Day
Lower Limit
Upper Limit
Baseline/Day
1
NA
1
Week 1
8
2
18
Week 4
29
19
56
Week 12
85
57
> 85
Table 3-3.
Analysis Visit Windows for Insulin and HOMA-IR
Analysis Visit
Study Day
Lower Limit
Upper Limit
Baseline/Day
1
NA
1
Week 4
29
2
56
Week 12
85
57
> 85


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Table 3-4.
Analysis Visit Windows for Waist Circumference, ECG, HbA1c,
and QoL-Questionnaire
Analysis Visit
Study Day
Lower Limit
Upper Limit
Baseline/Day
1
NA
1
Week 12
85
2
> 85
Table 3-5.
Analysis Visit Windows for FibroScan, MRE, and MRI-PDFF
Analysis Visit
Study Day
Lower Limit
Upper Limit
Baseline/Day
1
NA
29
Week 12
85
30
> 85
Data relating to unscheduled visits may be assigned to a particular visit or time point. The 
following conventions will be followed:

An unscheduled visit prior to the first dosing of study drug will be included in the 
calculation of the baseline value.

For subjects who prematurely discontinue from the study, early termination (ET) data 
will be summarized as a separate visit, labeled as “Early Termination Visit”

Data collected on a follow-up visit will be summarized as a separate visit, and labeled 
“Follow-up Visit.”
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each 
analysis window. For example, change from baseline by visit usually requires a single value, 
whereas a time-to-event analysis would not require 1 value per analysis window.
If multiple valid, nonmissing, continuous measurements exist in an analysis window, 
records will be chosen based on the following rules if a single value is needed:

In general, the baseline value will be the last nonmissing value on or prior to the first 
dosing date of study drug, unless specified differently. If multiple measurements occur 
on the same day, the last nonmissing value prior to the time of first dosing of study drug 
will be considered as the baseline value. If these multiple measurements occur at the 
same time or the time is not available, the average of these measurements (for 
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
For postbaseline values:

The record closest to the nominal day (the nominal day for Week x is Day 7x + 1) for 
that visit will be selected.

If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.

If there is more than 1 record on the selected day, the average will be taken, unless 
otherwise specified.
If multiple, valid nonmissing, categorical measurements exist in an analysis window, 
records will be chosen based on the following rules if a single value is needed:

For baseline, the last available record on or prior to the date of the first dose of study 
drug will be selected. If there are multiple records with the same time or no time 
recorded on the same day, the value with the lowest severity will be selected (eg, normal 
will be selected over abnormal for safety electrocardiogram [ECG] findings).

For postbaseline visits, if there are multiple records with the same time or no time 
recorded on the same day, the value with the highest severity within the window will be 
selected (eg, abnormal will be selected over normal for safety ECG findings).


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided for each investigator by treatment group 
and overall. For each column, the denominator for the percentage calculation will be the 
total number of subjects analyzed for that column.
A similar enrollment table will be provided by randomization stratum. The denominator for 
the percentage of subjects in the stratum will be the total number of randomized subjects in 
the All Randomized Analysis Set. If there are discrepancies in the value used for 
stratification assignment between the IXRS and the clinical database, including CRF and 
laboratory data, the value collected in the clinical database will be used for the summary. A 
listing of subjects with discrepancies in the value used for stratification assignment between 
the IXRS and the clinical database at the time of data finalization will be provided.
The randomization schedule used for the study will be provided as an appendix to the CSR.
A summary of subject disposition will be provided by treatment group and overall. This 
summary will present the number of subjects randomized, and the number and percentage of 
subjects in each of the categories listed below. 

Safety Analysis Set

Full Analysis Set

PK Analysis Set


Completed study drug

Did not complete study drug, with reasons for premature discontinuation of study drug

Completed study

Did not complete the study, with reasons for premature discontinuation of study
In addition, a flowchart will be provided to depict the disposition.
The following by-subject listings will be provided by subject identification (ID) number in 
ascending order to support the above summary tables:

Reasons for premature study drug or study discontinuation

Reasons for screen failure (will be provided by screening ID number in ascending order)

Lot number and kit ID
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The level of prescribed adherence will be expressed as a percentage using the following 
formula:
Total Amount of Study Drug Administered
Prescribed Adherence (%) =
 x 100
Total Amount of Study Drug Specified by Protocol






Note: If calculated adherence is greater than 100%, the result will be set to 100%.
Descriptive statistics for the level of prescribed adherence with the number and percentage 
of subjects belonging to adherence categories (< 75%, ≥ 75 to < 90%, and ≥90%) will be 
provided for each study drug by treatment group for the Safety Analysis Set.
No formal statistical testing is planned.  
By-subject listings of study drug administration and drug accountability will be provided 
separately by subject ID number (in ascending order) and visit (in chronological order).
4.3.
Protocol Deviations 
Subjects who did not meet the eligibility criteria for study entry, but enrolled in the study
will be summarized regardless of whether they were exempted by the medical monitor or 
not. The summary will present the number and percentage of subjects who did not meet at 
least 1 eligibility criterion and the number of subjects who did not meet specific criteria by 
treatment group based on the All Randomized Analysis Set. A by-subject listing will be 
provided for those subjects who did not meet at least 1 eligibility (inclusion or exclusion)
criterion. The listing will present the eligibility criterion (or criteria if more than 1 deviation) 
that subjects did not meet and related comments, if collected.
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. The number and percentage of subjects with important protocol deviations by 
deviation reason (e.g., nonadherence to study drug, violation of select inclusion/exclusion 
criteria) will be summarized by treatment group for the All Randomized Analysis Set. A by-
subject listing will be provided for those subjects with important protocol deviation.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics
Subject demographic variables (ie, age, sex, race, and ethnicity) will be summarized by 
treatment group and overall using descriptive statistics for age, and using number and 
percentage of subjects for sex, race, and ethnicity. Age is calculated in years at the date of 
first study drug administration. The summary of demographic data will be provided for the
Safety Analysis Set.
A by-subject demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include:

body weight (in kg)

height (in cm)

body mass index as a continuous variable and as categories (< 18.5 kg/m2, 18.5 to 
< 25 kg/m2, 25 to < 30 kg/m2,  and ≥ 30 kg/m2)

diabetes mellitus (diabetic or nondiabetic)

MRI-PDFF

MRE

FibroScan (if available)

FibroSURE/FibroTest

ELF test

ALP

ALT

AST

direct and total bilirubin

GGT


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
estimated glomerular filtration rate (eGFR) (Cockcroft-Gault)

homeostasis model assessment of insulin resistance (HOMA-IR)

fasting glucose

fasting insulin

international normalized ratio (INR)

hemoglobin A1c (HbA1c)

total cholesterol

triglycerides

high-density lipoprotein cholesterol (HDL-C)

calculated low-density lipoprotein cholesterol (LDL-C) 

calculated Non-HDL-C

calculated Very Low Density Lipoprotein cholesterol (VLDL-C) 

free fatty acid

C-reactive protein (CRP)

Total bile acids

waist circumference

systolic blood pressure treated status (treated/not treated)

smoking status
These baseline characteristics will be summarized by treatment group and overall using 
descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) for 
continuous variables and using number and percentage of subjects for categorical variables. 
The summary of baseline characteristics will be provided for the Safety Analysis Set. No 
formal statistical testing is planned.
A by-subject listing of then Other Baseline Characteristics will be provided by subject ID
number in ascending order.
5.3.
Medical History
General medical history data will be collected at screening and listed only. General medical 
history data will not be coded.


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6.
EFFICACY ANALYSES
6.1.
Exploratory Efficacy Endpoints
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Analysis Methods for Exploratory Efficacy Endpoints 
Statistical Analysis Models 
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6.2.2.
Statistical Analysis Methods
For exploratory efficacy endpoints, the number and percentage of subjects in each category 
will be presented for categorical variables. Descriptive statistics (n, mean, SD, median, Q1, 
Q3, minimum, and maximum) will be provided for continuous exploratory efficacy
variables by treatment group, as follows:
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
Baseline values

Values at each postbaseline visit

Change from baseline at each postbaseline visit

Percent change from baseline at each postbaseline (except for pooled cohort risk score)
Change from baseline at a postbaseline visit will be defined as the visit value minus the 
baseline value. Percent change from baseline will be defined as (the visit value −the 
baseline value)/the baseline value × 100%.  The mean, median, Q1, Q3, minimum, and 
maximum will be displayed to the same reported number of digits, and SD will be reported 
to the number of digits plus 1.
For continuous exploratory efficacy endpoints, mean (SD) of the observed change from 
baseline values will be plotted using a line plot by treatment group and visit.  
Listings of all exploratory efficacy endpoints will be provided.
6.2.3.
Missing MRI-PDFF Data Handling
For MRI-PDFF data, the first analyzable value from multiple echo (ME) series at each time 
point will be used.  The mean of all analyzable segments by time point reported will be 
used.  If there are subjects missing ME series results but have double double echo (DDE) 
series results, 95% CI based on t statistics will be calculated for the mean difference in ME 
and DDE series results.  If the 95% CI is within [−3%, 3%], then the DDE values (mean of 
analyzable segments reported) will be used to impute for missing ME results.  If a subject 
has both (baseline and Week 12) DDE series values available, and at least 1 ME series value 
requires imputation, then the corresponding DDE series result will be used for both visits.
6.2.4.
Imaging Data Repeat Scan and Re-read
For MRI-PDFF and MRE data, if a patient has an analyzable repeat scan, then only repeat 
scan for that visit will be used for analysis. For MRE data, if a patient has a re-read result, 
then the re-read result for that visit will be used for analysis.
6.3.
Subgroup Analysis of the Efficacy Endpoints
Subgrouping of subjects based on randomization stratification factors will be explored as 
follows:

presence of diabetes mellitus

absence of diabetes mellitus
Descriptive statistics for the above subgroups will be presented for the baseline values, 
values at each postbaseline visit, change from baseline, and percent change from baseline by 
visit for MRE and MRI-PDFF.
For each subgroup, the proportion of subjects with at least 30% reduction in MRI-PDFF at 
Week 12 and the proportion of subjects with at least 15% reduction in MRE at Week 12 will 
be reported for each treatment group by using a point estimate and 95% CI of the proportion 


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based on the Clopper-Pearson method. The 95% CI for the difference in proportion between 
GS-0976 and Placebo will also be provided.
Within each subgroup, the change from baseline of MRI-PDFF and MRE at Week 12 will 
be analyzed by using an ANCOVA model, with treatment group, and baseline MRI-PDFF 
or MRE as covariates. For change from baseline, LS means and 95% CIs of LS means will 
be reported for each treatment group. For treatment differences (GS-0976 – Placebo) of 
changes from baseline of MRI-PDFF or MRE at Week 12, LS means and 95% CIs will be 
reported.
Mean (SD) of the observed change from baseline value will be plotted using a line plot by 
treatment group and visit for subjects from each subgroup.
6.4.
Changes From Protocol-Specified Efficacy Analyses
There is no change from protocol specified analysis. 


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory AEs will be coded using the current version of MedDRA. System 
organ class (SOC), high-level group term (HLGT), high-level term (HLT), preferred term 
(PT), and lower-level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, 4, or 5 according to the 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03, detailed in 
Appendix 4. The severity grade of events for which the investigator did not record severity 
will be categorized as “missing” for tabular summaries and data listings. The missing 
category will be listed in summary presentations.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the 
investigator’s choice, not that of the medical monitor. Events for which the investigator did 
not record relationship to study drug will be considered related to study drug for summary 
purposes. However, by-subject data listings will show the relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs met the 
definitions of SAE specified in the study protocol. Serious adverse events captured and 
stored in the clinical database will be reconciled with the SAE database from the Gilead 
Drug Safety and Public Health Department before data finalization.
7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as 1 or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 
30 days after permanent discontinuation of study drug

Any AEs leading to premature discontinuation of study drug.


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7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing
date of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent 
if both of the following 2 criteria are met:

The AE onset is the same as or after the month and year (or year) of the first dosing date 
of study drug, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after the date of the last dose of study drug 
An AE with completely missing onset and stop dates, or with the onset date missing and a 
stop date later than the first dosing date of study drug, will be considered to be treatment
emergent. In addition, an AE with the onset date missing and incomplete stop date with the 
same or later month and year (or year alone if month is not recorded) as the first dosing date 
of study drug will be considered treatment emergent.
7.1.6.
Summaries of Adverse Events and Deaths
Treatment-emergent (TE) AEs will be summarized based on the Safety Analysis Set.
The number and percentage of subjects who experienced at least 1 TEAE will be provided 
and summarized by SOC, HLT, PT, and treatment group. For other AEs described below, 
summaries will be provided by SOC, PT, and treatment group.

TEAEs of Grade 3 or higher (by maximum severity)

TEAEs of Grade 2 or higher

All TE treatment-related AEs

TE treatment-related AEs of Grade 3 or higher (by maximum severity)

TE treatment-related AEs of Grade 2 or higher

All TE SAEs

All TE treatment-related SAEs 

All TEAEs leading to premature discontinuation of study drug

All TEAEs leading to premature discontinuation of study

All TEAEs leading to dose temporary interruption of study drug


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A brief, high-level summary of AEs described above will be provided by treatment group 
and by the number and percentage of subjects who experienced the above AEs. All deaths 
observed in the study will also be included in this summary.
Multiple events will be counted only once per subject in each summary. Adverse events will 
be summarized and listed first in alphabetic order of SOC and HLT within each SOC (if 
applicable), and then by PT in descending order of GS-0976 20 mg frequency within each 
SOC (HLT, if present). For summaries by severity grade, the most severe grade will be used 
for those AEs that occurred more than once in an individual subject during the study. 
In addition to the above summary tables, TEAEs and TE treatment-related AEs will be 
summarized by PT only for the following, in descending order of GS-0976 20 mg 
frequencies:

TE Adverse Events by Preferred Term

Grade 3 or Higher TEAEs by Preferred Term

Grade 2 or Higher TEAEs by Preferred Term

TE treatment-Related AEs by Preferred Term

Grade 3 or Higher TE treatment-Related AEs by Preferred Term

Grade 2 or Higher TE treatment-Related AEs by Preferred Term

All TE SAEs by Preferred Term

All TE treatment-related SAEs by Preferred Term

All TEAEs leading to premature discontinuation of study drug by Preferred Term

All TEAEs leading to premature discontinuation of study by Preferred Term

All TEAEs leading to temporary interruption of study drug by Preferred Term
In addition, data listings will be provided for the following:

All AEs, indicating whether the event is treatment emergent

All AEs of Grade 3 or higher

All AEs of Grade 2 or higher

SAEs


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
Deaths

AEs leading to premature discontinuation of study drug

AEs leading to premature discontinuation of study 

AEs leading to temporary interruption of study drug
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. The analysis will be based on values reported in 
conventional units. When values are below the LOQ, they will be listed as such, and the 
closest imputed value will be used for the purpose of calculating summary statistics as 
specified in Section 3.7.
A by-subject listing for laboratory test results will be provided by subject ID number and 
visit in chronological order for hematology, serum chemistry, and urinalysis separately. 
Values falling outside of the relevant reference range and/or having a severity grade of 1 or 
higher according to the CTCAE, Version 4.03 will be flagged in the data listings, as 
appropriate.
No formal statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics will be provided by treatment group for each laboratory test listed 
below:

Chemistry Panel:
Creatinine, fasting glucose, fasting insulin, eGFR using the Cockcroft-Gault equation, 
serum creatinine

Coagulation Panel: INR

Hematology: white blood cell (WBC), neutrophils, lymphocytes, hemoglobin, platelets
For each laboratory test specified above, the descriptive statistics will be provided as 
follows:

Baseline values 

Values at each postbaseline visit

Change from baseline at each postbaseline visit


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Change from baseline to a postbaseline visit will be defined as the postbaseline value minus 
the baseline value. The mean, median, Q1, Q3, minimum, and maximum values will be
displayed to the reported number of digits; SD values will be displayed to the reported 
number of digits plus 1.
Median (Q1, Q3) of the observed values for albumin, creatinine, glucose, fasting insulin, 
WBC, neutrophils, lymphocytes, hemoglobin, platelets, INR, and eGFR will be plotted 
using a line plot by treatment group and visit.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3.
7.2.2.
Graded Laboratory Values
The CTCAE, Version 4.03 will be used to assign toxicity grades (0 to 4) to laboratory 
results for analysis. Grade 0 includes all values that do not meet the criteria for an 
abnormality of at least Grade 1. For laboratory tests with criteria for both increased and 
decreased levels, analyses for each direction (ie, increased, decreased) will be presented 
separately.
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of 
last dose of study drug plus 30 days for subjects who permanently discontinued study drug. 
If the relevant baseline laboratory value is missing, any abnormality of at least Grade 1 
observed within the time frame specified above will be considered treatment emergent.
7.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities
Treatment-emergent marked laboratory abnormalities are defined as values that increase 
from baseline by at least 3 toxicity grades at any postbaseline time point, up to and 
including the date of the last dose of study drug plus 30 days for subjects who permanently 
discontinued study drug. If the relevant baseline laboratory value is missing, any Grade 3 or 
4 values observed within the timeframe specified above will be considered 
treatment-emergent marked abnormalities.
7.2.2.3.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of
subjects in the study with the given response at baseline and each scheduled postbaseline 
visit.
The following summaries (number and percentage of subjects) for treatment-emergent 
laboratory abnormalities will be provided by lab test and treatment group; subjects will be 
categorized according to the most severe postbaseline abnormality grade for a given lab test:

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
Grade 3 or 4 laboratory abnormalities

Marked laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects 
with nonmissing postbaseline values up to 30 days after last dosing date for the laboratory 
test of interest.
A by-subject listing of treatment-emergent Grade 3 or 4 laboratory abnormalities will be 
provided by subject ID number and visit in chronological order. This listing will include all 
test results that were collected throughout the study for the lab test of interest, with all 
applicable severity grades and abnormal flags displayed.
7.2.3.
Liver-related Laboratory Evaluations
Liver-related abnormalities after initial study drug dosing will be examined and summarized 
using the number and percentage of subjects who were reported to have the following 
laboratory test values listed in Section 7.2.3.1 for postbaseline measurements:
The summary will include data from all postbaseline visits up to 30 days after the last dose 
of study drug. For individual laboratory tests, subjects will be counted once based on the 
most severe postbaseline values. For both the composite endpoint of AST or ALT and total 
bilirubin, ALP, INR (as described below), subjects will be counted once when the criteria 
are met at the same postbaseline visit date. The denominator is the number of subjects in 
each reporting group (if applicable) in the Safety Analysis Set who have nonmissing 
postbaseline values of all relevant tests at the same postbaseline visit date. 
7.2.3.1.
Criteria for Observation of Drug Induced Liver Injury (DILI)
For subjects with ALT (AST) baseline meeting one of the following 2 categories, close 
observation for DILI should be considered if the subjects meet any of the postbaseline 
criteria corresponding to each baseline category below. 
1) For subjects with ALT (AST) below ULN at study baseline AND

meeting any of the following postbaseline criteria for liver-related events:
ALT (AST) > 3 ULN at any time
Total Bilirubin > 2 ULN
ALP > 3 ULN
INR > 1.5 (except for subjects on anticoagulant therapy)

meeting any of the following postbaseline criteria for drug withheld:
ALT (AST) > 3 ULN and Total Bilirubin > 2 ULN


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ALT (AST) > 3 ULN and INR > 1.5 (except for subjects on anticoagulant therapy)
ALT (AST) > 5 ULN
ALT (AST) > 8 ULN
2) For subjects with ALT (AST) greater than or equal to 1 ULN at study baseline AND 

meeting any of the following postbaseline criteria for liver-related events :
ALT (AST) > 2 Baseline at any time
Total Bilirubin > 2 ULN
ALP > 3 ULN
INR > 1.5 (except for subjects on anticoagulant therapy)

Meeting any of the following postbaseline  criteria for drug withheld:
ALT (AST) > 3 ULN and Total Bilirubin > 2 ULN
ALT (AST) > 3 ULN and INR > 1.5 (except for subjects on anticoagulant therapy)
ALT (AST) > 5 ULN
ALT (AST) > 8 ULN
7.2.3.2.
Summaries of Criteria for Observation of DILI
The subjects who meet the criteria for close observation of DILI described in Section 7.2.3.1
will be summarized (by using number and percentage of subjects) by treatment, ALT (AST)
baseline condition (whether below ULN, or greater than or equal to 1 ULN), and
corresponding postbaseline criteria listed in Section 7.2.3.1. 
A listing will be provided for the subjects who met at least 1 of the above criteria.
7.3.
Body Weight, Waist Circumference and Vital Signs
Descriptive statistics will be provided for the Safety Analysis Set by treatment group for 
body weight, BMI, waist circumference, and vital signs (systolic and diastolic blood 
pressures [mmHg], pulse [beats/min], respiration [breaths/min], and body temperature [°C]),
as follows:

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
Values at each postbaseline visit

Change from baseline at each postbaseline visit

Percent change from baseline (for weight and waist circumference only)
Change from baseline to a postbaseline visit will be defined as the postbaseline value minus 
the baseline value. Percent change from baseline will be defined as the change from baseline 
divided by the baseline value times 100 and displayed as percent (%). 
Median (Q1, Q3) of the observed change from baseline values for body weight and waist 
circumference will be plotted by treatment group and visit. In the case of multiple values in 
an analysis window, data will be selected for analysis as described in Section 3.8.3. No 
formal statistical testing is planned.
A by-subject listing of vital signs will be provided by subject ID number and visit in 
chronological order. In the same manner, a by-subject listing of body weight, height, and 
BMI will be provided.
7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current 
version of the World Health Organization (WHO) Drug dictionary.
7.4.1.
Prior Medications
Prior medications are defined as any medication taken before a subject took the first study 
drug.
Prior medications will be summarized by Anatomical Therapeutic Chemical (ATC) drug 
class Level 4 and preferred name using the number and percentage of subjects for each
treatment group and overall. A subject reporting the same medication more than once will 
be counted only once when calculating the number and percentage of subjects who received 
that medication. The summary will be ordered alphabetically by ATC medical class and 
then by preferred term in order of descending overall frequency within each ATC medical 
class. For drugs with the same frequency, sorting will be done alphabetically.
For the purposes of analysis, any medication with a start date prior to the first dosing date of 
study drug will be included in the prior medication summary regardless of when the stop 
date is. If a partial start date is entered the medication will be considered prior unless the 
month and year (if day is missing) or year (if day and month are missing) of the start date 
are after the first dosing date. Medications with a completely missing start date will be 
included in the prior medication summary, unless otherwise specified.
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7.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a subject took study drug.
Use of concomitant medications will be summarized by Anatomical Therapeutic Chemical 
(ATC) drug class Level 4 and preferred name using the number and percentage of subjects 
for each treatment group. A subject reporting the same medication more than once will be 
counted only once when calculating the number and percentage of subjects who received 
that medication. The summary will be ordered alphabetically by ATC medical class and 
then by preferred term in descending overall frequency within each ATC medical class. For 
drugs with the same frequency, sorting will be done alphabetically.
For the purposes of analysis, any medication with a start date prior to or on the first dosing 
date of study drug and continued to take after the first dosing date, or started after the first 
dosing date but prior to or on the last dosing date of study drug, will be considered 
concomitant medications. Medications started and stopped on the same day as the first 
dosing date or the last dosing date of study drug will also be considered concomitant. 
Medications with a stop date prior to the date of first dosing date of study drug or a start 
date after the last dosing date of study drug will be excluded from the concomitant 
medication summary. If a partial start date is entered, any medication with the month and 
year (if day is missing) or year (if day and month are missing) after the study drug stop date 
will be excluded from the concomitant medication summary. If a partial stop date is entered, 
any medication with the month and year (if day is missing) or year (if day and month are 
missing) prior to the date of first study drug administration will be excluded from the 
concomitant medication summary. Medications with completely missing start and stop dates 
will be included in the concomitant medication summary, unless otherwise specified. 
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned.
All prior and concomitant medications (other than per-protocol study drugs) will be 
provided in a by-subject listing sorted by subject ID number and administration date in 
chronological order.
7.5.
Electrocardiogram Results
A shift table of the investigators’ assessment of ECG results at Week 12 compared with
baseline values will be presented by treatment group using the following categories: normal; 
abnormal, not clinically significant; abnormal, clinically significant; or missing. The number 
and percentage of subjects in each cross-classification group of the shift table will be 
presented. Subjects with a missing value at baseline or postbaseline will not be included in 
the denominator for percentage calculation. No inferential statistics will be provided.
A by-subject listing for ECG assessment results will be provided by subject ID number and 
visit in chronological order.
7.6.
Other Safety Measures
A data listing will be provided for subjects experiencing pregnancy during the study.
7.7.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8. 
PHARMACOKINETIC ANALYSES 
8.1. 
PK Sample Collection 
Version 1.0 
A single PK blood sample will be collected at any time during each On-Treatment Visit for 
all subjects. 
8.2. 
PK Analyses Related to Intensive PK Sampling 
. Concentrntions of GS-0976 and its metabolites in plasma will be 
determined using validated bioanalytical assays. 
8.2.1. 
Estimation of PK Parameters 
Phaimacokinetic pai·ameters will be estimated using Phoenix WinNonlin® software using 
standard noncompartmental methods. The linear up/log down rnle will be used in 
conjunction with the appropriate noncompaii mental model, with input values for dose level, 
dosing time, plasma concentration, and coITesponding real-time values, based on chug 
dosing times whenever possible. 
All predose sample times before time zero will be conve1i ed to 0. 
For ai·ea under the cmve (AUC), samples BLQ of the bioanalytical assays occmTing prior to 
the achievement of the first quantifiable concentration will be assigned a concentration 
value of Oto prevent overestimation of the initial AUC. Samples that are BLQ at all other 
time points will be treated as missing data in WinNonlin. The nominal time point for a key 
event or dosing inte1val (r) may be used to pe1mit direct calculation of AUC over specific 
time inte1v als. The appropriateness of this approach will be assessed by the PK scientist on a 
profile-by-profile basis. 
Phaimacokinetic pai·ameters such as AUC1au, 1,,z., and t112 are dependent on an accurate 
estimation of the te1minal elimination phase of drng. The appropriateness of calculating 
these pai·aineters will be evaluated upon inspection of PK data on a profile-by-profile basis 
by the PK scientist. 
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8.2.2.
PK Parameters
Pharmacokinetic parameters will be generated for all subjects in the PK Substudy Analysis 
Set. For each subject, the following PK parameters will be calculated for GS-0976 and its 
metabolites as appropriate to evaluate the PK objectives of the study. 
Table 8-1.
Study Treatments and Associated Analytes
Treatment
Analyte
GS-0976 20 mg tablet 
GS-0976, GS-834773, and others as appropriate
GS-0976 5 mg tablet 
GS-0976, GS-834773, and others as appropriate
Table 8-2.
PK Parameters for Each Analyte
Analyte
Parameters
GS-0976 
AUClast, AUCtau, Cmax, Tmax, Clast, Tlast, Ctau, λz, CLss/F, and t1/2
GS-834773
AUClast, AUCtau, Cmax, Tmax, Clast, Tlast, Ctau, λz, and t1/2
Individual subject concentration data and individual subject PK parameters for GS-0976 and 
its metabolites will be listed and summarized using descriptive statistics by treatment. 
Summary statistics (n, mean, SD, coefficient of variation [%CV], median, min, max, Q1, 
and Q3) will be presented for both individual subject concentration data and individual 
subject PK parameters by time point and by treatment. Moreover, the geometric mean, 
95% CI, and the mean and SD of the natural log-transformed values will be presented for 
individual subject PK parameter data.
Individual concentration data listings and summaries will include all subjects with 
concentration data. The sample size for each time point will be based on the number of 
subjects with nonmissing concentration data at that time point. The number of subjects with 
concentration BLQ will be presented for each time point. For summary statistics, BLQ 
values will be treated as 0 at predose and imputed to one-half of the lower limit of 
quantitation (LLOQ) for postdose time points.
Individual PK parameter data listings and summaries will include all subjects for whom PK 
parameter(s) can be derived. The sample size for each PK parameter will be based on the 
number of subjects with nonmissing data for that PK parameter.
The following tables will be provided for each analyte by treatment for the PK Substudy:
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Individual and mean postdose concentration values that are ≤LLOQ will not be displayed in 
the figures and remaining points connected.
The following listings will be provided:

PK sampling details by subject including actual dosing time and actual draw time, 
calculated time postdose of sample collection, differences in scheduled and actual draw 
times, sample age, and sample concentration

Individual data on determination of plasma half-life and corresponding correlation 
coefficient
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9.
REFERENCES
Goff DC, Jr., Lloyd-Jones DM, Bennett G, Coady S, D'Agostino RB, Gibbons R, et al. 2013 
ACC/AHA guideline on the assessment of cardiovascular risk: a report of the 
American College of Cardiology/American Heart Association Task Force on 
Practice Guidelines. Circulation 2014;129 (25 Suppl 2):S49-73.
Koch GG, Carr GJ, Amara IA, Stokes ME, Uryniak TJ. Categorical Data Analysis. Chapter 
13 in Berry, D.A. (ed.).  Statistical Methodology in the Pharmaceutical 
Sciences. New York: Marcel Dekker, Inc., 1989:pp. 414-21. 


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10.
SOFTWARE
SAS® Software Version 9.X. SAS Institute Inc., Cary, NC, USA.


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


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12.
APPENDIX
Appendix 1.
Procedures Table for Study GS-US-426-3989
Assessments
Screeninga
Baseline / Day 1
On-treatment Visits
Follow-Up 
Visitb
(± 5 Days)
Week 1
± 3 days
Week 4
± 3 days
Week 8
± 3 days
Week 12/ETb
± 7 days
Clinical Assessments
Written Informed Consentc
X
Determine Eligibility 
X
X
Medical History
X
Physical Examination
X
Xd
Xd
Xd
Xd
Xd
Xd
Vital Signse including Weight
X
X
X
X
X
X
X
Height
X
Waist Circumference 
X
X
12- lead ECG
X
X
X
Ultrasoundf
X
MRE, MRI-PDFF
X
X
FibroScan®g
X
X
SF-36, WPAI, and CLDQ
Questionnairesh
X
X
Adverse Events
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
Dispense Study Drugs
X
X
X
Review of Study Drug Dosing 
Compliance (Pill Count)
X
X
X
X
Laboratory Assessments
Subject Fastingi
X
X
X
X
X
X
X


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Assessments
Screeninga
Baseline / Day 1
On-treatment Visits
Follow-Up 
Visitb
(± 5 Days)
Week 1
± 3 days
Week 4
± 3 days
Week 8
± 3 days
Week 12/ETb
± 7 days
Chemistry, Hematology, 
Coagulation Panel
X
X
X
X
X
X
X
Lipid Profile
X
X
X
X
X
X
Pregnancy Testj
X
X
X
X
X
X
Serum FSHk
X
Single PK Sampling
X
X
X
X
Hemoglobin A1c
X
X
X
Blood and Urine Collection 
(Biomarker)
X
X
X
X
Stool Collection (Biomarker)
X
X
Urine Drug Screeningl
X
HIV-1, HBV & HCVm Serology
X
Genomic Samplen
X
a
Screening assessments to be completed within 4 weeks prior to Day 1.  The Screening period also may be extended longer under special circumstances with the explicit 
approval of the Gilead Medical Monitor.
b
Subjects discontinuing treatment at any time for any reason (Early Termination – ET) should complete the procedures listed for the Week 12/ET visit AND the Follow-Up visit.
c
Obtain written informed consent before initiation of any screening procedure.
d
Symptom-driven physical examination
e
Vital signs include blood pressure, heart rate, respiration rate, and body temperature.
f
Ultrasound may be performed if necessary to confirm NAFLD.
g
Perform FibroScan® if available.
h
It is recommended that QoL questionnaires 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 questionnaire administration for subjects with QoL questionnaires available at Baseline/Day 1.
i
Subjects must be in a fasted state at least 8 hours prior to blood collection.
j
Females of childbearing potential only (See Appendix 3 in protocol). Serum pregnancy test at Screening and urine pregnancy test at all other visits, except Week 1.
k
l
Drug screen for amphetamines, cocaine, and opiates (i.e., heroin, morphine).
m
HCV Ab positive, reflex to HCV RNA. 
n
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Appendix 2.
Pooled Cohort Risk Score and Pooled Cohort Risk Calculation
No.
Parameters
Coefficient
Female
Male
White or 
Other
African 
America
White or 
Other
African 
America
1
Ln Age (y)
–29.799
17.114
12.344
2.469
2
Ln Age, Squared
4.884
N/A
N/A
N/A
3
Ln Total Cholesterol (mg/dL)
13.540
0.940
11.853
0.302
4
Ln Age × Ln Total Cholesterol
–3.114
N/A
–2.664
N/A
5
Ln HDL-C (mg/dL)
–13.578
–18.920
–7.990
–0.307
6
Ln Age × Ln HDL-C
3.149
4.475
1.769
N/A
7
Ln Treated Systolic BP (mm Hg)
2.019
29.291
1.797
1.916
8
Ln Age × Ln Treated Systolic BP
N/A
–6.432
N/A
N/A
9
Ln Untreated Systolic BP (mm Hg)
1.957
27.820
1.764
1.809
10
Ln Age × Ln Untreated Systolic BP
N/A
–6.087
N/A
N/A
11
Current Smoker (1=Yes, 0=No)
7.574
0.691
7.837
0.549
12
Ln Age × Current Smoker
–1.665
N/A
–1.795
N/A
13
Diabetes (1=Yes, 0=No)
0.661
0.874
0.658
0.645
A
Baseline Survival
0.9665
0.9533
0.9144
0.8954
B
Individual Sum = 
∑(coefficient*parameter) 
For each individual patient, individual sum is summation of product of each 
parameter and its corresponding coefficient for that sex-race group for all 
parameters listed above (#1 -#13).  
Note: N/A indicates that the specific coefficient is not available thus the 
corresponding parameter will not be included in calculation.
C
Group Wise Mean Sum of 
(Coefficient × parameter) 
Equal to the [sum of individual sum of all patients in sex- and race- specific 
group] divided by the [total number of patients in that sex- and race- specific 
group].
–29.18
86.61
61.18
19.54
D
Pooled Cohort Risk Score
= B – C 
= Individual Sum - Group Wise Mean Sum of (Coefficient × parameter)
E
Pooled Cohort Risk =Estimated 
probability of a first hard ASCVD 
event within 10 years *
= 1 - A˄exp(B-C)
= 1 - Baseline Survival ˄ exp (Individual Sum- Group wise mean sum) 
*
ASCVD = atherosclerotic cardiovascular disease; BP = blood pressure; HDL-C = high-density lipoprotein cholesterol; 
Ln = natural logarithm. Age is the actual age when the lab parameters are collected for the visit.. Total Cholesterol and 
HDL-C, Systolic BP are assessed at visit when risk score are collected. Smoker, Diabetes and status of hypertension 
treatment are collected at Screening/Baseline. Round Pooled Cohort Risk Score to 0.001. The lab parameters need to be 
measured from the same blood draw.
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Appendix 3.
Health Related QoL Score Calculation:

SF-36 (Short Form (36) Health Survey):
Scoring of the SF-36 scales will be performed as described in Chapter 6 of the SF-36 Health 
Survey Manual and Interpretation Guide, Version 2.  Summary will be done for 8 domains of 
the SF-36 (physical functioning, role-physical, bodily pain, general health, vitality, social 
functioning, role-emotional, and mental health), and for the physical component score and 
mental component summary. 

CLDQ (Chronic Liver Disease Questionnaire):
CLDQ scores are calculated using subject responses to 29 questions in the questionnaire. If 
Ri is the score for the patient’s response to the item i, for i=1, 2, …., 29 then the 6 domain 
scores are calculated as follows:
Abdominal (AB) = Mean of {R1, R5, R17}
Fatigue (FA) = Mean of {R2, R4, R8, R11, R13, R35}
Systemic (SY) = Mean of {R3, R6, R21, R23, R27, R36}
Activity (AC) = Mean of {R7, R9, R14, R30, R31}
Emotion (EM) = Mean of {R10, R12, R15, R16, R19, R20, R24, R26, R34}
Worry (WO) = Mean of {R18, R22, R25, R28, R29, R32, R33}
Here “Mean” is the average of nonmissing items (SAS mean function). Each score is 
calculated only if at least half of corresponding items are not missing. Otherwise, the score 
will be missing.
Overall CLDQ score is calculated by taking the mean of 6 domain scores {AB, FA, SY, AC, 
EM, WO}.  Overall CLDQ score will be summarized.

WPAI (Work Productivity and Activity Impairment): SHP
The response to Question 1 of this questionnaire provides the binary endpoint whether or not 
the subject had been in a paid employment during the week prior to assessment.
If the subject had been in a paid employment (Response to Q1 is “Yes”) at the visit when 
questionnaire was given, then following three scores are derived:
Percent work time missed (Absenteeism) = 100 × Q2 / (Q2 + Q4)
Percent impairment while working (Presenteesism) = 100 × Q5 / 10


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Percent overall work productivity loss =
Question 6 is applicable to all subjects:
Percent activity impairment  = 100 × Q6 / 10.
Percent overall work productivity loss and percent activity impairment will be summarized


















10
5
4
2
2
1
)
4
2
(
2
100
Q
Q
Q
Q
Q
Q
Q


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Appendix 4.
CTCAE Grade for Laboratory Parameters
CTCAE v4.03
CTCAE Grade
Adverse Event
1
2
3
4
5
Anemia
Hemoglobin (Hgb) <LLN -
10.0
g/dL; <LLN - 6.2 mmol/L; 
<LLN -
100 g/L
Hgb <10.0 - 8.0 g/dL; 
<6.2 - 4.9
mmol/L; <100 - 80g/L
Hgb <8.0 g/dL; <4.9 mmol/L;
<80 g/L; transfusion indicated
Life-threatening consequences;
urgent intervention indicated
Death
Hypoalbuminemia
<LLN - 3 g/dL; <LLN - 30 
g/L
<3 - 2 g/dL; <30 - 20 g/L
<2 g/dL; <20 g/L
Life-threatening consequences; 
urgent intervention indicated
Death
Alkaline phosphatase 
increased
>ULN – 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
-
Alanine 
aminotransferase 
(ALT) increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
-
Activated partial 
thromboplastin time 
(APTT) prolonged
>ULN - 1.5 x ULN
>1.5 - 2.5 x ULN
>2.5 x ULN; hemorrhage
-
-
Aspartate 
aminotransferase 
(AST) increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
-
Blood bilirubin 
increased
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 10.0 x ULN
>10.0 x ULN
-
Hypercalcemia
Corrected serum calcium of 
>ULN - 11.5 mg/dL; >ULN -
2.9mmol/L; Ionized calcium 
>ULN- 1.5 mmol/L
Corrected serum calcium 
of>11.5 - 12.5 mg/dL; 
>2.9 - 3.1 mmol/L; 
Ionized calcium >1.5 -1.6 
mmol/L; symptomatic
Corrected serum calcium of 
>12.5 - 13.5 mg/dL; >3.1 -
3.4 mmol/L; Ionized calcium 
>1.6 - 1.8 mmol/L; 
hospitalization indicated
Corrected serum calcium of 
>13.5 mg/dL; >3.4 mmol/L; 
Ionized calcium >1.8 mmol/L; 
life-threatening consequences
Death
Hypocalcemia
Corrected serum calcium of 
<LLN - 8.0 mg/dL; <LLN -
2.0 mmol/L; Ionized calcium 
<LLN - 1.0 mmol/L
Corrected serum calcium 
of <8.0 - 7.0 mg/dL; <2.0 -
1.75 mmol/L; Ionized 
calcium <1.0 - 0.9 
mmol/L; symptomatic
Corrected serum calcium of 
<7.0 - 6.0 mg/dL; <1.75 - 1.5 
mmol/L; Ionized calcium 
<0.9 - 0.8 mmol/L; 
hospitalization indicated
Corrected serum calcium of 
<6.0 mg/dL; <1.5 mmol/L; 
Ionized calcium <0.8 mmol/L; 
life-threatening consequences
Death


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Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 50
21 July 2017
CTCAE v4.03
CTCAE Grade
Adverse Event
1
2
3
4
5
Chronic kidney disease
eGFR (estimated Glomerular 
Filtration Rate) or CrCl 
(creatinine clearance) <LLN –
60 ml/min/1.73 m2 or 
proteinuria 2+ present; urine 
protein/creatinine >0.5
eGFR or CrCl 59 – 30 
ml/min/1.73 m2
eGFR or CrCl 29 – 15 
ml/min/1.73 m2
eGFR or CrCl <15 ml/min/1.73 
m2; dialysis or renal transplant 
indicated
Death
Creatinine increased
>1 - 1.5 x baseline; >ULN -
1.5 x ULN
>1.5 - 3.0 x baseline; >1.5 
- 3.0 x ULN
>3.0 baseline; >3.0 - 6.0 x 
ULN
>6.0 x ULN
-
Gamma-glutamyl 
transferase (GGT) 
increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
-
Hyperglycemia 
Fasting glucose value >ULN -
160 mg/dL; Fasting glucose
value >ULN - 8.9 mmol/L
Fasting glucose value 
>160 - 250 mg/dL; Fasting 
glucose value >8.9 - 13.9 
mmol/L
>250 - 500 mg/dL; >13.9 -
27.8 mmol/L; hospitalization
indicated
>500 mg/dL; >27.8 mmol/L; 
lifethreatening consequences
Death
Hypoglycemia
<LLN - 55 mg/dL; <LLN -
3.0 mmol/L
<55 - 40 mg/dL; <3.0 - 2.2 
mmol/L
<40 - 30 mg/dL; <2.2 - 1.7 
mmol/L
<30 mg/dL; <1.7 mmol/L; 
lifethreatening consequences; 
seizures
Death
Hemoglobin increased
Increase in >0 - 2 gm/dL 
above ULN or above baseline 
if baseline is above ULN
Increase in >2 - 4 gm/dL 
above ULN or above 
baseline if baseline is 
above ULN
Increase in >4 gm/dL above 
ULN or above baseline if 
baseline is above ULN
-
-
International 
normalized ratio (INR) 
increased
>1 - 1.5 x ULN; >1 - 1.5 
times above baseline if on 
anticoagulation
>1.5 - 2.5 x ULN; >1.5 -
2.5 times above baseline if 
on anticoagulation
>2.5 x ULN; >2.5 times 
above baseline if on 
anticoagulation
-
-
Hyperkalemia
>ULN - 5.5 mmol/L
>5.5 - 6.0 mmol/L
>6.0 - 7.0 mmol/L; 
hospitalization indicated
>7.0 mmol/L; life-threatening 
consequences
Death
Hypokalemia
<LLN - 3.0 mmol/L
<LLN - 3.0 mmol/L; 
symptomatic; intervention 
Indicated 
<3.0 - 2.5 mmol/L; 
hospitalization indicated
<2.5 mmol/L; life-threatening 
consequences
Death
Lymphocyte count 
decreased
<LLN - 800/mm3; <LLN -
0.8 x 10e9 /L
<800 - 500/mm3; <0.8 -
0.5 x 10e9 /L
<500 - 200/mm3; <0.5 - 0.2 x 
10e9 /L
<200/mm3; <0.2 x 10e9 /L
-


GS-0976
GS-US-426-3989
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 51
21 July 2017
CTCAE v4.03
CTCAE Grade
Adverse Event
1
2
3
4
5
Lymphocyte count 
increased
-
>4000/mm3 - 20,000/mm3
>20,000/mm3
-
-
Hypermagnesemia
>ULN - 3.0 mg/dL; >ULN -
1.23 mmol/L
-
>3.0 - 8.0 mg/dL; >1.23 -
3.30 mmol/L
>8.0 mg/dL; >3.30 mmol/L; 
lifethreatening consequences
Death
Hypomagnesemia
<LLN - 1.2 mg/dL; <LLN -
0.5 mmol/L
<1.2 - 0.9 mg/dL; <0.5 -
0.4 mmol/L
<0.9 - 0.7 mg/dL; <0.4 - 0.3 
mmol/L
<0.7 mg/dL; <0.3 mmol/L; 
lifethreatening consequences
Death
Neutrophil count 
decreased
<LLN - 1500/mm3; <LLN -
1.5 x 10e9 /L
<1500 - 1000/mm3; <1.5 -
1.0 x 10e9 /L
<1000 - 500/mm3; <1.0 - 0.5 
x 10e9 /L
<500/mm3; <0.5 x 10e9 /L
-
Hypophosphatemia
<LLN - 2.5 mg/dL; <LLN -
0.8 mmol/L
<2.5 - 2.0 mg/dL; <0.8 -
0.6 mmol/L
<2.0 - 1.0 mg/dL; <0.6 - 0.3 
mmol/L
<1.0 mg/dL; <0.3 mmol/L; 
lifethreatening consequences
Death
Platelet count 
decreased
<LLN - 75,000/mm3; <LLN -
75.0 x 10e9 /L
<75,000 - 50,000/mm3; 
<75.0 - 50.0 x 10e9 /L
<50,000 - 25,000/mm3; <50.0 
- 25.0 x 10e9 /L
<25,000/mm3; <25.0 x 10e9 /L
-
Hypernatremia
>ULN - 150 mmol/L
>150 - 155 mmol/L
>155 - 160 mmol/L; 
hospitalization indicated
>160 mmol/L; life-threatening 
consequences
Death
Hyponatremia
<LLN - 130 mmol/L
-
<130 - 120 mmol/L
<120 mmol/L; life-threatening 
consequences
Death
Hyperuricemia
>ULN - 10 mg/dL (0.59 
mmol/L) without physiologic 
consequences
-
>ULN - 10 mg/dL (0.59 
mmol/L) with physiologic 
consequences
>10 mg/dL; >0.59 mmol/L; 
lifethreatening consequences
Death
White blood cell 
(WBC) decreased
<LLN - 3000/mm3; <LLN -
3.0 x 10e9 /L
<3000 - 2000/mm3; <3.0 -
2.0 x 10e9 /L
<2000 - 1000/mm3; <2.0 - 1.0 
x 10e9 /L
<1000/mm3; <1.0 x 10e9 /L
-
Hypertriglyceridemia
150 mg/dL - 300 mg/dL; 1.71
mmol/L - 3.42 mmol/L
>300 mg/dL - 500 mg/dL; 
>3.42
mmol/L - 5.7 mmol/L
>500 mg/dL - 1000 mg/dL; 
>5.7
mmol/L - 11.4 mmol/L
>1000 mg/dL; >11.4 mmol/L;
life-threatening consequences
Death
Cholesterol high
>ULN - 300 mg/dL; >ULN -
7.75
mmol/L
>300 - 400 mg/dL; >7.75 -
10.34
mmol/L
>400 - 500 mg/dL; >10.34 -
12.92 mmol/L
>500 mg/dL; >12.92 mmol/L
-
Note: Refer to 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.


SAP GS-US-426-3989 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
PPD 
Clinical eSigned 
PPD 
Biostatistics eSigned 
Server Date 
yyyy-MM-dd hh:mm 
2017-07-28 09:22 
2017-07-28 17:38