Clinical trial NCT02891408
Conditions: Nonalcoholic Steatohepatitis (NASH)
Sponsor: Gilead Sciences
Start date: 2016-09-23; Completion date: 2019-05-13
Enrollment: 74 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of this study are to evaluate the single-dose pharmacokinetics (PK) of firsocostat in adults with normal hepatic function, and mild, moderate, or severe hepatic impairment and to evaluate the single-dose PK of fenofibrate in adults with normal hepatic function and mild hepatic impairment.

Detailed description:

Arms: arm 1: Participants with mild hepatic impairment will receive a single dose of firsocostat 20 mg (2 × 10 mg capsules). arm 2: Matched normal hepatic function participants to mild hepatic impairment participants will receive a single dose of firsocostat 20 mg (2 × 10 mg capsules). arm 3: Participants with moderate hepatic impairment will receive a single dose of firsocostat 20 mg (2 × 10 mg capsules). arm 4: Matched normal hepatic function participants to moderate hepatic impairment participants will receive a single dose of firsocostat 20 mg (2 × 10 mg capsules). arm 5: Participants with severe hepatic impairment will receive a single dose of firsocostat 5 mg (1 × 5 mg capsule). arm 6: Matched normal hepatic function participants to severe hepatic impairment participants will receive a single dose of firsocostat 5 mg (1 × 5 mg capsule). arm 7: Participants with mild hepatic impairment will receive a single dose of fenofibrate 48 mg (1 × 48 mg tablet). arm 8: Matched normal hepatic function participants to mild hepatic impairment participants, will receive a single dose of fenofibrate 48 mg (1 × 48 mg tablet).
Interventions: intervention 1: Firsocostat intervention 2: Fenofibrate
Intervention descriptions: intervention 1: Capsule(s) administered orally on Day 1 intervention 2: Tablet administered orally on Day 1

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 1 Open-Label, Parallel-Group, Single-Dose Study to 
Evaluate the Pharmacokinetics of GS-0976 or Fenofibrate in 
Subjects with Normal and Impaired Hepatic Function
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND No.:
Clinical Trials.gov 
Identifier:
124915
NCT02891408
Indication:
Nonalcoholic Steatohepatitis (NASH)
Protocol ID:
GS-US-426-3988
Gilead Medical Monitor:
Name:
Telephone:
Fax:
Cell:
Protocol Version/Date:
Original:
03 August 2016
Amendment 1:
01 September 2017
Amendment 2:
18 December 2018
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol.
You will not disclose any of the information to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
PPD
PPD
PPD
(r) GILEAU 


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Protocol GS-US-426-3988
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Amendment 2
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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....................................................................14
1.
INTRODUCTION ..............................................................................................................................................17
1.1.
Background ............................................................................................................................................17
1.2.
GS-0976 .................................................................................................................................................18
1.2.1.
General Information .............................................................................................................18
1.2.2.
Nonclinical Pharmacology ...................................................................................................18
1.2.3.
Nonclinical Toxicology........................................................................................................18
1.2.4.
Nonclinical Pharmacokinetics..............................................................................................19
1.2.5.
Clinical Trials of GS-0976 ...................................................................................................20
1.3.
Information about Fenofibrate ...............................................................................................................26
1.4.
Rationale for This Study ........................................................................................................................27
1.5.
Rationale for the Dose Selection of GS-0976 ........................................................................................28
1.6.
Rationale for Dose Selection of Fenofibrate ..........................................................................................28
1.7.
Risk/Benefit Assessment for the Study..................................................................................................29
1.8.
Compliance ............................................................................................................................................29
2.
OBJECTIVES.....................................................................................................................................................30
3.
STUDY DESIGN................................................................................................................................................31
3.1.
Study Design..........................................................................................................................................31
3.2.
Study Drug Administration ....................................................................................................................33
3.3.
Clinic Confinement ................................................................................................................................33
3.4.
Pharmacokinetic Assessments................................................................................................................33
3.4.1.
Plasma Pharmacokinetic Collection.....................................................................................33
3.4.2.
Safety Assessments ..............................................................................................................33
3.5.
Biomarker Testing..................................................................................................................................33
3.5.1.
Biomarker Samples to Address the Study Objectives:.........................................................33
3.6.
End of Study...........................................................................................................................................34
4.
SUBJECT POPULATION..................................................................................................................................35
4.1.
Number of Subjects and Subject Selection ............................................................................................35
4.2.
Inclusion Criteria....................................................................................................................................35
4.2.1.
All Subjects ..........................................................................................................................35
4.2.2.
Subjects with Impaired Hepatic Function ............................................................................36
4.2.3.
Healthy Matched Control Subjects.......................................................................................37
4.3.
Exclusion Criteria...................................................................................................................................38
4.3.1.
All Subjects ..........................................................................................................................38
4.3.2.
Subjects with Impaired Hepatic Function ............................................................................39
4.3.3.
Healthy Matched Control Subjects.......................................................................................40
5.
STUDY DRUGS.................................................................................................................................................41
5.1.
Enrollment..............................................................................................................................................41
5.2.
Description and Handling of GS-0976...................................................................................................41
5.2.1.
Formulation..........................................................................................................................41
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5.2.2.
Packaging and Labeling .......................................................................................................41
5.2.3.
Storage and Handling...........................................................................................................42
5.3.
Description and Handling of Fenofibrate...............................................................................................42
5.3.1.
Formulation..........................................................................................................................42
5.3.2.
Packaging and Labeling .......................................................................................................42
5.3.3.
Storage and Handling...........................................................................................................42
5.4.
Dosage and Administration of Study Drug ............................................................................................42
5.5.
Fasting and Meals ..................................................................................................................................43
5.6.
Dispensing, Accountability, and Disposal or Return of Study Drug......................................................43
5.7.
Concomitant Medications and Other Protocol Restrictions ...................................................................44
5.7.1.
Concomitant Medications.....................................................................................................44
5.7.2.
Other Protocol Restrictions ..................................................................................................46
6.
STUDY ASSESSMENTS...................................................................................................................................47
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................47
6.2.
Pretreatment Assessments......................................................................................................................50
6.2.1.
Screening Visit .....................................................................................................................50
6.2.2.
Admission Assessments .......................................................................................................50
6.3.
Check-in Assessments............................................................................................................................51
6.4.
Treatment Assessments..........................................................................................................................51
6.5.
Posttreatment Assessments ....................................................................................................................51
6.6.
Assessments for Premature Discontinuation from Study.......................................................................51
6.7.
Pharmacokinetic Assessments................................................................................................................51
6.7.1.
Plasma Pharmacokinetic Collection.....................................................................................51
6.7.2.
Protein Binding Samples......................................................................................................52
6.8.
Exploratory Biomarker Assessments .....................................................................................................52
6.10.
Safety Assessments ................................................................................................................................52
6.10.1.
Electrocardiogram Assessment ............................................................................................53
6.10.2.
Physical Examination...........................................................................................................53
6.10.3.
Vital Signs............................................................................................................................53
6.10.4.
Body Mass Index..................................................................................................................53
6.10.5.
Clinical Laboratory Tests/Assessments................................................................................53
6.10.6.
Creatinine Clearance ............................................................................................................54
6.10.7.
Adverse Events/Concomitant Medications/Protocol Restrictions........................................54
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................55
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................55
7.1.1.
Adverse Events.....................................................................................................................55
7.1.2.
Serious Adverse Events........................................................................................................55
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................56
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................56
7.2.2.
Assessment of Severity ........................................................................................................57
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................57
7.3.1.
Requirements for Collection Prior to Study Drug Initiation: ...............................................57
7.4.
Gilead Reporting Requirements.............................................................................................................58
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................59
7.6.
Toxicity Management ............................................................................................................................59
7.7.
Special Situations Reports......................................................................................................................60
7.7.1.
Definitions of Special Situations..........................................................................................60
7.7.2.
Instructions for Reporting Special Situations.......................................................................60
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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.
Secondary Endpoint .............................................................................................................62
8.2.
Analysis Conventions.............................................................................................................................62
8.2.1.
Analysis Sets ........................................................................................................................62
8.3.
Data Handling Conventions ...................................................................................................................63
8.4.
Demographic Data and Baseline Characteristics ...................................................................................63
8.5.
Interim Analysis.....................................................................................................................................63
8.6.
Safety Analysis.......................................................................................................................................63
8.6.1.
Extent of Exposure...............................................................................................................63
8.6.2.
Adverse Events.....................................................................................................................64
8.6.3.
Laboratory Evaluations ........................................................................................................64
8.6.4.
Other Safety Evaluations......................................................................................................64
8.7.
Pharmacokinetic Analysis......................................................................................................................64
8.8.
Sample Size............................................................................................................................................65
9.
RESPONSIBILITIES..........................................................................................................................................66
9.1.
Investigator Responsibilities ..................................................................................................................66
9.1.1.
Good Clinical Practice..........................................................................................................66
9.1.2.
Institutional Review Board/Independent Ethics Committee Review and 
Approval...............................................................................................................................66
9.1.3.
Informed Consent.................................................................................................................67
9.1.4.
Confidentiality......................................................................................................................67
9.1.5.
Study Files and Retention of Records ..................................................................................67
9.1.6.
Case Report Forms...............................................................................................................69
9.1.7.
Study Drug Accountability and Return ................................................................................69
9.1.8.
Inspections............................................................................................................................69
9.1.9.
Protocol Compliance............................................................................................................70
9.2.
Sponsor Responsibilities ........................................................................................................................70
9.2.1.
Protocol Modifications.........................................................................................................70
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................70
9.3.1.
Payment Reporting...............................................................................................................70
9.3.2.
Access to Information for Monitoring..................................................................................70
9.3.3.
Access to Information for Auditing or Inspections ..............................................................70
9.3.4.
Study Discontinuation..........................................................................................................70
10.
REFERENCES ...................................................................................................................................................71
11.
APPENDICES ....................................................................................................................................................73
Appendix 1.
Investigator Signature Page....................................................................................................74
Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................75
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............78
Appendix 4.
Child-Pugh Classification of Severity for Liver Disease......................................................100


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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 ................................................................................21
Table 1-2.
Summary of Single and Multiple Dose Pharmacokinetic Parameters of GS-0976 
Following Administration of 50 mg BID, 100 mg once daily, 100 mg BID, or 
200 mg once daily GS-0976 Under Fed Conditions...............................................................23
Table 1-3.
Summary of Single and Multiple Dose Pharmacokinetic Parameters of ND-011535 
Following Administration of 50 mg BID, 100 mg once daily, 100 mg BID, or 
200 mg once daily GS-0976 Under Fed Conditions...............................................................24
Table 1-4.
Preliminary Pharmacokinetic Results from Study GS-US-426-4074 Evaluating 
DDIs with GS-0976 (20 mg or 50 mg)...................................................................................26
Table 5-1.
List of Prohibited Medications ...............................................................................................45
Table 5-2.
List of Medications to be Used with Caution .........................................................................45
Table 6-1.
Schedule of Assessments........................................................................................................48
LIST OF IN-TEXT FIGURES
Figure 3-1.
High-Level Study Schema......................................................................................................32
Figure 3-2.
Cohort Study Schema.............................................................................................................32


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Amendment 2
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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 1 Open-Label, Parallel-Group, Single-Dose Study to 
Evaluate the Pharmacokinetics of GS-0976 or Fenofibrate in 
Subjects with Normal and Impaired Hepatic Function
IND Number:
Clinical Trials.gov 
Identifier:
124915
NCT02891408
Study Centers Planned:
Multiple Sites in the United States, Europe, and New Zealand
Objectives:
The primary objectives of this study are as follows:

To evaluate the single-dose pharmacokinetics (PK) of GS-0976 
in subjects with normal hepatic function, and mild, moderate, or 
severe hepatic impairment

To evaluate the single-dose PK of fenofibrate in subjects with
normal hepatic function and mild hepatic impairment 
The secondary objectives of this study are as follows:

To evaluate the safety and tolerability of GS-0976 single dose 
administration in subjects with normal hepatic function, and 
mild, moderate, or severe hepatic impairment

To evaluate the safety and tolerability of single dose fenofibrate 
administration in subjects with normal hepatic function and mild 
hepatic impairment 
Study Design:
Phase 1, open-label, single-dose, parallel-group, multi-center, 
pharmacokinetic (PK) study
Number of Subjects 
Planned:
Approximately 80 subjects (for 64 evaluable):
Cohort 1 (Mild Hepatic Impairment): Approximately 20 subjects 
(10 per group [mildly impaired and matched controls] for 
8 evaluable per group)
Cohort 2 (Moderate Hepatic Impairment): Approximately
20 subjects (10 per group [moderately impaired and matched 
controls] for 8 evaluable per group)
Cohort 3 (Severe Hepatic Impairment): Approximately
20 subjects (10 per group [severely impaired and matched controls] 
for 8 evaluable per group)


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Cohort 4 (Mild Hepatic Impairment): Approximately 20 subjects 
(10 per group [mildly impaired and matched controls] for 
8 evaluable per group)
A subject with normal hepatic function may serve as a matched 
control in Cohorts 1 and 2 but may only serve as a matched control 
to one hepatic impaired subject within a cohort.
Target Population:
Subjects with hepatic impairment will be enrolled based upon the 
Child-Pugh-Turcotte (CPT) classification system for mild hepatic 
impairment (CPT Class A; Cohort 1 and 4), moderate hepatic 
impairment (CPT Class B; Cohort 2), or severe hepatic impairment 
(CPT Class C; Cohort 3). The control group will consist of matched 
healthy subjects with normal hepatic function.
Duration of Dosing:
1 Day
Study Duration:
Up to 15 days (not including screening window)
Diagnosis and Main 
Eligibility Criteria:
Cohort 1 and 4 (Mild Hepatic Impairment): Male and 
non-pregnant/non-lactating female subjects, ages 18-70 years 
inclusive with mildly impaired and normal hepatic function. 
Subjects will be current non-smokers (no use of tobacco, 
nicotine-containing or THC-containing products within the last 
14 days). Each subject in the control group will be matched for age 
(± 10 years), gender, race, and body mass index (± 15% 18 < body 
mass index (BMI) < 36 kg/m2) with a subject in the mild hepatic 
impairment group. Subjects with mild hepatic impairment must have 
a score of 5-6 on the CPT Classification at Screening, have diagnosis 
of chronic (> 6 months), and stable hepatic impairment with no 
clinically significant changes within 3 months (or 90 days) prior to 
study drug administration (Day 1).
Cohort 2 (Moderate Hepatic Impairment): Male and 
non-pregnant/non-lactating female subjects, ages 18-70 years 
inclusive with moderately impaired and normal hepatic function. 
Subjects will be current non-smokers (no use of tobacco, 
nicotine-containing or THC-containing products within the last 
14 days). Each subject in the control group will be matched for age 
(± 10 years), gender, race, and body mass index 
(± 15% 18 < BMI < 36 kg/m2) with a subject in the moderate hepatic 
impairment group. Subjects with moderate hepatic impairment must 
have a score of 7-9 on the CPT Classification at Screening, have 
diagnosis of chronic (> 6 months), and stable hepatic impairment 
with no clinically significant changes within 3 months (or 90 days) 
prior to study drug administration (Day 1).


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Cohort 3 (Severe Hepatic Impairment): Male and 
non-pregnant/non-lactating female subjects, ages 18-70 years 
inclusive with severely impaired and normal hepatic function. 
Subjects will be current non-smokers (no smoking of tobacco, 
nicotine-containing or THC-containing products within the last 
14 days). Each subject in the control group will be matched for age 
(± 10 years), gender, race, and body mass index 
(± 15% 18 < BMI < 36 kg/m2) with a subject in the severe hepatic 
impairment group. Subjects with severe hepatic impairment must 
have a score of 10-15 on the CPT Classification at Screening, have 
diagnosis of chronic (> 6 months), and stable hepatic impairment 
with no clinically significant changes within 3 months (or 90 days) 
prior to study drug administration (Day 1).
Study Procedures/
Frequency:
Following completion of Screening and Day -2 admission 
assessments, eligible subjects will be enrolled in one of four cohorts
and will be administered the following study treatment on Day 1:

Cohorts 1 and 2: A single oral dose of 20 mg GS-0976 
(2 10 mg capsules)

Cohort 3: A single oral dose of 5 mg GS-0976 (1 5 mg tablet)

Cohort 4: A single oral dose of 48 mg fenofibrate (1 x 48 mg 
tablet)
In general, dosing in subjects with normal hepatic function will 
begin after a matched subject with hepatic impairment has 
completed all Day 1 PK assessments (eg, 96 hours postdose).
Cohorts 1 and 2 may be dosed in parallel, with dosing for Cohort 3 
(severe hepatic impairment) proceeding after review of safety and 
preliminary PK data (if available) from hepatic impaired subjects in 
the previous cohorts. Based on the cumulative review of safety and 
PK data from Cohorts 1 and 2, Cohort 3 may or may not be initiated 
at the discretion of the investigator and Sponsor.
Study Visits and Confinement
Following Screening and admission assessments, eligible subjects 
will be confined to the study center beginning Day -2 until the 
completion of assessments on Day 5. Subjects will return for a 
follow-up (FU) visit on Day 13 (± 2 days).


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Study Drug Administration
Study drug will be administered on Day 1 with 240 mL of water
following an overnight fast (no food or drinks except for water) for 
at least 10 hours. Subjects will continue to fast until after collection 
of the 4-hour PK sample, relative to study drug dosing. Additionally, 
subjects will be restricted from water consumption from 1 hour 
before through 2 hours after dosing, except for the water given with 
the study drug. A standardized meal may be provided to subjects 
after the 4-hour post-dose PK draw.
Pharmacokinetic Assessments
Plasma PK Collection
Intensive PK sampling will occur relative to dosing of GS-0976 or 
fenofibrate on Day 1 at the following time points for each cohort: 

Day 1: 0 (pre-dose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 
8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose
Plasma concentrations of GS-0976 or fenofibrate (and their 
metabolites, as applicable) will be determined and PK evaluated. 
Pharmacokinetic parameters will be estimated, as appropriate. 
A blood sample for PK analysis will be collected at the Early 
Termination (ET) visit (if applicable) and may be analyzed.
Exploratory Biomarker Assessments: 
 
 
 
 
 
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Protein Binding Samples
Plasma protein binding sampling will occur relative to dosing of 
GS-0976 or fenofibrate on Day 1 at the following time points for 
each cohort: 

Day 1: 1 and 3 hours post-dose
Plasma protein binding of GS-0976 or fenofibrate (and their 
metabolites as applicable) will be determined and summarized 
descriptively.
Safety Assessments
Complete physical exam: Screening and at the early termination 
(ET) visit (if applicable). 
Symptom-driven physical exam: Day -2, Day -1 (prior to biomarker 
sample collection), Day 1 (predose and approximately 4 hours 
postdose), Day 5, and at the FU visit.
Vital signs (blood pressure, heart rate, respiration rate, and body 
temperature): Screening, Day -2, Day -1 (prior to biomarker sample 
collection), Day 1 (predose and approximately 4 hours postdose), 
Day 5, and at the FU visit or ET visit (if applicable).
Height, Weight, and BMI: Screening
Clinical laboratory tests (hematology, chemistry, and urinalysis):
Screening, Day -2, Day 1, Day 5, and at the FU visit or ET visit 
(if applicable).
Note: On Day -2 (clinic admission), two sets of safety labs will be 
collected. One will be sent to the central lab and another will be sent 
to the sites' local lab to obtain results in time for enrollment on 
Day 1.
Coagulation tests (PT, PTT, INR): Screening and at the FU visit or 
ET visit (if applicable).
α-fetoprotein: Screening
Urine drug and alcohol assessments: Screening, Day -2, and at the 
FU visit or ET visit (if applicable).
12-lead electrocardiogram (ECG): Screening, Day -2, Day 1 
(predose and approximately 4 hours postdose), Day 5, and at the FU 
visit or ET visit (if applicable).
Serum pregnancy test (females of childbearing potential only): 
Screening and Day -2, Day 5, and at the FU visit or ET visit 
(if applicable).


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FSH (Female subjects ≤ 54 years old with amenorrhea 
> 12 months): Screening
Serology (Hepatitis B surface antigen [HBVsAg], Hepatitis C 
antibody [HCV-Ab], human immunodeficiency virus
(HIV)-1/2: Screening
Assessment of adverse events (AEs) and concomitant medications 
will continue throughout the study. All clinical and clinically 
significant laboratory toxicities will be managed according to 
uniform guidelines detailed in protocol Appendix 3.
 
 
 
 
 
Test Product, Dose, and 
Mode of 
Administration:
For Cohort 1 and 2, a single oral dose of 20 mg GS-0976 (2 10 mg 
capsule) administered on Day 1 
For Cohort 3, a single oral dose of 5 mg GS-0976 (1 5 mg tablet), 
administered on Day 1
For Cohort 4, a single oral dose of 48 mg fenofibrate (1 x 48 mg 
tablet), administered on Day 1
Reference Therapy, 
Dose, and Mode of 
Administration:
Not applicable
Criteria for Evaluation:
Safety:
Safety will be evaluated by physical examinations, vital signs, 
clinical laboratory tests and ECGs at various timepoints during the 
study, and by documentation of AEs.
Efficacy:
Not applicable.
Pharmacokinetics:
The following plasma PK parameters will be calculated for GS-0976
and fenofibrate (and their metabolites as applicable), as appropriate: 
% AUCexp, AUClast, AUCinf, Cmax, Tmax, Clast, Tlast, z, CL/F, Vz/F 
and t½.
Percent plasma protein binding will be determined and PK 
parameters adjusted for protein binding will be estimated.
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Statistical Methods:
Pharmacokinetics:
Plasma concentrations and PK parameters will be listed and 
summarized by hepatic function group within each cohort (normal 
and mildly impaired, moderately impaired, or severely impaired) 
using descriptive statistics (eg, sample size, arithmetic mean, 
geometric mean, % coefficient of variation [%CV], standard 
deviation [SD], median, minimum, and maximum). An analysis of 
variance (ANOVA) appropriate for a parallel design with hepatic 
function group as a fixed effect will be fit to the natural logarithmic 
transformation of PK parameters (AUClast, AUCinf, and Cmax) for 
each analyte. The 90% confidence intervals (CIs) will be constructed 
for the geometric least squares mean (GLSM) ratio of PK parameters 
for each analyte in the mild, moderate or severe hepatic impairment 
group versus the matched control (normal hepatic function) group.
Safety: 
The AE data will be listed by subject. Treatment-emergent AEs, 
serious adverse events (SAEs), and AEs leading to permanent study 
drug discontinuation will be summarized by hepatic function group
(according to study drug received), system organ class, and preferred 
term using the current version of the Medical Dictionary for 
Regulatory Activities (MedDRA). 
Listings of individual subject laboratory results will be provided. 
Laboratory results and change from predose values for selected lab 
tests will be summarized by hepatic function group (according to 
study drug received), at scheduled visits. The incidence of 
treatment-emergent laboratory abnormalities will be summarized by 
hepatic function group (according to study drug received).
Vital signs and ECG data will be summarized by hepatic function 
group.
Sample Size:
For cohorts 1 to 3, with 16 (8 per group) evaluable subjects, the 
estimated upper limit of one-sided 95% CI of the GLSM ratio of 
(mild, moderate or severe) hepatic impaired group vs control 
(normal hepatic function), with regards to AUCinf and Cmax, would 
be less than 200% with ≥ 72 and ≥ 57% probability, respectively, if 
the estimated GLSM ratio were 1.0. This is assuming a SD of no 
more than 0.588 for AUCinf and 0.722 for Cmax on a natural 
logarithm scale, supported by previous Gilead study 0976-101. With 
25% overage, a total sample size of 60 subjects (10 per group, 
20 per cohort) will be required.


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For cohort 4, with 16 (8 per group) evaluable subjects, the estimated 
two-sided 90% CI of the GLSM ratio of mild hepatic impaired group 
vs control (normal hepatic function), with regards to AUClast, AUCinf
and Cmax would be within [0.5, 2.0] with ≥ 90% probability, if the 
estimated GLSM ratio were 1.0. This is assuming a SD of no more 
than 0.387 on a natural logarithm scale, supported by information 
from Food and Drug Administration (FDA) {U. S. Food and Drug 
Administration 2004}. With 25% overage, a total sample size of 
20 subjects (10 per group) will be required.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
λz
terminal elimination rate constant, estimated by linear regression of the terminal 
elimination phase of the log concentration versus time curve of the drug
%AUCexp
percentage of AUC extrapolated between AUClast and AUCinf
%CV
percentage coefficient of variation
C 
degrees Celsius
F
degrees Fahrenheit
ACC
acetyl coenzyme A (acetyl-CoA) carboxylases
AE
adverse event
ALT
alanine aminotransferase (previously serum glutamic pyruvic transaminase
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUCinf
area under the concentration versus time curve extrapolated to infinite time, calculated as 
AUClast + (Clast/λz)
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
BID
twice a day
BMI
body mass index
BUN
blood urea nitrogen
CBC
complete blood count
CFR
Code of Federal Regulations
CI
confidence interval
CK
creatine kinase
CL/F
apparent oral clearance after administration of the drug:
CL/F = Dose/AUCinf, where “Dose” is the dose of the drug
Clast
last observed quantifiable concentration of the drug
CLcr
creatinine clearance
Cmax
maximum observed concentration of drug
CPK
creatine phosphokinase
CPT
Child-Pugh-Turcotte
CRF
case report form
CRO
contract (or clinical) research organization 
CSR
clinical study report
Ctau
observed drug concentration at the end of the dosing interval
CYP
cytochrome P450
DNA
deoxyribonucleic acid
DNL
de novo lipogenesis
EC
ethics committee
ECG
electrocardiogram


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eCRF
electronic case report form
EDC
electronic data capture
EudraCT
European Clinical Trials Database
eSAE
electronic serious adverse event
ET
early termination
EU
European Union
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
FU
follow-up
GCP
Good Clinical Practice
Gilead
Gilead Sciences, Inc.
GLSM
geometric least-squares mean
HBV
hepatitis B virus
HBsAb
hepatitis B surface antibody
HBSAg
hepatitis B surface antigen
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HDL
high-density lipoprotein
HDPE
high-density polyethylene
HI
hepatic impairment
HIV, HIV-1
human immunodeficiency virus, type 1
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
IEC
independent ethics committee
IND
investigational new drug (application)
IRB
institutional review board
IUD
intrauterine device
LDL
low-density lipoprotein
LLOQ
lower limit of quantitation
MAD
multiple ascending dose
MedDRA
Medical Dictionary for Regulatory Activities
MPR
metabolite-to-parent
NAFLD
Nonalcoholic fatty liver disease
NASH
nonalcoholic steatohepatitis
NDA
new drug application
NOAEL
no-observed-adverse-effects levels
NOEL
no-observed-effect level
PD
pharmacodynamic(s)


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PK
pharmacokinetic(s)
PTT
partial thromboplastin time
PVE
Pharmacovigilance and Epidemiology
QA
quality assurance
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
QTcF
QT interval corrected for heart rate using the Fridericia formulation
RBC
red blood cell
ROS
reactive oxygen species
SAD
single ascending dose
SADR
serious adverse drug reaction
SAE
serious adverse event 
SD
standard deviation
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
TIPS
transjugular intrahepatic portosystemic shunt
Tlast
time (observed time point) of Clast
Tmax
the time (observed time point) of Cmax
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 (λz)
ULN
upper limit of normal
US, USA
United States, United States of America
Vz/F
apparent volume of distribution of the drug
WBC
white blood cell
WHO
World Health Organization


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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, 


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as 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 investigator’s brochure (IB), including
information on the following:

Nonclinical pharmacokinetic (PK) and in vitro metabolism

Nonclinical pharmacology and toxicology

Clinical experience
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.


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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 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.
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 once daily 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.


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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.
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 PK profile in plasma and bile indicates 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 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 
 (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 
 (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 twice a day (BID) (100 mg daily) or placebo, 100 mg 
once daily (100 mg daily) or placebo, 100 mg BID (200 mg daily) or placebo, 200 mg once daily
(200 mg daily) or placebo, or 150 mg once daily (150 mg daily) or placebo. In each cohort, 
subjects received multiple oral doses of GS-0976 or placebo BID (every 12 hours) or once daily 
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. 
PPD
PPD--


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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 once daily, 
75% at 200 mg once daily, and 100% at 100 mg BID. One subject in the 200 mg once daily
cohort discontinued due to an AE on study Day 7 for Grade 4 elevated triglycerides. 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 once daily 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 once daily, 100 mg once daily, and 
200 mg once daily GS-0976 under fed conditions are presented Table 1-2 and Table 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 once daily 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 
once daily, 100 mg BID, or 200 mg once daily GS-0976 Under Fed 
Conditions
Plasma PK Parameter
Mean ± SD
GS-0976 Dose
50 mg BID Fed 
(N=6)
100 mg once daily 
Fed (N=6)
100 mg BID Fed 
(N=6)
200 mg once daily 
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 
once daily, 100 mg BID, or 200 mg once daily GS-0976 Under Fed 
Conditions
Plasma PK Parameter 
Mean ± SD
GS-0976 Dose
50 mg BID Fed 
(N=6)
100 mg once daily 
Fed (N=6)
100 mg BID Fed 
(N=6)
200 mg once daily 
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 
GS-0976 or matched placebo followed by a washout and administration of the opposite study 
medication in Period 2. 


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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 in response to oral fructose using 
[13C] acetate incorporation into palmitate and mass isotopomer distribution analysis. 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.
1.2.5.4.
Study GS-US-426-4074: Drug-Drug Interaction Study
Study GS-US-426-4074 is an ongoing, open-label, multiple-cohort study designed to evaluate 
transporter and CYP-mediated drug-drug interactions (DDIs) between GS-0976 (20 or 50 mg) 
and various probe drugs in healthy subjects.
Preliminary PK results from the following cohorts are presented below and in Table 1-4. The 
differences in PK parameters between subjects with hepatic impairment (test) versus healthy 
subjects (reference) were assessed using percent geometric mean ratios (%GMRs) and 
90% confidence intervals (CIs).
Cohort 1: Impact of OATP/MPR2/P-gp inhibition (single dose cyclosporine 600 mg: CsA) or 
OATP1B1/1B3 inhibition (single dose rifampin 600 mg: RIF) on single dose of GS-0976 20 mg 
(N=28). Single doses of CsA and RIF significantly increased GS-0976 exposure (21.2- and 
18.4-fold, respectively) and resulted in even greater increases in GS-834773 exposures 
(64.5- and 55.4-fold, respectively). These data indicate GS-0976 is a sensitive substrate of 
hepatic OATP with intestinal P-gp playing a minimal role in GS-0976 absorption as seen by a 
smaller increase in GS-0976 Cmax by CsA compared to single dose RIF.
Cohort 2: Impact of pan-UGT inhibition (probenecid 500 mg: PBC) and CYP3A4 inhibition
(voriconazole 200 mg: VORI) on single dose administration of GS-0976 20 mg (N=14).
Coadministration of GS-0976 with PBC resulted in a moderate increase in GS-0976 exposure


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(61%) indicating UGTs are involved in the metabolism of GS-0976. The moderate increase in 
GS-834773 exposure (74%) with PBC may be due to inhibition of other enzymes/transporters 
involved in the clearance of GS-834773. Coadministration of GS-0976 with VORI increased 
GS-0976 and GS-834773 exposures (37% and 44%, respectively) indication CYP3A4 plays a 
small role in the elimination of both parent and metabolite. 
Cohort 5: Impact of single and multiple doses of GS-0976 50 mg once daily on a sensitive 
CYP3A4 probe substrate (midazolam 2 mg: MDZ; N=12). Neither single dose nor multiple 
doses of GS-0976 altered MDZ exposure (90% CIs of the %GMR for AUC and Cmax with lack 
of effect bounds of 70-143%) indicating GS-0976 is not an inhibitor or inducer of CYP3A4.
Table 1-4.
Preliminary Pharmacokinetic Results from Study GS-US-426-4074 
Evaluating DDIs with GS-0976 (20 mg or 50 mg)
Inhibitor/Inducer 
Drug
GS-0976
%GMR (90% CIs)
GS-834773
%GMR (90% CIs)
AUCinf
Cmax
AUCinf
Cmax
CsA
2120 (1810, 2480)
2000 (1590, 2520)
6450 (5260, 7900)
7870 (6130, 10100)
RIF
1840 (1570, 2150)
2710 (2160, 3400)
5540 (4520, 6790)
10100 (7890, 13000)
PBC
161 (144, 180)
160 (132, 195)
174 (148, 204)
176 (145, 214)
VORI
137 (123, 152)
145 (119, 176)
144 (123, 170)
140 (116, 171)
MDZ + SD GS-0976
%GMR (90% CIs)
MDZ + MD GS-0976
%GMR (90% CIs)
AUCinf
Cmax
AUCinf
Cmax
GS-0976 (50 mg)
111 (99.8, 123)
102 (91.6, 115)
102 (91.4, 113)
106 (94.9, 119)
SD = single dose
MD = multiple dose
Data reported to 3 significant figures
1.3.
Information about Fenofibrate
Fenofibrate is a pro-drug of the active chemical moiety fenofibric acid which is a PPARα 
activator. Fenofibrate is indicated as an adjunct to diet to reduce elevated LDL-C, Total-C, 
triglyceride and ApoB, and to increase HDL-C in adult patients with primary 
hypercholesterolemia and for treatment of adult patients with severe hypertriglyceridemia. 
Fenofibrate is available as 48 or 145 mg tablets for once daily oral administration without regard 
to meals. The use of fenofibrate has not been evaluated in formal hepatic impairment studies; as 
such fenofibrate usage is contraindicated in subjects with active liver disease. However, use of 
fibrates (including fenofibrate) has been described in subjects with liver disease, including those 
with cirrhosis, due to primary biliary cholangitis. In these studies, the safety of fibrate therapy 
has been consistent with data in subjects without pre-existing liver disease {Corpechot 2018}.
Myopathy and rhabdomyolysis have been reported in patients taking fenofibrate (>2% and at 
least 1% greater than placebo. The risk for myopathy and rhabdomyolysis are increased when 
fibrates are co-administered with a statin, particularly in elderly patients and patients with 


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diabetes, renal failure, or hypothyroidism. Fenofibrate can increase serum transaminases and 
reversibly increase serum creatinine (>2% and at least 1% greater than placebo). Liver tests 
including ALT should be monitored periodically during therapy. Renal function should be 
monitored periodically in patients with renal impairment. Fenofibrate increases cholesterol 
excretion into the bile, which may lead to cholelithiasis. If cholelithiasis is suspected, gallbladder 
studies are indicated. Concomitant oral coumarin anticoagulants should be used with caution 
with fenofibrate. Dose of coumarin anticoagulants should be adjusted to maintain prothrombin 
time/INR at the desired level to prevent bleeding complications.
Further information regarding fenofibrate is available in the prescribing information.
1.4.
Rationale for This Study
Hepatic disease may alter absorption, disposition and elimination of drugs resulting in PK and 
subsequently PD changes. As such, the objective of this study is to investigate potential clinically 
relevant differences in the pharmacokinetics and safety of administration of a single dose of 
GS-0976 to subjects with mild (Class A), moderate (Class B) or severe (Class C) hepatic 
impairment (HI) as determined by Child-Pugh-Turcotte (CPT) classification {Pugh 1973}, 
compared to matched subjects with normal hepatic function with the goal to provide dosing 
recommendations for subjects with HI. Administration of GS-0976 as a single-dose is expected 
to accurately reflect alterations in PK under steady-state conditions and is thus deemed 
satisfactory for evaluation in this study.
The effect of hepatic impairment on the PK of fenofibrate has not been previously evaluated.
Thus, this study’s aim is to characterize the effect of mild hepatic impairment on fenofibrate PK 
by administration of fenofibrate as a single-dose to mild hepatic impaired subjects and matched 
control subjects with normal hepatic function. Administration of fenofibrate as a single-dose is 
expected to accurately reflect alterations in PK under-steady-state conditions and is thus deemed 
satisfactory for evaluation in this study.
This study design is consistent with recommendations as outlined in the FDA (Food and Drug 
Administration) Guidance for Industry entitled “Pharmacokinetics in Patients with Impaired
Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling” {U.S. 
Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER); Center for Biologics Evaluation and Research (CBER) 2003}. 
All subjects in the impairment group will have clinically manifested, confirmed, primary liver 
disease (and not HI due to some other cause). 
Evaluation of PK and safety of GS-0976 in mild and moderate HI will commence in parallel,
followed by evaluation of PK and safety of GS-0976 in subjects with severe HI.
The design of this study is supported by cumulative safety data in healthy subjects 
(Section 1.2.5) including administration of single doses of GS-0976 up to 1000 mg administered 
under fasted conditions (Study 0976-101). 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 well tolerated by
healthy subjects in these studies.


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Additionally, the trial will enroll healthy controls, matched for body mass index, age, race, and 
gender.
1.5.
Rationale for the Dose Selection of GS-0976
The proposed dose of GS-0976 (20 mg) in this study was selected for evaluation in an ongoing 
Phase 2 study in patients with NASH for 24 weeks (GS-US-426-3989), supported by the safety, 
tolerability and effects of GS-0976 from studies 0976-101, 0976-102, and 0976-103, and is 
50-fold lower than the highest single dose level previously evaluated (1000 mg) in study 
0976-101. Short-term safety data from clinical studies to date indicate that doses of GS-0976 up 
to 1000 mg (50-fold higher than the dose proposed in this study) were well tolerated with no 
clinically significant or treatment limiting adverse events or laboratory abnormalities. 
Based on preliminary data from studies 0976-101 (Section 1.2.5.1) and 0976-102 
(Section 1.2.5.2), GS-0976 exposures after administration of 20 mg GS-0976 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.
Thus, it is unlikely that plasma exposures of GS-0976 in subjects with mild or moderate hepatic 
impairment would exceed previously observed exposures in healthy volunteers or exceed 
exposures observed at the NOAEL in the toxicity studies. Based on preliminary PK data, 
GS-0976 plasma exposure was increased ~1.8- and ~8.7-fold in mild and moderate hepatic 
impairment, respectively. While GS-0976 20 mg was generally well-tolerated in the 
first 2 cohorts, a dose of 5-mg GS-0976 was selected for the severe hepatic impairment cohort to 
maintain adequate exposure margins. GS-0976 plasma exposures following a 5-mg dose of 
GS-0976 in subjects with severe hepatic impairment are unlikely to exceed previously observed 
exposures in healthy volunteers or those observed at the NOAEL in the toxicity studies and the 
exposure differences observed at 5-mg GS-0976 can be extrapolated to other dose levels of 
GS-0976.
Based on the known PK of GS-0976 across the range of doses evaluated, alterations of GS-0976 
PK observed in this study as a result of hepatic impairment are expected to reflect the magnitude 
of alteration of steady-state GS-0976 pharmacokinetics in subjects with NASH and HI.
1.6.
Rationale for Dose Selection of Fenofibrate
The dose of fenofibrate (48 mg) proposed for use in this study is the lowest dosage available, and 
is currently under evaluation in an ongoing Ph 2 study (GS-US-384-3914) in subjects with 
NASH. Only modest changes in exposure of fenofibrate or its metabolites are expected in 
subjects with mild hepatic impairment based on the known clearance mechanisms of fenofibrate 
and the effect of mild hepatic impairment on these mechanisms. In Gilead’s previous studies 
with simtuzumab in subjects with advanced fibrosis due to NASH (GS-US-321-0105, 
GS-US-321-0106), 32 out of 477 subjects (6.7%) were treated with fibrates during the trials. No 
clear safety signals were attributed to fibrate therapy in these subjects.


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1.7.
Risk/Benefit Assessment for the Study
Potential risks of a participant’s study involvement include unknown AEs, general risks 
associated with frequent clinic visits and laboratory blood draws, and the associated pain and 
discomfort of phlebotomy. Strategies to mitigate these risks include close monitoring of lab 
values as well as AEs. For this study, frequent assessments of hepatic function will also be 
performed from the collection of both blood and urine samples. Parameters for discontinuation of 
the study drug due to AEs will be well defined and closely followed.
There is no direct benefit to subjects participating in this study; however, data from this study 
will support the development of GS-0976 for the treatment of NASH. Potential benefits may 
include the participant’s contribution to understanding the safety and tolerability of a single-dose 
of GS-0976 and fenofibrate, how much GS-0976 and fenofibrate gets into the blood stream, and 
how these may differ in those with hepatic insufficiency.
Considering the above, the benefit-risk balance for this study is considered positive.
1.8.
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 objectives of this study are as follows:

To evaluate the single-dose PK of GS-0976 in subjects with normal hepatic function, and 
mild, moderate, or severe hepatic impairment

To evaluate the single-dose PK of fenofibrate in subjects with normal hepatic function and 
mild hepatic impairment 
The secondary objectives of this study are as follows:

To evaluate the safety and tolerability of GS-0976 single dose administration in subjects with 
normal hepatic function, and mild, moderate, or severe hepatic impairment

To evaluate the safety and tolerability of single dose fenofibrate administration in subjects 
with normal hepatic function and mild hepatic impairment 


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3.
STUDY DESIGN
3.1.
Study Design
This protocol describes a Phase 1, open-label, single-dose, parallel-group, PK study to evaluate 
the single-dose PK of GS-0976 or fenofibrate in subjects with normal and impaired hepatic
function and to evaluate the safety and tolerability of GS-0976 or fenofibrate single-dose 
administration in subjects with normal and impaired hepatic function. Approximately 80 subjects 
will be enrolled (for 64 evaluable). 
Cohort 1 (Mild Hepatic Impairment): Approximately 20 subjects (10 per group 
[mildly impaired and matched controls] for 8 evaluable per group)
Cohort 2 (Moderate Hepatic Impairment): Approximately 20 subjects (10 per group 
[moderately impaired and matched controls] for 8 evaluable per group)
Cohort 3 (Severe Hepatic Impairment): Approximately 20 subjects (10 per group 
[severely impaired and matched controls] for 8 evaluable per group)
Cohort 4 (Mild Hepatic Impairment): Approximately 20 subjects (10 per group 
[mildly impaired and matched controls] for 8 evaluable per group)
Eligible subjects include male and non-pregnant/non-lactating female subjects, ages 18-70 years 
inclusive with mildly impaired, moderately impaired, severely impaired, and normal hepatic 
function. Subjects will be current non-smokers (no use of tobacco, nicotine-containing or 
THC-containing products within the last 14 days). Each subject in the control group will be 
matched for age (± 10 years), gender, race, and body mass index (± 15% 18 ≤BMI ≤36 kg/m2) 
with a subject in the hepatic impairment group. A subject with normal hepatic function may 
serve as a matched control in Cohorts 1 and 2 but may only serve as a matched control to 
one hepatic impaired subject within a cohort.
Cohorts 1 and 2 may be dosed in parallel, with dosing for Cohort 3 (severe hepatic impairment) 
proceeding after review of safety and preliminary PK data (if available) from hepatically
impaired subjects in the previous cohorts. Based on the cumulative review of safety and PK data 
from Cohorts 1 and 2, Cohort 3 may or may not be initiated at the discretion of the investigator 
and Sponsor.
Dosing in subjects with normal hepatic function will begin after a matched subject with hepatic 
impairment has completed all Day 1 PK assessments (eg, 96 hours postdose). An overview of the 
study design is described below and shown in Figure 3-1.


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Figure 3-1. 
High-Level Study Schema 
Cohort 1 
Mild Hepatic -
Impairment 
20 mg GS-0976 
Available Safety and 
, 
preliminary PK data 
Cohort 2 
Moderate Hepatic -
Impairment 
20 mg GS-0976 
11 
Cohort 3 
Severe Hepatic 
Impairment 
5 mg GS-0976 
Cohort 4 
Mild Hepatic 
Impairment 
48 mg fenofibrate 
An overview of the coh01i study design is described below and shown in Figure 3-2. 
Figure 3-2. 
Cohort Study Schema 
Day -28 
-2 
-1 
l 
CONFIDENTIAL 
Screening 
• 
Dosing GS-09 6 or fenofibrat.e 
Biomarker Assessments (Cohort 3 only) 
Pharmacok:inetic Assessments. 
Clinic Confinement 
Fallow- p Period 
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• 
11 
15 
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3.2.
Study Drug Administration
Study drug will be administered on Day 1 with 240 mL of water following an overnight fast 
(no food or drinks except for water) for at least 10 hours. Subjects will continue to fast until after 
collection of the 4-hour PK sample, relative to study drug dosing. Additionally, subjects will be 
restricted from water consumption from 1 hour before through 2 hours after dosing, except for 
the water given with the study drug. A standardized meal may be provided to subjects after the 
4-hour post-dose PK draw.
Please refer to Section 5.3 for additional information for study drug dosage and administration.
3.3.
Clinic Confinement
Following screening and admission procedures, eligible subjects will be confined to the study 
center beginning Day -2 until the completion of assessments on Day 5. Subjects will return for a 
follow-up (FU) visit on Day 13 (± 2 days).
3.4.
Pharmacokinetic Assessments
Pharmacokinetic assessments will occur on assigned study days as outlined in Table 6-1 and 
Section 6.8.
3.4.1.
Plasma Pharmacokinetic Collection
Plasma concentrations of GS-0976 or fenofibrate (and their metabolites, as applicable) will be 
determined and PK parameters estimated. Pharmacokinetic parameters will be estimated, as 
appropriate.
3.4.2.
Safety Assessments
Safety assessments will be performed through the study as outlined in Table 6-1 and in 
Section 6.10.
3.5.
Biomarker Testing
3.5.1.
Biomarker Samples to Address the Study Objectives:
 
 
 
Biomarker samples will be collected as described in Table 6-1. Samples will be destroyed 
15 years after the end of the study.
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3.6.
End of Study
The end of this study will be the last subject’s last observation (or visit).
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 80 subjects will be enrolled in the study. Eligible subjects include healthy male 
and non-pregnant, non-lactating female subjects of 18 through 70 years of age, inclusive, with 
varying degrees of hepatic impairment and matched healthy controls. If necessary, replacement 
subjects may be enrolled with sponsor approval if subjects do not complete all intensive PK 
procedures. Replacement subjects will not be enrolled for subjects who discontinue the study due 
to study drug-related AEs.
Those subjects with hepatic impairment will be categorized based upon the CPT classification 
system for hepatic impairment as recommended by the United States FDA and international 
guidance documents {U.S. Department of Health and Human Services Food and Drug 
Administration Center for Drug Evaluation and Research (CDER); Center for Biologics 
Evaluation and Research (CBER) 2003}. Within the CPT system, subjects will be assigned to
Class A, B, or C (CPT Class A, B, or C) based on a cumulative score evaluating the presence and 
severity of hyperbilirubinemia, hypoalbuminemia, prolongation of INR for coagulation time, 
ascites, and hepatic encephalopathy. Classification of hepatic impairment will be assigned as 
follows:

Mild: Class A, CPT score of 5-6

Moderate: Class B, CPT score of 7-9

Severe: Class C, CPT score of 10-15
Based on CPT classification, subjects with hepatic impairment and healthy matched controls will 
be enrolled as described in Section 5.1. The control group will consist of matched healthy 
subjects with normal hepatic function. Each subject in the hepatic impairment group will be 
matched for age (± 10 years), gender, race, and BMI (± 15%, 18 ≤ BMI ≤ 36 kg/m2) with a 
subject in the healthy control group.
4.2.
Inclusion Criteria
4.2.1.
All Subjects
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1) Have the ability to understand and sign a written informed consent form (ICF), which must 
be obtained prior to initiation of study procedures.
2) Be aged 18 through 70 years of age, inclusive at Screening.
3) Have a calculated body mass index (BMI) of 18.0 and 36.0 kg/m2 at Screening.


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4) Have a creatinine clearance (CLcr) 80 mL/min (using the Cockcroft-Gault method 
{Cockcroft 1976}) based on serum creatinine and actual body weight as measured at 
screening, ie,
Male:
(140 – Age [years]) (Weight [kg]) CLcr (mL/min)
72 × (Serum Creatinine [mg/dL])
Female:
(140 – Age [years]) (Weight [kg]) 0.85 CLcr (mL/min)
72 (Serum Creatinine [mg/dL])
5) Be a non-smoker (no use of tobacco, nicotine-containing or THC-containing products within 
the last 14 days)
6) Females of childbearing potential (as defined in Appendix 2) must have a negative serum 
pregnancy test at Screening and on Day -2 (unless permanently sterile or greater than 2 years 
postmenopausal)
7) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in 
Appendix 2
8) Male subjects must refrain from sperm donation from clinic admission (eg, Day -2), 
throughout the study period, and continuing for at least 90 days following the last dose of 
study drug
9) Subjects have not donated blood within 56 days of study entry or plasma within 7 days of 
study entry and must refrain from blood donation from clinic admission, throughout the study 
period, and continuing for at least 30 days following the last dose of study drug.
10) Have either a normal 12-lead ECG or one with abnormalities that are considered clinically 
insignificant by the investigator
11) Must be willing and able to comply with all study requirements
4.2.2.
Subjects with Impaired Hepatic Function
Subjects with mild, moderate, or severe hepatic impairment must also meet the following 
additional inclusion criteria to be eligible for participation in the study:
12) Aside from hepatic insufficiency, the subject must, in the opinion of the investigator, be 
sufficiently healthy for study participation based upon medical history, physical examination,
vital signs, and screening laboratory evaluations
13) Must have diagnosis of chronic (> 6 months), stable hepatic impairment with no clinically
significant changes within 3 months (or 90 days) prior to study drug administration (Day 1)


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14) Must meet all of the following laboratory parameters at Screening:

ALT value ≤ 10 × ULN

AST value ≤ 10 × ULN

Absolute neutrophil count ≥ 1,000/mm3

Platelets ≥ 25,000/mm3

Hemoglobin ≥ 8 g/dL

α-fetoprotein ≤ 50 ng/mL
15) Subjects with mild hepatic impairment must have a score on the Child Pugh Turcotte scale of
5-6 at Screening. If a subject’s score changes during the course of the study, the score at
Screening will be used for classification
16) Subjects with moderate hepatic impairment must have a score on the Child Pugh Turcotte
scale of 7-9 at Screening. If a subject’s score changes during the course of the study, the
score at Screening will be used for classification
17) Subjects with severe hepatic impairment must have a score on the Child Pugh Turcotte scale
of 10-15 at Screening. If a subject’s score changes during the course of the study, the score at
Screening will be used for classification.
18) Subjects with hepatic impairment with comorbid diseases not associated with hepatic
impairment requiring medication(s) must be taking the medication(s) without a change in
dose for at least 4 weeks (or 5 half-lives, whichever is longer) prior to Screening. Any change
in the dosage during this timeframe should be reviewed and approved by the Sponsor.
4.2.3.
Healthy Matched Control Subjects
Healthy matched control subjects must also meet the following additional inclusion criteria to be 
eligible for participation in this study:
19) Must meet all of the following laboratory parameters at Screening:

INR ≤ 1 × ULN

Albumin ≥ 1 × LLN

Total bilirubin ≤ 1 × ULN

AST value ≤ 1 × ULN

ALT value ≤ 1 × ULN

Alkaline phosphatase ≤ 1 × ULN

α-fetoprotein ≤ 1 × ULN


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20) Must match in age (± 10 years), gender, race, and BMI (± 15% of ≥ 18 and ≤36) with the 
respective subject in the hepatic impairment group.
21) Must, in the opinion of the investigator, be in good health based upon medical history and 
physical examination, including vital signs.
4.3.
Exclusion Criteria
4.3.1.
All Subjects
Subjects who meet any of the following exclusion criteria will not be enrolled in this study:
1) Pregnant or lactating subjects
2) Have received any study drug or investigational compound within 30 days prior to study 
dosing
3) Have current alcohol or substance abuse judged by the investigator to potentially interfere 
with subject compliance or subject safety
4) Have a positive test result for human immunodeficiency virus type 1 (HIV-1/2) antibody
5) Have poor venous access that limits phlebotomy
6) Have been treated with systemic steroids, immunosuppressant therapies, or chemotherapeutic 
agents within 3 months prior to screening or is expected to receive these agents during the 
study (eg, corticosteroids, immunoglobulins, and other immune- or cytokine-based therapies)
7) Have a history of any of the following:
a) Significant serious skin disease, such as but not limited to rash, food allergy, eczema, 
psoriasis, or urticaria
b) Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity)
c) Known hypersensitivity to the study drugs their metabolites or to formulation excipients 
(see Section 5)
d) Significant cardiac disease (including history of myocardial infarction based on ECG 
and/or clinical history, any history of ventricular tachycardia, congestive heart failure, or 
dilated cardiomyopathy with left ventricular ejection fraction < 40%), a family history of 
long QT syndrome, or unexplained death in an otherwise healthy individual between the 
ages of 1 and 30 years
e) Syncope, palpitations, or unexplained dizziness


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f)
Severe peptic ulcer disease, gastroesophageal reflux disease, or other gastric acid 
hypersecretory conditions.
g) Medical or surgical treatment that permanently altered gastric absorption (eg, gastric or 
intestinal surgery). A history of cholecystectomy is not exclusionary. 
h) Implanted defibrillator or pacemaker
8) Are unable to comply with study requirements or are otherwise believed, by the study 
investigator, to be inappropriate for study participation for any reason.
4.3.2.
Subjects with Impaired Hepatic Function
Subjects with mild, moderate, or severe hepatic impairment meeting any of the following 
additional exclusion criteria are not to be enrolled in this study:
9) Aside from hepatic insufficiency, serious or active medical or psychiatric illness that, in the
opinion of the Investigator, would interfere with subject treatment, assessment, or
compliance with the protocol. This would include renal, cardiac, hematological, unstable
hepatic, pulmonary (including chronic asthma), endocrine (eg, diabetes), central nervous,
gastrointestinal (including an ulcer), vascular, metabolic (thyroid disorders, adrenal disease),
immunodeficiency disorders, active infection, or malignancy that are clinically significant or
requiring treatment.
10) Chronic hepatitis B virus (HBV) infection, defined as a positive test for hepatitis B surface
antigen (HBsAg), unless the patient has been treated with a nucleos(t)ide analog
(eg, tenofovir or entecavir) for at least 6 months and the HBV DNA by polymerase chain
reaction (PCR) assay has been persistently undetectable for at least 6 months.
11) Positive test for drugs of abuse, including alcohol at Screening or admission, with the 
exception of opioids and tetrahydrocannabinol (THC, marijuana) under prescription and
Investigator verification for pain management. Subjects who screen positive for
benzodiazepines may be allowed if prescribed under the care of a physician and after review
by Investigator and Sponsor.
12) Requires paracentesis > 1 time per month.
13) Subjects with hepatic impairment with comorbid diseases not associated with hepatic
impairment requiring medication(s) must be taking the medication(s) without a change in
dose for at least 4 weeks (or 5 half-lives, whichever is longer)prior to Screening. Any change 
in the dosage during this timeframe should be reviewed and approved by the Sponsor.
14) Changes in concomitant medications or dosage used to treat symptoms of hepatic impairment
or associated co-morbid conditions that could lead to clinically significant changes in
medical conditions during the course of the study that would affect the ability to interpret
potential drug-drug interactions within 28 days prior to dosing.


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15) Prior placement of a portosystemic shunt (such as TIPS), unless vascular imaging indicates 
the shunt has no current blood flow
16) For cohort 4, any contraindication to fenofibrate (other than mild hepatic impairment) per the 
approved package insert
All concomitant medications including over-the-counter and herbal products must be approved 
by the Investigator and Medical Monitor prior to study enrollment and study drug administration.
4.3.3.
Healthy Matched Control Subjects
Healthy matched controlled subjects meeting any of the following additional exclusion criteria 
are not to be enrolled in this study:
17) A positive test result for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) 
antibody
18) Positive test for drugs of abuse, including alcohol at Screening or admission.
19) Have any serious or active medical or psychiatric illness (including depression) that, in the 
opinion of the investigator, would interfere with subject treatment, assessment, or compliance 
with the protocol. This would include renal, cardiac, hematological, hepatic, pulmonary 
(including chronic asthma), endocrine (including diabetes), central nervous, gastrointestinal 
(including an ulcer), vascular, metabolic (thyroid disorders, adrenal disease), 
immunodeficiency disorders, active infection, or malignancy that are clinically significant or 
requiring treatment.
20) History of liver disease
21) Have taken any prescription medications or over-the-counter medications, including herbal 
products, within 28 days prior to start of study drug dosing, with the exception of vitamins 
and/or acetaminophen and/or ibuprofen and/or hormonal contraceptive medications.


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5.
STUDY DRUGS
5.1.
Enrollment
It is the responsibility of the investigator to ensure that the subject is eligible for the study prior 
to enrollment. Subjects will be assigned a screening number at the time of consent.
At screening, study participants will be assigned to a cohort within their respective part. Once 
eligibility has been confirmed following completion of the admission study procedures, eligible 
subjects will be assigned a subject number starting on Day 1 for Cohorts 1, 2 and 4 or on Day -1 
for Cohort 3, and will receive the study treatments as described in Section 5.3.
All screening and admission (Day -2) tests and procedures must be completed and reviewed by 
the investigator prior to the administration of the first dose of study drug on Day 1. Once a 
subject number has been assigned to a subject, it will not be reassigned to another subject. If 
necessary, replacement subjects may be enrolled after discussion and approval from sponsor. A 
new unique subject number will be assigned to the replacement subject. 
A subject number list will be provided to the study center by the sponsor.
5.2.
Description and Handling of GS-0976
5.2.1.
Formulation
GS-0976 capsules are white opaque size 0 hard gelatin capsules containing 10 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.
GS-0976 tablets are round, plain-faced, film-coated white tablets containing 5 mg GS-0976. In 
addition to the active ingredient, GS-0976 tablets contain the following inactive ingredients: 
lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, 
polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc, which are common 
pharmaceutical excipients.
5.2.2.
Packaging and Labeling
GS-0976 capsules are packaged in white, high density polyethylene (HDPE) bottles. Each bottle 
contains 30 or 200 capsules. Each bottle is enclosed with a white, continuous thread, 
child-resistant polypropylene screw cap with an induction-sealed and aluminum-faced liner.
GS-0976 tablets are packaged in white, high density polyethylene (HDPE) bottles. Each bottle 
contains 30 tablets and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child-resistant polypropylene screw cap with an induction-sealed and 
aluminum-faced liner.


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Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), EU Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal 
Products), and/or other local regulations.
5.2.3.
Storage and Handling
GS-0976 capsules and tablets should be stored at controlled room temperature of 25 °C (77 °F); 
excursions are permitted between 15 °C and 30 °C (59 °F and 86 °F). Storage conditions are 
specified on the label. Until dispensed to the subjects, all bottles of study drugs should be stored 
in a securely locked area, accessible only to authorized site personnel. 
To ensure the stability and proper identification, study drug(s) 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.
Description and Handling of Fenofibrate
5.3.1.
Formulation
Commercially available fenofibrate 48 mg will be used for the study. Information regarding the 
formulation of commercially available fenofibrate can be found in the prescribing information.
5.3.2.
Packaging and Labeling
Commercially available product of fenofibrate will be used for the study. Fenofibrate to be 
distributed to centers in the US and other participating countries shall be labeled to meet 
applicable requirements of the United States Food and Drug Administration (FDA), EU 
Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal Products), 
and/or other local regulations.
5.3.3.
Storage and Handling
Commercial product of fenofibrate will be used for the study. Further information regarding 
storage and handling are available in the Prescribing Information for commercial products.
5.4.
Dosage and Administration of Study Drug
On Day 1 of Cohorts 1 and 2, subjects will receive a single oral dose of 20 mg GS-0976 
(2 × 10 mg capsule). On Day 1 of Cohort 3, subjects will receive a single oral dose of 5 mg 
GS-0976 (1 × 5 mg tablet). On Day 1 of Cohort 4, subjects will receive a single oral dose of 
48 mg fenofibrate (1 × 48 mg tablet). Dosing in subjects with normal hepatic function will begin 
after a matched subject with hepatic impairment has completed all Day 1 PK assessments
(eg, 96 hours postdose).


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Cohorts 1 and 2 may be dosed in parallel, with dosing for Cohort 3 (severe hepatic impairment) 
proceeding after review of safety and preliminary PK data (if available) from hepatic impaired 
subjects in the previous cohorts. Based on the cumulative review of safety and PK data from 
Cohorts 1 and 2, Cohort 3 may or may not be initiated at the discretion of the investigator and 
Sponsor.
5.5.
Fasting and Meals
Study drug will be administered on Day 1 with 240 mL of water following an overnight fast 
(no food or drinks except for water) for at least 10 hours. Subjects will continue to fast until after 
collection of the 4-hour PK sample, relative to study drug dosing. Additionally, subjects will be 
restricted from water consumption from 1 hour before through 2 hours after dosing, except for 
the water given with the study drug. A standardized meal may be provided to subjects after the 
4-hour post-dose PK draw.
On Day -1 of Cohort 3, the timing of meals and meal compositions will be matched to Day 1.
All meals and/or snacks given to subjects during their stay in the clinical study facility will be 
standardized for all subjects and should be similar in calorie and fat content and taken at 
approximately the same time each day. All meals provided must be approved by the sponsor.
Components of meals (eg, margarine, jelly, bread) should be given to subjects in individual 
portions (eg, 1 tablespoon) per the approved meal schedule. The provision of meal components 
in bulk (eg, a jar of jelly for subjects to share) should not be practiced. All meals should be given 
at approximately the same time each day (eg, 07:30, 12:00, and 18:00).
5.6.
Dispensing, Accountability, and Disposal or Return of Study Drug
The investigator (or designee, eg, study center pharmacist) will acknowledge receipt of the study 
drug (after reviewing the shipment’s content and condition) from Gilead (or designee). The 
investigator will maintain an accurate inventory of all study drug(s). Each dose of the study 
drug(s) administered at the study center will be administered by qualified study center staff. The 
dose of study drug(s) administered to subjects in the clinic under the supervision of staff will be 
accurately recorded on the Study Drug Accountability form provided by Gilead (or on equivalent 
documentation maintained by the study center), which indicates the date and quantity of each 
dosage formulation dispensed to individual subjects.
Where possible, IMP should be destroyed at the site. If the site has an appropriate standard 
operating procedure (SOP) for drug destruction as determined by Gilead Sciences, the site may 
destroy used (empty or partially empty) and unused IMP supplies. A copy of the site’s IMP 
Disposal SOP or written procedure (signed and dated by the PI or designee) will be obtained for 
Gilead site files. If the site does not have acceptable procedures in place for drug destruction, 
study drug supplies can be sent back to GENCO Pharmaceutical Services.
For both options, the study monitor must first perform drug accountability during an on-site 
monitoring visit.


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5.7.
Concomitant Medications and Other Protocol Restrictions
5.7.1.
Concomitant Medications 
5.7.1.1.
Hepatic Impairment Groups
Concomitant use of certain medications or herbal/natural supplements with study drug may result 
in PK interactions resulting in increases or decreases in exposure of study drug or these 
medications. 
Concomitant medications taken within 30 days of Screening through the follow-up visit need to 
be recorded in the source documents and Case Report Form (CRF)/electronic Case Report Forms 
(eCRFs).
Subjects with hepatic impairment with comorbid diseases not associated with hepatic impairment 
requiring medication(s) must be taking the medication(s) without a change in dose for at least 
4 weeks (or 5 half-lives, whichever is longer) prior to Screening. Any change in the dosage 
during this timeframe should be reviewed and approved by the Sponsor.
All concomitant medications including over-the-counter and herbal products must be approved 
by the Investigator and Medical Monitor prior to study enrollment and study drug administration.
The following medications are prohibited from 28 days prior to Day 1 through discharge:

Any and all illegal or illicit drug use, including use of prescription drugs outside the care of 
the prescribing physician.

Hematologic stimulating agents (eg, erythropoiesis-stimulating agents [ESAs]; granulocyte 
colony stimulating factor [GCSF]; thrombopoietin [TPO] mimetics)

Chronic systemic immunosuppressants including, but not limited to, corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal 
antibodies (eg, infliximab). Use for ≤ 2 weeks total is allowed.

Investigational agents or devices for any indication

Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers 
of drug transporters P-gp, or OATP1B3 or 1B3 or inhibitors/inducers of UGT enzymes) 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 Day 1 through discharge are listed below in Table 5-1:


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Table 5-1.
List of Prohibited Medications
Drug Class
Agents Disallowed
Antibiotics
Azithromycin, Clarithromycin, Erythromycin
Acid Reducing Agents
Proton-Pump Inhibitors, H2-Receptor Antagonists, Antacidsa
Anticonvulsantsb
Phenobarbital, Phenytoin, Carbamazepine, Oxcarbazepine
Antifungals
Itraconazole, Ketoconazole
Antimycobacterialsb
Rifamycins, Isoniazid
Cardiac Medications
Bosentan
Herbal/Natural Supplementsb
St. John’s Wort, Echinaccea. Milk thistle (i.e. silymarin), Chinese herb 
sho-saiko-to (or Xiao-Shai-Hu-Tang)
Other
Modafinil, Probenecid
a
Proton pump inhibitors can be taken up to 7 days before study drug dosing (Day 1), H2-receptor antagonists can be taken up 
to 3 days before study drug dosing (Day 1). Antacids that directly neutralize stomach pH (ie, Tums, Maalox) are permitted 
but may not be taken within 4 hours (before or after) of study drug administration.
b
May result in a decrease in the concentrations of study drug.
Medications for disease conditions excluded from the protocol (eg, HIV-1, HBV, or HCV
infection, active cancer, transplantation) are not listed under this Concomitant Medication 
section and are disallowed in the study.
5.7.1.2.
Medications to be used with Caution with Fenofibrate
The prescribing information for fenofibrate should be consulted for medications that are 
prohibited and/or to be used with caution with fenofibrate.
Examples of representative medications that should be used with caution are listed in Table 5-2.
Table 5-2.
List of Medications to be Used with Caution
Drug Class
Use with Caution
Anticoagulantsa
Coumarin, coumadin, warfarin
Anti-gout agentsb
Colchicine
Bile acid sequestrantsc
Cholestyramine, colestipol, colesevelem
Lipid modifying agentsd
Simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, 
cerivastatin, rosuvastatin, pitavastatin
a
Fenofibrate can increase PT/INR. Increased frequency of PT/INR assessments when the subject is started on fenofibrate is at
the investigators discretion. Monitor and adjust anticoagulant dose as necessary based on prescribing information.
b
Concomitant use of colchicine with fenofibrates can increase the risk of rhabodmyolysis
c
Bile acid sequestrants are permitted but may not be taken within 4 hours (before or after) study drug administration.
d
Concomitant use of statins with fenofibrates can increase the risk of rhabodmyolysis


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5.7.1.3.
Subjects with Normal Hepatic Function
The following medications are excluded while subjects with normal hepatic function are 
participating in the study:

Any prescription medications or over-the-counter medications including herbal products and 
antacids within 28 days of commencing study drug dosing (Day 1) with the exception of 
vitamins, acetaminophen, ibuprofen and/or hormonal contraceptives. However, the short 
term use of topical hydrocortisone cream or A&D ointment to treat minor skin irritation due 
to ECG leads will be allowed. If a subject requires use of a disallowed medication, a request 
for such use must be reviewed by the Sponsor and if approved, subjects may continue to 
participate in the study. 

Any and all illegal or illicit drug use, including use of prescription drugs outside the care of 
the prescribing physician.
5.7.2.
Other Protocol Restrictions

Subjects will be required to refrain from smoking nicotine or nicotine-containing products
and THC-containing products for at least 14 days prior to first dose of study drug, and during
the course of the study through the follow-up visit.

Subjects will be required to refrain from the consumption of food and beverages containing 
alcohol products 72 hours prior to the first dose of study drug and during the course of the 
study through the follow-up visit.

Subjects will be required to refrain from consumption of grapefruit juice, grapefruits, and 
Seville orange juice 72 hours prior to the first dose of study drug and during the course of the 
study through the follow-up visit.

While confined at the study center, tea, coffee, chocolate, and other foods and beverages 
containing caffeine and other methyl xanthines will be prohibited on each dosing day. At all 
other times, caffeine-containing beverages and foodstuffs may be served or withheld in 
accordance with normal study center practice. Caffeine-containing beverages and foodstuffs 
will not be restricted while subjects are outside of the clinic.

Subjects will be encouraged to avoid strenuous or prolonged exercise, as well as saunas, 
steambaths, and sunbathing or other prolonged ultraviolet exposure (eg, in a tanning salon)
from the screening evaluation until completion of the follow-up visit, as these activities are 
known to affect certain clinical laboratory test parameters, (eg, creatine kinase) and will 
provide false indicators of a potentially treatment-related toxicity. 
Upon every admission to the clinic, each subject will be questioned as to their compliance with 
the above protocol restrictions. If a subject is unable to comply with any of the restrictions 
described above, the subject’s continued participation in the study will be reevaluated by the 
investigator in consultation with the sponsor.


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6.
STUDY ASSESSMENTS
The study procedures to be conducted for each subject enrolled in the study are detailed below.
Any deviation from protocol procedures should be noted in the subject’s clinical chart and 
appropriate CRFs/ eCRFs. In addition, the sponsor should be promptly notified of any protocol 
deviations. 
The study center will not initiate dosing until the following have all been met:

The institutional review board (IRB)/ethics committee (EC)/other applicable regulatory 
agencies have reviewed and approved the study and the informed consent document.

All requested regulatory documents have been submitted to and approved by Gilead.

A master services agreement and/or study agreement is executed.

The study initiation meeting has been conducted by the Gilead (or designee).
The initiation meeting will include but is not limited to a review of the protocol, the IB, study 
drugs, and investigator responsibilities.
Documentation of the personally signed and dated ICF for each subject, using the study-specific,
IRB/EC-approved ICF, is required before initiating the screening process. 
6.1.
Subject Enrollment and Treatment Assignment
Entry into screening does not guarantee enrollment into the study. In order to manage the total 
trial enrollment, Gilead, at its sole discretion, may suspend screening and/or enrollment at any 
site or trial wide at any time.
It is the responsibility of the investigator to ensure that subjects are eligible to participate in the 
study prior to enrollment and continue to remain eligible throughout the study.
Once informed consent has been obtained, all screening and admission tests and assessments
have been assessed, and study eligibility has been confirmed, subjects will be enrolled to receive 
study drug on Day 1.
Subjects will receive the study treatments as described in Section 5.3.


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Table 6-1.
Schedule of Assessments
Study Procedure
Screena
Day -2
Day -1
Day 1
Days 2-4
Day 5b
Day 13 (± 2 days)c
ETd
Written Informed Consent
X
Medical History 
X
Complete Physical Exam
X
X
Symptom-Driven Physical Examinatione
X
Xq
Xf
X
X
Height, Weight, BMI
X
Vital Signsg
X
X
Xq
Xf
X
X
X
HIV-1, HBV, and HCV Testing
X
Hematologyh
X
Xk
X
X
X
X
Chemistryh
X
Xk
X
X
X
X
Coagulationh
X
X
X
α-fetoprotein
X
Urinalysis 
X
Xk
X
X
X
X
Serum Pregnancy Testi
X
Xk
X
X
X
FSHj
X
Urine Drug and Alcohol Screen 
X
Xk
X
X
12-Lead ECG
X
X
Xf
X
X
X
Enrollment
Xl
X
Study Drug Administration
X
PK Assessmentsm
X
X
Biomarker Assessmentsp
X
X
Review Study Restrictions
X
X
X 
X
X
CCI


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Amendment 2
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Study Procedure
Screena
Day -2
Day -1
Day 1
Days 2-4
Day 5b
Day 13 (± 2 days)c
ETd
Clinic Confinement
X
Review AEs & Concomitant Medicationso
X
a
Prospective subjects should be screened no more than 28 days prior to administration of the first dose of study drug.
b
Subjects will be discharged from the clinic on Day 5, following all morning assessments.
c
Subjects will return for a follow-up visit on Day 13 (± 2 days).
d
Assessments will be performed within 72 hours of early termination from the study.
e
Symptom-driven PEs will be performed during confinement as needed, based on reported signs and symptoms.
f
Predose and approximately 4 hours postdose
g
Vital signs include blood pressure, heart rate, respiration rate, and body temperature.
h
Hematology, Chemistry, Coagulation: See Section 6.10.5.1 for specifics.
i
Females of child-bearing potential only.
j
Female subjects ≤ 54 years old with amenorrhea > 12 months as outlined in Appendix 2
k
Two sets of safety labs will be collected upon clinic admission; one will be sent to the central lab and another will be sent to the sites' local lab to obtain results in time for 
enrollment on Day 1.
l
Subjects of Cohort 3 will be enrolled on Day -1.
m
Intensive PK sampling will occur relative to dosing of GS-0976 or fenofibrate on Day 1 at the following time points for each cohort:
Day 1: 0 (pre-dose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose
A blood sample for PK analysis will be collected at the Early Termination (ET) visit (if applicable) and may be analyzed.
Plasma protein sampling will occur relative to dosing of GS-0976 or fenofibrate on Day 1 at the following time points for each cohort:
Day 1: 1 and 3 hours post-dose
o
From the time of obtaining informed consent through the first administration of study drug, record all SAEs, as well as any nonserious AEs related to protocol-mandated 
procedures on the AE CRF/eCRF.
All other untoward medical occurrences observed during the screening period, including exacerbation or changes in medical history, are to be captured on the medical history 
CRF/eCRF. See Section 7, Adverse Events and Toxicity Management for additional details.
p
Biomarker sampling will be collected relative to the planned or actual dosing time of GS-0976 at the following time points for Cohort 3 only: 
Day -1: 0, 1, 2, 3, 4, 6, 8, 12, and 16 hours postdose (relative to planned Day 1 dosing time)
Day 1: 0 (*pre-dose, ≤ 5 minutes prior to dosing), 1, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose 
*Pre-dose sample on Day 1 will also serve as 24 hour postdose sample on Day -1. 
q
Prior to biomarker sample collection (Cohort 3 only)
CCII 


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Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
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6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Prospective subjects should be screened no more than 28 days prior to administration of the 
first dose of study drug. If a subject does not begin the treatment phase within this 28-day 
window, all screening evaluation procedures must be repeated. Screening laboratory assessments 
may be repeated once within 28 days prior to administration of study drug to rule out laboratory 
error.
A sufficient number of subjects will be screened to identify up to 80 subjects for enrollment.
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.
Written informed consent must be obtained from each subject before initiation of any screening 
procedure. After a subject has provided informed consent, the investigator and other study 
personnel will determine if the subject is eligible for participation in the study. This assessment 
will include a review of the inclusion/exclusion criteria and completion of all screening 
procedures as outlined in Table 6-1 and described in the following text. 
Eligible subjects meeting all of the inclusion criteria and none of the exclusion criteria will be 
instructed on all protocol requirements, including the restrictions on concomitant medication 
usage and other substances as well as consumption of food or beverages containing alcohol, 
caffeine, or xanthine. Subjects will be asked to arrive at the study center on Day -2 for admission 
assessments.
From the time of obtaining informed consent through the first administration of study drug, 
record all SAEs, as well as any AE related to protocol-mandated procedures on the AE 
CRF/eCRF. All other untoward medical occurrences observed during the screening period, 
including exacerbation or changes in medical history are to be captured on the medical history 
CRF/eCRF. See Section 7 Adverse Events and Toxicity Management for additional details.
6.2.2.
Admission Assessments
6.2.2.1.
Admission
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.
Subjects meeting all eligibility criteria following the screening evaluation will return to the clinic 
for admission assessments on Day -2. The admission evaluations and/or procedures are outlined 
in Table 6-1.


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Prior to dosing on Day 1, the results of the clinical and laboratory evaluations (as described in 
Table 6-1) must be reviewed by the investigator to confirm the continued eligibility of each 
subject to participate in the study. At the time of enrollment, subjects will be assigned a 
sequential subject number as described in Section 5.1. Subjects will remain confined to the study 
clinic for the duration as described in Section 6.2.2.2 and Table 6-1.
6.2.2.2.
Clinic Confinement
Subjects will be confined to the study clinic starting on Day -2 until completion of assessments 
on Day 5. Subjects will return for a FU visit on Day 13 (± 2 days).
6.3.
Check-in Assessments
Following completion of screening and Day -2 assessments, eligible subjects will be assigned a 
subject number and receive study treatments as shown in Section 5.3.
6.4.
Treatment Assessments
Study procedures and assessments are outlined in Table 6-1.
6.5.
Posttreatment Assessments
Subjects will return for a FU visit on Day 13 (± 2 days). Posttreatment assessments are outlined 
in Table 6-1.
6.6.
Assessments for Premature Discontinuation from Study
If the subject discontinues prematurely from the study, the ET evaluations and/or procedures 
outlined in Table 6-1 should be performed within 72 hours of permanently discontinuing the 
study drug.
6.7.
Pharmacokinetic Assessments
6.7.1.
Plasma Pharmacokinetic Collection
Intensive PK sampling will occur relative to dosing of GS-0976 or fenofibrate on Day 1 at the 
following time points for each cohort: 

Day 1: 0 (pre-dose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 
and 96 hours post-dose
A blood sample for PK analysis will be collected at the Early Termination (ET) visit 
(if applicable) and may be analyzed.
Plasma concentrations of GS-0976 or fenofibrate (and their metabolites, as applicable) will be 
determined and PK evaluated. Pharmacokinetic parameters will be estimated, as appropriate.


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6.7.2.
Protein Binding Samples
Plasma protein binding sampling will occur relative to dosing of GS-0976 or fenofibrate on 
Day 1 at the following time points for each cohort: 

Day 1: 1 and 3 hours post-dose
Plasma protein binding of GS-0976 or fenofibrate (and their metabolites, as applicable) will be 
determined and summarized descriptively.
6.8.
Exploratory Biomarker Assessments
 
 
 
 
 
 
 
 
 
6.10.
Safety Assessments
Safety will be evaluated throughout the study. Refer to Table 6-1 for a schedule of assessments.
CCI
CCI
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6.10.1.
Electrocardiogram Assessment
Subjects should rest quietly in the supine position for a minimum of 10 minutes prior to each 
scheduled ECG acquisition and should remain in that position until the recording is complete.
There should be no environmental distractions (including TV, radio, video games, and 
conversation) while the subjects are resting prior to and during the recordings. 
Electrocardiograms will be recorded using the site’s standard ECG equipment. All ECGs will be 
obtained using instruments that analyze data using the same algorithms and produce the same 
data for interpretation. Electrode placement will be performed according to the method of 
Wilson, Goldberger, and Einthoven with a check to confirm that the aVR lead is not inverted.
The investigator or other qualified individuals at the study center will review ECGs to assess for 
changes in ECG intervals and morphology as compared with pretreatment ECGs. ECG interval 
measurements output by the machine will be used for bedside safety monitoring.
Collection of additional ECGs for routine safety monitoring at additional time points or days is at 
the discretion of the investigator based on GCP.
6.10.2.
Physical Examination
Physical examinations conducted throughout the study will be a complete physical examination 
or a symptom-directed physical examination, as outlined in Table 6-1. The complete physical 
examination conducted at screening will also include the following assessments:

Review medical history, including history of allergies, prior and current use of nicotine or 
nicotine-containing products, alcohol and illegal drug use, and prior (within 30 days) and 
current medication use
6.10.3.
Vital Signs
Vital sign measurements include blood pressure, heart rate, respiration rate, and temperature and 
should be taken once subjects have been seated or in the supine position. Subject position for 
measurement should be kept consistent throughout the study. Refer to Table 6-1 for vital signs 
collection time points.
6.10.4.
Body Mass Index
Height and weight will be collected at screening for calculation of BMI for inclusion criteria.
6.10.5.
Clinical Laboratory Tests/Assessments
Blood and urine samples for safety evaluations will be collected throughout the study as outlined 
in Table 6-1.
On Day -2 (clinic admission), two sets of safety labs will be collected. One will be sent to the 
central lab and another will be sent to the sites' local lab to obtain results in time for enrollment 
on Day 1.


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6.10.5.1.
Blood Sampling
Blood samples will be collected for the following laboratory analyses:

Hematology: CBC with differentials

Chemistry (fasting): alkaline phosphatase, AST, ALT, creatine phosphokinase (CPK)
(Cohort 4 only), GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, 
bicarbonate, blood urea nitrogen (BUN), calcium, chloride, creatinine (see below), glucose, 
phosphorus, magnesium, potassium, sodium, uric acid, total cholesterol, high-density 
lipoprotein-cholesterol (HDL-c), low-density lipoprotein--cholesterol (LDL-c), triglycerides, 
and amylase (reflex lipase testing is performed in subjects with total amylase > 1.5 × upper 
limit of normal [ULN]

Coagulation: PT, PTT, INR

α-fetoprotein

HIV-1/2, HBVaAg, and HCV-Ab testing

Serum pregnancy test (females of childbearing potential only)

Follicle-stimulating hormone (FSH) testing (Female subjects ≤ 54 years old with amenorrhea
> 12 months)
6.10.5.2.
Urine Samples
Urine samples will be collected for urinalysis and alcohol and drug screen assessments.
6.10.6.
Creatinine Clearance
Weight will be collected at Screening to calculate creatinine clearance (CLcr) for inclusion 
criteria.
6.10.7.
Adverse Events/Concomitant Medications/Protocol Restrictions
Evaluation for AEs, review of concomitant medications, and review of protocol restrictions will 
occur at the times shown in Table 6-1. See Section 7 for more information regarding AEs and 
Sections 4.3 and 5.7.1 for more information about concomitant medications.


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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 study drug, 
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 study drug, whether or not considered related to the study drug. Adverse events 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 7.7.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and that is 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 CRF/eCRF.
7.1.2.
Serious Adverse Events
A 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.)

Inpatient hospitalization or prolongation of existing hospitalization


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction; such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.2.
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 
drug using clinical judgment and the following considerations:

No: Evidence exists that the AE has an etiology other than the study drug. 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 drug.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the AE has an etiology other than the study procedure.

Yes: The AE occurred as a result of protocol procedures (eg, venipuncture).


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7.2.2.
Assessment of Severity
AE severity should be recorded and graded according to the modified GSI Grading Scale for
Severity of Adverse Events and Laboratory Abnormalities (see Appendix 3 for more 
information). 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.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
7.3.1.
Requirements for Collection Prior to Study Drug Initiation:
After obtaining informed consent, but prior to initiation of study drug, all SAEs and AEs related 
to protocol-mandated procedures should be reported on the CRF/eCRF.
7.3.1.1.
Adverse Events
Following initiation of study treatment, collect all AEs, regardless of cause or relationship, until 
30 days after last administration of study drug must be reported to the CRF/eCRF database as 
instructed.
All AEs should be followed up until resolution or until the AE is stable, if possible. Gilead 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 
CRF/eCRF database and Gilead Pharmacovigilance and Epidemiology (PVE) as instructed. This 
also includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.
Any SAEs and deaths that occur after the posttreatment follow-up visit but within 30 days weeks 
of the last dose of study drug, regardless of causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol-defined follow-up period;
however, if an investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of study drug, the investigator should promptly 
document and report the event to Gilead PVE.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.


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7.3.1.3.
Electronic Serious Adverse Event Reporting Process 

Site personnel record all SAE data in the CRF/eCRF database and from there transmit the 
SAE information to Gilead PVE within 24 hours of an investigator’s knowledge of the event. 
Detailed instructions may be found in the CRF/eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically 
(eg, the CRF/eCRF database is not functioning), record the SAE on the paper SAE reporting 
form and submit within 24 hours as described below.
Gilead PVE:
Fax:
E-mail:

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
CRF/eCRF database according to instructions in the CRF/eCRF completion guidelines.

If an SAE has been reported via a paper form because the CRF/eCRF database has been 
locked, no further action is necessary.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by email or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
form.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable United States 
(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 expedite to worldwide regulatory agencies reports of SAEs, serious adverse 
drug reactions (SADRs), or SUSARs. In accordance with the EU Clinical Trials Directive 
(2001/20/EC), Gilead or a specified designee will notify worldwide regulatory agencies and the 
relevant independent ethics committee (IEC) in concerned member states of applicable SUSARs
as outlined in current regulations.
PPD
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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 drug. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (eg, clinical chemistry, hematology, and urinalysis) independent of the underlying 
medical condition that require medical or surgical intervention or lead to investigational 
medicinal product interruption or discontinuation must be recorded as an AE, as well as an SAE, 
if applicable. In addition, laboratory or other abnormal assessments (eg, electrocardiogram, 
X rays, vital signs) that are associated with signs and/or symptoms must be recorded as an AE or 
SAE if they meet the definition of an AE (or SAE) as described in Sections 7.1.1 and 7.1.2. If the 
laboratory abnormality is part of a syndrome, record the syndrome or diagnosis (ie, anemia) not 
the laboratory result (ie, decreased hemoglobin).
Severity should be recorded and graded according to the modified GSI Grading Scale for 
Severity of Adverse Events and Laboratory Abnormalities as described in Appendix 3. The 
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities has been 
modified to be more appropriate for healthy volunteers and patients with inflammatory diseases 
(eg, rheumatoid arthritis, asthma, psoriasis). 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.
7.6.
Toxicity Management
Treatment-emergent toxicities will be noted by the investigator and brought to the attention of 
the Gilead medical monitor, who will have a discussion with the investigator and decide the 
appropriate course of action. 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.
Grade 3 and 4 clinically significant laboratory abnormalities should be repeated to confirm 
toxicity grade and followed until resolution or until stable, if possible. 
Any questions regarding toxicity management should be directed to the Gilead MM.


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7.7.
Special Situations Reports
7.7.1.
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.
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 that is above the maximum recommended dose 
as per protocol or in the product labeling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
Occupational exposure is defined as exposure to a medicinal product as a result of one’s 
professional or non-professional occupation.
7.7.2.
Instructions for Reporting Special Situations
7.7.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study drug and throughout the study, including the poststudy drug follow-up period, 
to Gilead PVE using the pregnancy report form within 24 hours of becoming aware of the 
pregnancy.
Refer to Section 7.3 and the CRF/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.


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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 PVE.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead PVE using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead PVE by emailing
 or faxing
 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead PVE using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead PVE by faxing
 or emailing
Refer to Appendix 2, Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.7.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead PVE within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study drug and/or Gilead concomitant 
medications but do not apply to non-Gilead concomitant medications.
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.
PPD
PPD
PPD
PPD


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objectives of this study are as follows:

To evaluate the single-dose PK of GS-0976 in subjects with normal hepatic function, and 
mild, moderate, or severe hepatic impairment

To evaluate the single-dose PK of fenofibrate in subjects with normal hepatic function and 
mild hepatic impairment
The secondary objectives of this study are as follows:

To evaluate the safety and tolerability of GS-0976 single dose administration in subjects with 
normal hepatic function, and mild, moderate, or severe hepatic impairment

To evaluate the safety and tolerability of single dose fenofibrate administration in subjects 
with normal hepatic function and mild hepatic impairment 
8.1.2.
Primary Endpoint
The primary endpoints are the PK parameters AUClast, AUCinf, and Cmax of GS-0976 or
fenofibrate (and their metabolites, as applicable). Additional PK parameters calculated include: 
% AUCexp, Tmax, Clast, Tlast, z, CL/F, Vz/F, and t½ as appropriate.
8.1.3.
Secondary Endpoint
The secondary endpoints include the incidence of AEs and laboratory abnormalities.
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Safety
The Safety Analysis Set will include all enrolled subjects who received at least 1 dose of study 
drug. Subjects who received treatment other than that to which they were assigned will be 
analyzed according to the treatment received.


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8.2.1.2.
Pharmacokinetics
The PK Analysis Set will include all enrolled subjects who received at least 1 dose of study drug
and had at least 1 nonmissing PK concentration datum reported by PK lab for each respective 
analyte.
8.3.
Data Handling Conventions
For summary statistics, PK concentration values below the limit of quantitation will be treated as 
zero at predose and 1-half of the lower limit of quantitation (LLOQ) for postdose time points.
Laboratory data that are continuous in nature but are less than the LLOQ or above the upper limit 
of quantitation will be imputed to the value of the lower or upper limit minus or plus
1 significant digit, respectively (eg, if the result of a continuous laboratory test is < 20, a value of 
19 will be assigned; if the result of a continuous laboratory test is < 20.0, a value of 19.9 will be 
assigned).
Missing data can have an impact upon the interpretation of the study data. As this study is of 
short duration, it is anticipated that missing data will be minimal. In general, values for missing 
data will not be imputed. However, a missing pretreatment laboratory result would be treated as 
normal (ie, no toxicity grade) for the laboratory abnormality summary.
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized and descriptive statistics will be 
provided by hepatic function groups (according to the study drug received).
8.5.
Interim Analysis
There is no formal interim analysis in this study.
8.6.
Safety Analysis
All safety data collected on or after the date that study drug was first administered up to the date 
of last dose of study drug plus 30 days will be summarized by hepatic function group
(according to the study drug received) using safety analysis set. 
8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug data will be generated from the study drug
administration page in CRF/eCRF. Exposure data will be listed.


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8.6.2.
Adverse Events
Clinical and laboratory AEs will be coded using the MedDRA. System organ class (SOC), 
high-level group term, high-level term, preferred term (PT), and lower-level term will be 
attached to the clinical database.
Adverse event data will be listed by subject. Treatment-emergent AEs (TEAEs), serious TEAEs, 
and TEAEs leading to discontinuation of treatment will be summarized by hepatic function 
group (according to the study drug received), SOC, and PT using the current version of 
MedDRA. 
8.6.3.
Laboratory Evaluations
Listings of individual subject laboratory results will be provided. Laboratory results and change 
from predose values for selected lab tests will be summarized by hepatic function group 
(according to the study drug received) at scheduled visits. The incidence of treatment-emergent 
graded laboratory abnormalities will be summarized by hepatic function group (according to the 
study drug received).
8.6.4.
Other Safety Evaluations
Vital signs and ECG data will be listed by subject and visit and will be summarized by hepatic 
function group (according to the study drug received) and visit.
8.7.
Pharmacokinetic Analysis
Plasma concentrations and PK parameters will be listed and summarized for GS-0976 or 
fenofibrate (and their metabolites as appropriate) using descriptive statistics by hepatic function 
group. 
In addition, an analysis of variance model with hepatic function group as a fixed effect will be 
fitted to the natural logarithmic transformation of PK parameters (AUClast, AUCinf, and Cmax) for 
each analyte within each cohort. Two-sided 90% CIs will be calculated for the ratios of GLSMs
of PK parameters for each analyte between mild, moderate or severe hepatic impairment group
and the control (normal hepatic function) group. If the upper bound of the two-sided 90% CIs of 
the GLSM ratio for AUClast, AUCinf, and Cmax is smaller than 2.0, the null hypothesis that 
subjects with mild, moderate or severe hepatic impairment exhibit average PK parameter 
increases of at least 100% for each analyte compared with subjects with normal hepatic function 
will be rejected.
GS-0976 or fenofibrate percent protein binding will be summarized by hepatic function group 
and data for individual subjects will be presented in a listing. Unbound PK parameters such as 
CLu/F and Vzu/F will be calculated and summarized by hepatic function group (according to the 
study drug received). Relationships between measures of hepatic function (ie, CPT score, serum 
albumin, total bilirubin, prothrombin time and INR) and PK parameters will be evaluated.


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Amendment 2
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8.8.
Sample Size
For cohorts 1 to 3, with 16 (8 per group) evaluable subjects, the estimated upper limit of 
one-sided 95% CI of the GLSM ratio of (mild, moderate or severe) hepatic impaired group vs 
control (normal hepatic function), with regards to AUCinf and Cmax, would be less than 200% 
with ≥72 and ≥ 57% probability, respectively, if the estimated GLSM ratio were 1.0. This is 
assuming a SD of no more than 0.588 for AUCinf and 0.721 for Cmax on a natural logarithm scale, 
supported by previous Gilead study 0976-101. With 25% overage, a total sample size of 
60 subjects (10 per group, 20 per cohort) will be required.
For cohort 4, with 16 (8 per group) evaluable subjects, the estimated two-sided 90% CI of the 
GLSM ratio of mild hepatic impaired group vs control (normal hepatic function), with regards to 
AUClast, AUCinf and Cmax would be within [0.5, 2.0] with ≥ 90% probability, if the estimated 
GLSM ratio were 1.0. This is assuming a SD of no more than 0.387 on a natural logarithm scale, 
supported by information from FDA {U. S. Food and Drug Administration 2004}. With 25% 
overage, a total sample size of 20 subjects (10 per group) will be required.


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Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
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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 Harmonization (ICH) guidelines, or with the laws 
and regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the EU Clinical Trials 
Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice (GCP), 
as outlined in 21 Code of Federal Regulations (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 drug under study. This 
documentation must be provided prior to the investigator’s (and any subinvestigator’s) 
participation in the study. The investigator and subinvestigator agree to notify Gilead of any 
change in reportable interests during the study and for 1 year following completion of the study. 
Study completion is defined as the date when the last subject completes the protocol-defined 
activities.
9.1.2.
Institutional Review Board/Independent Ethics Committee Review and 
Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, ICF, 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/EC. The investigator will not begin any study subject activities until approval 
from the IRB/IEC 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/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/EC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.


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


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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 enrolled

Participation in study (including study number)

Study discussed and date of informed consent

Dates of all visits

Documentation that protocol specific procedures were performed

Results of efficacy parameters, as required by the protocol

Start and end dates (including dose regimen) of study drug, including dates of dispensing and 
return

Record of all AEs and other safety parameters (start and end dates, and including causality 
and severity)

Concomitant medication (including start and end dates, dose if relevant, and 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.


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9.1.6.
Case Report Forms
For each subject enrolled, an CRF/eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. The CRF/eCRF 
should be completed on the day of the subject visit to enable the sponsor to perform central 
monitoring of safety data, whenever possible. The Eligibility Criteria CRF/eCRF should be 
completed only after all data related to eligibility have been received and the subject has been 
enrolled. Subsequent to data entry, a study monitor will perform source data verification within 
the electronic data capture (EDC) system. Original entries as well as any changes to data fields 
will be stored in the audit trail of the system. Prior to database lock (or any interim time points as 
described in the clinical data management plan), the investigator will use his/her login
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 
the information in the source documents. The CRF/eCRF captures the data required per the 
protocol schedule of events and procedures. System-generated or manual queries will be issued 
to the investigative site staff as data discrepancies are identified by the monitor or internal Gilead 
staff who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (eg, data entry error). At the conclusion of the study, Gilead will provide the site 
with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.5.
9.1.7.
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 SOP for drug destruction as determined by Gilead quality 
assurance (QA), the site may destroy used (empty or partially empty) and unused study drug
supplies in accordance with that site’s approved SOP. A copy of the site’s approved SOP will be 
obtained for central files. 
If study drug is destroyed on site, the investigator must maintain accurate records for all study 
drug destroyed. Records must show the identification and quantity of each unit destroyed, the 
method of destruction, and the person who disposed of the study drug. Upon study completion, 
copies of the study drug accountability records must be filed at the site. Another copy will be 
returned to Gilead.
The study monitor will review study drug supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this study to 
Gilead’s appointed study monitors, to IRB/EC, or to regulatory authority or health authority 
inspectors.


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Amendment 2
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9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to IRB/EC in 
accordance with local requirements and receive documented IRB/EC approval before 
modifications may be implemented.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol (eg, attendance at investigator's meetings). If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to federal and state agencies any 
expenses paid or reimbursed for such services, including any clinical study payments, meal, 
travel expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/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 CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both Gilead 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 subjects, 
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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Gilead Sciences, Inc.
Amendment 2
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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.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Corpechot C, Chazouilleres O, Rousseau A, Le Gruyer A, Habersetzer F, Mathurin P, et al. A 
Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis. N Engl J 
Med 2018;378 (23):2171-81.
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.
Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial 
fibrillation: the Framingham study. N Engl J Med 1982;306 (17):1018-22.
Koek GH, Liedorp PR, Bast A. The role of oxidative stress in non-alcoholic steatohepatitis. Clin 
Chim Acta 2011;412 (15-16):1297-305.
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.
Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
Oesophagus for Bleeding Oesophageal Varices. Br J Surg 1973;60 (8):646-9.
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.


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Gilead Sciences, Inc.
Amendment 2
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U. S. Food and Drug Administration. Center for Drug Evaluation and Research. Tricor 
(Fenofibrate) Tablets. Application Number: 21-656. Clinical Pharmacology and 
Biopharmaceutics Review(s). Available at: 
https://www.accessdata.fda.gov/drugsatfda docs/nda/2004/021656s000 TricorT
OC.cfm. 05 November, 2004.
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER); Center for Biologics Evaluation and Research 
(CBER). Guidance for Industry. Pharmacokinetics in Patients with Impaired 
Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and 
Labeling. May, 2003.
Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history 
of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. 
Aliment Pharmacol Ther 2011;34 (3):274-85.
Voulgari C, Tentolouris N, Papadogiannis D, Moyssakis I, Perrea D, Kyriaki D, et al. Increased 
left ventricular arrhythmogenicity in metabolic syndrome and relationship with 
myocardial performance, risk factors for atherosclerosis, and low-grade 
inflammation. Metabolism: clinical and experimental 2010;59 (2):159-65.
Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with 
analysis of risk factors. Hepatology 1990;12 (5):1106-10.
Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, et al. Prevalence of 
nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely 
middle-aged population utilizing ultrasound and liver biopsy: a prospective study. 
Gastroenterology 2011;140 (1):124-31.
Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing 
indication for liver transplantation in patients with hepatocellular carcinoma in the 
U.S. Hepatology 2014;59 (6):2188-95.
Yeh MM, Brunt EM. Pathological features of fatty liver disease. Gastroenterology 2014;147 
(4):754-64.


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Amendment 2
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 4.
Child-Pugh Classification of Severity for Liver Disease


PPD
PPD
GS-0976 
Protocol GS-US-426-3988 
Final 
Gilead Sciences, Inc. 
Amendment 2 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 1 Open-Label, Parallel-Group, Single-Dose Study to Evaluate the Pharmacokinetics of 
GS-0976 or Fenofibrate in Subjects with Normal and Impaired Hepatic Function 
GS-US-426-3988, Amendment 2, 18 December 2018 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Medical Monitor 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page74 
18 December 2018 


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Appendix 2.
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 postmenopausal, 
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
No formal studies have been conducted to evaluate the reproductive toxicity of GS-0976; 
therefore, the reproductive toxicity of GS-0976 in humans is unknown. However, mutant mice 
lacking ACC1, one of the targets of GS-0976, are embryonically lethal. Therefore, GS-0976 is 
contraindicated in pregnancy. Preclinical data in human hepatocytes indicate that GS-0976 is a 
mild inducer of CYP3A4 isoenzymes. Clinical data demonstrates no decrease in exposure of a 
representative oral hormonal contraceptive indicating no loss of contraceptive efficacy is 
expected upon administration of GS-0976 with hormonal contraceptives. Information regarding 
fenofibrate is available in the fenofibrate prescribing information.
b) Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures. They must have a negative serum pregnancy test at screening and at the 
check-in visit prior to enrollment; subsequently, serum pregnancy tests will be performed on 
Day 5, and at the FU visit or ET visit (if applicable). Female subjects must agree to one of the 
following from screening until 30 days after the last dose of study drug.


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
Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle. 
Or

Consistent and correct use of 1 of the following methods of birth control listed below.
Intrauterine device (IUD) with a failure rate of <1% per year
Intrauterine hormone-releasing system (IUS) with a failure rate of <1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Or

Consistent and correct use of one hormonal method and one barrier method
Barrier methods
■
Diaphragm with spermicide
■
Cervical cap with spermicide
■
Male condom (with or without spermicide)
Hormonal methods
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone
■
Implants of levonorgestrel
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the last dose of study drug.


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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 study drug.
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 drug.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 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 for female partners of male 
subjects) of last study drug dose. Subjects who become pregnant or who suspect that they are 
pregnant during the study must report the information to the investigator and discontinue study 
drug immediately. Subjects whose partner has become pregnant or suspects she is pregnant 
during the study must report the information to the investigator. Instructions for reporting 
pregnancy, partner pregnancy, and pregnancy outcome are outlined in Section 7.7.2.1.


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Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric,
≥ 7 Months#
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 79
18 December 2018
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0%
#
An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects. Please follow the Gilead convention of grading 
any result within the LLN and ULN a 0.


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 80
18 December 2018
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L
2.0 t o <2.5 mmolL
2.0 mEq/L
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant <1 Year
>ULN to 6.0 mEq/L
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 81
18 December 2018
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL
1.74 to <1.94 mmolL
6.1 to <7.0 mg/dL
1.51 to < 1.74 mmolL
< 6.1 mg/dL
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88 mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10 mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23 mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38 mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 82
18 December 2018
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypomagnesemia
1.40 to <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to 1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63 to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 83
18 December 2018
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypouricemia 
Adult and Pediatric
≥ 1 year
Infant < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL 
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L
Bicarbonate
Adult and Pediatric 
≥ 4 Years
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/Lto <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to 4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL
**
An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs. Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 84
18 December 2018
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 85
18 December 2018
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 

Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to 
Dipstick Hematuria.

With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.

If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 86
18 December 2018
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 87
18 December 2018
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV 
block OR Ventricular pause 
3.0 sec
Complete AV block 
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block 
Type II 2nd degree AV 
block 
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (eg, pulmonary 
embolism, life-threatening 
thrombus) 
Vasovagal Episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 88
18 December 2018
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Bronchospasm (acute)
FEV1 or peak flow reduced to 
70% to 80%
FEV1 or peak flow 50% to 69%
FEV1 or peak flow 25% to 
49% 
Cyanosis OR FEV1 or peak flow 
25% OR Intubation
Dyspnea or Respiratory 
Distress
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities 
Dyspnea on exertion causing 
greater than minimal interference 
with usual social & functional 
activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
Respiratory failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiratory rate for 
age
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 
90% to 95%
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
OR Pulse oximetry 90%
Respiratory failure with 
ventilatory support indicated
OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable 
on exam
Symptomatic anterior uveitis OR 
Medical intervention indicated
Posterior or pan-uveitis OR 
Operative intervention 
indicated
Disabling visual loss in affected 
eye(s) 
Visual Changes (from 
baseline)
Visual changes causing no or 
minimal interference with 
usual social & functional 
activities
Visual changes causing greater 
than minimal interference with 
usual social & functional 
activities
Visual changes causing 
inability to perform usual 
social & functional activities
Disabling visual loss in affected 
eye(s)


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 89
18 December 2018
SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Alopecia
Thinning detectable by 
study participant or 
caregiver (for disabled 
adults)
Thinning or patchy hair loss 
detectable by health care 
provider
Complete hair loss
NA
Cutaneous Reaction – Rash
Localized macular rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash OR Target 
lesions 
Diffuse macular, 
maculopapular, or morbilliform 
rash with vesicles or limited 
number of bullae OR 
Superficial ulcerations of 
mucous membrane limited to 
one site
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson syndrome 
OR Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Toxic epidermal 
necrolysis (TEN)
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized 
Marked or generalized
NA
NA
Pruritis (itching – no skin 
lesions) 
(See also Injection Site 
Reactions: Pruritis associated 
with injection)
Itching causing no or 
minimal interference with 
usual social & functional 
activities
Itching causing greater than 
minimal interference with 
usual social & functional 
activities
Itching causing inability to 
perform usual social & 
functional activities 
NA


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 90
18 December 2018
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated with 
decreased oral intake without 
significant weight loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening consequences 
OR Aggressive intervention 
indicated [eg, tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention
indicated (eg, diuretics or 
therapeutic paracentesis)
Symptomatic despite 
intervention
Life-threatening consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening consequences 
(eg, sepsis or perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening consequences 
(eg, obstruction)
Diarrhea 
Adult and Pediatric 
1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hr
Persistent episodes of unformed 
to watery stools OR Increase of 
4–6 stools over baseline per 
24 hrs. 
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening consequences 
(eg, hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 91
18 December 2018
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, 
Dysphagia-Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding 
OR Life-threatening 
consequences (eg, aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no 
or minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 24–48 
hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (eg, 
IV fluids)
Life-threatening consequences 
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(eg, sepsis, circulatory failure, 
hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical 
Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social/
functional activities OR 
Operative intervention 
indicated 
Life-threatening consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening consequences 
(eg, hypotensive shock)


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 92
18 December 2018
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in Personality-
Behavior or in Mood (eg, 
agitation, anxiety, 
depression, mania, 
psychosis)
Alteration causing no or 
minimal interference with 
usual social & functional 
activities 
Alteration causing greater than 
minimal interference with 
usual social & functional 
activities 
Alteration causing inability to 
perform usual social & 
functional activities 
Behavior potentially harmful 
to self or others (eg, 
suicidal/homicidal ideation or 
attempt, acute psychosis) OR 
Causing inability to perform 
basic self-care functions
Altered Mental Status 
For Dementia, see Cognitive 
and Behavioral/Attentional 
Disturbance (including 
dementia and ADD)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities
Delirium OR obtundation, OR 
coma
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no 
or minimal interference with 
usual social & functional 
activities
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities
Symptomatic ataxia causing 
inability to perform usual 
social & functional activities 
Disabling ataxia causing 
inability to perform basic self-
care functions
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and Attention 
Deficit Disorder) 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater than 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources on part-time basis 
indicated
Disability causing inability to 
perform usual social & 
functional activities OR 
Specialized resources on a
full-time basis indicated
Disability causing inability to 
perform basic self-care 
functions OR 
Institutionalization indicated
CNS Ischemia
(acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit 


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 93
18 December 2018
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Developmental delay –
Pediatric 16 Years
Mild developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate 
for the setting 
Moderate developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening tool 
appropriate for the setting 
Severe developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting 
Developmental regression,
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting
Headache 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities
Symptoms causing inability to 
perform usual social & 
functional activities
Symptoms causing inability to 
perform basic self-care 
functions OR Hospitalization 
indicated (other than ER visit) 
OR Headache with significant 
impairment of alertness or 
other neurologic function 
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic self-
care functions
Neuromuscular Weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on exam 
OR Minimal muscle weak-
ness causing no or minimal 
interference with usual 
social & functional activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities 
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia causing 
no or minimal interference 
with usual social & 
functional activities 
Sensory alteration or 
paresthesia causing greater 
than minimal interference with 
usual social & functional 
activities 
Sensory alteration or 
paresthesia causing inability to 
perform usual social & 
functional activities
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care 
functions


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 94
18 December 2018
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)
Seizure: (pre-existing) 
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase 
from Previous Level of 
Control to Any of These 
Levels
NA
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality (eg, 
severity or focality) 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)
Seizure 
– Pediatric 18 Years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 5–20 
minutes with 
< 24 hours post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
> 20 minutes 
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated 
with a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities 
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic self-
care functions


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 95
18 December 2018
MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia
See also Arthritis
Joint pain causing no or 
minimal interference with 
usual social & functional 
activities
Joint pain causing greater than 
minimal interference with usual 
social & functional activities
Joint pain causing inability 
to perform usual social & 
functional activities
Disabling joint pain causing 
inability to perform basic self-
care functions
Arthritis
See also Arthralgia
Stiffness or joint swelling 
causing no or minimal 
interference with usual 
social & functional activities
Stiffness or joint swelling causing 
greater than minimal interference 
with usual social & functional 
activities
Stiffness or joint swelling 
causing inability to perform 
usual social & functional 
activities
Disabling joint stiffness or 
swelling causing inability to 
perform basic self-care 
functions
Bone Mineral Loss
BMD t-score or z-score
–2.5 to –1.0 
BMD t-score or z-score –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Pediatric 21 Years
BMD z-score 
–2.5 to –1.0
BMD z-score < –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Myalgia
(non-injection site)
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities
Muscle pain causing greater than 
minimal interference with usual 
social & functional activities
Muscle pain causing 
inability to perform usual 
social & functional activities
Disabling muscle pain causing 
inability to perform basic self-
care functions
Osteonecrosis
NA
Asymptomatic with radiographic 
findings AND No operative 
intervention indicated
Symptomatic bone pain with 
radiographic findings OR 
Operative intervention 
indicated
Disabling bone pain with 
radiographic findings causing 
inability to perform basic self-
care functions


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 96
18 December 2018
SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Acute Systemic Allergic 
Reaction 
Localized urticaria 
(wheals) with no medical 
intervention indicated
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild 
bronchospasm
Acute anaphylaxis OR Life-
threatening bronchospasm OR 
laryngeal edema
Chills
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
Symptoms causing inability to 
perform usual social & 
functional activities
NA
Fatigue
Malaise
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & 
functional activities
Incapacitating fatigue/malaise 
symptoms causing inability to 
perform basic self-care 
functions
Fever (nonaxillary)
37.7C to 38.6C
99.8F to 101.5F
38.7C to 39.3C
101.6F to 102.8F
39.4C to 40.5C
102.9F to 104.9F
40.5C 
104.9F
Pain- Indicate Body Site
See also Injection Site 
Pain, Headache, 
Arthralgia, and Myalgia
Pain causing no or 
minimal interference with 
usual social & functional 
activities
Pain causing greater than minimal 
interference with usual social & 
functional activities
Pain causing inability to 
perform usual social & 
functional activities
Disabling pain causing 
inability to perform basic self-
care functions OR 
Hospitalization (other than ER 
visit) indicated
Unintentional Weight 
Loss
NA
5% to 9% loss in body weight from 
baseline
10% to 19% loss in body 
weight from baseline
20% loss in body weight 
from baseline OR Aggressive 
intervention indicated [eg, 
tube feeding or total parenteral 
nutrition]


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 97
18 December 2018
INJECTION SITE REACTION
Grade 1
Grade 2
Grade 3
Grade 4
Injection Site Pain (pain 
without touching)
Or Tenderness (pain when 
area is touched) 
Pain/tenderness causing no 
or minimal limitation of use 
of limb
Pain/tenderness limiting use of 
limb OR Pain/tenderness 
causing greater than minimal 
interference with usual social 
& functional activities
Pain/tenderness causing 
inability to perform usual 
social & functional activities
Pain/tenderness causing inability 
to perform basic self-care 
function OR Hospitalization 
(other than ER visit) indicated 
for management of 
pain/tenderness
Injection Site Reaction 
(Localized), 15 Years
Erythema OR Induration
of 5 5 cm to 9 9 cm (or 
2581 cm2)
Erythema OR Induration OR 
Edema 9 cm any diameter 
(or 81 cm2)
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR Drainage
Necrosis (involving dermis and 
deeper tissue)
Pediatric 15 Years
Erythema OR Induration 
OR Edema present but 
2.5 cm diameter
Erythema OR Induration OR 
Edema > 2.5 cm diameter but 
< 50% surface area of the 
extremity segment (eg, upper 
arm/thigh)
Erythema OR Induration 
OR Edema involving 50% 
surface area of the extremity 
segment (eg, upper 
arm/thigh) OR Ulceration 
OR Secondary infection OR 
Phlebitis OR Sterile abscess 
OR Drainage
Necrosis (involving dermis and 
deeper tissue)
Pruritis Associated with 
Injection 
See also Skin: Pruritis 
(itching—no skin lesions)
Itching localized to injection 
site AND Relieved 
spontaneously or with 
48 h treatment 
Itching beyond the injection 
site but not generalized OR 
Itching localized to injection 
site requiring 48 h treatment 
Generalized itching causing 
inability to perform usual 
social & functional activities
NA


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 98
18 December 2018
ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (eg, back 
of neck, breasts, 
abdomen)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious 
changes on casual visual 
inspection
NA
Diabetes Mellitus
NA
New onset without need to initiate 
medication OR Modification of 
current meds to regain glucose 
control
New onset with initiation of 
indicated med OR Diabetes 
uncontrolled despite treatment 
modification
Life-threatening consequences 
(eg, ketoacidosis, 
hyperosmolar non-ketotic 
coma) 
Gynecomastia
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA
Hyperthyroidism 
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid suppression therapy 
indicated
Symptoms causing inability to 
perform usual social &
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, thyroid storm)
Hypothyroidism
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid replacement therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, myxedema coma)
Lipoatrophy (eg, fat loss 
from the face, extremities, 
buttocks)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 99
18 December 2018
GENITOURINARY
Grade 1
Grade 2
Grade 3
Grade 4
Intermenstrual Bleeding 
(IMB)
Spotting observed by participant 
OR Minimal blood observed 
during clinical or colposcopic 
exam
Intermenstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle
Intermenstrual bleeding greater 
in duration or amount than usual 
menstrual cycle
Hemorrhage with life-
threatening hypotension OR 
Operative intervention 
indicated
Urinary Tract 
obstruction (eg, stone)
NA
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing life-
threatening consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other 
than HIV infection)
Localized, no systemic antiμbial 
treatment indicated AND 
Symptoms causing no or 
minimal interference with usual 
social & functional activities
Systemic antiμbial treatment 
indicated OR Symptoms 
causing greater than minimal 
interference with usual social 
& functional activities
Systemic antiμbial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than simple 
incision and drainage) indicated
Life-threatening 
consequences (eg, septic 
shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.


GS-0976
Protocol GS-US-426-3988
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 100
18 December 2018
Appendix 4.
Child-Pugh Classification of Severity for Liver Disease
Chi'ld-Pugh dassification of severity of liver disease 
Parameter 
Points assigned 
1 
2 
3 
Ascites 
Absent 
Slight 
Moderate 
Bilirubin 
<2 mg/dl 
2-3 mg/dl (34.2 
>3 mg/dl 
(<34.2 
to 51.3 
(>51.3 
micromol/liter) 
micromol/liter) 
micromol/liter) 
Albumin 
>3.S g/dl (35 
2.8-3.5 g/dl (28 
<2.8 g/dl (<28 
g/liter) 
to 35 9/liter) 
g/liter) 
Prothrombin time 
Seoonds over 
<4 
4-6 
>6 
control 
!NR 
<1.7 
l.7-2.3 
>2.3 
Encephalopatliy 
None 
Grade 1-2 
Grade 3-4 
Modified Child-Pugh dasslflcatlon of the seventy of liver disease 
according to the degree of ascites, the plasma concentrations 
of blllrubln and albumin, the prothrombln time, and the degree 
of encephalopathy. A total score of 5- 6 Is considered grade A 
(well-compensate,d disease); 7-9 Is grade B (significant 
functional compromise); and 10-15 is grade C (decompensated 
disease). These grades correla e with one- and two-year 
patient survival: grade A - 100 and 85 percent; grade B - 80 
and 60 percent; and grade C - 45 and 35 percent. 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 1 Open-Label, Parallel-Group, Single-Dose Study to 
Evaluate the Pharmacokinetics of GS-0976 or Fenofibrate in 
Subjects with Normal and Impaired Hepatic Function
Study Phase:
1
Name of Test Drug:
GS-0976
Study Number:
GS-US-426-3988
Protocol Version (Date):
Amendment 1 (01 September 2017)
Amendment 2 (18 December 2018)
Analysis Type:
Final Analysis
Analysis Plan Version:
1.0
Analysis Plan Date:
10 September 2019
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(r) GILEAU 
-


GS-0976
GS-US-426-3988
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 2
10 September 2019
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN..............................................................................................................................1
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF FIGURES.......................................................................................................................................................3
LIST OF ABBREVIATIONS........................................................................................................................................4
PHARMACOKINETIC ABBREVIATIONS................................................................................................................6
1.
INTRODUCTION ................................................................................................................................................7
1.1.
Study Objectives ......................................................................................................................................7
1.2.
Study Endpoints .......................................................................................................................................7
1.3.
Study Design............................................................................................................................................7
1.4.
Sample Size and Power..........................................................................................................................12
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................13
2.1.
Data Monitoring Committee Analyses...................................................................................................13
2.2.
Interim Analysis.....................................................................................................................................13
2.3.
Final Analysis ........................................................................................................................................13
2.4.
Changes from Protocol-Specified Analysis............................................................................................13
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................14
3.1.
Analysis Sets..........................................................................................................................................14
3.1.1.
All Enrolled Analysis Set.........................................................................................................14
3.1.2.
Safety Analysis Set ..................................................................................................................14
3.1.3.
Pharmacokinetic Analysis Sets................................................................................................14
3.2.
Strata and Covariates..............................................................................................................................14
3.3.
Examination of Subject Subsets.............................................................................................................15
3.4.
Multiple Comparisons............................................................................................................................15
3.5.
Missing Data and Outliers......................................................................................................................15
3.5.1.
Missing Data............................................................................................................................15
3.5.2.
Outliers ....................................................................................................................................15
3.6.
Data Handling Conventions and Transformations .................................................................................15
3.7.
Visit Windows........................................................................................................................................16
3.7.1.
Definition of Predose, Postdose, Study Day ............................................................................16
3.7.2.
Analysis Visit Windows ..........................................................................................................17
3.7.3.
Selection of Data in the Event of Multiple Records on the Same Day ....................................17
4.
SUBJECT DISPOSITION ..................................................................................................................................19
4.1.
Subject Enrollment and Disposition.......................................................................................................19
4.2.
Extent of Exposure.................................................................................................................................19
4.3.
Protocol Deviations................................................................................................................................19
5.
BASELINE CHARACTERISTICS....................................................................................................................20
5.1.
Demographics ........................................................................................................................................20
5.2.
Other Baseline Characteristics ...............................................................................................................20
5.3.
Medical History......................................................................................................................................20
6.
EFFICACY ANALYSES ...................................................................................................................................21
7.
SAFETY ANALYSES........................................................................................................................................22
7.1.
Adverse Events and Deaths....................................................................................................................22
7.1.1.
Adverse Event Dictionary........................................................................................................22
7.1.2.
Adverse Event Severity............................................................................................................22


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7.1.3.
Relationship of Adverse Events to Study Drug .......................................................................22
7.1.4.
Relationship of Adverse Events to Study Procedure ...............................................................22
7.1.5.
Serious Adverse Events ...........................................................................................................22
7.1.6.
Treatment-Emergent Adverse Events ......................................................................................23
7.1.6.1.
Definition of Treatment Emergent (TE) ..................................................................23
7.1.6.2.
Incomplete Dates .....................................................................................................23
7.1.7.
Summaries of Adverse Events and Deaths ..............................................................................23
7.1.8.
Additional Analysis of Adverse Events...................................................................................24
7.2.
Laboratory Evaluations ..........................................................................................................................24
7.2.1.
Summaries of Numeric Laboratory Results.............................................................................25
7.2.2.
Graded Laboratory Values.......................................................................................................25
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities......................................................25
7.2.2.2.
Summaries of Laboratory Abnormalities.................................................................26
7.3.
Vital Signs..............................................................................................................................................26
7.4.
Concomitant Medications ......................................................................................................................27
7.5.
Investigator Electrocardiogram Assessment ..........................................................................................27
7.6.
Other Safety Measures ...........................................................................................................................27
7.7.
Changes From Protocol-Specified Safety Analyses...............................................................................27
8.
PHARMACOKINETIC EVALUATION/ANALYSIS ......................................................................................28
8.1.
Estimation of Pharmacokinetic Parameters............................................................................................28
8.2.
Pharmacokinetic Parameters ..................................................................................................................28
8.3.
Statistical Analysis Methods ..................................................................................................................29
8.3.1.
General Considerations............................................................................................................29
8.3.2.
Statistical Methodology ...........................................................................................................30
8.4.
Sensitivity Analysis................................................................................................................................32
9.
REFERENCES ...................................................................................................................................................33
10.
SOFTWARE.......................................................................................................................................................34
11.
SAP REVISION..................................................................................................................................................35
12.
APPENDIX 1 SCHEDULE OF ASSESSMENTS .............................................................................................36
Appendix 1.
Schedule of Assessments........................................................................................................36
LIST OF TABLES
Table 3-1.
Predose and Postdose Visits for Laboratory Tests..................................................................17
Table 8-1.
Study Treatments and Associated Analytes ...........................................................................28
Table 8-2.
Pharmacokinetic Parameters for Each Analyte ......................................................................29
Table 8-3.
Statistical Comparisons for Pharmacokinetic Analyses of Normal and Impaired 
Hepatic Function ....................................................................................................................31
LIST OF FIGURES
Figure 1.
High-Level Study Schema........................................................................................................9
Figure 2.
Cohort Study Schema...............................................................................................................9


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LIST OF ABBREVIATIONS
%CV
% coefficient of variation
AE
adverse event
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
CFR
Code of Federal Regulations
CI
confidence interval
CLcr
creatinine clearance
CPT
Child-Pugh-Turcotte classification system
CRF
case report form
CSR
clinical study report
CV
coefficient of variation
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
ET
early termination
FSH
Follicle-stimulating hormone
FU
follow-up
Gilead
Gilead Sciences
GLSM
geometric least-squares mean
Hb
hemoglobin
HBVsAg
hepatitis B surface antigen
HCV-Ab
hepatitis C antibody
HIV
human immunodeficiency virus
HLGT
high-level group term
HLT
high-level term
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
ID
identification
INR
international normalized ratio
LLOQ
lower limit of quantitation
LT
lower-level term
LOQ
limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PT
preferred term or prothrombin time
PTT
partial thromboplastin time


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Q1, Q3
first quartile, third quartile
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SE
standard error
SI 
International System of Units (Systeme International d’Unites)
SOC
system organ class
TBD
to be determined
TE
treatment emergent
TEAE
treatment-emergent adverse events
TFLs
tables, figures, and listings
TOST
two one-sided tests
TQT
thorough QT
ULN
upper limit of normal
WHO
World Health Organization


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PHARMACOKINETIC ABBREVIATIONS
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination 
phase of the log plasma/serum concentration of drug versus time curve of the drug
%AUCexp
percentage of AUC extrapolated between AUClast and AUCinf
AUC
area under the plasma/serum concentration versus time curve
AUClast
area under the plasma/serum concentration versus time curve from time zero to the last 
quantifiable concentration
AUCinf
area under the plasma/serum concentration versus time curve extrapolated to infinite time, 
calculated as AUClast + (Clast/z)
AUCx xx
partial area under the plasma/serum concentration versus time curve from time “x” to time 
“xx”
CL
clearance
CL/F
apparent oral clearance after administration of the drug:
CL/F = Dose/AUCinf, where “Dose” is the dose of the drug
Clast
last observed quantifiable plasma/serum concentration of the drug
Cmax
maximum observed plasma/serum concentration of drug
F
estimated oral bioavailability of the drug (%), calculated as 
100(AUCoral Doseiv)/(AUCiv. Doseoral)
fu
unbound fraction
t½
estimate of the terminal elimination half-life of the drug in plasma/serum, 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
Vz/F
apparent volume of distribution of the drug


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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-426-3988. This SAP is based on the study protocol amendment 2 dated 
18 December 2018 and the electronic case report form (eCRF). The SAP will be finalized prior 
to database finalization. Any changes made after finalization of the SAP will be documented in 
the CSR.
1.1.
Study Objectives
The primary objectives of this study are as follows:

To evaluate the single-dose pharmacokinetics (PK) of GS-0976 in subjects with normal 
hepatic function, and mild, moderate, or severe hepatic impairment

To evaluate the single-dose PK of fenofibrate in subjects with normal hepatic function and
mild hepatic impairment
The secondary objectives of this study are as follows:

To evaluate the safety and tolerability of GS-0976 single dose administration in subjects with 
normal hepatic function, and mild, moderate, or severe hepatic impairment

To evaluate the safety and tolerability of single dose fenofibrate administration in subjects 
with normal hepatic function and mild hepatic impairment
1.2.
Study Endpoints
The primary endpoints are the PK parameters AUClast, AUCinf, and Cmax of GS-0976 or fenofibric 
acid (and their metabolites, as applicable). Additional PK parameters calculated include: 
% AUCexp, Tmax, Clast, Tlast, z, CL/F, Vz/F, and t½ as appropriate.
Secondary endpoints include the incidences of adverse events (AEs) and laboratory 
abnormalities.
1.3.
Study Design
This is a Phase 1, open-label, single-dose, parallel-group, multi-center, PK study of GS-0976 or 
fenofibrate in subjects with impaired hepatic function and matched normal hepatic function 
(control) groups. 
Subjects with hepatic impairment will be enrolled based upon the Child-Pugh-Turcotte (CPT) 
classification system of hepatic impairment:
1) Cohort 1 and 4: mild hepatic impairment (CPT Class A; score of 5-6) and matching controls
2) Cohort 2: moderate hepatic impairment (CPT Class B; score of 7-9) and matching controls
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The control group will consist of matched healthy subjects with normal hepatic function. A 
subject with normal hepatic function may serve as a matched control in Cohorts 1 and 2 but may 
only serve as a matched control to one hepatic impaired subject within a cohort.
Up to 80 (20 per cohort, 10 per group) male and non-pregnant/non-lactating female subjects aged 
18-70 years inclusive with impaired and normal hepatic function will be enrolled to ensure 
completion of 64 (16 per cohort, 8 per group) evaluable subjects. Each subject in the control 
group will be matched for age (± 10 years), gender, race, and body mass index (± 15%; 
18 ≤BMI ≤36 kg/m2) with a subject in the respective hepatic impairment group. Subjects with 
hepatic impairment must have the respective CPT classification at Screening, have a diagnosis of 
chronic (> 6 months) and stable hepatic impairment with no clinically significant changes within 
3 months (or 90 days) prior to study drug administration (Day 1).
Following completion of Screening and Day 2 admission assessments, eligible subjects will be 
enrolled in one of four cohorts and will be administered the following study treatment on Day 1: 

Cohorts 1 and 2: A single oral dose of 20 mg GS-0976 (2 10 mg capsules)

Cohort 3: A single oral dose of 5 mg GS-0976 (1 5 mg tablet)

Cohort 4: A single oral dose of 48 mg fenofibrate (1 48 mg tablet)
Subjects will be confined to the study center beginning Day 2 until the completion of 
assessments on Day 5. Subjects will return for a follow-up (FU) visit on Day 13 (± 2 days).
In general, dosing in subjects with normal hepatic function will begin after a matched subject 
with hepatic impairment has completed all Day 1 PK assessments (eg, 96 hours postdose).
Cohorts 1 and 2 may be dosed in parallel, with dosing for Cohort 3 (severe hepatic impairment) 
proceeding after review of safety and preliminary PK data (if available) from hepatic impaired 
subjects in the previous cohorts. Based on the cumulative review of safety and PK data from 
Cohorts 1 and 2, Cohort 3 may or may not be initiated at the discretion of the investigator and 
Sponsor.
If necessary, replacement subjects may be enrolled with sponsor approval if subjects do not 
complete all intensive PK procedures. Replacement subjects will not be enrolled for subjects 
who discontinue the study due to study drug-related AEs.
The study designs are presented in Figure 1 and Figure 2.


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Figure 1. 
High-Level Study Schema 
Cohort 1 
Mild Hepatic -
Impairment 
20 mg GS-0976 
... Available Safety and 
Cohort 2 
preliminary PK data 
Moderate Hepat ic -
Impairment 
20 mg GS-0976 
I! 
Figure 2. 
Cohort Study Schema 
Day -28 
-2 
-1 
1 
Screening 
• 
• 
. •.• 
Dosing GS-09 6 or fenpfibrate 
Biomarker Assessments (Cohort 3 only) 
Pharmacokinetic Assessments 
Clinic Confinement 
Follow-
Period 
CO FIDE TIAL 
Page 9 
5 
Cohort 3 
Severe Hepatic 
Impairment 
5 mgGS-0976 
Cohort4 
Mild Hepatic 
Impairment 
48 mg fenofibrate 
• • 
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Each of the four cohorts will consist of two groups:
1) Group 1 (test, N  10): Subjects with hepatic impairment 
2) Group 2 (reference, N  10): Subjects with normal hepatic function
Safety will be evaluated by physical examinations, vital signs, clinical laboratory tests and 
electrocardiograms (ECGs) at various timepoints during the study, and by documentation of 
AEs. 
PK Assessments
Plasma PK Collection
Intensive PK sampling will occur relative to dosing of GS-0976 or fenofibrate on Day 1 at the 
following time points for each cohort: 

Day 1: 0 (pre-dose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 
and 96 hours post-dose
A blood sample for PK analysis will be collected at the Early Termination (ET) visit 
(if applicable) and may be analyzed. 
Plasma concentrations of GS-0976 or fenofibric acid (and their metabolites, as applicable) will 
be determined and PK evaluated. PK parameters will be estimated, as appropriate. 
Protein Binding Samples
Plasma protein binding sampling will occur relative to dosing of GS-0976 or fenofibrate on 
Day 1 at the following time points for each cohort: 

Day 1: 1 and 3 hours post-dose
Plasma protein binding of GS-0976 or fenofibric acid (and their metabolites, as applicable) will 
be determined and summarized descriptively.
Exploratory Biomarker Assessments: 
 
 
 
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Safety Assessments

Complete physical exam: Screening and at the early termination (ET) visit (if applicable). 

Symptom-driven physical exam: Day 2, Day 1 (prior to biomarker sample collection), 
Day 1 (predose and approximately 4 hours postdose), Day 5, and at the FU visit.

Vital signs (blood pressure, heart rate, respiration rate, and body temperature): Screening, 
Day 2, Day 1 (prior to biomarker sample collection), Day 1 (predose and approximately 
4 hours postdose), Day 5, and at the FU visit or ET visit (if applicable). 

Height, Weight, and BMI: Screening

Clinical laboratory tests (hematology, chemistry, and urinalysis): Screening, Day 2, Day 1, 
Day 5, and at the FU visit or ET visit (if applicable).
Note: On Day 2 (clinic admission), two sets of safety labs will be collected. One will be sent to 
the central lab and another will be sent to the sites' local lab to obtain results in time for 
enrollment on Day 1.

Coagulation tests (prothrombin time [PT], partial thromboplastin time [PTT], international 
normalized ratio [INR]): Screening and at the FU visit or ET visit (if applicable).

α-fetoprotein: Screening

Urine drug and alcohol assessments: Screening, Day 2, and at the FU visit or ET visit 
(if applicable).

12-lead ECG: Screening, Day 2, Day 1 (predose and approximately 4 hours postdose), 
Day 5, and at the FU visit or ET visit (if applicable).

Serum pregnancy test (female subjects of childbearing potential only): Screening and 
Day 2, Day 5, and at the FU visit or ET visit (if applicable).

FSH (female subjects ≤ 54 years old with amenorrhea > 12 months): Screening

Serology (Hepatitis B surface antigen [HBVsAg], Hepatitis C antibody [HCV-Ab], human 
immunodeficiency virus HIV-1/2): Screening
Assessment of AEs and concomitant medications will continue throughout the study.
Additional details regarding study assessments can be found in Appendix 1.
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1.4.
Sample Size and Power
For Cohorts 1 to 3, with 16 (8 per group) evaluable subjects per cohort, the estimated upper limit 
of one-sided 95% CI of the geometric least-squares mean (GLSM) ratio of (mild, moderate, or 
severe) hepatic impaired group vs control (normal hepatic function), with regards to AUCinf and 
Cmax, would be less than 200% with ≥ 72% and ≥ 57% probability, respectively, if the estimated 
GLSM ratio were 1.0. This is assuming a standard deviation (SD) of no more than 0.588 for 
AUCinf and 0.722 for Cmax on a natural logarithmic scale, as supported by results from previous 
Study 0976-101. With 25% overage, a total sample size of 60 subjects (10 per group, 20 per 
cohort) will be required.
For Cohort 4, with 16 (8 per group) evaluable subjects, the estimated 2-sided 90% CI of the 
GLSM ratio of mild hepatic impaired group vs control (normal hepatic function), with regards to 
AUClast, AUCinf, and Cmax would be within [0.5, 2.0] with ≥ 90% probability, if the estimated 
GLSM ratio were 1.0. This is assuming a SD of no more than 0.387 on a natural logarithmic
scale, as supported by information from the US Food and Drug Administration (FDA) {U. S. 
Food and Drug Administration 2004}. With 25% overage, a total sample size of 20 subjects 
(10 per group) will be required.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Data Monitoring Committee Analyses
This study does not have a data monitoring committee (DMC). Therefore, no analyses will be 
conducted for the DMC.
2.2.
Interim Analysis
No interim analysis is planned.
2.3.
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 final analysis of 
the data will be performed.
2.4.
Changes from Protocol-Specified Analysis
No changes from protocol-specified analyses are planned.


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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, SD or standard error (SE), median, first quartile (Q1), 
third quartile (Q3), minimum, and maximum will be presented.
By-subject listings will be presented for all subjects in the All Enrolled Analysis Set, and sorted
by subject identification (ID) number in ascending order, visit date, and time (if applicable),
unless otherwise specified. Data collected on log forms, such as AEs, will be presented in 
chronological order within subject. The treatment group to which subjects were initially assigned 
will be used in the listings. Age, sex at birth, race, and ethnicity will be included in the listings, 
as space permits.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions
are provided in this section. 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 will be 
provided in the disposition table as detailed in Section 4. A listing of reasons for exclusion from 
analysis sets will be provided by subject.
3.1.1.
All Enrolled Analysis Set
The All Enrolled Analysis Set includes all subjects who received a study subject identification 
number in the study after screening.
This is the primary analysis set for safety listings.
3.1.2.
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.
3.1.3.
Pharmacokinetic Analysis Sets
The PK Analysis Sets will include all enrolled subjects who took at least 1 dose of study drug 
and have at least 1 nonmissing postdose concentration value reported by the PK laboratory for 
the corresponding analytes. These are the primary analysis sets for all PK analyses. 
3.2.
Strata and Covariates
This study does not use a stratified randomization schedule in enrolling subjects. No covariates 
will be included in the analyses.


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3.3.
Examination of Subject Subsets
There are no prespecified subject subsets for analyses.
3.4.
Multiple Comparisons
No multiplicity adjustments will be made for testing.
3.5.
Missing Data and Outliers
3.5.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.
The handling of missing or incomplete dates for AE onset is described in Section 7.1.6.2.
3.5.2.
Outliers
Outliers of non-PK data 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.
3.6.
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 enrollment 
date will be used instead of the first dosing date of study drug. If only the birth year is collected 
on the 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 lower LOQ will be used to calculate descriptive statistics if 
the datum is reported in the form of “x” (where x is considered the lower LOQ). For 
example, if the values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will 
be used to calculate 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 to calculate summary statistics.

A value that is 1 unit above the upper LOQ will be used to calculate descriptive statistics if 
the datum is reported in the form of “> x” (where x is considered the upper LOQ). Values 
with decimal points will follow the same logic as the bullet point above.

The LOQ will be used to calculate 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 logarithmic transformation will be used for analyzing concentrations and PK parameters. 
Concentration values that are below the limit of quantitation (BLQ) will be presented as “BLQ” 
in the concentration data listing. Values that are BLQ will be treated as 0 at predose time points, 
and one-half the value of the LOQ at postdose time points for summary purposes. 
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) and summary statistics will be 
displayed as “BLQ.”
PK parameters that are BLQ will be imputed as one-half LOQ before log transformation or 
statistical model fitting.
3.7.
Visit Windows
3.7.1.
Definition of Predose, Postdose, Study Day
Predose value is defined as the last available off-treatment value collected on or prior to the date 
and time of first dose of study drug.
Postdose value is defined as any value collected after the first dose of study drug and before the 
date of the last dose of study drug plus 30 days.
Study Day will be calculated from the first dosing date of study drug 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
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3.7.2.
Analysis Visit Windows
The nominal visit as recorded on the CRF will be used when data are summarized by visit. Any 
data relating to unscheduled visits will not be assigned to a particular visit or time point and in 
general will not be included in summaries. However, the following exceptions will be made:

An unscheduled visit prior to the first dose of study drug may be included in the calculation 
of predose value, if applicable.

Unscheduled visits after the first dose of study drug will be included in determining the 
maximum postbaseline toxicity grade.

For subjects who 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.”

Data obtained after the follow-up visit or last dose date plus 30 days (whichever is later) will 
be excluded from the summaries, but will be included in the listings.
The predose and postdose visits for laboratory tests are summarized in .
Table 3-1.
Predose and Postdose Visits for Laboratory Tests
Cohort
Visit Label
Study Day
All
Predose
<= dose time on Study Day 1
Day 5
5
Follow-up
Follow-up
3.7.3.
Selection of Data in the Event of Multiple Records on the Same Day
Depending on the statistical analysis method, single values may be required for each day. For 
example, change from predose by visit usually requires a single value. 
If multiple valid, nonmissing numeric observations exist on a day, records will be chosen based 
on the following rules if a single value is needed:

For predose, the last available record on or prior to the date and time 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, average (arithmetic or geometric mean, as appropriate) will be used for the 
predose value. 

For postdose values:
The record closest to the nominal day for that visit will be selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken, unless 
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If multiple, valid, nonmissing categorical observations exist on a day, records will be chosen 
based on the following rules if a single value is needed:

For predose, the last available record on or prior to the date and time 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 ECG findings).

For postdose values, follow the same rules described above for postbaseline numeric 
observations, except that if there are multiple records on the same day, the most conservative 
value 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 and disposition will be provided by treatment, cohort, and 
hepatic function group. This summary will present the number of subjects enrolled, and the 
number and percentage of subjects in each of the categories listed below. For the Safety Analysis 
Set category, the denominator for the percentage calculation will be the total number of subjects 
enrolled for each column. For all other categories, the denominator for the percentage calculation 
will be the total number of subjects in the Safety Analysis Set for each column.

Safety Analysis Set

PK Analysis Set for each analyte

Completed study drug

Completed the study

Did not complete the study with reason for premature discontinuation of study
In addition, the total number of subjects who were enrolled, and the number of subjects in each 
of the disposition categories listed above will be displayed in a flowchart.
The following by-subject listings will be provided by subject ID number in ascending order to 
support the above summary tables:

Reasons for premature study discontinuation
A by-subject listing of subject disposition including cohort, hepatic function group, date of the 
last dose of study drug(s) (study days), study completion status, reason for study discontinuation, 
and PK set status (indicating whether or not a subject is included in a PK analysis set) will be 
provided by subject ID number in ascending order.
4.2.
Extent of Exposure 
A subject’s extent of exposure to study drug data will be generated from the study drug 
administration page in the eCRF. Exposure data will be listed. 
4.3.
Protocol Deviations 
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 violation) that subjects did not meet and related comments, if collected.
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. Any deviations identified will be evaluated to determine if it justifies excluding the 
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5.
BASELINE CHARACTERISTICS
5.1.
Demographics 
Subject demographic variables (ie, age, sex, race, and ethnicity) will be summarized by
treatment, cohort, and hepatic function group using descriptive statistics for age, and using 
number and percentage of subjects for sex, race, and ethnicity. 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 
(BMI; in kg/m2), creatinine clearance (CLcr; in mL/min) using the Cockcroft-Gault method
{Cockcroft 1976}, and CPT score. These baseline characteristics will be summarized by 
treatment, cohort, and hepatic function group using descriptive statistics for continuous variables
and using number and percentage of subjects for categorical variables. For baseline body weight, 
height, and BMI, descriptive statistics will also be presented by sex in the same table. CPT score 
will be summarized for hepatic impaired subjects only by presenting the number and percentage 
of subjects in each score category. The summary of baseline characteristics will be provided for 
the Safety Analysis Set. No formal statistical testing is planned.
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.
5.3.
Medical History
Medical history data will be collected at screening and listed only. General medical history data 
will not be coded.
A by-subject listing of general medical history will be provided by subject ID number in 
ascending order. The listing will include relevant medical condition or procedure reported term, 
onset date, ongoing status, and resolution date (if applicable).


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6.
EFFICACY ANALYSES
Efficacy will not be evaluated in the study.


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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 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 provided in the
AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, or 4 according to toxicity criteria 
specified in the protocol. 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 presented last in the summary presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
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 from that captured on the 
CRF.
7.1.4.
Relationship of Adverse Events to Study Procedure
Study procedure related AEs are those for which the investigator selected “Yes” on the AE CRF 
to the question of “Related to Study Procedures.” Relatedness will always default to the 
investigator’s choice, not that of the medical monitor. Events for which the investigator did not 
record relationships to study procedure will be considered related to study procedure for 
summary purposes. However, by-subject data listings will show the relationship as missing from 
that captured on the CRF.
7.1.5.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met the 
definition of SAEs that was specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with the SAE database from the Gilead Pharmacovigilance 
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7.1.6.
Treatment-Emergent Adverse Events
7.1.6.1.
Definition of Treatment Emergent (TE)
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. If the AE onset date is the same as the date of 
study drug start date then the AE onset time must be on or after the study drug start time. If 
the AE onset time is missing when the start dates are the same, the AE will be considered 
treatment emergent.

Any AEs leading to premature discontinuation of study drug.
7.1.6.2.
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 date of first dose 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 date of the first dose 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.
7.1.7.
Summaries of Adverse Events and Deaths
Treatment-emergent 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, PT, treatment, and hepatic function group as follows:

All TEAEs

TEAEs of Grade 3 or higher (by maximum severity)

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
All TEAEs by severity

All TE treatment-related AEs

All TE treatment-related AEs by severity

All TEAEs related to study procedures

All TE SAEs

All TE treatment-related SAEs 

All TEAEs leading to premature discontinuation of study
A brief, high-level summary of AEs described above will be provided by treatment and hepatic 
function 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 then by PT in descending order of 
total frequency within each SOC. For summaries by severity, the maximum severity will be used 
for those AEs that occurred more than once in an individual subject during the study. 
In addition, data listings will be provided for the following:

All AEs, indicating whether the event is treatment emergent

SAEs

Deaths

AEs leading to discontinuation of study
7.1.8.
Additional Analysis of Adverse Events
No additional analysis of adverse events is planned.
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study drug plus 30 days
for subjects who have permanently discontinued study drug. The analysis will be based on values 
reported in conventional units. When values are BLQ, they will be listed as such, and the 
imputed value will be used for the purpose of calculating summary statistics. Hemolyzed test 
results will not be included in the analysis, but they will be listed in by-subject laboratory 
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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 on the 
Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities 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 and hepatic function group for each 
laboratory test specified in the study protocol as follows:

Predose values 

Values at each postdose visit

Change from predose at each postdose visit
Predose and postdose values will be defined as described in Section 3.7.1. Change from predose
to a postdose visit will be defined as the visit value minus the predose 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. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3.
7.2.2.
Graded Laboratory Values
The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities 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 predose at any postdose visit, 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 
predose laboratory value is missing, any abnormality of at least Grade 1 observed within the time 
frame specified above will be considered treatment emergent.


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7.2.2.2.
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 predose and each scheduled postdose visit.
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by lab test, treatment, and hepatic function group; subjects will be 
categorized according to the most severe postdose abnormality grade for a given lab test:

Graded laboratory abnormalities

Grade 3 or 4 laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postdose values up to 30 days after last dosing date.
A by-subject listing of treatment-emergent 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
displayed.
7.3.
Vital Signs
Descriptive statistics will be provided by treatment and hepatic function group for vital signs 
(systolic blood pressure, diastolic blood pressure, pulse, respiration rate, and temperature) as 
follows:

Predose value

Values at each postdose visit

Change from predose at each postdose visit
Predose and postdose values will be defined as described in Section 3.7.1. Change from predose
to a postdose visit will be defined as the postdose value minus the predose value. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3. No formal statistical testing is planned.
A by-subject listing of vital signs will be provided by subject ID number and visit in 
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7.4.
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.
A summary of concomitant medications will not be provided.
All 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.
Investigator Electrocardiogram Assessment
A shift table of the investigators’ assessment of ECG results at each visit compared with predose
values will be presented by treatment and hepatic function 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 predose or postdose will not be included in the 
denominator for percentage calculation. No formal statistical testing is planned.
A by-subject listing for ECG assessment results will be provided by subject ID number and visit
in chronological order.
7.6.
Other Safety Measures
A by-subject listing of subject pregnancies during the study will be provided by subject ID 
number. No additional safety measures are specified in the protocol.
Although not necessarily related to safety, a by-subject listing of all comments received during 
the study on the comments form will be provided by subject ID number, and form for which the 
comment applies.
7.7.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC EVALUATION/ANALYSIS
8.1.
Estimation of Pharmacokinetic Parameters
Pharmacokinetic (PK) parameters will be estimated using Phoenix WinNonlin® software using 
standard noncompartmental methods. The linear up/log down rule will be used in conjunction 
with the appropriate noncompartmental model, with input values for dose level, dosing time, 
plasma concentration, and corresponding real-time values, based on drug dosing times whenever 
possible.
All predose sample times before time-zero will be converted to zero.
For area under the curve (AUC), samples below the limit of quantitation of the bioanalytical 
assays occurring prior to the achievement of the first quantifiable concentration will be assigned 
a concentration value of zero to prevent overestimation of the initial AUC. Samples that are BLQ 
at all other time points will be treated as missing data in WinNonlin. The nominal time point for 
a key event or dosing interval (τ) may be used to permit direct calculation of AUC over specific 
time intervals. The appropriateness of this approach will be assessed by the PK scientist on a 
profile-by-profile basis.
Pharmacokinetic parameters such as AUCinf, λz, and t1/2 are dependent on an accurate estimation 
of the terminal elimination phase of the drug. The appropriateness of calculating these 
parameters will be evaluated upon inspection of PK data on a profile-by-profile basis by the PK 
scientist.
8.2.
Pharmacokinetic Parameters
Pharmacokinetic parameters will be generated for all subjects for whom parameters can be 
derived. The analytes presented in Table 8-1. will be evaluated if data are available. 
Table 8-1.
Study Treatments and Associated Analytes
Cohort
Treatment
Analytes
1 and 2
A single oral dose of 20 mg GS-0976 
(2 10 mg capsules) administered on Day 1
GS-0976 and its metabolite GS-834773, 
as applicable
3
A single oral dose of 5 mg GS-0976 (1 5 mg tablet) 
administered on Day 1
GS-0976 and its metabolite GS-834773, 
as applicable
4
A single oral dose of 48 mg fenofibrate
(1 48 mg tablet) administered on Day 1
fenofibric acid and its metabolite, 
as applicable
The analytes and parameters presented in Table 8-2. will be used to evaluate the PK objectives of 
the study. The primary PK parameters are AUClast, AUCinf, and Cmax of GS-0976 or fenofibric 
acid (and their metabolites, as applicable). The PK parameters to be estimated in this study are 
listed and defined in the Pharmacokinetic Abbreviations section.


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Table 8-2.
Pharmacokinetic Parameters for Each Analyte
Analyte
Parameters
GS 0976 and fenofibric 
acid (and their 
metabolites, as 
applicable)
%AUCexp, AUClastb, AUCinfab, Cmaxab, Clast, Tmax, Tlast, λZ, CL/Fb, VZ/Fb, t1/2, and metabolite to parent 
ratio (corrected for molecular weight) of AUClast, AUCinf, and Cmax, as appropriate
a
Parameter used in sample size and power calculations.
b
May be calculated as both total and unbound.
8.3.
Statistical Analysis Methods
8.3.1.
General Considerations
Individual subject concentration data and individual subject PK parameters (including percentage 
of protein binding) for GS-0976 and fenofibric acid (and their metabolites, as applicable) will be 
listed and summarized using descriptive statistics by hepatic function group within cohort. 
Summary statistics (numbers of subjects, mean, SD, coefficient of variation [%CV], median, 
minimum, maximum, Q1, and Q3) will be presented for both individual subject concentration 
data by time point and individual subject PK parameters by hepatic function group within cohort. 
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. 
The percentage unbound fraction (fu) for each analyte will be estimated either by averaging the 
available 1 hour postdose and the 3 hour postdose percentage unbound in plasma or from spiked
sample, where applicable. Individual subject unbound PK parameter estimates for AUCinf, 
AUClast, and Cmax may be calculated using PK parameter estimates multiplied by fu. The 
unbound CL/F may also be calculated by dividing the estimated CL/F by fu. Unbound Vz/F may
be calculated similarly.
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 
zero at predose and 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 
parameters 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 hepatic function group within each 
cohort:

Individual subject concentration data and summary statistics

Individual subject plasma PK parameters and summary statistics

Individual subject unbound PK parameters (as applicable) based on protein binding and 
summary statistics


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
Individual percentage of unbound and bound GS-0976 and its metabolite GS-834773 with 
summary statistics for each timepoints (1 and 3 hour and spike) and the individual average 
bound and unbound percentage with summary statistics

Spearman’s rank correlation coefficient between selected PK parameter estimates (AUClast, 
AUCinf, and Cmax) and overall CPT Score, albumin, total bilirubin, direct bilirubin, indirect 
bilirubin, prothrombin time, and INR
The following figures will be provided for each analyte by hepatic function group within each 
cohort:

Individual subject concentration data versus time (on linear and semilogarithmic scales)

Mean (± SD) concentration data versus time (on linear and semilogarithmic scales)

Median (Q1, Q3) concentration data versus time (on linear and semilogarithmic scales)

Scatter plots to show the relationship between dose-normalized PK parameter estimates 
(AUCinf, AUClast, and Cmax) and overall CPT score, serum albumin, total bilirubin, direct 
bilirubin, indirect bilirubin, PT, and INR. This set of plots may also be provided for overall 
enrolled subjects.
Individual, mean, and median postdose concentration values that are ≤LLOQ will not be 
displayed in the figures, and the remaining points will be connected. Dose normalization is 
calculated by dividing the PK parameter value by the ratio of the test dose/reference dose. The 
reference dose is 20 mg for GS-0976. Dose normalization will not be performed for fenofibric
acid.
The following listings will be provided:

PK sampling details by subject, including procedures, differences in scheduled and actual 
draw times, and sample age

Individual data on determination of plasma half-life and corresponding regression correlation 
coefficient

Individual data on protein binding
8.3.2.
Statistical Methodology
The statistical comparisons of the natural log-transformed PK parameters for each analyte and 
hepatic function group comparison of interest will be based on the PK analysis set for the analyte 
under evaluation. For each analyte, all subjects with available data for the PK parameter under 
evaluation will be included in the modeling. 
Comparisons of interest are shown in


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Table 8-3.
Table 8-3.
Statistical Comparisons for Pharmacokinetic Analyses of Normal and 
Impaired Hepatic Function
Analyte
Parameter
Comparison
Test
Reference
GS-0976 and its metabolite
GS-834773
AUClast
Mildly Impaired
Matched Normal
AUCinf
Cmax
AUClast
Moderately Impaired
Matched Normal
AUCinf
Cmax
AUClast
Severely Impaired
Matched Normal
AUCinf
Cmax
fenofibric acid and
metabolites, as applicable
AUClast
Mildly Impaired
Matched Normal
AUCinf
Cmax
For each analyte, and each PK parameter within each cohort, a parametric (normal theory) 
ANOVA will be fitted to the natural log-transformed values of the single dose PK parameter 
under evaluation. 
The statistical model will include hepatic function group as a fixed effect. The following SAS
PROC MIXED code will provide the comparison between the hepatic function groups and the 
90% CI calculations for natural log-transformed PK parameters.
proc mixed;
  by cohort analyte paramcd;
  class hepaticgrp subjid;
  model lnest  hepaticgrp / ddfm kr;
  repeated / group hepaticgrp;
  lsmeans hepaticgrp / e diff cl alpha  0.1;
  estimate ‘Impaired vs Normal’ hepaticgrp 1 -1 / cl alpha  0.1;
  * Adjust contrast accordingly based on the alphabetical order of the hepatic function groups 
being compared;
  ods output Estimates  LS_Diffs LSMeans  LS_Means CovParms  MSE;
run;


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The ESTIMATE statement will be used to produce the point estimate and the corresponding 
90% CI of the difference in PK parameters of interest on a logarithmic scale. The 
test-to-reference ratio and associated 90% CI will be calculated by exponentiation of the point 
estimate and the corresponding lower and upper limits, which is consistent with the two 1-sided 
tests approach {U.S. Department of Health and Human Services Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 2003}, {U.S. Department of Health and 
Human Services Food and Drug Administration Center for Drug Evaluation and Research 
(CDER) 2001}.
If the upper bound of the 2-sided 90% CI of the GLSM ratios for AUClast, AUCinf, and Cmax is 
less than 200%, we will reject the hypothesis that subjects with hepatic impairment exhibit 
average PK parameter (ie, AUClast, AUCinf, and Cmax) increases of at least 100% for the study 
drug received compared with subjects with normal hepatic function.
Nonparametric Analysis
Nonparametric analyses for the PK parameters (if calculated) CL/F, VZ/F, and t1/2, may be
performed using the Wilcoxon rank sum test for parallel design between the test and reference 
groups for each analyte.
data param;
  set adam.param;
  where cohort 1 and analyte ‘GS-0976’ and param ‘CL/F’;
run;
proc npar1way data param wilcoxon;
  class hepaticgrp;
  var est; 
run;
8.4.
Sensitivity Analysis
Sensitivity analysis may be conducted for the key PK analyses if the PK scientist identifies PK 
data as questionable. The sensitivity analysis will exclude specific data from analyses, 
if appropriate. If a sensitivity analysis is deemed necessary, a listing of the PK parameter(s) data 
being excluded, with associated reason(s) provided by the PK scientist, will be generated.


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9.
REFERENCES
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
U. S. Food and Drug Administration. Center for Drug Evaluation and Research. Tricor 
(Fenofibrate) Tablets. Application Number: 21-656. Clinical Pharmacology and 
Biopharmaceutics Review(s). Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/021656s000_TricorT
OC.cfm.  05 November, 2004.
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER). Guidance for Industry. Statistical Approaches 
to Establishing Bioequivalence.  January, 2001.
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER). Guidance for Industry. Bioavailability and 
Bioequivalence Studies for Orally Administered Drug Products - General 
Considerations (Revision 1).  March, 2003.


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10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.
Phoenix WinNonlin® 7.0. Pharsight Corporation, Princeton, NJ, USA.
nQuery Advisor(R) Version 6.0 or newer. Statistical Solutions, Cork, Ireland.


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


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12.
APPENDIX 1 SCHEDULE OF ASSESSMENTS
Appendix 1.
Schedule of Assessments
Study Procedure
Screena
Day -2
Day -1
Day 1
Days 2-4
Day 5b
Day 13 (± 2 days)c
ETd
Written Informed Consent
X
Medical History 
X
Complete Physical Exam
X
X
Symptom-Driven Physical Examinatione
X
Xq
Xf
X
X
Height, Weight, BMI
X
Vital Signsg
X
X
Xq
Xf
X
X
X
HIV-1, HBV, and HCV Testing
X
Hematologyh
X
Xk
X
X
X
X
Chemistryh
X
Xk
X
X
X
X
Coagulationh
X
X
X
α-fetoprotein
X
Urinalysis 
X
Xk
X
X
X
X
Serum Pregnancy Testi
X
Xk
X
X
X
FSHj
X
Urine Drug and Alcohol Screen 
X
Xk
X
X
12-Lead ECG
X
X
Xf
X
X
X
Enrollment
Xl
X
Study Drug Administration
X
PK Assessmentsm
X
X
Biomarker Assessmentsp
X
X


GS-0976
GS-US-426-3988
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 37
10 September 2019
Study Procedure
Screena
Day -2
Day -1
Day 1
Days 2-4
Day 5b
Day 13 (± 2 days)c
ETd
Review Study Restrictions
X
X
X
X
X
Clinic Confinement
X
Review AEs & Concomitant Medicationso
X
a
Prospective subjects should be screened no more than 28 days prior to administration of the first dose of study drug.
b
Subjects will be discharged from the clinic on Day 5, following all morning assessments.
c
Subjects will return for a follow up visit on Day 13 (± 2 days).
d
Assessments will be performed within 72 hours of early termination from the study.
e
Symptom driven PEs will be performed during confinement as needed, based on reported signs and symptoms.
f
Predose and approximately 4 hours postdose
g
Vital signs include blood pressure, heart rate, respiration rate, and body temperature.
h
Hematology, Chemistry, Coagulation: See Protocol Section 6.10.5.1 for specifics.
i
Female subjects of child bearing potential only.
j
Female subjects ≤ 54 years old with amenorrhea > 12 months as outlined in Protocol Appendix 2
k
Two sets of safety labs will be collected upon clinic admission; one will be sent to the central lab and another will be sent to the sites' local lab to obtain results in time for 
enrollment on Day 1.
l
Subjects of Cohort 3 will be enrolled on Day 1.
m
Intensive PK sampling will occur relative to dosing of GS 0976 or fenofibrate on Day 1 at the following time points for each cohort:
Day 1: 0 (pre dose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post dose
A blood sample for PK analysis will be collected at the Early Termination (ET) visit (if applicable) and may be analyzed.
Plasma protein sampling will occur relative to dosing of GS 0976 or fenofibrate on Day 1 at the following time points for each cohort:
Day 1: 1 and 3 hours post dose
o
From the time of obtaining informed consent through the first administration of study drug, record all SAEs, as well as any nonserious AEs related to protocol mandated 
procedures on the AE CRF/eCRF.
All other untoward medical occurrences observed during the screening period, including exacerbation or changes in medical history, are to be captured on the medical history 
CRF/eCRF. See Protocol Section 7, Adverse Events and Toxicity Management for additional details.
p
Biomarker sampling will be collected relative to the planned or actual dosing time of GS 0976 at the following time points for Cohort 3 only: 
Day 1: 0, 1, 2, 3, 4, 6, 8, 12, and 16 hours postdose (relative to planned Day 1 dosing time)
Day 1: 0 (*pre dose, ≤ 5 minutes prior to dosing), 1, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose 
*
Pre dose sample on Day 1 will also serve as 24 hour postdose sample on Day 1. 
q
Prior to biomarker sample collection (Cohort 3 only)
CCI
CCI
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I 
I 
I 
I 
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GS-US-426-3988-SAP
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Pharmacology
eSigned
11-Sep-2019
15:50:46
Clinical Research eSigned 11-Sep-2019
16:33:18
Biostatistics eSigned
12-Sep-2019
00:37:36
PPD
PPD
PPD
---