Clinical trial NCT02808312
Conditions: Nonalcoholic Steatohepatitis (NASH) Primary Sclerosing Cholangitis (PSC)
Sponsor: Gilead Sciences
Start date: 2016-07-13; Completion date: 2018-10-16
Enrollment: 57 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the single-dose pharmacokinetics of cilofexor in adults with impaired hepatic function relative to matched, healthy controls with normal hepatic function.

Detailed description:

Arms: arm 1: Participants with mild hepatic impairment will receive a single oral dose of cilofexor 30 mg (3 x 10 mg tablets). arm 2: Matched normal hepatic function participants to mild hepatic impairment participants will receive a single oral dose of cilofexor 30 mg (3 x 10 mg tablets). arm 3: Participants with moderate hepatic impairment will receive a single oral dose of cilofexor 30 mg (3 x 10 mg tablets). arm 4: Matched normal hepatic function participants to moderate hepatic impairment participants will receive a single oral dose of cilofexor 30 mg (3 x 10 mg tablets). arm 5: Participants with severe hepatic impairment will receive a single oral dose of cilofexor 10 mg (1 x 10 mg tablet). arm 6: Matched normal hepatic function participants to severe hepatic impairment participants will receive a single oral dose of cilofexor 10 mg (1 x 10 mg tablet).
Interventions: intervention 1: Cilofexor
Intervention descriptions: intervention 1: Tablet(s) administered orally in a fed state on Day 1

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 1 Open-Label, Parallel-Group, Adaptive, Single-Dose 
Study to Evaluate the Pharmacokinetics and Pharmacodynamics of 
GS-9674 in Subjects with Normal and Impaired Hepatic Function
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND No.:
127960
Clinical Trials.gov
Identifier:
NCT02808312
EudraCT No.:
Not Applicable
Indication:
Nonalcoholic Steatohepatitis (NASH)
Protocol ID:
GS-US-402-3885
Gilead Medical Monitor
Name:
Telephone:
Fax:
Mobile:
Protocol Version/Date:
Original:
03 May 2016
Amendment 1: 29 July 2016
Amendment 2: 23 March 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The information contained in this document, particularly unpublished data, is the property or 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


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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....................................................................13
1.
INTRODUCTION ..............................................................................................................................................17
1.1.
Background ............................................................................................................................................17
1.2.
GS-9674 .................................................................................................................................................18
1.2.2.
Preclinical Pharmacology, Pharmacokinetics and Toxicology.............................................18
1.2.3.
Nonclinical Pharmacology ...................................................................................................19
1.2.4.
Nonclinical Pharmacokinetics..............................................................................................20
1.2.5.
Clinical Trials of GS-9674 ...................................................................................................21
1.3.
Rationale for This Study ........................................................................................................................25
1.3.1.
Rationale for the Dose Selection..........................................................................................26
1.4.
Risk/Benefit Assessment for the Study..................................................................................................26
1.5.
Compliance ............................................................................................................................................27
2.
OBJECTIVES.....................................................................................................................................................28
3.
STUDY DESIGN................................................................................................................................................29
3.1.
Study Design..........................................................................................................................................29
3.2.
Study Drug Administration ....................................................................................................................30
3.3.
Clinic Confinement ................................................................................................................................31
3.4.
Pharmacokinetic Assessments................................................................................................................31
3.4.1.
Plasma Pharmacokinetic Collection.....................................................................................31
3.5.
Safety Assessments ................................................................................................................................31
3.6.
Pharmacodynamic Biomarker Assessments...........................................................................................31
3.7.
Optional Genomic Research...................................................................................................................31
3.8.
End of Study...........................................................................................................................................32
4.
SUBJECT POPULATION..................................................................................................................................33
4.1.
Number of Subjects and Subject Selection ............................................................................................33
4.2.
Inclusion Criteria....................................................................................................................................33
4.2.1.
All Subjects ..........................................................................................................................33
4.2.2.
Subjects with Impaired Hepatic Function ............................................................................34
4.2.3.
Healthy Matched Control Subjects.......................................................................................35
4.3.
Exclusion Criteria...................................................................................................................................36
4.3.1.
All Subjects ..........................................................................................................................36
4.3.2.
Subjects with Impaired Hepatic Function ............................................................................37
4.3.3.
Healthy Control Subjects......................................................................................................38
5.
STUDY DRUGS.................................................................................................................................................39
5.1.
Enrollment  and Blinding.......................................................................................................................39
5.2.
Description and Handling of GS-9674...................................................................................................39
5.2.1.
Formulation..........................................................................................................................39
5.2.2.
Packaging and Labeling .......................................................................................................39
5.2.3.
Storage and Handling...........................................................................................................40
5.3.
Dosage and Administration of Study Drug ............................................................................................40
5.4.
Fed State Dosing ....................................................................................................................................40


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5.5.
Meals......................................................................................................................................................40
5.6.
Dispensing, Accountability, and Disposal or Return of Study Drug......................................................41
5.7.
Concomitant Medications and Other Protocol Restrictions ...................................................................41
5.7.1.
Concomitant Medications.....................................................................................................41
5.7.2.
Other Protocol Restrictions ..................................................................................................43
6.
STUDY ASSESSMENTS...................................................................................................................................44
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................44
6.2.
Pretreatment Assessments......................................................................................................................48
6.2.1.
Screening Visit .....................................................................................................................48
6.2.2.
Admission Assessments .......................................................................................................48
6.3.
Check-in Assessments............................................................................................................................49
6.4.
Treatment Assessments..........................................................................................................................49
6.5.
Posttreatment Assessments ....................................................................................................................49
6.6.
Assessments for Premature Discontinuation from Study.......................................................................49
6.7.
Criteria for Discontinuation of Study Drug for Multiple Dose Studies..................................................49
6.8.
Pharmacokinetic Assessments................................................................................................................50
6.8.1.
Plasma PK Collection...........................................................................................................50
6.9.
Pharmacodynamic Assessments.............................................................................................................50
6.10.
Optional Genomic Sample .....................................................................................................................51
6.11.
Safety Assessments ................................................................................................................................51
6.11.1.
Electrocardiogram Assessment ............................................................................................51
6.11.2.
Physical Examination...........................................................................................................52
6.11.3.
Vital Signs............................................................................................................................52
6.11.4.
Body Mass Index..................................................................................................................52
6.11.5.
Clinical Laboratory Tests/Assessments................................................................................52
6.11.6.
Creatinine Clearance ............................................................................................................53
6.11.7.
Adverse Events/Concomitant Medications/Protocol Restrictions........................................53
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................54
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................54
7.1.1.
Adverse Events.....................................................................................................................54
7.1.2.
Serious Adverse Events........................................................................................................54
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................55
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................55
7.2.2.
Assessment of Severity ........................................................................................................56
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................56
7.3.1.
Requirements for collection prior to study drug initiation: ..................................................56
7.4.
Gilead Reporting Requirements.............................................................................................................57
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................58
7.6.
Toxicity Management ............................................................................................................................58
7.7.
Study Specific Stopping Criteria............................................................................................................59
7.8.
Special Situations Reports......................................................................................................................59
7.8.1.
Definitions of Special Situations..........................................................................................59
7.8.2.
Instructions for Reporting Special Situations.......................................................................60
8.
STATISTICAL CONSIDERATIONS................................................................................................................62
8.1.
Analysis Objectives and Endpoints........................................................................................................62
8.1.1.
Analysis Objectives..............................................................................................................62
8.1.2.
Primary Endpoint .................................................................................................................62
8.1.3.
Secondary Endpoint .............................................................................................................62
8.2.
Analysis Conventions.............................................................................................................................62


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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.
Pharmacodynamics Analysis..................................................................................................................65
8.9.
Pharmacokinetics and Pharmacodynamics Analysis..............................................................................65
8.10.
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............................................................................................................................70
9.1.9.
Protocol Compliance............................................................................................................70
9.2.
Sponsor Responsibilities ........................................................................................................................70
9.2.1.
Protocol Modifications.........................................................................................................70
9.2.2.
Study Report and Publications .............................................................................................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 ..............................................................71
9.3.4.
Study Discontinuation..........................................................................................................71
10.
REFERENCES ...................................................................................................................................................72
11.
APPENDICES ....................................................................................................................................................74
Appendix 1.
Investigator Signature Page....................................................................................................75
Appendix 2.
Management of Clinical and Laboratory Adverse Events......................................................76
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................77
Appendix 4.
Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities ..........79


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LIST OF IN-TEXT TABLES
Table 1-1.
Exposure Margins for GS-9674 Based on Observed GS-9674 Exposure after 
Administration of 300 mg GS-9674 QD under Fasting Conditions at Steady-State in 
Cohort 4 Compared to Exposures Observed at NOAEL doses in Mouse and 
Cynomolgous Monkey ...........................................................................................................19
Table 1-2.
Preliminary Plasma Pharmacokinetic Parameters of GS-9674 Following Single and 
Multiple Dose Administration of GS-9674 Under Fasting Conditions in Healthy 
Volunteers (GS-US-402-1851)...............................................................................................22
Table 1-3.
GS-US-402-3885: Preliminary GS-9674 and GS-716070 PK Parameters Following 
a Single Dose of GS-9674 30 mg in Subjects with Hepatic Impairment or Normal 
Hepatic Function ....................................................................................................................25
Table 5-1.
List of Disallowed Medications..............................................................................................42
Table 6-1.
Schedule of Assessments........................................................................................................45
LIST OF IN-TEXT FIGURES
Figure 3-1.
Cohorts 1, 2, and 3 Study Schema..........................................................................................30


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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, Adaptive, Single-Dose Study 
to Evaluate the Pharmacokinetics and Pharmacodynamics of GS-9674
in Subjects with Normal and Impaired Hepatic Function
IND Number:
EudraCT Number:
127960
Not Applicable
Study Centers 
Planned:
Multiple Sites in the United States and New Zealand
Objectives:
The primary objective of this study is as follows:

To evaluate the single-dose pharmacokinetics of GS-9674 in 
subjects with impaired hepatic function relative to matched, 
healthy controls with normal hepatic function
The secondary objective of this study is as follows:

To evaluate the safety and tolerability of GS-9674 single dose 
administration in subjects with normal hepatic function, or mild, 
moderate, and severe hepatic impairment

To evaluate Farnesoid X Receptor (FXR) activation by GS-9674
as measured by pharmacodynamic (PD) markers in subjects with 
normal hepatic function, or mild, moderate and severe hepatic 
impairment
Study Design:
Phase 1, open-label, single-dose, parallel-group, staggered-cohort, 
pharmacokinetic (PK) study
Number of Subjects 
Planned:
Enroll approximately 60 subjects for 48 evaluable:
Cohort 1: GS-9674: 20 [10 per group (mildly impaired and matched 
controls) for 8 evaluable per group]
Cohort 2: GS-9674: 20 [10 per group (moderately impaired and 
matched controls) for total 8 evaluable per group]
Cohort 3: GS-9674: 20 [10 per group (severely impaired and matched 
controls) for total 8 evaluable per group]
A subject with normal hepatic function may serve as a matched 
control across cohorts evaluating the same GS-9674 dose. 


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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) 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: Male and nonpregnant/nonlactating female subjects aged   
≥ 18 years with mildly impaired and normal hepatic function. 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 mild hepatic impairment group. Subjects with 
mild hepatic impairment must have a score of 5-6 on the CPT
Classification at Screening without evidence of worsening clinical 
and/or laboratory signs of hepatic impairment within 2 months prior 
or within the screening period.
Cohort 2: Male and nonpregnant/nonlactating female subjects aged ≥ 
18 years with moderately impaired and normal hepatic function. 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 without evidence of worsening 
clinical and/or laboratory signs of hepatic impairment within 2 
months prior or within the screening period.
Cohort 3: Male and nonpregnant/nonlactating female aged ≥ 18 years 
with severely impaired and normal hepatic function. Each subject in 
the control group will be matched for age (± 10 years), gender, race, 
and body mass index (± 15% 18 ≤BMI ≤36kg/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 without evidence of worsening clinical and/or laboratory 
signs of hepatic impairment within 2 months prior or within the 
screening period.


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Study Procedures/
Frequency:
Following screening procedures and Day -2 admission assessments, 
eligible subjects will be enrolled in 1 of three sequential cohorts. 
Subjects will undergo intensive sampling over 24 hours on Day -1 
after administration of placebo-to-match (PTM) for baseline PD 
markers.  On Day 1 subjects will receive a single dose of 
GS-967430 mg (3 x 10 mg tablet) orally for Cohorts 1 and 2 or 10 mg
(1 x 10 mg tablet) for Cohort 3. In general, dosing in subjects with 
normal hepatic function will begin after a matched subject with 
hepatic impairment has completed PK assessments.
Cohorts 1 through 3 will be dosed in a sequential manner, with dosing 
of subjects in Cohort 2 (moderate hepatic impairment) and Cohort 3 
(severe hepatic impairment) proceeding after review of safety and 
available preliminary pharmacokinetic data from hepatic impaired 
subjects in the previous cohorts. Based on the cumulative review of 
safety and PK data, sequential cohorts may or may not be initiated at 
the discretion of the investigator and Sponsor.
Study Visits and Confinement
Following screening assessments, eligible subjects will be admitted to 
the clinic on Day -2 and confined to the clinic for the duration of the 
study until discharge on Day 5.
Subjects will be required to return for a Follow-up (FU) visit 10-14 
days after study drug dosing.
Study Drug Administration
The study drug will be supplied as GS-9674 tablets strengths of 
10 mg or PTM.  All study treatments will be administered with 240 
mL of water.
Study Treatments will be administered in the fed state as described 
below.
Fed state dosing:
Study drugs will be administered following an overnight fast (no food 
or drinks except water) for at least 10 hours and within 5 minutes of 
completing a standardized meal (moderate-fat-calorie breakfast 
containing ~600 kcal and 25% to 30% fat will be provided). The meal 
should be initiated 30 minutes prior to study drug administration. 
Subjects will fast until after collection of the 4-hour PK/PD 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 drugs and the standardized meal.  A standardized meal 
may be provided to subjects after the 4-hour post-dose PK/PD draw.


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Pharmacokinetic Assessments
Plasma PK Collection
Intensive PK sampling will occur relative to dosing of GS-9674 at the 
following time points for each cohort:

Day 1: -0.5, 0 (pre-dose, ≤ 5 minutes prior to dosing), 0.25, 0.5, 1, 
1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours 
post-dose
Plasma concentrations of GS-9674 (and its metabolites, as applicable) 
will be determined and PK evaluated. Pharmacokinetic parameters 
will be estimated, as appropriate.
In addition, on Day 1 at the 3 and 5 hours post dose time-points, an 
additional plasma samples will be collected for plasma protein 
binding evaluation. Alternatively, pre-dose samples may be utilized 
for plasma protein binding evaluation.
A blood sample for PK analysis will also be collected at the Early 
Termination (ET) visit (if applicable) and may be analyzed.
Pharmacodynamic (PD) Assessments
Plasma and/or Serum PD Collection
Blood samples will be collected relative to dosing of GS-9674 or 
PTM to measure PD biomarkers including but not limited to FGF19 
(fibroblast growth factor 19) and C4 (7-alpha-hydroxy-4-cholesten-3-
one) for GS-9674 at the following time points for each cohort:

Day -1: -0.5, 0 (predose, ≤ 5 minutes prior to dosing), 0.25, 0.5, 1, 
1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, and 16 (relative to Day 1 
dosing time assignment)

Day 1: -0.5, 0 (pre-dose, ≤ 5 minutes prior to dosing), 0.25, 0.5, 1, 
1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours 
post-dose
A single blood sample will be collected for analysis including but not 
limited to bile acids at the following time point:
Day 1: -0.5 hours predose
A blood sample for PD analysis will also be collected at the Early 
Termination (ET) visit (if applicable) and may be analyzed.
Genomic Sample
For subjects who provide consent, an additional blood sample will be 
collected for genetic research to identify or validate genetic markers 
that may be predictive of the safety and/or tolerability of study drug 
used in this protocol. This sample should be collected on Day 1, but 


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may be collected at any time during the study or at a separate post-
study visit, if necessary.
Safety Assessments-- Cohorts 1, 2, and 3
Complete Physical exam: Screening and ET visit (if applicable) 
Symptom-directed physical exam: Days -2, 5, and FU visit
Vital signs (blood pressure, pulse, respiration rate, and temperature): 
Screening, Days -2, 1 (predose and at approximately 3 hours 
postdose), 5, and FU visit or ET visit (if applicable)
Height, Weight, and BMI: Screening
Clinical Laboratory Tests (hematology, fasting chemistry, and 
urinalysis: Screening, Days -2 (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) , 5, and FU visit or at ET visit (if applicable)
Coagulation (PT, PTT, INR): Screening and FU Visit
Urine drug/alcohol assessment: Screening, Day -2, and at the FU visit 
or at ET visit (if applicable).
12-lead ECG: Screening, Days -2, 5, and at the FU visit or ET visit (if 
applicable)
Serum Pregnancy Test (female subjects of childbearing potential): 
Screening
Urine Pregnancy Test (female subjects of childbearing potential): 
Days -2, 5, and at the FU visit or at 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 Adverse Events (AEs) and concomitant medications 
will continue throughout the study.
Test Product, Dose, 
and Mode of 
Administration:
Cohorts 1 and 2: A single oral dose of GS-9674 30 mg (3 x 10 mg
tablet) administered on Day 1
Cohort 3: A single oral dose of GS-9674 10 mg (1 x 10 mg tablet) 
administered on Day 1


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Reference Therapy, 
Dose, and Mode of 
Administration:
Cohorts 1 and 2: A single oral dose of PTM GS-9674 30 mg (3 x 
PTM 10 mg tablet) administered on Day -1 
Cohort 3: A single oral dose of PTM GS-9674 10 mg (1 x PTM 
10 mg tablet) administered on Day -1
Criteria for 
Evaluation:
Safety:
Safety will be evaluated by physical examinations, vital signs, clinical 
laboratory tests and ECGs at various time points during the study, and 
by documentation of adverse events (AEs)
Efficacy:
Not applicable.
Pharmacokinetics:
The following plasma PK parameters will be calculated for GS-9674, 
as applicable: % AUCexp, AUClast, AUCinf, Cmax, Tmax, Clast, Tlast, z, 
CL/F, V/F and T½.
Percent plasma protein binding will be determined and PK parameters 
adjusted for protein binding will be estimated.
Pharmacodynamics:
FXR activation will be evaluated by PD markers including but not 
limited to FGF19 and C4.
Statistical Methods:
GS-9674 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 (e.g., 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 
GS-9674. The 90% confidence intervals (CIs) will be constructed for
the geometric least squares mean (GLSM) ratio of PK parameters for 
GS-9674 in the mild, moderate, or severe hepatic impairment group 
versus the control (normal hepatic function) group.
Safety data will be listed by subject and summarized by hepatic 
function group and frequency of event/abnormality or descriptive 
statistical summaries, as appropriate.
Pharmacodynamic and PK/PD relationships will be explored as 
appropriate.
For each cohort, with 16 (8 per group) evaluable subjects, the 
estimated upper limit of one-sided 95% CI of the GLSM ratio of 


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(mild, moderate or severe) hepatic impaired group vs control (normal 
hepatic function), with regards to AUClast, AUCinf, and Cmax, would
be less than 200% with ≥ 88% probability, if the estimated GLSM 
ratio were 1.0. This is assuming a SD of no more than 0.463 on a 
natural logarithm scale, supported by previous Gilead study 
GS-US-402-1851. With 25% overage, a total sample size of
60 subjects (10 per group, 20 per cohort) 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
C 
degrees Celsius
F
degrees Fahrenheit
%CV
% coefficient of variation
AE
adverse event
AME
absorption, metabolism, and elimination
ALT
alanine aminotransferase (previously serum glutamic pyruvic transaminase
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
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
BLQ
below limit of quantitation
BMI
body mass index
bpm
beats per minute
BUN
blood urea nitrogen
C4
7-alpha-hydroxy-4-cholesten-3-one
CBC
complete blood count
CBER
Center for Biologics Evaluation and Research
CDER
Center for Drug Evaluation and Research
CFR
Code of Federal Regulations
CI
confidence interval
CK
creatine kinase
CL
systemic clearance
CL/F
apparent oral clearance after administration of the drug:
CL/F = Dose/AUCinf, where “Dose” is the dose of the drug
CLss/F
apparent oral clearance at steady state after administration of the drug:
CLss/F = Dose/AUCtau, 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
CRF
case report form
CRO
contract (or clinical) research organization 
CSR
clinical study report


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CTA
clinical trial application
Ctau
observed drug concentration at the end of the dosing interval
DDI
drug-drug interaction
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EudraCT
European Clinical Trials Database
eGFR
estimated glomerular filtration rate
ESA
erythropoiesis-stimulating agent
eSAE
electronic serious adverse event
ET
early termination
EU
European Union
E2
depressed estradiol
FDA
Food and Drug Administration
FGF19
fibroblast growth factor 19
FSH
follicle-stimulating hormone
FU
follow-up
FXR
Farnesoid X Receptor
GCP
Good Clinical Practice
GCSF
Granulocyte colony stimulating factor
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
HIV, HIV-1
human immunodeficiency virus, type 1
HLGT
high-level group term
HLT
high-level term
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonization (of Technical Requirements for Registration
of Pharmaceuticals for Human Use)
ID
identification


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IEC
independent ethics committee
IND
investigational new drug (application)
IRB
institutional review board
IUD
intrauterine device
LDL
low-density lipoprotein
LLT
lower-level term
LLOQ
lower limit of quantitation
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MM
medical monitor
NDA
new drug application
PD
pharmacodynamic(s)
PG
pharmacogenomics
PI
principal investigator, package insert
PK
pharmacokinetic(s)
PR interval
electrocardiographic interval occurring between the onset of the P wave and the QRS 
complex representing time for atrial and ventricular depolarization, respectively
PT
preferred term, prothrombin time
PTT
partial thromboplastin time
QA
quality assurance
QRS
electrocardiographic deflection between the beginning of the Q wave and termination of 
the S wave, representing time for ventricular depolarization
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
SADR
serious adverse drug reaction
SAE
serious adverse event 
SAP
statistical analysis plan
SD
standard deviation
SOC
system organ class
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
Tlast
time (observed time point) of Clast
Tmax
the time (observed time point) of Cmax
TOST
two one-sided tests
TQT
thorough QT
TT
thrombin time
t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the natural 


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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
%AUCexp
percentage of AUC extrapolated between AUClast and AUCinf
λz
elimination phase of the log serum/plasma/PBMC concentration versus time curve of the 
drug


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1.
INTRODUCTION
1.1.
Background
Chronic liver disease and the consequences of end-stage liver disease are increasing globally 
despite improved prevention and treatment of viral hepatitis. This is due to the emerging 
epidemics of obesity, metabolic syndrome, and diabetes mellitus that are leading to an increased 
incidence of nonalcoholic fatty liver disease (NAFLD). Nonalcoholic fatty liver disease is 
characterized by the excess accumulation of lipid droplets within the liver, also known as hepatic 
steatosis. Prevalence rates of NAFLD range from 6% to 37% worldwide {Vernon et al 2011},
{Ong et al 2007}. Nonalcoholic steatohepatitis (NASH), an aggressive form of NAFLD 
characterized by the presence of inflammation and hepatocellular ballooning, with or without 
fibrosis, is present in approximately 25% of patients with NAFLD. Nonalcoholic steatohepatitis 
is associated with increased liver-related mortality {Williams et al 2011}, {Ong et al 2007}. In 
the United States (US), it has been estimated that 3% to 6% of the population {Vernon et al 
2011}, {Wanless et al 1990}, or the equivalent of up to 15 million adults, have NASH.NASH 
represents a significant and growing unmet medical need for which there are no currently 
approved therapies. Furthermore, as NASH is a manifestation of the metabolic syndrome, risk 
factors for cardiovascular disease (eg, atherosclerotic disease, cardiac arrhythmogenicity) 
frequently coexist in these patients {Faramawi et al 2008}, {Voulgari et al 2010}, {Dietrich et al 
2014}. A treatment that targets the underlying metabolic disorder could potentially ameliorate 
these cardiovascular risks and associated morbidity and mortality.
Nonalcoholic steatohepatitis is primarily thought to occur as the result of the metabolic 
syndrome, the impact of obesity, insulin resistance, and dyslipidemia in the liver. Simple 
steatosis is not sufficient to cause liver injury; it is the presence of inflammation and 
hepatocellular injury on the background of steatosis that defines NASH and results in the 
progression to end-stage liver disease and its complications. The “2-hit” hypothesis of NASH 
suggests that in the setting of steatosis and metabolic dysfunction, increased oxidative stress and 
the generation of reactive oxygen species (ROS) likely mediate the inflammatory changes in the 
liver (steatohepatitis) that may lead to progressive fibrosis {Dowman et al 2010}, {Kannel et al 
1982}, {Koek et al 2011}, {Sumida et al 2013}. The major pathways in NASH disease 
progression include those involved in metabolic dysfunction in the hepatocyte, and activation of 
hepatic stellate cells and macrophages leading to progressive inflammation and liver fibrosis. 
Advanced fibrosis and cirrhosis are characterized by extensive collagen deposition and 
remodeling of the extracellular matrix.
Over time, NASH may result in progressive liver fibrosis, ultimately leading to cirrhosis in
10-20% of affected patients. Advanced fibrosis (bridging fibrosis or cirrhosis) is associated with 
increased morbidity and mortality {Ekstedt et al 2015}, {Yeh et al 2014}. Patients with cirrhosis 
may develop hepatocellular carcinoma (HCC) and other complications of end-stage liver disease, 
including jaundice, fluid retention (edema and ascites), portal hypertension and variceal
bleeding, impaired coagulation and hepatic encephalopathy. Decompensated liver disease, as 
defined by the development of one of the above complications, has a high mortality and the only


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known effective treatment is liver transplantation. With the increasing prevalence of obesity and 
obesity-related diseases, NASH is expected to become the leading indication for liver 
transplantation, and the leading etiology of HCC among liver transplant recipients in the US 
{Wong et al 2014}, {Afzali et al 2012}.
1.2.
GS-9674
GS-9674 is a potent agonist of Farnesoid X Receptor (FXR) whose activity in intestinal 
epithelial cells results in the release of fibroblast growth factor 19 (FGF19). FGF19 is an 
endocrine peptide which drives a signaling cascade to decrease lipogenesis, gluconeogenesis, 
hepatic triglyceride accumulation, and bile acid synthesis. Please refer to the Investigator’s 
Brochure (IB) for additional information on GS-9674 including:

In Vitro FXR agonism

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology
1.2.1.1.
General Information
For further information on GS-9674, refer to the current IB for GS-9674
1.2.2.
Preclinical Pharmacology, Pharmacokinetics and Toxicology
The nonclinical toxicity profile of GS-9674 has been assessed in mice and cynomolgus monkeys 
administered GS-9674 orally for up to 4 weeks. GS-9674-related effects were limited to non-
adverse findings in the liver for both species that are likely related to the pharmacology of the 
compound. In both mice and cynomolgus monkeys, mild increases in ALP activity, liver weight, 
and hepatocellular hypertrophy were observed. Minimal oval cell hyperplasia was also observed 
in the liver of cynomolgus monkeys. Additional findings in mice included mild decreases in 
cholesterol and triglycerides. Findings were observed at ≥ 100 mg/kg/day in mice and 
300 mg/kg/day in cynomolgus monkeys. Because these findings were considered non-adverse, 
the no observed adverse effect levels (NOAELs) in mice and cynomolgus monkeys were the 
highest doses evaluated (600 and 300 mg/kg/day, respectively).
Preliminary steady-state PK data from Cohort 4 (administration of GS-9674 300 mg) in the 
ongoing First-in-Human study of GS-9674 (GS-SU-402-1851: Section 1.2.5) indicate adequate 
safety margins based on GS-9674 exposures at the nonclinical NOAEL doses in mouse and 
cynomolgus monkey (Table 1-1).


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Table 1-1.
Exposure Margins for GS-9674 Based on Observed GS-9674 Exposure 
after Administration of 300 mg GS-9674 QD under Fasting 
Conditions at Steady-State in Cohort 4 Compared to Exposures 
Observed at NOAEL doses in Mouse and Cynomolgous Monkey
Species
NOAEL
Exposure Margina
Dose mg/kg/day
AUCtau
µg•h/mL
Mouse
600
189
15
Cynomolgus Monkey
300
148
12
a
Calculated using observed AUCtau of 12.5 μg•h/mL from Healthy Volunteers administered 300 mg GS-9674 QD
1.2.3.
Nonclinical Pharmacology
GS-9674 is a potent and selective agonist of FXR. This conclusion is supported by the following 
data: 1) modeling demonstrated an interaction of GS-9674 with the binding domain of FXR 
consistent with agonist activity, 2) GS-9674 induced an agonist response in a time-resolved 
fluorescence resonance energy transfer (TR-FRET) biochemical assay with an EC50 of 16 nM, 
which was comparable to that of other known FXR agonists, and 3) GS-9674 did not activate the 
structurally similar bile acid receptor TGR5, did not activate other nuclear hormone receptors, 
and did not bind to a panel of other off-target receptorsN and enzymes.
The cellular potency of GS-9674 to activate FXR-mediated transcription was characterized using 
a firefly luciferase reporter gene engineered under the control of a FXR/RXR response element 
(PC-402-2012). GS-9674 caused complete FXR activation with an EC50 value of 43 nM, which 
was more potent than chenodeoxycholic acid (EC50 of 1770 nM).
Oral dose-ranging experiments in male cynomolgus monkeys demonstrated maximal increases in 
plasma FGF19 at a dose of 5 mg/kg (PC-402-2016). In addition, the oral administration of
GS-9674 (30 mg/kg) to cynomolgus monkeys directly activated intestinal FXR, as measured by 
the expression of FXR-target genes in the ileum (15-fold increase in FGF19 mRNA, and a 2-fold 
increase in organic solute transporter (OST)α and OSTβ mRNA) (PC-402-2005).
The effects of GS-9674 on FGF19 levels were compared in cynomolgus monkeys following both 
oral and intravenous (IV) administration (PC-402-2016). Despite greater exposures following IV 
administration, only the oral administration of GS-9674 increased circulating FGF19 levels. 
These data indicate that intestinal FXR agonism by GS-9674 causes FGF19 production, whereas 
low systemic free drug concentrations limit effects following IV administration of GS-9674.
GS-9674 was evaluated in a choline-deficient high fat diet /NaNO2 rat model of liver fibrosis 
(PC-402-2015). This in vivo model utilized “2 hits” to mimic the metabolic and oxidative stress 
components of NASH disease in humans {Nakamoto et al 2009}, {Murakami et al 2013}. 
Treatment with GS-9674 dose-dependently reduced both biochemical and histological measures 
of liver fibrosis in this model.


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Safety pharmacology studies have been conducted to examine the potential effects of GS-9674
on the cardiovascular (CV), respiratory, and central nervous system (CNS) systems. There were 
no GS-9674-related effects on the CNS or respiratory system in mice administered up to
600 mg/kg. In addition, there was no significant human ether-a-go-go-related gene inhibition at 
concentrations up to 100 μM or GS-9674-related effects on the CV system in monkeys 
administered up to 300 mg/kg.
Overall, the results from these pharmacology studies demonstrate that GS-9674 is a potent and 
selective agonist of intestinal FXR with the potential to benefit NASH patients by inducing 
FGF19 production.
1.2.4.
Nonclinical Pharmacokinetics
GS-9674 is expected to be poorly absorbed in humans based on low oral bioavailability in 
nonclinical species (approximately 10% and 20% when dosed as 
 
). Low, pH-dependent solubility and efflux transport have been 
identified as factors likely limiting GS-9674 absorption.
The low systemic clearance (CL) of GS-9674 in rats, dogs and monkeys was considerably lower 
than the predicted hepatic clearance based on in vitro studies with hepatocytes. This discrepancy 
is most likely a result of protein-restricted clearance in vivo due to the very high plasma protein 
binding (> 99.6%) across species. The volume of distribution (Vss) of GS-9674 was consistent 
with extracellular fluid (ranging from 0.16-0.21 L/kg) in rats, dogs, and monkeys.
Using the estimates of bioavailability, CL, and Vss in nonclinical species, and assuming linear 
kinetics, a 300-mg twice-daily dose of GS-9674 is projected to give a Cmax of 3.8 μg/mL and 
AUC0-24 of 34.4 μg/mL•h in humans.
After oral dosing to albino and pigmented mice, [14C]GS-9674-derived radioactivity was 
distributed to most of the tissues, with the highest maximum concentrations of radioactivity 
determined in organs of absorption and excretion. Generally similar distribution patterns and 
tissue concentrations of [14C]GS-9674-derived radioactivity were observed in albino and 
pigmented mice with no observed binding to melanin. In both strains, no quantifiable 
radioactivity was detected in brain, suggesting [14C]GS-9674-derived radioactivity did not cross 
the blood:brain barrier. Fecal elimination was a predominant route of elimination of
[14C]GS-9674-derived radioactivity in both mice (85.7% and 5.45% recovered in feces and 
urine, respectively) and monkeys (78.2% and 69.7% recovered in feces in intact and bile duct 
cannulated animals) likely representing drug not absorbed from the gastrointestinal tract. 
Approximately 6% of the administered radioactivity was excreted in bile and urine in monkeys. 
Radiolabeled material was primarily excreted within the first 48 hours.
GS-9674 undergoes oxidative metabolism in human hepatocytes. Comparison of metabolism in 
hepatocytes from mice, rats, dogs, monkeys, and humans did not identify any metabolites unique 
to humans, supporting the selection of mice and monkeys for the assessment of the toxicology of 
GS-9674. Of the recombinant human CYP isozymes tested, CYP2C8, CYP3A4, and CYP2C19 
were shown to metabolize GS-9674. Potent inhibitors of these CYPs therefore may affect 
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metabolism of GS-9674. GS-9674 had little inhibitory effect on the activities of CYP1A2, 
CYP2B6, CYP2C19 or CYP2D6 (IC50 > 25 μM). For CYP2C8, CYP2C9, and CYP3A, IC50 
values of 2.4 to 13.6 μM were obtained but GS-9674 was not a mechanism-based inhibitor of 
these enzymes. GS-9674 showed moderate inhibition of human UGT1A1, sodium-taurocholate 
cotransporting polypeptide (NTCP), and bile salt export pump (IC50 2.8-7.7 μM). GS-9674
inhibited human OATP1B1, OATP1B3, and OATP2B1 with IC50 values of 0.68, 0.41, and 0.21 
μM, respectively. GS-9674 therefore has the potential to affect hepatic/intestinal uptake of 
OATP substrates or metabolism of CYP2C8, CYP2C9, or CYP3A4 substrates when its 
concentrations are sufficiently high. However, low solubility, high protein binding (> 99.98%) 
and low systemic levels reduce the potential for GS-9674 to cause drug-drug interactions via 
inhibition of metabolic enzymes and transporters.
GS-9674 was a substrate for efflux transporters P-glycoprotein and breast cancer resistance 
protein, as well as the uptake transporters OATP1B1, 1B3, and 2B1, and NTCP. Inhibitors or 
genetic polymorphisms affecting the activity of these transporters may affect GS-9674 intestinal 
absorption and hepatic uptake. This was illustrated in an in vivo study in monkeys where 
pretreatment with cyclosporin A, a known inhibitor of efflux transporters, increased the 
bioavailability of GS-9674 approximately 5-fold.
GS-9674 is highly selective for FXR over other nuclear hormone receptors in cell-based reporter 
assays, including those associated with potential for induction of human drug metabolizing 
enzymes and transporters (eg, pregnane X receptor, constitutive androstane receptor). Thus the 
liability of GS-9674 to cause drug-drug interactions through proteins regulated by these nuclear 
receptors is low.
1.2.5.
Clinical Trials of GS-9674
Ongoing clinical experience with GS-9674 includes a Phase 1 clinical study (GS-US-402-1851). 
A brief PK summary of results from this ongoing study is presented below.
1.2.5.1.
GS-US-402-1851
Study GS-US-402-1851 is an ongoing Phase 1, randomized, single-blind, placebo-controlled, 
single- and multiple-dose study in healthy volunteers with 4 pre-specified staggered dose-
escalation cohorts and 4 adaptive randomized, single-blind, placebo-controlled, single- and 
multiple dose cohorts with adaptive dose selection and dose frequency.
Approximately 60 subjects have been enrolled into the 4 pre-specified cohorts with preliminary 
data presented below.
Summary of subjects enrolled/dosed and safety data available for Cohorts 1-4 based on interim 
safety data from 13-April-2016:


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Preliminary safety data for GS-9674 after single and multiple dose administration of 10, 30, 100, 
or 300 mg GS-9674 demonstrated no adverse events of grade 3 or higher, no serious adverse 
events, and no subjects discontinued GS-9674 due to adverse event. Overall rate of any adverse 
event was  4/15 (27%) in the 10mg cohort, 4/15 (27%) in the 30mg cohort, 3/15 (20%) in the 
100mg cohort, and 4/15 (27%) in the 300mg cohort. All adverse events were grade 1 or 2 in 
severity, did not result in dose interruption or discontinuation and were not felt to be related to 
GS-9674 by the investigator.
Preliminary PK parameters for GS-9674 after single and multiple dose administration of 10, 30, 
100 or 300 mg GS-9674 under fasting conditions in healthy volunteers  are presented below in 
Table 1-2. GS-9674 was absorbed quickly with the maximum plasma concentration (Cmax) 
occurring between 1.25 to 3.25 hours post dose (median Tmax) with a bi-phasic decline after Cmax.  
Across the doses tested, GS-9674 exhibited a median half-life (T1/2) of 5.56 to 12.8 hours. The 
lower observed median half-life 5-6 hours in the 10 mg and 30 mg cohorts may be a result of 
plasma concentrations falling below the limit of quantitation during the distributional phase of 
the profile. In general, GS-9674 AUC and Cmax increased less than dose proportionally above 
10 mg upon single and multiple dosing.  As expected based on the short GS-9674 T1/2 and once 
daily dosing, minimal to no accumulation was observed for GS-9674 AUC, Cmax or C24 from 
single to multiple dose administration.
Table 1-2.
Preliminary Plasma Pharmacokinetic Parameters of GS-9674
Following Single and Multiple Dose Administration of GS-9674 Under
Fasting Conditions in Healthy Volunteers (GS-US-402-1851).
Parameter 
(N=12) Mean 
(%CV)
Cohort 1: 10 mg
(N=12)
Cohort 2: 30 mg
(N=12)
Cohort 3: 100 mg
(N=12)
Cohort 4: 300 mg
(N=12)
Single 
Dose
AUCinf (ng*hr/ml)
1260 (30.3)
2480 (37.2)
7740 (93.9)
12,500 (33.9)
Cmax (ng/ml)
304 (41.6)
580 (48.9)
2590 (118)
3060 (66.2)
C24 (ng/ml)
2.61 (49.9)b
6.04 (35.7)
23.5 (40.0)
76.0 (67.4)
Tmax (hr)a
3.00 (2.38, 4.00)
3.00 (2.38, 3.63)
1.75 (1.38, 2.63)
1.25 (1.00, 3.13)
T1/2 (hr)a
5.56 (5.46, 6.41)
8.10 (5.74, 9.58)
11.2 (8.30, 11.9)
12.4 (11.4, 13.9)
Mulitple 
Dose
AUCtau (ng*hr/ml)
1280 (35.8)
2890 (23.5)
6720 (59.2)
8490 (48.8)
Cmax (ng/ml)
322 (42.4)
718 (32.8)
2230 (75.9)
2330 (81.5)
Ctau (ng/ml)
2.75 (55.5)
7.90 (50.3)
36.3 (42.5)
70.1 (56.3)
Tmax (hr)a
2.50 (1.50, 3.50)
3.00 (1.88, 3.13)
1.50 (1.00, 2.63)
3.25 (1.00, 5.00)
T1/2 (hr)a
6.75 (5.64, 8.45)
5.95 (5.54, 6.55)
8.99 (6.84, 11.49)
12.8 (10.0, 14.7)
Pharmacokinetic parameters are presented as Mean (%CV), and shown to 3 significant digits 
a
Tmax and T1/2 are presented as median (Q1; Q3) 
b
N=11


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1.2.5.2.
GS-US-402-3885 (current study)
Study GS-US-402-3885 is an ongoing Phase 1, open-label, parallel-group, single dose study 
evaluating the safety, tolerability, PK, and PD of GS-9674 in subjects with normal hepatic 
function and mild, moderate, or severe hepatic impairment. Up to 60 subjects are planned for 
enrollment in 1 of 3 hepatic impairment cohorts: Cohort 1 (mild hepatic impairment, CPT Class
A), Cohort 2 (moderate hepatic impairment, CPT Class B), and Cohort 3 (severe hepatic 
impairment, CPT Class C).
Within each cohort, each subject with impaired hepatic function (N=10 per cohort) will be 
matched for age (± 10 years), sex, race, and body mass index (BMI: ± 15%) with a control 
subject with normal hepatic function (N=10 per cohort). Data from healthy subjects may be used 
in >1 cohort if a subject was an appropriate match for a subject with hepatic function in >1 
cohort. All subjects will receive a single oral dose of GS-9674 30 mg in the fed state on Day 1 
with PD collected on Day -1 and Day 1.
1.2.5.2.1.
Subject Disposition 
As of 1 November 2017, a total of 37 subjects were enrolled and 36 subjects had completed 
study treatment. One subject prematurely discontinued study treatment due to quality issues at 
the site that justified a suspension in dosing at the site. No subjects prematurely discontinued due 
to an AE, withdrew consent, or were lost to follow-up.
1.2.5.2.2.
Preliminary Safety Results 
Overall, 8.8% of subjects had a treatment-emergent adverse event (TEAE) of Grade 1 or 2. There 
was 1 SAE of gastrointestinal bleed that was not related to study drug. This subject had a history 
of esophageal variceal bleeding and experienced bleeding requiring hospitalization and blood 
transfusion. There were no pregnancies or deaths. 
In the mild hepatic impairment cohort, there were 2 subjects (20%) that had Grade 3 lab 
abnormalities of elevated GGT and low platelets. The Grade 3 GGT was stable from the 
subject’s baseline. There was 1 healthy matched control subject (10%) who had Grade 3 lab 
abnormalities in total cholesterol and LDL cholesterol, which were stable from their baseline. In 
the moderate hepatic impairment cohort, 2 subjects (20%) had Grade 3 lab abnormalities. One 
subject had low lymphocytes, and the other subject had elevated total bilirubin and low platelets. 
The platelet count was not changed from the subject’s baseline. One subject, who had a SAE of 
gastrointestinal bleeding in the moderate hepatic impairment cohort (described above), had a 
Grade 4 lab abnormality of low hemoglobin.


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1.2.5.3.
Preliminary PK Results
Preliminary PK results are presented below and in Table 1-3:

Cohort 1 (mild hepatic impairment; CPT Class A): GS-9674 exposure (AUCinf and Cmax) was 
higher in subjects with mild hepatic impairment (approximately 76% and 57%, respectively) 
as compared to subjects with normal hepatic function. In subjects with mild hepatic 
impairment, exposure (AUCinf and Cmax) of the metabolite GS-716070 was similarly higher 
(approximately 64% and 25%, respectively). Both analytes had minor changes in plasma 
protein binding (unbound fraction [fu] increased ~30%). GS-9674 is a substrate of hepatic 
OATP and CYP2C8 expression/activity of these transporters and enzymes may be altered in 
patients with hepatic impairment and may contribute to the observed higher systemic 
exposure of GS-9674. At a dose of 30 mg QD in subjects with mild hepatic impairment, 
exposure margins relative to preclinical NOAEL exposures for both parent and metabolite 
are expected to remain adequate.

Cohort 2 (moderate hepatic impairment; CPT Class B): GS-9674 exposure (AUCinf and Cmax) 
was higher in subjects with moderate hepatic impairment (approximately 2.3- and 1.6-fold, 
respectively) as compared to subjects with normal hepatic function. Exposure (AUCinf) of the 
metabolite GS-716070 was also higher (approximately 1.6-fold) with minimal change in 
Cmax. Plasma unbound fraction (fu) of GS-9674 and GS-716070 was  increased ~96% and 
~85%, respectively, in moderate hepatic impairment, leading to a > 4-fold and > 3-fold 
increase in free drug exposures of parent and metabolite, respectively.
Preliminary PD results for Cohort 1 are also available for change from baseline (Day 1) in 
plasma FGF19 and serum 7-alpha-hydroxy-4-cholesten-3-one (C4) levels following a single 
30 mg dose of GS-9674. Changes in FGF19 and C4 following a single dose of GS-9674 were 
similar in the mild hepatic impairment subjects as compared to the healthy matched controls as 
indicated by the PD parameter ratios (mild hepatic impairment/healthy) for Cmax and AUC2-12hr 
for FGF19 (1.1 and 1.1, respectively) and for Cmin and AUC2-12hr for C4 (0.82 and 0.87, 
respectively) in that the ratios were not significantly different from 1.
Based on the preliminary PK and PD data from this study as well as the overall safety profile of 
GS-9674, dose adjustments are not considered necessary in subjects with mild hepatic 
impairment.


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Table 1-3.
GS-US-402-3885: Preliminary GS-9674 and GS-716070 PK 
Parameters Following a Single Dose of GS-9674 30 mg in Subjects 
with Hepatic Impairment or Normal Hepatic Function
Cohort
Analyte
Mean (%CV) PK 
Parameter
Matched Healthy 
Control (N=10)
Hepatic 
Impairment 
(N=10)
%GMR
(90% CI)
1
GS-9674
AUCinf (hr ng/mL)
3030 (40.5)
5410 (40.2)
176 (127, 253)
AUClast (hr ng/mL)
2970 (41.4)
5380 (40.4)
178 (128, 247)
Cmax (ng/mL)
604 (45.6)
994 (53.7)
157 (108, 229)
GS-716070
AUCinf (hr ng/mL)
1440 (49.7)
2330 (44.8)
164 (104, 259)
AUClast (hr ng/mL)
1400 (51.1)
2300 (44.8)
169 (115, 247)
Cmax (ng/mL)
179 (42.6)
234 (50.8)
125 (85.0, 188)
2
GS-9674
AUCinf (hr ng/mL)
2810 (30.3)
8280 (91.4)
230  (163, 324)
AUClast (hr ng/mL)
2460 (30.9)
8220 (91.1)
249  (169, 367)
Cmax (ng/mL)
496 (40.2)
909 (52.5)
164  (115, 233)
GS-716070
AUCinf (hr ng/mL)
1380 (47.7)
3160 (81.8)
163  (95.1, 280)
AUClast (hr ng/mL)
1340 (48.8)
3090 (80.9)
197  (117, 329)
Cmax (ng/mL)
168 (51.6)
181 (61.5)
89.5 (54.3, 147)
Data reported to 3 significant figures
1.3.
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 the single dose of 
GS-9674 to subjects with mild (Class A), moderate (Class B) or severe (Class C) hepatic 
impairment as determined by Child-Pugh-Turcotte (CPT) classification {Pugh et al 1973}, 
compared to matched subjects with normal hepatic function with the goal to provide dosing 
recommendations to subjects with hepatic impairment. Administration of GS-9674 as a single-
dose is expected to accurately predict PK under steady-state conditions and is thus deemed 
satisfactory for an evaluation in this study.
This study design is consistent with recommendations as outlined in the FDA 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 hepatic 
impairment due to some other cause). Evaluation of pharmacokinetics and safety of GS-9674 in 
moderate or severe liver impairment will commence after the review of safety and available PK 


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data from subjects with mild, or moderate hepatic impairment respectively.   The trial will also 
enroll healthy controls, matched for body mass index, age, and sex.
1.3.1.
Rationale for the Dose Selection
This study will evaluate the impact of hepatic impairment on the single dose PK of 30 mg
(Cohorts 1 and 2) and 10 mg (Cohort 3) GS-9674 administered under fed conditions (moderate 
fat breakfast based on results from food effect evaluations in study GS-US-402-1851). These 
doses were selected based on the observed PK of single- and multiple-dose administration of 
GS-9674 up to 300 mg in study GS-US-402-1851 in healthy subjects and on the preliminary data 
from Cohorts 1 and 2 of this study, which showed increased unbound exposure with degree of 
hepatic impairment.  Based on the PK of GS-9674 across the range of doses evaluated, and 
GS-9674 exposure and PD response observed in study GS-US-402-1851, alterations of GS-9674
PK observed in this study as a result of hepatic impairment are expected to reflect the magnitude 
of alteration of steady-state GS-9674 pharmacokinetics in subjects with NASH.
Short-term safety data from clinical study GS-US-402-1851 and GS-US-402-2102  indicate that 
GS-9674 exposures higher than those expected in this study are well tolerated in healthy subjects
with no clinically significant or treatment limiting adverse events or laboratory abnormalities.
This study will proceed in three sequential cohorts starting with mild (CPT Class A), then 
moderate (CPT Class B), followed by severe (CPT Class C) hepatic impairment with evaluation 
of preliminary safety and PK data from hepatic impaired subjects from each cohort prior to 
initiation of subsequent cohorts. In addition, the proposed 30 mg dose of GS-9674 in Cohorts 1 
and 2 is 10-fold lower than the highest dose level previously evaluated (300 mg) in study 
GS-US-402-1851 which provided GS-9674 exposures 12- to 15- fold lower than those observed 
at the NOAEL in the 4-week repeat dose toxicity studies in the mouse and cynomolgous monkey 
(Section 1.2.21.2.2).   Based on the preliminary exposures observed in Cohort 1 and 2 
(Section 1.2.5.2) and expected further increases in unbound exposure in Cohort 3, the dose of 
GS-9674 is being reduced to 10 mg in subjects with severe hepatic impairment to cautiously
maintain adequate exposure margins.
With the proposed doses, it is unlikely that plasma exposures of GS-9674 in hepatic impairment 
subjects would exceed previously observed exposures in healthy volunteers or exceed exposures 
observed at the NOAEL in the toxicity studies.
1.4.
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. Parameters for discontinuation of the study drug due to AEs will be well‑
defined and closely followed.


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There is no direct benefit to subjects participating in this study; however, data from this study 
will support the development of GS-9674 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-9674, how much GS-9674 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.
1.5.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES
The primary objectives of this study are as follows:

To evaluate the single-dose pharmacokinetics of GS-9674 in subjects with impaired hepatic 
function relative to matched, healthy controls with normal hepatic function
The secondary objective of this study is as follows:

To evaluate the safety and tolerability of GS-9674 single dose administration in subjects with 
normal hepatic function, or mild, moderate, and severe hepatic impairment

To evaluate FXR activation by GS-9674 as measured by PD markers in subjects with normal 
hepatic function, or mild, moderate and severe hepatic impairment


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3.
STUDY DESIGN
3.1.
Study Design
This protocol describes a Phase 1, open-label, adaptive, single-dose, parallel-group, staggered-
cohort, PK study to evaluate the single-dose pharmacokinetics of GS-9674 in subjects with 
normal and impaired hepatic function. Up to approximately 60 subjects will be enrolled.
Cohort 1: GS-9674: 20 [10 per group (mildly impaired and matched controls) for 8 evaluable 
per group]
Cohort 2: GS-9674: 20 [10 per group (moderately impaired and matched controls) for total 
8 evaluable per group]
Cohort 3: GS-9674: 20 [10 per group (severely impaired and matched controls) for total 
8 evaluable per group]
Eligible subjects include male and nonpregnant/nonlactating female subjects, aged  ≥ 18 years 
with mildly, moderately impaired, severely impaired, and normal hepatic function will be 
enrolled into the study. 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) to a subject in the hepatic 
impairment group. A subject with normal hepatic function in a cohort may serve as a match to a 
subject with hepatic impairment in another cohort.
Cohorts 1 through 3 will be dosed in a sequential manner, with dosing of subjects in Cohort 2 
(moderate hepatic impairment) and Cohort 3 (severe hepatic impairment) proceeding after 
review of safety and available preliminary pharmacokinetic data from hepatic impaired subjects 
in the previous cohorts. Based on the cumulative review of safety and PK data, sequential
cohorts may or may not be initiated at the discretion of the investigator and Sponsor.
In general, dosing in subjects with normal hepatic function will begin after a matched subject 
with hepatic impairment has completed PK assessments. The study design is presented in
Figure 3-1.


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Figure 3-1.
Cohorts 1, 2, and 3 Study Schema
3.2.
Study Drug Administration
The study drug will be supplied as GS-9674 tablets or placebo to match, in strengths of 10 mg. 
All study treatments will be administered with 240 mL of water.
Study Treatments will be administered in the fed state as described below.
Fed state dosing:
Study drugs will be administered following an overnight fast (no food or drinks except water, for 
at least 10 hours) and within 5 minutes of completing a standardized meal (moderate-fat-calorie 
breakfast containing ~600 kcal and 25% to 30% fat will be provided). The meal should be 
initiated 30 minutes prior to study drug administration. Subjects will l fast until after collection 
of the 4-hour PK/PD 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 drugs and the standardized meal. 
A standardized meal may be provided to subjects after the 4-hour post-dose PK/PD draw.
Please refer to Section 5.3 for additional information for study drug dosage and administration.


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3.3.
Clinic Confinement
Eligible subjects will be confined beginning on Day -2 until the completion of assessments on 
Day 5. Subjects will be required to return for a Follow-up visit 10-14 days after study drug 
dosing.
3.4.
Pharmacokinetic Assessments
PK assessments will occur on assigned study days as outlined in Table 6-1.
3.4.1.
Plasma Pharmacokinetic Collection
Plasma concentrations of GS-9674 (its major metabolites, as applicable) will be determined and 
PK evaluated. PK parameters will be estimated as appropriate.
3.5.
Safety Assessments
Safety assessments will be performed through the study as outlined in Table 6-1.
3.6.
Pharmacodynamic Biomarker Assessments
PD assessments will be performed throughout the study as outlined in Table 6-1 and in 
Section 6.9.
3.7.
Optional Genomic Research
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.8.
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
A total of up to approximately 60 unique subjects will be enrolled in the study. Eligible subjects 
include male and nonpregnant/nonlactating female subjects at least 18 years of age with mildly 
impaired, moderately impaired, severely impaired, and normal hepatic function. If necessary, 
replacement subjects may be enrolled if subjects do not complete all intensive PK procedures 
with Sponsor approval. Replacement subjects will not be enrolled for subjects who discontinue 
the study due to treatment-related adverse events.
Classification of hepatic impairment will be assigned as follows:

Mild: Class A, CPT score 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, 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. Must be ≥ 18 years of age, inclusive at Screening.
3. Must be able to comply with the smoking restrictions at the study site.
4. Have a calculated body mass index (BMI) from 18 to 36 kg/m², inclusive, at study Screening.


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5. Have a creatinine clearance (CLcr) 80 mL/min (using the Cockcroft-Gault method 
{Cockcroft et al 1976}) based on serum creatinine and actual body weight as measured at
Screening
Male:
(140–ageinyears)(wtinkg) CrCl (mL/min)
72 (serum creatinine 
in mg/dL)
Female:
(140–ageinyears)(wtinkg) 0.85 CrCl (mL/min)
72 (serum creatinine 
in mg/dL)
6. Females of childbearing potential (as defined in Appendix 3) must have a negative serum 
pregnancy test at Screening and negative urine pregnancy at Day -2 unless permanently 
sterile or greater than two years post-menopausal
7. Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified highly effective method(s) of contraception 
as described in Appendix 3.
8. 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.
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 electrocardiogram (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 this 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 (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 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.
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 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
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, in the opinion of the Investigator, be in good health based upon medical history, 
physical examination, vital signs, and screening laboratory evaluations.
20. Must meet all of the following laboratory parameters at Screening:

INR ≤ 1 × ULN

Albumin ≥ 1 × LLN

Total bilirubin ≤ 1 × ULN


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
AST value ≤ 1 × ULN

ALT value ≤ 1 × ULN

Alkaline phosphatase ≤ 1 × ULN

α-fetoprotein ≤ 1 × ULN
21. Must match in age (± 10 years), gender, race, and BMI (± 15% of ≥ 18 and ≤ 36) with the 
respective subject in hepatic impairment group.
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 investigational compound within 30 days prior to study dosing (Day -1).
3. Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance or subject safety.
4. A positive test result for human immunodeficiency virus (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 expected to receive these agents during the 
study (eg, corticosteroids, immunoglobulins, and other immune- or cytokine-based 
therapies).
7. Significant serious skin disease, such as but not limited to rash, food allergy, eczema, 
psoriasis, or uticaria.
8. Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity).
9. Known hypersensitivity to the study drugs their metabolites or to formulation excipients (see 
Section 5.2.1).
10. 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%, implanted defibrillator or 
pacemaker), a family history of Long QT Syndrome, or unexplained death in an otherwise 
healthy individual between the ages of 1 and 30 years.


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11. Syncope, palpitations, or unexplained dizziness.
12. Severe peptic ulcer disease, gastroesophageal reflux disease, or other gastric acid 
hypersecretory conditions.
13. Medical or surgical treatment that permanently alters intestinal absorption (eg, gastric or 
intestinal surgery).  A history of cholecystectomy is not exclusionary.
14. 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:
15. 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.  
16. 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.
17. Positive test for drugs of abuse, including alcohol at Screening or on Day -2/check-in, 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.
18. Requires paracentesis > 1 time per month.
19. Subjects with hepatic impairment with co-morbid diseases not associated with hepatic 
impairment requiring medication(s) must be taking the medication(s) without a change in 
dose for > 3 months prior to Screening.
20. 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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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.
21. Prior placement of a portosystemic shunt (such as TIPS), unless vascular imaging indicates 
the shunt has no current blood flow.
4.3.3.
Healthy Control Subjects
Healthy matched controlled subjects meeting any of the following additional exclusion criteria 
are not to be enrolled in this study:
22. A positive test result for HCV antibody or HBVsAg.
23. Positive test for drugs of abuse, including alcohol at Screening or on Day -2/check-in.
24. Have any serious or active medical or psychiatric illness (including depression) which, 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.
25. History of liver disease.
26. Have taken any prescription medications or over-the-counter medications including herbal 
products within 28 days of commencing study drug dosing (Day -1) with the exception of 
vitamins, acetaminophen, ibuprofen, and hormonal contraceptive medications.


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5.
STUDY DRUGS
5.1.
Enrollment  and Blinding
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, eligible subjects will be assigned a subject number starting on 
Day 1 and will receive the study treatments as described in Section 5.3.
All Screening and Day -2 tests and procedures must be completed prior to the administration of 
the first dose of study drug on starting 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-9674
5.2.1.
Formulation
GS-9674 is supplied as 10 mg strength (as free form equivalent) tablets. The tablets contain 
 
 
 GS-9674 tablets 10 mg, are round, plain-faced, film-coated, orange tablets.
Placebo-to-match (PTM) GS-9674 tablets are identical in size, shape, color and appearance to 
their corresponding strength of active GS-9674 tablets. Placebo-to-match GS-9674 tablets 
contain the following inactive ingredients: 
 
5.2.2.
Packaging and Labeling
GS-9674 tablets, 10 mg, and PTM GS-9674 are packaged in white, high-density polyethylene 
(HDPE) bottles. Each bottle contains 30 tablets, a silica gel desiccant, and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant screw cap with 
an induction-sealed, aluminum-faced liner.
Study drugs 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 
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(FDA), EU Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal 
Products), and/or other local regulations.
5.2.3.
Storage and Handling
GS-9674 tablets and PTM GS-9674 tablets should be stored at controlled room temperature until 
required for administration. Controlled room temperature is defined as 25ºC (77ºF); excursions 
are permitted between 15ºC and 30ºC (59ºF and 86ºF).  Storage conditions are specified on the 
label.
Until study drug tablets are dispensed to the subjects, all bottles of study drugs should be stored 
in a securely locked area, accessible only to authorized site personnel. To ensure the stability and 
proper identification, the drug products should not be stored in a container other than the 
container in which they were supplied. Consideration should be given to handling, preparation, 
and disposal through measures that minimize drug contact with the body. Appropriate 
precautions should be followed to avoid direct eye contact or exposure through inhalation when 
handling GS-9674 tablets.
5.3.
Dosage and Administration of Study Drug
The study drugs will be supplied as GS-9674 tablets, in strengths of 10 mg and PTM GS-9674. 
All study treatments will be administered with 240 mL of water. Study treatments will be 
administered in the fed state.
5.4.
Fed State Dosing
Study drugs will be administered following an overnight fast (no food or drinks except water, for 
at least 10 hours). Study drugs will be administered within 5 minutes of completing a 
standardized meal (moderate-fat-calorie breakfast containing ~600 kcal and 25% to 30% fat will 
be provided). The meal should be initiated 30 minutes prior to study drug administration. 
Subjects will fast until after collection of the 4-hour PK/PD 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 drugs and the standardized meal. A 
standardized meal may be provided to subjects after the 4-hour post-dose PK/PD draw.
5.5.
Meals
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).


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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.
Gilead recommends that used and unused study drug supplies, including empty containers, be 
returned to the shipping facility from which it came or Gilead Sciences for destruction following 
drug accountability and drug inventory reconciliation.
If returning drug supplies to the shipping facility from which it came or to Gilead Sciences is not 
possible, the monitor will evaluate the site’s SOP for study drug disposal/destruction in order to 
ensure that it complies with Gilead’s requirements. At the end of the study, following final drug 
inventory reconciliation by the monitor, the study site will dispose of and/or destroy all unused 
study drug supplies, including empty containers, according to these procedures.
5.7.
Concomitant Medications and Other Protocol Restrictions
5.7.1.
Concomitant Medications
5.7.1.1.
Hepatic Impairment Group 
Concomitant use of certain medications or herbal/natural supplements with study drug may result 
in PK and/or PD interactions resulting in increases or decreases in exposure of study drug or 
these medications.
Concomitant medications taken within 30 days of Screening through the follow-up visit need to 
be recorded in the source documents and electronic Case Report Forms (eCRFs).
Subjects with hepatic impairment with co-morbid diseases requiring medication(s) must be 
taking the medication(s) without a change in dose within 28 days of Day 1.  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.


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The following medications are prohibited from 28 days prior to Day -1 through discharge:

Hematologic stimulating agents (e.g. erythropoiesis-stimulating agents (ESAs); granulocyte 
colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics)

Chronic systemic immunosuppressants including, but not limited to, corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal 
antibodies (e.g., infliximab)

Investigational agents or devices for any indication

Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers 
of drug transporters P-gp, BCRP, or OATP, or the drug metabolizing enzyme CYP3A) with 
study drug(s) may result in PK interactions resulting in increases or decreases in exposure of 
study drug(s) or concomitant medications. Examples of representative medications which are 
prohibited from 28 days prior to Day -1 through discharge are listed below in Table 5-1:
Table 5-1.
List of Disallowed 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
Amiodarone, Digoxin, Dronedarone, Felodipine, Verapamil, 
Quinidine, Ranolazine, Bosentan, Olmesartan, Telmisartan, 
Valsartan
Herbal/Natural Supplementsb
St. John’s Wort, Echinaccea. Milk thistle (i.e. silymarin), Chinese 
herb sho-saiko-to (or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase Inhibitorsc
fluvastatin, lovastatin, pitavastatin , pravastatin, rosuvastatin
Selective Serotonin Reuptake Inhibitors
Fluvoxamine
Other
Modafinil
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 (i.e. Tums, Maalox) are permitted 
but may not be taken within 4 hours (before or after) study drug administration.
b
May result in a decrease in the concentrations of study drugs.
c
Use with study drug may result in an increase in the concentration of the HMG-CoA Reductase Inhibitors. The 28 day 
washout period does not apply to HMG-CoA Reductase inhibitors, which can be taken up to the day before Day -1.
Medications for disease conditions excluded from the protocol (e.g., HIV-1 infection, active 
cancer, transplantation) are not listed under this Concomitant Medication section and are 
disallowed in the study.


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5.7.1.2.
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 
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 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 the use of nicotine or nicotine-containing products 
90 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 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 electronic case report forms (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 the ICF 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
Day 4
Day 5b
Day 10-14
FU Period
ETd
Written Informed Consent
X
Medical History 
X
Complete Physical Exam
X
X
Symptom-Driven Physical 
Examinatione
X
Height 
X
Weight 
X
BMI
X
Vital Signsf
X
X
X
X
X
X
HIV-1, HBV, and HCV 
Testingh
X
Hematologyg, h
X
X
X
X
X
Serum Chemistryh
X
X
X
X
X
Coagulation
X
Α-fetoprotein
X
Urinalysis 
X
X
X
X
X
Serum Pregnancy Testi
X
X
Urine Pregnancy Testi
X
X
X
X
FSHj
X


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Study Procedure
Screena
Day -2
Day -1
Day 1
Day 4
Day 5b
Day 10-14
FU Period
ETd
Urine Drug and Alcohol 
Screenh
X
X
X
X
12-Lead ECG
X
X
X
X
X
Enrollment
X
Placebo Administration
X
GS-9674 Administration
X
PK Assessmentsk
X
PD Assessmentsl
X
X
X
Genetic Samplem
X
Review Study Restrictions
X
X
X
X
X
Clinic Confinement
X  ------------------------------------------------------------------------ X
Review AEs & 
Concomitant Medicationsn
X
X  ------------------------------------------------------------------------ X
X
X
a.
Prospective subjects should be screened no more than 28 days prior to administration of the first dose of study drugs.
b.
Subjects will be discharged from the clinic on Day 5 following all morning assessments.
c.
Subjects will be required to return for a Follow-up visit 10-14 days after study drug dosing. 
d.
Assessments will be performed within 72 hours of early termination from the study.
e.
Symptom-driven PEs will be performed on Day 1 (predose), 4, and at the Follow-up Visit
f.
Vital signs include blood pressure, pulse rate, respiration rate, and body temperature. To be performed on Day -2, 1 (predose and at approximately 3 hours postdose), 5, and at 
the Follow-up Visit.
g.
Hematology: CBC with differentials
h.
Fasting serum chemistry: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect bilirubin, GGT, total protein, albumin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, total cholesterol, HDL, LDL, triglycerides, and amylase (reflex lipase testing is performed in 
subjects with total amylase > 1.5 x ULN).
i.
Female subjects of child-bearing potential.


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j.
Female subjects ≤ 54 years old with amenorrhea > 12 months as outlined in Appendix 3 kIntensive PK sampling will occur relative to the dosing at the following timepoints:
k.
Day 1: -0.5, 0 (pre-dose, ≤ 5 minutes prior to dosing), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose
In addition, on Day 1 at the 3 and 5 hours post dose timepoints, an additional plasma sample will be collected for plasma protein binding evaluation. Alternatively, pre-dose 
samples may be utilized for plasma protein binding evaluation
l.
Blood samples will be collected relative to dosing of GS-9674 to measure PD biomarkers for FGF19 and C4 GS-9674 at the following timepoints for each cohort: Day -1: -
0.5, 0 (pre-dose, ≤ 5 minutes prior to dosing), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, and 16 (relative to Day 1 dosing time assignment)
Day 1: -0.5, 0 (pre-dose, ≤ 5 minutes prior to dosing), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose
A single blood sample will be collected on Day 1, -0.5 hours predose for the determination including but not limited to individual bile acids.
m.
For subjects who provide consent, an additional blood sample will be obtained. This sample should be collected on Day 1, but may be collected at any time during the study 
or at a separate post-study visit, if necessary.
n.
From the time of obtaining informed consent through the first administration of study drug, record all SAEs, as well as any non-serious adverse events related to protocol-
mandated procedures on the AE 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. 
See Section 7 Adverse Events and Toxicity Management for additional details.


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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 planned number of 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 investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events case report form (AE eCRF). All 
other untoward medical occurrences observed during the screening period, including 
exacerbation or changes in medical history are to be captured on the medical history eCRF. See 
Section 7 Adverse Events and Toxicity Management for additional details.
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.
Prior to study drug administration, record any SAEs and all AEs related to protocol-mandated 
procedures. After drug administration, report all AEs and SAEs.
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.
6.3.
Check-in Assessments
Following completion of screening and Day -1 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 be required to return for a Follow-up visit 10-14 days after study drug dosing.
6.6.
Assessments for Premature Discontinuation from Study
If the subject discontinues 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.
6.7.
Criteria for Discontinuation of Study Drug for Multiple Dose Studies
Study treatment may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree

Unacceptable toxicity, as defined in the toxicity management section of the protocol, or
toxicity that, in the judgment of the investigator, compromises the ability to continue study-
specific procedures or is considered not to be in the subject’s best interest

Subject request to discontinue for any reason

Subject noncompliance


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
Pregnancy during the study (refer to Appendix 4)

Investigator discretion

Discontinuation of the study at the request of Gilead, regulatory agency, or an IRB/EC
6.8.
Pharmacokinetic Assessments
6.8.1.
Plasma PK Collection
Plasma concentrations of GS-9674 (and its metabolites, as applicable) will be determined and PK 
evaluated. PK parameters will be estimated, as appropriate.
Intensive PK sampling will occur relative to the morning dose of GS-9674 at the following time 
points:

Day 1: -0.5, 0 (pre-dose, ≤ 5 minutes prior to dosing), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 
8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose
In addition, on Day 1 at the 3 and 5 hours post dose time-points, an additional plasma samples 
will be collected for plasma protein binding evaluation. Alternatively, pre-dose samples may be 
utilized for plasma protein binding evaluation.
A blood sample for PK analysis will also be collected at the Early Termination (ET) visit (if 
applicable) and may be analyzed.
6.9.
Pharmacodynamic Assessments 
Blood samples will be collected relative to dosing of GS-9674 to measure PD biomarkers 
including but not limited to FGF19 and C4 for GS-9674 at the following time points for each 
cohort:

Day-1: -0.5, 0 (pre-dose, ≤ 5 minutes prior to dosing), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5,
5, 6, 8, 10, 12, and 16 (relative to Day 1 dosing time assignment)

Day1: -0.5, 0 (predose, ≤ 5 minutes prior to dosing), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8,
10, 12, 16, 24, 48, 72, and 96 hours post-dose
For analysis including but not limited to individual bile acids a single blood sample will be 
collected at the following time point for each cohort:

Day1: -0.5 hours predose
A blood sample for PD analysis will also be collected at the Early Termination (ET) visit (if 
applicable) and may be analyzed.


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6.10.
Optional Genomic Sample
 
 
 
 
 
 
6.11.
Safety Assessments
Safety will be evaluated throughout the study. Refer to Table 6-1 for a schedule of assessments.
6.11.1.
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.
CCI


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6.11.2.
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
6.11.3.
Vital Signs
Vital sign measurements include blood pressure, pulse, 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.
6.11.4.
Body Mass Index
Height and weight will be collected at screening for calculation of BMI for inclusion criteria.
6.11.5.
Clinical Laboratory Tests/Assessments
Blood and urine samples for safety evaluations will be collected throughout the study as outlined 
in Table 6-1.
6.11.5.1.
Blood Sampling
Blood samples will be collected for the following laboratory analyses:

Hematology: CBC with differential

Serum chemistry (fasting): alkaline phosphatase, AST, ALT, GGT total bilirubin, direct and 
indirect bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorus, magnesium, potassium, sodium, uric acid, total cholesterol, HDL, LDL, 
triglycerides, and amylase (reflex lipase testing is performed in subjects with total amylase

1.5 ULN).

HIV-1/2, HBVsAg, and HCV-Ab testing (Screening only)

Coagulation (PT, PTT, INR; Screening and FU Visit only)

α-fetoprotein test (Screening only)

Serum pregnancy test (females of childbearing potential only)

FSH  (Female subjects ≤54 years old with amenorrhea > 12 months, Screening only)


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6.11.5.2.
Urine Samples
Urine samples will be collected for urinalysis and alcohol and drug screen assessments.
6.11.6.
Creatinine Clearance
Weight will be collected at Screening to calculate creatinine clearance (eGFR) for inclusion 
criteria.
6.11.7.
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 7.8.1)

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 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.
7.1.2.1.
Protocol-Specific Serious Adverse Event Instructions
Protocol-specific SAEs: In this study, is to be considered medically important and, therefore,
“serious.”
Protocol-specific SAE reporting exemptions: 
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 4 for
moreinformation). 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.
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.
7.3.
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 informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all SAEs and AE related to protocol-
mandated procedures.
7.3.1.1.
Adverse Events
Following initiation of study medication, 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 
Sciences 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 post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead DSPH as instructed. This also includes any SAEs resulting from 
protocol-associated procedures performed after informed consent is signed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study drug, regardless of causality, should also be reported.


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Investigators are not obligated to actively seek SAEs after the protocol defined follow up period, 
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of study drug, he/she should promptly document and 
report the event to Gilead DSPH.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.
7.3.1.3.
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper SAE reporting form and submit 
within 24 hours as described below.
Gilead DSPH:
Fax:
E-mail:

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s 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 US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to
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worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the IB or relevant local label as applicable.
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study 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, ECG, 
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 Gilead Grading Scale for Severity of 
Adverse Events and Laboratory Abnormalities as described in Appendix 4. 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 (MM), 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 Grade 3 
or 4 clinically significant laboratory abnormalities should be managed as outlined in Appendix 2.
Any questions regarding toxicity management should be directed to the Gilead MM.


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7.7.
Study Specific Stopping Criteria
Study drug dosing of a cohort will be suspended and, based on full review of the clinical data by 
the MM and in discussion with the investigator, may be halted when:

2 healthy control subjects dosed with GS-9674 within a cohort experience elevations in liver 
function tests of ALT and/or AST > 5 x the upper limits of normal (ULN); or ALT > 3 x 
ULN and total bilirubin > 2 x ULN, confirmed by immediate repeat testing.

2 hepatic impairment subjects dosed with GS-9674 within a cohort experience elevation of 
baseline liver function tests of ALT and/or AST > 3 x baseline; or ALT > 2 x baseline and 
total bilirubin > 2 x baseline.

1 subject experiences a SAE possibly related to the study drug

The sponsor unilaterally requests it.
Decisions to reinitiate the study will be made in consultation with the sponsor and pending a 
safety review.
7.8.
Special Situations Reports
7.8.1.
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 
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Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
7.8.2.
Instructions for Reporting Special Situations
7.8.2.1.
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 DSPH using the pregnancy report form within 24 hours of becoming aware of the 
pregnancy. 
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.3. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must 
be reported to Gilead DSPH. The subject should receive appropriate monitoring and care until 
the conclusion of the pregnancy. The outcome should be reported to Gilead DSPH using the 
pregnancy outcome report form. If the end of the pregnancy occurs after the study has been
completed, the outcome should be reported directly to Gilead DSPH 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 DSPH using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the pregnancy should 
continue until its conclusion. If the end of the pregnancy occurs after the study has been 
completed, the outcome should be reported directly to Gilead DSPH by faxing
 
or emailing
 
Refer to Appendix 3, Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.8.2.2.
Reporting Other Special Situations
All special situations reports (SSRs) will be recorded in the CRF/eCRF database within the 
timelines outlined in the CRF/eCRF completion guideline.
Electronic Special Situations Report (eSSR) Reporting Process
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
Site personnel record all SSR data in the eCRF database and from there transmit the SSR 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SSR information electronically, i.e., the eCRF 
database is not functioning, record the SSR on the paper serious adverse event reporting form 
and submit within 24 hours to:
Gilead DSPH:
E-mail:
Fax:
As soon as it is possible to do so, any SSR reported via paper must be transcribed into the eCRF 
Database according to instructions in the eCRF completion guidelines.
If an SSR has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.
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.
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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of this study is as follows:

To evaluate the single-dose PK of GS-9674 in subjects with normal hepatic function, or mild, 
moderate and severe hepatic impairment
The secondary objectives of this study are as follows:

To evaluate the safety and tolerability of GS-9674 single dose administration in subjects with 
normal hepatic function, or mild, moderate, and severe hepatic impairment

To evaluate FXR activation by GS-9674 as measured by PD markers in subjects with normal 
hepatic function, or mild, moderate and severe hepatic impairment
8.1.2.
Primary Endpoint
The primary endpoints are single dose plasma PK parameters of GS-9674 AUClast, AUCinf, and 
Cmax. Additional PK parameters calculated include: %AUCexp, Clast, Tmax, Tlast, λz, CL/F, Vz/F, 
and T1/2 as appropriate.
8.1.3.
Secondary Endpoint
The secondary endpoints are the incidences of AEs and laboratory abnormalities, physical 
examinations, vital signs, ECGs, and PD markers including but not limited to FGF19 and C4.
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.
8.2.1.2.
Pharmacokinetics
The PK Analysis Set for GS-9674 will include all enrolled subjects who received at least 1 dose 
of GS-9674 and had at least 1 non-missing PK concentration data reported by PK lab for each 
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8.2.1.3.
Pharmacodynamics
Each PD analysis set will include all enrolled subjects who received at least 1 dose of study drug 
and have at least 1 non-missing PD value for each respective PD parameter.
8.3.
Data Handling Conventions
For summary statistics, PK concentration values below the limit of quantitation (BLQ) will be 
treated as zero at predose and one-half of the lower limit of quantitation (LLOQ) for postdose 
time points.
Laboratory data that are continuous in nature but are less than the lower limit of quantitation or 
above the upper limit of quantitation will be imputed to the value of the lower or upper limit 
minus or plus one 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 trial 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.
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 eCRF. Exposure data will be listed.


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8.6.2.
Adverse Events
Clinical and laboratory AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). System Organ Class (SOC), High-Level Group Term (HLGT), High-Level Term 
(HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be attached to the clinical 
database.
Adverse event data will be listed by subject.  Treatment-emergent AE (TEAE), Serious TEAE, 
and TEAE leading to discontinuation of treatment will be summarized by hepatic function group, 
system organ class, and preferred term using the current version the Medical Dictionary for 
Regulatory Activities (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 at 
scheduled visits. The incidence of treatment-emergent graded laboratory abnormalities will be 
summarized by hepatic function group.
8.6.4.
Other Safety Evaluations
Vital signs and ECG data will be listed by subject and visit, and summarized by hepatic function 
group and visit.
8.7.
Pharmacokinetic Analysis
Plasma concentrations and PK parameters will be listed and summarized for GS-9674  using 
descriptive statistics by hepatic function group (normal and mildly impaired, moderately 
impaired, or severely impaired) within cohort.
In addition, an ANOVA 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 GS-9674 for 
each cohort. Two-sided 90% CIs will be calculated for the ratios of GLSM of PK parameters for 
GS-9674 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 GS-9674 compared with subjects with normal liver function will be rejected.
GS-9674 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.  Relationships between 
measures of hepatic function (ie, CPT score, serum albumin, total bilirubin, prothrombin time 
and INR) and GS-9674 PK parameters will be evaluated.


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8.8.
Pharmacodynamics Analysis
Pharmacodynamics data will be listed and summarized using descriptive statistics by hepatic 
function within and across cohorts.
8.9.
Pharmacokinetics and Pharmacodynamics Analysis
The PK/PD relationship may be explored using a graphic approach and correlation coefficients 
as appropriate. 
8.10.
Sample Size
For each cohort, 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 AUClast, AUCinf, and Cmax, would be less than 200% 
with ≥ 88% probability, if the estimated GLSM ratio were 1.0. This is assuming a SD of no more 
than 0.463 on a natural logarithm scale, supported by previous Gilead study GS-US-402-1851. 
With 25% overage, a total sample size of 60 subjects (10 per group, 20 per cohort) will be 
required.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South 
Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, 
part 50, "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, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/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 consent form for documenting written 
informed consent. Each informed consent (or assent as applicable) will be appropriately signed 
and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by local 
requirements. The consent form will inform subjects about genomic testing and sample retention, 
and their right to receive clinically relevant genomic analysis results.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB/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 trial. Subject data will 
be processed in accordance with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, 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 and query forms, 
IRB/EC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and 
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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 
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in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject enrolled, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. The eCRF should 
be completed on the day of the subject visit to enable the sponsor to perform central monitoring 
of safety data, whenever possible. The Eligibility Criteria 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 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 
Where possible, Gilead recommends that used and/or unused study drug supplies be destroyed at 
the site. If the site has an appropriate SOP for drug destruction as determined by Gilead Sciences, 
the site may destroy used (empty or partially empty) and/or unused study drug supplies in 
accordance with that site’s approved SOP. A copy of the site’s IMP Disposal SOP or written 
procedure (signed and dated by PI or designee) will be obtained for Gilead’s site files. If the site 
does not have acceptable procedures in place for drug destruction, study drug supplies can be 
returned to the designated depot. The study monitor will provide instructions for the return. 
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.
For both options, the study monitor must first perform drug accountability during an on-site 
monitoring visit. Additionally, the study monitor will review study drug supplies and associated 
records at periodic intervals.


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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.
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.
9.2.2.
Study Report and Publications
A clinical study report will be prepared and provided to the regulatory agency. Gilead will ensure 
that the report meets the standards set out in the ICH Guideline for Structure and Content of 
Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases. 
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, eg, attendance at investigator's meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to federal and state agencies any 
expenses paid or reimbursed for such services, including any clinical study payments, meal, 
travel expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 


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verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
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 the Sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and ECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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10.
REFERENCES
Afzali A, Berry K, Ioannou GN. Excellent posttransplant survival for patients with nonalcoholic 
steatohepatitis in the United States. Liver Transpl 2012;18 (1):29-37.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Dietrich P, Hellerbrand C. Non-alcoholic fatty liver disease, obesity and the metabolic syndrome. 
Best practice & research 2014;28 (4):637-53.
Dowman JK, Tomlinson JW, Newsome PN. Pathogenesis of non-alcoholic fatty liver disease. 
QJM 2010;103 (2):71-83.
Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal P, Kechagias S, et al. Fibrosis stage is the 
strongest predictor for disease-specific mortality in NAFLD after up to 33 years 
of follow-up. Hepatology 2015;61 (5):1547-54.
Faramawi MF, Wildman RP, Gustat J, Rice J, Abdul Kareem MY. The association of the 
metabolic syndrome with QTc interval in NHANES III. Eur J Epidemiol 2008;23 
(7):459-65.
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.
Murakami T, Takigawa N, Ninomiya T, Ochi N, Yasugi M, Honda Y, et al. Effect of AZD1480 
in an epidermal growth factor receptor-driven lung cancer model. Lung Cancer 
2013.
Nakamoto K, Takayama F, Mankura M, Hidaka Y, Egashira T, Ogino T, et al. Beneficial Effects 
of Fermented Green Tea Extract in a Rat Model of Non-alcoholic Steatohepatitis. 
Journal of clinical biochemistry and nutrition 2009;44 (3):239-46.
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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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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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Management of Clinical and Laboratory Adverse Events
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 4.
Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities


PPD
PPD
G$-9674 
Protocol GS-US-402-3885 
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, Adaptive, Single-Dose Study to Evaluate the 
Pharmacokinetics and Pharmacodynamics of GS-9674 in Subjects with Normal and 
Impaired Hepatic Function 
GS-US-402-3885, Amendment 2, 23 March 2018 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approvaL 
Medical Monjtor 
Date 
[ 
Signature 
INVESTIGATOR STATEMENT 
[ 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 
CONFlDENTIAL 
Page 75 
23 March 2018 


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Appendix 2.
Management of Clinical and Laboratory Adverse Events
Ll 
IL_ _______ 
c._a_d•_4 ______ __J 
Repeat lab to confintt toxicity pade 
1 
If confirmed and possibly uprobably 
related to study drug, dismntinue study 
drug dosing permanently and fo&w at 
pe1iA>dic inteJV als at least weeldy "Wttil a 
to baseline or is: otketwise 
e>plained 
1 
Study Drug may be continued without dose 
irderruption for a 
3 
or 41aboratoty abnormality(eg. Grade 4 CK after 
strenuous exercise, or 
elevation, or blood in urine due to menses or that 
can be medically manage <!I or a clinical event 
considered unrelated to study drug 


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Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause. In 
addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
GS-9674 has not yet been studied in pregnant women. There are no preclinical data available to 
determine whether GS-9674 is teratogenic or fetotoxic in early human pregnancy. There are 
insufficient data to exclude the possibility of a clinically relevant interaction between GS-9674
and hormonal contraceptives that result in reduced contraception efficacy. Therefore, the use of 
hormonal contraception with GS-9674 is not recommended.
Therefore, in the GS-9674 clinical studies, women of childbearing potential must use a highly 
effective contraceptive measure or choose continuous heterosexual abstinence from intercourse 
from screening throughout the study period and for 30 days after last dose of GS-9674.
Please refer to the latest version of the investigator’s brochure for additional information.
b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures. They must have a negative serum pregnancy test at Screening and a 
negative pregnancy test on the Baseline/Day -2 visit prior to randomization.  At minimum, a 
pregnancy test will be performed at the end of relevant system exposure.  In the event of a
delayed menstrual period (over one month between menstruations), a pregnancy test must be 
performed to rule out pregnancy.  This is even true for women of childbearing potential with 


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infrequent or irregular periods. Female subjects must agree to one of the following from 
Screening until 30 days after last dose of GS-9674.

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below.
Intrauterine device (IUD) with a failure rate of <1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after last dose of GS-9674.
3) Contraception Requirements for Male Subjects
It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure of the male subject’s seminal fluid.  Therefore, male subjects with female 
partners of childbearing potential must use condoms during treatment and for 90 days after last 
dose of GS-9674.
Male subjects must agree to avoid sperm donation from baseline throughout the study period and 
for 90 days after last dose of GS-9674.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM).  Female condom and male condom should not 
be used together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator and discontinue study drug immediately, if 
they become pregnant at any time during the study, or if they become pregnant within 30 days 
(90 days of partner of male subject) of last study drug dose. Subjects 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 7.3.


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Appendix 4.
Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
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


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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
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


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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.  


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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


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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


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Protocol GS-US-402-3885
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
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23 March 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


GS-9674
Protocol GS-US-402-3885
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 85
23 March 2018
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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


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Protocol GS-US-402-3885
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 86
23 March 2018
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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-9674
Protocol GS-US-402-3885
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 87
23 March 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


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Protocol GS-US-402-3885
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 88
23 March 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 (eg, the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.


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Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 89
23 March 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-9674
Protocol GS-US-402-3885
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 90
23 March 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


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Final
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Amendment 2
CONFIDENTIAL
Page 91
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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)


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Protocol GS-US-402-3885
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 92
23 March 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-9674
Protocol GS-US-402-3885
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 93
23 March 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


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Protocol GS-US-402-3885
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 94
23 March 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)


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Protocol GS-US-402-3885
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 95
23 March 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 


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Final
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Amendment 2
CONFIDENTIAL
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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


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Protocol GS-US-402-3885
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 97
23 March 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-9674
Protocol GS-US-402-3885
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 98
23 March 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-9674
Protocol GS-US-402-3885
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 99
23 March 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]


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Protocol GS-US-402-3885
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 100
23 March 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-9674
Protocol GS-US-402-3885
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 101
23 March 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-9674
Protocol GS-US-402-3885
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 102
23 March 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.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 1 Open-Label, Parallel-Group, Adaptive, Single-Dose 
Study to Evaluate the Pharmacokinetics and 
Pharmacodynamics of GS-9674 in Subjects with Normal and 
Impaired Hepatic Function
Study Phase:
1
Name of Test Drug:
GS-9674
Study Number:
GS-US-402-3885
Protocol Version (Date):
Original (03 May 2016)
Amendment 1 (29 July 2016)
Amendment 2 (23 March 2018)
Analysis Type:
Final Analysis
Analysis Plan Version:
1.0
Analysis Plan Date:
26 April 2019
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD


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GS-US-402-3885
Statistical Analysis Plan – Final Analysis
Version 1.0
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF TABLES.........................................................................................................................................................3
LIST OF FIGURES.......................................................................................................................................................3
LIST OF ABBREVIATIONS........................................................................................................................................4
PHARMACOKINETIC AND PHARMACODYNAMIC 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..........................................................................................................................11
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................12
2.1.
Data Monitoring Committee Analyses...................................................................................................12
2.2.
Interim Analysis.....................................................................................................................................12
2.3.
Final Analysis ........................................................................................................................................12
2.4.
Changes from Protocol-Specified Analysis............................................................................................12
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................13
3.1.
Analysis Sets..........................................................................................................................................13
All Enrolled Analysis Set.........................................................................................................13
Safety Analysis Set ..................................................................................................................13
Pharmacokinetic Analysis Sets................................................................................................13
Pharmacodynamic Analysis Sets .............................................................................................14
3.2.
Strata and Covariates..............................................................................................................................14
3.3.
Examination of Subject Subsets.............................................................................................................14
3.4.
Multiple Comparisons............................................................................................................................14
3.5.
Missing Data and Outliers......................................................................................................................14
Missing Data............................................................................................................................14
Outliers ....................................................................................................................................14
3.6.
Data Handling Conventions and Transformations .................................................................................14
3.7.
Visit Windows........................................................................................................................................16
Definition of Predose, Postdose and Study Day ......................................................................16
Analysis Visit Windows ..........................................................................................................16
Selection of Data in the Event of Multiple Records on the Same Day ....................................16
4.
SUBJECT DISPOSITION ..................................................................................................................................18
4.1.
Subject Enrollment and Disposition.......................................................................................................18
4.2.
Extent of Exposure.................................................................................................................................18
4.3.
Protocol Deviations................................................................................................................................19
5.
BASELINE CHARACTERISTICS....................................................................................................................20
5.1.
Demographics ........................................................................................................................................20
5.2.
Baseline Characteristics .........................................................................................................................20
5.3.
Medical History......................................................................................................................................20
6.
EFFICACY ANALYSES ...................................................................................................................................21
7.
SAFETY ANALYSES........................................................................................................................................22
7.1.
Adverse Events and Deaths....................................................................................................................22


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Adverse Event Dictionary........................................................................................................22
Adverse Event Severity............................................................................................................22
Relationship of Adverse Events to Study Drug .......................................................................22
Relationship of Adverse Events to Study Procedure ...............................................................22
Serious Adverse Events ...........................................................................................................22
Treatment-Emergent Adverse Events ......................................................................................23
Summaries of Adverse Events and Deaths ..............................................................................23
Additional Analysis of Adverse Events...................................................................................24
7.2.
Laboratory Evaluations ..........................................................................................................................24
Summaries of Numeric Laboratory Results.............................................................................25
Graded Laboratory Values.......................................................................................................25
7.3.
Vital Signs..............................................................................................................................................26
7.4.
Prior and 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
General Considerations............................................................................................................29
Statistical Methodology ...........................................................................................................30
8.4.
Sensitivity Analysis................................................................................................................................32
9.
PHARMACODYNAMIC EVALUATION/ANALYSIS ...................................................................................33
9.1.
Estimation of Pharmacodynamic Parameters.........................................................................................33
9.2.
Pharmacodynamic Parameters ...............................................................................................................33
9.3.
Statistical Analysis Methods ..................................................................................................................34
General Considerations............................................................................................................34
Statistical Methodology ...........................................................................................................35
10.
REFERENCES ...................................................................................................................................................37
11.
SOFTWARE.......................................................................................................................................................38
12.
SAP REVISION..................................................................................................................................................39
13.
APPENDIX 1 SCHEDULE OF ASSESSMENTS .............................................................................................40
LIST OF TABLES
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
Table 9-1.
Pharmacodynamic Parameters for FGF19 and C4 .................................................................33
Table 9-2.
Statistical Comparisons for Pharmacodynamic Analyses.......................................................35
LIST OF FIGURES
Figure 1-1.
Cohorts 1, 2, and 3 Study Schema............................................................................................9


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Statistical Analysis Plan – Final Analysis
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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
C4
7-alpha-hydroxy-4-cholesten-3-one
CFR
Code of Federal Regulations
CI
confidence interval
CLcr
creatinine clearance
CPT
Child-Pugh-Turcotte classification system for hepatic impairment
CRF
case report form
CSR
clinical study report
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
ET
early termination
FGF19
fibroblast growth factor 19
FU
follow-up
FSH
follicle-stimulating hormone
Gilead
Gilead Sciences
GLSM
geometric least-squares mean
Hb
hemoglobin
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
LLOQ
lower limit of quantitation
LLT
lower-level term
LOQ
limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamic
PK
pharmacokinetics
PT
preferred term
PTM
placebo-to-match
Q1, Q3
first quartile, third quartile
SAE
serious adverse event


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SAP
statistical analysis plan
SD
standard deviation
SE
standard error
SI 
International System of Units (Systeme International d’Unites)
SOC
system organ class
TE
treatment-emergent
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
TOST
two one-sided tests
ULN
upper limit of normal
WHO
World Health Organization


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Statistical Analysis Plan – Final Analysis
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PHARMACOKINETIC AND PHARMACODYNAMIC 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
%Doseexcreted
percentage of given dose excreted in the urine as unchanged drug calculated as 100(Ae/dose)
Ae
amount of unchanged drug excreted in urine calculated either over a specific interval 
(Ae(interval)) or cumulatively over all collection intervals, calculated as (concentration of 
unchanged drug in urine) (volume of urine collected)
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
CLp
plasma clearance
Cmax
maximum observed plasma/serum concentration of drug
Cmin
minimum 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
Vd
volume of distribution
Vz
volume of distribution of the drug after intravenous administration
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-402-3885. This SAP is based on the study protocol amendment 2 dated 
23 March 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 objective of this study is as follows:

To evaluate the single-dose pharmacokinetics (PK) of GS-9674 in subjects with impaired 
hepatic function relative to matched, healthy controls with normal hepatic function
The secondary objectives of this study are as follows:

To evaluate the safety and tolerability of GS-9674 single dose administration in subjects with
normal hepatic function, or mild, moderate, and severe hepatic impairment

To evaluate Farnesoid X Receptor (FXR) activation by GS-9674 as measured by 
pharmacodynamic (PD) markers in subjects with normal hepatic function, or mild, moderate 
and severe hepatic impairment
1.2.
Study Endpoints
The primary endpoints are single dose plasma PK parameters of GS-9674 AUClast, AUCinf, and 
Cmax.
Secondary endpoints are the incidences of adverse events (AE) and laboratory abnormalities, 
physical examinations, vital signs, electrocardiogram (ECG), and PD parameters.
1.3.
Study Design
This is a Phase 1, open-label, single-dose, parallel-group, staggered-cohort, PK study of 
GS-9674 in subjects with mildly, moderately and severely impaired hepatic function and 
matched normal (control) groups. 
Subjects with hepatic impairment in each cohort will be enrolled based upon the Child-Pugh-
Turcotte (CPT) classification system for hepatic impairment:

Cohort 1: mild hepatic impairment (CPT Class A; score of 5-6) and matched control 

Cohort 2 : moderate hepatic impairment (CPT Class B; score of 7-9) and matched control

Cohort 3: severe hepatic impairment (CPT Class C; score of 10-15) and matched control


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The matched control group will consist of matched healthy subjects with normal hepatic 
function.
Up to approximately 60 (20 per cohort, 10 per group) male and non-pregnant/non-lactating 
female subjects aged ≥ 18 years with impaired and normal hepatic function will be enrolled to 
ensure completion of 48 (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 hepatic impairment group. A subject with normal 
hepatic function may serve as a matched control across cohorts evaluating the same GS-9674 
dose. Subjects with hepatic impairment must have the respective CPT Classification at Screening 
without evidence of worsening clinical and/or laboratory signs of hepatic impairment within 
2 months prior or within the screening period.
Following screening procedures and Day -2 admission assessments, eligible subjects will be 
enrolled in one of three sequential cohorts. Subjects will undergo intensive sampling over 24 
hours on Day -1 after administration of placebo-to-match (PTM) for baseline PD markers. On 
Day 1 subjects will receive a single dose of GS-9674 30 mg (3 x 10 mg tablet) orally for Cohorts 
1 and 2, or 10 mg (1 x 10mg tablet) for Cohort 3. Study Treatments will be administered in the 
fed state. Subjects will be confined to the clinic for the duration of the study until discharge on 
Day 5. Subjects will be required to return for a Follow-up (FU) visit 10-14 days after study drug 
dosing.
In general, dosing in subjects with normal hepatic function will begin after a matched subject 
with hepatic impairment has completed PK assessments. 
Cohorts 1 through 3 will be dosed in a sequential manner, with dosing of subjects in Cohort 2 
(moderate hepatic impairment) and Cohort 3 (severe hepatic impairment) proceeding after 
review of safety and available preliminary PK data from hepatic impaired subjects in the 
previous cohorts. Based on the cumulative review of safety and PK data, sequential cohorts may 
or may not be initiated at the discretion of the investigator and Sponsor.
If necessary, replacement subjects may be enrolled if subjects do not complete all intensive PK 
procedures with Sponsor approval. Replacement subjects will not be enrolled for subjects who 
discontinue the study due to treatment-related AEs.
The study design is presented in Figure 1-1.


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Version 1.0
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Figure 1-1.
Cohorts 1, 2, and 3 Study Schema
Each of the three cohorts will consist of two groups:

Group 1 (test, N = 10): Subjects with mild/moderate/severe hepatic impairment 

Group 2 (reference, N = 10): Subjects with normal hepatic function
Safety will be evaluated by assessment of physical examinations, vital signs, clinical laboratory 
tests and ECGs at various time points during the study, and by documentation of AEs. 
PK Assessments
Plasma PK Collection
Intensive PK sampling will occur relative to dosing of GS-9674 at the following time points for 
each cohort:

Day 1: -0.5, 0 (pre-dose, ≤ 5 minutes prior to dosing), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 
8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose
Plasma concentrations of GS-9674 (and its metabolites, as applicable) will be determined and PK 
evaluated. PK parameters will be estimated, as appropriate.


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In addition, on Day 1 at the 3 and 5 hours post dose time-points, additional plasma samples will 
be collected for plasma protein binding evaluation. Alternatively, pre-dose samples may be 
utilized for plasma protein binding evaluation.
A blood sample for PK analysis will also be collected at the Early Termination (ET) visit (if 
applicable) and may be analyzed.
PD Assessments
Plasma and/or Serum PD Collection
Blood samples will be collected relative to dosing of GS-9674 or PTM to measure PD 
biomarkers including but not limited to FGF19 (fibroblast growth factor 19) and 7-alpha-
hydroxy-4-cholesten-3-one (C4) for GS-9674 at the following time points for each cohort:

Day -1: -0.5, 0 (predose, ≤ 5 minutes prior to dosing), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 
5, 6, 8, 10, 12, and 16 hours post-dose (relative to Day 1 dosing time)

Day 1: -0.5, 0 (pre-dose, ≤ 5 minutes prior to dosing), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 
8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose 
A single blood sample will be collected for analysis including but not limited to bile acids at the 
following time point: 

Day 1: -0.5 hours predose
A blood sample for PD analysis will also be collected at the ET visit (if applicable) and may be 
analyzed.
Safety Assessments

Complete Physical exam: Screening and ET visit (if applicable) 

Symptom-directed physical exam: Days -2, 5, and FU visit

Vital signs (blood pressure, pulse, respiration rate, and temperature): Screening, Days -2, 1 
(predose and at approximately 3 hours postdose), 5, and FU visit or ET visit (if applicable)

Height, Weight, and BMI: Screening

Clinical Laboratory Tests (hematology, fasting chemistry, and urinalysis): Screening, Days -
2 (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), 5, and FU visit or at ET visit (if applicable)

Coagulation (PT, PTT, INR): Screening and FU Visit 


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
Urine drug/alcohol assessment: Screening, Day -2, and at the FU visit or at ET visit (if 
applicable).

12-lead ECG: Screening, Days -2, 5, and at the FU visit or ET visit (if applicable)

Serum Pregnancy Test (female subjects of childbearing potential): Screening

Urine Pregnancy Test (female subjects of childbearing potential): Days -2, 5, and at the FU 
visit or at 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 Section 13.
1.4.
Sample Size and Power
For each cohort, with 16 (8 per group) evaluable subjects, the estimated upper limit of one-sided 
95% confidence intervals (CIs) of the geometric least squares mean (GLSM) ratio of (mild, 
moderate or severe) hepatic impaired group vs. control (normal hepatic function), with regards to 
AUClast, AUCinf, and Cmax, would be less than 200% with ≥ 88% probability, if the estimated 
GLSM ratio were 1.0. This is assuming a standard deviation (SD) of no more than 0.463 on a 
natural logarithm scale, supported by previous Gilead study GS-US-402-1851. With 25% 
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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.
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.
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.
Pharmacokinetic Analysis Sets
The Pharmacokinetic (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 
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Pharmacodynamic Analysis Sets
The Pharmacodynamic (PD) Analysis Sets will include all enrolled subjects who received at 
least 1 dose of study drug and have at least 1 nonmissing PD value for each respective PD 
parameter.
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.
3.3.
Examination of Subject Subsets
There are no prespecified subject subsets for analyses.
3.4.
Multiple Comparisons
All endpoint tests will be done at the significance level of 0.05 with no multiplicity adjustments
made for testing.
3.5.
Missing Data and Outliers
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.
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 
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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, 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 lower LOQ, or upper LOQ respectively).
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.”


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3.7.
Visit Windows
Definition of Predose, Postdose and Study Day
Predose value is defined as the last available off-treatment value collected prior to the 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
Therefore, study day 1 is the day of first dose of study drug administration.
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.”

Data collected on a follow-up visit will be summarized as a separate visit, and labeled 
“Follow-up.”

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.
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. 


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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 visits: 
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 
otherwise specified.
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 hepatic function group and 
by hepatic function group within cohort. 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

PD Analysis Set for each biomarker

Completed study drug

Did not complete study drug with reason for premature discontinuation of 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 drug or study discontinuation
A by-subject listing of subject disposition including cohort, hepatic function group, date of the 
last dose of study drug (study days), study drug completion status, reason for study drug
discontinuation, study completion status, reason for study discontinuation, PK set status 
(indicating whether or not a subject is included in a PK analysis set), and PD set status 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. 


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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 entry 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 hepatic 
function group and by hepatic function group within cohort using descriptive statistics for age,
and using numbers and percentages 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 identification (ID) number in ascending order.
5.2.
Baseline Characteristics
Baseline characteristics include body weight (in kg), height (in cm), and body mass index (BMI; 
in kg/m2), calculated creatinine clearance (CLcr; in mL/min) by Cockcroft-Gault method 
{Cockcroft 1976}, and CPT score. These baseline characteristics will be summarized by hepatic 
function group and by hepatic function group within cohort 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
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.
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.
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.
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.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs met the definitions 
of SAE specified in the study protocol. SAEs captured and stored in the clinical database will be 
reconciled with the SAE database from the Gilead Pharmacovigilance and Epidemiology 
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Treatment-Emergent Adverse Events
7.1.6.1.
Definition of Treatment Emergent
Treatment-emergent adverse events (TEAEs) are defined as 1 or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug.

Any AEs leading to premature discontinuation of study drug.
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.
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, and hepatic function group as follows:

All TEAEs

TEAEs of Grade 3 or above

TEAEs of Grade 2 or above

All TEAEs by severity

All TE treatment-related AEs


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
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 drug

All TEAEs leading to premature discontinuation of study
A brief, high-level summary of AEs described above will be provided by 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 premature discontinuation of study drug

AEs leading to discontinuation of study
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 


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results will not be included in the analysis, but they will be listed in by-subject laboratory 
listings.
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.
Summaries of Numeric Laboratory Results
Descriptive statistics will be provided by 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. 
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 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 hepatic function group for vital signs 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 
chronological order. 


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7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version
of the World Health Organization (WHO) Drug dictionary.
A summary of prior and concomitant medications will not be provided.
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.
7.5.
Investigator Electrocardiogram Assessment
A shift table of the investigators’ assessment of ECG results at each visit compared with predose
values will be presented by 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 changes from the protocol-specified safety analyses.


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PHARMACOKINETIC EVALUATION/ANALYSIS
8.1.
Estimation of Pharmacokinetic Parameters
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 (BLQ) 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 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 GS-9674 30 mg 
(3 10 mg tablet) administered on Day 1
GS-9674 and its metabolite GS-716070, 
GS-1056756 and GS-1056757, as 
applicable
3
A single oral dose of GS-9674 10 mg 
(1 10 mg tablet) administered on Day 1
GS-9674 and its metabolite GS-716070, 
GS-1056756 and GS-1056757, 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-9674. The PK 
parameters to be estimated in this study are listed and defined in the Pharmacokinetics 
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Table 8-2.
Pharmacokinetic Parameters for Each Analyte
Analyte
Parameters
GS-9674, and its 
metabolite
GS-716070,
GS-1056756 and 
GS-1056757, as 
applicable
%AUCexp, AUClast*†, AUCinf*†, Cmax*†, Clast, Tmax, Tlast, λZ, CL/F†, VZ/F, and t1/2, as 
appropriate
*
Parameter used in sample size and power calculations.
†
May be calculated as both total and unbound.
8.3.
Statistical Analysis Methods
General Considerations
Individual subject concentration data and individual subject PK parameters (including percentage 
of protein binding) for GS-9674, GS-716070, GS-1056756 and GS-1056757 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 (where applicable) will be estimated by 
averaging the percentage unbound in plasma from 3 hour postdose, 5 hour postdose, and spike-in 
samples. Individual subject unbound PK parameter estimates for AUCinf, AUClast, Cmax may be 
calculated using PK parameter estimates multiplied by fu. The unbound CL/F may also be 
calculated by using the estimated CL/F divided by fu.
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 (total) and summary statistics


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
Individual subject fu and unbound PK parameters (as applicable) based on protein binding 
and summary statistics

Percentage of unbound and bound GS-9674, GS-716070, and GS-1056756 at 3 hours 
postdose, 5 hours postdose, and spike-in samples

Spearman’s rank correlation coefficient between selected PK parameter estimates (AUClast, 
AUCinf, and Cmax) and overall CPT Score, albumin, total bilirubin, prothrombin time, 
International Normalized Ratio, and serum creatinine
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, 
prothrombin time, International Normalized Ratio, and serum creatinine. 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 remaining points connected. Dose normalization is calculated by 
dividing the PK parameter value by the ratio of the test dose/reference dose.  The reference dose 
is 30 mg.
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
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 Table 8-3.


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Table 8-3. 
Statistical Comparisons for Pharmacokinetic Analyses of Normal and 
Impaired Hepatic Function 
Comparison 
Analyte 
Parameter 
Test 
Reference 
AUCmr 
Mild hepatic impainnent 
Matched normal hepatic 
ftmction 
Cmax 
AUC1ast 
GS-9674, 
Matched nonnal hepatic 
GS-716070, GS-1056756 
AUCmr 
Moderate hepatic impaliment 
function 
and GS-1056757 
Cmax 
AUCinf 
Severe hepatic impaliment 
Matched nonnal hepatic 
function 
Cmax 
For each analyte and each PK parameter within each coh01t, a parametric (n01mal the01y) 
ANOV A will be fitted to the naturallog-transf01med values of the single dose PK parameter 
under evaluation. 
The statistical model will include hepatic ftmction group as a fixed effect. The following SAS® 
PROC MIXED code will provide the comparison between the hepatic ftmction groups and the 
90% CI calculations for naturallog-transf01med PK parameters. 
proc mixed; 
by coh01t analyte paramcd; 
class hepaticgrp subjid; 
modellnest = hepaticgrp I ddfm=kr s; 
repeated I group=hepaticg1p; 
lsmeans hepaticg1p I e diff cl alpha = 0.1; 
estimate 'Mild impailment vs N01mal' hepaticgtp 1 -1 I cl alpha = 0.1; 
(estimate 'Moderate impailment vs N01mal' hepaticgrp 1 -1 I cl alpha= 0.1;) 
(estimate 'Severe impai1ment vs N onnal' hepaticgtp -1 1 I cl alpha = 0.1 ;) 
ods output Estimates= LS_Diffs LSMeans = LS_Means CovPa1ms = MSE; 
mn; 
The ESTIMATE statement will be used to produce the point estimate and the conesponding 
90% CI of the difference in PK parameters of interest on a logm·ithmic scale. The test-to-
reference ratio and associated 90% CI will be calculated by exponentiation of the poil1t estimate 
and the conesponding lower and upper limits, which is consistent with the two 1-sided tests 
approach {U.S. Department of Health and Human Services Food and Dmg Administration 
Center for Dmg Evaluation and Research (CDER) 2003}, {U.S. Depmtment of Health and 
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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 ratio for AUClast, AUCinf, and Cmax is 
smaller than 2.0, 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 GS-9674 
compared to 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 GS-9674, GS-716070, GS-1056756 and GS-1056757.
data param;
  set adam.param;
  where cohort=1 and analyte=’GS-9674’ and param=‘CL/F’;
run;
proc npar1way data=param wilcoxon;
  class hepaticgrp;
  var result; 
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.
PHARMACODYNAMIC EVALUATION/ANALYSIS
9.1.
Estimation of Pharmacodynamic Parameters
PD parameters will be calculated for FGF19 and C4 on Days -1, and 1.  In particular AUC 
calculations will be based on the linear trapezoidal rule, summing trapezoids over the particular 
time period (0 – 24 hours or x – y hours) on a particular day.  Cmax, Cmin, Tmax, and Tmin will be 
determined empirically for the data.  
9.2.
Pharmacodynamic Parameters
PD parameters in 
Table 9-1 will be generated for all subjects for whom parameters can be derived for biomarkers, 
FGF19 and C4, if data are available. 
Table 9-1.
Pharmacodynamic Parameters for FGF19 and C4
Day
Parameter
-1
AUC0-24
1
AUC0-24
1
AUC0-24 ratio: AUC0-24, (Day 1) / AUC0-24,(Day-1)
-1
AUCPartial
1
AUCPartial
1
AUCPartial ratio: AUCPartial, (Day 1) / AUCPartial,(Day-1)
-1
Cmin
1
Cmin
1
Cmin, ratio: Cmin, (Day 1) / Cmin, (Day -1)
-1
Cmax
1
Cmax
1
Cmax ratio: Cmax, (Day 1) / Cmax, (Day -1)
-1
Tmin
1
Tmin
1
Tmin ratio: Tmin, (Day 1) / Tmin, (Day -1)
-1
Tmax
1
Tmax
1
Tmax ratio: Tmax, (Day 1) / Tmax, (Day -1)
1
AUC0-24 Area under the curve calculated by the trapezoidal rule for the time from 0 to 24 hours for the day given in the first 
column. For Day -1, take -0.5 and 0 hours of Day 1 as 23.5 and 24 hours of Day -1.
2
AUCpartial (AUC2-8 and AUC2-12) Area under the curve calculated by the trapezoidal rule for the time from 2 to 8 and 2 to 12 
hours for the day given in the first column.
3
Cmax, Cmin   Concentration of FGF19 at the maximum or C4 at the minimum respectively for each subject from 0 to 24 hours 
for the day given in the first column. For Day -1, take -0.5 and 0 hours of Day 1 as 23.5 and 24 hours of Day -1.
4
Tmax, Tmin   Time of maximum or minimum concentration of FGF19 or C4 respectively for each subject from 0 to 24 hours 
for the day given in the first column. For Day -1, take -0.5 and 0 hours of Day 1 as 23.5 and 24 hours of Day -1.


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9.3.
Statistical Analysis Methods
General Considerations
Individual subject concentration data and individual subject PD parameters shown in Table 9-1
will be listed and summarized using descriptive statistics by hepatic function group within each 
cohort. Summary statistics (numbers of subjects, geometric mean, 95% CI, %CV, median, 
minimum, maximum, Q1, and Q3) will be presented at specific time points as shown in
Table 9-1. 
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. 
Individual PD parameter data listings and summaries will include all subjects for whom PD
parameters can be derived. The sample size for each PD parameter will be based on the number 
of subjects with nonmissing data for that PD parameter.
The following tables will be provided for each biomarker by hepatic function group within each 
cohort:

PD concentrations and summary statistics

PD parameters and summary statistics
The following figures will be provided for each biomarker by hepatic function group within each 
cohort:

Mean (± SD) concentration data versus time on a linear (and semilogarithmic) scale for days 
-1 and 1.

Boxplots of AUCs and AUC ratios as indicated in Table 9-1 on a linear (and logarithmic) 
scale, categorized by days -1 and 1, and by hepatic function group.

Boxplots of Cmax and Cmax ratios as indicated in Table 9-1 on a linear (and logarithmic) scale, 
categorized by days -1 and 1, and by hepatic function group.

Boxplots of Cmin and Cmin ratios as indicated in Table 9-1 on a linear (and logarithmic) scale, 
categorized by days -1 and 1, and by hepatic function group.
The following listings will be provided:

PD sampling details by subject, including procedures, differences in scheduled and actual 
draw times, and sample age.


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Statistical Methodology
The statistical comparisons of the natural log-transformed PD parameters for each biomarker and 
treatment comparison of interest will be performed. The statistical modeling will be based on the 
PD analysis set for the biomarker under evaluation. For each biomarker, all subjects with 
available data for the PD parameter under evaluation will be included in the modeling. 
Treatment comparisons of interest are shown in Table 9-2.
Table 9-2.
Statistical Comparisons for Pharmacodynamic Analyses
Treatment
Biomarker
Parameter
Comparison
Test
Reference
GS-9674 
FGF19
Day 1 / Day -1: AUC2-8, 
AUC2-12, Cmax
Mild Impairment
Matched normal 
hepatic function
C4
Day 1 / Day -1: AUC2-8, 
AUC2-12, Cmin
FGF19
Day 1 / Day -1: AUC2-8, 
AUC2-12, Cmax
Moderate 
Impairment
Matched normal 
hepatic function
C4
Day 1 / Day -1: AUC2-8, 
AUC2-12, Cmin
FGF19
Day 1 / Day -1: AUC2-8, 
AUC2-12, Cmax
Severe Impairment
Matched normal 
hepatic function
C4
Day 1 / Day -1: AUC2-8, 
AUC2-12, Cmin
For each biomarker, each cohort and each PD parameter, a parametric (normal theory) mixed-
effects ANOVA model will be fitted to the natural log-transformed values of the single and
multiple dose PD parameter under evaluation using SASPROC MIXED. 
The statistical model will include hepatic function group as a fixed effect. The following SAS 
PROC MIXED code will provide the hepatic function group comparison analysis and the 
90% CI calculations for natural log-transformed PD parameters.
proc mixed;
  where biomarker ={‘C4} and param={‘Cmax};
  class hepaticgrp subjid;
  model lnest = hepaticgrp / ddfm=kr;
  repeated / group=hepaticgrp;
  lsmeans hepaticgrp / e diff cl alpha = 0.1;
  estimate ‘Mildly Impaired vs Normal’ hepaticgrp 1 -1 / cl alpha = 0.1;
  (estimate ‘Moderately Impaired vs Normal’ hepaticgrp 1 -1 / cl alpha = 0.1;)
  (estimate ‘Severely Impaired vs Normal’ hepaticgrp -1 1 / cl alpha = 0.1;)
  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 PD parameters of interest on a logarithmic scale. The 
test-to-reference ratio and associated 90% CI will be calculated by taking the exponential 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}. 


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10.
REFERENCES
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
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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11.
SOFTWARE
SAS® Software Version 9.4 or newer, 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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12.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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13.
APPENDIX 1 SCHEDULE OF ASSESSMENTS
Study Procedure
Screena
Day -2
Day -1
Day 1
Day 4
Day 5b
Day 10-14
FU Period
ETd
Written Informed Consent
X
Medical History 
X
Complete Physical Exam
X
X
Symptom-directed Physical 
Examinatione
X
X
X
Height 
X
Weight 
X
BMI
X
Vital Signsf
X
X
X
X
X
X
HIV-1, HBV, and HCV 
Testingh
X
Hematologyg, h
X
X
X
X
X
Serum Chemistryh
X
X
X
X
X
Coagulation
X
X
α-fetoprotein
X
Urinalysis 
X
X
X
X
X
Serum Pregnancy Testi
X
Urine Pregnancy Testi
X
X
X
X
FSHj
X
Urine and Alcohol Drug 
Screenh
X
X
X
X
12-Lead ECG
X
X
X
X
X


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Study Procedure
Screena
Day -2
Day -1
Day 1
Day 4
Day 5b
Day 10-14
FU Period
ETd
Enrollment
X
Placebo Administration
X
GS-9674 Administration
X
PK Assessments k
X
X
PD Assessments l
X
X
X
Genetic Sample m
X
Review Study Restrictions
X
X
X
X
X
Clinic Confinement
X-----------------------------------------------------------------------X
Review AEs & 
Concomitant Medicationsn
X
X-----------------------------------------------------------------------X
X
X
a
Prospective subjects should be screened no more than 28 days prior to administration of the first dose of study drugs.
b
Subjects will be discharged from the clinic on Day 5 following all morning assessments.
c
Subjects will be required to return for a Follow-up visit 10-14 days after study drug dosing.
d
Assessments will be performed within 72 hours of early termination from the study.
e
Symptom-driven PEs will be performed on Day 1 (predose), 4, and at the Follow-up Visit 
f
Vital signs include blood pressure, pulse rate, respiration rate, and body temperature. To be performed on Day -2, 1 (predose and at approximately 3 hours postdose), 5, and at 
the Follow-up Visit.
g
Hematology: CBC with differentials
h
Fasting serum chemistry: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect bilirubin, GGT, total protein, albumin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, total cholesterol, HDL, LDL, triglycerides, and amylase (reflex lipase testing is performed in 
subjects with total amylase > 1.5 ULN).
i
Female subjects of child-bearing potential.
j
Female subjects ≤ 54 years old with amenorrhea > 12 months as outlined in Protocol Appendix 3
k
Intensive PK sampling will occur relative to the dosing at the following timepoints:
Day 1: -0.5, 0 (pre-dose, ≤ 5 minutes prior to dosing), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose
In addition, on Day 1 at the 3 and 5 hours post dose timepoints, an additional plasma sample will be collected for plasma protein binding evaluation
l 
Blood samples will be collected relative to dosing of GS-9674 to measure PD biomarkers for FGF19 and C4 at the following timepoints for each cohort:
Day -1: -0.5, 0 (pre-dose, ≤ 5 minutes prior to dosing), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, and 16 (relative to Day 1 dosing time assignment)
Day 1: -0.5, 0 (pre-dose, ≤ 5 minutes prior to dosing), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose


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A single blood sample will be collected on Day 1, -0.5 hours predose for the determination including but not limited to individual bile acids.
m
For subjects who provide consent, an additional blood sample will be obtained. This sample should be collected on Day 1, but may be collected at any time during the study 
or at a separate post-study visit, if necessary.
n 
From the time of obtaining informed consent through the first administration of study drug, record all SAEs, as well as any non-serious adverse events related to protocol-
mandated procedures on the AE 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.  
See Protocol Section 7 Adverse Events and Toxicity Management for additional details.


GS-US-402-3885 SAP
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Pharmacology
eSigned
23-Apr-2019
15:40:02
Clinical Research eSigned
23-Apr-2019
16:00:01
Biostatistics eSigned
24-Apr-2019
18:04:59
PPD
PPD
PPD