Clinical trial NCT02959138
Conditions: Inflammatory Disease
Sponsor: Gilead Sciences
Start date: 2016-11-21; Completion date: 2018-10-05
Enrollment: 36 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the pharmacokinetics (PK) of lanraplenib in participants with impaired renal function relative to matched healthy controls. Participants in this study will be enrolled using an adaptive design that includes up to 3 enrolled cohorts. Based on safety and/or PK data in Cohort 1, participants will be enrolled in adaptive Cohorts 2 and/or 3.

Detailed description:

Arms: arm 1: Participants with moderate renal impairment and matched healthy controls will receive a single dose of lanraplenib arm 2: Participants with severe renal impairment and matched healthy controls will receive a single dose of lanraplenib arm 3: Participants with mild renal impairment and matched healthy controls will receive a single dose of lanraplenib
Interventions: intervention 1: Lanraplenib.
Intervention descriptions: intervention 1: 20 mg (2 X 10 mg) tablets administered orally in a fasted state on Day 1

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 1 Open-Label Study to Evaluate the Pharmacokinetics of 
GS-9876 in Subjects with Impaired Renal Function
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND No.:
EudraCT No.:
123903
2016-003823-47
Indication:
Inflammatory Diseases
Protocol ID:
GS-US-379-1932
Gilead Medical Monitor
Name:
Telephone:
Fax:
Mobile:
Email:
Protocol Version/Date:
Original:
10 October 2016
Amendment 1:
09 January 2017
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The information contained in this document, particularly unpublished data, is the property or 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
PPD


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TABLE OF CONTENTS
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................12
1.
INTRODUCTION ..............................................................................................................................................16
1.1.
Background ............................................................................................................................................16
1.2.
GS-9876 .................................................................................................................................................16
1.2.1.
General Information .............................................................................................................16
1.2.2.
Preclinical Pharmacology, Pharmacokinetics and Toxicology.............................................17
1.2.3.
Additional Clinical Studies of GS-9876...............................................................................19
1.3.
Rationale for This Study ........................................................................................................................20
1.4.
Rationale for the Dose Selection............................................................................................................21
1.5.
Risk/Benefit Assessment for the Study..................................................................................................21
1.6.
Compliance ............................................................................................................................................22
2.
OBJECTIVES.....................................................................................................................................................23
3.
STUDY DESIGN................................................................................................................................................24
3.1.
Study Design..........................................................................................................................................24
3.2.
Study Drug Administration ....................................................................................................................26
3.3.
Clinic Confinement ................................................................................................................................26
3.4.
Pharmacokinetic Assessments................................................................................................................26
3.4.1.
Plasma Pharmacokinetic Collection.....................................................................................27
3.4.2.
Urine Pharmacokinetic Collection .......................................................................................27
3.5.
Safety Assessments ................................................................................................................................27
3.6.
End of Study...........................................................................................................................................27
4.
SUBJECT POPULATION..................................................................................................................................28
4.1.
Number of Subjects and Subject Selection ............................................................................................28
4.2.
Inclusion Criteria....................................................................................................................................28
4.2.1.
All Subjects ..........................................................................................................................28
4.2.2.
For Subjects with Renal Impairment....................................................................................29
4.2.3.
For Healthy Matched Controlled Subjects (Subjects with Normal Renal 
Function) ..............................................................................................................................30
4.3.
Exclusion Criteria...................................................................................................................................30
4.3.1.
All Subjects ..........................................................................................................................30
4.3.2.
For Subjects with Renal Impairment....................................................................................32
4.3.3.
For Healthy Matched Controlled Subjects (Subjects with Normal Renal 
Function) ..............................................................................................................................32
5.
STUDY DRUGS.................................................................................................................................................33
5.1.
Enrollment and Treatment Code ............................................................................................................33
5.2.
Description and Handling of GS-9876...................................................................................................33
5.2.1.
Formulation..........................................................................................................................33
5.2.2.
Packaging and Labeling .......................................................................................................33
5.2.3.
Storage and Handling...........................................................................................................34
5.3.
Dosage and Administration of Study Drug ............................................................................................34
5.4.
Fasting and Meals ..................................................................................................................................34
5.5.
Accountability for Study Drug...............................................................................................................34


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5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................35
5.6.
Concomitant Medications and Other Protocol Restrictions ...................................................................35
5.6.1.
Concomitant Medications.....................................................................................................35
5.6.2.
Other Protocol Restrictions ..................................................................................................36
6.
STUDY ASSESSMENTS...................................................................................................................................38
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................38
6.2.
Pretreatment Assessments......................................................................................................................41
6.2.1.
Screening Visit .....................................................................................................................41
6.2.2.
Admission Assessments .......................................................................................................41
6.3.
Check-in Assessments............................................................................................................................42
6.4.
Treatment Assessments..........................................................................................................................42
6.5.
Posttreatment Assessments ....................................................................................................................42
6.6.
Assessments for Premature Discontinuation from Study.......................................................................42
6.7.
Criteria for Discontinuation of Study.....................................................................................................42
6.8.
Pharmacokinetic Assessments................................................................................................................43
6.8.1.
Plasma PK Collection...........................................................................................................43
6.8.2.
Urine Pharmacokinetic Collection .......................................................................................43
6.9.
Safety Assessments ................................................................................................................................43
6.9.1.
Electrocardiogram Assessment ............................................................................................43
6.9.2.
Physical Examination...........................................................................................................44
6.9.3.
Vital Signs............................................................................................................................44
6.9.4.
Body Mass Index..................................................................................................................44
6.9.5.
Clinical Laboratory Tests/Assessments................................................................................44
6.9.6.
Creatinine Clearance and Estimated Glomerular Filtration Rate .........................................45
6.9.7.
Adverse Events/Concomitant Medications/Protocol Restrictions........................................45
6.10.
Sample Storage.......................................................................................................................................45
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................46
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................46
7.1.1.
Adverse Events.....................................................................................................................46
7.1.2.
Serious Adverse Events........................................................................................................46
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................47
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................47
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................47
7.2.2.
Assessment of Severity ........................................................................................................48
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................48
7.3.1.
Requirements for Collection Prior to Study Drug Initiation: ...............................................48
7.4.
Gilead Reporting Requirements.............................................................................................................49
7.5.
Toxicity Management ............................................................................................................................50
7.6.
Special Situations Reports......................................................................................................................50
7.6.1.
Definitions of Special Situations..........................................................................................50
7.6.2.
Instructions for Reporting Special Situations.......................................................................51
8.
STATISTICAL CONSIDERATIONS................................................................................................................53
8.1.
Analysis Objectives and Endpoints........................................................................................................53
8.1.1.
Analysis Objectives..............................................................................................................53
8.1.2.
Primary Endpoint .................................................................................................................53
8.1.3.
Secondary Endpoint .............................................................................................................53
8.2.
Analysis Conventions.............................................................................................................................53
8.2.1.
Analysis Sets ........................................................................................................................53
8.3.
Data Handling Conventions ...................................................................................................................54


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8.4.
Demographic Data and Baseline Characteristics ...................................................................................54
8.5.
Interim Analysis.....................................................................................................................................54
8.6.
Safety Analysis.......................................................................................................................................54
8.6.1.
Extent of Exposure...............................................................................................................54
8.6.2.
Adverse Events.....................................................................................................................54
8.6.3.
Laboratory Evaluations ........................................................................................................55
8.6.4.
Other Safety Evaluations......................................................................................................55
8.7.
Pharmacokinetic Analysis......................................................................................................................55
8.8.
Sample Size............................................................................................................................................55
9.
RESPONSIBILITIES..........................................................................................................................................56
9.1.
Investigator Responsibilities ..................................................................................................................56
9.1.1.
Good Clinical Practice..........................................................................................................56
9.1.2.
Institutional Review Board/Independent Ethics Committee Review and 
Approval...............................................................................................................................56
9.1.3.
Informed Consent.................................................................................................................56
9.1.4.
Confidentiality......................................................................................................................57
9.1.5.
Study Files and Retention of Records ..................................................................................57
9.1.6.
Case Report Forms...............................................................................................................58
9.1.7.
Study Drug Accountability and Return ................................................................................59
9.1.8.
Inspections............................................................................................................................59
9.1.9.
Protocol Compliance............................................................................................................59
9.2.
Sponsor Responsibilities ........................................................................................................................60
9.2.1.
Protocol Modifications.........................................................................................................60
9.2.2.
Study Report and Publications .............................................................................................60
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................60
9.3.1.
Payment Reporting...............................................................................................................60
9.3.2.
Access to Information for Monitoring..................................................................................60
9.3.3.
Access to Information for Auditing or Inspections ..............................................................60
9.3.4.
Study Discontinuation..........................................................................................................61
10.
REFERENCES ...................................................................................................................................................62
11.
APPENDICES ....................................................................................................................................................63
Appendix 1.
Investigator Signature Page....................................................................................................64
Appendix 2.
Management of Clinical and Laboratory Adverse Events......................................................65
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................66
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) v 4.03...................................68


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LIST OF IN-TEXT TABLES
Table 1-1.
Margins for GS-9876 Based on Systemic Exposure Relative to the Observed 
Human Exposure at 20 mg (AUC) .........................................................................................19
Table 5-1.
Examples of Prohibited Medications for Subjects with Renal Impairment............................36
Table 6-1.
Schedule of Assessments........................................................................................................39
LIST OF IN-TEXT FIGURES
Figure 3-1.
High Level Schema ................................................................................................................25
Figure 3-2.
Study Schema.........................................................................................................................26


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc. 
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 1 Open-Label Study to Evaluate the Pharmacokinetics of 
GS-9876 in Subjects with Impaired Renal Function
IND Number:
EudraCT Number:
123903
2016-003823-47
Study Centers 
Planned:
Multiple centers in the United States, Germany, and New Zealand
Objectives:
The primary objective of this study is as follows:

To evaluate the pharmacokinetics (PK) of GS-9876 in subjects 
with impaired renal function relative to matched, healthy controls
The secondary objective of this study is as follows:

To evaluate the safety and tolerability of GS-9876 in subjects with 
normal and impaired renal function
Study Design:
Phase 1, open-label, parallel-group, adaptive, single-dose, multi-
center, pharmacokinetic study 
Number of Subjects 
Planned:
This study will target enrolling 20 subjects per cohort, and a 
maximum of 60 subjects using an adaptive design that includes up to 
3 enrolled cohorts of subjects with renal impairment and matched 
healthy controls. Based on safety and PK results from subjects with 
moderate renal impairment (Cohort 1), subjects with severe renal 
impairment (Cohort 2) and/or mild renal impairment (Cohort 3) will 
be enrolled as follows:

Cohort 1 (Moderate Renal Impairment): Up to 20 subjects (10 per 
group, moderate renal impairment and matched healthy controls) 
for 8 evaluable subjects per group.

Adaptive Cohort 2 (Severe Renal Impairment): Up to 20 subjects 
(10 subjects with severe renal impairment and up to 10 matched 
healthy control subjects if none of the healthy subjects from a 
previous cohort is an appropriate match for a severe impairment 
subject) for 8 evaluable subjects per group.


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
Adaptive Cohort 3 (Mild Renal Impairment): Up to 20 subjects 
(10 subjects with mild renal impairment and up to 10 matched 
healthy control subjects if none of the healthy subjects from a 
previous cohort is an appropriate match for a mild impairment 
subject) for 8 evaluable subjects per group.
Adaptive Cohorts 2 and/or 3 will be enrolled as determined by safety 
and/or PK data in Cohort 1. Specifically, Cohort 2 (Severe Renal 
Impairment) will be evaluated if supported by safety and/or PK data 
from Cohort 1 (Moderate Renal Impairment). Cohort 3 (Mild Renal 
Impairment) will be evaluated if supported by safety and if substantial 
changes (≥2-fold mean difference from matched controls) in the 
exposure of GS-9876 is observed in subjects with moderate renal 
impairment in Cohort 1. Cohorts 2 and 3 may not be enrolled or may 
be enrolled sequentially or in parallel, as governed by safety and PK 
data in Cohort 1. Each control subject may be matched to multiple 
renal impaired subjects across different cohorts and can be matched to 
only 1 renal impaired subject within a cohort.
Target Population:
Male and non-pregnant/non-lactating female subjects, ages ≥ 18 and 
≤ 75 years, with normal or impaired renal function. Subjects with 
renal impairment must have a renal impairment classification (mild, 
moderate, or severe) at Screening that has been unchanged during the 
3 months prior to first study drug. Subjects may not be taking 
moderate or strong inhibitors or inducers of CYP3A during the study 
or within 2 weeks prior to the first dose. Each subject in the control 
group will be matched for age (± 10 years), gender, and body mass 
index (± 20%, 18 kg/m2 and 36 kg/m2).
Duration of Dosing:
1 day
Study Duration:
15 days
Diagnosis and Main 
Eligibility Criteria:
Subjects will comprise those with normal and impaired renal 
function. Those with impaired renal function will be categorized 
based on estimated creatinine clearance (CLcr) using the 
Cockcroft-Gault (C-G) equation for renal function as recommended 
by the Food and Drug Administration (FDA) and international 
guidance documents. Classification of renal impairment is defined as 
follows:

Mild: 
CLcr 60-89 mL/min

Moderate:
CLcr 30-59 mL/min

Severe:
CLcr 15-29 mL/min
Severe renal impairment subjects requiring or anticipated to require 
dialysis within 90 days of study entry are not eligible. The control 
group will consist of matched control subjects with normal renal 
function (CLcr ≥ 90 mL/min).


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Subjects will also be categorized using the estimated glomerular 
filtration rate (eGFR) using the Modification of Diet in Renal Disease 
(MDRD) Study equation and select results from this study will also 
be analyzed using these criteria {National Institute of Diabetes and 
Digestive and Kidney Diseases (NIH) 2016}.
eGFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if 
female) × (1.212 if African American)

Normal:
eGFR ≥ 90 mL/min/1.73 m2

Mild: 
eGFR 60-89 mL/min/1.73 m2

Moderate:
eGFR 30-59 mL/min/1.73 m2

Severe:
eGFR 15-29 mL/min/1.73 m2
Study Procedures/
Frequency:
Following completion of Screening and Day -1 assessments, eligible 
subjects will receive a single oral dose of the following study drug on 
Day 1:

20 mg GS-9876 (2 × 10 mg tablet) in the fasted state
Dosing in a matched subject with normal renal function will occur 
after the corresponding subject with impaired renal function has 
completed his/her PK assessment, except for control subjects that 
were already matched to a subject with impaired renal function in a 
previous cohort, as permitted in adaptive Cohorts 2 and 3.
Study Visits and Confinement
Following screening and Day -1 procedures, eligible subjects will be 
confined to the study center beginning Day -1 until the completion of 
assessments on Day 6. Subjects will return 14 (± 1) days after last 
dose for an in-clinic follow up visit (ie. Day 15).
Study Drug Administration
Following an overnight fast of at least 8 hours (no food or drink 
except water), study drug will be administered in the morning with 
240 mL of water. Subjects will continue to fast until after collection 
of the 4-hour PK sample, relative to study drug dosing. Additionally, 
subjects will be restricted from water consumption 1 hour before until 
2 hours after dosing, except for the 240 mL given with the study 
treatment.
Pharmacokinetic Assessments
Plasma PK collection
Plasma concentrations of GS-9876 will be measured and PK 
parameters determined. Plasma concentrations of GS-9876 
metabolites may be determined and pharmacokinetics explored, as 
applicable.


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Intensive PK sampling will occur relative to dosing of GS-9876 at the 
following time points:

Day 1: 0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 60, 
72, 96 and 120 hours postdose
Protein binding of GS-9876 (and its metabolites, as applicable) will 
be assessed at or near their Tmax timepoint(s) as well as another later 
time point.
Urine PK Sampling
Urine PK samples will be collected relative to dosing of GS-9876 at 
the following intervals:

Day 1: Pre-dose void, 0-6, 6-12, 12-24, 24-48, 48-72, 72-96 and 
96-120 hours postdose 
Urine concentrations of GS-9876 and/or metabolites may be 
determined and PK parameters estimated.
Safety Assessments
Complete physical exam: Screening, Days -1, 6, and at the follow-up
visit 14 (± 1) days after last dose or at the Early Termination (ET)
visit, if applicable
Symptom driven physical exam: every day during confinement as
needed, based on reported signs and symptoms
Vital signs (blood pressure, pulse, respiration rate, and temperature):
Screening, Days -1, 1 (predose, 1, 3, 6, and 12 hours postdose), 2, 3, 
4, 5, 6, and at the follow-up visit 14 (± 1) days after last dose or at the 
ET visit, if applicable
Height: Screening
Weight: Screening, Day -1
Clinical laboratory tests (blood chemistry, and urinalysis):  
Screening, Days -1, 1 (4 hours postdose), 2, 3, 6, and at the follow-up 
visit 14 (± 1) days after last dose or at the ET visit, if applicable
Clinical laboratory tests (hematology and coagulation): Screening, 
Days -1, 1 (4 hours postdose), 3, 6, and at the follow-up visit 14 (± 1) 
days after last dose or at the ET visit, if applicable.
Urine Drug and Alcohol Assessments: Screening, Day -1
12-lead ECG: Screening, Days -1, 1 (postdose), 6, and at the 
follow-up visit 14 (± 1) days after last dose or at the ET visit, if 
applicable
Serum Pregnancy Test (women of childbearing potential only):
Screening, Day -1, 6, and at the follow-up visit 14 (± 1) days after last 
dose or at the ET visit, if applicable


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Serology Test (HBV, HCV, HIV): Screening
Assessment of adverse events and concomitant medications will 
continue throughout the study. 
Test Product, Dose, 
and Mode of 
Administration:
GS-9876 2 × 10 mg tablet, oral, administered fasted
Criteria for 
Evaluation:
Safety:
Safety will be assessed during the study through the reporting of AEs, 
and by clinical laboratory tests, physical examinations, vital signs, 
and ECGs at various time points during the study. Concomitant 
medication usage will be assessed throughout the study.
Efficacy:
Not applicable.
Pharmacokinetics:
The following plasma PK parameters will be calculated, as 
appropriate: Cmax, Tmax, Clast, Tlast, λz, AUClast, AUC0-24, AUCinf, 
%AUCexp, t½, CL/F, and Vz/F.
PK of predominant GS-9876 metabolites (if applicable) may be 
explored. In addition, urine parameters (e.g. renal clearance and 
percentage of dose excreted in urine) may be estimated.
Statistical Methods:
Pharmacokinetics:
Pharmacokinetic parameters for GS-9876 will be listed and 
summarized by renal function group (normal, mild, moderate, and 
severe impairment) using descriptive statistics.
An analysis of variance appropriate for a parallel design will be fit to 
the natural logarithm-transformed PK parameters (AUClast, AUCinf,
and Cmax) for GS-9876. Two-sided 90% confidence intervals (CIs) 
will be constructed for the geometric least-squares means (GLSM) 
ratio of PK parameters for GS-9876 in groups of subjects with renal 
impairment versus matched controls.
Safety:
Safety data will be listed by subject and summarized by renal 
function group and the frequency of event/abnormality or descriptive 
statistical summaries, as appropriate.Sample Size:  
With 16 (8 per group) evaluable subjects, the estimated two-sided 
90% CI of the GLSM ratio of test versus reference groups, with 
regards to PK parameters (AUC and Cmax) would be within (50%, 
200%) with over 95% probability. This calculation is based on a two 


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group t-test of equivalence in means at the significance level of 0.05, 
assuming the expected geometric means ratio of 1.0 and inter-subject 
standard deviation (SD) of no more than 0.35 on a natural logarithm 
scale. The assumption about the inter-subject SD is supported by 
previous Gilead study GS-US-379-1372 using the maximum 
variability for AUC and Cmax from the closest dose levels (15 mg and 
30 mg) of the dose in this study. An overage of 2 subjects per group 
will be enrolled to accommodate subject drop-outs, thus requiring a 
total enrollment of 20 subjects (10 per group) for each cohort.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
λz
terminal elimination rate constant, estimated by linear regression of the terminal 
elimination phase of the log concentration versus time curve of the drug
%AUCexp
percentage of AUC extrapolated between AUClast and AUCinf
C 
degrees Celsius
ADME
absorption, distribution, metabolism, and elimination
AE
adverse event
AhR
aryl hydrocarbon receptor
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATP
adenosine triphosphate
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 
AUC0-24
area under the concentration versus time curve during 24 hours
BCR
B-cell receptor
BCRP
breast cancer resistance protein
BLQ
below limit of quantitation
BMI
body mass index
bpm
beats per minute
BUN
blood urea nitrogen
CBC
complete blood count
CD
Cluster of differentiation
CFR
Code of Federal Regulations
C-G
Cockcroft-Gault
CI
confidence interval
CIA
collagen-induced arthritis
CL/F
apparent oral clearance after administration of the drug:
CL/F = Dose/AUCinf, where “Dose” is the dose of the drug
Clast
last observed quantifiable concentration of the drug
CLcr
creatinine clearance
Cmax
maximum observed concentration of drug
CNS
central nervous system
CPK
creatine phosphokinase
CRF
case report form
CRO
contract (or clinical) research organization 


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CTCAE
Common Terminology Criteria for Adverse Events
Ctau
observed drug concentration at the end of the dosing interval
CYP
cytochromes P450
DMARD
disease modifying antirheumatic drugs
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health
EC50
half maximal effective concentration
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
ED50
median effective dose
EDC
electronic data capture
EudraCT
European Clinical Trials Database
eGFR
estimated glomerular filtration rate
eSAE
electronic serious adverse event
ET
early termination
EU
European Union
FceRI
Fc epsilon receptor I alpha
FDA
Food and Drug Administration
FU
follow-up
GCP
Good Clinical Practice
Gilead
Gilead Sciences, Inc.
GLP
Good Laboratory Practice
GLSM
geometric least-squares mean
GN
glomerulonephritis
HBV
hepatitis B virus
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
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
IC50
half maximal inhibitory concentration
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
Ig
immunoglobulin
IL
interleukins
IMP
investigational medicinal product
IND
investigational new drug (application)
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
LAM
lactational amenorrhea method
LDH
lactic acid dehydrogenase
LDL
low-density lipoprotein
LLT
lower-level term
LLOQ
lower limit of quantitation
MCV
mean corpuscular volume
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MM
medical monitor
mTOR
mammalian target of rapamycin
nM
nanometers
NOAEL
no-observed-adverse-effect level
NOEL
no-observed-effect level
NSAID
nonsteroidal anti-inflammatory drug
OATP
organic anion-transporting polypeptide
PD
pharmacodynamic(s)
PG
pharmacogenomics
P-gp
P-glycoprotein
PI
principal investigator
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
PTT
partial thromboplastin time
PXR
pregnane X receptor
Q1
first quartile
Q3
third quartile
QA
quality assurance
QD
quaque die (every day or once daily)
QRS
electrocardiographic deflection between the beginning of the Q wave and 
termination of the S wave, representing time for ventricular depolarization


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QT
electrocardiographic interval between the beginning of the Q wave and 
termination of the T wave, representing the time for both ventricular 
depolarization and repolarization to occur
QTc
QT interval corrected
QTcF
QT interval corrected for heart rate using the Fridericia formulation
RA
rheumatoid arthritis
RBC
red blood cell
SADR
serious adverse drug reaction
SAE
serious adverse event 
SAP
statistical analysis plan
SD
standard deviation
SI
International system of units
SOC
system organ class
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
SYk
spleen tyrosine kinase
TEAE
treatment-emergent adverse event
Tlast
time (observed time point) of Clast
Tmax
the time (observed time point) of Cmax
TNF
tumor necrosis factor
TOST
two one-sided tests
TQT
thorough QT
TV
television
t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing 
the natural log of 2 by the terminal elimination rate constant (λz)
ULN
upper limit of normal
μM
micrormeter
US, USA
United States, United States of America
Vz/F
apparent volume of distribution of the drug
WBC
white blood cell
WHO
World Health Organization


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1.
INTRODUCTION
1.1.
Background
GS-9876 is a potent and selective inhibitor of SYK and is being developed by Gilead Sciences, 
Inc. (Gilead) as an oral agent for the treatment of inflammatory diseases. Spleen tyrosine kinase 
is a nonreceptor cytoplasmic tyrosine kinase primarily expressed in cells of hematopoietic 
lineage, where it functions as a key signaling molecule mediating immunoreceptor signaling in a 
range of cells involved in inflammatory disease. Given its central role in immune cell signaling, 
inhibition of SYK is expected to affect multiple steps in the pathogenesis of several autoimmune 
diseases such as rheumatoid arthritis (RA) resulting in pleiotropic anti-inflammatory effects.
Rheumatoid Arthritis is a chronic, systemic inflammatory disease that affects approximately 
1.3 million adults in the United States (US) {Helmick et al 2008}. Rheumatoid Arthritis manifests 
principally as an attack on peripheral joints and may lead to marked destruction and deformity of 
joints, with considerable disability and impact on quality of life. It is characterized by the 
production of autoantibodies, synovial inflammation with formation of pannus tissue, and 
erosion of underlying cartilage and bone. Although people of any age can be affected, the onset 
of RA is most frequent between the age of 40 and 50 years, and women are affected 3 times 
more often than men. While the cause of RA is still not completely understood, aberrant B-cell 
activation, T-cell co-stimulation, osteoclast differentiation, and cytokine release all have been 
implicated in its pathogenesis. Subjects with RA experience a high risk of disability and 
mortality {Arthritis Foundation 2008}.
Despite the currently available treatment options for RA, there is still a need for new treatments 
because not all subjects respond adequately (or maintain response) to current therapies and some 
subjects experience toxicities and/or intolerance that limit the use of such therapies. All currently 
available treatments have safety considerations that can develop during chronic use that may 
require a change to a different therapy. The unmet medical need for new therapeutic options with 
a favorable efficacy and safety profile that do not require injection/infusion have prompted 
efforts to develop oral small molecule inhibitors of protein kinases involved in cellular signaling 
associated with the underlying RA disease pathology. 
There are several potential causes of nephropathy in patients with RA: drug-related renal disease, 
where drugs such as NSAIDs and DMARDs, secondary renal amyloidosis and various types of 
glomerulonephritis (GN) {Karie et al 2008}. Kidney disease and impairment is thought to be 
highly prevalent in the RA population and therefore a renal impairment study is indicated. 
1.2.
GS-9876
1.2.1.
General Information
For further information on GS-9876 refer to the current investigator’s brochure (IB).


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1.2.2.
Preclinical Pharmacology, Pharmacokinetics and Toxicology
1.2.2.1.
Nonclinical Pharmacology and Safety Pharmacology
GS-9876 is a selective and potent adenosine triphosphate (ATP)-competitive inhibitor of SYK
with an IC50 value of 9.5 nM. Overall, GS-9876 is at least 7-fold more selective biochemically 
for SYK relative to all other protein kinases assayed. Functionally, GS-9876 inhibited 
anti-IgM-induced BCR/SYK-mediated phosphorylation and activation of multiple downstream
signaling pathways in primary human B-cells, suppressed anti-IgM mediated CD69 and CD86 
activation marker expression on B-cells, and proliferation of peripheral B cells.  GS-9876 
showed a 12-fold selectivity for B-cell proliferation versus anti-CD3/anti-CD28 costimulation of 
T-cell proliferation.  Furthermore, GS-9876 inhibited immune-complex stimulated TNFand 
IL-1release from primary human monocytes. In human blood, GS-9876 inhibited SYK
autophosphorylation, anti-IgD/BCR-induced CD69 expression on B-cells, and
anti-FceRI-stimulated CD63 expression on basophils with geometric mean EC50 values ranging 
from 171 nM to 301 nM.
In two independent rat collagen-induced arthritis (CIA) models in animals with established 
disease, treatment with GS-9876 caused significant and dose-dependent amelioration of clinical 
and histopathology parameters when dosed either early (at initiation of ankle swelling) or late 
(at time of peak ankle swelling) after disease onset. Histological evaluation of joints in the 
animals from the study demonstrated that GS-9876 treatment reduced pannus formation, 
cartilage damage, bone resorption, and periosteal bone formation with an effective dose inducing 
a 50% inhibitory effect (ED50) of < 6.25 mg/kg, QD and 11.6 mg/kg, QD in the early and late 
CIA models, respectively.  Significant efficacy was seen with GS-9876 doses that produced 
Cave exposures that were calculated to inhibit SYK phosphorylation by 50% (EC50).  GS-9876 
was well tolerated at all doses and there were no treatment-related adverse effects on body 
weight, food and drink intake, in-life observations or clinical pathology parameters.  
Safety pharmacology studies were conducted to examine the potential effects of GS-9876 on the
cardiovascular system, respiratory system, and central nervous system (CNS). There were no 
clinically-relevant effects on the respiratory, and CNS systems after single oral doses up to 
300 mg/kg. Cardiovascular effects in telemetered cynomolgus monkeys at ≥20 mg/kg included 
prolonged QTc interval from 5 through 25 hours postdose, slightly higher systolic, diastolic, and 
mean arterial pressure with lower heart rate through 6 hours postdose, and higher heart rate from 
9 through 25 hours postdose. While differences in QTc interval were generally small, the 
changes were of sufficient magnitude to be considered biologically relevant. There were no 
inhibitory effects on the hERG potassium current when GS-9876 was tested up to a free drug 
concentration of 30 μM, approximately 207-fold above the observed steady state Cmax at a 30 mg 
QD clinical dose. Further, no cardiovascular effects were observed in telemetered cynomolgus 
monkeys administered GS-9876 for 13 weeks at doses up to 15 mg/kg/day. The potential for 
GS-9876 to prolong the QTc interval was assessed with intensive time matched ECG monitoring 
in Gilead studies GS-US-379-1372 and GS-US-379-1900 (cohorts 1 and 2), and no clinical 
significant change in time matched QTc intervals was observed. No clinical significant changes 
in vital signs during serial vital sign measurements were observed.


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1.2.2.2.
Nonclinical Toxicology
In the repeat-dose studies, the toxicity profile of GS-9876 was assessed in rats and monkeys 
administered GS-9876 orally for up to 26 weeks. Dose-dependent effects on lymphocytes in both 
rats and monkeys were consistent with the expected pharmacology of SYK inhibition. Effects on 
hemostasis were observed in rats and monkeys, with increased erythrocyte turnover in rats at 
≥10 mg/kg/day, and hemorrhage and thrombosis in monkeys at ≥20 mg/kg/day. At higher doses 
in rats (≥30 mg/kg/day), mortality associated with bacterial infections, likely resulting from the 
immunomodulatory activity of GS-9876, was seen. Additional findings included lymphoid 
depletion in the thymus, changes in the pancreas, with secondary effects related to the 
immunomodulatory activity of GS-9876, and likely opportunistic bacterial infection, observed in 
several tissues. The no-observed-adverse-effect level (NOAEL) in rats was 10 mg/kg/day after 
26 weeks dosing. For the 20 mg single dose proposed in this study, estimated exposure margins 
are 3.1-/7.6- fold based on exposures at the NOAELs in the 26 week study in male/female rats.  
Subjects will be closely monitored for any infection and changes in the differential CBC.
In monkeys, the NOAEL in the 28-day study was identified at 10 mg/kg/day, which was 
associated with AUC0-24hr of 4290 ng•hr/mL. In the 13-week monkey study, there were no effects 
on hemostasis, and the NOAEL was the high dose of 15 mg/kg/day. In the 39-week monkey 
study, there was no evidence of effects on hemostasis at the high dose of 15 mg/kg/day, and the
NOAEL was 15 mg/kg/day, associated with an AUC0-24hr of 8040 ng•h/mL. For the 20 mg 
single dose proposed in this study, the estimated exposure margin is 2.8-fold based on exposures 
at the 15 mg/kg/day NOAEL in the 39-week monkey study.
In GLP range-finding developmental toxicity studies in pregnant rats and rabbits, no 
Caesarean-sectioning, litter parameters, or gross external or visceral alterations were affected by 
GS-9876 at dose levels up to 100 mg/kg/day in rats, or up to 30 mg/kg/day in rabbits. In rabbits 
at 100 mg/kg/day, mortality, clinical observations, reduced body weights and food consumption
in does were associated with increased resorptions and reduced fetal body weights.  In rats, the 
maternal no-observed-effect level (NOEL) was 30 mg/kg/day, and the embryo-fetal development 
NOEL was 100 mg/kg/day. In rabbits, the maternal and embryo-fetal development NOEL was 
30 mg/kg/day.
GS-9876 was negative in the bacterial reverse mutation (Ames) assay, in vitro chromosomal
aberration assay, and in vivo rat micronucleus assay and is therefore considered to be
nongenotoxic. In the in vitro chromosome aberration assay in human lymphocytes, slight, but
statistically significant increases in the number of polyploid cells was observed at the highest
GS-9876 dose level evaluated. GS-9876 did not induce structural chromosome breakage when
evaluated in the in vitro assay. 


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Table 1-1.
Margins for GS-9876 Based on Systemic Exposure Relative to the 
Observed Human Exposure at 20 mg (AUC)
Species
Duration
Route
NOAEL
(mg/kg/day)
AUC0-24
(ng•h/mL)a
Margin b
Rat
Once daily 
x 26 weeks
Oral
10
8800/21,800
(male/female)
3.1/7.6
(male/female)
Cynomolgus Monkey
Once daily 
x 39 weeks
Oral
15c
8040
2.8
a
NOAEL, no observed adverse effect level. Week 4 male and female rat AUC and week 13 Cynomolgus monkey AUC
(combined sex)
b
Margins of exposure were calculated using predicted 20 mg single dose exposure in humans of 2865 ng•h/mL (extrapolated 
from 30 mg single dose data in study GS-US-379-1372).
c
One animal was euthanized moribund during Week 22 at the 15 mg/kg/day dose level.
1.2.2.3.
Nonclinical Drug Metabolism and Pharmacokinetics
GS-9876 exhibits high absorption in rats, dogs and monkeys. Plasma protein binding is moderate 
in all species with the mean free fraction in humans being of 20.4%.
After oral dosing to albino and pigmented rats, [14C]GS-9876-derived radioactivity was rapidly 
distributed to most tissues and concentrations of radioactivity were below the limit of 
quantitation by 168 hours postdose. The lowest levels of radioactivity were observed in the 
brain, bone, adipose, and testis. Melanin containing tissues exhibited higher concentrations than 
their non-pigmented counterparts but binding was reversible.  Recovery of radioactivity was high 
(≥ 97.8%) and the main route of elimination of GS-9876 was hepatobiliary with ≤5.1% orally 
dosed radioactivity found in urine and 69.4% in bile.
In vitro, GS-9876 exhibits high metabolic stability with human hepatocytes, liver fractions and 
individual metabolizing enzymes.  GS-9876 had little inhibitory effect on the activities of the 
major human drug metabolizing CYP enzymes and was a weak inhibitor of human UGT1A1.   
GS-9876 is a weak inhibitor of P-gp and BCRP and is a substrate for those efflux transports.  It is 
a weak inhibitor of the hepatic uptake transporters OATP1B1 and OATP1B3 but is a substrate 
for neither. Drug-drug interactions in vivo are unlikely through inhibition of human CYP 
enzymes, UGT1A1, or efflux or uptake transporters.  The potential of GS-9876 to cause 
drug-drug interactions through induction is low as there is little activation of PXR or AhR in 
vitro.
1.2.3.
Additional Clinical Studies of GS-9876
As of 12 February 2016, 62 healthy volunteers have been dosed with GS-9876 in two clinical 
studies.
1.2.3.1.
Completed Clinical Trial
GS-US-379-1372: This was a first-in-human, Phase 1, single-dose ranging study of GS-9876 in 
healthy adult volunteers to evaluate the safety, tolerability, PK, PD, food effect, and drug-drug 


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interaction potential using a representative acid reducing agent (omeprazole). No risks were 
identified and no grade 3 or 4 AEs were reported. There were no clinically significant changes in 
vital signs, physical findings, bleeding times, or ECGs. For further information, refer to the 
current IB.
1.2.3.2.
Ongoing Clinical Trials
GS-US-379-1582: This is a 12 week proof of concept trial of GS-9876 in patients with RA to 
evaluate efficacy, safety, tolerability and PK of GS-9876.
GS-US-379-1900: This is a single- and multiple-dose Phase 1 study of GS-9876 in healthy 
volunteers to evaluate the safety, tolerability, PK and PD of GS-9876. No risks were identified; 
all AEs were Grade 1 in severity. No dose relationships were observed between GS-9876 and 
any AE. No AE was assessed by the investigator as related to study drug .There were no 
clinically significant changes in vital signs, physical findings, laboratory parameters, or ECGs.
1.3.
Rationale for This Study
Renal dysfunction may alter the elimination of drugs resulting in PK and subsequently 
pharmacodynamic changes. Available data indicate the disposition of GS-9876 is primarily via 
hepatic metabolism and elimination with minimal excretion expected in urine. In a nonclinical 
ADME study in rat (AD-379-2001), 2.7% to 5.1% of the administered radioactivity was excreted 
in urine. In study GS-US-379-1372 in humans, 0.6% to 4.1% of the dose of GS-9876 was 
excreted unchanged in urine following single oral doses from 2 to 50 mg. However, renal 
impairment may alter the disposition of hepatically cleared drugs due to possible changes in 
hepatic/gut drug metabolism, absorption and plasma protein binding. Thus, the objective of this 
study is to investigate the potential for clinically relevant alterations in the PK and safety of 
GS-9876 in subjects with renal impairment.
This study will be conducted in accordance with regulatory guidance and good scientific
practice. This study will enroll subjects with moderate renal impairment (Cohort 1) with a 
screening estimated creatinine clearance (CLcr) of 30-59 mL/min using the Cockcroft-Gault 
(C-G) equation for renal function as recommended by the Food and Drug Administration (FDA) 
and international guidance documents. Data from these subjects will be compared to matched 
subjects with normal renal function (CLcr ≥ 90 mL/min). Subjects with severe renal impairment 
(Cohort 2; CLcr 15-29 mL/min) will be evaluated if supported by safety and/or PK data from 
Cohort 1. Should substantial changes in exposure be observed in Cohort 1, these data would 
inform the need for an expanded study including subjects with lesser degrees of renal 
dysfunction (Cohort 3; CLcr 60-89 mL/min).
As renal impairment may be associated with changes in protein binding, a measurement of 
plasma protein binding will be conducted at or near Tmax and at another later timepoint following 
GS-9876 dosing. Administration of GS-9876 as a single-dose is expected to accurately predict 
PK under steady-state conditions and is thus deemed satisfactory for evaluation in this study.


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1.4.
Rationale for the Dose Selection
The dose of GS-9876 to be used in this study is a 20 mg single dose in the fasted state. Results 
from study GS-US-379-1372 indicated that GS-9876 was safe and well tolerated when 
administered as a single dose of 2 mg to 50 mg. Similarly, preliminary results from study 
GS-US-379-1900 have indicated that GS-9876 was safe and well tolerated following 7 days 
dosing of GS-9876 15 mg QD, 30 mg QD or 50 mg QD. GS-9876 doses of 10 mg QD and 30 mg 
QD are currently under investigation in subjects with rheumatoid arthritis in study 
GS-US-379-1582. Thus a single dose of 20 mg GS-9876 represents a safe dose that's clinically 
relevant and allows for potential increase of GS-9876 exposures in subjects with renal 
impairment. Although food (high fat breakfast) only had minimal impact (reducing Cmax by 
13% and delaying Tmax but no effect on AUC, on GS-9876 PK study GS-US-379-1372),
GS-9876 will be administered in the fasted state in this study to avoid any potential confounding 
effect of food on assessing the effect of renal impairment on GS-9876 PK.
1.5.
Risk/Benefit Assessment for the Study
While there is no direct benefit for the subject participating in the renal impairment study of 
GS-9876, the risks are considered to be minimal for the following reasons:
GS-9876 has been in a battery of nonclinical animal studies, and no renal toxicity was identified. 
GS-9876 has been tested in humans as a single ascending dose over a dose range of 2 to 50 mg 
(GS-US-379-1372) and as a multiple ascending dose over a dose range of 15 to 50 mg 
(GS-US-379-1900) and no evidence of nephrotoxicity has been observed. In general GS-9876 
was well tolerated at all dose levels. The planned single dose of 20 mg of GS-9876 is well below 
the highest dose given in the healthy volunteers and is expected to be tolerated well. 
As discussed in Section 1.3, the disposition of GS-9876 is primarily via hepatic metabolism and 
elimination with minimal excretion expected in urine and the impact on renal impairment on 
GS-9876 PK is expected to be limited. Subjects in this study will receive a single 20 mg dose of 
GS-9876, which is expected to provide a margin of 2.8-fold to the NOAEL exposure in the 
39-week Cynomolgus monkey toxicology study.
Evidence of deterioration in kidney function in humans can readily be detected and monitored 
using routine laboratory tests. For this study, frequent assessments of kidney function will be 
performed from the collection of both blood and urine samples. While subjects with renal 
impairment will be enrolled, the risk of further kidney injury in these subjects should be 
minimized by this close renal monitoring. Further, this study will enroll subjects with moderate 
renal impairment (Cohort 1) with a screening estimated creatinine clearance (CLcr) of 
30-59 mL/min first. Data from these subjects will be compared to matched subjects with normal 
renal function (CLcr ≥ 90 mL/min). Subjects with severe renal impairment (Cohort 2; 
CLcr 15-29 mL/min) will only be evaluated if supported by safety and/or PK data from Cohort 1. 
There are several potential causes of nephropathy in patients with chronic autoimmune diseases: 
primary autoimmune attack on the kidney, secondary renal amyloidosis, drug-related renal 
disease due to necessary drugs used to treat the primary autoimmune disease. Kidney disease and 


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impairment is thought to be highly prevalent in patients with autoimmune disease and therefore a 
renal impairment study is indicated and is in line with the FDA draft guidance Pharmacokinetics 
in patients with Impaired Renal Function indicating that a PK study in patients with renal 
impairment should be conducted for most drugs intended for chronic use. 
The benefit-risk assessment for this study is favorable.
1.6.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP),
and all applicable regulatory requirements.


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2.
OBJECTIVES
The primary objective of this study is as follows:

To evaluate the pharmacokinetics (PK) of GS-9876 in subjects with impaired renal function 
relative to matched healthy controls.
The secondary objective of this study is as follows:

To evaluate the safety and tolerability of GS-9876 in subjects with normal and impaired renal 
function.


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3.
STUDY DESIGN
3.1.
Study Design
This protocol describes a Phase 1, open-label, parallel-group, adaptive, single-dose, multi-center, 
pharmacokinetic study in subjects with renal impairment and matched healthy controls. A 
maximum of 60 subjects using an adaptive design that includes up to 3 enrolled cohorts.

Cohort 1 (Moderate Renal Impairment): Up to 20 subjects (10 per group, moderate renal 
impairment and matched healthy controls) for 8 evaluable subjects per group.

Adaptive Cohort 2 (Severe Renal Impairment): Up to 20 subjects (10 subjects with severe 
renal impairment and up to 10 matched healthy control subjects if none of the healthy 
subjects from a previous cohort is an appropriate match for a severe impairment subject) for 
8 evaluable subjects per group.

Adaptive Cohort 3 (Mild Renal Impairment): Up to 20 subjects (10 subjects with mild renal 
impairment and up to 10 matched healthy control subjects if none of the healthy subjects 
from a previous cohort is an appropriate match for a mild impairment subject) for 8 evaluable 
subjects per group.
Adaptive Cohorts 2 and/or 3 will be enrolled as determined by safety and/or PK data in Cohort 1. 
Specifically, Cohort 2 (Severe Renal Impairment) will be evaluated if supported by safety and/or 
PK data from Cohort 1 (Moderate Renal Impairment). Cohort 3 (Mild Renal Impairment) will be 
evaluated if supported by safety and if substantial changes (≥2-fold mean difference from 
matched controls) in the exposure of GS-9876 is observed in subjects with moderate renal 
impairment in Cohort 1. Cohorts 2 and 3 may not be enrolled or may be enrolled sequentially or 
in parallel, as governed by safety and PK data in Cohort 1. Each control subject may be matched 
to multiple renal impaired subjects across different cohorts and can be matched to only 1 renal 
impaired subject within a cohort.
Male and nonpregnant, nonlactating female subjects 18 to75 years of age, inclusive, with normal 
or impaired renal function will be enrolled into the study. Each subject in the control group will 
be matched for age (± 10 years), gender, and body mass index (± 20%, 18 kg/m2 and 36 
kg/m2).
An overview of the study design is described below and shown in Figure 3-1 and Figure 3-2.


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Figure 3-1.
High Level Schema
;--- - -----·- --
' 
Cohort 1 
Moderate Renal 
Impairment 
0 ,_----
,;-----------------
1 
0 
\ 
I 
0 
---------)-: 
0 
0 
I 
Adaptive Cohort 2 
Severe Renal 
Impairment 
\ 
I 
\ ' 
I 
,;---------------
I ' 
\ 
i 
I 
1 
I 
: Adaptive Cohort 3 : 
--------? : 
Mild Renal 
Impairment 
', ------------------' 


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Figure 3-2.
Study Schema
3.2.
Study Drug Administration
Following an overnight fast of at least 8 hours (no food or drink except water), study drug will be 
administered in the morning with 240 mL of water. Subjects will continue to fast until after 
collection of the 4-hour PK sample, relative to study drug dosing. Additionally, subjects will be 
restricted from water consumption 1 hour before until 2 hours after dosing, except for the 
240 mL given with the study treatment.
Please refer to Section 5.3 for additional information for study drug dosage and administration.
3.3.
Clinic Confinement
Following screening and Day -1 procedures, eligible subjects will be confined to the study center 
beginning Day -1 until completion of assessments on Day 6. Subjects will return 14 (± 1) days
after last dose for an in-clinic follow up visit (ie. Day 15).
3.4.
Pharmacokinetic Assessments
Pharmacokinetic assessments will occur on assigned study days as outlined in Table 6-1 and 
Section 6.7.


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3.4.1.
Plasma Pharmacokinetic Collection
Plasma concentrations of GS-9876 will be measured and PK parameters determined. Plasma 
concentrations of GS-9876 metabolites may be determined and pharmacokinetics explored, as 
applicable.
3.4.2.
Urine Pharmacokinetic Collection
All urine voided will be collected and pooled for the determination of PK parameters as outlined 
in Section 6.8.2. Urine concentrations of GS-9876, as well as its metabolites, may be analyzed.
3.5.
Safety Assessments
Safety assessments will be performed through the study as outlined in Table 6-1 and in 
Section 6.9.
3.6.
End of Study
The end of this study will be the last subject’s last observation (or visit).


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
A total of up to 60 subjects will be enrolled in the study (up to 20 subjects per cohort), consisting 
of healthy male and nonpregnant, nonlactating female subjects of 18 through 75 years of age, 
inclusive. 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 study drug-related AEs. Each control subject may be 
matched to multiple renal impaired subjects across different cohorts and can be matched to only 
1 renal impaired subject within a cohort.
Subjects will comprise those with normal and impaired renal function. Those with impaired renal 
function will be categorized based on estimated creatinine clearance (CLcr) using the 
Cockcroft-Gault (C-G) equation for renal function as recommended by the Food and Drug 
Administration (FDA) and international guidance documents. Classification of renal impairment 
is defined as follows:

Mild: 
CLcr 60-89 mL/min

Moderate:
CLcr 30-59 mL/min

Severe:
CLcr 15-29 mL/min
Severe renal impairment subjects requiring or anticipated to require dialysis within 90 days of 
study entry are not eligible. The control group will consist of matched control subjects with 
normal renal function (CLcr ≥ 90 mL/min).
Each subject in the control group will be matched for age (± 10 years), gender, and body mass 
index (± 20%, 18 kg/m2 and 36 kg/m2).
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study:
4.2.1.
All Subjects
1) Have the ability to understand and sign a written informed consent form (ICF), which must 
be obtained prior to initiation of study procedures
2) Be between 18 through 75 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) of 18 kg/m2 and 36 kg/m2 at screening


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5) Females of childbearing potential (as defined in Appendix 3) must have a negative serum 
pregnancy test at screening and clinic admission (Day -1).
6) Female subjects must refrain from egg donation and in vitro fertilization during treatment 
and until at least 36 days after the last dose of study drug.
7) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in 
Appendix 3.
8) Male subjects must refrain from sperm donation from clinic admission (eg, Day −1), 
throughout the study period, and continuing for at least 90 days following the last dose of 
study drug
9) Subjects have not donated blood within 56 days of study entry or plasma within 7 days of 
study entry and must refrain from blood donation from clinic admission, throughout the study 
period, and continuing for at least 30 days following the last dose of study drug.
10) Have either a normal 12-lead ECG or one with abnormalities that are considered clinically 
insignificant by the investigator in consultation with the sponsor
11) Must be willing and able to comply with all study requirements
12) Must, in the opinion of the investigator, be in good health based upon medical history and 
physical examination, including vital signs
13) Subjects must have the following laboratory parameters at screening:
a) Hemoglobin ≥8.0 g/dL (International System of Units [SI]: ≥80 g/L)
b) White blood cells ≥3.0 x 103 cells/mm3 (SI: ≥3.0 × 109 cells/L)
c) Neutrophils ≥1.5 x 103 cells/mm3 (SI: ≥1.5 × 109 cells/L)
d) Lymphocytes ≥0.5 x 103 cells/mm3 (SI: ≥0.5 × 109 cells/L)
e) Platelets ≥100 x 103 cells/mm3 (SI: ≥100 × 109 cells/L)
f)
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 1.5 × ULN
g) Total bilirubin level < 2 × ULN 
4.2.2.
For Subjects with Renal Impairment
Subjects with mild, moderate, or severe renal impairment must also meet the following 
additional inclusion criteria to be eligible for participation in this study:
1) Must have diagnosis of chronic (> 6 months), stable renal impairment with no clinically
significant change in renal function status within 90 days prior to study drug administration
(Day 1).


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2) Have a creatinine clearance (CLcr) < 90 mL/min (using the Cockcroft-Gault method 
{Cockcroft et al 1976}) based on serum creatinine and actual body weight as measured at 
screening, ie,
Male:
(140 – Age [years]) (Weight [kg]) CLcr (mL/min)
72 (Serum Creatinine [mg/dL])
Female:
(140 – Age [years]) (Weight [kg]) 0.85 CLcr (mL/min)
72 (Serum Creatinine [mg/dL])

Mild: 
CLcr 60-89 mL/min

Moderate:
CLcr 30-59 mL/min

Severe:
CLcr 15-29 mL/min
4.2.3.
For Healthy Matched Controlled Subjects (Subjects with Normal Renal 
Function)
Healthy matched control subject must also meet the following additional inclusion criteria to be 
eligible for participation in this study:
1) Must, in the opinion of the investigator, be in good health based upon medical history and 
physical examination, including vital signs.
2) Have a creatinine clearance (CLcr) 90 mL/min (using the Cockcroft-Gault method 
{Cockcroft et al 1976}) based on serum creatinine and actual body weight as measured at 
screening, ie,
Male:
(140 – Age [years]) (Weight [kg]) CLcr (mL/min)
72 (Serum Creatinine [mg/dL])
Female:
(140 – Age [years]) (Weight [kg]) 0.85 CLcr (mL/min)
72 (Serum Creatinine [mg/dL])
3) Match in age (± 10 years), gender, and body mass index (± 20%, 18 kg/m2 and 36 
kg/m2).
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) Be a lactating female


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2) Have received any investigational compound within 30 days prior to study dosing
3) Have current alcohol or substance abuse judged by the investigator to potentially interfere 
with subject compliance or subject safety as judged by the investigator
4) Have a positive test result for human immunodeficiency virus type 1 (HIV-1) antibody, 
hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C virus
(HCV) antibody
5) Have poor venous access that limits phlebotomy
6) Have been treated with systemic steroids, immunosuppressant therapies, or chemotherapeutic 
agents within 3 months prior to screening or is expected to receive these agents during the 
study (eg, corticosteroids, immunoglobulins, and other immune- or cytokine-based therapies)
7) Have a history of any of the following:
a) Significant serious skin disease, such as but not limited to rash, food allergy, eczema, 
psoriasis, or urticaria
b) Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity)
c) Known hypersensitivity to the study drugs, their metabolites or to formulation excipients 
(see Section 5)
d) Significant cardiac disease (including history of myocardial infarction based on ECG 
and/or clinical history, any history of ventricular tachycardia, congestive heart failure, or 
dilated cardiomyopathy with left ventricular ejection fraction < 40%), a family history of 
long QT syndrome, or unexplained death in an otherwise healthy individual between the 
ages of 1 and 30 years
e) Syncope, palpitations, or unexplained dizziness
f)
Implanted defibrillator or pacemaker
g) Liver disease, including Gilbert disease
h) Severe peptic ulcer disease, gastroesophageal reflux disease, or other gastric acid 
hypersecretory conditions requiring prolonged (> 6 months) medical treatment.
i)
Medical or surgical treatment that permanently altered gastric absorption (eg, gastric or 
intestinal surgery). A history of cholecystectomy is not exclusionary. 
j)
History of any major bleeding event defined as Grade 3 severity and above (as defined by
the modified CTCAE 4.03[Appendix 4]) within the last year or personal or family history 
of bleeding disorder
k) Current use of chronic anticoagulant or anti-platelet agent, not including daily aspirin for 
cardiac prophylaxis.


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8) Have any serious or active medical or psychiatric illness (including depression) that, in the 
opinion of the investigator, would interfere with subject treatment, assessment, or compliance 
with the protocol. This would include 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.
9) Recent significant changes in the use of nicotine or nicotine containing products 
(ie, initiation, substantial increase or decrease or cessation of use) in the 90 days prior to 
study drug dosing, or anticipated significant changes in the use of nicotine or nicotine 
containing products during the course of the study through the follow-up visit.
4.3.2.
For Subjects with Renal Impairment 
1) Require or are anticipated to require dialysis within 90 days of study dosing
2) Require during the study or have received moderate or strong inhibitors or inducers of 
CYP3A within 2 weeks prior to study drug administration.
All concomitant medications including over-the-counter and herbal products must be approved 
by the Investigator and Medical Monitor (or Clinical Pharmacologist) prior to study enrollment 
and study drug administration.
4.3.3.
For Healthy Matched Controlled Subjects (Subjects with Normal Renal 
Function)
1) Have taken any prescription medications or over-the-counter medications, including herbal 
products and antacids, within 28 days prior to start of study drug dosing, with the exception 
of vitamins and/or acetaminophen and/or ibuprofen and/or hormonal contraceptive 
medications and/or stable hormone replacement therapy in peri- /post-menopausal females


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5.
STUDY DRUGS
5.1.
Enrollment and Treatment Code
This is a non-randomized, open-label study.
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.
Once eligibility has been confirmed following completion of the study procedures on Day -1, 
subjects will be enrolled and assigned a subject number. 
All Day -1 tests and procedures must be completed prior to the administration of the first dose of 
GS-9876 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. Study drug will be 
dispensed by the study pharmacist, or designee, in an open-label fashion to subjects.
5.2.
Description and Handling of GS-9876
5.2.1.
Formulation
GS-9876 will be supplied as 10 mg tablets that are round, plain-faced and film-coated blue. Each 
tablet contains 10 mg of GS-9876 free base as the succinate form (GS-9876-02). The GS-9876 
tablets contain commonly used excipients including microcrystalline cellulose, mannitol, 
croscarmellose sodium, magnesium stearate, polyvinyl alcohol, polyethylene glycol, titanium 
dioxide, talc, and FD&C blue #2/indigo carmine aluminum lake. 
5.2.2.
Packaging and Labeling
GS-9876 tablets are packaged in white, high-density polyethylene (HDPE) bottles. Each bottle 
contains 30 tablets, silica gel desiccant and polyester packing material. Each bottle is enclosed 
with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed and aluminum-faced liner.
Study drug(s) to be distributed to centers in the US and other participating countries will be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), European Union (EU) Guideline to Good Manufacturing Practice – Annex 13 
(Investigational Medicinal Products), and/or other local regulations.


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5.2.3.
Storage and Handling
GS-9876 tablets should be stored at controlled room temperature of 25 ºC (77 ºF); excursions are 
permitted between 15 ºC and 30 ºC (59 ºF and 86 ºF). Storage conditions are specified on the 
label. 
Until dispensed to the subjects, all drug products should be stored in a securely locked area, 
accessible only to authorized site personnel. To ensure the stability of the study drugs and to 
ensure proper product identification, the drug products should not be stored in a container other 
than the containers in which they are supplied. Consideration should be given to handling, 
preparation, and disposal through measures that minimize drug contact with the body. 
Appropriate precautions should be followed to avoid direct eye contact or exposure when 
handling.
5.3.
Dosage and Administration of Study Drug
Following completion of Screening and Day -1 assessments, eligible subjects will be enrolled in 
1 of the 3 cohorts and receive a single oral dose of GS-9876 20 mg (2 × 10 mg tablet) in a fasted 
state on Day 1.
5.4.
Fasting and Meals
Study drug will be administered in the morning with 240 mL of water. Subjects will continue to 
fast until after collection of the 4-hour PK sample, relative to study drug dosing. Additionally, 
subjects will be restricted from water consumption 1 hour before and 2 hours after dosing, except 
for the 240 mL given with the study drug. Water may be freely consumed following the 2-hour 
blood draw and for the remainder of the collection period. 
All meals and/or snacks given to subjects during their stay in the clinical study facility will be 
standardized for all subjects and should be similar in calorie and fat content and taken at 
approximately the same time each day. All meals provided must be approved by the sponsor.
Components of meals (eg, margarine, jelly, bread) should be given to subjects in individual 
portions (eg, 1 tablespoon) per the approved meal schedule. The provision of meal components 
in bulk (eg, a jar of jelly for subjects to share) should not be practiced. All meals should be given 
at approximately the same time each day (eg, 07:30, 12:00, and 18:00).
5.5.
Accountability for Study Drug
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug bottles. This includes acknowledgement of receipt of each shipment of study drug (quantity 
and condition). All used and unused study drug bottles dispensed to subjects must be returned to 
the site.
Study drug accountability records will be provided to each study site to:

Record the date received and quantity of study drug bottles


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
Record the date, subject number, subject initials, and the study drug bottle number dispensed

Record the date, quantity of used and unused study drug tablets returned, along with the 
initials of the person recording the information.
5.5.1.
Investigational Medicinal Product Return or Disposal
Please refer to Section 9.1.7
5.6.
Concomitant Medications and Other Protocol Restrictions
5.6.1.
Concomitant Medications
5.6.1.1.
Subjects with Normal Renal Function
The following medications are excluded while subjects are participating in the study (from 
screening until discharge). This list does not include medications such as anti-HIV agents that 
would be contraindicated for other exclusion criteria.

Any prescription medications and over-the-counter medications, including herbal products 
and antacids, with the exception of vitamins, and/or acetaminophen and/or ibuprofen and/or 
hormonal contraceptive medications and/or stable hormone replacement therapy in 
peri- / post-menopausal females. 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.
5.6.1.2.
Subjects with Renal Impairment 
Concomitant use of certain medications or herbal/natural supplements with study drug may result 
in PK interactions resulting in increases or decreases in exposure of study drug or these 
medications.
Concomitant medications taken within 30 days of Screening through the follow-up visit need to 
be recorded in the source documents and electronic Case Report Forms (eCRFs).
The following medications are excluded while subjects are participating in the study (from 
screening until discharge). This list does not include medications such as anti-HIV agents that 
would be contraindicated for other exclusion criteria.

Any and all illegal or illicit drug use, including use of prescription drugs outside the care of 
the prescribing physician.

Current alcohol or substance abuse judged by the Investigator to potentially interfere with
subject compliance (eg. amphetamines, cocaine, opiates).

Moderate or strong CYP3A4 inhibitors or inducers within 2 weeks prior to study drug 
administration and through the follow up visit.


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
Concurrent therapy with any anti-coagulant (eg, coumadin [warfarin], any Vitamin K
antagonist, any novel oral anticoagulant, any heparin or low molecular heparins, inhibitors of 
factor Xa)

Concurrent therapy with any anti-platelet therapy (eg, adenosine diphosphate [ADP] receptor
inhibitors, phosphodiesterase inhibitors, PAR-1 antagonists, Glycoprotein 2b/3a inhibitors)
with the exception of ≤ 100 mg daily of aspirin and other NSAIDs

Subjects with renal impairment with co-morbid diseases requiring medication(s) must be 
taking the medication(s) without a change in dose for > 3 months prior to screening.
All concomitant medications including over-the-counter and herbal products must be approved 
by the Investigator and Medical Monitor (or the Clinical Pharmacologist) prior to study 
enrollment and study drug administration.
Table 5-1 includes examples of prohibited medicines in subjects with renal impairment.
Table 5-1.
Examples of Prohibited Medications for Subjects with Renal 
Impairment
Drug Class
Agents Disallowed
Strong CYP3A4 Inhibitorsa
clarithromycin, conivaptan, itraconazole, ketoconazole, nefazodone, 
posaconazole, telithromycin, voriconazole, telaprevir, boceprevir, grapefruit 
juice, idelalisib, Viekira Pak (ombitasvir, paritaprevir, ritonavir, dasabuvir), 
troleandomycin, mibefradil
Strong CYP3A4 Inducersb
carbamazepine, phenytoin, rifampin, fosphenytoin, pentobarbital, primidone, 
rifabutin, rifapentine, phenobarbital, mitotane, avasimibe, St. John’s Wort, 
enzalutamide
Moderate CYP3A4 Inhibitorsa
fluconazole, erythromycin, diltiazem, dronedarone, aprepitant, casopitant, 
imatinib, verapamil, tofisopam, ciprofloxacin, cimetidine, cyclosporine, 
Schisandra sphenanthera, crizotinib, netupitant, nilotinib, isavuconazole
Moderate CYP3A4 Inducersb
bosentan, thioridazine, nafcillin, modafinil, semagacestat, genistein
Anti-plateletc
adenosine diphosphate (ADP) receptor inhibitors, phosphodiesterase 
inhibitors, PAR-1 antagonists, Glycoprotein 2b/3a inhibitors
Anti-coagulant
warfarin, any Vitamin K antagonist, any novel oral anticoagulant, any heparin 
or low molecular heparins, inhibitors of factor Xa
a
In vitro data indicate GS-9876 is a substrate of CYP3A4. Co-administration of CYP3A4 inhibitors may increase GS-9876
exposure. These agents are prohibited while subject is on study drug and 2 weeks prior to study drug administration.
b
In vitro data indicate GS-9876 is a substrate of CYP3A4. Co-administration of CYP3A4 inducers may decrease GS-9876
exposure. These agents are prohibited while subject is on study drug and 2 weeks prior to study drug administration.
c
≤ 100 mg aspirin and NSAIDs are permitted 
5.6.2.
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 must be able to comply with the smoking restrictions at the study site.


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
Subjects will be required to refrain from consumption of grapefruit juice, grapefruits, and 
Seville orange juice 96 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
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 −1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6b
Day 15 (±1)
Follow-Upc
ETd
Written Informed Consent
X
Medical History 
X
Complete Physical Exam
X
X
X
X
X
Symptom-Driven Physical 
Examinatione
X
X
X
X
X
Height 
X
Weight 
X
X
Vital Signsf
X
X
X
X
X
X
X
X
X
X
HIV-1, HBV, and HCV 
Testing
X
Hematologyg
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
Chemistryh
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
Serum Pregnancy Testi
X
X
X
X
X
Creatinine Clearance
X
X
Urine Drug and Alcohol 
Screen 
X
X
12-Lead ECG
X
X
X
X
X
X
Study Drug Administration
X
Intensive Plasma PKj
X
X
X
X
X
X
Urine PKk
X
X
X
X
X
X


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Study Procedure
Screena
Day −1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6b
Day 15 (±1)
Follow-Upc
ETd
Review Study Restrictions
X
X
X
X
Clinic Confinement
X
X
X
X
X
X
Review AEs & 
Concomitant Medicationsl
X
X
X
X
X
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 drug.
b
Subjects will be discharged from the clinic on Day 6, following all morning assessments.
c
14(± 1) days after the last administration of study drug, all subjects will return for an in-clinic follow-up visit and complete procedures as outlines.
d
Assessments will be performed within 72 hours of early termination from the study.
e
Symptom-driven PEs will be performed during confinement as needed, based on reported signs and symptoms.
f
Vital signs include blood pressure, heart rate, respiration rate, and temperature.
g
Hematology: CBC with differential.
h
See Section 6.9.5 for specifics.
i
Females of child-bearing potential only.
j
Intensive PK sampling will occur relative to the morning dosing of GS-9876 at the following time points:
Day 1: 0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96 and 120 hours postdose.
k
All urine voided will be collected and pooled relative to dosing of GS-9876 at the following collection intervals:
Day 1: Predose void, 0-6, 6-12, 12-24, 24-48, 48-72, 72-96, and 96-120 hours postdose
l
From the time of obtaining informed consent through the first administration of study drug, record all SAEs, as well as any nonserious AEs related to protocol-mandated 
procedures on the AE eCRF.
All other untoward medical occurrences observed during the screening period, including exacerbation or changes in medical history are to be captured on the medical history 
eCRF. See Section 7, Adverse Events and Toxicity Management for additional details.


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6.2.
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 -1 for admission 
assessments.
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 -1. The admission evaluations and/or procedures are outlined 
in Table 6-1.
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.


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6.2.2.2.
Clinic Confinement
Clinic confinement is outlined in Section 3.3, as well as in Table 6-1. 
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
All subjects will return 14 days (±1) after last dose of study drug for an in-clinic follow-up visit.
Study procedures and assessments are outlined in Table 6-1.
6.6.
Assessments for Premature Discontinuation from Study
If a subject discontinues study treatment dosing, for example as a result of an AE, every attempt 
should be made to keep the subject in the study and continue to perform the required 
study-related procedures until stabilization per the investigator. If this is not possible or 
acceptable to the subject or investigator, the subject may be withdrawn from the study. 
Evaluations indicating abnormal results believed to be possibly or probably related to study 
treatment at the ET visit should be repeated weekly or as often as deemed appropriate by the 
investigator until the abnormality resolves, returns to baseline visit levels, or is otherwise 
explained.
If the subject withdraws from the study, the ET evaluations and/or procedures outlined in 
Table 6-1 should be performed within 72 hours of permanently discontinuing the study drug.
6.7.
Criteria for Discontinuation of Study
Study confinement 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 3)

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-9876 will be determined and PK parameters estimated. Plasma 
concentrations of GS-9876 metabolites may be determined, if necessary. Intensive PK sampling 
will occur relative to the morning dose of GS-9876 at the following time points:
Intensive PK sampling will occur relative to dosing of GS-9876 at the following time points:
Day 1: 0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96 and 120 hours postdose
Protein binding of GS-9876 (and its metabolites, as applicable) will be assessed at or near their 
Tmax timepoint(s) as well as another later time point.
6.8.2.
Urine Pharmacokinetic Collection
All urine voided will be collected and pooled relative to dosing of GS-9876 at the following 
collection intervals:
Day 1: Pre-dose void, 0-6, 6-12, 12-24, 24-48, 48-72, 72-96 and 96-120 hours postdose
Urine concentrations of GS-9876 and/or metabolites may be determined and PK parameters 
estimated.
6.9.
Safety Assessments
Safety will be evaluated throughout the study. Refer to Table 6-1 for a schedule of assessments.
6.9.1.
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.


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The investigator or other qualified individuals at the study center will review ECGs to assess for 
changes in ECG intervals and morphology as compared with pretreatment ECGs. ECG interval 
measurements output by the machine will be used for bedside safety monitoring.
Collection of additional ECGs for routine safety monitoring at additional time points or days is at 
the discretion of the investigator based on GCP.
6.9.2.
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:

A complete physical examination must include source documentation of general 
appearance, and the following body systems: head, neck, thyroid; eyes, ears nose, throat, 
mouth and tongue; chest (excluding breasts); respiratory; cardiovascular; lymph nodes, 
abdomen; skin, hair, nails; musculoskeletal; neurological.

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.
6.9.3.
Vital Signs
Vital sign measurements include blood pressure, heart rate, respiration rate, and temperature and 
should be taken once subjects have been seated or in the supine position for a minimum of 
5-10 minutes. Subject position for measurement should be kept consistent throughout the study. 
Refer to Table 6-1 for vital signs collection time points.
6.9.4.
Body Mass Index
Height and weight will be collected at screening for calculation of BMI for inclusion criteria.
6.9.5.
Clinical Laboratory Tests/Assessments
Blood and urine samples for safety evaluations will be collected throughout the study as outlined 
in Table 6-1.
6.9.5.1.
Blood Sampling
Blood samples will be collected for the following laboratory analyses:

Hematology: Hematocrit, hemoglobin, platelet count, red blood cell (RBC) count, white 
blood cell (WBC) count with differential (absolute and percentage), including lymphocytes, 
monocytes, neutrophils, eosinophils, basophils, and mean corpuscular volume (MCV) 


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
Coagulation panel: D-Dimer, prothrombin time (PT), activated partial thromboplastin time 
(aPTT) and international normalized ratio (INR)

Chemistry (fasting): alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect 
bilirubin, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), 
triglycerides, total protein, albumin, lactic acid dehydrogenase (LDH), creatine 
phosphokinase (CPK), bicarbonate, blood urea nitrogen (BUN), calcium, chloride, creatinine 
(see below), glucose, phosphorus, magnesium, potassium, sodium, uric acid, and amylase 
(reflex lipase testing is performed in subjects with total amylase > 1.5 × upper limit of 
normal [ULN] )

Serum pregnancy test (females of childbearing potential only)

HIV-1, HBV(HbsAg and HBcAb), and HCV testing (screening only)
6.9.5.2.
Urine Samples
Urine samples will be collected for urinalysis and alcohol and drug screen assessments.
6.9.6.
Creatinine Clearance and Estimated Glomerular Filtration Rate 
Weight will be collected at screening and upon admission to calculate creatinine clearance (CLcr) 
and estimate glomerular filtration rate (eGFR), however CLcr will be used for inclusion criteria.
eGFR (mL/min/1.73 m2) = 175 × (*Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African 
American)
*Scr – serum creatinine
6.9.7.
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 5.6.1 for more information about concomitant medications.
6.10.
Sample Storage
 
 
PPD


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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, lack of efficacy, overdose, drug abuse/misuse reports, or occupational exposure.
Preexisting events that increase in severity or change in nature during or as a consequence of 
participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an 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 7.4)

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.)

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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction; such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, urinalysis) that require 
medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, 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 (eg, anemia), not the laboratory result (ie, decreased 
hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5.
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.


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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).
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, 4 or 5 using the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. 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 only modification to the CTCAE criteria is the addition of a Grade 1 upper respiratory, as 
described in Appendix 4.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
7.3.1.
Requirements for Collection Prior to Study Drug Initiation:
After obtaining informed consent, but prior to initiation of study drug, all SAEs and AEs related 
to protocol-mandated procedures should be reported on the eCRF.
7.3.1.1.
Adverse Events
Following initiation of study treatment, collect all AEs, regardless of cause or relationship, until 
30 days after last administration of study drug must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the AE is stable, if possible. Gilead may 
request that certain AEs be followed beyond the protocol-defined follow-up period.
7.3.1.2.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required posttreatment follow-up period, must be reported to the 
eCRF database and Gilead DSPH as instructed. This also includes any SAEs resulting from 
protocol-associated procedures performed after informed consent is signed.


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Any SAEs and deaths that occur after the posttreatment follow-up visit but within 30 days of the 
last dose of study drug, regardless of causality, should also be reported.
Investigators are not obligated to actively seek SAEs after the protocol-defined follow-up period;
however, if an investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of study drug, the investigator should promptly 
document and report the event to Gilead DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline.
7.3.1.3.
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 may be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning record the SAE on the paper serious adverse event reporting form 
and submit within 24 hours to:

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 email or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable United States 
(US) FDA Code of Federal Regulations, the European Union (EU) Clinical Trials Directive 
Gilead DSPH
Email: 
Fax: 
PPD
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(2001/20/EC) and relevant updates, and other country-specific legislation or regulations, Gilead 
may be required to expedite to worldwide regulatory agencies reports of SAEs, serious adverse 
drug reactions (SADRs), or SUSARs. In accordance with the EU Clinical Trials Directive 
(2001/20/EC), Gilead or a specified designee will notify worldwide regulatory agencies and the 
relevant independent ethics committee (IEC) in concerned member states of applicable SUSARs
as outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the IB. 
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.
Toxicity Management 
Treatment-emergent toxicities will be noted by the investigator and brought to the attention of 
the Gilead Sciences medical monitor, who will have a discussion with the investigator and 
decide the appropriate course of action. Whether or not considered treatment-related, all subjects 
experiencing AEs must be monitored periodically until symptoms subside, any abnormal 
laboratory values have resolved or returned to baseline levels or they are considered irreversible, 
or until there is a satisfactory explanation for the changes observed.
Grade 3 or 4 clinically significant laboratory abnormalities should be managed as outlined in 
Appendix 2.
Severity should be recorded and graded according to the modified CTCAE Grading Scale as 
described in (Appendix 4). 
For adverse events associated with laboratory abnormalities, the event should be graded on the 
basis of the clinical severity in the context of the underlying conditions; this may or may not be 
in agreement with the grading of the laboratory abnormality.
Any questions regarding toxicity management should be directed to the Gilead Sciences 
Medical Monitor.
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose,
occupational exposure with an AE, AE in an infant following exposure from breastfeeding, 
reports of AEs associated with product complaints, and pregnancy reports regardless of an 
associated AE.  


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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 labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Occupational exposure is the exposure to a medicinal product as a result of one's professional or 
non-professional occupation.
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study 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 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.


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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 subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead DSPH by faxing
or emailing
 
Refer to Appendix 3, Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPHwithin 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study drug and/or Gilead concomitant 
medications but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.6.2 and the eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.
PPD
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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 PK of GS-9876 in subjects with impaired renal function relative to matched, 
healthy controls
The secondary objective of this study is as follows:

To evaluate the safety and tolerability of GS-9876 in subjects with normal and impaired renal 
function
8.1.2.
Primary Endpoint
The primary endpoints are PK parameters AUClast, AUCinf, and Cmax for GS-9876.
8.1.3.
Secondary Endpoint
The secondary endpoints include incidences of AEs, laboratory abnormalities, abnormal findings 
in vital signs and safety ECG monitoring.
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
All Enrolled
The All Enrolled Analysis Set includes all subjects enrolled into the study after screening. This is 
primary analysis set for listings.
8.2.1.2.
Safety
The Safety Analysis Set will include all enrolled subjects who received 1 dose of GS-9876. 
8.2.1.3.
Pharmacokinetics
The PK Analysis Set will include all enrolled subjects who received 1 dose of GS-9876 and had 
at least 1 nonmissing PK concentration datum reported by PK lab. 


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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 1-half of the lower limit of quantitation (LLOQ) for postdose time 
points.
Laboratory data that are continuous in nature but are less than the LLOQ or above the upper limit 
of quantitation will be imputed to the value of the lower or upper limit minus or plus
1 significant digit, respectively (eg, if the result of a continuous laboratory test is < 20, a value of 
19 will be assigned; if the result of a continuous laboratory test is < 20.0, a value of 19.9 will be 
assigned).
Missing data can have an impact upon the interpretation of the study data. As this study is of 
short duration, it is anticipated that missing data will be minimal. In general, values for missing 
data will not be imputed. However, a missing pretreatment laboratory result would be treated as 
normal (ie, no toxicity grade) for the laboratory abnormality summary.
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized and descriptive statistics will be 
provided.
Demographic summaries will include sex, race/ethnicity, enrollment, and age.
8.5.
Interim Analysis
Review of available safety and PK data will be conducted by the sponsor to facilitate the 
decision of enrolling adaptive cohorts.
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 renal function group 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.
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.


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Adverse event data will be listed by subject. Treatment-emergent AEs (TEAEs), serious TEAEs, 
and TEAEs leading to discontinuation of treatment will be summarized by treatment, SOC, and 
PT using the current version of MedDRA. 
8.6.3.
Laboratory Evaluations
Listings of individual subject laboratory results will be provided. Laboratory results and change 
from predose values for selected lab tests will be summarized by renal function group at 
scheduled visits. The incidence of treatment-emergent graded laboratory abnormalities will be 
summarized by treatment.
8.6.4.
Other Safety Evaluations
Vital signs and ECG data will be summarized by renal function group.
8.7.
Pharmacokinetic Analysis
Plasma concentrations and PK parameters for GS-9876 will be listed and summarized by renal 
function group using descriptive statistics (eg, sample size, mean, SD, % coefficient of variation, 
median, first quartile [Q1], third quartile [Q3], minimum, and maximum).
In addition, an analysis of variance appropriate for a parallel design will be fitted to the natural 
logarithmic transformation of PK parameters (AUClast, AUCinf, and Cmax) for GS-9876. 
Two-sided 90% CIs will be calculated for the GLSM ratios of PK parameters between renal 
impairment group versus the control (normal renal function) group.
If determined, urine concentrations of GS-9876 over sampling time will be listed and 
summarized by renal function group using descriptive statistics. Urine concentrations versus time 
profiles of GS-9876 and its metabolites (if applicable) may be displayed by renal function group, 
as appropriate. When possible, urinary PK parameters (Ae, CLr and % Doseexcreted) will be 
calculated.
Protein binding of GS-9876 in plasma (at or near Tmax and a later timepoint) will also be 
summarized by renal function group using descriptive statistics.
The PK of GS-9876 metabolites (if applicable) may also be evaluated.
8.8.
Sample Size
With 16 (8 per group) evaluable subjects, the estimated two-sided 90% CI of the GLSM ratio of 
test versus reference groups, with regards to PK parameters (AUC and Cmax) would be within 
(50%, 200%) with over 95% probability. This calculation is based on a two group t-test of 
equivalence in means at the significance level of 0.05, assuming the expected geometric means 
ratio of 1.0 and inter-subject SD of no more than 0.35 on a natural logarithm scale. The 
assumption about the inter-subject SD is supported by previous Gilead study GS-US-379-1372 
using the maximum variability for AUC and Cmax from the closest dose levels (15 mg and 
30 mg) of the dose in this study. An overage of 2 subjects per group will be enrolled to 
accommodate subject drop-outs, thus requiring a total enrollment of 20 subjects (10 per group) 
for each cohort.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South 
Africa), International Conference on Harmonization (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the EU Clinical Trials 
Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice (GCP), 
as outlined in 21 Code of Federal Regulations (CFR) 312, Subpart D, “Responsibilities of 
Sponsors and Investigators,” 21 CFR, Part 50, "Protection of Human Subjects," and 21 CFR, 
Part 56, "Institutional Review Boards."
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 
"Financial Disclosure by Clinical Investigators," providing documentation of their financial 
interest or arrangements with Gilead, or proprietary interests in the study drug under study. This 
documentation must be provided prior to the investigator’s (and any subinvestigator’s) 
participation in the study. The investigator and subinvestigator agree to notify Gilead of any 
change in reportable interests during the study and for 1 year following completion of the study. 
Study completion is defined as the date when the last subject completes the protocol-defined
activities.
9.1.2.
Institutional Review Board/Independent Ethics Committee Review and 
Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, ICF, and any accompanying material to be provided to the subject (such as 
advertisements, subject information sheets, or descriptions of the study used to obtain informed 
consent) to an IRB/EC. The investigator will not begin any study subject activities until approval 
from the IRB/EChas 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.
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 


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potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB- or EC-approved ICF for documenting written 
informed consent. Each ICF will be appropriately signed and dated by the subject or the subject’s 
legally authorized representative and the person conducting the consent discussion, and also by 
an impartial witness if required by IRB/EC local requirements. 
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law), and an identification code will be recorded on any 
form or biological sample submitted to the sponsor, IRB/EC, or laboratory. Laboratory 
specimens must be labeled in such a way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions or in accordance 
with local regulations. NOTE: The investigator must keep a screening log showing codes, names, 
and addresses for all subjects screened and for all subjects enrolled in the study. Subject data will 
be processed in accordance with all applicable regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
IB, this protocol, 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, eCRF, IRB/EC and 
governmental approval with correspondence, ICF, drug records, staff curriculum vitae and 
authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender)

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria)

Documentation of the reason(s) a consented subject is not enrolled


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
Participation in study (including study number)

Study discussed and date of informed consent

Dates of all visits

Documentation that protocol specific procedures were performed

Results of efficacy parameters, as required by the protocol

Start and end dates (including dose regimen) of study drug, including dates of dispensing and 
return

Record of all AEs and other safety parameters (start and end dates, and including causality 
and severity)

Concomitant medication (including start and end dates, dose if relevant, and dose changes)

Date of study completion and reason for early discontinuation, if it occurs
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
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 


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Amendment 1
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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, IMP should be destroyed at the site. At the start of the study, the study monitor 
will evaluate each study center’s IMP disposal procedures and provide appropriate instruction for 
disposal or return of unused IMP supplies. If the site has an appropriate standard operating 
procedure (SOP) for drug destruction as determined by Gilead Sciences, the site may destroy 
used (empty or partially empty) and unused IMP supplies as long as performed in accordance 
with the site’s SOP. This can occur only after the study monitor has performed drug 
accountability during an on-site monitoring visit. 
A copy of the site’s IMP Disposal SOP or written procedure (signed and dated by the PI 
or designee) will be obtained for Gilead site files. If the site does not have acceptable 
procedures in place, arrangements will be made between the site and Gilead Sciences 
(or Gilead Sciences’ representative) for return of unused study drug supplies. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMPs
destroyed. Upon study completion, copies of the IMP accountability records must be filed at the 
site. Another copy will be returned to Gilead.
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.


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Amendment 1
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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to 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(ies). Gilead will 
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content 
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases. 
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, eg, attendance at investigator's meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to federal and state agencies any 
expenses paid or reimbursed for such services, including any clinical study payments, meal, 
travel expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
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.


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9.3.4.
Study Discontinuation
Both Gilead and the investigator reserve the right to terminate the study at any time. Should this 
be necessary, both parties will arrange discontinuation procedures and notify the subjects, 
appropriate regulatory authority(ies), IRBs, and ECs. In terminating the study, Gilead and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.


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Amendment 1
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10.
REFERENCES
Arthritis Foundation. Rheumatoid Arthritis Fact Sheet.  2008.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, et al. Estimates of the 
prevalence of arthritis and other rheumatic conditions in the United States. Part I. 
Arthritis Rheum 2008;58 (1):15-25.
Karie S, Gandjbakhch F, Janus N, Launay-Vacher V, Rozenberg S, Mai Ba CU, et al. Kidney 
disease in RA patients: prevalence and implication on RA-related drugs 
management: the MATRIX study. Rheumatology (Oxford) 2008;47 (3):350-4.
National Institute of Diabetes and Digestive and Kidney Diseases (NIH). Estimating Glomerular 
Filtration Rate (GFR). Available at: https://www.niddk.nih.gov/health-
information/health-communication-programs/nkdep/lab-
evaluation/gfr/estimating/Pages/estimating.aspx. Accessed 06 October.  2016:


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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.
Common Terminology Criteria for Adverse Events (CTCAE) v 4.03


PPD
PPD
OS-9876 
Protocol GS-US-3 79-1932 
Final 
Gilead Sciences, Inc. 
Amendment 1 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 1 Open-label Study to Evaluate the Pharmacokinetics of GS-9876 in Subjects with 
Impaired Renal Function 
GS-US-379-1932, Amendment 1 Protocol, 09 January 2017 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Medical Monitor 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
Twill provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 64 
09 January 20 l 7 


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Amendment 1
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Appendix 2.
Management of Clinical and Laboratory Adverse Events
Grade I 
Ll 
May continue dosing at 
the discretion of the 
investigator 
Repeat lab to confirm toxicity grade 
1 
If confirmed and possibly or probably 
related to study drug, discontinue study 
drug dosing permanently and follow at 
periodic intervals at least weekly until a 
return to baseline or is otherwise 
explained 
1 
Study Drug may be continued without dose 
interruption for a clinically non-significant Grade 3 
or 4 laboratory abnormality (eg, Grade 4 CK after 
strenuous exercise, or nonfasting triglyceride 
elevation, or blood in urine due to menses or that 
can be medically managed) or a clinical event 
considered unrelated to study drug. 


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Amendment 1
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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 postmenopausal unless the 
subject is permanently sterile or has medically documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b) Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless the subject is permanently sterile by bilateral orchidectomy or medical 
documentation.
2) Contraception Requirements for Female Subjects
a) Study Drug Effects on Pregnancy and Hormonal Contraception
GS-9876 is contraindicated in pregnancy as its teratogenicity/fetotoxicity profile is unknown. 
GS-9876 has insufficient data to exclude the possibility of a clinically relevant interaction with 
hormonal contraception that results in reduced contraception efficacy.  In this study,
contraceptive steroids are not recommended as a contraceptive method either solely or as a part 
of a contraceptive regimen.  Subjects may remain on their hormonal contraception if they prefer 
to do so, but will still be required to choose from contraceptive methods delineated below as the 
efficacy of their hormonal contraception during study dosing is unknown. 
Please refer to the latest versions of the GS-9876 IBs for additional information.
b) Contraceptive Methods Permitted for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective
contraceptive measures.  Women must agree to also not rely on hormone-containing 
contraceptives as a form of birth control during the study, though they may continue hormonal 
contraception if they prefer to do so.  Women must have a negative serum pregnancy test at 
Screening and a negative pregnancy test on the Day -1 visit prior to first dose of study drug.  
Pregnancy tests will be performed as defined by the schedule of assessments (Table 6-1). 


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Amendment 1
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Female subjects of childbearing potential must agree to one of the following from Screening 
until 36 days following the last dose of study drug.

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or
Consistent and correct use of 1 of the following methods of birth control listed below. 

Intrauterine device (IUD) with a failure rate of <1% per year

Tubal sterilization

Essure micro-insert system (provided confirmation of success 3 months after procedure)

Vasectomy in the male partner (provided that the partner is the sole sexual partner and had 
confirmation of surgical success at least 3 months after procedure)
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 36 days after the last dose of study drug.
c) 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 agree to use condoms during treatment and until 90 days 
after the last dose of study drug.  Additional contraception recommendations should also be 
considered if the female partner is of childbearing potential.
Male subjects must also 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.
d) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM).  Female condom and male condom should not be used 
together.
e) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 36 days of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately.  Subjects whose partner 
has become pregnant or suspects she is pregnant during the study or up to 90 days after the last 
dose of study drug must report the information to the investigator.  Instructions for reporting 
pregnancy, partner pregnancy, and pregnancy outcome are outlined in Section 7.6.2.1


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Amendment 1
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Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) v 4.03
CTCAE v4.03 can be accessed from the below link:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf
The only modification to the CTCAE criteria is the addition of a Grade 1 upper respiratory 
infection as follows:
CTCAE 
v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.03 
AE Term 
Definition
Upper 
respiratory 
infection
Mild 
symptoms; 
symptomatic 
relief (eg, 
cough 
suppressant, 
decongestant)
Moderate 
symptoms; 
oral 
intervention 
indicated 
(eg, antibiotic, 
antifungal, 
antiviral)
IV antibiotic, 
antifungal, or 
antiviral 
intervention 
indicated; 
radiologic, 
endoscopic, or 
operative 
intervention 
indicated
Life-
threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder 
characterized by 
an infectious 
process involving 
the upper 
respiratory tract 
(nose, paranasal 
sinuses, pharynx, 
larynx, or 
trachea).

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 1 Open-Label Study to Evaluate the Pharmacokinetics 
of GS-9876 in Subjects with Impaired Renal Function
Study Phase:
1
Name of Test Drug:
GS-9876
Study Number:
GS-US-379-1932
Protocol Version (Date):
Original (10 October 2016)
Amendment 1 (09 January 2017)
Analysis Type:
Final Analysis
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
13 February 2019
Analysis Plan Author:
 
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD


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Statistical Analysis Plan – Final Analysis
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
LIST OF IN-TEXT FIGURES ......................................................................................................................................4
LIST OF ABBREVIATIONS........................................................................................................................................5
PHARMACOKINETIC ABBREVIATIONS AND DEFINITIONS ............................................................................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 ..................................................................................................................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
3.1.1.
All Enrolled Analysis Set.....................................................................................................13
3.1.2.
Safety Analysis Set...............................................................................................................13
3.1.3.
Pharmacokinetic Analysis Set..............................................................................................13
3.2.
Strata and Covariates..............................................................................................................................13
3.3.
Examination of Subject Subsets.............................................................................................................14
3.4.
Multiple Comparisons............................................................................................................................14
3.5.
Missing Data and Outliers......................................................................................................................14
3.5.1.
Missing Data ........................................................................................................................14
3.5.2.
Outliers.................................................................................................................................14
3.6.
Data Handling Conventions and Transformations .................................................................................14
3.7.
Visit Windows........................................................................................................................................15
3.7.1.
Definition of Predose, Postdose, Study Day.........................................................................15
3.7.2.
Analysis Windows................................................................................................................16
3.7.3.
Selection of Data in the Event of Multiple Records on the Same Day.................................17
4.
SUBJECT DISPOSITION ..................................................................................................................................19
4.1.
Subject Enrollment and Disposition.......................................................................................................19
4.2.
Extent of Exposure.................................................................................................................................19
4.3.
Protocol Deviations for Eligibility .........................................................................................................20
4.4.
Important Protocol Deviations ...............................................................................................................20
5.
BASELINE CHARACTERISTICS....................................................................................................................21
5.1.
Demographics ........................................................................................................................................21
5.2.
Baseline Characteristics .........................................................................................................................21
5.3.
Medical History......................................................................................................................................21
6.
EFFICACY ANALYSES ...................................................................................................................................22
7.
SAFETY ANALYSES........................................................................................................................................23
7.1.
Adverse Events and Deaths....................................................................................................................23


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7.1.1.
Adverse Event Dictionary ....................................................................................................23
7.1.2.
Adverse Event Severity........................................................................................................23
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................23
7.1.4.
Relationship of Adverse Events to Study Procedure............................................................23
7.1.5.
Serious Adverse Events........................................................................................................23
7.1.6.
Treatment-Emergent Adverse Events...................................................................................24
7.1.6.1.
Definition of Treatment Emergent..................................................................24
7.1.6.2.
Incomplete Dates ............................................................................................24
7.1.7.
Summaries of Adverse Events and Deaths...........................................................................24
7.1.8.
Additional Analysis of Adverse Events ...............................................................................25
7.2.
Laboratory Evaluations ..........................................................................................................................25
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................26
7.2.2.
Graded Laboratory Values ...................................................................................................26
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities.............................................26
7.2.2.2.
Summaries of Laboratory Abnormalities........................................................26
7.3.
Body Weight, Height, BMI and Vital Signs...........................................................................................27
7.4.
Concomitant Medications ......................................................................................................................27
7.5.
Electrocardiogram Results .....................................................................................................................27
7.5.1.
Investigator Electrocardiogram Assessment ........................................................................27
7.6.
Other Safety Measures ...........................................................................................................................28
7.7.
Changes From Protocol-Specified Safety Analyses...............................................................................28
8.
PHARMACOKINETIC EVALUATION/ANALYSIS ......................................................................................29
8.1.
Estimation of Pharmacokinetic Parameters............................................................................................29
8.1.1.
Pharmacokinetic Parameters ................................................................................................29
8.2.
Statistical Analysis Methods ..................................................................................................................30
8.2.1.
General considerations .........................................................................................................30
8.2.2.
Statistical Methodology........................................................................................................31
8.3.
Sensitivity Analysis................................................................................................................................33
9.
REFERENCES ...................................................................................................................................................34
10.
SOFTWARE.......................................................................................................................................................35
11.
SAP REVISION..................................................................................................................................................36
12.
APPENDICES ....................................................................................................................................................37
Appendix 1.
Schedule of Assessments........................................................................................................37


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LIST OF IN-TEXT TABLES
Table 3-1.
Predose and Postdose Visits of Vital Signs ............................................................................16
Table 3-2.
Predose and Postdose Visits of Laboratory Tests...................................................................16
Table 3-3.
Predose and Postdose Visits for Electrocardiogram...............................................................17
Table 8-1.
Plasma Pharmacokinetic Parameters......................................................................................30
Table 8-2.
Urine Pharmacokinetic Parameters.........................................................................................30
Table 8-3.
Statistical Comparisons for Pharmacokinetic Analysis of Normal and Impaired 
Renal Function .......................................................................................................................32
LIST OF IN-TEXT FIGURES
Figure 1-1.
Study Design ............................................................................................................................8
Figure 1-2.
Study Schema...........................................................................................................................9


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LIST OF ABBREVIATIONS
AE
adverse event
ANOVA
analysis of variance
AUC
area under the curve
BLQ
below the limit of quantitation
BMI
body mass index
CI
confidence interval
CLcr
creatinine clearance
CRF
case report form
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
ECG
Electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
ET
early termination
GLSM
geometric least squares mean
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
ID
Identification
LLOQ
lower limit of quantitation
LOQ
limit of quantitation
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
PD
Pharmacodynamics
PK
pharmacokinetic(s)
PT
prothrombin time
PT
preferred term
Q1
first quartile
Q3
third quartile
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SE
standard error
SOC
system organ class
WHO
World Health Organization


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PHARMACOKINETIC ABBREVIATIONS AND DEFINITIONS
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)
%AUCexp
percentage of AUC extrapolated between AUClast and AUCinf
Cmax
maximum observed plasma/serum concentration of drug
Clast
last observed quantifiable plasma/serum concentration of the drug
CL/F
apparent oral clearance after administration of the drug:
CL/F = Dose/AUCinf, where “Dose” is the dose of the drug
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
Tmax
time (observed time point) of Cmax
Tlast
time (observed time point) of Clast
t ½
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)
Vz/F
apparent volume of distribution of the drug
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)
CLr
The renal clearance of unchanged drug in a specific interval (CLr(interval)) or cumulatively over 
all collection intervals
% Doseexcreted
The percentage of given dose excreted in the urine as unchanged 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 in the clinical study report (CSR) for 
Study GS-US-379-1932. This SAP is based on the study protocol amendment 1 dated 9 January 
2017, and the electronic case report form (eCRF). The SAP will be finalized before database 
finalization. Any changes made after the finalization of the SAP will be documented in the CSR.
1.1.
Study Objectives
The primary objective of this study is as follows:

To evaluate the pharmacokinetics (PK) of GS-9876 in subjects with impaired renal function 
relative to matched, healthy controls
The secondary objective of this study is as follows:

To evaluate the safety and tolerability of GS-9876 in subjects with normal and impaired renal 
function
1.2.
Study Endpoints
The primary endpoints are PK parameters AUClast, AUCinf, and Cmax for GS-9876.
The secondary endpoints include the incidence of adverse events (AEs), laboratory 
abnormalities, vital sign changes and safety ECG abnormalities.
1.3.
Study Design
Study GS-US-379-1932 is an open-label, parallel-group, adaptive, single-dose, multi-center 
Phase 1 study to evaluate the PK of GS-9876 in subjects with impaired renal function. 
This study will target enrolling 20 to 60 subjects using an adaptive design that includes up to 
3 enrolled cohorts of subjects with renal impairment and matched healthy controls. Based on 
safety and PK results from subjects with moderate renal impairment (Cohort 1), subjects with 
severe renal impairment (Cohort 2) and/or mild renal impairment (Cohort 3) will be enrolled as 
follows:

Cohort 1 (Moderate Renal Impairment): Up to 20 subjects (10 per group, moderate renal 
impairment and matched healthy controls) for 8 evaluable subjects per group.

Adaptive Cohort 2 (Severe Renal Impairment): Up to 20 subjects (10 subjects with severe 
renal impairment and up to 10 matched healthy control subjects if none of the healthy 
subjects from a previous cohort is an appropriate match for a severe impairment subject) for 
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
Adaptive Cohort 3 (Mild Renal Impairment): Up to 20 subjects (10 subjects with mild renal 
impairment and up to 10 matched healthy control subjects if none of the healthy subjects 
from a previous cohort is an appropriate match for a mild impairment subject) for 8 evaluable 
subjects per group.
Adaptive Cohorts 2 and/or 3 will be enrolled as determined by safety and/or PK data in Cohort 1. 
Specifically, Cohort 2 (Severe Renal Impairment) will be evaluated if supported by safety and/or 
PK data from Cohort 1 (Moderate Renal Impairment). Cohort 3 (Mild Renal Impairment) will be 
evaluated if supported by safety and if substantial changes (≥2-fold mean difference from 
matched controls) in the exposure of GS-9876 is observed in subjects with moderate renal 
impairment in Cohort 1. Cohorts 2 and 3 may not be enrolled or may be enrolled sequentially or 
in parallel, as governed by safety and PK data in Cohort 1. Each control subject may be matched 
to multiple renal impaired subjects across different cohorts and can be matched to only 1 renal 
impaired subject within a cohort.
An overview of the study design is shown in Figure 1-1.
Figure 1-1.
Study Design
The categorization of renal impairment is based on creatinine clearance (CLcr) using the 
Cockcroft-Gault formula from the screening visit. Specifically, a subject will be considered as 
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
Mild impairment if CLcr (rounding to the nearest integer) is 60-89 mL/min

Moderate impairment if CLcr (rounding to the nearest integer) is 30-59 mL/min

Severe impairment if CLcr (rounding to the nearest integer) is 15-29 mL/min
A subject with CLcr (rounding to the nearest integer) higher than or equal to 90 mL/min is 
categorized as having normal renal function.   
Following screening and Day -1 procedures, eligible subjects will be confined to the study center 
beginning Day -1 until the completion of assessments on Day 6. Subjects will return 14 (±1) 
days after last dose for an in-clinic follow up visit (ie, Day 15).
The study schema is shown in Figure 1-2.
Figure 1-2.
Study Schema


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Pharmacokinetic Assessments
Plasma PK Assessment
Plasma concentrations of GS-9876 will be measured and PK parameters determined. Plasma 
concentrations of GS-9876 metabolites may be determined and pharmacokinetics explored, as 
applicable.
Intensive PK sampling will occur relative to dosing of GS-9876 at the following time points:

Day 1: 0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96 and 120 hours 
postdose
Urine PK Assessment
Urine PK samples will be collected relative to dosing of GS-9876 at the following intervals:

Day 1: Pre-dose void, 0-6, 6-12, 12-24, 24-48, 48-72, 72-96 and 96-120 hours postdose 
Urine concentrations of GS-9876 and/or metabolites may be determined and PK parameters 
estimated.
Protein Binding Assessment
Protein binding of GS-9876 (and its metabolites, as applicable) will be assessed at or near their 
Tmax timepoint(s) as well as another later time point.
Safety Assessments
Safety will be evaluated by assessment of clinical laboratory tests, electrocardiogram (ECG), 
periodic physical examinations including vital signs at various time points during the study, and 
by documentation of adverse events (AEs).
Complete physical exam: Screening, Days -1, 6, and at the follow-up visit 14 (±1) days after last 
dose or at the Early Termination (ET) visit, if applicable
Symptom driven physical exam: every day during confinement as needed, based on reported 
signs and symptoms
Height: Screening
Weight: Screening and Day -1 
Urine Drug and Alcohol Assessments: Screening, Day -1
Serology Test (hepatitis B virus [HBV], hepatitis C virus [HCV], human immunodeficiency 
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Serum Pregnancy Test (women of childbearing potential only): Screening, Day -1, 6, and at the 
follow-up visit 14 (±1) days after last dose or at the ET visit, if applicable
Vital signs (blood pressure, pulse, respiration rate, and temperature): Screening, Days -1, 1 
(predose, 1, 3, 6, and 12 hours postdose), 2, 3, 4, 5, 6, and at the follow-up visit 14 (±1) days 
after last dose or at the ET visit, if applicable
Clinical laboratory tests (blood chemistry, and urinalysis):  Screening, Days -1, 1 (4 hours 
postdose), 2, 3, 6, and at the follow-up visit 14 (±1) days after last dose or at the ET visit, if 
applicable
Clinical laboratory tests (hematology and coagulation): Screening, Days -1, 1 (4 hours postdose), 
3, 6, and at the follow-up visit 14 (±1) days after last dose or at the ET visit, if applicable.
12-lead ECG: Screening, Days -1, 1 (postdose), 6, and at the follow-up visit 14 (±1) days after 
last dose or at the ET visit, if applicable
Assessment of AEs and concomitant medications will continue throughout the study.
1.4.
Sample Size and Power
With 16 (8 per group) evaluable subjects, the estimated two-sided 90% CI of the GLSM ratio of 
test versus reference groups, with regards to PK parameters (AUC and Cmax) would be within 
(50%, 200%) with over 95% probability. This calculation is based on a two group t-test of 
equivalence in means at the significance level of 0.05, assuming the expected geometric means 
ratio of 1.0 and inter-subject standard deviation (SD) of no more than 0.35 on a natural logarithm 
scale. The assumption about the inter-subject SD is supported by previous Gilead study GS-US-
379-1372 using the maximum variability for AUC and Cmax from the closest dose levels (15 mg 
and 30 mg) of the dose in this study. An overage of 2 subjects per group will be enrolled to 
accommodate subject drop-outs, thus requiring a total enrollment of 20 subjects (10 per group) 
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2.
TYPE OF PLANNED ANALYSIS
2.1.
Data Monitoring Committee
This study does not have a data monitoring committee.
2.2.
Interim Analysis
No formal interim analyses are planned for this study. 
2.3.
Final Analysis
After all subjects have completed the study, outstanding data queries have been resolved or 
adjudicated as unresolvable,, and the database has 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, 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. 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. 
3.1.1.
All Enrolled Analysis Set
The All Enrolled Analysis Set includes all subjects who received a study subject ID number in 
the study after screening.
This is the primary analysis set for listings.
3.1.2.
Safety Analysis Set
The Safety Analysis Set includes all enrolled subjects who received GS-9876. This is the 
primary analysis set for safety tables.
3.1.3.
Pharmacokinetic Analysis Set
The PK Analysis Sets include all enrolled subjects who took study drug and have at least 1 
nonmissing postdose concentration value reported by the PK laboratory for the corresponding 
analytes. These are the primary analysis sets for all PK analyses. 
3.2.
Strata and Covariates
This study does not use a stratified randomization schedule in enrolled subjects. No covariates 
will be included in analyses.


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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.
3.5.
Missing Data and Outliers
3.5.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. 
The handling of missing or incomplete dates for AE onset is described in Section 7.1.6.2.
3.5.2.
Outliers
Outliers of non-PK data will be identified during the data management and data analysis process, 
but no sensitivity analyses will be conducted. All data will be included in the data analysis.
3.6.
Data Handling Conventions and Transformations
In general, age (in years) on the date of the first dose of study drug will be used for analyses and 
presentation in listings. If an enrolled subject was not dosed with any study drug, the enrollment 
date will be used instead of the first dosing date of study drug. If only the birth year is collected 
on the CRF, “01 July” will be used for the unknown birth day and month for the purpose of age 
calculation. If only birth year and month are collected, “01” will be used for the unknown birth
day. 
Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ)
or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “x” (where x is considered the LOQ). For example, if the 
values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to 
calculate summary statistics. An exception to this rule is any value reported as < 1 or <0.1, 
etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to 
calculate summary statistics.

A value that is 1 unit above the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “> x” (where x is considered the LOQ). Values with decimal 
points will follow the same logic as the bullet point above.

The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of 
“≤ x” or “≥ x” (where x is considered the LOQ).


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If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data or nonparametric analysis methods may be used, 
as appropriate.
Natural logarithmic transformation will be used for analyzing concentrations and PK parameters. 
Concentration values that are below the limit of quantitation (BLQ) will be presented as “BLQ” 
in the concentration data listing. Values that are BLQ will be treated as 0 at predose time points, 
and one-half the value of the lower limit of quantitation (LLOQ) at postdose time points for 
determination of summary and order statistics. 
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.”
Pharmacokinetic parameters that are BLQ will be imputed as one-half LOQ before log 
transformation or statistical model fitting.
3.7.
Visit Windows
3.7.1.
Definition of Predose, Postdose, Study Day
Predose value is defined as the last available value off-treatment collected prior to study drug 
administration.
Postdose value is defined as any value collected after the study drug administration and before 
the dosing date plus 30 days.
Study Day will be calculated from the date of GS-9876 administration and derived as follows:

For postdose study days: assessment date –dosing date + 1

For days prior to the dose: assessment date – dosing date
Therefore, study day 1 is the day of study drug administration.


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3.7.2.
Analysis 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.

For subjects who prematurely discontinue from the study, ET data will be summarized as a 
separate visit, labeled ‘Early Termination’.
The predose and postdose visits for vital signs for different cohorts are summarized in Table 3-1.
Table 3-1.
Predose and Postdose Visits of Vital Signs
Visit Label
Study Day and Time points
Predose
1 (predose)
Day 1
1 (1, 3, 6, and 12 hours postdose)
Day 2
2
Day 3
3
Day 4
4
Day 5
5
Day 6
6
Follow-up
15 (±1)
Early Termination
Early Termination (if applicable)
The predose and postdose visits for laboratory tests for different cohorts are summarized in
Table 3-2.
Table 3-2.
Predose and Postdose Visits of Laboratory Tests
Visit Label
Study Day and Time points
Predose
-1
Day 1
1 (4 hours postdose)
Day 2
2 (chemistry and urinalysis only)
Day 3
3
Day 6
6
Follow-up
15 (±1)
Early Termination
Early Termination (if applicable)


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The predose and postdose visits for ECG for different cohorts are summarized in Table 3-3.
Table 3-3.
Predose and Postdose Visits for Electrocardiogram
Visit Label
Study Day and Time points
Predose
-1
Day 1
1
Day 6
6
Follow-up
15 (±1)
Early Termination
Early Termination (if applicable)
3.7.3.
Selection of Data in the Event of Multiple Records on the Same Day
Depending on the statistical analysis method, single values may be required for each day. For 
example, change from predose by visit usually requires a single value. 
If multiple, valid, nonmissing numeric observations exist on a day, records will be chosen based 
on the following rules if a single value is needed:

For predose, the last available record on or prior to the date and time of the first dose of study 
drug will be selected. If there are multiple records with the same time or no time recorded on 
the same day, average (arithmetic or geometric mean, as appropriate) will be used for the 
predose value. 

For postdose 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).


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
For postdose visits, if there are multiple records with the same time or no time recorded on 
the same day, the most conservative value within the window will be selected (eg, abnormal 
will be selected over normal for safety ECG findings).


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment and disposition will be provided by renal function group and 
by renal function group within each cohort. The number and percentage of subjects in each of the 
categories listed below will be provided. The denominator for the percentage calculation will be 
the total number of subjects in the renal function groups included in the All Enrolled Analysis 
Set.

Safety Analysis Set

PK Analysis Set

Completed study drug

Did not complete study drug with reasons for study drug discontinuation, as applicable

Completed study

Did not complete study with reasons for study discontinuation, as applicable
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 renal function group, date of study drug 
administration (study days), study drug completion status, reason for study drug discontinuation
(if applicable), study completion status, reason for study discontinuation (if applicable) will be 
provided by subject ID number in ascending order.
For a control subject may be matched to multiple renal impaired subjects across different 
cohorts, a by-subject listing of subject match and cohort affiliation will be provided. 
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. Study drug administration data for subjects who received study 
drug will be listed.


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A listing for subjects who were enrolled but not dosed will also be provided. 
4.3.
Protocol Deviations for Eligibility
A by-subject listing will be provided for the enrolled subject who failed to meet all inclusion 
criteria or met at least 1 exclusion criterion. The listing will present the eligibility criterion (or 
criteria if more than 1 violation) that subjects did not meet and related comments, if collected.
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. Any deviations identified will be evaluated to determine if it justifies excluding the 
subject from any analysis sets.
4.4.
Important Protocol Deviations 
A by-subject listing will be provided for those subjects who had important protocol deviations.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics 
Subject demographic variables (ie, age, sex, race, and ethnicity) will be summarized by renal
function group and overall using descriptive statistics for age, and using number and percentage 
of subjects for sex, race, and ethnicity. The summary of demographic data will be provided for 
the Safety Analysis Set.
A by-subject demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order. 
5.2.
Baseline Characteristics
Baseline characteristics include body weight (in kg), height (in cm), and body mass index (BMI; 
in kg/m2), CLcr (mL/min) using Cockcroft-Gault formula, and estimated glomerular filtration 
rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) Study equation {National 
Institute of Diabetes and Digestive and Kidney Diseases (NIH) 2016}. The equation used for 
MDRD-based eGFR is as follows:
eGFR (mL/min/1.73m2) = 175 x (Scr)-1 154 x (Age)-0 203 x (0.742 if female) x (1.212 if African American),
where Scr is serum creatinine in mg/dL.
These baseline characteristics will be summarized by renal function group (determined based on 
CLcr value from Cockcroft-Gault formula) using descriptive statistics (numbers of subjects, 
mean, SD, median, Q1, Q3, minimum, and maximum) for continuous variables and using the 
numbers and percentages of subjects for categorical variables. For baseline body weight, height, 
BMI, CLcr and eGFR, descriptive statistics also will be presented by sex in the same table. The 
summary of baseline characteristics will be provided for the Safety Analysis Set. No formal 
statistical testing is planned.
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.
5.3.
Medical History
Medical history data will be collected at screening and listed only. General medical history data 
will not be coded.
A by-subject listing of general medical history will be provided by subject ID number in 
ascending order. The listing will include relevant medical condition or procedure reported term, 
onset date, ongoing status, and resolution date (if applicable).


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


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory AEs will be coded using the current version of the Medical Dictionary 
for Regulatory Activities (MedDRA). System organ class (SOC), high-level group term, 
high-level term, preferred term (PT), and lower-level term will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, 4 or 5 according to 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 listed last in summary presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Study drug related AEs are those for which the investigator selected “Related” on the AE CRF to 
the question of “Related to Study Treatment”. Relatedness will always default to the 
investigator’s choice, not that of the medical monitor. Events for which the investigator did not 
record relationships to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing from that captured on the 
CRF.
7.1.4.
Relationship of Adverse Events to Study Procedure
Study procedure related AEs are those for which the investigator selected “Related” 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 procedures will be considered related to study procedures for 
summary purposes. However, by-subject data listings will show the relationship as missing from 
that captured on the CRF.
7.1.5.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs met the definitions 
of SAE specified in the study protocol. Serious adverse events captured and stored in the clinical 
database will be reconciled with the SAE database from the Gilead pharmacovigilance
department before database finalization.


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7.1.6.
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. If the AE onset date is the same as the date of 
study drug start date then the AE onset time must be on or after the study drug start time. If 
the AE onset time is missing when the start dates are the same the AE will be considered 
treatment emergent.

Any AEs leading to premature discontinuation of study drug.
7.1.6.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met:

The AE onset is the same as or after the month and year (or year) of the date of first dose of 
study drug, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after the date of the last dose of study drug 
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the date of the first dose of study drug, will be considered to be treatment 
emergent. In addition, an AE with the onset date missing and incomplete stop date with the same 
or later month and year (or year alone if month is not recorded) as the first dosing date of study 
drug will be considered treatment emergent.
7.1.7.
Summaries of Adverse Events and Deaths
Treatment-emergent AEs will be summarized based on the Safety Analysis Set.
The number and percentage of subjects who experienced at least 1 TEAE will be provided and 
summarized by SOC, PT, and renal function group based on the Safety Analysis Set as follows:

All TEAEs

All TEAEs by SOC and PT

All TEAEs by severity

All treatment-related AEs


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
All TEAEs of Grade 2 or higher

All treatment-related AEs by severity

All treatment-emergent SAEs

All treatment-related SAEs

All TEAEs leading to study discontinuation
A brief, high-level summary of AEs described above will be provided by renal 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 most severe grade will be used 
for those AEs that occurred more than once in an individual subject per treatment during the 
study. 
In addition, data listings will be provided for the following:

All AEs (indicating whether the event is treatment emergent)

All SAEs

Deaths
7.1.8.
Additional Analysis of Adverse Events
No additional analysis of AEs is planned.
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study drug plus 30 days
for subjects who have permanently discontinued study drug. The analysis will be based on values 
reported in conventional units. When values are BLQ, they will be listed as such, and the 
imputed value will be used for the purpose of calculating summary statistics. Hemolyzed test 
results will not be included in the analysis, but they will be listed in by-subject laboratory 
listings.
A by-subject listing for laboratory test results will be provided by subject ID number and time 
point in chronological order for hematology, chemistry, and urinalysis separately. Values falling 
outside of the relevant reference range and/or having a severity grade of 1 or higher on the 
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No inferential statistical testing is planned for laboratory assessments.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics will be provided by renal function group for each laboratory test as follows:

Predose values

Values at each postdose time point

Change from predose at each postdose time point
Predose and postdose values will be defined as described in Section 3.7.1. Change from predose
to a postdose visit will be defined as the visit value minus the predose value. The mean, median, 
Q1, Q3, minimum, and maximum values will be displayed to the reported number of digits; SD
values will be displayed to the reported number of digits plus 1.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3. 
7.2.2.
Graded Laboratory Values
The Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03 will be used to assign 
toxicity grades 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 assessment at any postdose time point, up to and including the date 
of last dose of study drug plus 30 days for subjects who permanently discontinued study drug. If 
the relevant predose laboratory value is missing, any abnormality of at least Grade 1 observed 
within the time frame specified above will be considered treatment emergent.
7.2.2.2.
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 time point.
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by laboratory test and renal function group; subjects will be 
categorized according to the most severe postdose abnormality grade for a given laboratory test:

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
Treatment-emergent Grade 3 or higher 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 time point in chronological order. This listing will include all test results that 
were collected throughout the study for the lab test of interest, with all applicable severity grades 
displayed.
7.3.
Body Weight, Height, BMI and Vital Signs
Descriptive statistics will be provided by renal function group for vital signs (including body 
temperature, pulse rate, respiratory rate, systolic and diastolic blood pressure) as specified below:

Predose value

Values at each postdose time point

Change from predose at each postdose time point
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 inferential statistical testing is planned.
A by-subject listing of vital signs will be provided by subject ID number and time point in 
chronological order. Body weight, height, and BMI will be included in the vital signs listing, if 
space permits, otherwise they will be provided separately.
7.4.
Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization (WHO) Drug dictionary.
A summary of concomitant medications will not be provided.
All concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.
7.5.
Electrocardiogram Results
7.5.1.
Investigator Electrocardiogram Assessment
A shift table of the investigator’s assessment of ECG results at each scheduled visit compared 
with predose values will be presented by renal function group using the following categories: 


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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 time 
point 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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8.
PHARMACOKINETIC EVALUATION/ANALYSIS
8.1.
Estimation of Pharmacokinetic Parameters
Pharmacokinetic parameters will be estimated using Phoenix WinNonlin® software using 
standard noncompartmental methods. The linear/log trapezoidal rule will be used in conjunction 
with the appropriate noncompartmental model, with input values for dose level, dosing time, 
plasma concentration, and corresponding real-time values, based on drug dosing times whenever 
possible.
All predose sample times before time-zero will be converted to zero.
For area under the curve (AUC), samples below the limit of quantitation of the bioanalytical 
assays occurring prior to the achievement of the first quantifiable concentration will be assigned 
a concentration value of zero to prevent overestimation of the initial AUC. Samples that are BLQ 
at all other time points will be treated as missing data in WinNonlin. The nominal time point for 
a dosing interval (τ) may be used to permit direct calculation of AUC over specific time 
intervals. The appropriateness of this approach will be assessed by the PK scientist on a 
profile-by-profile basis.
Pharmacokinetic parameters such as AUCinf, λz, and t1/2 are dependent on an accurate estimation 
of the terminal elimination phase of the drug. The appropriateness of calculating these 
parameters will be evaluated upon inspection of PK data on a profile-by-profile basis by the PK 
scientist.
Renal clearance (CLr) will be derived by dividing amount excreted in urine (Ae) through t hours 
postdose (eg. t = 120 hrs)  by AUC0-t (eg. AUC0-120). The determination of t will be based on the 
availability of data and assessed by the PK scientist. Fraction excreted unchanged through t 
hours postdose (fe0-t) will be derived by dividing amount excreted in urine (Ae, μg) through the 
last urine sampling timepoint over the dose (mg) administered. A conversion factor may be 
deployed to adjust the differences in reported units before deriving CLr and fe0-t. For example, if 
the units of Ae, AUC0-t, and the dose are μg, h*ng/mL, and mg, respectively, the following 
equations will be utilized: 
CLr (mL/min) = (Ae×1000) / (60×AUC0-t);
fe0-t = 100×Ae / (Dose×1000).
8.1.1.
Pharmacokinetic Parameters
Pharmacokinetic parameters for GS-9876 will be generated for all subjects for whom parameters 
can be derived. 
The parameters presented in Table 8-1 and Table 8-2 will be used to evaluate the PK objectives 
of the study. The primary parameters are plasma PK parameters AUClast, AUCinf, and Cmax of 


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GS-9876. The PK parameters to be estimated in this study are listed and defined in PK 
Abbreviations section.
Table 8-1.
Plasma Pharmacokinetic Parameters
Analyte
Parameters
GS-9876
AUClast, AUCinf, %AUCexp, Cmax, Tmax, Clast, Tlast, λz, CL/F,  Vz/F, and t1/2, as applicable
Table 8-2.
Urine Pharmacokinetic Parameters
Analyte
Parameters
GS-9876
CLr, Ae, and fe, as applicable
8.2.
Statistical Analysis Methods
8.2.1.
General considerations
Individual subject concentration data and individual subject PK parameters including percentage 
of protein binding for GS-9876 will be listed and summarized using descriptive statistics by renal 
function group. Summary statistics (numbers of subjects, mean, SD, coefficient of variation, 
median, minimum, maximum, Q1, and Q3) will be presented for both individual subject 
concentration data by time point and individual subject PK parameters by renal function group. 
Moreover, the geometric mean, 95% CI, and the mean and SD of the natural log-transformed 
values will be presented for individual subject PK parameter data. 
Individual concentration data listings and summaries will include all subjects with concentration 
data. The sample size for each time point will be based on the number of subjects with 
nonmissing concentration data at that time point. The number of subjects with concentration 
BLQ will be presented for each time point. For summary statistics, BLQ values will be treated as 
zero at predose and one-half of the LLOQ for postdose time points. 
Individual PK parameter data listings and summaries will include all subjects for whom PK 
parameter(s) can be derived. The sample size for each PK parameter will be based on the number 
of subjects with nonmissing data for that PK parameter.
In addition to the renal function categorization based on CLcr throughout this study, 
MDRD-based eGFR will be used for subject categorization in PK analysis. Subjects from all 
cohorts will be pooled and regrouped according to their MDRD-based eGFR values as follows:

Normal renal function if eGFR (rounding to the nearest integer) is ≥ 90 mL/min/1.73m2

Mild impairment if eGFR (rounding to the nearest integer) is 60-89 mL/min/1.73m2

Moderate impairment if eGFR (rounding to the nearest integer) is 30-59 mL/min/1.73m2


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
Severe impairment if eGFR (rounding to the nearest integer) is 15-29 mL/min/1.73m2

End stage renal impairment if eGFR (rounding to the nearest integer) is ≤ 14 mL/min/1.73m2
The following tables will be provided for GS-9876 by two sets of categorization (CLcr and 
MDRD-based eGFR) of renal function group:

Individual subject concentration data and summary statistics

Individual subject plasma PK parameters and summary statistics
The following figures will be provided for GS-9876 by two sets of categorization of renal 
function group:

Mean (± SD) concentration data versus time (on linear and semilogarithmic scales)

Median (Q1, Q3) concentration data versus time (on linear and semilogarithmic scales)
A figure of individual subject concentration data versus time (on linear and semilogarithmic 
scales) will be provided.
Individual, mean, and median postdose concentration values that are ≤LLOQ will not be 
displayed in the figures and remaining points will be connected.
The following listings will be provided:

Pharmacokinetic sampling details by subject, including differences in scheduled and actual 
draw times, and sample age

Individual data on determination of plasma half-life and corresponding regression  
correlation coefficient
8.2.2.
Statistical Methodology
The statistical comparisons of the natural log-transformed PK parameters for GS-9876 between 
renal impaired subjects and healthy controls will be performed. All subjects with available data 
for the PK parameter under evaluation will be included in the modeling. 
Consistent with using two sets of renal function categorization in PK summaries, two 
corresponding sets of comparisons will be performed. Details of these comparisons are shown in
Table 8-3. To ensure the appropriateness of applications of statistical testing, the comparisons 
will only be implemented when there are at least 3 subjects in both test and reference groups. 
The ratio of geometric least squares means (GLSMs) for the PK parameter in comparison 
between the test and reference groups and the 90% CI for the ratio will be provided.


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Table 8-3. 
Statistical Comparisons for Pharmacokinetic Analysis of Normal and 
Impaired Renal Function 
Renal Func.tion 
Compal'ison 
Categol'ization 
Pal'ametel' 
Test Gt'oup 
Refel'ence Gt'oup 
Creatinine 
AUCwr, AUC,ast, Cmax 
Mild Impainnent 
N01mal 
Clearance 
CLcr 60-89 mL/min 
CLcr 90 mL/min 
(rotmding to the 
AUCwr, AUC,ast, Cmax 
Moderate Impairment 
N01mal 
nearest integer) 
CLcr 30-59 mL/nlin 
CLcr 90 mL/min 
AUCwr, AUC,ast, Cmax 
Severe Impainnent 
Notmal 
CLcr 15-29 mL/nlin 
CLcr 90 mL/min 
MDRD-based 
AUCwr, AUC,ast, Cmax 
Mild Impairment 
Notmal 
eGFR 
eGFR 60-89 mL/min/1. 73m2 
eGFR 90 mL/min/1. 73m2 
(rormding to the 
AUCwr, AUC,ast, Cmax 
Moderate Impainnent 
Normal 
nearest integer) 
eGFR 30-59 mL/min/1.73m2 
eGFR 90 mL/min/1. 73m2 
AUCwr, AUC,ast, Cma." 
Severe Impainnent 
Notmal 
eGFR 15-29 mL/min/1.73m2 
eGFR 90 mL/min/1. 73m2 
AUCwr, AUC,ast, Cma." 
End Stage Impaitment 
Notmal 
14 mL/min/1.73m2 
eGFR 90 mL/min/1. 73m2 
For each PK parameter in comparison, a parametric (n01mal the01y) analysis of variance 
(ANOVA) model will be fitted to the natural log-transf01med values of PK parameter under 
evaluation. The statistical model will include renal function group as a fixed effect. 
The following SAS PROC MIXED code will provide the group comparison analysis between the 
renal ftmction groups and the 90% CI calculations for natural log-transformed PK parameters. 
proc mixed; 
class 
subjid; 
modellnest = renalgrp I ddfm=kr; 
repeated I group = 
lsmeans 
I e diff cl alpha = 0.1; 
estimate 'Impaired versus N01mal' treat 1 -1 I cl alpha= 0.10; 
ods output Estimates = LS _ Diffs LSMeans = LS _Means CovPatms = MSE; 
nm; 
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 logarithmic scale. The 
test-to-reference ratio (GLSM ratio) and associated 90% CI will be calculated by taking the 
exponential of the point 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) 2001, U.S. 
Depatiment of Health and Human Services Food and Dmg Administration Center for Dmg 
Evaluation and Research (CDER) 2003}. 
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Nonparametric analyses for the PK parameters CL/F, Vz/F, and t1/2, are routinely performed. 
When needed, these analyses can be performed using the Wilcoxon rank sum test for parallel 
design between the test and reference groups for GS-9876.
The following SAS PROC NPARLWAY code will provide the comparison.
proc npar1way data = param wilcoxon;
  class treat;
  var result; 
run;
To evaluate the protein binding of GS-9876, the percent of unbound GS-9876 at Tmax and a later 
time point will be summarized by time point and renal function group. Protein binding data for 
individual subject will be presented in a listing.
8.3.
Sensitivity Analysis
Sensitivity analysis may be conducted for the key PK analyses if the PK scientist identifies PK 
data as questionable. The sensitivity analysis will exclude specific data from analyses, if 
appropriate. If a sensitivity analysis is deemed necessary, a listing of the PK parameter(s) data 
being excluded, with associated reason(s) provided by the PK scientist, will be generated.


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9.
REFERENCES
National Institute of Diabetes and Digestive and Kidney Diseases (NIH). Estimating Glomerular 
Filtration Rate (GFR). Available at: https://www.niddk.nih.gov/health-
information/health-communication-programs/nkdep/lab-
evaluation/gfr/estimating/Pages/estimating.aspx. Accessed 06 October.  2016:
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER). Guidance for Industry. Statistical Approaches 
to Establishing Bioequivalence.  January, 2001.
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER). Guidance for Industry. Bioavailability and 
Bioequivalence Studies for Orally Administered Drug Products - General 
Considerations (Revision 1).  March, 2003.


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10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.
Phoenix WinNonlin® 7.0. Pharsight Corporation, Mountain View, CA, USA.


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


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12.
APPENDICES
Appendix 1.
Schedule of Assessments
Study Procedure
Screena
Day −1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6b
Day 15 (±1)
Follow-Upc
ETd
Written Informed Consent
X
Medical History 
X
Complete Physical Exam
X
X
X
X
X
Symptom-Driven Physical 
Examinatione
X
X
X
X
X
Height 
X
Weight 
X
X
Vital Signsf
X
X
X
X
X
X
X
X
X
X
HIV-1, HBV, and HCV 
Testing
X
Hematologyg
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
Chemistryh
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
Serum Pregnancy Testi
X
X
X
X
X
Creatinine Clearance
X
X
Urine Drug and Alcohol 
Screen 
X
X
12-Lead ECG
X
X
X
X
X
X
Study Drug Administration
X
Intensive Plasma PKj
X
X
X
X
X
X


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Study Procedure
Screena
Day −1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6b
Day 15 (±1)
Follow-Upc
ETd
Urine PKk
X
X
X
X
X
X
Review Study Restrictions
X
X
X
X
Clinic Confinement
X
X
X
X
X
X
Review AEs & 
Concomitant Medicationsl
X
X
X
X
X
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 drug.
b
Subjects will be discharged from the clinic on Day 6, following all morning assessments.
c
14(± 1) days after the last administration of study drug, all subjects will return for an in-clinic follow-up visit and complete procedures as outlines.
d
Assessments will be performed within 72 hours of early termination from the study.
e
Symptom-driven PEs will be performed during confinement as needed, based on reported signs and symptoms.
f
Vital signs include blood pressure, heart rate, respiration rate, and temperature.
g
Hematology: CBC with differential.
h
See Protocol Amendment 1 Section 6.9.5 for specifics.
i
Females of child-bearing potential only.
j
Intensive PK sampling will occur relative to the morning dosing of GS-9876 at the following time points:
Day 1: 0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96 and 120 hours postdose.
k
All urine voided will be collected and pooled relative to dosing of GS-9876 at the following collection intervals:
Day 1: Predose void, 0-6, 6-12, 12-24, 24-48, 48-72, 72-96, and 96-120 hours postdose
l
From the time of obtaining informed consent through the first administration of study drug, record all SAEs, as well as any nonserious AEs related to protocol-mandated 
procedures on the AE 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.


GS-US-379-1932 Final SAP
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Biostatistics eSigned
14-Feb-2019
19:28:48
Clinical Research eSigned 16-Feb-2019
04:38:36
Clinical Pharmacology
eSigned
19-Feb-2019
19:21:57
PPD
PPD
PPD