A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase 2 Proof-of-Concept Study to Evaluate Safety, Tolerability, and Efficacy of GS-9876 in Subjects With Active Rheumatoid Arthritis on Background Therapy With Methotrexate
Phase: PHASE2
Conditions: Rheumatoid Arthritis
Sponsor: Gilead Sciences

Study Title: 
Sponsor: 
INDNumber: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
~ GILEAU 
CLINICAL STUDY PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Multicenter, 
Proof-of-Concept Study to Evaluate Safety, Tolerability, and Efficacy 
of GS-987 6 in Subjects with Active Rheumatoid Arthritis on 
Background Therapy with Methotrexate 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
IND 123903 
2016-001496-75 
TBD 
Rheumatoid Arthritis 
GS-US-379-1582 
Gilead Clinical 
Name: 
Minnie Kuo 
PPD 
PPD 
Program Manager: 
Telephone: 
Fax: 
Gilead Medical 
Name: 
Monitor: 
Telephone: 
Fax: 
Mobile: 
Protocol Version/Date: 
Original: 
Franziska Matzkies 
PPD 
PPD 
PPD 
08 Apr 2016 
CONFIDENTIALITY STATEMENT 
The infmmation contained in this document, pruiicularly unpublished data, is the propeliy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The infonnation is only to be used by you in 
com1ection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infmmation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessaty to obtain infmm ed consent from those 
persons to whom the dmg may be administered. 

GS-9876
Protocol GS-US-379-1582
Gilead Sciences, Inc. 
Original
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................11
1.
INTRODUCTION ..............................................................................................................................................15
1.1.
Background ............................................................................................................................................15
1.2.
GS-9876 .................................................................................................................................................15
1.2.1.
General Information .............................................................................................................15
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................15
1.2.3.
Clinical Trials of GS-9876 ...................................................................................................19
1.3.
Information about Methotrexate.............................................................................................................20
1.4.
Rationale for Current Study ...................................................................................................................20
1.5.
Rationale for Dose Selection..................................................................................................................21
1.6.
Risk/Benefit Assessment for the Study..................................................................................................21
1.7.
Compliance ............................................................................................................................................22
2.
OBJECTIVES.....................................................................................................................................................23
3.
STUDY DESIGN................................................................................................................................................24
3.1.
Endpoints ...............................................................................................................................................24
3.2.
Study Design..........................................................................................................................................24
3.3.
Study Treatments ...................................................................................................................................25
3.4.
Duration of Treatment............................................................................................................................25
3.5.
Discontinuation Criteria.........................................................................................................................25
3.6.
End of Study...........................................................................................................................................27
3.7.
Post Study Care......................................................................................................................................27
3.8.
Pharmacokinetic (PK) Assessments.......................................................................................................27
3.9.
Biomarker Testing..................................................................................................................................28
3.9.1.
Optional Genomic Research.................................................................................................28
4.
SUBJECT POPULATION..................................................................................................................................29
4.1.
Number of Subjects and Subject Selection ............................................................................................29
4.2.
Inclusion Criteria....................................................................................................................................29
4.3.
Exclusion Criteria...................................................................................................................................30
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................33
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................33
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................33
5.2.
Description and Handling of GS-9876 and Placebo-To-Match (PTM) GS-9876 ..................................33
5.2.1.
Formulation..........................................................................................................................33
5.2.2.
Packaging and Labeling .......................................................................................................34
5.2.3.
Storage and Handling...........................................................................................................34
5.3.
Dosage and Administration of GS-9876 ................................................................................................34
5.4.
Other Medication Administered.............................................................................................................35
5.5.
Prior and Concomitant Medications.......................................................................................................35
5.6.
Investigational Medicinal Product Accountability and Disposal or Return ...........................................38
6.
STUDY PROCEDURES ....................................................................................................................................39

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6.1.
Subject Enrollment and Treatment Assignment.....................................................................................39
6.2.
Pretreatment Assessments......................................................................................................................39
6.2.1.
Screening Visit (within 28 days prior to randomization) .....................................................39
6.3.
Randomization (Day 1)..........................................................................................................................41
6.4.
Treatment Assessments..........................................................................................................................41
6.4.1.
Day 1 ....................................................................................................................................41
6.4.2.
Week 2 (+ 3 days) ................................................................................................................42
6.4.3.
Week 4 (+ 3 days) ................................................................................................................43
6.4.4.
Week 8 (+ 3 days) ................................................................................................................44
6.4.5.
Week 12 (+ 3 days) ..............................................................................................................45
6.5.
Early Termination (+ 3 days) .................................................................................................................46
6.6.
Post-Treatment Assessments (+ 5 days).................................................................................................47
6.7.
Sample Storage.......................................................................................................................................48
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................49
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................49
7.1.1.
Adverse Events.....................................................................................................................49
7.1.2.
Serious Adverse Events........................................................................................................49
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................50
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................50
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................50
7.2.2.
Assessment of Severity ........................................................................................................51
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................51
7.3.1.
Requirements for collection prior to study drug initiation: ..................................................51
7.4.
Gilead Reporting Requirements.............................................................................................................53
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................53
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................53
7.5.2.
Grades 3 and 4 Laboratory Abnormality or Clinical Event..................................................53
7.6.
Toxicity Management ............................................................................................................................54
7.7.
Special Situations Reports......................................................................................................................54
7.7.1.
Definitions of Special Situations..........................................................................................54
7.7.2.
Instructions for Reporting Special Situations.......................................................................55
8.
STATISTICAL CONSIDERATIONS................................................................................................................57
8.1.
Analysis Objectives and Endpoints........................................................................................................57
8.1.1.
Analysis Objectives..............................................................................................................57
8.1.2.
Primary Endpoint .................................................................................................................57
8.1.3.
Secondary Endpoint .............................................................................................................57
8.1.4.
Exploratory Endpoints..........................................................................................................57
8.2.
Analysis Conventions.............................................................................................................................58
8.2.1.
Analysis Sets ........................................................................................................................58
8.3.
Data Handling Conventions ...................................................................................................................58
8.4.
Demographic Data and Baseline Characteristics ...................................................................................59
8.5.
Efficacy Analysis ...................................................................................................................................59
8.6.
Safety Analysis.......................................................................................................................................59
8.6.1.
Extent of Exposure...............................................................................................................60
8.6.2.
Adverse Events.....................................................................................................................60
8.6.3.
Laboratory Evaluations ........................................................................................................60
8.6.4.
Other Safety Evaluations......................................................................................................60
8.7.
Pharmacokinetic Analysis......................................................................................................................61
8.8.
Biomarker Analysis................................................................................................................................61

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Protocol GS-US-379-1582
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8.9.
Data Monitoring Committee ..................................................................................................................61
8.10.
Sample Size............................................................................................................................................62
9.
RESPONSIBILITIES..........................................................................................................................................63
9.1.
Investigator Responsibilities ..................................................................................................................63
9.1.1.
Good Clinical Practice..........................................................................................................63
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................63
9.1.3.
Informed Consent.................................................................................................................63
9.1.4.
Confidentiality......................................................................................................................64
9.1.5.
Study Files and Retention of Records ..................................................................................64
9.1.6.
Case Report Forms...............................................................................................................65
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................66
9.1.8.
Inspections............................................................................................................................66
9.1.9.
Protocol Compliance............................................................................................................67
9.2.
Sponsor Responsibilities ........................................................................................................................67
9.2.1.
Protocol Modifications.........................................................................................................67
9.2.2.
Study Report and Publications .............................................................................................67
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................67
9.3.1.
Payment Reporting...............................................................................................................67
9.3.2.
Access to Information for Monitoring..................................................................................68
9.3.3.
Access to Information for Auditing or Inspections ..............................................................68
9.3.4.
Study Discontinuation..........................................................................................................68
10.
REFERENCES ...................................................................................................................................................69
11.
APPENDICES ....................................................................................................................................................71
Appendix 1.
Investigator Signature Page....................................................................................................72
Appendix 2.
Study Procedures Tables ........................................................................................................73
Appendix 3.
Laboratory Assessments Table...............................................................................................76
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03....................................77
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................78
Appendix 6.
The 2010 American College of Rheumatology –European League Against 
Rheumatism Collaborative Initiative Classification Criteria for Rheumatoid 
Arthritis {Aletaha et al 2010}.................................................................................................80
Appendix 7.
American College of Rheumatology Response Evaluations/ Preliminary Definition 
of Improvement in Rheumatoid Arthritis {Felson et al 1995} ...............................................82
Appendix 8.
Disease Activity Score for 28 Joint Count (DAS28) {Prevoo et al 1995} .............................84
Appendix 9.
Procedures and Specifications................................................................................................85

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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 30 mg once daily (AUC)........................................................................18
Table 5-1.
Examples of Disallowed Medications ....................................................................................37
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema.........................................................................................................................25

GS-9876 
Protocol GS-US-379-1582 
Gilead Sciences, Inc. 
Study Title: 
INDNumber: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Study Centers 
Planned: 
Objectives: 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
Original 
A Randomized, Double-Blind, Placebo-Controlled, Multicenter, 
Proof-of-Concept Study to Evaluate Safety, Tolerability, and 
Efficacy of GS-9876 in Subjects with Active Rheumatoid Arthritis 
on Backgrmmd Therapy with Methotrexate 
IND 123903 
Not Available 
Not Available 
Approximately 30-40 centers globally 
The primaty objective of this study is as follows: 
• 
To evaluate the effect ofGS-9876 versus placebo for the 
treatment of signs and symptoms of rheumatoid atihritis (RA) in 
subjects with active RA as measmed by change from baseline in 
Disease Activity Score for 28 joint count using C-reactive protein 
(CRP) (DAS28 [CRP]) at Week 12 
The secondaty objective of this study is as follows: 
• 
To evaluate the safety and tolerability of GS-9876 in subjects 
withRA 
• 
To explore the effect of GS-9876 on other disease-specific 
outcomes in RA 
The explorat01y objectives of this study are: 
I 
I 
Page 6 
08 April2016 

GS-9876
Protocol GS-US-379-1582
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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08 April 2016
Study Design:
This is a randomized, double-blind, placebo-controlled, 
proof-of-concept (POC) study evaluating the safety, tolerability, and 
efficacy of GS-9876 in adult male and female subjects with active 
RA despite MTX therapy who had an inadequate response to MTX 
(either alone or in combination with biological disease modifying 
anti-rheumatic drug [bDMARDs]).
Approximately 60 subjects will be randomized in a 1:1:1 ratio to 
receive 30 mg GS-9876, 10 mg GS-9876 or placebo-to-match (PTM) 
in addition to background therapy with MTX for up to 12 weeks:

GS-9876 (30 mg QD) (N=20)

GS-9876 (10 mg QD) (N=20)

GS-9876 PTM (QD) (N=20)
Randomization will be stratified by prior inadequate response to 
biologic therapy and geographic region.  
Subjects will be followed for 4 weeks after their last dose of study 
drug. 
Number of Subjects 
Planned:
Approximately 60 subjects
Target Population:
Subjects with active RA on background MTX therapy who had an 
inadequate response to MTX (either alone or in combination with
bDMARDs). 
Duration of 
Treatment:
Up to 12 weeks
Diagnosis and Main 
Eligibility Criteria:
Male or non-pregnant female subjects with active RA, between 
18 and 75 years of age (inclusive)
Key Inclusion Criteria include:
1) Active RA disease as defined by: a tender joint count (TJC) of
≥6 (out of 68), a swollen joint count (SJC) of ≥6 (out of 66),
and a CRP ≥ 5 mg/l
2) Inadequate response  to treatment with oral or parenteral MTX 
7.5 to 25 mg/week continuously for at least 12 weeks, with at 
least 6 weeks at a stable dose prior to the first dose of study drug
3) Subjects must be receiving a folic or folinic acid supplementation 
at a stable dose. Subjects who are not taking folic or folinic acid 
at Screening, should be initiated on an adequate dose of folic acid 
(≥5 mg/week total dose or as per local practice) or equivalent and 
maintained throughout the study.

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Protocol GS-US-379-1582
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4) Use of oral corticosteroids of no more than 10 mg prednisone or 
its equivalent per day is allowed if the dose is stable for at least 
28 days prior to the first dose of study drug 
5) Nonsteroidal Anti-inflammatory Drugs (NSAIDs) or other 
analgesics (including aspirin ≤ 100 mg daily) are allowed if doses 
are stable for at least 14 days prior to the first dose of study drug  
Key Exclusion Criteria include:
1) Prior treatment with B-cell depleting agents (eg, rituximab), 
unless more than 6 months prior and documented return of 
CD19+ cells
2) Prior treatment with any commercially available or 
investigational SYK inhibitor 
3) Current treatment with any other conventional DMARD 
(cDMARD) other than MTX and/or hydroxychloroquine (HCQ) 
(unless appropriate wash out as defined in Section 5.5)
4) Current treatment with any bDMARD (unless appropriate wash 
out as defined in Section 5.5)
5) QT interval corrected for heart rate using the Fredericia formula 
(QTcF) > 450 msec determined by the average of values at the 
Screening visit
6) History of any major bleeding event defined as Grade 3 severity 
and above [as defined by modified the Common Terminology 
Criteria for Adverse Events (CTCAE) 4.03] within the last year
or personal or family history of bleeding disorder
7) If no history of a documented negative tuberculosis (TB) test 
within the last 12 months or documented course of adequate 
therapy for either latent or active TB, a Quantiferon must be 
performed according to local standards. Subjects with a positive 
Quantiferon at Screening are not eligible
8) Ongoing treatment with moderate or strong CYP3A inducers or 
inhibitors or within 2 weeks prior to study drug administration
Additional inclusion and exclusion criteria are outlined in Section 4
Subject Population.
Study Procedures/
Frequency:
All subjects will complete the following study visits: Screening, 
Day 1 (first dose), and on-treatment visits at Weeks 2, 4, 8, and 12.  
All subjects will be followed for safety for an additional 4 weeks 
after their last dose of study drug. 
Screening assessments will be completed no more than 28 days prior 
to the Day 1 visit and will include a complete physical examination
(PE), joint count assessment, medical history, vital signs, height and 
weight, electrocardiogram (ECG), adverse events (AEs) related to 

GS-9876 
Protocol GS-US-379-1582 
Gilead Sciences, Inc. 
Test Product, Dose, 
and Mode of 
Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration 
Required Background 
therapy 
Criteria for 
Evaluation: 
Safety: 
CONFIDENTIAL 
Original 
screening procedures, concomitant medications, safety laboratmy 
tests (including hematology, chemistiy, and coagulation), CRP, 
serology (HIV, HCV, HBV), leukocyte subsets, biomarkers, RNA, 
TB test as applicable and as outlined in the protocol, urinalysis, urine 
dmg screen, and CD19 count as applicable and as outlined in the 
protocol. Pregnancy testing will be perfmmed for females of 
childbearing potential. 
On-ti·eatment assessments include a symptom driven PE, joint count 
assessment, disease-specific questionnaires and activity scales, vital 
signs, ECGs, AEs, concomitant medications, safety laboratmy tests 
(including hematology, chemistiy, and coagulation), leukocyte 
subsets (Day 1 and Week 12 ), quantitative imnllmoglobulins (Day 1 
and Week 12 or ET), RNA (Day 1, Week 4, and Week 12 or ET), 
RF/CCP [Day 1 and Week 12 or ET], CRP, urine pregnancy test, and 
biomarkers (Day 1, Week 4, and Week 12 or ET). Additional testing 
will include PK sampling (Day 1, Weeks 2, 4, 8 and 12 or ET). 
Post-treatment assessments include symptom driven PE, vital signs, 
ECGs, AEs, concomitant medications, safety laborato1y tests 
(including hematology, chemistly, and coagulation), CRP, and urine 
pregnancy test where indicated. 
For sub'ects who provide their additional and s ecific consent, 
PPD 
For subjects who provide their additional and specific consent, PO 
GS-9876 30 mg (1 x 30 mg tablet), administered orally once daily 
GS-9876 10 mg (1 x 10 mg tablet), administered orally once daily 
GS-9876 PTM (1 tablet), administered orally once daily 
MTX 7.5 to 25 mg, administered orally or parenterally once a week 
Safety will be assessed through the repmting of AEs, clinical 
laboratmy tests, PEs, vital sign assessments, and ECGs at various 
time points during the study. Concomitant medication usage will 
also be documented throughout the study. 
Page 9 
08 April2016 

GS-9876 
Protocol GS-US-379-1582 
Gilead Sciences, Inc. 
Efficacy: 
Phru.macokinetics: 
Exploratoty: 
Statistical Methods: 
Original 
The primru.y endpoint is change from baseline in DAS28 (CRP) at 
Week 12. 
The secondru.y endpoints include: 
• 
The propottion of subjects who achieve ACR 20/50/70 at 
Week 12 
• 
Change from baseline in Heath Assessment 
Questionnaire- Disability Index (HAQ-DI) score at Week 12 
Plasma concentrations ofGS-9876 will be detetmined. 
PPD 
The primmy endpoint is change from baseline in DAS28 (CRP) at 
Week 12. The primmy analysis will consist of a superiority test of 
each of the GS-9876 doses compared to placebo based on the change 
from baseline in DAS28 (CRP) at Week 12. 
All continuous endpoints will be summm·ized using an 8-number 
summaty [n, mean, standard deviation (SD), median, 1st quartile 
(Ql), 3rd quattile (Q3), minimum, maximum] by treatment group. 
All categorical endpoints will be summm·ized by the number and 
percentage of subjects who meet the endpoint definition. 
Safety endpoints will be analyzed by the mnnber and percent of 
subjects with events or abnonnalities for categorical values or 
8-number Slllllllla.J.Y (n, mean, SD, medim1, Ql, Q3, minimum, 
maximum) for continuous data by tl'eatment group. 
Sample size is detetmined based on the superiority test of one dose of 
GS-9876 compared to placebo based on the change from baseline in 
DAS28 (CRP) at Week 12. When assuming a difference of 
1.2 between the two groups and a common standard deviation of 
1.35, 20 subjects in each of the GS-9876 groups and 20 in the 
placebo group are required to obtain 78% power at a 2-sided 
0.05-level. Therefore, the total sample size will be 60 (20 per 
treatment group). 
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents. 
CONFIDENTIAL 
Page 10 
08 April2016 

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Protocol GS-US-379-1582
Gilead Sciences, Inc. 
Original
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
°C
degrees Celsius
°F
degrees Fahrenheit 
β-hCG
beta-human chorionic gonadotropin
μM
micromolar
ACPA
anti-citrullinated protein antibody
ACR
American College of Rheumatology
ACR 20/50/70 
American College of Rheumatology 20/50/70%  improvement
ADP
adenosine di-phosphate
AE
adverse event
AhR
aryl hydrocarbon receptor
AKT
protein kinase B
ALT
alanine aminotransferase
APC
antigen-presenting cell
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the curve
AUC0-last
area under the plasma/serum concentration versus time curve from time zero to 
the last quantifiable concentration
BCR
B-cell receptor
BCRP
breast cancer resistance protein
BDC
bile duct-cannulated
bDMARD
biological disease modifying anti-rheumatic drug
BLNK
B-cell linker protein
BLQ
below the limit of quantitation
BTK
Bruton’s tyrosine kinase
BUN
blood urea nitrogen
CBC
complete blood count
CCP
cyclic citrullinated peptide
CDAI
Clinical Disease Activity Index
CFR
Code of Federal Regulations
CG
Cockcroft-Gault
CIA
collagen-induced arthritis 
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear cell 
concentration of drug
CMH
Cochran–Mantel–Haenszel
CNS
central nervous system
CRO
contract research organization
CRP
C-reactive protein

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CTCAE
Common Toxicity Criteria for Adverse Events
CYP
cytochrome P450 
DAS28
Disease Activity Score for 28 joint count
DMARD
disease modifying anti-rheumatic drug
DMC
Data Monitoring Committee
DSPH
Drug Safety and Public Health
EC50
estimated concentration of drug for a half maximal response
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
ERK
extracellular signal-regulated kinase
eSAE
electronic serious adverse event
ESR
erythrocyte sedimentation rate
ET
early termination
EU
European Union
FAS
Full Analysis Set
FDA
(United States) Food and Drug Administration
g
gram
GCP
Good Clinical Practice
Gilead
Gilead Sciences, Inc.
GLP
Good Laboratory Practice
HAQ-DI
Health Assessment Questionnaire – Disability Index
HBV
hepatitis B virus
HCQ
hydroxychloroquine
HCV
hepatitis C virus
HDPE
high density polyethylene
hERG
human ether-a-go-go-related gene
HIV
human immunodeficiency virus
HLGT
high-level group term
HLT
high-level term
IB
Investigator’s Brochure 
IC
immune complex
IC50
concentration that results in 50% inhibition
ICH
International Conference on Harmonization 
ICH E3
ICH Guideline for Structure and Content of Clinical Study Reports
ie
id est (that is)
IEC
Independent Ethics Committee
Ig
immunoglobulin
IL
interleukin
IMP
investigational medicinal product

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INR
International Normalized Ratio of prothrombin time
IR
inadequate response
IRB
Institutional Review Board
IU
international units
IUD
intrauterine device
IXRS
Interactive Web and Mobile Response System
kg
kilogram
L
liter
LAM
lactational amenorrhea method
LLT
lower-level term
MAPK
mitogen-activated protein kinase
MCV
mean corpuscular volume 
MedDRA
Medical Dictionary for Regulatory Activities
MEK
MAPK/ERK kinase
mg
milligram
MMRM
mixed model repeated measures
msec
millisecond
MTX
methotrexate
ng
nanogram
nM
nanomolar
NOEAL
no-observed-adverse-effect-level 
NSAID
nonsteroidal anti-inflammatory drug
OATP
organic anion transporting polypeptide
PAR-1
protease-activated receptor
PD
pharmacodynamics
PE
physical examination
P-gp
P-glycoprotein
PK
pharmacokinetics
PKC
protein kinase C
POC
proof-of-concept
prn
pro re nata (as needed)
PT
preferred term or prothrombin time
PTM
placebo-to-match
PTT
partial thromboplastin time
PXR
pregnane X receptor
Q1
first quartile
Q3
third quartile
QD
quaque die (each day)

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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
corrected QT interval
QTcF
QT interval corrected for heart rate using the Fridericia formula
RA
rheumatoid arthritis
RBC
red blood cell
RF
rheumatoid factor
RNA
ribonucleic acid
s
second
SADR
serious adverse drug reaction
SAE
serious adverse event
SD
standard deviation 
SDAI
Simplified Disease Activity Index
SJC
swollen joint count
SOC
system organ class
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
TEAE
treatment-emergent adverse event
TJC
tender joint count
TNF
tumor necrosis factor
UGT
uridine disphosphate glucuronosyltransferase
ULN
upper limit of normal
US, USA
United States, United States of America
VAS
visual analog scale
WBC
white blood cell

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1.
INTRODUCTION
1.1.
Background
Rheumatoid Arthritis is a chronic, systemic inflammatory disease that affects approximately 
1.3 million adults in the United States (US) {Helmick et al 2008}. RA 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. Patients 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 patients respond adequately (or maintain response) to current therapies and some 
patients 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. 
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 RA resulting in 
pleiotropic anti-inflammatory effects.
1.2.
GS-9876
1.2.1.
General Information
For further information on GS-9876, refer to the current Investigator’s Brochure (IB).
1.2.2.
Preclinical Pharmacology and Toxicology
1.2.2.1.
Preclinical Pharmacology and Safety Pharmacology
In biochemical assays, GS-9876 is a selective and potent 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 

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SYK relative to all other protein kinases assayed. The potency of GS-9876 to inhibit SYK
activation was also assessed in human and rat whole blood. Levels of autophosphorylation and 
activation of SYK on tyrosines (Y)525/6 in blood samples preincubated with GS-9876 showed 
potent inhibition of phosphoSYK -Y525/6 levels in human and rat whole blood with EC50 values 
of 171 nM and 230 nM, respecitively. Studies with human whole blood also showed that 
GS-9876 inhibited anti-IgD/BCR-induced CD69 expression on B-cells (geometric mean 
EC50 = 301 nM) and anti-FceRI-stimulated CD63 expression on basophils (geometric mean 
EC50 = 73.2 nM in 25% human blood and 221.8 nM in 67% blood).
The ability of GS-9876 to inhibit SYK signaling in primary human B-cells, lymphocytes, and 
macrophages was assessed in vitro. GS-9876 inhibited anti-IgM-induced BCR/SYK-mediated 
phosphorylation and activation of multiple downstream signaling pathways in primary human 
B-cells including AKT, BLNK, BTK, ERK, MEK, and PKC with EC50 values ranging from 
24 to 51 nM. GS-9876 also suppressed anti-IgM-induced CD69 and CD86 expression on human 
peripheral blood B-cells with EC50 values of 112 nM and 164 nM, respectively. BCR and 
CD40 costimulation of B-cell proliferation and anti-CD3/anti-CD28 costimulation of T-cell 
proliferation was also inhibited by GS-9876 with EC50 values of 108 nM and 1291 nM, 
respectively, demonstrating a 12-fold relative functional selectivity of GS-9876 for B-cells 
compared to T-cells. In immune complex (IC)-stimulated cytokine release assays in primary 
human monocyte differentiated macrophages, GS-9876 inhibited IC-stimulated TNF-α, IL-1, and 
IL-6 secretion with geometric mean EC50 values of 121 nM, 93 nM, and 909 nM, respectively, 
demonstrating that GS-9876 inhibition of SYK blocks B-cell and macrophage receptor signaling 
in vitro with similar potencies.
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, respiratory, and CNS systems. 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, 

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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.
1.2.2.2.
Preclinical 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 highest proposed dose 30 mg dose, estimated exposure margins are 
2.4-/5.9- fold based on exposures at the NOAELs in the 26 week study in male/female rats.  
Patients 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. However in the ongoing 
39-week study, one 15 mg/kg/day monkey was euthanized moribund during Week 22 with 
persistent fecal changes, weight loss, deteriorating clinical condition, and large bowel 
inflammation. All other animals survived to their scheduled necropsy after 39-weeks dosing. For 
the highest proposed dose 30 mg dose, the estimated exposure margin is 2.7-fold based on 
exposures at the 15 mg/kg/day NOAEL in the 13-week monkey study. Although the relationship 
of the moribund animal to GS-9876 treatment is uncertain, Gilead considers it prudent to limit 
exposures to mean exposures achieved in monkeys at the 10 mg/kg/day mid-dose at Week 13 of 
the 39-week study (6750 ng.h/mL), which were 1.8-fold above estimated exposures at the 
highest proposed dose 30 mg dose.
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.

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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. 
Table 1-1.
Margins for GS-9876 Based on Systemic Exposure Relative to the 
Observed Human Exposure at 30 mg once daily (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)
2.4/5.9
(male/female)
Cynomolgus Monkey
Once daily 
x 13 weeks
Oral
15c
10,100
2.7
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 observed steady-state exposure (AUCtau) in humans of 3708 ng•h/mL at 30 mg 
once daily in study GS-US-379-1900.
c
One animal was euthanized moribund during Week 22 at the 15 mg/kg/day dose level.
1.2.2.3.
Preclinical Drug Metabolism and Pharmacokinetics
Consistent with the high absorption observed in nonclinical species, GS-9876 shows high
permeability and low efflux transport across human Caco-2 cell monolayers. Efflux is likely
mediated by P-gp and BCRP.
The whole blood to plasma ratios determined in rats, dogs, cynomolgus and rhesus monkeys, and
humans ranged from 0.83 in rats to 2.38 in cynomolgus monkeys. GS-9876 plasma protein
binding at 2 μM is moderate in all species with the free fraction ranging from 11.8% in rat to 
38.5% in dog. In human plasma, GS-9876 has an average free fraction of 20.4%.
The oral bioavailability of GS-9876 is high in rat, dog, and cynomolgus monkey and is
independent of the formulation used (F ≥ 60%). GS-9876 had low to intermediate clearance
relative to liver blood flow in rats, dogs, and cynomolgus and rhesus monkeys. Across species,
the in vivo clearance is similar to the predicted hepatic clearance obtained in primary hepatocytes
leading to confidence in the human prediction based on in vitro hepatocyte data. The volume of
distribution is approximately equal to (rat) or higher than (all other species) total body water
(0.7 L/kg).
After oral dosing to albino and pigmented rats, [14C]GS-9876-derived radioactivity was
distributed to most of the tissues by the first collection time point (0.25 hours postdose). Most
tissues reached maximum GS-9876 concentration by 1 hour postdose and concentrations of
radioactivity were below the limit of quantitation by 168 hours postdose. The tissues showing the
highest maximum concentrations of radioactivity included liver, adrenal glands, and kidney. The
lowest levels of radioactivity were observed in the brain, bone, adipose, and testis. Generally

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similar distribution patterns and tissue concentrations of [14C]GS-9876-derived radioactivity
were observed in albino and pigmented rats except for the pigmented skin and eye uveal tract
where higher tissue/blood ratios were seen in melanin-containing tissues. Binding was reversible.
In both strains, the brain/blood concentration ratio was low (< 0.1), suggesting
[14C]GS-9876-derived radioactivity was relatively excluded by the blood:brain barrier.
Recovery of radioactivity dosed orally to rats was high (≥ 97.8%). The main route of elimination
of GS-9876 is likely hepatobiliary with ≤ 5.1% orally dosed radioactivity found in rat urine and
69.4% in bile of BDC rats.
GS-9876 undergoes slow oxidative metabolism in human hepatocytes. Comparison of
metabolism in hepatocytes from rats, dogs, monkeys, and humans did not identify any
metabolites unique to humans, supporting the selection of rat and cynomolgus monkey as
toxicology species. No detectable turnover of GS-9876 by recombinant human CYP enzymes
(CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4) was observed
confirming the high metabolic stability in human hepatocytes. The clearance of GS-9876 may be
increased by inducers of CYP enzymes.
GS-9876 had little inhibitory effect on the activities of human CYP1A2, CYP2B6, CYP2C8,
CYP2C9, CYP2C19, CYP2D6, or CYP3A. GS-9876 was a weak inhibitor of human UGT1A1 
(IC50 = 31.1 μM). The low systemic concentrations anticipated in the clinic for GS-9876 make it 
unlikely to cause drug-drug interactions in vivo through inhibition of human CYP enzymes or 
UGT1A1.
GS-9876 is a weak inhibitor of the efflux transporters P-gp (IC50 > 23.2 μM) and BCRP
(IC50 > 100 μM) as well as the hepatic uptake transporters OATP1B1 (IC50 = 10.3 μM) and
OATP1B3 (IC50 = 12.3 μM). The low dose and low systemic concentrations anticipated in the
clinic for GS-9876 suggest that the potential for clinically relevant drug-drug interactions with
GS-9876 as an inhibitor of these transporters is low.
GS-9876 is a substrate for P-gp and BCRP, but not OATP1B1 or OATP1B3. Inhibitors of
intestinal P-gp and BCRP are unlikely to have a marked effect on GS-9876 absorption due to its
high permeability and high oral bioavailability expected in the clinic.
It is unlikely that GS-9876 would activate PXR- or AhR-regulated genes at the maximum plasma
concentrations expected in the clinic. Thus, the potential of GS-9876 to cause drug-drug
interactions through induction is low.
1.2.3.
Clinical Trials of GS-9876
As of 08 April 2016, 62 healthy volunteers have been dosed with GS-9876 in two clinical 
studies.

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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 
interaction potential using a representative acid reducing agent (omeprazole). 
Ongoing Clinical Trial
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.
1.3.
Information about Methotrexate 
Subjects will continue to receive stable weekly doses of MTX. Further information regarding
side effects, dosage and administration is available in the current local prescribing information.
1.4.
Rationale for Current Study
Over the last decade, changes in RA treatment strategies accompanied by advances in drug 
development and the addition of targeted biological therapies have greatly improved the 
outcomes for subjects with RA. Despite these developments, therapeutic challenges remain. The 
current conventional and biological DMARDs may be ineffective, produce only partial responses 
or loose therapeutic response over time due to development of neutralizing antibodies in some 
subjects and are associated with significant safety and tolerabilityconcerns. There is an unmet 
medical need for simple, orally administered therapies with novel and targeted mechanisms of 
action that can effectively improve the disease course while being safe and well tolerated.
Given its central role in immune cell signaling, inhibition of SYK is expected to have pleiotropic
anti-inflammatory effects and affect multiple steps in RA pathogenesis. B cells have been
implicated as playing a critical role in the pathogenesis of RA as demonstrated by the clinical
activity of the anti-CD20 monoclonal antibody, rituximab, in RA patients {Leandro et al 2006, 
Navarro-Millan et al 2013}. B cells contribute to the pathogenesis of RA through their ability to 
act as antigen presenting cells (APCs) presenting self-antigens to auto-reactive T cells 
{Shlomchik 2008}, and through the production of autoantibodies and pro-inflammatory 
cytokines {Martin et al 2006, Song et al 2010}. As a critical mediator of BCR signaling, SYK
inhibition suppresses BCR-stimulated proliferation, co-stimulatory molecule expression, and 
autoantibody production in B cells {Braselmann et al 2006, Coffey et al 2012}. 
Additionally, SYK inhibition suppresses IC-stimulated cytokine release from 
monocytes/macrophages and prevents osteoclastogenesis {Liao et al 2013}. Spleen tyrosine 
kinase is expressed in the rheumatoid synovium {Cha et al 2006} and SYK inhibition reduces 
cellular infiltrates into synovial tissue {Coffey et al 2012}. Pharmacologic inhibition of SYK has 
been shown to inhibit disease progression and reduce inflammation in multiple animal models of 
RA, and has demonstrated disease modifying anti-rheumatic drug (DMARD) activity on
endpoints such as cartilage destruction and bone erosion {Coffey et al 2012, Liao et al 2013, 
Pine et al 2007}.  A consistent finding in these nonclinical studies is that significant efficacy can 
be achieved with minimum plasma concentrations (Cmin) that result in target coverage less than 
50% {Liao et al 2013}.

GS-9876 
Protocol GS-US-379-1582 
Gilead Sciences, Inc. 
Original 
Taken together, the in vitro and in vivo data suggest that inhibition of SYK may decrease several 
pathologically active mechanisms implicated in RA including B-cell activation, T -cell 
costimulation, and cytokine release. 
This study is designed to evaluate the efficacy, safety, tolerability, PK, and PPD 
1.5. 
Rationale for Dose Selection 
In the rat CIA model, predicted GS-9876 exposure at the 30 mg and 10 mg QD doses are 
estimated to provide 75% and 37% of the maximal treatment response observed with GS-9876, 
respectively. The maximal treatment response observed with GS-9876 in this model was similar 
to the positive control dexamethasone. In the multiple ascending dose study (GS-US-379-1900), 
doses up to 30 mg QD of GS-9876 for 7 days were well tolerated in healthy volunteers. 
Therefore both doses (10 mg QD and 30 mg QD) are expected to be safe and have the potential 
to be efficacious in RA. 
1.6. 
Risk/Benefit Assessment for the Study 
As of08 April 2016, GS-9876 has been well tolerated by 62 healthy subjects. In the clinical 
studies GS-US-379-1372 (single ascending dose) and GS-US-379-1900 (cohorts 1 and 2; 
multiple ascending dose over 7 days), no risks were identified, and observed AEs were mainly 
Grades 1 and 2 in severity. The majority of AEs were assessed by the investigator as not related 
to GS-9876. The majority of graded laboratory abnormalities was Grade 1 or Grade 2 and mostly 
related to cholesterol. No prolongation of bleeding time duration was noted during the study. No 
clinically significant changes in vital signs, physical findings, or ECGs were reported during this 
study and no clinically relevant QTcF interval prolongation was noted in time matched ECGs in 
cohort 1 and cohort 2. 
In the repeat dose toxicology studies, 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 
2: 10 mg/kg/day, and hemorrhage and thrombosis in monkeys at 2: 20 mg/kg/day. At higher doses 
in rats (2: 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 NOAEL in rats was 10 mg/kg/day after 26 weeks dosing. For the proposed 
30 mg dose in planned Study GS-US-379-1582, estimated exposure margins are 2.4-/5.9- fold 
based on exposures at the NOAELs in the 26 week study in male/female rats. Patients will be 
closely monitored for any infection, changes in the differential CBC and cell subsets. 
In monkeys, the NOAEL in the 28-day study was identified at 10 mg/kg/day, which was 
associated with AUCo-24 hr 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. However in the 
ongoing 39-week study, one 15 mg/kg/day monkey was euthanized moribund during Week 22 
CONFIDENTIAL 
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with persistent fecal changes, weight loss, deteriorating clinical condition, and large bowel 
inflammation. Gilead considers it prudent to limit exposures in Study GS-US-379-1582 to mean 
exposures achieved in monkeys at the 10 mg/kg/day mid-dose at Week 13 of the 39-week study 
(6750 ng•h/mL). For the highest proposed dose of 30 mg in this study the estimated exposure 
margin is 2.7- fold based on exposures at the NOAEL in the 13-week monkey study.
In clinical studies GS-US-379-1372 and GS-US-379-1900 (cohorts 1 and 2) no change in 
platelets numbers, prothrombin time (PT), partial thromboplastin time (PTT), international 
normalized ration (INR) as well as bleeding time were observed. The risk for bleeding at the 
doses proposed for this POC study is therefore considered to be low.
An independent and experienced Data Monitoring Committee (DMC) appointed to monitor the 
study will provide an additional level of risk mitigation. Refer to Section 8.9 Data Monitoring 
Committee.
The overall risk:benefit balance of this study is considered favorable. For additional information 
about the risks of GS-9876, reference is made to the investigator brochure.
1.7.
Compliance
This study will be conducted in compliance with this protocol, GCP, and all applicable 
regulatory requirements.

GS-9876 
Protocol GS-US-379-1582 
Gilead Sciences, Inc. 
2. 
OBJECTIVES 
The primary objective of this study is: 
Original 
• 
To evaluate the effect of GS-987 6 versus placebo for the treatment of signs and symptoms of 
RAin subjects with active RA as measured by change from baseline in DAS28 (CRP) at 
Week 12 
The secondru.y objectives of this study are: 
• 
To evaluate the safety and tolerability of GS-9876 in subjects with RA 
• 
To explore the effect of GS-9876 on other disease-specific outcomes in RA 
The explorat01y objectives of this study are: 
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GS-9876 
Protocol GS-US-379-1582 
Gilead Sciences, Inc. 
3. 
STUDY DESIGN 
3.1. 
Endpoints 
The primaty endpoint of this study is: 
• 
Change from baseline in DAS28 (CRP) at Week 12 
The secondaty endpoints of the study are: 
• 
The proportion of subjects who achieve ACR 20/50/70 at Week 12 
• 
Change from baseline in HAQ-DI score at Week 12 
The explorat01y endpoints include: 
IT 
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I 
3.2. 
Study Design 
Original 
This is a randomized, double-blind, placebo-controlled, POC study evaluating the safety, 
tolerability, and efficacy of GS-9876 in adult male and female subjects with active RA despite 
MTX therapy who had an inadequate response to MTX (either alone or in combination with 
bDMARDs). 
A total of approximately 60 subjects will be randomized in this study. 
CONFIDENTIAL 
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Figure 3-1.
Study Schema
3.3.
Study Treatments
Following completion of Screening assessments, eligible subjects will be randomized in a 
blinded fashion in a 1:1:1 ratio as follows:
Group 1:
GS-9876 (30 mg QD) (N=20)
Group 2:
GS-9876 (10 mg QD) (N=20)
Group 3:
GS-9876 PTM (QD) (N=20)
Randomization will be stratified by prior inadequate response to biologic therapy and geographic 
region.  
3.4.
Duration of Treatment
Subjects will be treated for up to 12 weeks and then followed for 4 weeks after their last dose of 
study drug. 
3.5.
Discontinuation Criteria
When medically feasible, the Medical Monitor should be consulted prior to subject 
discontinuation. Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator affect assessment of 
clinical status to a significant degree. Following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator.

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
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

Subjects use of non-permitted concurrent therapy

Serious infections (those requiring parenteral antimicrobial therapy or hospitalization)

Any opportunistic infections

Complicated herpes zoster infection (multi-dermatomal, disseminated, ophthalmic or CNS 
involvement)

Pregnancy during the study; refer to Appendix 5

Investigator discretion

Discontinuation of the study at the request of Gilead, regulatory agency or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC)

Laboratory abnormalities:
■
2 sequential total WBCs <2000 cells/mm3 (SI: <2.0x109 cells/L).
■
2 sequential neutrophil counts <1000 neutrophils/mm3 (SI: <1.0x109 cells/L).
■
2 sequential lymphocyte counts <750 lymphocytes/mm3 (SI: <0.75x109 cells/L).
■
2 sequential hemoglobin values <8.0 g/dL (SI: <80 g/L).
■
2 sequential platelet counts <75,000 platelets/mm3 (SI: <75.0x109 cells/L).
■
2 sequential AST or ALT elevations >3xULN with ≥1 total bilirubin value >2xULN.1
■
2 sequential AST or ALT elevations >3xULN accompanied by elevated international 
normalized ratio (INR).1
                                                
1 In each case, there is a need for additional investigations, such as review of ethanol, recreational drug and dietary 
supplement consumption; testing for acute hepatitis A, B or C infection and biliary tract imaging should be promptly 
discussed with the study Medical Monitor.

GS-9876 
Protocol GS-US-379-1582 
Gilead Sciences, Inc. 
Original 
3.6. 
• 
2 sequential ASTor ALT elevations >5xULN, regardless of total bilimbin or 
accompanying symptoms.1 
• 
2 sequential increases in semm creatinine >50% over the average of Screening and 
Day 1 values. 2 
• 
After becoming aware of any of the above described abnonnallaborat01y changes 
occmTing at any one time, an unscheduled visit (i.e. second sequential) must occur to 
retest within 3 to 5 days. Subjects who stop study medication for any reason will not 
be replaced. Subjects withdrawing from the study will be encouraged to complete the 
same fmal evaluations as subjects completing the study according to the protocol, 
particularly safety evaluations in the subject's interest so that data can 
End of Study 
End of Study is defined as when the last patient has completed up to 12 weeks of treatment and 
4 weeks of follow-up. 
3.7. 
Post Study Care 
Subjects may be offered the opp01tunity to emoll into an open-label extension of GS-9876 at a 
future date. At this time there are no confmned post study care options to subjects that have 
patiicipated on this study and the long tenn care of subjects will remain the responsibility of their 
primaty treating physician. 
3.8. 
Pharmacokinetic (PK) Assessments 
Plasma concentrations ofGS-9876 will be measured and PK parameters detetmined. Plasma 
concentrations of GS-9876 metabolites may be detetmined and PK parameters may be explored, 
as applicable. PK sampling will occur relative to study dmg dosing at Weeks 2, 8, and 12 or ET, 
corresponding to a trough concentration taken approximately 24 hours after the previous dose of 
GS-9876, but prior to the next dose of GS-9876. At Week 4, PK sampling will occur at 2 hours 
postdose. The samples will be used to evaluate PK of GS-9876 and may also be used to measure 
protein binding of GS-9876. Plasma concentrations of GS-9876 metabolites and/or MTX may be 
detetmined. 
PPD 
2 At the time of study completion or discontinuation, if a subject should exhibit elevations in serum creatinine :;::33 % 
above the average of Screening and Day 1 values, they should be re-tested every 1 to 2 weeks until the senun 
creatinine elevation is fully reversed to within 10% of the average of Screening and Day 1 values. 
CONFIDENTIAL 
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3.9. 
Biomarker Testing 
PO 
Original 
Sampling for markers relevant to inflammation (including but not limited to disease-associated 
markers ofRA and/or the SYK pathway) may be perfonned at Baseline, Day 1, Week 4, and 
Week 12 or ET. Sampling time points may be modified by the Sponsor based upon emerging 
data and assay feasibility. Samples for CRP will be drawn at evety visit. 
The testing outlined in this protocol is based upon the cunent state of scientific knowledge. It 
may be modified dming or after the end of the study to remove tests no longer indicated and/or 
to add new tests based upon the growing state of knowledge. Samples may be stored at Gilead 
Sciences for a period of up to 15 years after the end of the study. 
3.9.1. 
Optional Genomic Research 
PO 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 60 subjects will be enrolled in this study with active RA who have an inadequate 
response to MTX (either alone or in combination with bDMARDs). In order to manage the total 
study enrollment, Gilead, at its sole discretion, may suspend screening and/or enrollment at any 
site or study-wide at any time.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1)
Male or female subjects who are between 18 and 75 years of age, inclusive, on the day of 
signing informed consent
2)
Have a diagnosis of RA as defined by the 2010 American College of 
Rheumatology - European League Against Rheumatism Collaborative Initiative 
Classification Criteria for Rheumatoid Arthritis (Appendix 6)
3)
Active RA disease as defined by a TJC of ≥6 (out of 68), a SJC of  ≥6 (out of 66), and a 
CRP ≥ 5 mg/l
4)
Inadequate response to treatment with oral or parenteral MTX 7.5 to 25 mg/week 
continuously for at least 12 weeks, with at least 6 weeks at a stable dose prior to the first 
dose of study drug
5)
Subjects must be receiving a folic or folinic acid supplementation at a stable dose. Subjects 
who are not taking folic or folinic acid at Screening should be initiated on an adequate dose 
of folic acid (>5 mg/week total dose or as per local practice) or equivalent and maintained 
throughout the study.
6)
Use of oral corticosteroids of no more than 10 mg prednisone or its equivalent per day is 
allowed if the dose is stable for at least 28 days prior to the first dose of study drug  
7)
NSAIDs or other analgesics (including aspirin ≤ 100 mg daily) are allowed if doses are 
stable for at least 14 days prior to the first dose of study drug  
8)
Able and willing to sign the informed consent as approved by the IRB/IEC. Written consent 
must be provided before initiating any Screening evaluations. Subjects must have read and 
understood the informed consent form (ICF), must fully understand the requirements of the 
study, and must be willing to comply with all study visits and assessments.
9)
A negative serum pregnancy test is required for female subjects 

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10) Lactating females must agree to discontinue nursing before the investigational medicinal 
product (IMP) is administered.
11) 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 5.
4.3.
Exclusion Criteria
1) Prior treatment with B-cell depleting agents (eg, rituximab), unless more than 6 months prior 
and documented return of CD19+ cells
2) Prior treatment with any commercially available or investigational SYK inhibitor 
3) Current treatment with any other cDMARD other than MTX and/or HCQ (unless appropriate 
wash out as defined in Section 5.5)
4) Current treatment with any bDMARD (unless appropriate wash out as defined in 
Section 5.5). Prior failure to treatment with bDMARDs is not an exclusion criterion.
5) QT interval corrected for heart rate using the Fredericia formula (QTcF) > 450 msec 
determined by the average of values at the Screening visit
6) History of any major bleeding event defined as Grade 3 severity and above [as defined by 
modified the Common Terminology Criteria for Adverse Events (CTCAE) 4.03] within the 
last year or personal or family history of bleeding disorder
7) If no history of a documented negative TB test within the last 12 months or documented 
course of adequate therapy for either latent or active TB, a Quantiferon must be performed 
according to local standards. Subjects with a positive Quantiferon at Screening are not 
eligible
8) Ongoing treatment with moderate or strong CYP3A inducers or inhibitors or within 2 weeks 
prior to study drug administration
9) Joint injections within 4 weeks prior to the first dose of study drug
10) Administration of a live or attenuated vaccine within 30.
11) Participation in any investigational drug/device clinical study within 4 weeks or 5 half-lives 
prior to Screening, whichever is longer. Exposure to investigational biologics should be 
discussed with the sponsor. 
12) Have a diagnosis of any generalized musculoskeletal disorder (eg, generalized osteoarthritis, 
or systemic inflammatory condition other than RA such as, but not limited to: juvenile 
idiopathic arthritis, Felty’s syndrome, ankylosing spondylitis, reactive arthritis, psoriatic 
arthritis, inflammatory bowel disease associated arthropaties, systemic lupus erythematosus, 
scleroderma inflammatory myopathy, mixed connective tissue disease, any overlap 
syndrome, systemic vasculitis or gout [participants with secondary Sjogren's syndrome or 
secondary limited cutaneous vasculitis with RA are not excluded]).

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13) History of or current moderate to severe congestive heart failure (New York Heart 
Association [NYHA] class III or IV), or within the last 6 months, a cerebrovascular accident, 
myocardial infarction, unstable angina, unstable arrhythmia or any other cardiovascular 
condition which, in the opinion of the investigator, would put the subject at risk by 
participation in the study.
14) History of malignancy within the past 5 years prior to Screening (except for adequately 
treated or excised basal cell carcinoma or non-metastatic squamous cell carcinoma of the 
skin or cervical carcinoma in situ with no evidence of recurrence). 
15) History of lymphoproliferative disease or possible current lymphoproliferative disease
16) History of demyelinating disease or current signs and symptoms suggestive of demyelinating 
disease, or immediate family history of demyelinating disease.
17) History of organ or bone marrow transplant.
18) Positive serology for human immunodeficiency virus (HIV) 1 or 2, hepatitis B virus 
(i.e., surface antigen [Ag] or core antibody [Ab] positive) or hepatitis C virus (i.e., HCV Ab 
positive) or any history of infectious hepatitis from any cause with the exception of hepatitis 
A.
19) History of opportunistic infection or immunodeficiency syndrome.
20) Known active infection of any kind (excluding fungal infections of nail beds) or any major 
episode of infection requiring hospitalization or treatment with IV anti-infectives within 
4 weeks of Screening or 8 weeks of Day 1 visit or completion of oral anti-infectives within 
2 weeks of the Screening or 6 weeks of Day 1 visit.
21) Currently on any therapy for chronic infection (such as pneumocystis, cytomegalovirus, 
herpes zoster, and atypical mycobacteria). Past history of disseminated Staphylococcus 
aureus or disseminated Herpes simplex infection.
22) History of symptomatic herpes zoster or herpes simplex infection within 12 weeks prior to 
Screening or have history of disseminated/complicated herpes zoster infection 
(multi-dermatomal involvement, ophthalmic zoster, central nervous system involvement or 
postherpetic neuralgia).
23) History of an infected joint prosthesis or other implanted device with retention of the 
prosthesis or device in situ.
24) History within the previous 2 years or current evidence of drug or alcohol abuse.
25) Any condition including active fibromyalgia that based on the investigator’s opinion would 
make it difficult to appropriately assess RA activity for the purposes of this study.

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26) Any condition or circumstances which in the opinion of the investigator or sponsor may 
make a subject unlikely or unable to complete the study or comply with study procedures and 
requirements.
27) Significant blood loss (>450 mL) or transfusion of any blood product within 12 weeks prior 
to Day 1.
28) Male subjects must refrain from sperm donation throughout the study period and continuing 
for at least 90 days following the last dose of study drug.
29) Female subjects must refrain from egg donation or harvest throughout the study period and 
continuing for at least 30 days after last dose.
30) 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.
31) The results of the following laboratory tests performed at the central laboratory at Screening 
meet any of the criteria below:
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 x 109 cells/L); 
c) Neutrophils <1.5 x 103 cells/mm3 (SI: <1.5 x 109 cells/L);
d) Lymphocytes <0.5 x 103 cells/mm3 (SI: <0.5 x 109 cells/L);
e) Platelets <100 x 103 cells/mm3 (SI: <100 x 109 cells/L);
f)
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥1.5x ULN;
g) Total bilirubin level ≥2x ULN unless the subject has been diagnosed with Gilbert’s  
disease and this is clearly documented;
h) Creatinine clearance < 60 mL/min based on the Cockcroft-Gault (CG) formula3
                                                
3 Creatinine clearance (mL/min) = [ (140 – age) * weight in kg] / [ 815 * serum creatinine in mmol/L ]

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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
An Interactive Web and Mobile Response System (IXRS) will be employed to manage subject 
randomization and treatment assignments. 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.
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator or qualified designee may obtain treatment assignment directly 
from the IXRS system for that subject. Gilead recommends but does not require that the 
investigator contact the Gilead medical monitor before breaking the blind. Treatment assignment 
should remain blinded unless that knowledge is necessary to determine subject emergency 
medical care. The rationale for unblinding must be clearly explained in source documentation 
and on the electronic case report form (eCRF), along with the date on which the treatment 
assignment was obtained. The investigator is requested to contact the Gilead medical monitor 
promptly in case of any treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).
5.2.
Description and Handling of GS-9876 and Placebo-To-Match (PTM) GS-
9876
5.2.1.
Formulation
GS-9876 will be supplied as 10 or 30 mg tablets that are round, biconvex, plain-faced and film-
coated blue. Each tablet contains either 10 mg or 30 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. 
Matching placebo tablets will be supplied that are identical in physical appearance to the 
10 or 30 mg GS-9876 tablets and contain the following inactive ingredients: 
microcrystalline cellulose, lactose, croscarmellose sodium, magnesium stearate, 
polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, and FD&C blue #2/indigo carmine 
aluminum lake.

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5.2.2.
Packaging and Labeling
GS-9876 tablets, 10 mg or 30 mg, and PTM 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 shall 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.
5.2.3.
Storage and Handling
GS-9876 tablets and PTM tablets should be stored at controlled room temperature of 25ºC 
(77ºF); excursions are permitted between 15ºC and 30ºC (59ºF and 86ºF). Storage conditions are 
specified on the label. Until dispensed to the subjects, all bottles of study drugs should be stored 
in a securely locked area, accessible only to authorized site personnel.
To ensure the stability and proper identification, study drugs should not be stored in a container 
other than the container in which they were supplied. 
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling. 
5.3.
Dosage and Administration of GS-9876
GS-9876 30 mg (1 x 30 mg tablet), GS-9876 10 mg (1 x 10 mg tablet), or GS-9876 PTM
(1 tablet) will be provided by Gilead Sciences, Inc. and are to be administered orally once daily
with water. The study drug should be swallowed whole. GS-9876 may be taken with or without 
food. Each subject will be given instructions to maintain approximately the same daily dosing 
interval between study drug doses. Subjects will be instructed to take study drug at 
approximately the same time each morning. On Day 1, subjects will be instructed to take their 
dose in clinic as the last in-clinic study procedure (after all other procedures for that visit have 
been completed). At Weeks 2, 8 and 12, subjects will be instructed to take their dose after 
predose assessments have been completed (eg, PK sample collection). At Week 4, subjects will 
be instructed to take their dose in clinic as the first study procedure prior to any others scheduled 
for that visit. 
For missed dose(s) of study medication, subject should be instructed to take the missed dose(s) 
of study medication, as soon as possible, during the same day. If more than 8 hours has elapsed 
since the scheduled time of the missed dose, the subject should be instructed to wait and take the 
next dose at the regularly scheduled time. Subjects should be cautioned never to double the next 
dose with a missed dose of study drug under any circumstances. 

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5.4.
Other Medication Administered
Methotrexate should be administered weekly at a dose of 7.5 to 25 mg. 
5.5.
Prior and Concomitant Medications
At Screening, all medication taken up to 30 days prior to the Screening visit will be recorded on 
the eCRF. At each study visit, the site will capture any and all medications taken by the subject
since the last visit or during the visit (as applicable). Concomitant medications include
prescription, non-prescription medications, therapies, dietary supplements, and minerals.
Allowed Medications:

Subjects must have taken oral or parenteral MTX 7.5 to 25 mg/week continuously for at least 
12 weeks, with at least 6 weeks of stable dose prior to first study dose and throughout the 
duration of the study. Subjects will continue to receive stable weekly doses of MTX. Further 
information regarding side effects, dosage and administration is available in the current local 
prescribing information.

Subjects are allowed to remain on hydroxychloroquine, with at least 8 weeks of stable dose 
prior to first study dose

Chronic use of systemic corticosteroids up to a maximum of 10 mg/day of prednisone or 
equivalent is allowed if dose is stable for at least 28 days prior to first study dose and 
maintained at a stable dose throughout the study.

NSAIDs or other analgesics (including aspirin ≤100 mg) are allowed if doses are stable for 
at least 14 days prior to first study dose. 

For pain while on study, the patient may take acetaminophen or other non-NSAID pain 
medications as directed by the treated physician.  Any scheduled or pro re nata (prn) pain 
medication should be taken after the Baseline and Week 12 visits are completed.
Prohibited Medications:

Any herbal/natural supplements, unless approved by the Medical Monitor

Any and all illegal or illicit drug use, including use of prescription drugs outside the care of 
the prescribing physician

Changes in the doses of background MTX, anti-malarial therapy, corticosteroids and/or 
NSAIDS are not permitted during the study period except to avoid adverse effects

Use of moderate or strong CYP3A4 inhibitors or moderate or strong CYP3A4 inducers 
within 2 weeks prior to the first dose of study drug and while on study drug is prohibited

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
The following medications are prohibited from 4 weeks prior to the first dose of study drug 
and throughout the study: 
minocycline, penicillamine, sulfasalazine, anakinra, etanercept, etanercept biosimilar, 
azathioprine, cyclosporine, tacrolimus, sirolimus, everolimus, mycophenolate mofetil, 
tofacitinib

The following medications are prohibited within 10 weeks of the first dose of study drug and 
throughout the study: 
infliximab, infliximab biosimilar, golimumab, certolizumab pegol, abatacept, 
tocilizumab, adalimumab

Treatment with antibiotics for a clinical infection or other medical condition within 30 days
prior to first dose 

Previous treatment with B-cell depleting agents (ie, rituximab) within 6 months of treatment 

Treatment with any other investigational study drug within 1 month prior or within 
5 half-lives of the prior investigational agent (whichever is longer) prior to Screening

Prior treatment with any commercially available or investigational SYK inhibitor 

Joint injections during the course of the study are not permitted. If a joint injection has been 
used within 6 weeks of first dose, the joint will be considered unevaluable throughout the 
study.

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
Vaccine Guidelines:
Vaccination with live components is prohibited during the study and for 6 weeks after the last 
dose of study medication. Also routine household contact with persons vaccinated with live 
vaccine components should be avoided. These vaccines include varicella, oral polio and inhaled 
flu vaccine. General guidelines suggest that exposure should be avoided following vaccination 
with these vaccines for the stated time period:

varicella or attenuated typhoid fever vaccination for 4 weeks following vaccination

oral polio vaccination for 6 weeks following vaccination

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
attenuated rotavirus vaccine for 10 days following vaccination

inhaled flu vaccine for 1 week following vaccination
When inactivated flu vaccines are to be used during the study, it should be borne in mind that 
vaccination responses have not been studied during the administration of GS-9876. Currently, 
there are no available data on continuous use of IMP and its impact on immune responses 
following vaccination.
Examples of representative medications which are prohibited are listed below: 
Table 5-1.
Examples of Disallowed Medications
Drug Class
Agents Disallowed
Strong CYP3A4 Inhibitorsa
clarithromycin, conivaptan,  itraconazole, ketoconazole, nefazodone, 
posaconazole, telithromycin, voriconazole, ritonavir, cobicistat, telaprevir, 
boceprevir, grapefruit juice, idelalisib, 
Strong CYP3A4 Inducersb
carbamazepine, phenytoin, rifampin, fosphenytoin, pentobarbital, primidone, 
rifabutin, rifapentine, phenobarbital, mitotane, avasimibe, St. John’s Wort
Moderate CYP3A4 Inhibitorsa
fluconazole, erythromycin, diltiazem, dronedarone, aprepitant, imatinib, 
verapamil, tofisopam, ciprofloxacin, cimetidine, cyclosporine, Schisandra 
sphenanthera
Moderate CYP3A4 Inducersb
efavirenz, tipranavir/ritonavir, bosentan, thioridazine, nafcillin, talviraline, 
lopinavir, modafinil, etravirine, lersivirine, semagacestat, genistein
Immunosuppressants
mycophenolate mofetil, azathioprine, quinacrin, gold, leflunomide
Calcineurin inhibitor
cyclosporine, tacrolimus
mTOR inhibitor
sirolimus, everolimus
Herbal/Natural Supplementsd
grapefruit juicea, St. John’s Wortb, fish oil, borage oil, Schisandra 
sphenanthera
Anti-platelet
adenosine diphosphate(ADP) receptor inhibitors, phosphodiesterase 
inhibitors, PAR-1 antagonists, Glycoprotein 2b/3a inhibitorsc
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 
d
Herbal/Natural supplements not listed require Medical Monitor review and approval.

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5.6.
Investigational Medicinal Product Accountability and Disposal or Return
The investigator is responsible for ensuring adequate accountability of all used and unused IMP.
This includes acknowledgement of receipt of each shipment of IMP (quantity and condition). All 
used and unused IMP dispensed to subjects must be returned to the site.
GS-9876 accountability records will be provided to each study site to:

Record the date received and quantity of IMP; 

Record the date, subject number, subject initials, and the IMP number dispensed; and

Record the date, quantity of used and unused IMP returned, along with the initials of the 
person recording the information.
For additional information about study drug accountability and return, refer to Section 9.1.7.

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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled are presented in tabular form in 
Appendix 2 and described in the text that follows. The investigator must document any 
deviation from protocol procedures and notify the sponsor or contract research organization 
(CRO).
The study center will not initiate dosing until:

The IRB and IEC and 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 informed consent of each subject, using the 
study-specific, IRB-approved Informed Consent Forms (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 informed consent has been obtained, all screening tests and procedures have been assessed, 
and study eligibility has been confirmed, eligible subjects will be randomized to study treatment
as described in Section 5.1.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit (within 28 days prior to randomization)
Written informed consent must be obtained from each subject before initiation of any visit 
procedures. After a subject has provided informed consent, the investigator will determine if the 
subject is eligible for participation in the study.  Subjects will be screened within 28 days before 
randomization to determine eligibility for participation in the study. The assessment will include 
a review of the Inclusion/Exclusion criteria and completion of all Screening Visit procedures as 
outlined in Appendix 2. A sufficient number of subjects will be screened to identify
approximately 60 subjects for enrollment.

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The following will be performed and documented at Screening:

Obtain written informed consent

Obtain medical history including but not limited to RA, prior RA medication history any 
personal or family histories of bleeding disorders

Perform complete physical examination (refer to Appendix 9)

Obtain vital signs, to include height and weight at Screening (refer to Appendix 9)

Complete 12-lead ECG (refer to Appendix 9)

Perform 66 swollen and 68 tender joint count assessment (refer to Appendix 7 and 
Appendix 9)

Obtain blood samples for (refer to Appendix 3):
Hematology, Chemistry, and Coagulation
CRP
Leukocyte subsets
Serology (HIV, HCV, and HBV)
Serum pregnancy test
RNA

Perform Quantiferon test, as applicable (refer to exclusion criteria)

Obtain a CD19 count, as applicable (refer to exclusion criteria)

Obtain urine for urinalysis and urine drug screen (refer to Appendix 3)

Collect biomarker samples

Record any serious adverse events (SAEs) and all AEs related to protocol mandated 
procedures occurring after signing of the consent form (refer to Section 7).

Record any prior and concomitant medications
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic after screening for randomization into the study.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all SAEs, as well as any AEs related to protocol-mandated procedures 

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on the adverse events 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.
Screening labs may be repeated once within 28 days prior to administration of study drug to rule 
out laboratory error.
6.3.
Randomization (Day 1)
Subjects who meet all inclusion and exclusion criteria and complete screening will return for 
randomization into one of the three treatments as described in Section 3.3. Randomization will 
be completed as described in Section 5.1.
6.4.
Treatment Assessments
6.4.1.
Day 1
Study procedures and assessments are outlined in Appendix 2. The HAQ-DI, Patient’s 
Assessment of Pain, and Patient’s Global Assessment of Disease Activity are recommended to 
be done prior to the 66 swollen and 68 tender joint count assessments and before any invasive 
study procedures. Blood draws should be done at the end of the study visit prior to dosing.
The following will be performed and documented on Day 1, within a + 3-day window:

Confirm study eligibility

Perform symptom driven physical examination 

Obtain vital signs 

Perform 12-lead ECG (predose)

Assess AEs and concomitant medications

Subject completes disease specific questionnaires and activity scales (refer to Appendix 9): 
HAQ-DI
Patient’s Assessment of Pain
Patient’s Global Assessment of Disease Activity   

Perform 66 swollen and 68 tender joint count assessment (refer to Appendix 9)

Investigator completes Physician’s Global Assessment of Disease Activity (refer to 
Appendix 9)

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• 
Obtain blood samples for: 
-
Hematology, Chemistiy, and Coagulation 
-
CRP 
-
Leukocyte subsets 
-
RF/CCP 
-
IgA, IgG, and IgM 
-
RNA 
Original 
• 
Obtain urine sample for urine pregnancy test for females of childbearing potential only 
• 
Collect biomarker samples 
• PPD 
• 
Dmg Administration 
-
Dispense study chugs as directed by the IXRS 
-
Instluct the subject on the packaging, storage and administration of all study ch·ugs 
-
Observe the subject taking the first dose of study ch11g and record the time of the 
first dose. Study chug should be administered as the last study procedure on Day 1. 
-
Inst111ct subjects not to take study <hug until after predose assessments at Week 2, Week 
8, and Week 12 visits. Instmct subjects not to take study ch11g until in clinic and 
instmcted to do so at Week 4. 
6.4.2. 
Week 2 (±3 days) 
Study procedures and assessments are outlined in Appendix 2. The following will be perfonned 
and documented at Week 2, within a± 3-day window: 
• 
Perfmm symptom ch·iven physical examination 
• 
Obtain vital signs 
• 
Perfmm 12-lead ECG 
• 
Assess AEs and concomitant medications 
• 
Subject completes disease specific questionnaires and activity scales: 
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HAQ-DI 
-
Patient's Assessment of Pain 
-
Patient's Global Assessment of Disease Activity 
• 
Perform 66 swollen and 68 tender joint count assessment 
• 
Investigator completes Physician's Global Assessment of Disease Activity 
• 
Obtain blood samples for: 
-
Hematology, Chemistry, and Coagulation 
-
CRP 
Original 
• 
Obtain urine sample for urine pregnancy test for females of childbearing potential only 
• 
Collect PK sample (predose) 
• 
Study drug administration after predose assessments completed (eg, PK sample collection). 
• 
Complete medication pill count 
• 
Review study drug compliance and drug administration instructions with subject. 
6.4.3. 
Week 4 (± 3 days) 
Study procedures and assessments are outlined in Appendix 2. The following will be performed 
and documented at Week 4, within a± 3-day window: 
• 
Study drug administration Qrior to other study procedures ~PPD 
) 
------------------~ 
~--------------------------~ 
• 
Perform symptom driven physical examination 
• 
Obtain vital signs 
• 
Perform 12-lead ECG 
• 
Assess AEs and concomitant medications 
• 
Subject completes disease specific questionnaires and activity scales: 
-
HAQ-DI 
-
Patient's Assessment of Pain 
-
Patient's Global Assessment of Disease Activity 
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• 
Perf01m 66 swollen and 68 tender joint cmmt assessment 
• 
Investigator completes Physician's Global Assessment of Disease Activity 
• 
Obtain blood samples for: 
-
Hematology, Chemistly, and Coagulation 
-
CRP 
-RNA 
Original 
• 
Obtain urine sample for mine pregnancy test for females of childbearing potential only 
• 
Collect biomarker samples 
• 
Collect PK sample (2 hours postdose) 
• PPD 
• 
Study dmg will be dispensed as directed by IXRS. 
• 
Complete medication pill cmmt 
• 
Review study d.mg compliance and dmg adminisn·ation instluctions with subject. 
6.4.4. 
Week 8 (± 3 days) 
Study procedures and assessments are outlined in Appendix 2. The following will be perf01med 
and documented at Week 8, within a± 3-day window: 
• 
Perf01m symptom driven physical examination 
• 
Obtain vital signs 
• 
Perf01m 12-lead ECG 
• 
Assess AEs and concomitant medications 
• 
Subject completes disease specific questionnaires and activity scales: 
-
HAQ-DI 
-
Patient's Assessment of Pain 
-
Patient's Global Assessment of Disease Activity 
• 
Perf01m 66 swollen and 68 tender joint count assessment 
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• 
Investigator completes Physician's Global Assessment of Disease Activity 
• 
Obtain blood samples for: 
-
Hematology, Chemist1y, and Coagulation 
-
CRP 
Original 
• 
Obtain urine sample for urine pregnancy test for females of childbearing potential only 
• 
Collect PK sample (predose) 
• PPD 
• 
Study drug administration after predose assessments completed (eg, PK sample collection). 
• 
Study dmg will be dispensed as directed by IXRS. 
• 
Complete medication pill cmmt 
• 
Review study dmg compliance and dmg administration instmctions with subject. 
6.4.5. 
Week 12 (±3 days) 
Study procedures and assessments are outlined in Appendix 2. The HAQ-DI, Patient's 
Assessment of Pain, and Patient's Global Assessment of Disease Activity are recommended to 
be done prior to the 66 swollen and 68 tender joint count assessments and before any invasive 
study procedures. Blood draws should be done at the end of the study visit. 
The following will be perf01med and documented on Day I, within a± 3-day window: 
• 
Perf01m symptom driven physical examination 
• 
Obtain vital signs 
• 
Perf01m 12-lead ECG 
• 
Assess AEs and concomitant medications 
• 
Subject completes disease specific questionnaires and activity scales: 
-
HAQ-DI 
-
Patient's Assessment of Pain 
-
Patient's Global Assessment of Disease Activity 
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• 
Perf01m 66 swollen and 68 tender joint cmmt assessment (prior to Physician's Global 
Assessment of Disease Activity) 
• 
Investigator completes Physician's Global Assessment of Disease Activity 
• 
Obtain blood samples for: 
-
Hematology, Chemistty, and Coagulation 
-
CRP 
-
Leukocyte subsets 
-
RF/CCP 
-
IgA, IgG, and IgM 
-RNA 
Original 
• 
Obtain urine sample for mine pregnancy test for females of childbearing potential only 
• 
Collect biomarker samples 
• 
Collect PK sample (predose) 
• 
PD 
• 
Study drug administt·ation after predose assessments completed (eg, PK sample collection). 
• 
All study drug must be retumed by subject. Study dmg not previously retumed by the subject 
should also be collected. 
• 
Complete medication pill count 
• 
Review study dmg compliance and dmg administration insttu ctions with subject. 
6.5. 
Early Termination(± 3 days) 
If a subject discontinues study dosing (for example, as a result of an AE), eve1y attempt should 
be made to perf01m the required study-related follow-up and procedures (see Section 3.5, 
Discontinuation Criteria). 
Evaluations indicating abn01mal 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 tmtil the abn01mality resolves, retums to baseline visit levels, or is othe1w ise 
explained. 
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If the subject discontinues prematurely from the study, the ET evaluations and/or procedures 
should be completed as outlined in Appendix 2 within 72 hours of subject’s early termination 
from the study. The following will be performed and documented at ET, within a + 3-day 
window:

Perform symptom driven physical examination 

Obtain vital signs 

Perform 12-lead ECG

Assess AEs and concomitant medications

Subject completes disease specific questionnaires and activity scales: 
HAQ-DI
Patient’s Assessment of Pain 
Patient’s Global Assessment of Disease Activity    

Perform 66 swollen and 68 tender joint count assessment 

Investigator completes Physician’s Global Assessment of Disease Activity   

Obtain blood samples for:
Hematology, Chemistry, and Coagulation
CRP
RF/CCP
IgA, IgG, and IgM
RNA

Obtain urine sample for urine pregnancy test for females of childbearing potential only

Collect biomarker samples 

Collect PK sample
6.6.
Post-Treatment Assessments (+ 5 days)
Study procedures and assessments are outlined in Appendix 2. The 4 Weeks Post-Treatment 
Follow-Up Visit will occur 28 days (+ 5 days) from the last administration of study drug. The 
following will be performed and documented:

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
Perform symptom driven physical examination 

Obtain vital signs 

Perform 12-lead ECG

Assess AEs and concomitant medications

Obtain blood samples for:
Hematology, Chemistry, and Coagulation
CRP

Obtain urine sample for urine pregnancy test for females of childbearing potential only
6.7.
Sample Storage
From subjects who provide additional consent, residual samples from blood drawn at all visits 
will be frozen and stored. These stored samples may be used by Gilead or our research partners 
to help answer questions about the RA and related diseases, study drug, or clinical laboratory 
testing to provide additional safety data. No human genetic testing will be performed without 
express consent of the study subjects. At the conclusion of this study, these samples and samples 
collected for RNA may be retained in storage for Gilead for a period of up to 15 years.

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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
product, which does not necessarily have a causal relationship with the treatment. An AE can 
therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal product.
AEs may also include pre- or post-treatment 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 adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
Screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.7.2.2)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
eCRF.
7.1.2.
Serious Adverse Events
An SAE is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization

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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
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 sub-investigator 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 sub-investigator is responsible for assessing the relationship to IMP
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.

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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures (eg, venipuncture)
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3 or 4 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 informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the eCRF: all SAEs and adverse events related to protocol-mandated 
procedures.
7.3.1.1.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30 days after last administration of study drug must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
7.3.1.2.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
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 post treatment follow-up visit but within 4 weeks of 
the last dose of study drug, regardless of causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period; 
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline.
7.3.1.3.
Electronic Serious Adverse Event (eSAE) Reporting Process 

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours to:
Gilead DSPH
Email: Safety_FC@gilead.com
Fax: +1 650-522-5477

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.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the
eCRF completion guideline. 

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form.

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7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
SUSARs. In accordance with the EU Clinical Trials Directive (2001/20/EC), Gilead or a 
specified designee will notify worldwide regulatory agencies and the relevant IEC in concerned 
Member States of applicable SUSARs as outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB/IEC of SUSAR reports as soon as is 
practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (eg, clinical chemistry, hematology, and urinalysis) independent of the 
underlying medical condition that require medical or surgical intervention or lead to 
investigational medicinal product interruption or discontinuation must be recorded as an AE, as 
well as an SAE, if applicable. In addition, laboratory or other abnormal assessments 
(eg, electrocardiogram, X-rays, vital signs) that are associated with signs and/or symptoms must 
be recorded as an AE or SAE if they meet the definition of an AE (or SAE) as described in 
Sections 7.3.1.1 and 7.3.1.2. If the laboratory abnormality is part of a syndrome, record the 
syndrome or diagnosis (ie, anemia) not the laboratory result (ie, decreased hemoglobin).
Severity should be recorded and graded according to the modified CTCAE Grading Scale as 
described in Appendix 4. For AEs associated with laboratory abnormalities, the event should be 
graded on the basis of the clinical severity in the context of the underlying conditions; this may 
or may not be in agreement with the grading of the laboratory abnormality.
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue study drug at the discretion of the investigator.
7.5.2.
Grades 3 and 4 Laboratory Abnormality or Clinical Event
For a Grade 3 and 4 clinical event or clinically significant Grade 3 and 4 laboratory abnormality 
confirmed by repeat testing (preferably within 3 calendar days after receipt of the original 
test results), study drug should be permanently discontinued and the subject managed according 
to local practice. The subject should be followed as clinically indicated until the laboratory 
abnormality returns to baseline or is otherwise explained, whichever occurs first. A clinically 

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significant Grade 3 and 4 laboratory abnormality that is not confirmed by repeat testing should 
be managed according to the algorithm for the new toxicity grade.
7.6.
Toxicity Management 
Treatment-emergent toxicities will be noted by the investigator and brought to the attention of 
the Gilead Sciences Medical Monitor or designee. 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 confirmed by repeat testing 
as soon as possible, and preferably within 3 calendar days after receipt of the original test results.
Grade 3 or 4 clinically significant laboratory abnormalities should be managed as outlined in 
Section 7.5.2.
Any questions regarding toxicity management should be directed to the Gilead Sciences Medical 
Monitor or designee.
7.7.
Special Situations Reports
7.7.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  

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7.7.2.
Instructions for Reporting Special Situations
7.7.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to Gilead DSPH using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.3. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must 
be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported Gilead DSPH using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead DSPH. Gilead DSPH contact information is as follows: 
Email: Safety_FC@gilead.com and Fax: +1 (650) 522-5477. 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead DSPH using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead DSPH, fax number 
+1 650 522-5477 or email Safety_FC@gilead.com.
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.7.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 

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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 3 and the eCRF completion guidelines for full instructions on the mechanism of 
special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.

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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The primaty objective is: 
Original 
• 
To evaluate the effect of GS-987 6 versus placebo for the treatment of signs and symptoms of 
RA in subjects with active RA as measured by change from baseline in DAS28 (CRP) at 
Week 12 
The secondaty objectives are: 
• 
To evaluate the safety and tolerability of GS-9876 in subjects with RA 
• 
To explore the effect of GS-9876 on other disease-specific outcomes in RA 
The exploratmy objectives are: 
IT 
I 
I 
8.1.2. 
Primary Endpoint 
The primaty endpoint is change from baseline in DAS28 (CRP) at Week 12. 
8.1.3. 
Secondary Endpoint 
The secondaty endpoints include: 
• 
The proportion of subjects who achieve ACR 20/50/70 at Week 12 
• 
Change from baseline in HAQ-DI score at Week 12 
8.1.4. 
Exploratory Endpoints 
PPD 
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I 
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I 
8.2. 
8.2.1. 
8.2.1.1. 
Analysis Conventions 
Analysis Sets 
All Randomized 
Original 
The all randomized analysis set includes all subjects who are randomized in the study. This is the 
primary analysis set for by-subject listings. 
8.2.1.2. 
Efficacy 
The primary analysis set for efficacy analyses will be the Full Analysis Set (F AS), which 
includes all randomized subjects who received at least 1 dose of study drug. 
8.2.1.3. 
Safety 
The primary analysis set for safety analyses will be the Safety Analysis Set, which includes all 
subjects who received at least 1 dose of study drug. 
8.2.1.4. 
Pharmacokinetics 
8.2.1.4.1. 
PK Substudy Analysis Set 
The primary analysis set for intensive PK analyses will be the PK substudy analysis set, which 
includes all subjects in the Safety Analysis Set who have enrolled into the PK substudy, and have 
intensive PK concentration data to provide interpretable results for the specific parameters of 
interest for the analyte under evaluation. 
8.2.1.4.2. 
PK Analysis Set 
The primary analysis set for general PK analyses will be the PK analysis set, which includes all 
subjects in the Safety Analysis Set who have at least 1 non-missing PK concentration data for 
GS-9876 and/or its metabolite(s). 
8.3. 
Data Handling Conventions 
PK concentration values and PK parameter values below the limit of quantitation (BLQ) will be 
presented as "BLQ" in the data listings. BLQ values that occur prior to the first dose will be 
treated as 0, BLQ values at all other time points will be treated as 112 of the lower limit of 
quantitation (LLOQ). 
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Laboratory data that are continuous in nature but are less than the lower limit of quantitation or 
above the upper limit of quantitation will be imputed to the value of the lower or upper limit 
minus or plus one significant digit, respectively (eg, if the result of a continuous laboratory test is 
< 20, a value of 19 will be assigned; if the result of a continuous laboratory test is < 20.0, a value 
of 19.9 will be assigned).
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline characteristics will be summarized using standard descriptive 
methods including sample size, mean, SD, median, Q1, Q3, minimum, and maximum for 
continuous variables and frequency and percentages for categorical variables.
Demographic data will include sex, race, ethnicity, and age.
Baseline characteristics will include DAS28 (CRP), HAQ-DI, SDAI, and CDAI.
8.5.
Efficacy Analysis
The primary endpoint for the study is change from baseline in DAS28 (CRP) at Week 12, which 
will be analyzed using a mixed model repeated measures (MMRM) approach. The model may 
include the fixed effects of treatment, visit, treatment by visit interaction, and baseline value.  
Subjects will be included as a random effect. 
Secondary endpoints include proportion of subjects who achieve ACR20/50/70 at Week 12 and 
change from baseline in HAQ-DI score at Week 12. The ACR20/50/70 response rates between 
each of the 2 GS-9876 treated groups and the placebo group will be compared using a stratified 
Cochran-Mantel-Haenszel (CMH) Chi-square test adjusting for stratification factor in 
randomization.  The difference in response rates between treatment groups and the 
corresponding 95% confidence intervals will be presented. The difference in change from 
baseline in HAQ-DI between treatment groups will be analyzed using a similar MMRM 
approach.
Sensitivity analyses may be performed for the efficacy assessment.
Details on efficacy analyses will be described in the statistical analysis plan.
8.6.
Safety Analysis
All safety analyses will be performed using the safety analysis set.
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, vital 
signs measurements at various time points during the study, and by the documentation of AEs.
All safety data collected on or after the first dose of study drug administration up to 30 days after 
the last dose of study drug, unless specified otherwise, will be summarized by treatment group 
according to the study drug received.

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8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug
administration page of the eCRF. Exposure data will be summarized by treatment group.
Duration of exposure to study drug will be expressed as the number of weeks between the first 
and last dose of the study drug, inclusive, regardless of temporary interruptions in study drug 
administration and summarized by treatment group.
8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Treatment-emergent adverse events (TEAEs) are defined as one or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug.

Any AEs leading to premature discontinuation of study drug.
Summaries (number and percentage of subjects) of TEAEs by SOC and PT will be provided. 
Treatment-emergent AEs will also be summarized by relationship to study drug and severity. In 
addition, TEAEs leading to premature discontinuation of study drug and study will be 
summarized and listed.
8.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) by treatment group. Absolute values and change from baseline at all scheduled 
timepoints will be summarized.
Graded laboratory abnormalities will be defined using CTCAE 4.03 grading scale (Appendix 4).
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least
one toxicity grade from baseline at any time post baseline up to the date of last dose of study 
drug plus 30 days, will be summarized by treatment.
8.6.4.
Other Safety Evaluations
Individual data for physical examination findings, prior and concomitant medications and 
medical history will be provided. Twelve-lead ECGs and vital signs will be listed by subject or 
summarized by descriptive statistics as appropriate.

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8.7. 
Pharmacokinetic Analysis 
Original 
Plasma concentrations of GS-9876 will be listed and smmnarized using descriptive statistics 
( eg, sample size, arithmetic mean, geometric mean, % coefficient of variation, standard 
deviation, median, minimum, and maximum). 
PD 
Plasma concentrations ofGS-9876 metabolite(s) and/or MTX may also be detennined and 
analyzed. 
8.8. 
Biomarker Analysis 
PD 
8.9. 
Data Monitoring Committee 
An extemal multidisciplinruy DMC will review the progress of the study and perf01m interim 
reviews of safety data in order to protect subject welfare and preserve study integrity. The DMC 
is to recommend to the sponsor whether the nature, frequency, and severity of adverse effects 
associated with treatment watTant the eru·ly termination of the study, whether the study should 
continue as planned, or the study should continue with modifications. 
DMC will review unblinded safety data. The initial DMC review will be conducted after the 
21st subject in the study has been treated for 4 weeks. Unblinded safety data will be reviewed 
quarterly thereaft.er. 
The DMC will provide recommendations as needed regarding study design, conduct and the 
need for additional meetings or an altemative meeting schedule. While the DMC will be asked to 
advise Gilead regarding future conduct of the study, including possible early study tennination, 
Gilead retains fmal decision-making authority on all aspects of the study. 
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8.10.
Sample Size
Sample size is determined based on the superiority test of one dose of GS-9876 compared to 
placebo based on the change from baseline in DAS28 (CRP) at Week 12. When assuming a 
difference of 1.2 between the two groups and a common standard deviation of 1.35, 20 subjects 
in each of the GS-9876 groups and 20 in the placebo group are required to obtain 78 percent 
power at a 2-sided 0.05-level. Therefore, the total sample size will be 60 (20 per treatment 
group).

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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the 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, as 
outlined in 21 Code of Federal Regulations (CFR) 312, subpart D, “Responsibilities of Sponsors 
and Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable sub-investigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any sub-investigator’s) participation in the study. The investigator and 
sub-investigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 

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

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
Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. Electronic CRFs

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should be completed on the day of the subject visit to enable the sponsor to perform central 
monitoring of safety data.  The Eligibility Criteria eCRF should be completed only after all data 
related to eligibility have been received.  Subsequent to data entry, a study monitor will perform 
source data verification within the electronic data capture (EDC) system. Original entries as well 
as any changes to data fields will be stored in the audit trail of the system.  Prior to database lock 
(or any interim timepoints as described in the clinical data management plan), the investigator 
will use his/her log in credentials to confirm that the forms have been reviewed, and that the 
entries accurately reflect the information in the source documents. The eCRF 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 trial, Gilead 
will provide the site with a read-only archive copy of the data entered by that site. This archive 
must be stored in accordance with the records retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product 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.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs or IECs, or to regulatory authority or health authority 
inspectors.

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9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/IEC in 
accordance with local requirements and receive documented IRB/IEC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to applicable regulatory agencies.
Gilead will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be 
prepared in certain cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:
The results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, eg, attendance at Investigator's Meetings.  If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.

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

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10.
REFERENCES
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, 3rd, et al. 2010 
Rheumatoid arthritis classification criteria: an American College of 
Rheumatology/European League Against Rheumatism collaborative initiative. 
Arthritis Rheum 2010;62 (9):2569-81.
Arthritis Foundation. Rheumatoid Arthritis Fact Sheet.  2008.
Braselmann S, Taylor V, Zhao H, Wang S, Sylvain C, Baluom M, et al. R406, an orally available 
spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune 
complex-mediated inflammation. J Pharmacol Exp Ther 2006;319 (3):998-1008.
Cha HS, Boyle DL, Inoue T, Schoot R, Tak PP, Pine P, et al. A novel spleen tyrosine kinase 
inhibitor blocks c-Jun N-terminal kinase-mediated gene expression in 
synoviocytes. J Pharmacol Exp Ther 2006;317 (2):571-8.
Coffey G, DeGuzman F, Inagaki M, Pak Y, Delaney SM, Ives D, et al. Specific inhibition of 
spleen tyrosine kinase suppresses leukocyte immune function and inflammation in 
animal models of rheumatoid arthritis. J Pharmacol Exp Ther 2012;340 (2):350-9.
Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College 
of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. 
Arthritis Rheum 1995;38 (6):727-35.
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.
Leandro MJ, Cambridge G, Ehrenstein MR, Edwards JC. Reconstitution of peripheral blood B 
cells after depletion with rituximab in patients with rheumatoid arthritis. Arthritis 
Rheum 2006;54 (2):613-20.
Liao C, Hsu J, Kim Y, Hu DQ, Xu D, Zhang J, et al. Selective inhibition of spleen tyrosine 
kinase (SYK) with a novel orally bioavailable small molecule inhibitor, RO9021, 
impinges on various innate and adaptive immune responses: implications for SYK 
inhibitors in autoimmune disease therapy. Arthritis research & therapy 2013;15 
(5):R146.
Martin F, Chan AC. B cell immunobiology in disease: evolving concepts from the clinic. Annu 
Rev Immunol 2006;24:467-96.
Navarro-Millan I, Curtis JR. Newest clinical trial results with antitumor necrosis factor and 
nonantitumor necrosis factor biologics for rheumatoid arthritis. Current opinion in 
rheumatology 2013;25 (3):384-90.

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Pine PR, Chang B, Schoettler N, Banquerigo ML, Wang S, Lau A, et al. Inflammation and bone 
erosion are suppressed in models of rheumatoid arthritis following treatment with 
a novel Syk inhibitor. Clin Immunol 2007;124 (3):244-57.
Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. 
Modified disease activity scores that include twenty-eight-joint counts. 
Development and validation in a prospective longitudinal study of patients with 
rheumatoid arthritis. Arthritis Rheum 1995;38 (1):44-8.
Shlomchik MJ. Sites and stages of autoreactive B cell activation and regulation. Immunity 
2008;28 (1):18-28.
Song YW, Kang EH. Autoantibodies in rheumatoid arthritis: rheumatoid factors and 
anticitrullinated protein antibodies. QJM 2010;103 (3):139-46.

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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Tables
Appendix 3.
Laboratory Assessments Table
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 6.
The 2010 American College of Rheumatology –European League Against 
Rheumatism Collaborative Initiative Classification Criteria for Rheumatoid 
Arthritis {Aletaha et al 2010}
Appendix 7.
American College of Rheumatology Response Evaluations/ Preliminary Definition 
of Improvement in Rheumatoid Arthritis {Felson et al 1995}
Appendix 8.
Disease Activity Score for 28 Joint Count (DAS28) {Prevoo et al 1995}
Appendix 9.
Procedures and Specifications

GS-9876 
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Appendix 1. 
Original 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
STUDY ACKNOWLEDGEMENT 
A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Proof-of-Concept Study to 
Evaluate Safety, Tolerability, and Efficacy of GS-9876 in Subjects with Active Rheumatoid 
Arthritis on Background Therapy with Methotrexate 
GS-US-379-1582, Original Protocol, 08 April2016 
~!sa~;~:~ has been approved by Gilead Scien ~p
unc_Ilp
l~folJ.outD
ina Ri.QU::tture documents 
Franziska Matzkies, MD 
Medical Monitor Name (Printed) 
~plr,Q - Ill - 2iJ I c 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
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Appendix 2. 
Study Procedures Tables 
Visit 
Screeninga 
Window in Days 
-28 
Written Infonned Consent for Main Study 
X 
lPPD 
I 
X 
Medical History d 
X 
Physical Examination e 
X 
Vital Signs f 
X 
12-LeadECG 
X 
66 swollen and 68 tender joint count assessment h 
X 
Hematology, chemistry and coagulation h,i,j 
X 
CRPh,i,i 
X 
Serum or Urine Pregnancy Test h,i,j,k 
X 
Biomarkers h,j,I 
X 
RNA Sample h, i,i 
X 
Leukocyte subsets h, i,j 
X 
Serology i 
X 
Urinalysis and Urine Drug Screen i 
X 
Quantiferon i, m 
X 
CD19 Count i,m 
X 
Randomization 
Disease-specific questionnaires and activity scores h, n 
CONFIDENTIAL 
Dayl 
X 
X 
xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 73 
Original 
4-weeks Post-
Treatment 
Week2 
Week4 
WeekS 
Week12 
ETb 
Follow-Up< 
±3 
±3 
±3 
±3 
±3 
±5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
08 April 2016 

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Visit 
Screeninga 
Dayl 
Week2 
Week4 
Week8 
Window in Days 
-28 
±3 
±3 
±3 
RF /CCP h, i, i 
X 
h .. 
IgA, IgG, and IgM ''· J 
X 
-~ 
X 
PK SamplesP 
X 
X 
X 
-
rr 
X 
Study Drug Dispensation 
X 
X 
X 
Study Drug Administration (In-Clinic) r 
X 
X 
X 
X 
Adverse Events' 
Continuous 
Concomitant Medications 1 
Continuous 
a 
Prospective subjects should be screened no more than 28 days prior to administration of the first dose of study drug. 
b 
Early Termination assessments should be performed within 72 hours of early termination from the study. 
c 
28 (±5) days after the last administration of study drug, all subjects will return for an in-clinic follow-up visit. 
Week12 
±3 
X 
X 
X 
X 
d 
Medical history, including but not limited to, RA, prior RA medication history, and any personal or family histories of bleeding disorders 
Original 
4-weeks Post-
Treatment 
ETb 
Follow-Upc 
±3 
±5 
X 
X 
X 
e 
Screening visit includes complete PEas outlined in Appendix 9. All other PEs are symptom driven. A symptom driven PE should be performed after Screening when a 
subject reports a new symptom or a worsening symptom at a study visit. If a subject reports no change in symptoms, then noPE is necessary. 
f 
Vital signs include resting blood pressure, pulse, respiration rate, temperature (obtained orally), height and weight. Height and weight will be collected at Screening only. 
g 
Conduct Day 1 ECG predose (prior to study drug administration). 
h 
At Day 1 and Week 12 visits, the HAQ-DI, Patient's Assessment of Pain, and Patient's Global Assessment of Disease Activity are recommended to be done prior to the 66 
swollen and 68 tender joint count assessments and before any invasive study procedures. Blood draws should be done at the end of the study visit. 
Refer to Appendix 3 for complete laboratory assessments. 
J 
Samples to be collected prior to dosing, except at Week 4 visit. 
k 
At Screening, a serum pregnancy test will be collected. At all other visits, a urine pregnancy test will be collected. If a urine pregnancy test is positive, a serum pregnancy test 
will also be collected. 
Samples will be collected at Day 1, Week 4, and Week 12 or ET visits for exploratory disease and/or pathway markers relevant to rheumatoid arthritis. Sampling timepoints 
and assessments may be modified during the study based on assay availability and/or emerging data. 
m 
As needed per exclusion criteria (refer to Section 4.3) 
n 
Disease-specific questionnaires and activity scales include the HAQ-DI, Patient's Assessment of Pain, Patient's Global Assessment of Disease Activity, and Physician's 
Global Assessment of Disease Activi!Y:..;.·----------------------------------. 
0 
I PD 
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p 
PK samples will be collected prior to study drug administration (pre·-dose at Weeks 2, 8, and 12 or ET. At Week 4, PK samples will be collected 2 hours ost dose. 
q 
PPD 
r 
On Day 1, study diug adnumstratiOii'"(iil-Clilli.Cj"ShOUid betile"Iast study procedw·e pet'lonued. On Week 4, study dmg administJ·ation (in-clinic) should be the first study 
procedtu-e perfom1ed (with the exception of predose PK for[PPD 
I subjects only). At all other tJ·eatJuent visits, study drug administJ·ation should occur after 
predose assessments are completed. 
s 
After infonued consent, but prior to initiation of study medication, all SAEs and adverse events related to protocol-mandated procedw·es shall be collected. Following 
initiation of study medication, all SAEs and all AEs, regardless of cause or relationship, shall be collected. Refer to Section 7.3 for more detail. 
At Screening, all medication taken up to 30 days prior to the Screening visit will be recorded on the eCRF. 
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Appendix 3.
Laboratory Assessments Table
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Hemoglobin
Platelet count
Red blood cell (RBC) 
count
White blood cell (WBC) 
count
Differentials (absolute 
and percentage), 
including:
Leukocytes
Monocytes
Neutrophils
Eosinophils
Basophils
Reticulyte count
Mean corpuscular 
volume (MCV)
Alkaline phosphatase
Aspartate aminotransferase
(AST)
Alanine aminotransferase
(ALT)
Total bilirubin
Direct and indirect 
bilirubin
Total protein
Albumin
Bicarbonate
Blood urea nitrogen 
(BUN)
Calcium
Chloride
Serum creatinine
Glucose
Phosphorus
Magnesium
Potassium
Sodium
Amylase
Lipase 
Appearance
Blood
Color
Glucose
Leukocyte esterase
pH
Protein
Urobilinogen
Reflex to microscopic 
urinalysis if dipstick result 
is abnormal.
Urine drug screen for:
Amphetamines
Cocaine
Methadone
Opiates
Leukocyte subsets
IgA, IgG, IgM
C-reactive protein (CRP)
Rheumatoid factor and cyclic 
citrullinated peptide (RF/CCP)
Quantiferon (if required per 
exclusion criteria)
CD19 (if required per 
exclusion criteria)
RNA
Coagulation
Serology
Pregnancy
Activated partial 
thromboplastin time 
(aPTT)
Prothrombin time (PT)
International normalized 
ratio (INR)
Hepatitis BsAg and core 
Ab 
Hepatitis C Ab
HIV
In females of childbearing 
potential:
Serum β-hCG (Screening and 
if positive urine β-hCG)
Urine β-hCG (all other visits)
Ab = antibody
β-hCG = beta-human chorionic gonadotropin
BsAg = B surface antigen
IgA, IgG, IgM = immunoglobulins A, G, M

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Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03
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).

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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a) Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause.  
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b) Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a) Study Drug Effects on Pregnancy and Hormonal Contraception
GS-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.  Therefore, 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 version of the investigator’s brochure 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 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 (Appendix 2).
Female subjects of childbearing potential must agree to one of the following from Screening 
until 30 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.

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Or

Consistent and correct use of 1 of the following methods of birth control listed below. 
Intrauterine device (IUD) with a failure rate of <1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the last dose of study drug.
3) Contraception Requirements for Male Subjects
It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure of the male subject’s seminal fluid.  Therefore, male subjects with female 
partners of childbearing potential must use condoms during treatment and 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 during treatment and until at least 90 days 
after the last dose of study drug
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM).  Female condom and male condom should not be used 
together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study must report the information to 
the investigator.  Instructions for reporting pregnancy, partner pregnancy, and pregnancy 
outcome are outlined in Section 7.7.2.1.

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Appendix 6.
The 2010 American College of Rheumatology –European League
Against Rheumatism Collaborative Initiative Classification Criteria 
for Rheumatoid Arthritis {Aletaha et al 2010}
Target population (Who should be tested?): Patients who have at least 1 joint with 
definite clinical synovitis (swelling)a with the synovitis not better explained by 
another diseaseb
Classification criteria for RA (score-based algorithm: add score of categories A - D;
a score of ≥6/10 is needed for classification of a patient as having definite RA)c
A. Joint involvementd
1 large jointe
0
2-10 large joints
1
1-3 small joints (with or without involvement of large joints)f
2
4-10 small joints (with or without involvement of large joints)
3
>10 joints (at least 1 small joint)g
5
B. Serology (at least 1 test result is needed for classification)h
Negative RF and negative ACPA
0
Low-positive RF or low-positive ACPA
2
High-positive RF or high-positive ACPA
3
C. Acute-phase reactants (at least 1 test result is needed for classification)i
Normal CRP and normal ESR
0
Abnormal CRP or abnormal ESR
1
D. Duration of symptomsj
<6 weeks
0
≥6 weeks
1
a
The criteria are aimed at classification of newly presenting patients. In addition, patients with erosive disease typical of 
rheumatoid arthritis (RA) with a history compatible with prior fulfillment of the 2010 criteria should be classified as having 
RA. Patients with longstanding disease, including those whose disease is inactive (with or without treatment) who, based on 
retrospectively available data, have previously fulfilled the 2010 criteria should be classified as having RA.
b
Differential diagnoses vary among patients with different presentations, but may include conditions such as systemic lupus 
erythematosus, psoriatic arthritis, and gout. If it is unclear about the relevant differential diagnoses to consider, an expert 
rheumatologist should be consulted.
c
Although patients with a score of <6/10 are not classifiable as having RA, their status can be reassessed and the criteria 
might be fulfilled cumulatively over time.
d
Joint involvement refers to any swollen or tender joint on examination, which may be confirmed by imaging evidence of 
synovitis. Distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints are excluded from 
assessment. Categories of joint distribution are classified according to the location and number of involved joints, with 
placement into the highest category possible based on the pattern of joint involvement.
e
"Large joints" refers to shoulders, elbows, hips, knees, and ankles.
f
"Small joints" refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through 
fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists.
g
In this category, at least 1 of the involved joints must be a small joint; the other joints can include any combination of large 
and additional small joints, as well as other joints not specifically listed elsewhere (eg, temporomandibular, 
acromioclavicular, sternoclavicular).

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h
Negative refers to IU values that are less than or equal to the ULN for the laboratory and assay; low-positive refers to IU 
values that are higher than the ULN but ≤3 times the ULN for the laboratory and assay; high-positive refers to IU values that 
are >3 times the ULN for the laboratory and assay. Where rheumatoid factor (RF) information is only available as positive 
or negative, a positive result should be scored as low-positive for RF. ACPA = anti-citrullinated protein antibody.
i
Normal/abnormal is determined by local laboratory standards. CRP = C-reactive protein; ESR = erythrocyte sedimentation 
rate.
j
Duration of symptoms refers to patient self-report of the duration of signs or symptoms of synovitis (eg, pain, swelling, 
tenderness) of joints that are clinically involved at the time of assessment, regardless of treatment status.

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Appendix 7.
American College of Rheumatology Response Evaluations/ 
Preliminary Definition of Improvement in Rheumatoid Arthritis 
{Felson et al 1995}
ACR 20/50/70 Requires
≥20%/50%/70% improvement in tender joint count, AND
≥20%/50%/70% improvement in swollen joint count, AND
≥20%/50%/70% improvement in at least 3 of the following 5:

Patient’s Assessment of Pain

Patient’s Global Assessment of Disease Activity

Physician’s Global Assessment of Disease Activity

Patient’s assessment of physical  function (HAQ-DI)

Acute-phase reactant (CRP)
The following lists the disease activity measure followed by the method of assessment
1.
Tender joint count
ACR tender joint count is an assessment of 68. The joint count should be done by scoring several 
different aspects of tenderness, as assessed by pressure and joint manipulation on physical 
examination. The information on various types of tenderness should then be collapsed into a 
single tender-versus-nontender dichotomy.
2.
Swollen joint count
ACR swollen joint count is an assessment of 66. Joints are classified as either swollen or not 
swollen.
3.
Patient’s Assessment of Pain
A horizontal visual analog scale (VAS) will be used to assess the patient’s current level of pain.4
How much pain have you had because of your condition over the past week? Place a mark on the 
line below to indicate how severe your pain has been: 
No Pain
Unbearable Pain
                                                
4 Visual analog scales provided in this protocol are not to scale and should not be utilized for assessments.

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4.
Patient’s Global Assessment of Disease Activity
A horizontal VAS will be used to provide the patient’s overall assessment of how the arthritis is 
doing.
Place a mark on the line below to indicate how you assess your current arthritis disease 
activity:
No arthritis activity
Extremely active arthritis
5.
Physician’s Global Assessment of Disease Activity
A horizontal VAS will be used to measure the physician’s assessment of the patient’s current 
disease activity.
Place a mark on the line below to indicate disease activity (independent of the subject’s 
self-assessment):
No Disease Activity
Maximum Disease Activity
6.
Patient’s Assessment of Physical Function
The HAQ-DI will be used to provide a patient’s self-assessment of physical function.
7.
Acute-phase reactant value
C-reactive protein level

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Appendix 8.
Disease Activity Score for 28 Joint Count (DAS28) {Prevoo et al 1995}
Assessments of RA in patients by the Disease Activity Score (modified to include the 28 joint 
counts according to Smolen* 1995) will be conducted at the measured timepoints. The DAS28 
consists of a composite score of the following variables: tender joint count, swollen joint count, 
CRP, and Patient’s Global Assessment of Disease Activity score. The following equation will be 
used to calculate the DAS28 (CRP)

DAS28 (CRP) 0.56 √TJC28 0.28√SJC28 0.36ln(CRP 1) 0.014×(Patient’s Global 
Assessment of Disease Activity) 0.96
TJC28 = number of joints tender out of 28
SJC28 = number of joints swollen out of 28
CRP = C-reactive protein
Patient’s Global Assessment of Disease Activity on a 100 mm VAS recorded by the 
patient

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Appendix 9.
Procedures and Specifications 
Complete Physical Examination
A complete physical examination must include source documentation of general appearance, and 
the following body systems: Head, neck and thyroid; eyes, ears, nose, throat, mouth and tongue; 
chest (excluding breasts); respiratory; cardiovascular; lymph nodes, abdomen; skin, hair, nails; 
musculoskeletal; neurological (must be performed at Screening). 
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature. Body weight and height will also be included at Screening only.
Blood pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.
12-Lead ECG
Subjects will be required to rest in a supine position for 5 minutes prior to making a recording.
The investigator (or qualified designee) should review the ECG traces recorded in real time for 
clinically significant abnormalities.  On treatment ECGs should be compared to the subject’s 
Baseline as part of routine safety monitoring.  
Fredericia Formula (QTcF)
QTc = QT/(RR^0.33) 
Health Assessment Questionnaire – Disability Index
The HAQ-DI is a patient reported questionnaire specific for RA.  It consists of 20 questions 
referring to 8 component sets:  dressing/grooming, arising, eating, walking, hygiene, reach, grip, 
and activities.  
Physician’s and Patient’s Global Assessment of Disease Activity and Patient’s Global 
Assessment of Pain
The physician’s and the patient’s global assessment of disease activity will be recorded on a 
100-mm horizontal VAS that ranges from “none” (0 mm, symptom free and no RA symptoms) 
to “maximum” (100 mm, maximum RA activity).  The patient’s global assessment of pain will 
be recorded on a 100-mm horizontal VAS that ranges from “none” (0 mm) to “unbearable” 
(100 mm).

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Joint Assessment
An assessment of 66 joints for swelling and 68 joints for tenderness will be performed. Joints 
will be assessed and classified as swollen or not swollen and tender or not tender by pressure and 
joint manipulation upon physical examination.  Joint exams should be performed by a trained 
and experienced joint assessor.   Every effort should be made for the same joint assessor to 
perform the joint exams on the same subject particularly during the blinded phase of the study.