Clinical trial NCT02862574
Conditions: Rheumatoid Arthritis
Keywords: Rheumatoid Arthritis Tumor Necrosis Factor Inhibitor TNF-IR Methotrexate
Sponsor: Gilead Sciences
Start date: 2016-12-15; Completion date: 2017-08-07
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the efficacy of andecaliximab (GS-5745) versus placebo as an add-on therapy to a tumor necrosis factor (TNF) inhibitor and methotrexate in adults with moderate to severe rheumatoid arthritis (RA).

Detailed description:

Arms: arm 1: Andecaliximab 300 mg for 12 weeks, in addition to their current regimen of a TNF inhibitor and methotrexate. arm 2: Andecaliximab 150 mg + placebo for 12 weeks, in addition to their current regimen of a TNF inhibitor and methotrexate. arm 3: Placebo weekly for 12 weeks, in addition to their current regimen of a TNF inhibitor and methotrexate. arm 4: On the Week 12 visit, eligible participants may choose to participate in the open-label portion of the study to receive open-label andecaliximab 300 mg for 52 weeks, in addition to their current regimen of a TNF inhibitor and methotrexate.
Interventions: intervention 1: Andecaliximab intervention 2: Placebo intervention 3: Methotrexate intervention 4: TNF Inhibitor
Intervention descriptions: intervention 1: Administered via subcutaneous injection once weekly intervention 2: Administered via subcutaneous injection once weekly intervention 3: Administered orally weekly as part of the participant's current treatment regimen intervention 4: An approved stable subcutaneous formulation of one of the following TNF inhibitors may include adalimumab, certolizumab, etanercept, or golimumab.

Protocol documents:
Prot_002.pdf: 


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Prot_001.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Study Director 
or Clinical Program 
Manager: 
Gilead Medical 
Monitor: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
Evaluation of the Efficacy and Safety ofGS-5745 as Add-On 
Therapy to a Tumor Necrosis Factor Inhibitor and Methotrexate 
Regimen in Subjects with Moderate to Severe Rheumatoid Ali hritis 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City CA 94404 
110523 
2016-000897-39 
TBD 
Rheumatoid Alihritis 
GS-US-373-1499 
Name: 
PPD 
Telephone: 
1-'1-'U 
Fax: 
PPD 
Mobile: 
PPD 
Name: 
David Gossage 
Telephone: 
PPD 
Fax: 
PPD 
Mobile: 
PPD 
Original 
14 March 2016 
Amendment 1 
24 June 2016 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, pmi icularly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessa1y to obtain infonned consent from those 
persons to whom the dmg may be administered. 


GS-5745
Protocol GS–US-373-1499
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 2
24 June 2016
TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT FIGURES ......................................................................................................................................4
PROTOCOL SYNOPSIS ..............................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................14
1.
INTRODUCTION ..............................................................................................................................................17
1.1.
Background ............................................................................................................................................17
1.2.
GS-5745 .................................................................................................................................................17
1.2.1.
General Information .............................................................................................................17
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................18
1.2.3.
Clinical Trials of GS-5745 ...................................................................................................19
1.3.
Rationale for This Study ........................................................................................................................19
1.3.1.
Clinical Rationale.................................................................................................................19
1.3.2.
Toxicology Rationale ...........................................................................................................21
1.3.3.
Dose Selection......................................................................................................................21
1.4.
Risk/Benefit Assessment for the Study..................................................................................................22
1.5.
Compliance ............................................................................................................................................23
2.
OBJECTIVES.....................................................................................................................................................24
3.
STUDY DESIGN................................................................................................................................................25
3.1.
Endpoints ...............................................................................................................................................25
3.2.
Study Design..........................................................................................................................................25
3.3.
Study Treatments ...................................................................................................................................26
3.3.1.
Open Label Extension ..........................................................................................................26
3.3.2.
Home Administration of Study Drug ...................................................................................27
3.4.
Duration of Treatment............................................................................................................................27
3.5.
Study Subject Discontinuation Criteria..................................................................................................28
3.6.
End of Study...........................................................................................................................................28
3.7.
Biomarker Testing..................................................................................................................................28
3.7.1.
Biomarker Samples to Address the Study Objectives:.........................................................28
3.7.2.
Biomarker Samples for Optional Future Research...............................................................29
3.7.3.
Biomarker Samples for Optional Genomic Research...........................................................29
4.
SUBJECT POPULATION..................................................................................................................................30
4.1.
Number of Subjects and Subject Selection ............................................................................................30
4.2.
Inclusion Criteria....................................................................................................................................30
4.3.
Exclusion Criteria...................................................................................................................................32
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................35
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................35
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................35
5.2.
Description and Handling of GS-5745 and Placebo...............................................................................35
5.2.1.
Formulation..........................................................................................................................35
5.2.2.
Packaging and Labeling .......................................................................................................36
5.2.3.
Storage and Handling...........................................................................................................36
5.3.
Dosage and Administration of GS-5745 and Placebo............................................................................36
5.4.
Prior and Concomitant Medications.......................................................................................................37
5.4.1.
Allowed Prior and Concomitant Medications: .....................................................................37
5.4.2.
Disallowed Concomitant Medications .................................................................................38
5.5.
Accountability for Study Drug...............................................................................................................39


GS-5745
Protocol GS–US-373-1499
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 3
24 June 2016
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................40
6.
STUDY PROCEDURES ....................................................................................................................................41
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................41
6.2.
Pretreatment Assessments......................................................................................................................41
6.2.1.
Screening Visit (Day -35 to Day 0)......................................................................................41
6.2.2.
Baseline/Randomization Assessments (Day 1/Week 0).......................................................42
6.3.
Blinded Treatment Assessments (Week 1 through Week 12)................................................................42
6.3.1.
30-Day Follow-up Visit........................................................................................................45
6.4.
Open Label Extension Assessments (Week 12 through Week 64) ........................................................45
6.4.1.
Open Label Extension 30-day Follow-up Visit....................................................................46
6.5.
Assessments for Premature Discontinuation from Study.......................................................................46
6.6.
Criteria for Subject Temporary Interruption of Study Treatment ..........................................................46
6.7.
Criteria for Subject Discontinuation of Study........................................................................................46
6.8.
End of Study...........................................................................................................................................47
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................48
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................48
7.1.1.
Adverse Events.....................................................................................................................48
7.1.2.
Serious Adverse Events........................................................................................................48
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................49
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 ........................................................................................................50
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................50
7.4.
Gilead Reporting Requirements.............................................................................................................53
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................53
7.6.
Toxicity Management ............................................................................................................................53
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................54
7.6.2.
Grades 3 Laboratory Abnormality or Clinical Event ...........................................................54
7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................54
7.7.
Special Situations Reports......................................................................................................................55
7.7.1.
Definitions of Special Situations..........................................................................................55
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 Endpoints............................................................................................................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 ...................................................................................58
8.5.
Efficacy Analysis ...................................................................................................................................59
8.6.
Safety Analysis.......................................................................................................................................59
8.6.1.
Extent of Exposure...............................................................................................................59
8.6.2.
Adverse Events.....................................................................................................................59
8.6.3.
Laboratory Evaluations ........................................................................................................60
8.7.
Pharmacokinetic Analysis......................................................................................................................60


GS-5745
Protocol GS–US-373-1499
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 4
24 June 2016
8.8.
Immunogenicity Analysis ......................................................................................................................60
8.9.
Sample Size............................................................................................................................................60
8.10.
Data Monitoring Committee ..................................................................................................................60
9.
RESPONSIBILITIES..........................................................................................................................................62
9.1.
Investigator Responsibilities ..................................................................................................................62
9.1.1.
Good Clinical Practice..........................................................................................................62
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................62
9.1.3.
Informed Consent.................................................................................................................62
9.1.4.
Confidentiality......................................................................................................................63
9.1.5.
Study Files and Retention of Records ..................................................................................63
9.1.6.
Case Report Forms...............................................................................................................64
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................65
9.1.8.
Inspections............................................................................................................................65
9.1.9.
Protocol Compliance............................................................................................................65
9.2.
Sponsor Responsibilities ........................................................................................................................66
9.2.1.
Protocol Modifications.........................................................................................................66
9.2.2.
Study Report and Publications .............................................................................................66
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................66
9.3.1.
Payment Reporting...............................................................................................................66
9.3.2.
Access to Information for Monitoring..................................................................................67
9.3.3.
Access to Information for Auditing or Inspections ..............................................................67
9.3.4.
Study Discontinuation..........................................................................................................67
10.
REFERENCES ...................................................................................................................................................68
11.
APPENDICES ....................................................................................................................................................70
Appendix 1.
Investigator Signature Page....................................................................................................71
Appendix 2.
Study Visit Schedule ..............................................................................................................72
Appendix 3.
Management of Clinical and Laboratory Adverse Events......................................................77
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03....................................78
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................79
Appendix 6.
American College of Rheumatology:  1991 Revised Criteria for the Classification of 
Global Functional Status of Rheumatoid Arthritis* ...............................................................82
Appendix 7.
The 2010 American College of Rheumatology –European League Against 
Rheumatism Collaborative Initiative Classification Criteria for Rheumatoid 
Arthritis {Aletaha et al 2010}.................................................................................................83
Appendix 8.
American College of Rheumatology Response (ACR 20/50/70): {Felson et al 1995}..........84
Appendix 9.
Disease Activity Score DAS28 CRP {Prevoo et al 1995} .....................................................86
Appendix 10.
Frederica’s Formula and Estimated Glomerular Filtration.....................................................87
Appendix 11.
Clinical criteria for diagnosing anaphylaxis modified from the NIAID/FAAN 
Criteriaref.................................................................................................................................88
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema.........................................................................................................................27


GS-5745 
Protocol GS-US-373-1499 
Gilead Sciences, Inc. 
Study Title: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Study Centers 
Planned: 
Objectives: 
Study Design: 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
USA 
Final 
Amendment 1 
Evaluation of the Efficacy and Safety ofGS-5745 as Add-On Therapy 
to a Tumor Necrosis Factor Inhibitor and Methou·exate Regimen in 
Subjects with Moderate to Severe Rheumatoid Arthritis 
110523 
2016-000897-39 
TBD 
Approximately 40 centers globally 
The primmy objective of this study is as follows: 
To assess the efficacy of GS-5745 versus placebo as an add-on 
therapy to a TNF inhibitor and methou·exate in subjects with 
moderate to severe rheumatoid milu·itis (RA) 
The secondmy objectives of this study m·e as follows: 
• 
To assess the safety and tolerability of GS-5745 versus placebo as 
an add-on therapy with a TNF inhibitor and methou·exate in 
subjects with moderate to severe RA 
• 
To assess the phmmacokinetics (PK) ofGS-5745 as an add-on 
therapy with a TNF inhibitor and methou·exate in subjects with 
moderate to severe RA 
The explorat01y objectives of the study m·e as follows: 
This is a Phase 2, double-blind, placebo-conu·olled, randomized 
multi-center study evaluating the efficacy and safety ofGS-5745 as 
add-on therapy in subjects with moderate to severe RA who have had 
an inadequate response to anti-TNF biologic therapy (TNF-IR) as 
detennined by the study investigator. 
Page5 
24 Jnne 2016 


GS-5745
Protocol GS–US-373-1499
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 6
24 June 2016
Subjects will be stratified by high and moderate disease activity as 
determined by the Disease Activity Score for 28 joints using CRP 
(DAS28-CRP).  High disease activity is defined as DAS28-CRP > 5.1 
and moderate disease activity is defined as a DAS28-CRP > 3.2 and
≤5.1. In addition, subjects will be stratified by prior use of RA
biologics including the TNF inhibitor being administered during 
Screening. Low RA biologic use will include subjects with 1 - 2 prior 
RA biologics and high RA biologic use will include subjects with 3 or 
more previous RA biologics. Subjects will be followed for 4 weeks 
after last dose of study drug. 
Eligible subjects who complete the blinded phase of the study may
participate in an open-label extension (OLE) phase and will receive 
weekly SC injections of 300 mg of GS-5745 for 52 weeks, in addition 
to their current SC administration of a TNF inhibitor.
Number of Subjects 
Planned:
Approximately 75 subjects
Target Population:
Subjects with moderate to severe RA currently treated with a stable 
dose of TNF-inhibitor for at least 12 weeks and methotrexate (MTX)
currently treated for at least 12 weeks and on a stable dose for at least 
6 weeks at Screening.
Duration of 
Treatment:
Subjects will receive SC injections once a week for 12 weeks in the 
blinded phase and weekly injections through Week 64 in the Open 
Label Extension phase (OLE). 
Diagnosis and Main 
Eligibility Criteria:
For a complete list of inclusion and exclusion criteria, please refer to 
Sections 4.2 and 4.3.
Key inclusion criteria include:

Male or female subjects between 18 and 80 years of age inclusive, 
at time of signing informed consent

Diagnosis of RA (according to the 2010 ACR/EULAR 
classification criteria 

Must have taken oral or parenteral methotrexate (MTX) 7.5 to 
25 mg/week continuously for at least 12 weeks and tolerated this 
medication, with at least 6 weeks of stable dose (defined as no 
change in prescription) prior to Baseline and able to continue 
MTX throughout the duration of the study

Subjects on MTX may also be on concurrent chloroquine or 
hydroquinone at a stable dose (defined as no change in 
prescription) for at least 4 weeks prior to Baseline; if so, they 
should plan to continue this medication for the duration of the 
study


GS-5745
Protocol GS–US-373-1499
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 7
24 June 2016

Must have an inadequate response to ≥ 12 weeks of current 
treatment with an approved dose  of SC formulation of  
adalimumab, certolizumab, entanercept, or golimumab as 
determined by the investigator
AND
Must have a DAS28- CRP >3.2, with ≥ 3 swollen and ≥ 3 tender 
joints among the 28 joints assessed in the DAS28 during 
Screening 
AND
Must have  > 3 swollen joints and > 3 tender joints among 28 
joints assessed in the DAS28 at Baseline

The last dose of SC TNF inhibitor must have been administered as 
below :
Adalimumab within 2 weeks of Baseline
Certolizumab between 2 or 4 weeks of Baseline according to 
the subject’s prescribed dosing regimen.
Etanercept within 1 week of Baseline
Golimumab within 4 weeks of Baseline

Non-steroidal anti-inflammatory drugs (NSAIDs) and/or oral 
corticosteroids (≤ 10 mg prednisone/day or equivalent) at a stable 
dose (defined as no change in prescription ) for ≥ 4 weeks prior to 
Baseline are allowed and should be continued throughout the 
duration of the study; prn NSAID for indications other than RA 
are also allowed

Subjects of child-bearing potential (as defined in protocol) must 
agree to use protocol specified contraceptive measures throughout 
study duration and for 30 days after the last dose of study drug
Key exclusion criteria include

Current treatment with any disease modifying anti-rheumatic drug 
(DMARD) except MTX alone or in combination with chloroquine
or hydroxychloroquine

Other immune modulating/suppressive non-biologic and biologic 
medications as described in Section 5.4.3

Intra-articular corticosteroid injection of any joint within 4 weeks 
of Baseline


GS-5745
Protocol GS–US-373-1499
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 8
24 June 2016

Women who are pregnant or breastfeeding, or who are planning to 
become pregnant or breastfeed during the study

History of any infection requiring oral antimicrobial therapy 
within 2 weeks prior to Baseline

History of current inflammatory joint disease, other than RA, such 
as gout, reactive arthritis, psoriatic arthritis, seronegative 
spondylarthritis, or Lyme disease, OR other current autoimmune 
diseases such as: systemic lupus erythematosus (SLE), 
inflammatory bowel disease, polymyalgia rheumatica, 
scleroderma, inflammatory myopathy, mixed connective tissue 
disease, or other overlap syndrome that would interfere with the 
evaluation of RA or require protocol prohibited medication
(subjects with  Sjogren’s syndrome or controlled thyroiditis are 
not excluded

Active  systemic involvement secondary to RA such as vasculitis 
or Felty’s syndrome

History of any of the following  within 12 months of Baseline: 
a) infection requiring parenteral antibiotics or hospitalization,
b) any life-threatening infection, 
c) sepsis

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) Estimated glomerular filtration rate <40 mL/min based on the 
Modification of Diet in Renal Disease (MDRD) formula. (See 
Appendix 10)


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
Any uncontrolled clinically significant laboratory abnormality that 
would affect interpretation of study data or the subject’s 
participation in the study

Any chronic, uncontrolled medical condition which would put the 
subject at increased risk during the study participation such as 
uncontrolled: diabetes, hypertension, morbid obesity, thyroid, 
adrenal, pulmonary, hepatic, renal, neurologic or psychiatric 
disease, or other disease of concern, as per judgment of the 
investigator

Positive HIV serology, or hepatitis B sAg during Screening

Positive hepatitis C serology unless subject has undetectable 
hepatitis C virus via PCR during Screening

A positive QuantiFERON-TB Gold test during Screening, OR a 
history of either untreated or inadequately treated latent or active 
tuberculosis (TB) infection OR receiving current treatment for or 
active TB during Screening

A subject with a malignancy or a history of malignancy or 
lymphoproliferative disorder within 10 years with the following 
exceptions:
a) Carcinoma in situ of the cervix that has been successfully 
treated
b) Basal or squamous cell cancer that has been successfully 
treated
Study Procedures/
Frequency:
All subjects will have the following study visits at the study site 
during the blinded phase of the study: Screening, Day 1 first dose of 
study drug) and Weeks 1, 4, 8 and 12. Subjects will receive the first 
two injections of study drug (Day 1 and Week 1) at the study site.  
Subjects electing not to participate in the OLE will complete Week 12 
assessments and will not receive open label study drug. These subjects 
will be followed for safety for an additional 30 days after the last dose 
of study drug. 
Subjects that are eligible and choose to participate in the OLE will 
receive their first dose of study drug in the OLE phase of the study at 
Week 12 after completing all the required assessments of the Week 12 
visit.  Additional study visits at the study site in the OLE will occur at 
Weeks 13, 19, 24, 30,  36, 42, 48, 54, 60, and  64, with a 30-day 
follow-up visit after the last dose of study drug.  


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Screening Assessments

Confirmation of RA diagnosis

Medical/Surgical history

Vital signs (VS) and weight

Height, complete physical exam (CPE)

12 lead ECG

Central laboratory tests including Rheumatoid Factor, anti-CCP, 
hematology, urinalysis, chemistry panel, serum ß-HCG (women of 
childbearing potential), QuantiFERON –Gold (QFT), HIV 
Serology, HBsAg, HCVAb and c-Reactive Protein,  Erythrocyte 
Sedimentation Rate (ESR) local lab and  Estimated Glomerular 
Filtration Rate (based on MDRD study equation),  TSH and 
HbA1c. Flow cytometry for absolute CD19 B-cell counts on 
subjects who have been on rituximab

66 swollen and 68 tender joint count

Patient and Provider Global Assessment of Health

Patient Assessment of Pain

DAS28-CRP calculation
On-Treatment Assessments

Concomitant medications

Vital signs and weight

CPE  (Blinded phase Week 12 and OLE Week 64 only)

Targeted Physical exam (TPE) at all other visits

12-lead ECG (Week 12 of the blinded phase and Week 64 of the 
OLE)

Safety blood draws to include: Hematology, urinalysis, chemistry 
panel (in the blinded phase Study Day 1, Weeks 1, 4, 12, and the 
30-day safety follow-up. In the OLE every 12 weeks and at the 
30-day follow-up visit.

Serum βHCG pregnancy test (30-day follow-up only), and urine 
pregnancy (Day 1 and every 4 weeks) in women of child-bearing 
potential 

In the blinded phase questionnaires and disease activity measures
will be administered at Day 1, Weeks 1, 4, 8, 12 and at the 30-day 
safety follow-up visit. In the OLE phase, these assessments will be 
performed every 12 weeks, at Week 64 and at the 30-day safety 
follow-up visit. 


GS-5745 
Protocol GS-US-373-1499 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Study Dmg Adminisu·ation: 
Blinded Phase 
Final 
Amendment 1 
In the blinded phase, SC study dmg adminisu·ation will occm at the 
study site on study Day 1, Weeks 1, 4, and 8. Subjects will remain at 
the study site for 30 minutes after the first 2 injections of study dmg 
for observation. This time may be extended per judgment of 
investigator. After receiving SC instruction at the study site dming the 
first 2 d.mg SC injections subjects (or their caretaker) who are judged 
capable will be allowed to self-administer SC injections at home 
dming the weeks where on-site visits are not required. 
OLE Phase 
In the OLE phase, study d.mg adminisu·ation will occm weekly from 
Week 12 to Week 64. SC study d.mg adminisu·ation will occm at the 
study site for the first 2 doses in the OLE at Week 12 and Week 13. 
Subjects will remain at the study site for 30 minutes after the first 
2 injections of study dmg for observation. This time may be extended 
per judgment of the investigator. If subjects (or their caretaker) are 
judged capable of self-injection, they may administer study dmg at 
home for the remainder of the study except for the in-office visits 
(please refer to Appendix 2). Subjects will be scheduled for a 30-day 
follow-up visit after the last dose of study dmg. 
Routine SC adminisu·ation of the subject's own TNF inhibitor 
identified dming Screening should continue throughout the study, as 
per the local label. 
PK and Biomarker Sampling: 
PK Blood Draws: PK blood draws will be done prior to dosing at 
Weeks 1, 4, 8, anytime on Week 12 and at ESDD (if applicable) of the 
blinded phase and prior to dosing at Week 24 and anytime at Week 
64 of the OLE phase. 
0 tional PK Sub-stud 
PD 
Anti-GS-5745 Antibodies (ADA) : Blood draws for ADAs will be done 
prior to dosing on Day 1, Weeks 4, and 8; and anytime at Week 12 
and the 30-day follow-up visit of the blinded phase. Blood draws for 
ADAs will be done prior to dosing at Week 24, anytime at Week 64, 
and anytime dming the 30-day follow-up visit of the OLE. 
Biomarker Blood Draws: Blood biomarkers will be collected dming 
the blinded phase at Day 1, Weeks 4 and 12. For the OLE, samples 
will be collected every 3 months strui ing at Week 24. 
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GS-5745 
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Gilead Sciences, Inc. 
Test Product, Dose, 
and Mode of 
Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Criteria for 
Evaluation: 
Safety: 
Efficacy: 
Phrumacokinetics: 
Explorat01y: 
Statistical Methods: 
CONFIDENTIAL 
Genomic Testing 
Optional Genomic TestingjPPD 
Group 1: 
I 
Final 
Amendment 1 
GS-5745 300 mg (2 x 1 mL GS-5745 [150 mg/ml] SC injections) 
administered weekly 
Group 2: 
GS-5745 150 mg (1 x 1 mL GS-5745 [150 mg/ml] + Placebo-to-match 
1 x 1 mL SC injections) administered weekly 
Group 3: 
Placebo-to-match (2x 1 ml SC injections) administered weekly 
Safety will be assessed during the study through the reporting of AEs, 
and by clinical laborat01y tests, physical examination, and vital signs 
(VS) assessments at vru·ious time points during the study. 
The primruy efficacy endpoint is mean change from Baseline in 
DAS28- CRP at Week 12. Key secondruy endpoints will be the 
proportion of subjects who achieve 1 DAS28-CRP ~3 .2 and the 
proportion of subjects who achieve DAS28-CRP < 2.6 at Week 12. 
Plasma concentrations of GS-5745 will be detennined. 
PPD 
The primruy analysis set for efficacy analyses will be the Full 
Analysis Set (F AS), which includes all randomized subjects who 
received at least one dose of study dmg. The primruy endpoint is mean 
change from Baseline in DAS28- CRP at Week 12. The primruy 
analysis will compru·e each of the 2 GS-5745 u·eated groups to the 
placebo group using a mixed model repeated measures (MMRM) 
approach. 
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Secondary endpoints include the proportion of subjects who achieve  
DAS28-CRP <3.2) at Week 12 and the proportion of subjects who 
achieve DAS28- CRP <2.6 at Week 12. Cochran-Mantel-Haemszel 
approach adjusting for the randomization stratification factors will be 
used to compare each of the GS-5745 treated group to the placebo 
group.
All continuous endpoints will be summarized using an 8-number 
summary (n, mean, standard deviation [SD], median, 1st quartile [Q1], 
3rd quartile [Q3], minimum, maximum) by treatment group. All 
categorical endpoints will be summarized by the number and 
percentage of subjects who meet the endpoint definition.
Safety endpoints will be analyzed by the number and percent of 
subjects with events or abnormalities for categorical values or 
8-number summary (n, mean, SD, median, Q1, Q3, minimum, 
maximum) for continuous data by treatment group.
A total sample size of 75 subjects is planned for this study. Each of the 
two GS-5745 treated groups will be compared to the placebo group. A 
sample size of 25 per group will provide a power of 80% with a 2-
sided α level of 0.05 to detect a Minimal Clinically Important 
Improvement (MCII) in DAS28- CRP change from Baseline of 1.2 at 
Week 12 between a GS-5745 treated group and the placebo group, 
assuming a common standard deviation of 1.35 and 15% early dropout 
rate.  
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
°C
degrees Celsius
°F
degrees Fahrenheit 
β-HCG
beta-human chorionic gonadotropin
ACR
American College of Rheumatology
ACR 20/50/70 
American College of Rheumatology 20/50/70%  improvement
AE
adverse events
ALT
alanine aminotransferase
AST
aspartate aminotransferase
CCP
cyclic citrullinated peptide
CDAI
Clinical Disease Activity Index
CIA
collagen-induced arthritis 
CFR
Code of Federal Regulations
CK
creatine kinase
cm
Centimeter
CRF
case report form
CRO
contract research organization
CRP
C-reactive protein
CTCAE
Common Toxicity Criteria for Adverse Events
DAS28
Disease Activity Score
DMARD
disease modifying anti-rheumatic drug
DMC
Data Monitoring Committee
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eSAE
electronic serious adverse event
ESDD
Early Study Drug Discontinuation
ESR
erythrocyte sedimentation rate
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FSH
follicle-stimulating hormone
g
Gram
GCP
Good Clinical Practice
Gilead
Gilead Sciences, Inc.
HAQ-DI
Health Assessment Questionnaire Disability Index
HBsAg
hepatitis B surface antigen
HCVab
hepatitis C antibody


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HIV
human immunodeficiency virus
CRP
C-Reactive Protein
IB
Investigator’s Brochure 
ICH
International Conference on Harmonization 
ICH E3
ICH Guideline for Structure and Content of Clinical Study Reports
ie
that is
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IR
inadequate response
IRB
Institutional Review Board
IU
international units
IUD
intrauterine device
IWRS
Interactive Web Response System
kg
Kilogram
L
Liter
LLT
lower-level term
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MMP9
matrix metallopeptidase-9
MTX
Methotrexate
NSAID
nonsteroidal anti-inflammatory drug
PE
physical examination
PK
Pharmacokinetics
Q1
first quartile
Q3
third quartile
QA
quality assurance
QT
electrocardiographic interval between the beginning of the Q wave and 
termination of the T wave, representing the time for both ventricular 
depolarization and repolarization to occur
QTcF
QT interval corrected for heart rate using the Fridericia formula
RA
rheumatoid arthritis
RF
rheumatoid factor
s
Second
SADR
serious adverse drug reaction
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SD
standard deviation 
SDAI
Simplified Disease Activity Index
SF-36
Short Form (36) Health Survey


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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
TNF- IR
tumor necrosis factor – Inadequate Response
ULN
upper limit of normal
US, USA
United States, United States of America
VAS
visual analogue scale
VS
Vital signs


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1.
INTRODUCTION
1.1.
Background
Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that affects approximately 
1.3 million adults in the United States (US) {Helmick et al 2008}. Rheumatoid arthritis 
manifests principally as an attack on peripheral joints and may lead to marked destruction and 
deformity of joints, with considerable disability and impact on quality of life. It is characterized 
by the production of autoantibodies, synovial inflammation with formation of pannus tissue, and 
erosion of underlying cartilage and bone. Although people of any age can be affected, the onset 
of RA is most frequent between the ages of 40 and 50 years, and women are affected 3 times 
more often than men {Lawrence et al 1998}. While the cause of RA is still not completely 
understood, aberrant B-cell activation, T-cell costimulation, osteoclast differentiation, and 
cytokine release all have been implicated in its pathogenesis. Subjects with RA experience a high 
risk of disability and mortality {Arthritis Foundation 2008}.
Despite recent advances in RA treatment, including TNF-targeted therapeutics, a number of 
subjects experience insufficient response to these agents and continue to suffer from 
disease-related symptoms, as well as incurring joint damage. Matrix metalloproteinase 9 
(MMP9) has been reported to play an important role in the progression of RA, and is known to 
be expressed in human RA as well as animal models of disease. The role of MMP9 in disease 
progression in RA is supported by findings in the MMP9 knockout mouse, which is significantly 
protected against increased disease severity in a collagen-induced arthritis model of RA, whereas 
matrix metalloproteinase 2 (MMP2) knockout mice develop more severe disease than littermate 
controls {Itoh et al 2002}. Tartrate resistant acid phosphatase (TRAP) positive mononuclear and 
multinucleated cells are often found in the synovium at the sites of cartilage and bone 
destruction. TRAP-positive multinucleated cells from RA subjects, including osteoclasts, secrete 
MMP9 and are key participants in joint destruction {Tsuboi et al 2003}. Furthermore, MMP9 
has been shown to play a critical role in osteoclast invasion {Engsig et al 2000}. Studies in a 
variety of different disease models and correlations in human disease support a role for MMP9 in 
driving inflammation through increased vascular permeability and through promoting the 
activation or increasing the bioavailability of cytokines and growth factors {Gearing et al 1995}. 
Selective inhibition of MMP9 by GS-5745 has the potential to slow and/or halt progression of 
bone and joint erosion, as well as to reduce inflammation in RA subjects.
1.2.
GS-5745
1.2.1.
General Information
For further information on GS-5745, refer to the current investigator’s brochure for GS-5745.


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1.2.2.
Preclinical Pharmacology and Toxicology
GS-5745 is a fully humanized high-affinity monoclonal IgG4 antibody that is a selective and 
potent allosteric inhibitor of MMP9. In subjects with Ulcerative Colitis (UC) and Crohn’s 
disease, MMP9 expression is strongly induced and is associated with progressive disease. 
Matrix metalloproteinase 9 (MMP9) expression has also been shown in the synovial tissue in 
human RA, and in macrophages and other cells in lung tissue in human COPD. Murine 
surrogates of GS-5745, with similar epitope specificity and inhibitory activity, have 
demonstrated significant anti-inflammatory and tissue-protective activity in rodent models of
colitis and arthritis. Similarly, MMP9 is expressed in a number of solid tumors such as lung, 
gastric, and pancreatic adenocarcinomas and lung squamous cell and hepatocellular carcinomas. 
In addition, anti-MMP9 antibodies demonstrated efficacy in a mouse xenograft model of human 
colorectal carcinoma with respect to both primary tumor volume and weight. Unlike pan-MMP 
inhibitors, specific inhibition of MMP9 with a murine surrogate of GS-5745 showed no evidence 
of inducing musculoskeletal symptoms or pathology in a rat model. Furthermore, there were no 
effects on safety pharmacology endpoints (clinical observations, EGCs, respiratory rate) in the 
4-week repeat-dose toxicity studies at doses of up to 100 mg/kg/dose.
The toxicology program consists of completed 4-week and 26-week repeat-dose intravenous (IV)
toxicity studies in both rats and monkeys and a human tissue cross-reactivity study. To support 
the transition to a subcutaneous (SC) formulation, a SC local tolerability study in rats was 
conducted and the 26-week toxicity studies in rats and cynomolgus monkeys included both IV 
and SC routes. 
Findings associated with GS-5745 treatment in the 4-week repeat-dose toxicity studies have been 
limited to reversible physeal hypertrophy in rats, an expected response to MMP9 inhibition, and 
reversible increased adrenal gland weight in female monkeys at all doses, which was associated 
with slight hypertrophy of the zona fasciculata in a single 100-mg/kg/dose female monkey. In the 
26-week studies, there were no findings of toxicological concern in rats or cynomolgus monkeys 
following weekly IV or SC administration at doses up to 100 mg/kg and 150 mg/kg, 
respectively. The lack of physeal hypertrophy observed in the rat 26-week study is presumably 
due to the reversible nature of this finding as longitudinal bone growth and growth plate closure 
slows/completes. There were no adverse injection site reactions observed in the 26-week studies, 
and no adverse findings in the local tolerability study.  There was no specific GS-5745 staining 
observed in normal human tissues.
The rat and rabbit embryo fetal development studies and the rat fertility study have also been 
completed. As expected, there was no specific GS-5745 staining observed in normal human 
tissues. At doses of GS-5745 up to 100 mg/kg/dose IV, data indicate no test article-related 
maternal or fetal effects in rats and rabbits, and no test article-related effects on male or female 
fertility in rats.
In summary, in these studies at exposure multiples of the anticipated clinical exposure, there was 
no evidence of GS-5745 induced hematological changes, no effects on immune system organ 
weights, including thymus, spleen and lymph nodes, and no observed immunosuppressive 
effect.


GS-5745 
Protocol GS-US-373-1499 
Gilead Sciences, Inc. 
1.2.3. 
Clinical Trials of GS-5745 
Final 
Amendment 1 
Gilead is cmTently conducting clinical trials with GS-5745 in ulcerative colitis, Crohn's Disease, 
solid tumors, chronic obstmctive pulmonaty disease, and cystic fibrosis (CF). For inf01m ation on 
all Gilead sponsored u·ials for GS-5745, please refer to the cmTent Investigators Brochme for 
GS-5745. 
1.3. 
Rationale for This Study 
1.3.1. 
Clinical Rationale 
CmTent RA u·eatment guidelines from the American College of Rheumatology and Emopean 
League Against Rheumatism (ACRIEULAR), the 2013 American College of Rheumatology 
Guideline for the Treatment of Rheumatoid Arthritis and the EULAR Recommendations for the 
Management of Rheumatoid Arthritis with Synthetic and Biological Disease-Modifying 
Antirheumatic Dmgs: 2013 Update, respectively, recommend switching subjects who have an 
inadequate response to TNF inhibitors (TNF-IR) to an altemate TNF inhibitor or another class of 
biologic. Several biologics have been approved for use in TNF-IR subjects, but responses to 
these single biologics tend to be lower than in TNF inhibitor naive RA subjects. Thus, there 
remains an unmet need patticulm·ly for the TNF-IR subjects. 
Gilead Sciences, Inc. (Gilead) conducted a Phase 1 double-blind, randomized, placebo-conu·olled 
study in RA subjects in Emope. Subjects were randomized in a 4:1 ratio to receive an IV 
infusion of GS-57 45 ( 400 mg) or matched placebo eve1y 2 weeks for a total of 3 infusions 
(Days 1, 15, and 29). Subjects pruticipated in the study for up to 117 days; which included up to 
2 screening visits, 3 infusion visits, 4 follow-up visits, and 2 follow-up telephone calls. The 
screening visits were conducted a maximum of 15 days before the first infusion. Follow-up visits 
occmTed on Days 3, 8, 36, and 43, and follow-up telephone calls occmTed on Days 57 and 100. 
Subjects were required to have a mean CRP value dming Screening:=::: 8 mg/L and not allowed to 
have received recent concomitant RA biologics within a defined period prior to Screening or 
dming the study. 
PPD 
CONFIDENTIAL 
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No subjects were considered mild or in remission. In contrast to GS-5745-treated subjects at 
Day 43, the placebo group had no subjects with mild disease activity or remission. All 3 placebo 
subjects at Day 43 had moderate disease activity.
Interestingly, these clinical improvements occurred despite a lack of major change in CRP 
values. Among subjects treated with GS-5745 during the study (n=15), the mean values at 
Baseline and Day 43 were 37.21 (18.688) mg/L and 21.10 (18.977) mg/L, respectively, a mean 
decrease of 6.11 (22.577) mg/L. Among subjects treated with placebo (n=3), the mean CRP 
values at Baseline and Day 43 were 16.57 (11.153) mg/L and 12.46 (10.572) mg/L, respectively, 
a mean decrease of 4.12 (5.922) mg/L.
No deaths, serious adverse events (SAEs), AEs that caused study drug discontinuation, or
pregnancies were reported in this study. All AEs were Grade 1 or Grade 2 in severity. The most
frequently reported AEs among subjects randomized to GS-5745 (ie, reported for ≥ 10% of 
subjects in the GS-5745 group) were hypertension (2 of 15 subjects, 13.3%) and nasopharyngitis 
(2 of 15 subjects, 13.3%). Overall, no AE/SAE safety signals were noted during the study. All 
graded laboratory abnormalities were Grade 1 or Grade 2 in severity. One subject (6.7%) 
randomized to GS-5745 had a Grade 2 chemistry abnormality, and 2 subjects (13.3%) 
randomized to GS-5745 had Grade 2 hematology abnormalities. No clinically important changes 
from Baseline in vital signs or ECG results occurred during the study. Overall, these data 
indicate GS-5745 was well tolerated during the study and that GS-5745 may be beneficial in 
subjects with RA.
Though the sample size of the Phase 1 RA study is small and the study duration brief, results 
indicate GS-5745 may have clinical activity in RA. It is not yet known if the magnitude of the 
clinical response is sufficiently high that GS-5745 could be differentiated as a single agent for 
RA. However, combining GS-5745 with a TNF-α inhibitor has the potential to augment the 
clinic benefit of either agent alone. Therapeutic strategies that employ combinations of 
conventional and biologic disease-modifying antirheumatic drugs have demonstrated superior 
clinical responses compared to single agent approaches. Combining 2 biologics is an extension 
of this treatment strategy and offers an approach to achieving the treat-to-target approach to RA 
management specified in the ACR/EULAR treatment guidelines. Given the lack of significant 
immunosuppression seen with GS-5745, clinical benefit may be obtained in subjects with RA 
when combining this agent with a biologic DMARD, as GS-5745 is postulated to decrease RA 
disease activity via novel pathways which are unique or at least partially unique from those 
inhibited by anti-TNF or MTX.
The efficacy of the combination of a mouse specific anti-MMP9 agent (AB0046) and an 
anti-TNF agent (Enbrel) was evaluated in a collagen induced arthritis (CIA) mouse model. Using 
a chronic model of advanced disease, therapies were administered after an average clinical score 
of > 2 was reached (Day 28) and were continued through Day 43. Treatment with AB0046 and 
Enbrel, each on its own or in combination, resulted in significant efficacy with respect to clinical 
scores as compared to the control group for: ankle diameter, paw swelling, body weight change, 
and histopathological assessment of soft tissue damage, bone erosion, and joint destruction. At 
Day 43, treatment AB0046 and Enbrel combined therapy resulted in significant improvements in 


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clinical score (p < 0.05 as compared to control group). Moreover, the combination of 
AB0046 and Enbrel resulted in a trend for superior therapeutic benefit as compared to each agent
alone; however a statistically significant difference as compared to each single agent was not 
observed. Similar findings were apparent for other metrics such as body weight and 
histopathology. In an alternative analysis that evaluated the number of limbs scored with mild or 
no disease at the end of treatment, combination therapy yielded a significant benefit over each 
individual agent or a beneficial trend as compared to Enbrel alone. Analysis of complete blood 
count at the end of study revealed no abnormalities in any treatment group. Overall, these data 
indicate that the addition of anti-MMP9 to anti-TNF therapy does not compromise the activity of 
either agent, is well tolerated in this murine model as judged by both body weight and complete 
blood count, and could potentially provide a larger therapeutic benefit in arthritis.
Unlike other current biologics marketed to treat RA, the mechanism of action of GS-5745 as a 
protease inhibitor of MMP9 does not have a direct effect on systemic immune function. As of 
17 Jan 2016 GS-5745 has been administered to approximately 255 subjects in multiple 
indications (oncology, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, and chronic 
obstructive lung disease) and thus far no safety signals have been identified, including any risk of 
serious or opportunistic infections, despite many of the subjects enrolled in these studies being 
immunocompromised due to cancer chemotherapy or receiving systemic immunosuppression to 
treat their primary disease. 
1.3.2.
Toxicology Rationale
Based on the toxicology profile of GS-57455745 and the known clinical safety of TNF 
inhibitors, there is no evidence of overlapping toxicity with the TNF inhibitors and combination 
toxicology testing of GS-5745 is not considered warranted.
1.3.3.
Dose Selection
Clinical experience includes IV dosing of GS-5745 up to 1800 mg every other week in oncology 
indications, which has been well tolerated.
In the Phase 1 RA study (GS-US-373-1276) dosing of GS-5745 400 mg IV every 2 weeks for a 
total of 3 infusions demonstrated clinical benefit and was well tolerated. 
Subsequent to study GS-US-373-1276 in RA, a SC formulation of GS-5745 was developed for 
use in inflammatory diseases. A bridging study was performed in healthy subjects (Study 
GS-US-326-1430) and demonstrated that the SC formulation of GS-5745 has an absolute 
bioavailability of 44.1%. Subsequent studies of GS-5745 in inflammatory disease have used the 
SC formulation.
The doses selected for this RA study are based upon clinical experience with the SC formulation 
of GS-5745 in ulcerative colitis. In a Phase 1 study of subjects with moderately to severely active 
UC (GS-US-326-0101) subjects received IV (every other week) or SC GS-5745 (weekly) for one
month. Of the 10 subjects dosed with SC GS-5745 once weekly, 4 subjects (40.0%) met the 
Mayo Score criteria for response, 2 out of 10 subjects (20.0%) met the criteria for remission, and 


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5 subjects (50.0%) met the criteria for mucosal healing. The weekly SC dose of 150 mg of 
GS-5745 was well tolerated. Comparable clinical responses were observed in subjects who 
received IV GS-5745 at doses 1.0 and 2.5 mg/kg administered every 2 weeks for a total of 
3 doses. Accordingly, subsequent studies of GS-5745 are currently being conducted in Crohn’s 
disease (300 mg and 150 mg SC once weekly, and 150 mg SC every other week) and ulcerative 
colitis (150 mg SC weekly, and 150 mg SC every other week). Additionally, there has been no 
apparent difference in GS-5745 PK between subjects with UC and RA, indicating similar target 
inhibition between subjects with UC and RA at the same dose of GS-5745. Based upon these 
findings, in this RA study, SC doses of 300 mg and 150 mg once weekly were selected based on  
dose (150 mg) shown to have evidence of efficacy in ulcerative colitis, and a higher dose of 
300 mg which represent the top dose level in ongoing trials in Crohn’s disease. 
1.4.
Risk/Benefit Assessment for the Study
GS-5745 is currently being evaluated for the treatment of solid tumors, UC, Crohn’s Disease, 
chronic obstructive pulmonary disease, cystic fibrosis, and RA. From the adverse events (AEs)
reported in completed and ongoing trials in these indications, no drug-related safety signal has 
been identified.. Also, no drug interactions or contraindications have been reported.
Potential risks may include local injection site reactions and the rare possibility of
hypersensitivity or allergic reactions. A single hypersensitivity reaction was observed after a 
second infusion in a UC subject. The subject was evaluated at the local emergency room and was 
discharged home in satisfactory condition. Despite this single hypersensitivity reaction after an 
IV infusion of GS-5745, it should be noted that GS-5745 is not considered to be a ‘high risk’ 
agonist as it acts by antagonism and targets MMP9. In this study, GS-5745 will be administered 
in a SC formulation which reduces the risk of severe hypersensitivity reactions. In addition, the 
first 2 doses of study drug in the blinded and OLE phases of the study will be administered at the 
study site clinic so that subjects can be observed for possible unexpected injection reactions.
While TNF inhibitors have demonstrated great benefit for subjects with more difficult to treat 
RA, this class of biologics has a mechanism of action that down modulates cellular and humoral 
immunity and has demonstrated an increased risk for infections{Ali et al 2013}.  Furthermore, 
treatment of  RA subjects with TNF inhibitors combined with other biologics that directly affect 
the immune system {Genovese et al 2004}, {Greenwald et al 2011}, {Weinblatt et al 2006} all 
increased the risk of serious infections.
In contrast, GS-5745 is a biologic with a mechanism of action that does not directly affect innate 
or adaptive immunity. It binds to and inhibits the zinc-dependent endopeptidase, MMP9, an 
enzyme that degrades extracellular matrix proteins. Pre-clinical and clinical studies performed to 
date with GS-5745 or rodent equivalent have failed to observe an increased risk of infections. 
Thus, combining GS-5745 with a TNF inhibitor is not expected to increase the risk of serious 
infections.  As a safety precaution this study protects study enrollees by screening for TB, 
limiting the number and amount of immune modulating agents and excluding subjects with a 
previous history of serious infections.


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Lastly, investigators will closely monitor the subjects for the possible infections. In parallel the 
DMC will review safety data at scheduled intervals to assess for possible emerging safety 
signals. 
With the above safety measures in place, this clinical study will provide information about the 
benefits GS-5745 in combination with TNF-inhibitors in RA subjects and potentially provide an 
additional therapy to improve the health and quality of life of subjects living with this condition. 
These benefits are believed to outweigh any potential risks, particularly in the context of this 
clinical trial.  
1.5.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2. 
OBJECTIVES 
The prima1y objective of this study is as follows: 
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To assess the efficacy of GS-5745 versus placebo as an add-on therapy to a TNF inhibitor and 
methotrexate in subjects with moderate to severe rheumatoid arthritis (RA) 
The secondmy objectives of this study m·e as follows: 
• 
To assess the safety and tolerability of GS-57 45 versus placebo as an add-on therapy with a 
TNF inhibitor and methotrexate in subjects with moderate to severe RA 
• 
To assess the phan nacokinetics (PK) of GS-5745 as an add-on therapy with a TNF inhibitor 
and methotrexate in subjects with moderate to severe RA 
The explorat01y objectives of this study m·e as follows: 
IT 
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3. 
STUDY DESIGN 
3.1. 
Endpoints 
The prima1y endpoint of this study includes: 
• 
Change in DAS28- CRP from Baseline to Week 12 
The secondmy endpoints of this study include: 
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• 
Proportion of subjects that achieve low disease activity (DAS28- CRP ~3 .2) at Week 12 
• 
Prop01tion of subjects that achieve remission (DAS28- CRP < 2.6) at Week 12 
• 
Assess plasma concentrations of GS-5745 
The Explorat01y Endpoints include: 
PPO 
I 
I 
I 
• • • • 
3.2. 
Study Design 
This is a Phase 2, double-blind, placebo-controlled, randomized, multi-center study evaluating 
the efficacy and safety of GS-5745 as add-on therapy in subjects with moderate to severe RA 
who have had an inadequate response to anti-TNF biologic therapy (TNF-IR) as detennined by 
study investigator. 
Subjects will be stratified by their DAS28-CRP score, either DAS28-CRP > 5.1 or DAS28-CRP 
> 3.2 and :S 5 .1. In addition, subjects will be stratified by prior use of RA biologics including the 
TNF inhibitor being administered during Screening. Low RA biologic use will be comprised of 
subjects with 1-2 prior RA biologics and high RA biologic use will be comprised of subjects 
with 3 or more previous RA biologics. 
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Eligible subjects who complete the blinded phase of the study and are eligible to participate may 
participate in an open label extension (OLE) phase and will receive weekly SC  injections of 
300 mg of GS-5745 for 52 weeks, in addition to their current SC administration of a TNF 
inhibitor.
3.3.
Study Treatments
Subjects will receive weekly injections of 150 mg of GS-5745, 300 mg of GS-5745 or placebo  
for 12 weeks, in addition to their current SC administration of a TNF inhibitor and ongoing 
MTX. Subjects who are eligible to participate in the OLE will receive weekly injections of 
300 mg of GS-5745 for 12 months.  
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-5745 300 mg (2 x 1 mL GS-5745 [150 mg/ml] SC injections) administered weekly (N=25)
Group 2:
GS-5745 150 mg (1 x 1 mL GS-5745 [150 mg/ml] + Placebo-to-match 1 x 1 mL SC injection 
administered weekly (N=25)
Group 3:
Placebo-to-match (2 x 1 ml SC injections) administered weekly (N=25)
3.3.1.
Open Label Extension
On the Week 12 visit, eligible subjects (on active and placebo treatments) may choose to 
participate in the OLE portion of the study.
Subjects who choose to participate in the OLE will receive weekly SC injections of 300 mg of 
GS-5745 for 52 weeks, in addition to their current SC administration of a TNF inhibitor and 
continued MTX


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Figure 3-1.
Study Schema 
3.3.2.
Home Administration of Study Drug
Weekly clinic visits during the study may pose a significant burden to study subjects. This 
burden must be balanced against the need to monitor these potentially vulnerable subjects during 
the early doses of study drug.
In the blinded phase, SC study drug administration will occur at the study site on Day1, Weeks 1 
and 8. After receiving SC instruction at the study site during the first 2 drug SC injections, 
subjects (or their caretaker) judged capable will be allowed to self-administer remaining SC 
injections at home except from the in-office visits.  Subjects will remain at the study site for at 
least 30 minutes after the first 2 injections of study drug for observation.
In the OLE phase, study drug administration will occur at the study site for the first 2 doses at 
Weeks 12 and 13. Subjects will remain at the study site for at least 30 minutes after the first 
2 injections of study drug for observation. Subjects (or their caretaker) may administer study 
drug at home for the remainder of the study except for study visit days at the study site.
3.4.
Duration of Treatment
Subjects will receive 12 doses of weekly injections in the blinded phase and weekly doses 
through week 64 in the OLE phase and 30 days of follow-up after last dose of study drug.


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3.5.
Study Subject Discontinuation Criteria
The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. Study medication may be discontinued in the following instances

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree or medical conditions that are exclusionary based on the 
protocol exclusion criteria (Section 4.3). 

Unacceptable toxicity or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest

Subject requests to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 5

Discontinuation of the study at the request of Gilead, a regulatory agency or IRB/IEC
3.6.
End of Study
The end of this study is defined as 30 days after the last subject has completed the final visit in 
the OLE phase .
3.7.
Biomarker Testing
3.7.1.
Biomarker Samples to Address the Study Objectives:
Blood will be collected in this study and will be used to evaluate the association of biomarkers 
with the safety and clinical response to GS-5745 and to increase the knowledge and 
understanding of the biology of RA and/or autoimmune and related inflammatory diseases such 
as Lupus.  The samples collected can be used for the validation of diagnostics. The specific 
analyses will include, but may not be limited to, MMP9 levels and activity in blood. Because 
biomarker science is a rapidly evolving area of investigation, and AEs in particular are difficult 
to predict, it is not possible to specify prospectively all tests that will be done on the specimens 
provided. The testing of MMP9 and markers related to MMP9 pathway, inflammation, 
autoimmunity, and TNF pathway is based upon the current state of scientific knowledge. It may
be modified during or after the end of the study to remove tests no longer indicated and/or to add 
new tests based upon the growing state of art knowledge. Samples for future research will be 
stored for 15 years after the end of the study. These analyses are exploratory and subject results 
will not be provided to the study subjects or to the investigators.


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3.7.2. 
Biomarker Samples for Optional Future Research 
PD 
3.7.3. 
Biomarker Samples for Optional Genomic Research 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 75 subjects will be enrolled in the study with moderate to severe RA who are 
currently treated with a TNF-inhibitor for at least 12 weeks and methotrexate currently treated for at 
least 12 weeks and on a stable dose for at least 6 weeks.
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 between 18 and 80 years of age inclusive, at time of signing an 
informed consent
2) Diagnosis of RA (according to the 2010 ACR/EULAR classification criteria)
3) Subjects must meet Class I, II, or III of the ACR 1991 Revised Criteria for Global Functional
Status in RA (Appendix 6) at Screening
4) Must have taken oral or parenteral methotrexate (MTX) 7.5 to 25 mg/week continuously for 
at least 12 weeks and tolerated this medication, with at least 6 weeks of stable dose (defined 
as no change in prescription) prior to the first study drug dose and throughout the duration of 
the study.

Subjects on MTX may also be on concurrent chloroquine or hydroxychloroquine at a 
stable dose (defined as no change in prescription) for at least 4 week prior to Baseline: if 
so, they should plan to continue this medication for the duration of the study
5) Must be receiving folic or folinic acid supplementation at on Day 1 and throughout the 
duration of the study, dosed as per investigator
6) Must have an inadequate response to ≥12 weeks of current treatment with an approved,
stable SC formulation of adalimumab, certolizumab, entanercept, or golimumab as 
determined by the investigator
AND
Must have a DAS28- CRP >3.2, with ≥ 3 swollen and ≥ 3 tender joints among the 28 joints 
assessed in the DAS28 during Screening.
AND
Must have > 3 swollen joints and > 3 tender joints among 28 joints assessed in the DAS28 
at Baseline


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7) Subjects who have previously received other TNF inhibitors or biologics for the treatment of 
RA are eligible providing the following washout periods for these are used:

Rituximab – none for at least 6 months prior to Baseline and CD-19 B cell count in 
normal range (per central lab) at Screening

Infliximab – none for at least 8 weeks prior to Baseline

Tocilizumab – none for at least 8 weeks prior to Baseline
8) The last dose of SC TNF inhibitor must have been administered as below prior to Baseline 
visit:
a) Adalimumab within 2 weeks of Baseline
b) Certolizumab between 2 or 4 weeks of Baseline according to the subject’s prescribed 
dosing regimen
c) Entanercept within 1 week of Baseline
d) Golimumab within 4 weeks of Baseline
9) Non-steroidal anti-inflammatory drugs (NSAIDs) and /or oral corticosteroids (≤10 mg 
prednisone/day or equivalent) at a stable dose for ≥4 weeks prior to Screening are allowed 
and throughout the duration of the study, PRN NSAID for indications other than RA are also 
allowed.
10) Subjects of childbearing potential (as defined per protocol) must agree to use protocol-
specified contraceptive measures throughout the study duration and for 30 days after the last 
dose of study drug (refer to Appendix 5 for details)
11) A negative pregnancy test is required for female subjects (unless permanently sterile or 
greater than two years post-menopausal) as defined per protocol, at Screening and at
Baseline.
12) Lactating females must agree to discontinue nursing before study drug is administered and 
for the duration of the study.
13) 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
14) Must have the ability to understand and sign a written informed consent form, which must be 
obtained prior to initiation of the study procedures; subjects who need a
representative/guardian to provide consent are not permitted in this study


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4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Current treatment with any other disease modifying anti-rheumatic drug (DMARD) other 
than MTX alone or in combination with chloroquine or hydroxychloroquine), or other 
immune modulating/suppressive non-biologic and biologic medications as described in 
Section 5.4.3
2) Intra-articular corticosteroid injection within 4 weeks of Screening
3) Women who are pregnant or breastfeeding or who are planning to become pregnant or to 
breastfeed during the study
4) History of any infection requiring oral antimicrobial therapy within 2 weeks prior to
Baseline.
5) Previous treatment with GS-5745
6) Known hypersensitivity to GS-5745  or its formulation excipients.
7) Known hypersensitivity to the TNF inhibitor or its formulation excipients that the subject is 
receiving at Screening 
8) Any subject vaccinated with live or attenuated vaccines within the 4 weeks prior to the first 
dose of study drug or is to be vaccinated with these vaccines at any time during treatment or 
within 4 weeks following discontinuation of study drug.
9) History of current inflammatory joint disease, other than RA, such as gout, reactive arthritis, 
psoriatic arthritis, seronegative spondylarthritis, or Lyme disease, OR other current 
autoimmune diseases such as: systemic lupus erythematosus (SLE), inflammatory bowel 
disease, fibromyalgia, polymyalgia rheumatica, scleroderma, inflammatory myopathy, mixed 
connective tissue disease, or other overlap syndrome that would interfere with the evaluation 
of RA or require protocol prohibited medication (subjects with Sjogren’s syndrome or 
controlled thyroiditis as defined by the investigator are not excluded)
10) Active systemic involvement secondary to RA such as vasculitis or Felty’s syndrome
11) History of any of the following within 12 months of Baseline:
a) infection requiring parenteral antibiotics or hospitalization, 
b) any life-threatening infection,
c) sepsis
12) History of infected prosthetic joint at any time, with the prosthesis still in situ


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13) 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) Estimated glomerular filtration rate <40 mL/min based on the Modification of Diet in 
Renal Disease (MDRD) formula.
14) AST or ALT greater than 1.5 times the upper limit of normal at screening or any 
uncontrolled clinically significant laboratory abnormality that would affect interpretation of 
study data or the subject’s participation in the study.
15) A positive pregnancy test at Screening or Baseline (women of child-bearing potential only)
16) Positive HIV serology, or hepatitis B sAg during screening
17) Positive hepatitis C serology that has not been successfully treated defined as undetectable 
hepatitis C virus via PCR during Screening
18) A positive QuantiFERON-TB Gold test during Screening, OR a history of either untreated or 
inadequately treated latent or active TB infection OR receiving current treatment for active 
TB during Screening
19) A subject with a malignancy, a history of malignancy or lymphoproliferative disorder within 
10 years with the following exceptions:
a) Carcinoma in situ of the cervix that has been successfully treated
b) Adequately treated basal or squamous cell cancer or other localized non-melanoma skin 
cancer that has been successfully treated
20) Participation in another investigational drug study within 1 month of Screening for a small 
molecule or within 3 months or 5 half-lives which longer for a biologic agent prior to 
screening


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21) Male subjects unwilling to refrain from sperm donation for at least 90 days after the last dose  
of study drug
22) Females who may wish to become pregnant and/or plan to undergo egg donation or egg  
harvesting for the purpose of current or future fertilization during the course of the study and 
up to 30 days of the last dose of the study drug
23) Presence of any condition that could, in the opinion of the investigator, compromise the 
subject’s ability to participate in the study, such as history of substance abuse, alcoholism, or 
an unstable psychiatric condition.
24) Known hypersensitivity to rubber or latex
25) Have undergone surgical treatments for RA including synovectomy and arthroplasty in 
> 4 joints and/or within the last 12 weeks prior to Screening or planned elective surgery 
during the study
26) 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, new or significant ECG finding 
at Screening, or any other cardiovascular condition which, in the opinion of the investigator, 
would put the subject at risk by participation in the study.
27) 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. 
28) Any chronic, uncontrolled medical condition which would put the subject at increased risk 
during the study participation such as uncontrolled: diabetes, hypertension, morbid obesity, 
thyroid, adrenal, pulmonary, hepatic, renal, neurologic or psychiatric disease, or other disease 
of concern, as per judgment of the investigator


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
Subjects will be assigned a screening number at the time of consent. The randomization and 
Day 1 visit cannot occur until the investigator has received the results of the screening tests and 
subject eligibility has been confirmed.
Once eligibility has been confirmed, each subject will be assigned a unique subject number. 
Once a subject number has been assigned to a subject, it will not be reassigned to any other 
subject. During the Day 1 visit, subjects will be randomized in a 1:1:1 ratio to Treatment Group
1, Treatment Group 2, or Treatment Group 3. The IWRS will assign blinded study drug numbers 
at each study drug administration visit. Study drug will be dispensed to the subject in a blinded 
fashion until Week 12. Randomization will be stratified by disease activity DAS28- CRP > 5.1 
or DAS28- CRP > 3.2 and ≤ 5.1. In addition, subjects will be stratified by prior use of RA 
biologics including the TNF inhibitor being administered during Screening. Low RA biologic 
use will include subjects with 1-2 prior RA biologics and high RA biologic use will include 
subjects with 3 or more previous RA biologics
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 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 case report 
form/ electronic case report form (CRF/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-5745 and Placebo
5.2.1.
Formulation
GS-5745 for SC injection is formulated as a sterile, aqueous buffered solution in a single-use
pre-filled syringe (PFS) with a plunger stopper. The buffered solution contains the same 
excipients as the GS-5745 formulation, acetate at pH 5.0, sucrose and polysorbate 20. Each PFS
is intended to deliver 1 mL containing 150 mg GS-5745 at a concentration of 150 mg/mL.


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Placebo for SC injection is formulated as a sterile, aqueous buffered solution in a single-use PFS
with plunger stopper. The buffered placebo solution contains acetate at pH 5.0, sucrose and 
polysorbate 20 added for stabilization.  Each PFS is intended to deliver 1 mL of buffered 
solution.
5.2.2.
Packaging and Labeling
GS-5745 and placebo for SC injection will be supplied in 1 mL type I clear single-use glass PFS
with gray butyl coated stoppers.
Study drug(s) to be distributed to centers in the United States (US) and other participating
countries shall be labeled to meet applicable requirements of the US Food and Drug
Administration (FDA), EU Guideline to Good Manufacturing Practice – Annex 13
(Investigational Medicinal Products), and/or other local regulations.
Gilead or designated distribution depots will distribute study drug to centers as per
Good Manufacturing Practice (GMP) requirements.
5.2.3.
Storage and Handling
GS-5745 and placebo for SC injection will be shipped and stored under refrigeration between 
2 to 8 °C (36 to 46 °F). Storage conditions are specified on the label.
Upon arrival at the clinical center, the study drug products must be stored in a secure area,
accessible only to authorized study site personnel. To ensure drug stability and proper product
identification, the drug products should be stored in the kits in which they are supplied until
needed.
Consideration should be given to handling, preparation, and disposal through measures that
minimize drug contact with the body.
5.3.
Dosage and Administration of GS-5745 and Placebo
GS-5745 or placebo for SC injection will be administered to subjects on the thighs or the 
stomach area (abdomen). If the abdomen area is chosen, the area 5 cm (2 inches) around the 
umbilicus should be avoided. GS-5745 or placebo will be administered SC at the research center 
at Day 1and Weeks , 4 and 8 study visits during the blinded phase of the study. All injections 
should be delivered within 1 hour. The investigator or a qualified designee must be present 
during the administration during the SC injections at Day 1 and Week 1 in blinded phase of the 
study. After training the subject will be allowed to administer the remaining weekly SC study 
drug doses (+/-3 days) at home, except for in-office visits. During the OLE portion of the study, 
GS-5745 or placebo will be administered SC at the research center at Weeks 12 and 13 study 
visits. Afterwards, subject will continue to administer the remaining weekly SC study drug 
doses (+/-5 days) at home, except for in-office visits.


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In the blinded phase or OLE of the study, if the subject has a body temperature of > 38ºC 
(100.4ºF), or the subject feels unwell or is otherwise unfit to receive study drug at a given 
scheduled weekly injection, the subject should not be administered study drug. In consultation 
with the medical monitor, the Investigator may delay dosing until the parameters above are met.
If a subject fails to dose the study drug within the 3 day window of the scheduled SC weekly 
dose, they should contact the study site for instructions on dosing. The investigator and the 
Medical Monitor will determine if a late dose of study drug is acceptable or if the dose should be 
skipped. If a subject misses >3 of the 12 scheduled doses of study drug the Gilead medical 
monitor should be contacted to discuss if the subject should be withdrawn from the study.
5.4.
Prior and Concomitant Medications
At each study visit, the study center will capture any and all medications taken by the subject 
since the last visit or during the visit (as applicable). Concomitant medications include 
prescription medications, non-prescription medications, therapies, vitamins, herbal medicines,
and other dietary supplements.
5.4.1.
Allowed Prior and Concomitant Medications:

Antimalarials (hydroxychloroquine, chloroquine): will be allowed as concomitant 
medications in this study. If discontinued, they must be discontinued for 4 weeks prior to the 
first dose of study drug. If continued throughout the study through Week 12, the dose must 
be stable for at least 8 weeks prior to first dose of study drug.

Chronic NSAIDs/COX-2 inhibitors, opioids, and acetaminophen/paracetamol use may be 
allowed provided that the subject is on a stable prescription at least 4 weeks prior to Baseline. 
Dosing should be maintained throughout the Screening period and through Week 12. If these 
medications are to be discontinued, they should be discontinued at least 1 week prior to the 
first dose of study drug.
NOTE: All analgesics (including chronic NSAIDs) should be held on the day of study 
visits,   until after all study procedures for that day have been completed.

Low dose oral corticosteroids: daily doses ≤ 10 mg of prednisone or equivalent per day are 
allowed, and should remain stable through the study through Week 12. During the OLE 
phase of the study, oral corticosteroids may be modified as judged clinically indicated by the 
investigator. However, the chronic daily dose should never exceed 10 mg/day of prednisone 
equivalent.
5.4.2.
Rescue Therapy
No RA rescue therapies are allowed through week 12 of the study including 
acetaminophen/paracetamol or opiods.  However, if the study investigator thinks a corticosteroid 
injection in a small joint (not one counted in DAS28) is medically indicated, the investigator 
should contact the medical monitor for approval prior to injection.  In the OLE, medications may 
be used as judged medically necessary by the study investigator or another physician treating the 
subject.


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5.4.3.
Disallowed Concomitant Medications
The disallowed DMARDs, Biologic Response Modifiers and Other Medications below require 
a drug-specific washout period prior to dosing of study drug as defined below. These 
medications are also not allowed at any time during the 12 week blinded phase of the study and 
the OLE phase unless otherwise specified:
DMARDs

Minocycline/doxycycline, penicillamine, and sulfasalazine: must have been discontinued 
for 4 weeks prior to the first dose of study drug. 

Leflunomide (Arava®) must have been discontinued 12 weeks prior to the first dose of
study drug or at least 4 weeks if an appropriate washout method is utilized using either 
cholestyramine or activated charcoal.

Auranofin (Ridaura®), injectable gold (aurothiglucose or aurothiomalate): must have been 
discontinued for 4 weeks prior to first dose of study drug

Tofacitinib (Jeljanz®), a Janus kinase inhibitor (Jak inhibitor): must have been discontinued 
for 4 weeks prior to the first dose of study drug. Any other marketed Jak inhibitor for RA 
must also be discontinued for 4 weeks prior to the first dose of study drug.
Biologic Response Modifiers
All must be discontinued for entry into this study and are prohibited while the subject is 
receiving study drug:

All other TNF inhibitors except the TNF inhibitor being administered during 
Screening: Discontinued for at least 12 weeks prior to the first dose of study drug;

Abatacept (Orencia®), anakinra (Kineret®), tocilizumab (Actemra®): Discontinued for 
12 weeks prior to first dose of study drug; other bDMARDS should be discussed with the 
Sponsor.

Rituximab or other selective B lymphocyte depleting agents (either marketed or
investigational): Discontinued for 6 months prior to the first dose of study drug. 
Other Medications

Intramuscular, or intravenous corticosteroids: None may be administered within 30 days
prior to first dose of study drug. In addition, intravenous or intramuscular corticosteroids are 
not allowed during this study either as a stable concomitant medication or as rescue 
medication. However, in the OLE these medications may be used as judged medically 
necessary by the study investigator or another physician treating the subject.


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
Intra-articular injections: Intra-articular injections during the blinded phase of the study 
are discouraged. However, if the study investigator thinks a corticosteroid injection in a small 
joint (one not counted in DAS28) is medically indicated, the investigator should contact the 
medical monitor for approval prior to the injection. 
In the OLE (after the Week 12 visit has been completed) a maximum of 80 mg 
methylprednisolone or equivalent of intra-articular corticosteroids will be allowed as rescue 
medication after the Week 12 visit has been completed. This total allowed intra-articular 
corticosteroid dose may be divided into separate injections.
Also in the OLE (after the Week 12 visit has been completed), intra-articular hyaluronate 
sodium injections may be administered for indications in accordance with the local label in 
no more than 2 joints in any 6 month study period. 
Any injected joints will be classified as having their pre-injection status (tender/painful and 
swollen joint count) for the remainder of the study.

Cyclosporine, tacrolimus or other calcineurin inhibitors, azathioprine, mycophenolate:
All must be discontinued 4 weeks prior to the first dose of study drug and are prohibited 
while the subject is receiving study drug (including the OLE).

Alkylating agents:  Any prior treatments ever with these agents (eg chlorambucil or 
cyclophophsamide) is exclusionary and are prohibited while the subject is receiving study 
drug (including during the OLE).

Prosorba Device/Column: This must be discontinued 4 weeks prior to the first dose of study 
drug.

Experimental NSAIDS (including Cox-2 inhibitors): These must be discontinued 4 weeks 
prior to the first dose of study drug.

Any investigational treatment not mentioned elsewhere must be discontinued for 4 weeks 
for small molecules, 3 months for biologics or 5 half -lives, whichever is longer and are 
prohibited while the subject is receiving study drug (including during the OLE). Prior
exposure to investigational biologics should be discussed with the Sponsor.
5.5.
Accountability for Study Drug
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug. This includes acknowledgement of receipt of each shipment of study drug (quantity and 
condition). All used and unused study drug dispensed to subjects must be returned to the site.


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Study drug accountability records will be provided to each study site to:

Record the date received and quantity of study drug kits

Record the date, subject number, subject initials, the study drug kit number dispensed

Record the date, quantity of used and unused study drug returned, along with the initials of 
the person recording the information.
5.5.1.
Investigational Medicinal Product Return or Disposal
Study drug return and disposal will be performed as outlined in Section 9.1.7


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. Additional information is 
provided in the study procedures manual.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that subjects are eligible to participate in the
study prior to randomization or enrollment and throughout the study.
Once 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.
The study center will not be released to initiate dosing until:

The Institutional Review Board (IRB) or Ethics Committee (EC) reviewed and approved the
study and the informed consent document;

All required regulatory documents have been submitted to and approved by Gilead or the
CRO;

A master services agreement and/or study agreement is executed;

The site initiation meeting has been conducted by the Gilead clinical monitor (or designee).
The initiation meeting will include a review of the protocol, the IB, and investigator
responsibilities.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit (Day -35 to Day 1)
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 35 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.
Subjects who do not meet the eligibility criteria will be excluded from randomization and may be 
considered for rescreening one time for the study in consultation with the Sponsor or its designee


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Screening Assessments will include confirmation of RA diagnosis; medical history; vital signs 
(VS) to include blood pressure, pulse, respirations, temperature, and weight; height; complete 
physical exam (CPE); 12 lead ECG; and central laboratory tests including Rheumatoid Factor, 
anti-CCP, hematology, urinalysis, chemistry panel, serum ß-HCG (women of childbearing 
potential), QuantiFERON –Gold (QFT), HIV Serology, HBsAg, HCVAb, c-Reactive Protein, 
Estimated Glomerular Filtration Rate (based on MDRD study equation), TSH and HbA1c and flow 
cytometry for subjects who have been on rituximab.  Also included are 66 swollen and 68 tender 
joint count assessment, Patient and Provider Global Health Assessment, and Patient Assessment 
of Pain.
RA disease activity will be determined by DAS28-CRP for inclusion criteria and for 
randomization stratification purposes upon study entry.

Record any serious adverse events (SAEs) and all AEs related to protocol mandated 
procedures occurring after signing of the consent form.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 35 days 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 adverse events related to protocol-mandated 
procedures on the adverse events case report form (CRF/eCRF).  All other untoward medical 
occurrences observed during the screening period, including exacerbation or changes in medical 
history are to be captured on the medical history CRF/eCRF.  See Section 7 Adverse Events and 
Toxicity Management for additional details.
6.2.2.
Baseline/Randomization Assessments (Day 1)
Subjects who met the eligibility criteria will undergo the evaluations listed in Appendix 2.
Day 1 evaluations will include the following: Review of AEs and concomitant medications, VS, 
targeted physical exam, urine pregnancy test safety laboratory examinations (hematology, 
urinalysis, chemistry panel), CRP, Erythrocyte Sedimentation Rate (ESR) local by the
Westergren method, GS-5745 anti-drug antibodies (ADA) blood draw, biomarker blood draws, 
study drug administration, tender and swollen joint counts, patient global assessment of pain,  
provider assessment of global disease activity, patient global assessment of disease activity,
SF-36, Health Assessment Questionnaire (HAD-QI), and optional collection of blood for DNA 
analysis (genomic testing).
All Day 1 procedures and assessments must be completed prior to randomization and study drug 
administration.
6.3.
Blinded Treatment Assessments (Week 1 through Week 12)
All visit tests and procedures should be completed as indicated in Appendix 2.  Joint counts, 
patient global assessment of pain, physical assessment of global disease activity, subjects 
assessment of physical function, SF-36, HAD-QI should be administered prior to lab draws and 
study drug administration as much as possible.


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On-Treatment Assessments 
• 
Concomitant medications 
• 
Vital signs 
• 
CPE at Week 12 
• 
Targeted Physical exam (TPE) 
• 
12 leadECG 
Final 
Amendment 1 
• 
Safety blood draws: Hematology, urinalysis, chemistry panel (in the blinded phase Study 
Day 1, Weeks 1, 4, 12, and the 30-day safety follow-up 
• 
Semm ~HCG (30-day follow-up only), and urine pregnancy (Day 1 and every 4 weeks) 
• 
In the blinded phase questionnaires and disease activity measures will be administered at 
Day 1, Weeks 1, 2, 4, 8 and 12 and hsCRP will be collected 
Pharmacokinetics: 
PK blood draws: PK blood draws will be done prior to dosing at Weeks 1, 4 and 8, anytime on 
Week 12 and at ESDD (if applicable) 
GS-5745 Anti-Drng Antibodies (ADA}: Blood draws for ADAs will be done prior to dosing on 
Study Days 1Day 1, Weeks 4 and 8, anytime at Week 12 and the 30-day follow-up visit of the 
blinded phase. Blood draws for ADAs will be done prior to dosing at Week 24, anytime at 
Week 64, and anytime during the 30-day follow-up visit of the OLE. 
Biomarker Blood Draws: Blood biomarkers will be collected at Day 1, Weeks 4 and 12 in the 
blinded phase of the study. In the OLE biomarker samples will be collected eve1y 3 months 
stmiing at week 24. 
Optional PK Sub-study: PPD 
[ 
I 
~------------------------------~ 
Genomic Testing 
Qlltional Genomic Testin : PPD 
Description of Selected Assessments 
Physical Exam 
A CPE is required at Screening, Week 12 of the blinded phase, and Week 64) of the OLE phase. 
A TPE will be perf01med at other study visits. A limited physical exam is defined as an 
examination driven by subject signs/symptoms and/or adverse events. Height is captured at 
screening only. 
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Vital Signs
Vital signs to be collected include resting blood pressure, pulse, respiratory rate, weight, and 
temperature.
SF-36 Health Survey
The SF-36 is a health related quality of life instrument consisting of 36 questions belonging to 
8 domains in 2 components and covers a 4-week recall period:

physical well-being: 4 domains: physical functioning (10 items), role physical (4 items), 
bodily pain (2 items), and general health perceptions (5 items)

mental well-being: 4 domains: vitality (4 items), social functioning (2 items), role emotional 
(3 items), and mental health (5 items).
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 visual analog scale (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).
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.
Simplified Disease Activity Index
The Simplified Disease Activity Index (SDAI) is the numerical sum of five outcome parameters: 
tender and swollen joint count (based on a 28-joint assessment), patient and physician global 
assessment of disease activity [visual analogue scale (VAS) 0-10 cm] and level of C-reactive 
protein (mg/dl).


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Clinical Disease Activity Index
Clinical Disease Activity Index (CDAI) is a composite index (without acute-phase reactant) for 
assessing disease activity. CDAI is based on the simple summation of the count of 
swollen/tender joint count of 28 joints along with patient and physician global assessment on 
VAS (0–10 cm) Scale for estimating disease activity
6.3.1.
30-Day Follow-up Visit
Subjects not willing and not eligible to participate in the OLE phase will return to the clinic for a 
follow-up visit 30 days after the Week 12 study visit in the blinded phase. Procedures should be 
completed as indicated in Appendix 2.
6.4.
Open Label Extension Assessments (Week 12 through Week 64)
All OLE test and procedures should be completed as indicated in Appendix 2.  All tests and 
procedures in Week 12 of the blinded phase must be completed prior to beginning study drug 
dosing the OLE phase.
On-Treatment Assessments

Concomitant medications

Vital signs

CPE Week 64 only

Targeted Physical exam (TPE)

12 lead ECG  at Week 64 only

Safety blood draws: Every 12 weeks, Week 64 and at the 30-day follow-up visit

Serum βHCG (30-day follow-up only), and urine pregnancy (every 4 weeks) 
In the OLE phase disease specific questionnaires and activity scores will be administered every 
12 weeks, Week 64 and at the 30-day safety follow-up visit.
Pharmacokinetics:
PK blood draws: PK blood draws will be done prior to dosing at Week 24 and anytime at 
Week 64.
GS-5745 Anti-Drug Antibodies: Blood draws for ADAs will be done prior to dosing at Week 24,
anytime at Week 64, and anytime during the 30-day follow-up visit.
Biomarker Blood Draws:  Blood biomarkers will be collected every 3 months starting at 
Week 24. 


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Additional on-treatment assessments will include symptom-driven physical examination, and 
disease-specific questionnaires and activity scores will be administered every 12 weeks, and at 
the end of the 30-day follow-up visit in the OLE.
6.4.1.
Open Label Extension 30-day Follow-up Visit
Thirty days after the Week 64 study visit, subjects will return to the clinic for a follow-up visit.
Procedures should be completed as indicated in Appendix 2.
6.5.
Assessments for Premature Discontinuation from Study
If a subject discontinues study dosing (for example, as a result of an AE or needed for prohibited 
medication), every attempt should be made to keep the subject in the study and continue to 
perform the required study-related follow-up and procedures (see Section 6.6, Criteria for 
Discontinuation of Study Treatment) as long as it is medically appropriate for the subjects to 
continue. If this is not possible or acceptable to the subject or investigator, the subject may be 
withdrawn from the study and will be asked to return for the Early Study Drug Discontinuation 
(ESDD) visit. These subjects will not be eligible for the OLE phase of the study
6.6.
Criteria for Subject Temporary Interruption of Study Treatment
Study medication may be temporarily interrupted in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator in consultation with the 
Medical Monitor.

A request by the investigator that is reviewed and approved by the Medical Monitor.
6.7.
Criteria for Subject Discontinuation of Study
The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. Study medication may be discontinued in the following instances

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree or medical conditions that were exclusionary based on 
the protocol exclusion criteria (Section 4.3). 

Unacceptable toxicity or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest

Subject requests to discontinue for any reason

Subject noncompliance


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
Pregnancy during the study; refer to Appendix 5

Discontinuation of the study at the request of Gilead, a regulatory agency or IRB/IEC

The medical need to initiate a chronic dosing regimen of a prohibited immunosuppressive 
agent or increase the chronic dose of prednisone to >10 mg/day to treat worsening RA or 
another medical condition prior to completion of Week 12 study visit

Use of intravenous or intramuscular corticosteroids during the study prior to completion of 
Week 12 study visit

Use of RA rescue acetaminophen/paracetamol or opiods prior to completion of the Week 12 
study visit.
6.8.
End of Study
The end of this study is defined as 30 days after the last subject has completed the final visit in 
the OLE phase and 30 days of follow-up.


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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, 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 7.7.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
7.1.2.
Serious Adverse Events
A SAE is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)


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
In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.2.1.
Protocol-Specific Adverse Event Instructions
Anaphylaxis is a rare event that may occur after subcutaneous injections of monoclonal 
antibodies already approved for clinical use or those in clinical development such as such as 
GS-5745. In an effort to standardize the collection of adverse events that may comprise an 
anaphylactic event, in this study the definition developed by the National Institute of Allergy and 
Infectious Disease (NIAID)/Food Allergy and Anaphylaxis Network (FAAN) symposium will be 
utilized.  Information reported by subjects regarding adverse events associated with the study 
drug will be collected and reviewed; the event causality will be assessed by the study 
investigator. If any of the AEs reported by the subject fulfill either Criteria 1 or Criteria 2 of the 
NIAID/FAAN definition of anaphylaxis (See Appendix 11) the event will be classified as 
anaphylaxis by the site investigator.  The event will be considered medically significant and will 
be reported as an AE or SAE according to guidance in section 7.3. The medical monitor will be 
notified immediately. The subject may resume the study dosing in the discretion of investigator 
in consultation with the medical monitor for review and confirmation. 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 and 7.6


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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 that is more likely 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.
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 of AEs will be graded using the CTCAE, version 4.03.  For each episode, the 
highest grade attained should be reported.
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: Grade 1 
(mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening) or Grade 5 (fatal) to 
describe the maximum intensity of the adverse event.  For purposes of consistency with the 
CTCAE, these intensity grades are defined in Appendix 4.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.


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Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 55-days after last administration of GS-5745must be reported to the CRF/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.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 55-days or of 
the last dose of study GS-5745, 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 GS-5745, he/she should promptly document and 
report the event to Gilead DSPH.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.

At the time of study start, SAEs may be reported using a paper serious adverse event 
reporting form. During the study conduct, sites may transition to an electronic SAE (eSAE) 
system. Gilead will notify sites in writing and provide training and account information prior 
to implementing an eSAE system.
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by faxing
or emailing the report form within 24 hours of the investigator’s knowledge of the event to 
the attention of Gilead DSPH.
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.


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
If for any reason it is not possible to record the SAE information electronically, i.e., the 
eCRF database is not functioning, record the SAE on the paper serious adverse event 
reporting form and submit within 24 hours as described above.

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. 
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 :
Fax:
1-650-522-5477 
E-mail: Safety_fc@gilead.com or 

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
form.


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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 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the 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 or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., clinical chemistry, hematology, 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 (e.g., 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 (i.e., anemia) not 
the laboratory result (i.e., decreased hemoglobin).
Adverse events will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Severity should be recorded and graded according to the 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, which can be 
found at:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf
For adverse events associated with laboratory abnormalities, the event should be graded on the 
basis of the clinical severity in the context of the underlying conditions; this may or may not be 
in agreement with the grading of the laboratory abnormality.
7.6.
Toxicity Management 

All clinical and clinically significant laboratory toxicities will be managed according to 
uniform guidelines detailed in Appendix 3. 


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
Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat
testing within 3 calendar days of receipt of results and before investigational medicinal 
product discontinuation, unless such a delay is not consistent with good medical practice.

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, which can be 
found at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf

When restarting investigational medicinal product following resolution of the adverse event, 
the investigational medicinal product should be restarted at full dose or modified dose that is 
dependent upon discussion with the Gilead Sciences Medical Monitor.

Any recurrence of the investigational medicinal product-related Grade 3 or 4 clinical or 
clinically significant laboratory adverse event following dose interruption mandates 
permanent discontinuation of investigational medicinal product.

Any questions regarding toxicity management should be directed to the Gilead Sciences 
Medical Monitor.
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event

Continue investigational medicinal product at the discretion of the investigator.
7.6.2.
Grades 3 Laboratory Abnormality or Clinical Event

For Grade 3 clinically significant laboratory abnormality or clinical event, investigational 
medicinal product may be continued if the event is considered to be unrelated to 
investigational medicinal product.

For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to investigational medicinal product, 
investigational medicinal product should be withheld until the toxicity returns to ≤Grade 2.

If a laboratory abnormality recurs to ≥Grade 3 following re-challenge with investigational 
medicinal product and is considered related to investigational medicinal product, then 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. Recurrence of laboratory abnormalities considered 
unrelated to investigational medicinal product may not require permanent discontinuation.
7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event

For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing that is considered related to investigational medicinal product, 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. The subject should be followed as clinically indicated 


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until the laboratory abnormality returns to Baseline or is otherwise explained, whichever 
occurs first. A clinically significant Grade 4 laboratory abnormality that is not confirmed by 
repeat testing should be managed according to the algorithm for the new toxicity grade.
Investigational medicinal product may be continued without dose interruption for a clinically 
non-significant Grade 4 laboratory abnormality (e.g., Grade 4 CK after strenuous exercise or 
triglyceride elevation that is non-fasting or that can be medically managed) or a clinical event 
considered unrelated to investigational medicinal product.
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, occupational exposure with an AE 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.  
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 CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting.


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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 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH 
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead DSPH. Gilead DSPH contact information is as follows: 
Email: 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
should 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 pregnant partner 
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. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
Final 
Amendment 1 
The prima1y objective of the study is to assess the efficacy of GS-57 45 versus placebo as an 
add-on therapy to a TNF inhibitor and methotrexate in subjects with moderate to severe 
rheumatoid ruthritis (RA) 
The secondruy objectives ofthis study ru·e as follows: 
• 
To assess the safety and tolerability of GS-5745 versus placebo as an add-on therapy with a 
TNF inhibitor and methotrexate in subjects with moderate to severe RA 
• 
To assess the phrumacokinetics (PK) of GS-57 45 as an add-on therapy with a TNF inhibitor 
and methotrexate in subjects with moderate to severe RA 
The explorat01y objectives of the study are as follows: 
PPO 
8.1.2. 
Primary Endpoint 
The prima1y endpoint is change from Baseline in DAS28 - CRP at Week 12. 
8.1.3. 
Secondary Endpoints 
Secondruy endpoints ru·e: 
• 
Proportion of subjects that achieve low disease activity (DAS28- CRP ~ 3.2) at Week 12 
• 
Prop01tion of subjects that achieve remission (DAS28-CRP < 2.6) at Week 12 
• 
Plasma concentrations of GS-5745 
8.1.4. 
Exploratory Endpoints 
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8.2. 
8.2.1. 
8.2.1.1. 
Analysis Conventions 
Analysis Sets 
Full Analysis Set (F AS) 
Final 
Amendment 1 
The prima1y analysis set for efficacy analyses will be the F AS, which includes all randomized 
subjects who received at least one dose of study dmg. 
8.2.1.2. 
Safety Analysis Set 
The prima1y analysis set for safety analyses will be the Safety Analysis Set which includes all 
subjects who received at least one dose of study dmg 
8.2.1.3. 
Phrumacokinetic (PK) Analysis Set 
The PK analysis sets includes all subjects in the safety Analysis Set who have the necessruy 
Day 1 and on-study measmements to provide inte1pretable results for the specific parameters of 
interest. 
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 occm prior to the first dose will be 
treated as 0, BLQ values at all other time points will be treated as 1/2 of the lower limit of 
quantitation (LLOQ). 
Laborat01y data that ru·e continuous in natme but ru·e 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 laborat01y 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 measmements will be summarized using standard descriptive 
methods by treatment group and overall. 
Baseline chru·acteristics may include prior use of bDMARD, DAS28-CRP, HAQ-DI, SDAI, 
CDAI, and other vru·iables of interest. 
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8.5.
Efficacy Analysis
The primary endpoint for the study is change in from Baseline in DAS28 - CRP at Week 12, 
which will be analyzed using a mixed model repeated measures (MMRM) approach that includes 
the fixed effects of treatment, visit, treatment by visit interaction, and Baseline value, and subject 
as a random effect.
Secondary endpoints include proportion of subjects that achieve (DAS28- CRP <  3.2) and 
proportion of subjects that achieve (DAS28- CRP <2.6) at Week 12. The response rates
between each of the 2 GS-5745 treated groups and the placebo group will be compared using a 
stratified Cochran-Mantel-Haenszel (CMH) Chi-square test adjusting for stratification factors in 
randomization.  The difference in response rates between treatment groups and the 
corresponding 95% confidence intervals will be presented.
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 will be summarized by treatment group according to the study drug 
received.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration data. Exposure data will be summarized by treatment group.
8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database. Treatment-Emergent Adverse Events (TEAEs) are:

Any AEs with an onset date of on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug or

any AEs leading to premature discontinuation of study drug.


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Summaries (number and percentage of subjects) of TEAEs by SOC and PT will be provided by 
treatment group. TEAEs will also be summarized by relationship to study drug and severity. In 
addition, TEAEs leading to premature discontinuation of study drug 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 and study visit along with corresponding change from Baseline. 
The incidence of treatment-emergent graded laboratory abnormalities will be summarized 
similarly. Graded laboratory abnormalities will be defined using CTCAE 4.03 grading scale
8.7.
Pharmacokinetic Analysis
The plasma concentration data of GS-5745will be summarized by nominal sampling time using 
descriptive statistics (eg, sample size, arithmetic mean, geometric mean, coefficient of variation 
(%) standard deviation, median, minimum, and maximum). PK parameters (Cmax, Tmax, Clast, Tlast, 
AUClast, as applicable) for optional PK sub-study may be listed and summarized using 
descriptive statistics.
Exposure-response analysis may be explored as appropriate.
8.8.
Immunogenicity Analysis
Immunogenicity of GS-5745 will be evaluated based upon the incidence of anti-drug (GS-5745) 
antibody (ADA) formation. The number and percentage of subjects exhibiting positive ADA 
results at each specified time point will be summarized. ADA results with supporting data will be 
included in a listing as well. Impact of ADA on GS-5745 PK, safety, and efficacy may be 
evaluated as applicable.
8.9.
Sample Size
A total sample size of 75 subjects will be required for this study. Each of the 2 GS-5745 treated 
groups will be compared to the placebo group. A sample size of 25 per group will provide a 
power of 80% with a two-sided α level of 0.05 to detect a Minimal Clinically Important 
Improvement (MCII) in DAS28-CRP change from Baseline of 1.2 at Week 12 between a 
GS-5745 treated group and the placebo group, assuming a common standard deviation of 1.35
and 15% early dropout rate.  
8.10.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim unblinded reviews of safety data at designated scheduled intervals and
provide recommendation to Gilead whether the nature, frequency, and severity of adverse effects 
associated with study treatment warrant the early termination of the study in the best interests of 
the participants, whether the study should continue as planned, or the study should continue with 
modifications. The DMC may also provide recommendations as needed regarding study design, 


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The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, 
part 50, 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/EC. The investigator will not begin any study subject activities until 
approval from the IRB/EC has been documented and provided as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/EC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB- or IEC-approved consent form for documenting 


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written informed consent. Each informed consent will be appropriately signed and dated by the 
subject  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 
pharmacogenomic testing and sample retention, and their right to receive clinically relevant 
pharmacogenomic 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, CRF/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, CRF 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);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);


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
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 study drug 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. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data.  The Eligibility Criteria eCRF should be completed only after all data related to 


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eligibility have been received.  Subsequent to data entry, a study monitor will perform source 
data verification within the EDC system. Original entries as well as any changes to data fields 
will be stored in the audit trail of the system.  Prior to database lock (or any interim time points 
as described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 
the information in the source documents. The eCRF capture the data required per the protocol 
schedule of events and procedures. System-generated or manual queries will be issued to the 
investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, 
who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (e.g. data entry error). At the conclusion of the trial, Gilead will provide the site 
with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead QA, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. 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, or to regulatory authority or health authority inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.


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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB [or] 
IEC in accordance with local requirements and receive documented IRB [or] 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 the regulatory agency. Gilead will 
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content 
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases.
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 
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, e.g. 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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Gilead Sciences, Inc. 
Amendment 1
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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 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both 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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Gilead Sciences, Inc. 
Amendment 1
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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.
Ali T, Kaitha S, Mahmood S, Ftesi A, Stone J, Bronze MS. Clinical use of anti-TNF therapy and 
increased risk of infections. Drug, healthcare and patient safety 2013;5:79-99.
Arthritis Foundation. Rheumatoid Arthritis Fact Sheet.  2008.
Engsig MT, Chen QJ, Vu TH, Pedersen AC, Therkidsen B, Lund LR, et al. Matrix 
metalloproteinase 9 and vascular endothelial growth factor are essential for 
osteoclast recruitment into developing long bones. J Cell Biol 2000;151 (4):879-
89.
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.
Gearing AJ, Beckett P, Christodoulou M, Churchill M, Clements JM, Crimmin M, et al. Matrix 
metalloproteinases and processing of pro-TNF-alpha. J Leukoc Biol 1995;57 
(5):774-7.
Genovese MC, Cohen S, Moreland L, Lium D, Robbins S, Newmark R, et al. Combination 
therapy with etanercept and anakinra in the treatment of patients with rheumatoid 
arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 
2004;50 (5):1412-9.
Greenwald MW, Shergy WJ, Kaine JL, Sweetser MT, Gilder K, Linnik MD. Evaluation of the 
safety of rituximab in combination with a tumor necrosis factor inhibitor and 
methotrexate in patients with active rheumatoid arthritis: results from a 
randomized controlled trial. Arthritis Rheum 2011;63 (3):622-32.
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.
Itoh T, Matsuda H, Tanioka M, Kuwabara K, Itohara S, Suzuki R. The role of matrix 
metalloproteinase-2 and matrix metalloproteinase-9 in antibody-induced arthritis. 
J Immunol 2002;169 (5):2643-7.


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Amendment 1
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Lawrence RC, Helmick CG, Arnett FC, Deyo RA, Felson DT, Giannini EH, et al. Estimates of 
the prevalence of arthritis and selected musculoskeletal disorders in the United 
States. Arthritis Rheum 1998;41 (5):778-99.
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.
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary 
report--Second National Institute of Allergy and Infectious Disease/Food Allergy 
and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117 (2):391-
7.
Tsuboi H, Matsui Y, Hayashida K, Yamane S, Maeda-Tanimura M, Nampei A, et al. Tartrate 
resistant acid phosphatase (TRAP) positive cells in rheumatoid synovium may 
induce the destruction of articular cartilage. Annals of the rheumatic diseases 
2003;62 (3):196-203.
Weinblatt M, Combe B, Covucci A, Aranda R, Becker JC, Keystone E. Safety of the selective 
costimulation modulator abatacept in rheumatoid arthritis patients receiving 
background biologic and nonbiologic disease-modifying antirheumatic drugs: A 
one-year randomized, placebo-controlled study. Arthritis Rheum 2006;54 
(9):2807-16.


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Amendment 1
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Visit Schedule
Appendix 3.
Management of Clinical and Laboratory Adverse Events
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.
American College of Rheumatology:  1991 Revised Criteria for the Classification of 
Global Functional Status of Rheumatoid Arthritis*
Appendix 7.
The 2010 American College of Rheumatology –European League Against 
Rheumatism Collaborative Initiative Classification Criteria for Rheumatoid 
Arthritis {Aletaha et al 2010}
Appendix 8.
American College of Rheumatology Response (ACR 20/50/70): {Felson et al 1995}
Appendix 9.
Disease Activity Score DAS28 CRP {Prevoo et al 1995}
Appendix 10.
Frederica’s Formula and Estimated Glomerular Filtration
Appendix 11.
Clinical criteria for diagnosing anaphylaxis modified from the NIAID/FAAN 
Criteria


GS-5745 
Protocol GS-US-373-1499 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY CA 94404 
STUDY ACKNOWLEDGEMENT 
Final 
Amendment I 
Evaluation of the Efficacy and Safety ofOS-5745 as Add-On Therapy to a Tumor Necrosis 
Factor Inhibitor and Methotrexate Regimen in Subjects with Moderate to Severe Rheumatoid 
Arthritis 
GS-US-373-l499 Protocol Amendment 1 (24 June 2016) 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Name (Printed) 
David Gossage, MD 
Date 
PPD 
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 
CONFLDENTIAL 
Page 71 
24June2016 


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Amendment 1
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24 June 2016
Appendix 2.
Study Visit Schedule
Blinded Phase Study Visits
Weeka
Screeningb
Day 1
1
4
8
12o
ESDDd
Unscheduled Visit
30 Day 
Follow-up
Window in Days
-35 days
0
3
3
3
3
Written Informed Consent c
X
Confirmation of RA dx
X
Medical History 
X
Complete Physical Exam
X
X
X
Targeted Physical Exam e
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
Vital Signs & Weight f
X
X
X
X
X
X
X
X
X
Height
X
Adverse Events
X
X
X
X
X
X
X
X
X
12 lead ECG-performed supine
X
X
Hs C-Reactive Protein (hsCRP) 
X
X
X
X
X
X
X
X
X
Serum  ß-HCG Pregnancy Test g
X
X
X
Urine Pregnancy test g
X
X
X
X
X
Rheumatoid Factor 
X
Anti-CCP
X
QuantiFERON-Gold (QFT)
X
HIV Serology, HBsAg, HCVab
X
Estimated Glomerular Filtration Rate 
(based on MDRD study equation)
X
X
X


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Gilead Sciences, Inc. 
Amendment 1
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Blinded Phase Study Visits
Weeka
Screeningb
Day 1
1
4
8
12o
ESDDd
Unscheduled Visit
30 Day 
Follow-up
Window in Days
-35 days
0
3
3
3
3
Erythrocyte Sedimentation Rate 
(ESR) Local  Lab 
X
X
X
Hematology h
X
X
X
X
X
X
X
X
Chemistry i
X
X
X
X
X
X
Per Investigator 
Discretion 
X
Urinalysis
X
X
X
X
X
X
X
X
66 swollen and 68 tender joint count 
assessment
X
X
X
X
X
X
X
Per Investigator 
Discretion
X
Thyroid Stimulating Hormone (TSH)
X
Glycated Hemoglobin (HbA1c )
X
CD19 Flow cytometry (patients who 
have been on rituxan only)
X
Patient and Provider Global 
Assessment of Health
X
X
X
X
X
X
X
Per Investigator 
Discretion
X
Patient Assessment of Pain
X
X
X
X
X
X
X
Per Investigator 
Discretion
X
Health Assessment Questionnaire 
Disability Index (HAQ-DI)
X
X
X
X
X
X
X
Short Form (36) Health  Survey 
(SF-36)
X
X
X
X
X
X
X
Pharmacokinetics (PK) j
X
X
X
X
X
Optional PK Sub-Study (Day 4 or 
Day 6) k
GS-5745 ADA collection l
X
X
X
X
X
X


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Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 74
24 June 2016
Blinded Phase Study Visits
Weeka
Screeningb
Day 1
1
4
8
12o
ESDDd
Unscheduled Visit
30 Day 
Follow-up
Window in Days
-35 days
0
3
3
3
3
Biomarkers
X
X
X
Optional genomic testing m
X
Randomize
X
Study Drug Administration n
NA
Study Drug Dispensing Visit p
X
X
X
X
a
All visits scheduled relative to day 1
b
Evaluations are to be completed within 35 days prior to Day 1. 
c
Consent must be signed prior to any study evaluations
d
Early Study Drug Discontinuation visit to occur within 72 hours of last dose of study drug 
e
Symptom-directed physical exam as needed 
f
Vital Signs include blood pressure, pulse, respirations, temperature 
g
Women of child-bearing potential only
h
Hematology: Complete blood count with differential and reticulocytes
i
Chemistry: Alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, serum creatinine
j
Prior to dose at Week 1,4,8, and anytime at week 12 and ESDD (if applicable) 
k
Anytime on Day 4 (+/-1) or Day 6 (+/- 1) after Day 1 dose (for subjects who consent to optional PK substudy only)
l
Prior to dose on Study Days 1 , Week 4,8 ,  anytime on Week 12 , and 30 day follow-up 
m
Collection of blood for DNA analysis will be optional for subjects and will be collected at Day 1 or at any other visit during the course of the study
n
Subjects will receive weekly injections of GS-5745SC Study Drug Administration will occur at the study site on study Day 1, Week 1, Week 4, and Week 8.Subjects will 
remain at the study site for 30 minutes after the injection for observation on Day 1 and Week 1 After receiving SC instruction at the study site during the first 2 drug SC 
injections, subjects judged capable will be allowed to self-administer weekly SC injections at home. SC Study drug administration and TNF inhibitor administration must be 
separated in time by at least 24 hours in the blinded and OLE phase of the study. Subjects not eligible or choosing not to participate in the OLE will come in for Week 12 visit 
assessments will not be administered study drug. Subjects that are eligible and choose to participate in the OLE will receive their first dose of study drug in the OLE phase of 
the study on Week 12 after completing all the requirements of Week 12 of the blinded phase of the study.  
o
Subjects not participating in the OLE will complete all week 12 assessments but will not receive an injection of study drug. If subjects are eligible to participate in the OLE, 
then subjects complete all Week 12 assessments for the blinded phase and then receive the first dose of the drug for OLE.
p
Study drug for 4 weekly doses will be dispensed at Weeks 1, 4 and 8    


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Amendment 1
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Open Label Extension Phase Study Visits
Week
12
13
19
24
30
36
42
48
54
60
64
30 FU
Unscheduled 
Visit
ESDD
Window in Days
3
5
5
5
5
5
5
5
5
5
Complete physical exam
X
X
Vital signs and  weight a
X
X
X
X
X
X
X
X
12 lead ECG
X
Targeted physical exam b   
X
X
X
X
X
X
X
66 swollen and 68 tender joint count 
assessment
X
X
X
X
X
X
Per Investigator 
Discretion
X
Patient and Physician Global 
assessment of Health
X
X
X
X
X
X
Per Investigator 
Discretion
X
HAQ-DI
X
X
X
X
X
X
Per Investigator 
Discretion
X
SF-36
X
X
X
X
X
X
Per Investigator 
Discretion
X
Hematology c
X
X
X
X
X
X
X
X
Chemistry panel c
X
X
X
X
X
X
Per Investigator 
Discretion
X
Urinalysis
X
X
X
X
X
X
X
Erythrocyte Sedimentation Rate (ESR) 
Local lab
X
X
X
X
X
X
X
serum  ß-HCG Pregnancy Test d
X
X
Urine Pregnancy – every 4 weeks 
Home kit testd 
PK collection e
X
X
X
GS-5745 ADA collection f
X
X
X
X


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Protocol GS-US-373-1499
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 76
24 June 2016
Open Label Extension Phase Study Visits
Week
12
13
19
24
30
36
42
48
54
60
64
30 FU
Unscheduled 
Visit
ESDD
Window in Days
3
5
5
5
5
5
5
5
5
5
Biomarker collection 
X
X
X
X
X
X
X
C-Reactive Protein
X
X
X
X
X
X
X
X
Study Drug Dispensing Visit g
X
X
X
X
X
X
X
X
X
X
X
Study Drug Administration h
Concomitant medications i
X
Adverse Events i
a
Vital Signs include blood pressure, pulse, respirations, temperature 
b
Symptom-directed physical exam as needed 
c
Hematology: Complete blood count with differential and reticulocytes. Chemistry: Alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect bilirubin, total protein, 
albumin, bicarbonate, BUN, calcium, chloride, serum creatinine
d
Women of child bearing potential only. Patients will be supplied with home urine pregnancy kits and instructed to test every 4 weeks. Site will follow-up with a phone call. 
Pregnancy form should be completed should a pregnancy occur,
e
Prior to drug dose on  (Week 24) and anytime on  (Week 64)
f
Prior to study dose on  (Week 24) and any time on  (week 64) and the 30 day follow-up   
g
a 6 week supply of drug (6 doses)will be dispensed at these visits except for Week 12, 13  and week 64 when 1 dose will be dispensed. Site personel will administer study 
drug at office visits when drug is dispensed
h
Patients receive SC injections once a week SC Study drug administration will occur at the study site for the first 2 doses in the OLE phase at Week 12 and Week 13. Subjects 
will remain at the study site for 30 minutes after the injection for observation at week 12 and week 13. If subjects are judged capable, subjects may administer study drug at 
home for the remainder of the study. SC Study drug administration and anti-TNF administration must be separated in time by at least 24 hours in the blinded and OLE phase 
of the study. Subjects should record study drug administration in study drug diary
i
Con meds and adverse events will be recorded throughout the study. Patients will be questioned on con med and adverse events at in office visits


GS-5745 
Protocol GS-US-373-1499 
Final 
Gilead Sciences, Inc. 
Amendment 1 
Appendix 3. 
Management of Clinical and Laboratory Adverse Events 
Grade 1 
~----G-ra_d_e_2----~ 
~
~ _____ c_~_d_e_3----~~ ~
~ -------G-r-a-de-4------~ 
May continue 
Repeat lab to 
dosing at the 
con(U'm toxicity 
di~retion of the 
grade 
investigator 
If confirmed and possibly and/or probably related to 
investigational medicinal products: 
I. Withhold investigational medicinal products until 
S Grade2 
2. 
Restart all investie:ational medicinal nroduets at fu ll dose 
j 
If Grade 3 or 4 recurrence that is confirmed and possibly or 
probably related to investi.gational medicinal products, 
discontinue all investigational medicinal products dosing 
oermanentlv 
CONFIDENTIAL 
1 
lfc 
Repeat lab to 
confirm toxicity 
grade 
1 
onfirmed and unrelated to 
stigational medicinal 
inve 
pro 
the 
ducts, dosing may continue at 
discretion of the investigator 
If confirmed and 
possibly or probably 
--+ relatedto 
investigational 
medicinal products, 
discontinue 
investigational 
medicinal products 
dosing permanently 
and follow at 
periodic intervals at 
least weekly until a 
return to baseline or 
is otherwise 
explained 
If Grade 3 or 4 r~-cu rrencc that is considered unrelated to 
investigational medicinal products, continue all 
investigational medicinal products at the same dose at the 
discretion of the investigator 
Page 77 
24 Jrme 2016 


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Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 78
24 June 2016
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03
CTCAE v4.03 can be accessed from the below link:
http://www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-%20DMCC.pdf
CTCAE v4.03 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Mild; asymptomatic or 
mild symptoms; clinical or 
diagnostic observations 
only; intervention not
indicated.
Moderate; minimal, 
local or noninvasive 
intervention indicated;  
limiting age-
appropriate
instrumental ADL*.
Severe or medically 
significant but not 
immediately life-threatening;
hospitalization or 
prolongation of
hospitalization indicated; 
disabling; limiting self -care 
ADL**.
Life-threatening 
consequences; urgent 
intervention indicated.
Death related to 
AE.
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.


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Protocol GS-US-373-1499
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 79
24 June 2016
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.  In 
addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
The risks of treatment with GS-5745 during pregnancy have not been evaluated in humans. The 
potential for genotoxicity is not expected given that GS-5745 is a monoclonal antibody. In both 
the rat and rabbit definitive embryo-fetal developmental toxicity studies, there were no 
GS-5745-related effects on embryo-fetal survival and growth and no fetal anomalies. In a 
fertility study in male and female rats, no test article-related effects on reproductive performance 
and intrauterine survival were observed at any dosage level. In addition, male and female 
reproductive organ weights were unaffected by GS 5745 at all dose levels. There were no test 
article-related effects on spermatogenic endpoints at any dose level. The animal peri/post-natal 
study is ongoing. Women of childbearing potential should be informed of the potential risk and 
use highly effective methods of birth control during treatment with GS-5745 from screening until 
30 days after the end of relevant systemic exposure. A clinically relevant interaction between 
GS-5745 and contraceptive steroids is not expected because of their distinct metabolic pathways 
and therefore, hormonal contraception may be used as part of the birth control methods.
Please refer to the latest version of the investigator’s brochure of GS-5745 for additional 
information.


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Gilead Sciences, Inc. 
Amendment 1
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b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures.  They must have a negative serum pregnancy test at Screening and a 
negative pregnancy test on the Day 1 visit prior to randomization.  Pregnancy tests will be 
performed at monthly intervals thereafter. Female subjects must agree to one of the following 
from Screening until 30 days following the last dose of GS-5745.

Complete abstinence from intercourse. Abstinence is an acceptable method of contraception 
only when it is in line with the subject’s preferred and usual lifestyle. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception,
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 male partner (provided that the partner is the sole sexual partner and had 
confirmation of surgical success 3 months after procedure)
These above described methods are considered preferred methods of highly effective 
contraception in this protocol.
Female subjects who wish to use a hormonally based method must use it in conjunction with a
barrier method used either by the female subject or by her male partner. Female subjects who
utilize a hormonal contraceptive as one of their birth control methods must have consistently
used the same method for at least 3 months prior to study dosing. Hormonally-based
contraceptives and barrier methods permitted for use in this protocol are as follows:

Hormonal methods (each method must be used with a barrier method, preferably a male
condom)
Oral contraceptives (either combined estrogen/progestin or progesterone only)
Injectable progesterone
Implants of levonorgestrel
Transdermal contraceptive patch
Contraceptive vaginal ring


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
Barrier methods (each method must be used with a hormonal method)
Male or female condom with or without spermicide
Diaphragm with spermicide
Cervical cap with spermicide
Sponge with spermicide
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 GS-5745.
3) Contraception Requirements for Male Subjects

All male study participants must agree to consistently and correctly use a condom from 
Baseline until 90 days after the last dose of study drug. Female partners of male study 
subjects should consider using one of the above methods of contraception as well.

Male subjects must agree to refrain from sperm donation for 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 (90 days for partners male subjects) of last 
study drug dose. Subjects who become pregnant or who suspect that they are pregnant during the 
study must report the information to the investigator and discontinue study drug immediately. 
Subjects whose partner has become pregnant or suspects she is pregnant during the study must 
report the information to the investigator.  Instructions for reporting pregnancy, partner 
pregnancy, and pregnancy outcome are outlined in Section 7.7.2.1


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Appendix 6.
American College of Rheumatology:  1991 Revised Criteria for the 
Classification of Global Functional Status of Rheumatoid Arthritis*
Criterion
Definition
Class I
Completely able to perform usual activities of daily living (self-care, 
vocational, and avocational)
Class II
Able to perform usual self-care and vocational activities, but limited in 
avocational activities
Class III
Able to perform usual self-care activities, but limited in vocational and 
avocational activities
Class IV
Limited in ability to perform usual self-care, vocational, and avocational 
activities
*
Usual self-care activities include dressing, feeding, bathing, grooming and toileting. Avocational (recreational and/or 
leisure) and vocational (work, school, homemaking) activities are patient-desired and age and sex specific


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Appendix 7.
The 2010 American College of Rheumatology –European League 
Against Rheumatism Collaborative Initiative Classification Criteria 
for Rheumatoid Arthritis {Aletaha et al 2010}
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).
h
Negative refers to IU values that are less than or equal to the upper limit of normal (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 (e.g., pain, swelling, 
tenderness) of joints that are clinically involved at the time of assessment, regardless of treatment status.


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Appendix 8.
American College of Rheumatology Response (ACR 20/50/70): {Felson 
et al 1995}
ACR Criteria used to assess treatment response levels, reported as % improvement from 
Baseline.  The definition of ACR 20/50/70 is 20/50/70% improvement in tender and swollen 
joints plus a ≥20/50/70 % improvement in at least three of the following five parameters:

Subject assessment of  pain 

Subject Assessment of global disease activity

Physician assessment of global disease activity

Subject’s assessment of physical function

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-non tender 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 will be used to assess the patient’s current level of pain using a 
Visual Analog Scale from 0-100 mm.
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


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4.
Patient’s global assessment of disease activity
A horizontal, visual analog scale 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 visual analog scale 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 9.
Disease Activity Score DAS28 CRP {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
CRP consists of a composite score of the following variables: tender joint count, swollen joint 
count, CRP, and patient global score. The following equation will be used to calculate the 
DAS28- CRP

DAS28-CRP = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP+1) + 0.014*GH + 0.96
o
TJC28 = number of joints tender out of 28
o
SJC28 = number of joints swollen out of 28
o
CRP = C-reactive protein
o
GH = 100 mm global health VAS recorded by the patient (patient’s global   
assessment of disease activity )
Place a mark on the line below to indicate how you assess your current arthritis disease 
activity:
No arthritis activity
Extremely active arthritis


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Appendix 10.
Frederica’s Formula and Estimated Glomerular Filtration
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) 
http://www.thecalculator.co/health/QTc-Calculator-385.html
Estimated Glomerular Filtration
Modification of Diet in Renal Disease (MDRD) formula.- Standardized Formula
175 x serum Creatinine (mg/dl) -1.154 x Age -0.203 x 1.212 (if Black) x 0.742 (if Female)


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Appendix 11.
Clinical criteria for diagnosing anaphylaxis modified from the 
NIAID/FAAN Criteria
Anaphylaxis is highly likely when any one of the following 2 criteria are fulfilled:
CRITERIA 1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING
a.
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], 
syncope, incontinence)
OR, 
CRITERIA 2. Two or more of the following that occur rapidly after exposure to a likely 
allergen for that patient (minutes to several hours):
a.
Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-
tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
c.
Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
Reference: {Sampson et al 2006}

Prot_000.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Study Director 
or Clinical Program 
Manager: 
Gilead Medical 
Monitor: 
Protocol Version/Date: 
(!') GILEAU 
CLINICAL STUDY PROTOCOL 
Evaluation ofthe Efficacy and Safety ofGS-5745 as Add-On 
Therapy to a Tumor Necrosis Factor Inhibitor and Methotrexate 
Regimen in Subjects with Moderate to Severe Rheumatoid Alihritis 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City CA 94404 
110523 
2016-000897-39 
TBD 
Rheumatoid Alihritis 
GS-US-373-1499 
Name: 
Telephone: 
Fax: 
Mobile: 
Name: 
Telephone: 
Fax: 
Mobile: 
Original 
PPD 
1-'1-'U 
PPD 
PPD 
David Gossage 
PPD 
PPD 
PPD 
14 March 2016 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, pruiicularly lmpublished data, is the prope1iy or 
lmder 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 Boru·d or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the inf01m ation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessa1y to obtain inf01m ed consent from those 
persons to whom the dmg may be administered. 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT FIGURES ......................................................................................................................................4
PROTOCOL SYNOPSIS ..............................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................13
1.
INTRODUCTION ..............................................................................................................................................16
1.1.
Background ............................................................................................................................................16
1.2.
GS-5745 .................................................................................................................................................16
1.2.1.
General Information .............................................................................................................16
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................16
1.2.3.
Clinical Trials of GS-5745 ...................................................................................................17
1.3.
Rationale for This Study ........................................................................................................................18
1.3.1.
Clinical Rationale.................................................................................................................18
1.3.2.
Toxicology Rationale ...........................................................................................................20
1.3.3.
Dose Selection......................................................................................................................20
1.4.
Risk/Benefit Assessment for the Study..................................................................................................20
1.5.
Compliance ............................................................................................................................................21
2.
OBJECTIVES.....................................................................................................................................................22
3.
STUDY DESIGN................................................................................................................................................23
3.1.
Endpoints ...............................................................................................................................................23
3.2.
Study Design..........................................................................................................................................23
3.3.
Study Treatments ...................................................................................................................................23
3.3.1.
Open Label Extension ..........................................................................................................24
3.3.2.
Home Administration of Study Drug ...................................................................................24
3.4.
Duration of Treatment............................................................................................................................25
3.5.
Study Subject Discontinuation Criteria..................................................................................................25
3.6.
End of Study...........................................................................................................................................25
3.7.
Biomarker Testing..................................................................................................................................25
3.7.1.
Biomarker Samples to Address the Study Objectives:.........................................................25
3.7.2.
Biomarker Samples for Optional Future Research...............................................................26
3.7.3.
Biomarker Samples for Optional Genomic Research...........................................................26
4.
SUBJECT POPULATION..................................................................................................................................27
4.1.
Number of Subjects and Subject Selection ............................................................................................27
4.2.
Inclusion Criteria....................................................................................................................................27
4.3.
Exclusion Criteria...................................................................................................................................28
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................31
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................31
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................31
5.2.
Description and Handling of GS-5745 and Placebo...............................................................................32
5.2.1.
Formulation..........................................................................................................................32
5.2.2.
Packaging and Labeling .......................................................................................................32
5.2.3.
Storage and Handling...........................................................................................................32
5.3.
Dosage and Administration of GS-5745 and Placebo............................................................................32
5.4.
Prior and Concomitant Medications.......................................................................................................33
5.4.1.
Allowed Prior and Concomitant Medications: .....................................................................33
5.4.2.
Disallowed Concomitant Medications .................................................................................33


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5.4.3.
Rescue Therapy....................................................................................................................35
5.5.
Accountability for Study Drug...............................................................................................................35
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................35
6.
STUDY PROCEDURES ....................................................................................................................................36
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................36
6.2.
Pretreatment Assessments......................................................................................................................36
6.2.1.
Screening Visit (Day -35 to Day 0)......................................................................................36
6.2.2.
Baseline/Randomization Assessments (Day 1/Week 0).......................................................37
6.3.
Blinded Treatment Assessments (Day 1 through Week 12)...................................................................37
6.3.1.
30-Day Follow-up Visit........................................................................................................40
6.4.
Open Label Extension Assessments (Week 12 through Week 64) ........................................................40
6.4.1.
Open Label Extension 30-day Follow-up Visit....................................................................41
6.5.
Assessments for Premature Discontinuation from Study.......................................................................41
6.6.
Criteria for Subject Temporary Discontinuation of Study Treatment....................................................41
6.7.
Criteria for Subject Discontinuation of Study........................................................................................41
6.8.
End of Study...........................................................................................................................................42
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................43
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................43
7.1.1.
Adverse Events.....................................................................................................................43
7.1.2.
Serious Adverse Events........................................................................................................43
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................44
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................44
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................45
7.2.2.
Assessment of Severity ........................................................................................................45
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................45
7.4.
Gilead Reporting Requirements.............................................................................................................47
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................48
7.6.
Toxicity Management ............................................................................................................................48
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................49
7.6.2.
Grades 3 Laboratory Abnormality or Clinical Event ...........................................................49
7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................49
7.7.
Special Situations Reports......................................................................................................................50
7.7.1.
Definitions of Special Situations..........................................................................................50
7.7.2.
Instructions for Reporting Special Situations.......................................................................50
8.
STATISTICAL CONSIDERATIONS................................................................................................................52
8.1.
Analysis Objectives and Endpoints........................................................................................................52
8.1.1.
Analysis Objectives..............................................................................................................52
8.1.2.
To explore biomarkers of clinical benefit, mechanism of action and 
impact of GS-5745 as add-on therapy in subjects with moderate to severe 
RA Primary Endpoint...........................................................................................................52
8.1.3.
Secondary Endpoints............................................................................................................52
8.1.4.
Exploratory Endpoints..........................................................................................................52
8.2.
Analysis Conventions.............................................................................................................................53
8.2.1.
Analysis Sets ........................................................................................................................53
8.3.
Data Handling Conventions ...................................................................................................................53
8.4.
Demographic Data and Baseline Characteristics ...................................................................................53
8.5.
Efficacy Analysis ...................................................................................................................................53
8.6.
Safety Analysis.......................................................................................................................................54


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8.6.1.
Extent of Exposure...............................................................................................................54
8.6.2.
Adverse Events.....................................................................................................................54
8.6.3.
Laboratory Evaluations ........................................................................................................54
8.7.
Sample Size............................................................................................................................................55
8.8.
Data Monitoring Committee ..................................................................................................................55
9.
RESPONSIBILITIES..........................................................................................................................................56
9.1.
Investigator Responsibilities ..................................................................................................................56
9.1.1.
Good Clinical Practice..........................................................................................................56
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................56
9.1.3.
Informed Consent.................................................................................................................56
9.1.4.
Confidentiality......................................................................................................................57
9.1.5.
Study Files and Retention of Records ..................................................................................57
9.1.6.
Case Report Forms...............................................................................................................58
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................59
9.1.8.
Inspections............................................................................................................................59
9.1.9.
Protocol Compliance............................................................................................................59
9.2.
Sponsor Responsibilities ........................................................................................................................60
9.2.1.
Protocol Modifications.........................................................................................................60
9.2.2.
Study Report and Publications .............................................................................................60
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................60
9.3.1.
Payment Reporting...............................................................................................................60
9.3.2.
Access to Information for Monitoring..................................................................................61
9.3.3.
Access to Information for Auditing or Inspections ..............................................................61
9.3.4.
Study Discontinuation..........................................................................................................61
10.
REFERENCES ...................................................................................................................................................62
11.
APPENDICES ....................................................................................................................................................64
Appendix 1.
Investigator Signature Page....................................................................................................65
Appendix 2.
Study Visit Schedule ..............................................................................................................66
Appendix 3.
Management of Clinical and Laboratory Adverse Events......................................................71
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03....................................72
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................73
Appendix 6.
American College of Rheumatology:  1991 Revised Criteria for the Classification of 
Global Functional Status of Rheumatoid Arthritis* ...............................................................76
Appendix 7.
The 2010 American College of Rheumatology –European League Against 
Rheumatism Collaborative Initiative Classification Criteria for Rheumatoid 
Arthritis {Aletaha et al 2010}.................................................................................................77
Appendix 8.
American College of Rheumatology Response (ACR 20/50/70): {Felson et al 1995}..........78
Appendix 9.
Disease Activity Score DAS28- CRP {Prevoo et al 1995}....................................................80
Appendix 10.
Frederica’s Formula................................................................................................................81
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema.........................................................................................................................24


GS-5745 
Protocol GS-US-373-1499 
Gilead Sciences, Inc. 
Study Title: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Study Centers 
Planned: 
Objectives: 
Study Design: 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
USA 
Final 
Original 
Evaluation of the Efficacy and Safety ofGS-5745 as Add-On Therapy 
to a Tumor Necrosis Factor Inhibitor and Methotrexate Regimen in 
Subjects with Moderate to Severe Rheumatoid Arthritis 
110523 
2016-000897-39 
TBD 
Approximately 40 centers globally 
The primruy objective of this study is as follows: 
To assess the efficacy of GS-5745 versus placebo as an add-on 
therapy to a TNF inhibitor and methotrexate in subjects with 
moderate to severe rheumatoid ruthritis (RA) 
The secondruy objectives of this study ru·e as follows: 
• 
To assess the safety and tolerability of GS-5745 versus placebo as 
an add-on therapy with a TNF inhibitor and methotrexate in 
subjects with moderate to severe RA 
• 
To assess the phannacokinetics (PK) of GS-5745 as an add-on 
therapy with a TNF inhibitor and methotrexate in subjects with 
moderate to severe RA 
The explorat01y objectives of the study ru·e as follows: 
IT 
This is a Phase 2, double-blind, placebo-controlled, randomized study 
evaluating the efficacy and safety ofGS-5745 as add-on therapy in 
subjects with moderate to severe RA . 
Subjects will be su·atified by high and moderate disease activity as 
detennined by the Disease Activity Score for 28 joints using CRP 
(DAS28-CRP). High disease activity is defined as DAS28-CRP > 5.1 
and moderate disease activity is defined as a DAS28-CRP > 3.2 and 
:::; 5 .1. In addition, subjects will be stratified by prior use of RA 
Page5 
14 March 2016 


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biologics including the TNF inhibitor being administered during 
Screening. Low RA biologic use will include subjects with 1 - 2 prior 
RA biologics and high RA biologic use will include subjects with 3 or 
more previous RA biologics. Subjects will be followed for 4 weeks 
after last dose of study drug. 
Eligible subjects who complete the blinded phase of the study may
participate in an open-label extension (OLE) phase.
Number of Subjects 
Planned:
Approximately 75 subjects
Target Population:
Subjects with moderate to severe RA currently treated with a stable 
dose of TNF-inhibitor for at least 12 weeks and methotrexate (MTX)
currently treated for at least 12 weeks and on a stable dose for at least  
weeks 6 weeks
Duration of 
Treatment:
Subjects will receive 12 weekly injections in the blinded phase and 
weekly doses through Week 64 in the Open Label extension phase. 
Diagnosis and Main 
Eligibility Criteria:
For a complete list of inclusion and exclusion criteria, please refer to 
Sections 4.2 and 4.3.
Key inclusion criteria include:
1) Male or female subjects between 18 and 80 years of age inclusive, 
at time of Screening 
2) Diagnosis of RA (according to the 2010 ACR/EULAR 
classification criteria at least 6 months prior to the date of first 
Screening
3) Must have taken oral or parenteral methotrexate (MTX) 7.5 to 
25 mg/week continuously for at least 12 weeks and tolerated this 
medication, with at least 6 weeks of stable dose prior to the first 
study drug dose and throughout the duration of the study.
4) Must have an inadequate response to ≥ 12 weeks of treatment with 
an approved, stable SC formulation of  adalimumab, certolizumab, 
entanercept, or golimumab regimen as defined as a DAS28- CRP
>3.2, with ≥ 3 swollen and ≥ 3 tender joints  among the 28 joints 
assessed in the DAS28 during Screening and at Baseline.
5) The last dose of SC TNF inhibitor must have been administered as 
below prior to dosing of study drug:
a) Adalimumab within 2 weeks
b) Certolizumab between 2 or 4 weeks according to the subject’s 
prescribed dosing regimen.


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c) Etanercept within 1 week
d) Golimumab within 4 weeks
6) Stable doses of non-steroidal anti-inflammatory drugs (NSAIDs) 
and/or oral corticosteroids (≤ 10 mg prednisone/day or equivalent) 
at a stable dose for ≥ 4 weeks prior to Baseline are allowed and 
throughout the duration of the study
Key exclusion criteria include
1) Current treatment with any other disease modifying anti-rheumatic 
drug (DMARD) except MTX alone or in combination with 
chloroquine or hydroxychloroquine, OR other immune 
modulating/suppressive non-biologic and biologic medications as 
described in Section 5.4.2
2) Intrarticular corticosteroid injection of any joint within 4 weeks of 
Baseline
3) History of any infection requiring antimicrobial therapy within 
2 weeks prior to the first dose of study drug. 
4) History of current inflammatory joint disease, other than RA, such 
as gout, reactive arthritis, psoriatic arthritis, seronegative 
spondylarthritis, or Lyme disease, OR other current autoimmune 
diseases such as: systemic lupus erythematosus (SLE), 
inflammatory bowel disease, fibromyalgia, polymyalgia 
rheumatica, scleroderma, inflammatory myopathy, mixed 
connective tissue disease, or other overlap syndrome (subjects 
with secondary Sjogren’s syndrome are not excluded
5) Active  systemic involvement secondary to RA such as vasculitis 
or Felty’s syndrome
6) History of any of the following  within 12 months of Baseline 
(Day 1): 
a) infection requiring parenteral antibiotics or hospitalization,
b) any life-threatening infection, 
c) sepsis
7) 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); 


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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) Estimated glomerular filtration rate <40 mL/min based on the 
Modification of Diet in Renal Disease (MDRD) formula.
8) Any uncontrolled clinically significant laboratory abnormality that 
would affect interpretation of study data or the subject’s 
participation in the study.
9) Positive HIV serology, or hepatitis B sAg
10) Positive hepatitis C serology that has not been successfully treated 
defined as undetectable hepatitis C virus via PCR
11) A positive QuantiFERON-TB Gold test during Screening, OR a 
history of either untreated or inadequately treated latent or active 
tuberculosis (TB) infection OR receiving current treatment for or 
active TB during Screening
12) A subject with a malignancy or a history of malignancy or 
lymphoproliferative disorder within 10 years with the following 
exceptions:
a) Carcinoma in situ of the cervix
b) Adequately treated basal or squamous cell cancer or other 
localized non-melanoma skin cancer
Study Procedures/
Frequency:
All subjects will complete the following study visits at the study site 
during the blinded phase of the study: Screening, Day 1 (Baseline, 
first dose of study drug) and Weeks 1, 4, 8, 11 and 12. Subjects will 
receive the first two doses of study drug (Day 1 and Week 1) at the 
study site.  Subjects electing not to participate in the OLE will 
complete all Week 12 assessments and will not receive study drug. 
These subjects will be followed for safety for an additional 30 days 
after the last dose of study drug.
Subjects that are eligible and choose to participate in the OLE will 
receive their first dose of study drug in the OLE phase of the study at 
Week 12 after completing all the required assessments of the Week 12 
visit.  Additional study visits at the study site in the OLE will occur at 
Weeks 13, 24,  36, 48,  60, and  64, and a 30-day follow-up visit after 
the last dose of study drug.  


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Screening Assessments

Confirmation of RA diagnosis

Medical history

Vital signs (VS)

Height, complete physical exam (CPE)

12 lead ECG

Central laboratory tests including Rheumatoid Factor, anti-CCP, 
hematology, urinalysis, chemistry panel, serum ß-HCG (women of 
childbearing potential), QuantiFERON –Gold (QFT), HIV 
Serology, HBsAg, HCVAb and c-Reactive Protein,  Erythrocyte 
Sedimentation Rate (ESR) local lab and  estimated Glomerular 
Filtration Rate (based on MDRD study equation)
On-Treatment Assessments

Concomitant medications

Vital signs

CPE  (Blinded phase Week 12 and OLE Week 64 only)

Targeted Physical exam (TPE)

12-lead ECG (Week 12 of the blinded phase and Week 64 of the 
OLE)

Safety blood draws: Hematology, urinalysis, chemistry panel 
(in the blinded phase Study Day 1, Weeks 1, 4, 12, and the 30-day 
safety follow-up. In the OLE every 12 weeks and at the 30-day 
follow-up visit.

Serum βHCG (30-day follow-up only), and urine pregnancy 
(baseline and every 4 weeks) in women of child-bearing potential 

In the blinded phase disease specific questionnaires and activity 
scores will be administered at Baseline, Weeks 1, 4, 8, 12 and at 
the 30-day safety follow-up visit. In the OLE phase, these 
assessments will be performed every 12 weeks, at Week 64and at 
the 30-day safety follow-up visit. 
Study Drug Administration:
In the blinded phase, SC study drug administration will occur at the 
study site on study Day 1 (Baseline), Weeks 1, 4, and 8. Subjects will 
remain at the study site for 30 minutes after the first 2 injections of 
study drug for observation. After receiving SC instruction at the study 
site during the first 2 drug SC injections subjects who have 
experienced no major AEs associated with the SC injections and are  
judged capable will be allowed to self-administer SC injections at 
home during the weeks where on-site visits are not required.


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In the OLE phase, study dmg administration will occur weekly from 
Week 12 to Week 64. SC study dmg administration will occur at the 
study site for the first 2 doses in the OLE at Week 12 and Week 13. 
Subjects will remain at the study site for 30 minutes after the first 
2 injections of study dmg for observation. If subjects are judged 
capable of self-injection and who have experienced no major AEs 
associated with the SC injections, may administer study dmg at home 
for the remainder of the study except for the in-office visits. Patients 
will retum for a 30-day follow-up visit after the last dose of study 
chug. 
Routine SC administration of the subject's specific TNF inhibitor 
during Screening should continue throughout the study. 
Phannacokinetics: 
PK blood ch·aws will be done prior to dosing at Weeks 1, 4, 8, anytime 
on Week 12 and at ESDD (if applicable) of the blinded phase and 
prior to dosing at Week 24 and anytime at Week 64 of the OLE phase. 
Anti-GS-5745 Antibodies (ADA): Blood ch·aws for ADAs will be done 
prior to dosing on Day 1 (Baseline), Weeks 4, and 8; and anytime at 
Week 12 and the 30-day follow-up visit of the blinded phase. Blood 
ch·aws for ADAs will be done prior to dosing at Week 24, anytime at 
Week 64, and anytime during the 30-day follow-up visit of the OLE. 
Biomarker Blood Draws: Several blood biomarkers will be obtained 
including but not limited to total and free MMP9, MMP9 activity, 
calprotectin, and at Study Day 1 (Baseline), Weeks 1, 4, 12, and at the 
end of the 30-day follow-up in the blinded phase of the study, eve1y 
12 weeks, Week 64 and at the end of the 30-day follow-up in the 
blinded phase of the study and OLE. 
P'-~~--------------------~ 
Qlltional PK Sub-stud 
PD 
Gen01nic Testing 
Optional Genomic Testin : PPD 
Additional on-treatment assessments will include symptom-ch·iven 
physical examination, and disease-specific questionnaires and activity 
scores perf01m ed at Day 1 (Baseline), Weeks 1, 4, 8, 12 and the 
30-day follow-up visit in the blinded phase of the study, every 
12 weeks and at the 30-day follow-up visit in the OLE. 
Page 10 
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Test Product, Dose, 
and Mode of 
Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Criteria for 
Evaluation: 
Safety: 
Efficacy: 
Phrumacokinetics: 
Explorat01y: 
Statistical Methods: 
CONFIDENTIAL 
Group 1: 
Final 
Original 
GS-5745 300 mg (2 x 1 mL GS-5745 [150 mg/ml] SC injections) 
administered weekly 
Group 2: 
GS-5745 150 mg (1 x 1 mL GS-5745 [150 mg/ml] + Placebo 1 x 1 mL 
SC injections) administered weekly 
Placebo-to-match (2x 1 ml SC injections) administered weekly 
Safety will be assessed during the study through the rep01i ing of AEs, 
and by clinicallaborat01y tests, physical examination, and vital signs 
(VS) assessments at vru·ious time points during the study. Concomitant 
medication usage will also be assessed throughout the study. 
The primaty efficacy endpoint is change from baseline in DAS28-
CRP at Week 12. Key seconda1y endpoints will be the prop01i ion of 
subjects who achieve low disease activity (LDA) DAS28- CRP <=3 .2 
and the prop01iion of subjects who achieve remission 
DAS28- CRP < 2.6 at Week 12. 
Plasma concentrations ofGS-5745 will be dete1mined. 
PPD 
The prima1y analysis set for efficacy analyses will be the Full 
Analysis Set (F AS), which includes all randomized subjects who 
received at least one dose of study dmg. The primaty endpoint is 
change from baseline in DAS28- CRP at Week 12. The primaty 
analysis will compru·e each of the 2 GS-5745 treated groups to the 
placebo group using a mixed model repeated measures (MMRM) 
approach. 
Seconda1y endpoints include the proportion of subjects who achieve 
LDA DSA28- CRP <=3.2) at Week 12 and the prop01i ion of subjects 
who achieve remission (DAS28- CRP <2.6 at Week 12). Cochran-
Mantel-Haemszel approach adjusting for the stratification factors will 
be used to compm·e each of the GS-5745 treated group to the placebo 
group. 
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All continuous endpoints will be summarized using an 8-number 
summary (n, mean, standard deviation [SD], median, 1st quartile [Q1], 
3rd quartile [Q3], minimum, maximum) by treatment group. All 
categorical endpoints will be summarized by the number and 
percentage of subjects who meet the endpoint definition.
Safety endpoints will be analyzed by the number and percent of 
subjects with events or abnormalities for categorical values or 
8-number summary (n, mean, SD, median, Q1, Q3, minimum, 
maximum) for continuous data by treatment group.
A total sample size of 75 subjects will be required for this study. Each 
of the 2 GS-5745 treated groups will be compared to the placebo 
group. A sample size of 25 per group will provide a power of 80% 
with a 2-sided α level of 0.05 to detect a Minimal Clinically Important 
Improvement (MCII) in DAS28- CRP change from baseline of 1.2 at 
12 weeks between a GS-5745 treated group and the placebo group, 
assuming a common standard deviation of 1.35 and 15% early dropout 
rate.  
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
°C
degrees Celsius
°F
degrees Fahrenheit 
β-HCG
beta-human chorionic gonadotropin
μg
Microgram
ACR
American College of Rheumatology
ACR 20/50/70 
American College of Rheumatology 20/50/70%  improvement
AE
adverse events
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BW
body weight
CCP
cyclic citrullinated peptide
CDAI
Clinical Disease Activity Index
CIA
collagen-induced arthritis 
CFR
Code of Federal Regulations
CK
creatine kinase
CLCr
creatinine clearance
cm
Centimeter
CRF
case report form
CRO
contract research organization
CRP
C-reactive protein
CTCAE
Common Toxicity Criteria for Adverse Events
DAS28
Disease Activity Score
DMARD
disease modifying anti-rheumatic drug
DMC
Data Monitoring Committee
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eSAE
electronic serious adverse event
ESDD
Early Study Drug Discontinuation
ESR
erythrocyte sedimentation rate
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FSH
follicle-stimulating hormone
g
Gram
GCP
Good Clinical Practice
Gilead
Gilead Sciences, Inc.


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HAQ-DI
Health Assessment Questionnaire Disability Index
HBsAg
hepatitis B surface antigen
HCVab
hepatitis C antibody
HIV
human immunodeficiency virus
CRP
C-Reactive Protein
IB
Investigator’s Brochure 
ICH
International Conference on Harmonization 
ICH E3
ICH Guideline for Structure and Content of Clinical Study Reports
ie
that is
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IR
inadequate response
IRB
Institutional Review Board
IU
international units
IUD
intrauterine device
IWRS
Interactive Web Response System
kg
Kilogram
L
Liter
LLT
lower-level term
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MMP9
matrix metallopeptidase-9
MTX
Methotrexate
NSAID
nonsteroidal anti-inflammatory drug
PE
physical examination
PK
Pharmacokinetics
Q1
first quartile
Q3
third quartile
QA
quality assurance
QT
electrocardiographic interval between the beginning of the Q wave and 
termination of the T wave, representing the time for both ventricular 
depolarization and repolarization to occur
QTcF
QT interval corrected for heart rate using the Fridericia formula
RA
rheumatoid arthritis
RF
rheumatoid factor
s
Second
SADR
serious adverse drug reaction
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous


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SD
standard deviation 
SDAI
Simplified Disease Activity Index
SF-36
Short Form (36) Health Survey
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
TNF- IR
tumor necrosis factor – Inadequate Response
ULN
upper limit of normal
US, USA
United States, United States of America
VAS
visual analogue scale
VS
Vital signs
WBC
white blood cell


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1.
INTRODUCTION
1.1.
Background
Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that affects approximately 
1.3 million adults in the United States (US) {Helmick et al 2008}. Rheumatoid arthritis 
manifests principally as an attack on peripheral joints and may lead to marked destruction and 
deformity of joints, with considerable disability and impact on quality of life. It is characterized 
by the production of autoantibodies, synovial inflammation with formation of pannus tissue, and 
erosion of underlying cartilage and bone. Although people of any age can be affected, the onset 
of RA is most frequent between the ages of 40 and 50 years, and women are affected 3 times 
more often than men {Lawrence et al 1998}. While the cause of RA is still not completely 
understood, aberrant B-cell activation, T-cell costimulation, 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 recent advances in RA treatment, including TNF-targeted therapeutics, a number of 
patients experience insufficient response to these agents and continue to suffer from 
disease-related symptoms, as well as incurring joint damage. Matrix metalloproteinase 9 
(MMP9) has been reported to play an important role in the progression of RA, and is known to 
be expressed in human RA as well as animal models of disease. The role of MMP9 in disease 
progression in RA is supported by findings in the MMP9 knockout mouse, which is significantly 
protected against increased disease severity in a collagen-induced arthritis model of RA, whereas 
matrix metalloproteinase 2 (MMP2) knockout mice develop more severe disease than littermate 
controls {Itoh et al 2002}. Tartrate resistant acid phosphatase (TRAP) positive mononuclear and 
multinucleated cells are often found in the synovium at the sites of cartilage and bone 
destruction. TRAP-positive multinucleated cells from RA patients, including osteoclasts, secrete 
MMP9 and are key participants in joint destruction {Tsuboi et al 2003}. Furthermore, MMP9 
has been shown to play a critical role in osteoclast invasion {Engsig et al 2000}. Studies in a 
variety of different disease models and correlations in human disease support a role for MMP9 in 
driving inflammation through increased vascular permeability and through promoting the 
activation or increasing the bioavailability of cytokines and growth factors {Gearing et al 1995}. 
Selective inhibition of MMP9 by GS-5745 has the potential to slow and/or halt progression of 
bone and joint erosion, as well as to reduce inflammation in RA patients.
1.2.
GS-5745
1.2.1.
General Information
For further information on GS-5745, refer to the current investigator’s brochure for GS-5745.
1.2.2.
Preclinical Pharmacology and Toxicology
GS-5745 is a fully humanized high-affinity monoclonal IgG4 antibody that is a selective and 
potent allosteric inhibitor of MMP9. In human UC and Crohn’s disease, MMP9 expression is 


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strongly induced and is associated with progressive disease. Matrix metalloproteinase 9 (MMP9)
expression has also been shown in the synovial tissue in human RA, and in macrophages and 
other cells in lung tissue in human COPD. Murine surrogates of GS-5745, with similar epitope 
specificity and inhibitory activity, have demonstrated significant anti-inflammatory and 
tissue-protective activity in rodent models of colitis and RA. Similarly, MMP9 is expressed in a 
number of solid tumors such as lung, gastric, and pancreatic adenocarcinomas and lung 
squamous cell and hepatocellular carcinomas. In addition, anti-MMP9 antibodies demonstrated 
efficacy in a mouse xenograft model of human colorectal carcinoma with respect to both primary 
tumor volume and weight. Unlike pan-MMP inhibitors, specific inhibition of MMP9 with a 
murine surrogate of GS-5745 showed no evidence of inducing musculoskeletal symptoms or 
pathology in a rat model. Furthermore, there were no effects on safety pharmacology endpoints 
(clinical observations, EGCs, respiratory rate) in the 4-week repeat-dose toxicity studies at doses 
of up to 100 mg/kg/dose.
The toxicology program consists of completed 4-week and 26-week repeat-dose intravenous (IV)
toxicity studies in both rats and monkeys and a human tissue cross-reactivity study. To support 
the transition to a subcutaneous (SC) formulation, a SC local tolerability study in rats was 
conducted and the 26-week toxicity studies in rats and cynomolgus monkeys included both IV 
and SC routes. The rat and rabbit embryo fetal development studies and the rat fertility study 
have also been completed. As expected, there was no specific GS-5745 staining observed in 
normal human tissues. At doses of GS-5745 up to 100 mg/kg/dose IV, data indicate no test 
article-related maternal or fetal effects in rats and rabbits, and no test article-related effects on 
male or female fertility in rats. Findings associated with GS-5745 treatment in the 4-week 
repeat-dose toxicity studies have been limited to reversible physeal hypertrophy in rats, an 
expected response to MMP9 inhibition, and reversible increased adrenal gland weight in female 
monkeys at all doses, which was associated with slight hypertrophy of the zona fasciculata in a 
single 100-mg/kg/dose female monkey. In the 26-week studies, there were no findings of 
toxicological concern in rats or cynomolgus monkeys following weekly IV or SC administration 
at doses up to 100 mg/kg/dose and 150 mg/kg/dose, respectively. The lack of physeal 
hypertrophy observed in the rat 26-week study is presumably due to the reversible nature of this 
finding as longitudinal bone growth and growth plate closure slows/completes. There were no 
adverse injection site reactions observed in the 26-week studies, and no adverse findings in the 
local tolerability study.
In summary, in these studies at exposure multiples of the anticipated clinical exposure, there was 
no evidence of GS-5745 hematological changes, no effects on immune system organ weights, 
including thymus, spleen and lymph nodes, and no immunosuppressive effect.
1.2.3.
Clinical Trials of GS-5745
Gilead is currently conducting clinical trials with GS-5745 in ulcerative colitis, Crohn’s Disease, 
solid tumors, chronic obstructive pulmonary disease, and cystic fibrosis (CF). For information on 
all Gilead sponsored trials for GS-5745, please refer to the current Investigators Brochure for 
GS-5745.


GS-5745 
Protocol GS-US-373-1499 
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1.3. 
Rationale for This Study 
1.3.1. 
Clinical Rationale 
Final 
Original 
Cunent RA u·eatment guidelines from the American College of Rheumatology and Emopean 
League Against Rheumatism (ACR/EULAR), the 2013 American College of Rheumatology 
Guideline for the Treatment of Rheumatoid Ali hritis and the EULAR Recommendations for the 
Management of Rheumatoid Ali hritis with Synthetic and Biological Disease-Modifying 
Antirheumatic Dmgs: 2013 Update, respectively, recommend switching subjects who have an 
inadequate response to TNF inhibitors (TNF-IR) to an altemate TNF inhibitor or another class of 
biologic. Several biologics have been approved for use in TNF-IR patients, but responses to 
these single biologics tend to be less than in TNF inhibitor na'ive RA patients. Thus, there 
remains an munet need pruiicularly for the TNF-IR patients. 
Gilead Sciences, Inc. (Gilead) conducted a Phase 1 double-blind, randomized, placebo-conu·olled 
study in RA subjects in Emope. Subjects were randomized in a 4:1 ratio to receive an IV 
infusion of GS-57 45 ( 400 mg) or matched placebo evety 2 weeks for a total of 3 infusions 
(Days 1, 15, and 29). Subjects participated in the study for up to 117 days; which included up to 
2 screening visits, 3 infusion visits, 4 follow-up visits, and 2 follow-up telephone calls. The 
screening visits were conducted a maximum of 15 days before the first infusion. Follow-up visits 
occmTed on Days 3, 8, 36, and 43, and follow-up telephone calls occmTed on Days 57 and 100. 
Subjects were required to have a mean CRP value dming Screening ~ 8 mg/L and not allowed to 
have received recent concomitant RA biologics within a defmed period prior to Screening or 
dming the study. 
PPD 
Interestingly, these clinical improvements occmTed despite a lack of major change in CRP 
values. Among subjects u·eated with GS-5745 dming the study (n=1 5), the mean values at 
Baseline and Day 43 were 37.21 (18.688) mg/L and 21.10 (18.977) mg/L, respectively, a mean 
decrease of 6.11 (22.577) mg/L. Alnong subjects u·eated with placebo (n=3), the mean CRP 
values at Baseline and Day 43 were 16.57 (11.153) mg/L and 12.46 (10.572) mg/L, respectively, 
a mean decrease of 4.12 (5.922) mg/L. 
CONFIDENTIAL 
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No deaths, serious adverse events (SAEs), AEs that caused study drug discontinuation, or
pregnancies were reported in this study. All AEs were Grade 1 or Grade 2 in severity. The most
frequently reported AEs among subjects randomized to treatment with GS-5745 (ie, reported for
≥ 10% of subjects in the GS-5745 group) were hypertension (2 of 15 subjects, 13.3%) and
nasopharyngitis (2 of 15 subjects, 13.3%). Overall, no AE/SAE safety signals were noted during
the study. All graded laboratory abnormalities were Grade 1 or Grade 2 in severity. One subject
(6.7%) randomized to treatment with GS-5745 had a Grade 2 chemistry abnormality, and
2 subjects (13.3%) randomized to treatment with GS-5745 had Grade 2 hematology
abnormalities. No clinically important changes from Baseline in vital signs or ECG results
occurred during the study. Overall, these data indicate GS-5745 was well tolerated during the
study and that GS-5745 may be beneficial in patients with RA.
Though the sample size of the Phase 1 RA study is small and the study duration brief, results 
indicate GS-5745 has clinical activity in RA. It is not yet known if the magnitude of the clinical 
response is sufficiently high that GS-5745 could be differentiated as a single agent for RA. 
However, combining GS-5745 with a TNF-α inhibitor has the potential to augment the clinic 
benefit of either agent alone. Therapeutic strategies that employ combinations of conventional 
and biologic disease-modifying antirheumatic drugs have demonstrated superior clinical 
responses compared to single agent approaches. Combining 2 biologics is an extension of this 
treatment strategy and offers an approach to achieving the treat-to-target approach to RA 
management specified in the ACR/EULAR treatment guidelines.
The efficacy of the combination of an anti-MMP9 agent (using AB0046) and an anti-TNF agent 
(using Enbrel) was evaluated in a therapeutic murine CIA mouse model. In this chronic model of 
advanced disease, therapies were administered after an average clinical score of > 2 was reached 
(Day 28) and continued through Day 43. Treatment with AB0046 and Enbrel, each on its own or 
in combination, resulted in significant efficacy with respect to clinical scores: ankle diameter, 
paw swelling, body weight change, and histopathological assessment of soft tissue damage, bone 
erosion, and joint destruction. For example, at Day 43, treatment with all therapies resulted in 
significant improvements in clinical score (p < 0.05 as compared to control group). Treatment 
with a combination of AB0046 and Enbrel resulted in a trend for superior therapeutic benefit as 
compared to each individual agent; however a statistically significant difference as compared to 
each single agent was not observed. Similar findings were apparent for other metrics such as 
body weight and histopathology. In an alternative analysis that evaluated the number of limbs 
scored with mild or no disease at the end of treatment, combination therapy yielded a significant 
benefit over each individual agent or a compelling trend as compared to Enbrel treatment alone. 
Analysis of complete blood count at the end of study revealed no abnormalities in any treatment 
group. Overall, these data indicate that the addition of anti-MMP9 to anti-TNF therapy does not 
compromise the activity of either agent, is well tolerated in this murine model as judged by both 
body weight and complete blood count, and could potentially provide a larger therapeutic benefit 
in affected joints.
Unlike other current biologics marketed to treat RA, the mechanism of action of GS-5745 as a 
protease inhibitor of MMP9 does not have a direct effect on systemic immune function. As of 
17 Jan 2016 GS-5745 has been administered to approximately 255 subjects in multiple 


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indications (oncology, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, and chronic 
obstructive lung disease) and thus far no safety signals have been identified, including any risk of 
serious or opportunistic infections, despite many of the subjects enrolled in these studies being 
immunocompromised due to cancer chemotherapy or receiving systemic immunosuppression to 
treat their primary disease. 
1.3.2.
Toxicology Rationale
Based on the toxicology profile of GS-57455745 and the known clinical safety of TNF 
inhibitors, there is no evidence of overlapping toxicity with the TNF inhibitors and combination 
toxicology testing of GS-5745 is not considered warranted.
1.3.3.
Dose Selection
In the Phase 1 RA study (GS-US-373-1276) dosing of GS-5745 400 mg IV every 2 weeks for a 
total of 3 infusions demonstrated clinical benefit and was well tolerated. Clinical experience also 
includes, IV dosing of GS-5745 up to 1800 mg every other week in oncology indications which 
has been well tolerated. 
Subsequent to study GS-US-373-1276 in RA, a SC formulation of GS-5745 was developed for 
use in inflammatory diseases. A bridging study was performed in healthy subjects (Study 
GS-US-326-1430) and demonstrated that the SC formulation of GS-5745 has an absolute 
bioavailability of 44.1%. Subsequent studies of GS-5745 in inflammatory disease have used the 
SC formulation.
The doses selected for this RA study are based upon clinical experience with the SC formulation 
of GS-5745 in ulcerative colitis. In a Phase 1 study of subjects with moderately to severely active 
UC (GS-US-326-0101) subjects received both IV (every other week) and SC GS-5745 (weekly) 
for one month. Of the 10 subjects dosed with SC GS-5745 once weekly, 4 subjects (40.0%)met 
the Mayo Score criteria for response, 2 out of 10 subjects (20.0%) met the criteria for remission, 
and 5 subjects (50.0%) met the criteria for mucosal healing. The weekly SC dose of 150 mg of 
GS-5745 was well tolerated. Comparable clinical responses were observed in subjects who 
received IV GS-5745 at doses 1.0 and 2.5 mg/kg administered every 2 weeks for a total of 
3 doses. Accordingly, subsequent studies of GS-5745 in inflammatory bowel disease are 
currently being conducted in Crohn’s disease (300 mg and 150 mg SC once weekly, and 150 mg
SC every other week) and ulcerative colitis (150 mg SC weekly, and 150 mg SC every other 
week). Based upon these findings, in this RA study, SC doses of 300 mg and 150 mg once 
weekly were selected based on a low dose (150 mg) shown to have evidence of efficacy in 
ulcerative colitis, and a higher dose of 300 mg which represent the top dose level in ongoing 
trials in Crohn’s disease. 
1.4.
Risk/Benefit Assessment for the Study
GS-5745 is currently being evaluated for the treatment of solid tumors, UC, Crohn’s Disease, 
chronic obstructive pulmonary disease, cystic fibrosis, and RA. From the adverse events (AEs)
reported in completed and ongoing trials in these indications, no drug-related safety signal has 
been identified.. Also, no drug interactions or contraindications have been reported.


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Potential risks may include local injection site reactions and the rare possibility of
hypersensitivity or allergic reactions. A single hypersensitivity reaction was observed after a 
second infusion in a UC subject. The subject was evaluated at the local emergency room and was 
discharged home in satisfactory condition. Despite this single hypersensitivity reaction after an 
IV infusion of GS-5745, it should be noted that GS-5745 is not considered to be a ‘high risk’ 
agonist as it acts by antagonism and targets MMP9. In this study, GS-5745 will be administered 
in a SC formulation which reduces the risk of severe hypersensitivity reactions. In addition, the 
first 2 doses of study drug in the blinded and OLE phases of the study will be study site clinic so 
that subjects can be observed for possible unexpected injection reactions.
While TNF inhibitors have demonstrated great benefit for patients with more difficult to treat 
RA, this class of biologics has a mechanism of action that down modulates cellular and humoral 
immunity. The FDA has issued a black box warning that treatment with these agents may 
“increase the risk of serious infections leading to hospitalization or death, including tuberculosis 
(TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis), and infections due to 
other opportunistic pathogens”. {Ali et al 2013}. Furthermore, treatment of  RA patients with 
TNF inhibitors combined with other biologics that directly affect the immune system {Genovese 
et al 2004, Greenwald et al 2011, Weinblatt et al 2006} all increased the risk of serious 
infections.
In contrast, GS-5745 is a biologic with a mechanism of action that does not directly affect innate 
or adaptive immunity. It binds to and inhibits the zinc-dependent endopeptidase, MMP9, an 
enzyme that degrades extracellular matrix proteins. Pre-clinical and clinical studies performed to 
date with GS-5745 or rodent equivalent have failed to observe an increased risk of infections. 
Thus, combining GS-5745 with a TNF inhibitor is not expected to increase the risk of serious 
infections.  As a safety precaution this study protects study enrollees by screening for TB, 
limiting the number and amount of immune modulating agents and excluding subjects with a 
previous history of serious infections.
Lastly, investigators will closely monitor subjects for the possible onset of serious infections. In 
parallel the DMC will review safety data at scheduled intervals to assess for possible emerging 
safety signals. 
With the above safety measures in place, this clinical study will provide information about the 
benefits GS-5745 in combination with TNF-inhibitors in RA  subjects and potentially provide an 
additional therapy to improve the health and quality of life of patients living with this condition. 
These benefits are believed to outweigh any potential risks, particularly in the context of this 
clinical trial.  
1.5.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2. 
OBJECTIVES 
The primaty objective of this study is as follows: 
Final 
Original 
To assess the efficacy of GS-5745 versus placebo as an add-on therapy to a TNF inhibitor and 
methotrexate in subjects with moderate to severe rheumatoid atihritis (RA) 
The secondaty objectives of this study are as follows: 
• 
To assess the safety and tolerability of GS-5745 versus placebo as an add-on therapy with a 
TNF inhibitor and methotrexate in subjects with moderate to severe RA 
• 
To assess the phrum acokinetics (PK) of GS-57 45 as an add-on therapy with a TNF inhibitor 
and methou·exate in subjects with moderate to severe RA 
The explorat01y objectives of this study m·e as follows: 
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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoint of this study includes:

Change in DAS28- CRP from Baseline to Week 12
The secondary endpoints of this study include:

Proportion of subjects that achieve low disease activity (DAS28- CRP <= 3.2) at Week 12

Proportion of subjects that achieve Remission (DAS28- CRP < 2.6) at Week 12

Assess plasma concentrations of GS-5745
3.2.
Study Design
This is a Phase 2, double-blind, placebo-controlled, randomized study evaluating the efficacy 
and safety of GS-5745 as add-on therapy in subjects with moderate to severe RA
Subjects will be stratified by high and moderate disease activity as determined by their 
DAS28-CRP score.  High disease activity is defined as DAS28-CRP > 5.1 and moderate disease 
activity is defined as a DAS28-CRP > 3.2 and ≤ 5.1. In addition, subjects will be stratified by 
prior use of RA biologics including the TNF inhibitor being administered during Screening. Low 
RA biologic use will include subjects with 1-2 prior RA biologics and high RA biologic use will 
include subjects with 3 or more previous RA biologics. Subjects will be followed for 4 weeks 
after last dose of study drug.
Eligible subjects who complete the blinded phase of the study will be invited to participate in an 
OLE phase.
3.3.
Study Treatments
Subjects with moderate to severe RA TNF-IR will receive weekly injections of 150 mg of
GS-5745, 300 mg of GS-5745 or placebo weekly for 12 weeks, in addition to their current SC 
administration of a TNF inhibitor. Subjects who are eligible to participate in the OLE will 
receive weekly injections of 300 mg of GS-5745 for 12 months.  
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-5745 300 mg (2 x 1 mL GS-5745 [150 mg/ml] SC injections) administered weekly. (N=25)
Group 2:
GS-5745 150 mg (1 x 1 mL GS-5745 [150 mg/ml] + Placebo 1 x 1 mL SC injection 
administered weekly (N=25)
Group 3:
Placebo (2 x 1 ml SC injections) administered weekly (N=25)


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3.3.1.
Open Label Extension
On the Week 12 visit, eligible subjects (active and placebo) may choose to participate in the 
OLE portion of the study.
Subjects who choose to participate in the OLE will receive weekly SC injections of 300 mg of 
GS-5745 for 52 weeks, in addition to their current SC administration of a TNF inhibitor
Figure 3-1.
Study Schema 
3.3.2.
Home Administration of Study Drug
Weekly clinic visits during the study may pose a significant burden to study subjects. This 
burden must be balanced against the need to monitor these potentially vulnerable subjects during 
the early doses of study drug.
In the blinded phase, SC study drug administration will occur at the study site on Day 1
(Baseline), Weeks 1 and 8. After receiving SC instruction at the study site during the first 2 drug 
SC injections, subjects judged capable will be allowed to self-administer remaining SC injections 
at home.  Subjects will remain at the study site for 30 minutes after the first 2 injections of study 
drug for observation.
In the OLE phase, study drug administration will occur at the study site for the first 2 doses at 
Weeks 12 and 13. Subjects will remain at the study site for 30 minutes after the first 2 injections 
of study drug for observation. Subjects may administer study drug at home for the remainder of 
the study except for in-office visits


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3.4.
Duration of Treatment
Subjects will receive 12 doses of weekly injections in the blinded phase and weekly doses 
through week 64 in the OLE phase and 30 days of follow-up after last dose of study drug.
3.5.
Study Subject Discontinuation Criteria
The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. Study medication may be discontinued in the following instances

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree or medical conditions that were exclusionary based on 
the protocol exclusion criteria (Section 4.3). 

Unacceptable toxicity or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest

Subject requests to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 5

Discontinuation of the study at the request of Gilead, a regulatory agency or IRB/IEC
3.6.
End of Study
The end of this study is defined as 30 days after the last subject has completed the final visit in 
the OLE phase and 30 days of follow-up.
3.7.
Biomarker Testing
3.7.1.
Biomarker Samples to Address the Study Objectives:
Blood will be collected in this study and will be used to evaluate the association of biomarkers 
with the safety and clinical response to GS-5745 and to increase the knowledge and 
understanding of the biology of RA and/or autoimmune and related inflammatory diseases such 
as Lupus.  The samples collected can be used for the validation of diagnostics. The specific 
analyses will include, but may not be limited to, MMP9 levels and activity in blood. Because 
biomarker science is a rapidly evolving area of investigation, and AEs in particular are difficult 
to predict, it is not possible to specify prospectively all tests that will be done on the specimens 
provided. The testing of MMP9 and markers related to MMP9 pathway, inflammation, 
autoimmunity, and TNF pathway is based upon the current state of scientific knowledge. It may
be modified during or after the end of the study to remove tests no longer indicated and/or to add 
new tests based upon the growing state of art knowledge. 


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3.7.2. 
Biomarker Samples for Optional Future Research 
PPD 
3.7.3. 
Biomarker Samples for Optional Genomic Research 
PPD 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 75 subjects will be enrolled in the study with moderate to severe RA who are 
currently treated with a TNF-inhibitor for at least 12 weeks and methotrexate currently treated for at 
least 12 weeks and on a stable dose for at least six weeks.
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 between 18 and 80 years of age inclusive, at time of Screening
2) Diagnosis of RA (according to the 2010 ACR/EULAR classification criteria at least
6 months prior to the date of first Screening)
3) Subjects must meet Class I, II, or III of the ACR 1991 Revised Criteria for Global Functional
Status in RA (Appendix 6)
4) Must have taken oral or parenteral methotrexate (MTX) 7.5 to 25 mg/week continuously for 
at least 12 weeks and tolerated this medication, with at least 6 weeks of stable dose prior to 
the first study drug dose and throughout the duration of the study.
5) Must be receiving folic or folinic acid supplementation at on Day 1 and throughout the 
duration of the study.
6) Must have an inadequate response to ≥12 weeks of treatment with an approved, stable SC
formulation of adalimumab, certolizumab, entanercept, or golimumab as defined as a
DAS28- CRP ≥ 3.2, with ≥ 3 swollen and ≥ 3 tender joints among the 28 joints assessed in 
the DAS28 during Screening and at Baseline
7) Subjects who have previously received other TNF inhibitors or biologics for the treatment of 
RA are eligible
8) The last dose of SC TNF inhibitor must have been administered as below prior to dosing of 
study drug:
a) Adalimumab within 2 weeks
b) Certolizumab between 2 or 4 weeks according to the subject’s prescribed dosing regimen
c) Entanercept within 1 week
d) Golimumab within 4 weeks
9) Stable doses of non-steroidal anti-inflammatory drugs (NSAIDs) and /or oral corticosteroids 
(≤10 mg prednisone/day or equivalent) at a stable dose for ≥4 weeks prior to Screening are 
allowed and throughout the duration of the study


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10) A negative serum pregnancy test is required for female subjects (unless permanently sterile 
or greater than two years post-menopausal) at Screening and at Baseline.
11) Lactating females must agree to discontinue nursing before study drug is administered.
12) 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 
Appendix 5
13) Must have the ability to understand and sign a written informed consent form, which must be 
obtained prior to initiation of the study procedures
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Current treatment with any other disease modifying anti-rheumatic drug (DMARD) other 
than MTX alone or in combination with chlorquine or hydroxychloroquine), or other immune
modulating/suppressive non-biologic and biologic medications as described in Section 5.4.2
2) Intra-articular corticosteroid injection within 4 weeks of Screening
3) History of any infection requiring antimicrobial therapy within 2 weeks prior to the first dose 
of study drug.
4) Previous treatment with GS-5745
5) Known hypersensitivity to GS-5745 or, its metabolites, or its formulation excipients.
6) Known hypersensitivity, or, to the TNF inhibitor the subject is receiving at the first Screening 
visit
7) Any subject vaccinated with live or attenuated vaccines within the 4 weeks prior to the first 
dose of study drug or is to be vaccinated with these vaccines at any time during treatment or 
within 4 weeks following discontinuation of study drug.
8) History of current inflammatory joint disease, other than RA, such as gout, reactive arthritis, 
psoriatic arthritis, seronegative spondylarthritis, or Lyme disease, OR other current 
autoimmune diseases such as: systemic lupus erythematosus (SLE), inflammatory bowel 
disease, fibromyalgia, polymyalgia rheumatica, scleroderma, inflammatory myopathy, mixed 
connective tissue disease, or other overlap syndrome (subjects with secondary Sjogren’s 
syndrome are not excluded)
9) Active systemic involvement secondary to RA such as vasculitis or Felty’s syndrome


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10) History of any of the following within 12 months of Baseline (Day 1):
a) infection requiring parenteral antibiotics or hospitalization, 
b) any life-threatening infection,
11) History of infected prosthetic joint at any time, with the prosthesis still in situ
12) 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) Estimated glomerular filtration rate <40 mL/min based on the Modification of Diet in 
Renal Disease (MDRD) formula.
13) AST or ALT greater than 1.5 times the upper limit of normal at screening or any 
uncontrolled clinically significant laboratory abnormality that would affect interpretation of 
study data or the subject’s participation in the study.
14) A positive serum βHCG test during Screening, or positive urine pregnancy test at Baseline 
prior to study drug administration in women of child-bearing potential only, or pregnant or 
lactating females
15) Positive HIV serology, or hepatitis B sAg
16) Positive hepatitis C serology that has not been successfully treated defined as undetectable 
hepatitis C virus via PCR
17) A positive QuantiFERON-TB Gold test during Screening, OR a history of either untreated or 
inadequately treated latent or active TB infection OR receiving current treatment for active 
TB during screening


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18) A subject with a malignancy, a history of malignancy or lymphoproliferative disorder within 
10 years with the following exceptions:
a) Carcinoma in situ of the cervix
b) Adequately treated basal or squamous cell cancer or other localized non-melanoma skin 
cancer
19) Participation in another investigational drug study within 1 month of Screening for a small 
molecule or within 3 months or 5 half-lives which longer for a biologic agent prior to 
screening
20) Male subjects unwilling to refrain from sperm donation for at least 90 days after the last dose  
of study drug
21) Females who may wish to become pregnant and/or plan to undergo egg donation or egg  
harvesting for the purpose of current or future fertilization during the course of the study and 
up to 30 days of the last dose of the study drug
22) Presence of any condition that could, in the opinion of the investigator, compromise the 
subject’s ability to participate in the study, such as history of substance abuse, alcoholism, or 
an  unstable psychiatric condition.
23) Known hypersensitivity to rubber or latex
24) Have undergone surgical treatments for RA including synovectomy and arthroplasty in 
> 4 joints and/or within the last 12 weeks prior to Screening or planned elective surgery 
during the study
25) 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, new or significant ECG finding 
at Screening, or any other cardiovascular condition which, in the opinion of the investigator, 
would put the subject at risk by participation in the study.
26) 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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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
Subjects will be assigned a screening number at the time of consent. The randomization and 
Baseline/Day 1 visit cannot occur until the investigator has received the results of the screening 
tests and subject eligibility has been confirmed.
Once eligibility has been confirmed, each subject will be assigned a unique subject number. 
Once a subject number has been assigned to a subject, it will not be reassigned to any other 
subject. Prior to or during the Baseline/Day 1 visit, subjects will be randomized in a 1:1:1 ratio to 
Treatment Group 1, Treatment Group 2, or Treatment Group 3. The IWRS will assign blinded 
study drug numbers at each study drug administration visit. Study drug will be dispensed to the 
subject in a blinded fashion until Week 11. Randomization will be stratified by high and 
moderate disease activity with those with high disease activity defined as a DAS28- CRP > 5.1 
and those with moderate disease activity defined as a DAS28- CRP > 3.2 and ≤ 5.1. In addition,
In addition, subjects will be stratified by prior use of RA biologics including the TNF inhibitor 
being administered during Screening. Low RA biologic use will include subjects with 1-2 prior 
RA biologics and high RA biologic use will include subjects with 3 or more previous RA
biologics
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 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 case report 
form/ electronic case report form (CRF/eCRF), along with the date on which the treatment 
assignment was obtained. The investigator is requested to contact the Gilead medical monitor 
promptly in case of any treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).


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5.2.
Description and Handling of GS-5745 and Placebo
5.2.1.
Formulation
GS-5745 for SC injection is formulated as a sterile, aqueous buffered solution in a single-use
pre-filled syringe (PFS) with a plunger stopper. The buffered solution contains the same 
excipients as the GS-5745 formulation, acetate at pH 5.0, sucrose and polysorbate 20. Each PFS
is intended to deliver 1 mL containing 150 mg GS-5745 at a concentration of 150 mg/mL.
Placebo for SC injection is formulated as a sterile, aqueous buffered solution in a single-use PFS
with plunger stopper. The buffered placebo solution contains acetate at pH 5.0, sucrose and 
polysorbate 20 added for stabilization.  Each PFS is intended to deliver 1 mL of buffered 
solution.
5.2.2.
Packaging and Labeling
GS-5745 and placebo for SC injection will be supplied in 1 mL type I clear single-use glass PFS
with gray butyl coated stoppers.
Study drug(s) to be distributed to centers in the United States (US) and other participating
countries shall be labeled to meet applicable requirements of the US Food and Drug
Administration (FDA), EU Guideline to Good Manufacturing Practice – Annex 13
(Investigational Medicinal Products), and/or other local regulations.
Gilead or designated distribution depots will distribute study drug to centers as per
Good Manufacturing Practice (GMP) requirements.
5.2.3.
Storage and Handling
GS-5745 and placebo for SC injection will be shipped and stored under refrigeration between 
2 to 8 °C (36 to 46 °F). Storage conditions are specified on the label.
Upon arrival at the clinical center, the study drug products must be stored in a secure area,
accessible only to authorized study site personnel. To ensure drug stability and proper product
identification, the drug products should be stored in the kits in which they are supplied until
needed.
Consideration should be given to handling, preparation, and disposal through measures that
minimize drug contact with the body.
5.3.
Dosage and Administration of GS-5745 and Placebo
GS-5745 or placebo for SC injection will be administered to subjects on the thighs or the 
stomach area (abdomen). If the abdomen area is chosen, the area 5 cm (2 inches) around the 
umbilicus should be avoided. GS-5745 or placebo will be administered SC at the research center 
at Day 1and Weeks , 4 and 8 study visits during the blinded phase of the study. If a dose requires 
multiple injections, all injections should be delivered within 1 hour. The investigator or a 


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qualified designee must be present during the administration during the SC injections at Day 1
and Week 1 in blinded phase of the study. After training the subject will be allowed to administer 
the remaining weekly SC study drug doses (+/-3 days) at home. During the OLE portion of the 
study, GS-5745 or placebo will be administered SC at the research center at Weeks 12 and 13 
study visits. Afterwards, subject will continue to administer the remaining weekly SC study drug 
doses (+/-5 days) at home.
In the blinded phase or OLE of the study, if the subject has a body temperature of > 38ºC 
(100.4ºF), or the subject feels unfit to receive study drug at a given scheduled weekly injection, 
the subject should not be administered study drug. In consultation with the medical monitor, the 
Investigator may delay dosing until both the parameters above are met.
If a subject fails to dose the study drug within the 3 day window of the scheduled SC weekly 
dose, they should contact the study site for instructions on dosing. The investigator and the 
Medical Monitor will determine if a late dose of study drug is acceptable or if the dose should be 
skipped. If a subject misses >3 of the 12 scheduled doses of study drug the Gilead medical 
monitor should be contacted to discuss if the study drug should be withdrawn for that subject due 
to poor adherence to the dosing regimen.
5.4.
Prior and Concomitant Medications
At each study visit, the study center will capture any and all medications taken by the subject 
since the last visit or during the visit (as applicable). Concomitant medications include 
prescription medications, non-prescription medications, therapies, and dietary supplements.
5.4.1.
Allowed Prior and Concomitant Medications:

Antimalarials (hydroxychloroquine, chloroquine): will be allowed as concomitant 
medications in this study. If discontinued, they must be discontinued for 4 weeks prior to the 
first dose of study drug. If continued throughout the study through Week 12, the dose must 
be stable for at least 8 weeks prior to first dose of study drug.

Chronic NSAIDs/COX-2 inhibitors, opioids, and acetaminophen/paracetamol use may be 
allowed provided the investigator submits the mg dose and dosing interval to the medical 
monitor during Screening for approval. If approved, the mg dose and dosing interval should 
be stable throughout the Screening period and be maintained through Week 12. If these 
medications are to be discontinued, they should be discontinued at least 1 week prior to the 
first dose of study drug.

Low dose oral corticosteroids: daily doses ≤ 10 mg of prednisone or equivalent per day are 
allowed and should remain stable through the study through Week 12. 
5.4.2.
Disallowed Concomitant Medications
The disallowed DMARDs, Biologic Response Modifiers and Other Medications below require 
a drug-specific washout period prior to dosing of study drug as defined below. These 


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medications are also disallowed during the 12 week blinded phase of the study unless otherwise 
specified:
DMARDs

Minocycline/doxycycline, penicillamine, and sulfasalazine: must have been discontinued 
for 4 weeks prior to the first dose of study drug. 

Leflunomide (Arava®) must have been discontinued 8 weeks prior to the first dose of study 
drug .

Auranofin (Ridaura®), injectable gold (aurothiglucose or aurothiomalate): must have been 
discontinued for 4 weeks prior to first dose of study drug

Tofacitinib (Jeljanz®), a Janus kinase inhibitor (Jak inhibitor): must have been discontinued 
for 4 weeks prior to the first dose of study drug. Any other marketed Jak inhibitor for RA 
must also be discontinued for 4 weeks prior to the first dose of study drug.
Biologic Response Modifiers
All must be discontinued for entry into this study:

All other TNF inhibitors except the TNF inhibitor being administered during 
Screening : Discontinued for at least 12 weeks prior to the first dose of study drug;

Abatacept (Orencia®), anakinra (Kineret®), tocilizumab (Actemra®): Discontinued for 
12 weeks prior to first dose of study drug;

Rituximab or other selective B lymphocyte depleting agents (either marketed or
investigational): Discontinued for 1 year prior to the first dose of study drug. 
Other Medications

Oral corticosteroids: Subjects who are already on oral corticosteroids must be on a stable 
dose of ≤10 mg/day of prednisone or equivalent for 4 weeks prior to first dose of study drug
and if should remain on this dose through Week 12 study visit.

Intramuscular, or intravenous corticosteroids: None may be administered within 30 days
prior to first dose of study drug. In addition, intravenous or intramuscular corticosteroids are 
not allowed during this study either as a stable concomitant medication or as rescue 
medication. 

Cyclosporine, tacrolimus or other calcineurin inhibitors, azathioprine, mycophenolate:
All must be discontinued 4 weeks prior to the first dose of study drug.


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
Alkylating agents:  Any prior treatments ever with these agents ( e.g. chlorambucil or 
cyclophosamide)

Prosorba Device/Column: This must be discontinued 4 weeks prior to the first dose of study 
drug.

Experimental NSAIDS (including Cox-2 inhibitors): These must be discontinued 4 weeks 
prior to the first dose of study drug.

Any investigational treatment not mentioned elsewhere must be discontinued for 4 weeks 
for small molecules, 3 months for biologics or 5 half -lives, whichever is longer. Exposure to 
investigational biologics should be discussed with the Sponsor.
5.4.3.
Rescue Therapy
No rescue therapies are allowed through Week 12 of the study including 
acetaminophen/paracetamol or opiods
5.5.
Accountability for Study Drug
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug. This includes acknowledgement of receipt of each shipment of study drug (quantity and 
condition). All used and unused study drug dispensed to subjects must be returned to the site.
Study drug accountability records will be provided to each study site to:

Record the date received and quantity of study drug kits

Record the date, subject number, subject initials, the study drug kit number dispensed

Record the date, quantity of used and unused study drug returned, along with the initials of 
the person recording the information.
5.5.1.
Investigational Medicinal Product Return or Disposal
Study drug return and disposal will be performed as outlined in Section 9.1.7


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. Additional information is 
provided in the study procedures manual.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that subjects are eligible to participate in the
study prior to randomization or enrollment and throughout the study.
Once 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.
The study center will not be released to initiate dosing until:

The Institutional Review Board (IRB) or Ethics Committee (EC) reviewed and approved the
study and the informed consent document;

All required regulatory documents have been submitted to and approved by Gilead or the
CRO;

A master services agreement and/or study agreement is executed;

The site initiation meeting has been conducted by the Gilead clinical monitor (or designee).
The initiation meeting will include a review of the protocol, the IB, and investigator
responsibilities.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit (Day -35 to Day 0)
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 35 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.


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Screening Assessments
Screening Assessments will include confirmation of RA diagnosis; medical history; vital signs 
(VS) to include blood pressure, pulse, respirations, temperature, and weight; height; complete 
physical exam (CPE); 12 lead ECG; and central laboratory tests including Rheumatoid Factor, 
anti-CCP, hematology, urinalysis, chemistry panel, serum ß-HCG (women of childbearing 
potential), QuantiFERON –Gold (QFT), HIV Serology, HBsAg, HCVAb,c-Reactive Protein, and
Erythrocyte Sedimentation Rate (ESR) local by the Westergren method.

Record any serious adverse events (SAEs) and all AEs related to protocol mandated 
procedures occurring after signing of the consent form.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 35 days 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 adverse events related to protocol-mandated 
procedures on the adverse events case report form (CRF/eCRF).  All other untoward medical 
occurrences observed during the screening period, including exacerbation or changes in medical 
history are to be captured on the medical history CRF/eCRF.  See Section 7 Adverse Events and 
Toxicity Management for additional details.
6.2.2.
Baseline/Randomization Assessments (Day 1/Week 0)
Subjects who met the eligibility criteria will undergo the evaluations listed in detail in
Appendix 2.
Baseline/Day 1 evaluations will include the following: Review of AEs and concomitant 
medications, VS, targeted physical exam, safety laboratory examinations (hematology, 
urinalysis, chemistry panel), CRP, GS-5745 anti-drug antibodies (ADA) blood draw, biomarker 
blood draws, study drug administration, tender and swollen joint counts, patient global 
assessment of pain,  provider assessment of global disease activity, patient global assessment of 
disease activity, SF-36, Health Assessment Questionnaire (HAD-QI), and optional collection of 
blood for DNA analysis.
All Baseline/Week 0 procedures and assessments must be completed prior to randomization and 
study drug administration
6.3.
Blinded Treatment Assessments (Day 1 through Week 12)
All visit tests and procedures should be completed as indicated in Appendix 2.  Joint counts, 
patient global assessment of pain, physical assessment of global disease activity, subjects 
assessment of physical function, SF-36, HAD-QI should be administered prior to lab draws and 
study drug administration


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On-Treatment Assessments 
• 
Concomitant medications 
• 
Vital signs 
• 
CPE at Week 12 
• 
Targeted Physical exam (TPE) 
• 
12lead ECG at Week 12 
Final 
Original 
• 
Safety blood draws: Hematology, minalysis, chemistiy panel (in the blinded phase Study 
Day 1, Weeks 1, 4, 12, and the 30-day safety follow-up 
• 
Sennn ~HCG (30-day follow-up only), and mine pregnancy (baseline and evety 4 weeks) 
• 
In the blinded phase disease specific questionnaires and activity scores will be administered 
at Baseline, Weeks 1, 2, 4, 8 and 12 
Pharmacokinetics: 
PK blood draws: PK blood draws will be done prior to dosing at Weeks 1, 4 and 8, anytime on 
Week 12 and at ESDD (if applicable) 
GS-5745 Anti-Drug Antibodies (ADA) : Blood draws for ADAs will be done prior to dosing on 
Study Days 1 (Baseline), Weeks 4 and 8, anytime at Week 12 and the 30-day follow-up visit of 
the blinded phase. Blood draws for ADAs will be done prior to dosing at Week 24, anytime at 
Week 64, and anytime dming the 30-day follow-up visit of the OLE. 
Biomarker Blood Draws: Several blood biomarkers will be obtained including but not limited to 
total and free MMP9, MMP9 activity, and at Study Days 1 (Baseline), Weeks 1, 4, 12, and at the 
end of the 30-day follow-up in the blinded phase of the study. 
Optional PK Sub-study: PPD 
~-------------------------------------------------
Genomic Testing 
tional Genomic Testin : PPD 
Additional on-treatinent assessments will include symptom-driven physical examination, and 
disease-specific questionnaires and activity scores perfonned at Day 1 (Baseline), Week 1, 
Weeks 4 and 8, Day Week 12 and the 30-day Safety study in the blinded p01iion and evety 
12 weeks and at the end of the 30-day follow-up visit in the OLE. 
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Description of Selected Assessments
Physical Exam
A CPE is required at Screening, Week 12 of the blinded phase, and Week 64) of the OLE phase. 
A TPE will be performed at other study visits. A limited physical exam is defined as an 
examination driven by patient signs/symptoms and/or adverse events. Height is captured at 
screening only.
Vital Signs
Vital signs to be collected include resting blood pressure, pulse, respiratory rate, weight, and 
temperature.
SF-36 Health Survey
The SF-36 is a health related quality of life instrument consisting of 36 questions belonging to 
8 domains in 2 components and covers a 4-week recall period:

physical well-being: 4 domains: physical functioning (10 items), role physical (4 items), 
bodily pain (2 items), and general health perceptions (5 items)

mental well-being: 4 domains: vitality (4 items), social functioning (2 items), role emotional 
(3 items), and mental health (5 items).
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.  
Provider 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 visual analog scale (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).
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.


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6.3.1.
30-Day Follow-up Visit
Subjects not eligible to participate in the OLE phase will return to the clinic for a follow-up visit 
30 days after the Week 12 study visit in the blinded phase. Procedures should be completed as 
indicated in Appendix 2.
6.4.
Open Label Extension Assessments (Week 12 through Week 64)
All OLE test and procedures should be completed as indicated in Appendix 2.  All tests and 
procedures in Week 12 of the blinded phase must be completed prior to beginning the OLE
phase.
On-Treatment Assessments

Concomitant medications

Vital signs

CPE   Week 64 only

Targeted Physical exam (TPE)

12 lead ECG  at Week 64 of the OLE

Safety blood draws: Every 12 weeks, Week 64 and at the 30-day follow-up visit.

Serum βHCG (30-day follow-up only), and urine pregnancy (baseline and every 4 weeks) 
In the blinded phase disease specific questionnaires and activity scores will be administered 
every 12 weeks and at the 30-day safety follow-up visit.
Pharmacokinetics:
PK blood draws: PK blood draws will be done prior to dosing at Week 24 and anytime at 
Week 64.
GS-5745 Anti-Drug Antibodies: Blood draws for ADAs will be done prior to dosing at Week 24,
anytime at Week 64, and anytime during the 30-day follow-up visit.
Biomarker Blood Draws:  Several blood biomarkers will be obtained including but not limited to 
total and free MMP9, MMP9 activity and every 12 weeks, at week 64 and at the end of the 
30-day follow-up.
Additional on-treatment assessments will include symptom-driven physical examination, and 
disease-specific questionnaires and activity scores will be administered every 12 weeks, and at 
the end of the 30-day follow-up visit in the OLE.


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6.4.1.
Open Label Extension 30-day Follow-up Visit
Thirty days after Week 64 study visit, subjects will return to the clinic for a follow-up visit. 
Procedures should be completed as indicated in Appendix 2.
6.5.
Assessments for Premature Discontinuation from Study
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perform the required study-related 
follow-up and procedures (see Section 6.6, Criteria for Discontinuation of Study Treatment). If 
this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study and will be asked to return for the Early Drug Discontinuation (EDD) visit. These
subjects will not be eligible for the OLE phase of the study
6.6.
Criteria for Subject Temporary Discontinuation of Study Treatment
Study medication may be temporarily discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator in consultation with the 
Medical Monitor.

A request by the investigator that is reviewed and approved by the Medical Monitor.
6.7.
Criteria for Subject Discontinuation of Study
The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. Study medication may be discontinued in the following instances

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree or medical conditions that were exclusionary based on 
the protocol exclusion criteria (Section 4.3). 

Unacceptable toxicity or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest

Subject requests to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 5

Discontinuation of the study at the request of Gilead, a regulatory agency or IRB/IEC


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
The medical need to initiate a chronic dosing regimen of a prohibited immunosuppressive 
agent or increase the chronic dose of prednisone to >10 mg/day to treat worsening RA or 
another medical condition prior to completion of Week 12 study visit

Use of intravenous or intramuscular corticosteroids during the study prior to completion of 
Week 12 study visit

Use of rescue acetaminophen/paracetamol or opiods prior to completion of the Week 12 
study visit.
6.8.
End of Study
The end of this study is defined as 30 days after the last subject has completed the final visit in 
the OLE phase and 30 days of follow-up.


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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, 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 7.7.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
7.1.2.
Serious Adverse Events
A SAE is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)


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
In-patient hospitalization or prolongation of existing hospitalization

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 and 7.6
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.


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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.
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 of AEs will be graded using the CTCAE, version 4.03.  For each episode, the 
highest grade attained should be reported.
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: Grade 1 
(mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening) or Grade 5 (fatal) to 
describe the maximum intensity of the adverse event.  For purposes of consistency with the 
CTCAE, these intensity grades are defined in Appendix 4.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 55-days after last administration of study investigational medicinal product study drug must 
be reported to the CRF/eCRF database as instructed.


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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.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 55-days or of 
the last dose of study IMP, 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 CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.

At the time of study start, SAEs may be reported using a paper serious adverse event 
reporting form. During the study conduct, sites may transition to an electronic SAE (eSAE) 
system. Gilead will notify sites in writing and provide training and account information prior 
to implementing an eSAE system.
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by faxing
or emailing the report form within 24 hours of the investigator’s knowledge of the event to 
the attention of Gilead DSPH.
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, i.e., the 
eCRF database is not functioning, record the SAE on the paper serious adverse event 
reporting form and submit within 24 hours as described above.


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
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. 
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 :
Fax:
1-650-522-5477 
E-mail: Safety_fc@gilead.com or 

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
form.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 


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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 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the 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 or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., clinical chemistry, hematology, 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 (e.g., 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 (i.e., anemia) not 
the laboratory result (i.e., decreased hemoglobin).
Adverse events will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Severity should be recorded and graded according to the 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, which can be 
found at:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf
For adverse events associated with laboratory abnormalities, the event should be graded on the 
basis of the clinical severity in the context of the underlying conditions; this may or may not be 
in agreement with the grading of the laboratory abnormality.
7.6.
Toxicity Management 

All clinical and clinically significant laboratory toxicities will be managed according to 
uniform guidelines detailed in Appendix 3. 

Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before investigational medicinal 
product discontinuation, unless such a delay is not consistent with good medical practice.


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
Clinical events and clinically significant laboratory abnormalities will be graded according to 
the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, which can be 
found at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf

When restarting investigational medicinal product following resolution of the adverse event, 
the investigational medicinal product should be restarted at full dose or modified dose that is 
dependent upon discussion with the Gilead Sciences Medical Monitor.

Any recurrence of the investigational medicinal product-related Grade 3 or 4 clinical or 
clinically significant laboratory adverse event following dose interruption mandates 
permanent discontinuation of investigational medicinal product.

Any questions regarding toxicity management should be directed to the Gilead Sciences 
Medical Monitor.
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event

Continue investigational medicinal product at the discretion of the investigator.
7.6.2.
Grades 3 Laboratory Abnormality or Clinical Event

For Grade 3 clinically significant laboratory abnormality or clinical event, investigational 
medicinal product may be continued if the event is considered to be unrelated to 
investigational medicinal product.

For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to investigational medicinal product, 
investigational medicinal product should be withheld until the toxicity returns to ≤Grade 2.

If a laboratory abnormality recurs to ≥Grade 3 following re-challenge with investigational 
medicinal product and is considered related to investigational medicinal product, then 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. Recurrence of laboratory abnormalities considered 
unrelated to investigational medicinal product may not require permanent discontinuation.
7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event

For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing that is considered related to investigational medicinal product, 
investigational medicinal product 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 significant Grade 4 laboratory abnormality that is not confirmed by 
repeat testing should be managed according to the algorithm for the new toxicity grade.


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Investigational medicinal product may be continued without dose interruption for a clinically 
non-significant Grade 4 laboratory abnormality (e.g., Grade 4 CK after strenuous exercise or 
triglyceride elevation that is non-fasting or that can be medically managed) or a clinical event 
considered unrelated to investigational medicinal product.
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.  
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 CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.


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Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH 
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead DSPH. Gilead DSPH contact information is as follows: Email: 
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. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.


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STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
Final 
Original 
The prima1y objective of the study is to assess the efficacy of GS-5745 versus placebo as an 
add-on therapy to a 1NF inhibitor and methotrexate in subjects with moderate to severe 
rheumatoid ruihritis (RA) 
The secondruy objectives of this study ru·e as follows: 
• 
To assess the safety and tolerability of GS-57 45 versus placebo as an add-on therapy with a 
1NF inhibitor and methotrexate in subjects with moderate to severe RA 
• 
To assess the phrum acokinetics (PK) of GS-57 45 as an add-on therapy with a 1NF inhibitor 
and methotrexate in subjects with moderate to severe RA 
The explorat01y objectives of the study ru·e as follows: 
8.1.3. 
Secondary Endpoints 
Seconda1y endpoints ru·e: 
• 
Prop01iion of subjects that achieve low disease activity (DAS28- CRP ~ 3.2) at Week 12 
• 
Prop01iion of subjects that achieve remission (DAS28-CRP < 2.6) at Week 12 
• 
Plasma concentrations of GS-5745 
8.1.4. 
Exploratory Endpoints 
I 
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8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Full Analysis Set (FAS)
The primary analysis set for efficacy analyses will be the FAS, which includes all randomized 
subjects who received at least one dose of study drug.
8.2.1.2.
Safety Analysis Set
The primary analysis set for safety analyses will be the Safety Analysis Set which includes all 
subjects who received at least one dose of study drug
8.2.1.3.
Pharmacokinetic (PK) Analysis Set
The PK analysis sets includes all subjects in the safety Analysis Set who have the necessary 
Day 1 and on-study measurements to provide interpretable results for the specific parameters of 
interest.
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 1/2 of the lower limit of 
quantitation (LLOQ).
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 measurements will be summarized using standard descriptive
methods by treatment group and overall.
8.5.
Efficacy Analysis
The primary endpoint for the study is change in from baseline in DAS28- CRP at Week 12, 
which will be analyzed using a mixed model repeated measures (MMRM) model that includes 
the fixed effects of treatment, visit, treatment by visit interaction, and baseline value.  Subjects 
will be a random effect and compound symmetry correlation structure will be assumed.
Secondary endpoints include proportion of subjects that achieve LDA (DAS28- CRP <=3.2) and 
proportion of remission with (DAS28- CRP <2.6) at Week 12. The response rates between each 


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of the 2 GS-5745 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.
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
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 will be summarized by treatment group according to the study drug 
received.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration data. Exposure data will be summarized by treatment group.
8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database. Treatment-Emergent Adverse Events (TEAEs) are:

Any AEs with an onset date of on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug or

any AEs leading to premature discontinuation of study drug.
Summaries (number and percentage of subjects) of TEAEs by SOC and PT will be provided by 
treatment group. TEAEs will also be summarized by relationship to study drug and severity. In 
addition, TEAEs leading to premature discontinuation of study drug 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 and study visit along with corresponding change from Baseline. 
The incidence of treatment-emergent graded laboratory abnormalities will be summarized 
similarly. Graded laboratory abnormalities will be defined using CTCAE 4.03 grading scale


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8.7.
Sample Size
A total sample size of 75 subjects will be required for this study. Each of the 2 GS-5745 treated 
groups will be compared to the placebo group. A sample size of 25 per group will provide a 
power of 80% with a two-sided α level of 0.05 to detect a Minimal Clinically Important 
Improvement (MCII) in DAS28- CRP change from baseline of 1.2 at 12 weeks between a 
GS-5745 treated group and the placebo group, assuming a common standard deviation of 1.35
and 15% early dropout rate.  
8.8.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety data at designated scheduled intervals and provide 
recommendation to Gilead whether the nature, frequency, and severity of adverse effects 
associated with study treatment warrant the early termination of the study in the best interests of 
the participants, whether the study should continue as planned, or the study should continue with 
modifications. The DMC may also provide recommendations as needed regarding study design, 
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, 
part 50, 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/EC. The investigator will not begin any study subject activities until 
approval from the IRB/EC has been documented and provided as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/EC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB- or IEC-approved consent form for documenting 


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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 pharmacogenomic testing and 
sample retention, and their right to receive clinically relevant pharmacogenomic 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, CRF/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, CRF 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);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);


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
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 study drug 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. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data.  The Eligibility Criteria eCRF should be completed only after all data related to 


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eligibility have been received.  Subsequent to data entry, a study monitor will perform source 
data verification within the EDC system. Original entries as well as any changes to data fields 
will be stored in the audit trail of the system.  Prior to database lock (or any interim time points 
as described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 
the information in the source documents. The eCRF capture the data required per the protocol 
schedule of events and procedures. System-generated or manual queries will be issued to the 
investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, 
who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (e.g. data entry error). At the conclusion of the trial, Gilead will provide the site 
with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead QA, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. 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, or to regulatory authority or health authority inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.


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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB [or] 
IEC in accordance with local requirements and receive documented IRB [or] 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 the regulatory agency. Gilead will 
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content 
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases.
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 
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, e.g. 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 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both 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 
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Ali T, Kaitha S, Mahmood S, Ftesi A, Stone J, Bronze MS. Clinical use of anti-TNF therapy and 
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Arthritis Foundation. Rheumatoid Arthritis Fact Sheet.  2008.
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metalloproteinase 9 and vascular endothelial growth factor are essential for 
osteoclast recruitment into developing long bones. J Cell Biol 2000;151 (4):879-
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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.
Gearing AJ, Beckett P, Christodoulou M, Churchill M, Clements JM, Crimmin M, et al. Matrix 
metalloproteinases and processing of pro-TNF-alpha. J Leukoc Biol 1995;57 
(5):774-7.
Genovese MC, Cohen S, Moreland L, Lium D, Robbins S, Newmark R, et al. Combination 
therapy with etanercept and anakinra in the treatment of patients with rheumatoid 
arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 
2004;50 (5):1412-9.
Greenwald MW, Shergy WJ, Kaine JL, Sweetser MT, Gilder K, Linnik MD. Evaluation of the 
safety of rituximab in combination with a tumor necrosis factor inhibitor and 
methotrexate in patients with active rheumatoid arthritis: results from a 
randomized controlled trial. Arthritis Rheum 2011;63 (3):622-32.
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.
Itoh T, Matsuda H, Tanioka M, Kuwabara K, Itohara S, Suzuki R. The role of matrix 
metalloproteinase-2 and matrix metalloproteinase-9 in antibody-induced arthritis. 
J Immunol 2002;169 (5):2643-7.


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Lawrence RC, Helmick CG, Arnett FC, Deyo RA, Felson DT, Giannini EH, et al. Estimates of 
the prevalence of arthritis and selected musculoskeletal disorders in the United 
States. Arthritis Rheum 1998;41 (5):778-99.
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.
Tsuboi H, Matsui Y, Hayashida K, Yamane S, Maeda-Tanimura M, Nampei A, et al. Tartrate 
resistant acid phosphatase (TRAP) positive cells in rheumatoid synovium may 
induce the destruction of articular cartilage. Annals of the rheumatic diseases 
2003;62 (3):196-203.
Weinblatt M, Combe B, Covucci A, Aranda R, Becker JC, Keystone E. Safety of the selective 
costimulation modulator abatacept in rheumatoid arthritis patients receiving 
background biologic and nonbiologic disease-modifying antirheumatic drugs: A 
one-year randomized, placebo-controlled study. Arthritis Rheum 2006;54 
(9):2807-16.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Visit Schedule
Appendix 3.
Management of Clinical and Laboratory Adverse Events
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.
American College of Rheumatology:  1991 Revised Criteria for the Classification of 
Global Functional Status of Rheumatoid Arthritis*
Appendix 7.
The 2010 American College of Rheumatology –European League Against 
Rheumatism Collaborative Initiative Classification Criteria for Rheumatoid 
Arthritis {Aletaha et al 2010}
Appendix 8.
American College of Rheumatology Response (ACR 20/50/70): {Felson et al 1995}
Appendix 9.
Disease Activity Score DAS28- CRP {Prevoo et al 1995}
Appendix 10.
Frederica’s Formula


GS-5745 
Protocol GS- US-373-1499 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 Lakeside Drive 
FOSTER CITY CA 94404 
STUDY ACKNOWLEDGEMENT 
Finai 
Original 
Evaluation of the Efficacy and Safety ofGS-5745 as Add-On Therapy to a Tumor Necrosis 
Factor Inhibitor and Methotrexate Regimen in Subjects with Moderate to Severe Rheumatoid 
Arthritis 
GS-US-373-1499 Protocol Original (14 March 2016) 
This protocol has been approved by Gilead sc·ences.jnc . ..Ihe..fo.llo..win~Ulirnatur.e ocuments 
iliis approvru. 
p p D 
£}4~W 6oSfliJtJD; gtJ 
Name (Printed) 
1gnature 
David Gossage, MD 
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 tbis material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 65 
14 March 2016 


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Appendix 2.
Study Visit Schedule
Blinded Phase
Weeka
Screeningb
Baseline/Day 
1
Week 0
1
4
8
11
12o
ESDDd
Unscheduled 
Visit
30 Day 
Follow-up
Window in Days
-35 days
0
3
3
3
3
3
Written Informed Consent c
X
Confirmation of RA dx
X
Medical History 
X
Complete Physical Exam
X
X
X
Targeted Physical Exam e
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
Vital Signs & Weight f
X
X
X
X
X
X
X
X
X
Height
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
12 lead ECG-performed supine
X
X
CRP
X
X
X
X
X
X
X
X
X
Serum  ß-HCG Pregnancy Test g
X
X
Urine Pregnancy test g
X
X
X
X
Rheumatoid Factor
X
Anti-CCP
X
Genomic Sample (Optional)
X
QuantiFERON-Gold (QFT)
X
HIV Serology, HBsAg, HCVab
X


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Blinded Phase
Weeka
Screeningb
Baseline/Day 
1
Week 0
1
4
8
11
12o
ESDDd
Unscheduled 
Visit
30 Day 
Follow-up
Window in Days
-35 days
0
3
3
3
3
3
Estimated Glomerular Filtration 
Rate (based on MDRD study 
equation)
X
Erythrocyte Sedimentation Rate 
(ESR) Local Lab
X
X
X
X
X
X
X
Hematology h
X
X
X
X
X
X
X
X
Chemistry i
X
X
X
X
X
X
Per Investigator 
Discretion 
X
Urinalysis
X
X
X
X
X
X
X
X
66 swollen and 68 tender joint 
count assessment
X
X
X
X
X
X
X
Per Investigator 
Discretion
X
Patient and Provider Global 
Assessment of Health
X
X
X
X
X
X
X
Per Investigator 
Discretion
X
Patient Assessment of Pain
X
X
X
X
X
X
X
Per Investigator 
Discretion
X
HAQ-DI
X
X
X
X
X
X
X
SF-36
X
X
X
X
X
X
X
PK j
X
X
X
X
X
X
Optional PK Sub-Study (Day 4 or 
Day 6) k
GS-5745 ADA collection l
X
X
X
X
X
X
Biomarkers
X
X
X
X
X
Optional genomic testing m
X


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Blinded Phase
Weeka
Screeningb
Baseline/Day 
1
Week 0
1
4
8
11
12o
ESDDd
Unscheduled 
Visit
30 Day 
Follow-up
Window in Days
-35 days
0
3
3
3
3
3
Randomize
X
Study Drug Administration n
NA
a
All visits scheduled relative to day 1
b
Evaluations are to be completed within 35 days prior to Day 1. 
c
Conset must be signed prior to any study evaluations
d
Early Study Drug Discontinuation visit to occur within 72 hours of last dose of study drug 
e
Symptom-directed physical exam as needed 
f
Vital Signs include blood pressure, pulse, respirations, temperature 
g
Women of child-bearing potential only
h
Hematology: Complete blood count with differential and reticulocytes
i
Chemistry: Alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, serum creatinine
j
Prior to dose at Week 1,4,8, and anytime at week 12 and ESDD (if applicable) 
k
Anytime on Day 4 (+/-1) or Day 6 (+/- 1) after Day 1 dose (for subjects who consent to optional PK substudy only)
l
Prior to dose on Study Days 1 (Baseline), Week 4,8 ,  anytime on Week 12 , and 30 day follow-up 
m    Collection of blood for DNA analysis will be optional for subjects and will be collected at Day 1 or at any other visit during the course of the study
n
SC Study Drug Administration will occur at the study site on study Day 1 (Baseline), Week 1, Week 4, and Week 8.Subjects will remain at the study site for 30 moinutes after 
the injection for observation on Day 1 and Week 1 After receiving SC instruction at the study site during the first 2 drug SC injections, subjects judged capable will be 
allowed to self-administer weekly SC injections at home. SC Study drug administration and TNF inhibitor administration must be separated in time by at least 24 hours in the 
blinded and OLE phase of the study. Subjects not eligible or choosing not to participate in the OLE will come in for Week 12 visit assessments will not be administered study 
drug. Subjects that are eligible and choose to participate in the OLE will receive their first dose of study drug in the OLE phase of the study on Week 12 after completing all 
the requirements of Week 12 of the blinded phase of the study.  
o
Subjects not participating in the OLE will complete all week 12 assessments but will not receive an injection of study drug.     If subjects are eligible to participate in the OLE, 
then subjects complete all Week 12 assessments for the blinded phase and then receive the first dose of the drug for OLE.     


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Open Label Extension Phase Study Visits
Week
12
13
24
36
48
60
64
30 FU
Unscheduled Visit
ESDD
Window in Days
5
5
5
5
5
5
5
5
5
5
Complete physical exam
X
X
Vital signs and  weight a
X
X
X
X
X
X
X
X
12 lead ECG
X
Targeted physical exam b   
X
X
X
X
X
X
X
66 swollen and 68 tender joint count assessment
X
X
X
X
X
X
Per Investigator 
Discretion
X
Patient and Provider Global assessment of 
Health
X
X
X
X
X
X
Per Investigator 
Discretion
X
HAQ-DI
X
X
X
X
X
X
Per Investigator 
Discretion
X
SF-36
X
X
X
X
X
X
Per Investigator 
Discretion
X
Hematology c
X
X
X
X
X
X
X
X
Chemistry panel c
X
X
X
X
X
X
Per Investigator 
Discretion
X
Urinalysis
X
X
X
X
X
X
X
Erythrocyte Sedimentation Rate (ESR) Local 
lab
X
X
X
X
X
X
X
serum  ß-HCG Pregnancy Test d
X
X
Urine Pregnancy – every 4 weeks Home kit testd 
PK collection e
X
X
X


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Open Label Extension Phase Study Visits
Week
12
13
24
36
48
60
64
30 FU
Unscheduled Visit
ESDD
Window in Days
5
5
5
5
5
5
5
5
5
5
GS-5745 ADA collection f
X
X
X
X
Biomarker collection g
X
X
X
X
X
X
X
C-Reactive Protein
X
X
X
X
X
X
X
X
Study Drug Administration h
Concomitant medications, adverse events
X
a
Vital Signs include blood pressure, pulse, respirations, temperature 
b
Symptom-directed physical exam as needed 
c
Hematology: Complete blood count with differential and reticulocytes. Chemistry: Alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect bilirubin, total protein, 
albumin, bicarbonate, BUN, calcium, chloride, serum creatinine
d
Women of child bearing potential only. Patients will be supplied with home urine pregnancy kits and instructed to test every 4 weeks. Site will follow-up with a phone call. 
Pregnancy form should be completed should a pregnancy occur,
e
Prior to drug dose on  (Week 24) and anytime on  (Week 64)
f
Prior to study dose on  (Week 24) and any time on  (week 64) and the 30 day follow-up   
h
Patients receive weekly SC injections. SC Study drug administration will occur at the study site for the first 2 doses in the OLE phase at Week 12 and Week 13. Subjects will 
remain at the study site for 30 minutes after the injection for observation at week 12 and week 13. If subjects are judged capable, subjects may administer study drug at home 
for the remainder of the study. SC Study drug administration and anti-TNF administration must be separated in time by at least 24 hours in the blinded and OLE phase of the 
study
i
Con meds and adverse events will be recorded throughout the study. Patients will be questioned on con med and adverse events at in office visits


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Appendix 3.
Management of Clinical and Laboratory Adverse Events


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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://www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-%20DMCC.pdf
CTCAE v4.03 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Mild; asymptomatic or 
mild symptoms; clinical or 
diagnostic observations 
only; intervention not
indicated.
Moderate; minimal, 
local or noninvasive 
intervention indicated;  
limiting age-
appropriate
instrumental ADL*.
Severe or medically 
significant but not 
immediately life-threatening;
hospitalization or 
prolongation of
hospitalization indicated; 
disabling; limiting self -care 
ADL**.
Life-threatening 
consequences; urgent 
intervention indicated.
Death related to 
AE.
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.


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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.  In 
addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
The risks of treatment with GS-5745 during pregnancy have not been evaluated in humans. The 
potential for genotoxicity is not expected given that GS-5745 is a monoclonal antibody. In both 
the rat and rabbit definitive embryo-fetal developmental toxicity studies, there were no 
GS-5745-related effects on embryo-fetal survival and growth and no fetal anomalies. In a 
fertility study in male and female rats, no test article-related effects on reproductive performance 
and intrauterine survival were observed at any dosage level. In addition, male and female 
reproductive organ weights were unaffected by GS 5745 at all dose levels. There were no test 
article-related effects on spermatogenic endpoints at any dose level. The animal peri/post-natal
study is ongoing. Women of childbearing potential should be informed of the potential risk and 
use highly effective methods of birth control during treatment with GS-5745 from screening until 
30 days after the end of relevant systemic exposure. A clinically relevant interaction between 
GS-5745 and contraceptive steroids is not expected because of their distinct metabolic pathways 
and therefore, hormonal contraception may be used as part of the birth control methods.
Please refer to the latest version of the investigator’s brochure of GS-5745 for additional 
information.


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b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures.  They must have a negative serum pregnancy test at Screening and a 
negative pregnancy test on the Baseline/Day 1 visit prior to randomization.  Pregnancy tests will 
be performed at monthly intervals thereafter.  Female subjects must agree to one of the following 
from Screening until 30 days following the end of relevant systemic exposure.

Complete abstinence from intercourse. Abstinence is an acceptable method of contraception 
only when it is in line with the subject’s preferred and usual lifestyle. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception, Or

Consistent and correct use of 1 of the following methods of birth control listed below, in 
addition to a male partner who correctly uses a condom from the date of screening until 
30 days after last dose of study drug:
intrauterine device (IUD) with a failure rate of < 1% per year
female barrier method: cervical cap or diaphragm with spermicidal agent
tubal sterilization
vasectomy in male partner
implants of levonorgestrel
injectable progesterone
oral contraceptives (either combined or progesterone only)
contraceptive vaginal ring 
transdermal contraceptive patch
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the end of relevant systemic exposure.
3) Contraception Requirements for Male Subjects

All male study participants must agree to consistently and correctly use a condom from 
Baseline until 90 days after the last dose of study drug. If their female partner is of 
childbearing potential (as defined above), their female partner must use 1 of the methods of 
birth control listed above for the same duration.

Male subjects must agree to refrain from sperm donation for at least 90 days after the 
last dose of study drug.


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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 (90 days for partners male subjects) of last 
study drug dose. Subjects who become pregnant or who suspect that they are pregnant during the 
study must report the information to the investigator and discontinue study drug immediately. 
Subjects whose partner has become pregnant or suspects she is pregnant during the study must 
report the information to the investigator.  Instructions for reporting pregnancy, partner 
pregnancy, and pregnancy outcome are outlined in Section 7.7.2.1


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Appendix 6.
American College of Rheumatology:  1991 Revised Criteria for the 
Classification of Global Functional Status of Rheumatoid Arthritis*
Criterion
Definition
Class I
Completely able to perform usual activities of daily living (self-care, 
vocational, and avocational)
Class II
Able to perform usual self-care and vocational activities, but limited in 
avocational activities
Class III
Able to perform usual self-care activities, but limited in vocational and 
avocational activities
Class IV
Limited in ability to perform usual self-care, vocational, and avocational 
activities
*
Usual self-care activities include dressing, feeding, bathing, grooming and toileting. Avocational (recreational and/or 
leisure) and vocational (work, school, homemaking) activities are patient-desired and age and sex specific


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Appendix 7.
The 2010 American College of Rheumatology –European League 
Against Rheumatism Collaborative Initiative Classification Criteria 
for Rheumatoid Arthritis {Aletaha et al 2010}
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).
h
Negative refers to IU values that are less than or equal to the upper limit of normal (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 (e.g., pain, swelling, 
tenderness) of joints that are clinically involved at the time of assessment, regardless of treatment status.


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Appendix 8.
American College of Rheumatology Response (ACR 20/50/70): {Felson 
et al 1995}
ACR Crtieria used to assess treatment response levels, reported as % improvement from 
baseline.  The definition of ACR 20/50/70 is 20/50/70% improvement in tender and swollen 
joints plus a ≥20/50/70 % improvement in at least three of the following five parameters:

Subject assessment of  pain 

Subject Assessment of global disease activity

Provider’s assessment of global disease activity

Subject’s assessment of physical function

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-non tender 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 will be used to assess the patient’s current level of pain using a 
Visual Analog Scale from 0-100 mm.
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


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4.
Patient’s global assessment of disease activity
A horizontal, visual analog scale 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 visual analog scale 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 9.
Disease Activity Score DAS28- CRP {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
[CRP] consists of a composite score of the following variables: tender joint count, swollen joint 
count, CRP, and patient global score. The following equation will be used to calculate the 
DAS28- CRP

DAS28-CRP(4) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP+1) + 0.014*GH + 0.96
TJC28 = number of joints tender out of 28
SJC28 = number of joints swollen out of 28
CRP = C-reactive protein

= 100 mm or 10 cm VAS recorded by the patient (patient’s global assessment )
Place a mark on the line below to indicate how you assess your current arthritis disease 
activity:
No arthritis activity
Extremely active arthritis


GS-5745
Protocol GS-US-373-1499
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 81
14 March 2016
Appendix 10.
Frederica’s Formula
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) 
http://www.thecalculator.co/health/QTc-Calculator-385.html