A Randomized, Double-blind, Placebo- and Active-controlled, Multicenter, Phase 3 Study to Assess the Efficacy and Safety of Filgotinib Administered for 52 Weeks Alone and in Combination With Methotrexate (MTX) to Subjects With Moderately to Severely Active Rheumatoid Arthritis Who Are Naïve to MTX Therapy
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Sponsor: Gilead Sciences

CLINICAL STUDY PROTOCOL
Study Title:
A Randomized, Double-blind, Placebo- and Active-controlled, 
Multicenter, Phase 3 Study to Assess the Efficacy and Safety of 
Filgotinib Administered for 52 Weeks Alone and in Combination 
with Methotrexate (MTX) to Subjects with Moderately to Severely
Active Rheumatoid Arthritis Who Are Naïve to MTX Therapy
Sponsors:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
115,510
2016-000570-37
TBD
Indication:
Rheumatoid Arthritis
Protocol ID:
GS-US-417-0303
Gilead Clinical 
Program Manager: 
Name:
Telephone:
Gilead 
Medical Monitor:
Name:
Telephone:
Fax:
Mobile:
Protocol Version/Date:
Original:
22 April 2016
Amendment 1:
05 July 2016
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
Institutional Review Board or Independent Ethics Committee. The information is only to be used 
by you in connection with authorized clinical studies of the investigational drug described in the 
protocol. You will not disclose any of the information to others without written authorization 
from Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
PPD
PPD
PPD
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................15
1.
INTRODUCTION ..............................................................................................................................................18
1.1.
Background ............................................................................................................................................18
1.2.
Filgotinib................................................................................................................................................19
1.2.1.
General Information .............................................................................................................19
1.2.2.
Nonclinical Pharmacology, Absorption, Distribution, Metabolism, and 
Excretion (ADME) and Toxicology.....................................................................................19
1.2.3.
Clinical Trials of Filgotinib..................................................................................................21
1.3.
Rationale for This Study ........................................................................................................................26
1.3.1.
Rationale for Study Design ..................................................................................................27
1.3.2.
Rationale for the Outcome Measures ...................................................................................27
1.3.3.
Rationale for the Choice of Dose and Dosing Interval.........................................................28
1.4.
Risk/Benefit Assessment for the Study..................................................................................................29
1.5.
Compliance ............................................................................................................................................30
2.
OBJECTIVES.....................................................................................................................................................31
3.
STUDY DESIGN................................................................................................................................................33
3.1.
Endpoints ...............................................................................................................................................33
3.2.
Study Design..........................................................................................................................................34
3.3.
Study Treatments ...................................................................................................................................35
3.4.
Duration of Treatment............................................................................................................................36
3.5.
Criteria for Interruption or Discontinuation of Study Treatment ...........................................................36
3.5.1.
Study drug interruption considerations: ...............................................................................36
3.5.2.
Study drug discontinuation considerations:..........................................................................37
3.6.
End of Study...........................................................................................................................................38
3.7.
Post Study Care......................................................................................................................................39
3.8.
Biomarker Samples ................................................................................................................................39
3.8.1.
Biomarker Samples to Address the Study Objectives:.........................................................39
3.8.2.
Biomarker Samples for Optional Future Research...............................................................40
4.
SUBJECT POPULATION..................................................................................................................................42
4.1.
Number of Subjects and Subject Selection ............................................................................................42
4.2.
Inclusion Criteria....................................................................................................................................42
4.3.
Exclusion Criteria...................................................................................................................................44
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................49
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................49
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................49
5.2.
Description and Handling of Filgotinib and PTM Filgotinib .................................................................49
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5.2.1.
Formulation of Filgotinib and PTM Filgotinib.....................................................................49
5.2.2.
Packaging and Labeling for Filgotinib and PTM Filgotinib.................................................50
5.2.3.
Storage and Handling for Filgotinib and PTM Filgotinib ....................................................50
5.2.4.
Dosage and Administration of Filgotinib .............................................................................50
5.3.
Description and Handling of Methotrexate (MTX) and PTM MTX......................................................51
5.3.1.
Formulation for MTX and PTM MTX.................................................................................51
5.3.2.
Packaging and Labeling for MTX and PTM MTX ..............................................................51
5.3.3.
Storage and Handling for MTX and PTM MTX..................................................................51
5.3.4.
Dosage and Administration of MTX....................................................................................51
5.4.
Prior and Concomitant Medications.......................................................................................................52
5.5.
Accountability for Study Drugs .............................................................................................................55
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................55
6.
STUDY PROCEDURES ....................................................................................................................................57
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................57
6.2.
Pretreatment Assessments......................................................................................................................57
6.2.1.
Screening Visit .....................................................................................................................57
6.2.2.
Day 1 Assessments...............................................................................................................59
6.3.
Randomization .......................................................................................................................................60
6.4.
Week 2 through Week 44 Assessments .................................................................................................60
6.5.
Week 52/Early Termination (ET)...........................................................................................................62
6.6.
Post Treatment Week 4 ..........................................................................................................................63
6.7.
Study Assessments.................................................................................................................................64
6.7.1.
Efficacy ................................................................................................................................64
6.7.2.
Safety and Tolerability.........................................................................................................68
6.7.3.
Clinical Laboratory Evaluations...........................................................................................68
6.7.4.
Vital Signs............................................................................................................................68
6.7.5.
Physical Examination...........................................................................................................68
6.7.6.
Other Safety Assessments ....................................................................................................69
6.8.
Pharmacokinetics Assessments..............................................................................................................69
6.9.
Biomarker Assessments .........................................................................................................................69
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................70
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................70
7.1.1.
Adverse Events.....................................................................................................................70
7.1.2.
Serious Adverse Events........................................................................................................70
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................71
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................71
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................71
7.2.2.
Assessment of Severity ........................................................................................................72
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................72
7.4.
Gilead Reporting Requirements.............................................................................................................74
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................74
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................75
7.5.2.
Grades 3 Laboratory Abnormality or Clinical Event ...........................................................75
7.5.3.
Grades 4 Laboratory Abnormality or Clinical Event ...........................................................75
7.6.
Toxicity Management ............................................................................................................................76
7.7.
Special Situations Reports......................................................................................................................76
7.7.1.
Definitions of Special Situations..........................................................................................76
7.7.2.
Instructions for Reporting Special Situations.......................................................................77

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8.
STATISTICAL CONSIDERATIONS................................................................................................................79
8.1.
Analysis Objectives and Endpoint .........................................................................................................79
8.1.1.
Analysis Objectives..............................................................................................................79
8.1.2.
Primary Endpoint .................................................................................................................80
8.1.3.
Secondary Endpoints............................................................................................................80
8.2.
Analysis Conventions.............................................................................................................................81
8.2.1.
Analysis Sets ........................................................................................................................81
8.3.
Data Handling Conventions ...................................................................................................................82
8.4.
Demographic Data and Baseline Characteristics ...................................................................................82
8.5.
Efficacy Analysis ...................................................................................................................................82
8.5.1.
Primary Analysis..................................................................................................................82
8.5.2.
Secondary Analyses .............................................................................................................83
8.6.
Safety Analysis.......................................................................................................................................84
8.6.1.
Extent of Exposure...............................................................................................................84
8.6.2.
Adverse Events.....................................................................................................................84
8.6.3.
Laboratory Evaluations ........................................................................................................85
8.7.
Pharmacokinetic Analysis......................................................................................................................85
8.8.
Biomarker Analysis................................................................................................................................85
8.9.
Sample Size............................................................................................................................................85
8.10.
Data Monitoring Committee ..................................................................................................................86
8.11.
Cardiovascular Endpoint Adjudication Committee................................................................................86
8.12.
Analysis Schedule ..................................................................................................................................86
9.
RESPONSIBILITIES..........................................................................................................................................87
9.1.
Investigator Responsibilities ..................................................................................................................87
9.1.1.
Good Clinical Practice..........................................................................................................87
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................87
9.1.3.
Informed Consent.................................................................................................................87
9.1.4.
Confidentiality......................................................................................................................88
9.1.5.
Study Files and Retention of Records ..................................................................................88
9.1.6.
Case Report Forms...............................................................................................................89
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................90
9.1.8.
Inspections............................................................................................................................90
9.1.9.
Protocol Compliance............................................................................................................90
9.2.
Sponsor Responsibilities ........................................................................................................................91
9.2.1.
Protocol Modifications.........................................................................................................91
9.2.2.
Study Report and Publications .............................................................................................91
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................91
9.3.1.
Payment Reporting...............................................................................................................91
9.3.2.
Access to Information for Monitoring..................................................................................92
9.3.3.
Access to Information for Auditing or Inspections ..............................................................92
9.3.4.
Study Discontinuation..........................................................................................................92
10.
REFERENCES ...................................................................................................................................................93
11.
APPENDICES ....................................................................................................................................................95
Appendix 1.
Investigator Signature Page....................................................................................................96
Appendix 2.
Study Procedures Table..........................................................................................................97
Appendix 3.
Management of Clinical and Laboratory Adverse Events....................................................102
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03..................................103
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Methods.........................................................................................................104

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Appendix 6.
Laboratory Assessment Table ..............................................................................................108
Appendix 7.
List of Joints to be Evaluated (66/68 Joint Count) ...............................................................109
Appendix 8.
The 2010 American College of Rheumatology –European League Against 
Rheumatism Collaborative Initiative Classification Criteria for Rheumatoid 
Arthritis {Aletaha et al 2010}...............................................................................................110
Appendix 9.
American College of Rheumatology Response Evaluations/ Preliminary Definition 
of Improvement in Rheumatoid Arthritis {Felson et al 1995} .............................................112
Appendix 10.
Disease Activity Score (DAS28) {Prevoo et al 1995} .........................................................114
Appendix 11.
Procedures and Specifications..............................................................................................115
LIST OF IN-TEXT TABLES
Table 1-1.
Summary and analysis of ACR20/50/70 response at Weeks 12 and 24 (NRI [ITT 
Population]), GLPG0634-CL-203..........................................................................................22
Table 1-2.
Summary and analysis of ACR20/50/70 response at Weeks 12 and 24 (NRI [ITT 
Population]); GLPG0634-0204 ..............................................................................................25
Table 7-1.
Grading of Adverse Event Severity........................................................................................72
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Design ..........................................................................................................................35

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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404 
USA
Study Title: 
A Randomized, Double-blind, Placebo- and Active-controlled, 
Multicenter, Phase 3 Study to Assess the Efficacy and Safety of 
Filgotinib Administered for 52 Weeks alone and in Combination 
with Methotrexate (MTX) to Subjects with Moderately to Severely 
Active Rheumatoid Arthritis Who Are Naïve to MTX Therapy
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
115,510
2016-000570-37
TBD
Study Centers Planned:
Approximately 200-250 centers worldwide
Objectives:
The primary objective of this study is:

To evaluate the effects of filgotinib in combination with MTX 
versus MTX alone for the treatment of signs and symptoms of 
rheumatoid arthritis (RA) as measured by the proportion of 
subjects achieving an American College of Rheumatology 20% 
improvement response (ACR20) at Week 24
The secondary objectives of this study include: 

To evaluate the effect of filgotinib in combination with MTX 
versus MTX alone on physical function as measured by change 
from Baseline in the Health Assessment Questionnaire 
Disability Index (HAQ-DI) score at Week 24.

To evaluate the effects of filgotinib in combination with MTX 
versus MTX alone for the treatment of signs and symptoms of 
RA as measured by the proportion of subjects achieving 
Disease Activity Score for 28 joint count using C-reactive 
protein (DAS28 [CRP]) < 2.6 at Week 24 

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
To evaluate the effect of filgotinib alone versus MTX alone for 
the treatment of signs and symptoms of RA as measured by the 
proportion of subjects achieving ACR20 at Week 24

To evaluate the effect of filgotinib alone versus MTX alone on 
physical function as measured by change from Baseline in 
HAQ-DI score at Week 24 

To evaluate the effect of filgotinib alone versus MTX alone for 
the treatment of signs and symptoms of RA as measured by the 
proportion of subjects achieving DAS28(CRP) <2.6 at Week 
24

To evaluate the effects of filgotinib in combination with MTX
versus MTX alone on preservation of joint structure as 
measured by change from Baseline in the van der Heijde 
modified Total Sharp Score (mTSS) at Week 24 and 52

To evaluate the effects of filgotinib alone versus MTX alone 
on preservation of joint structure as measured by change from 
Baseline in mTSS at Week 24 and 52

To evaluate the safety and tolerability of filgotinib alone and in 
combination with MTX 

To evaluate the effects of filgotinib alone and in combination 
with MTX on work productivity, fatigue, and general quality 
of life as measured by SF-36, FACIT-Fatigue, EQ-5D and 
WPAI-RA
The exploratory objectives of this study include:
 
 
 
Study Design:
This is a randomized, double-blind, placebo- and active-controlled, 
Phase 3 study in adult male and female subjects with moderately to 
severely active RA who are naïve to MTX therapy. The study is 
designed to evaluate the efficacy, safety and tolerability of 
filgotinib alone and in combination with MTX as well as its effect 
on work productivity, fatigue, and quality of life.
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Approximately 1200 subjects will be randomized in a 2:1:1:2 ratio
to filgotinib 200 mg with MTX, filgotinib 100 mg with MTX, 
filgotinib 200 mg alone, or MTX alone for up to 52 weeks:

Filgotinib 200 mg + MTX group: Filgotinib (200 mg q.d.) +
PTM filgotinib 100 mg (PTM q.d.) + MTX (once weekly up to 
20 mg) (N=400)

Filgotinib 100 mg + MTX group: Filgotinib (100 mg q.d.) +
PTM filgotinib 200 mg (PTM q.d.) + MTX (once weekly up to 
20 mg) (N=200)

Filgotinib 200 mg monotherapy group: Filgotinib (200 mg 
q.d.) + PTM filgotinib 100 mg (PTM q.d.) + PTM MTX (PTM 
once weekly) (N=200)

MTX monotherapy group: PTM filgotinib 100 mg (PTM q.d.)
+ PTM filgotinib 200 mg (PTM q.d.) + MTX (once weekly up 
to 20 mg) (N=400)
Randomization will be stratified by geographic region and 
presence of rheumatoid factor (RF) or anti-CCP (cyclic 
citrullinated peptide) antibody (Ab) at Screening.
At Week 24, subjects who have not achieved at least a 20% 
improvement from Day 1 in both swollen joint count (SJC) and 
tender joint count (TJC) will discontinue investigational study 
drug dosing but will continue with study visits and assessments per 
protocol. All subjects meeting this criterion who discontinue from 
investigational therapy are to receive standard of care treatment for 
their RA as determined by the investigator. Subjects achieving at 
least a 20% improvement in SJC and TJC at Week 24 will 
continue on the dosing regimens to which they were randomized 
through Week 52. 
All subjects who continue on study drug will be evaluated for loss 
of therapeutic response from Week 30 through Week 52. Subjects 
failing to maintain at least a 20% improvement from Day 1 in TJC 
and SJC, (which is confirmed at 2 consecutive visits), will
discontinue from investigational study drug dosing but will 
continue with study visits and assessments per protocol. All 
subjects meeting this criterion who discontinue from 
investigational study drug dosing are to receive standard of care 
treatment for their RA as determined by the investigator.
All subjects who have received at least one dose of study drug and 
exit the study early will complete an early termination (ET) visit at 
the time of study discontinuation, with a post treatment visit 
four weeks after the last dose of study drug (Post Treatment 
Week 4) regardless of dosing duration.

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At completion of the 52-week study period, subjects who have not 
discontinued assigned study drug dosing, will be provided the 
option to enroll into a separate Long Term Extension (LTE) study 
(GS-US-417-0304).
Study Design
Number of Subjects 
Planned:
Approximately 1200 subjects
Target Population:
Male or female subjects who are ≥18 years of age with a diagnosis 
of RA meeting the 2010 ACR/ European League Against 
Rheumatism (EULAR) criteria, who have active RA and had 
limited or no prior exposure to MTX.
Duration of Treatment:
Up to 52 weeks
Diagnosis and Main 
Eligibility Criteria:
For a complete list of study inclusion and exclusion criteria, please 
refer to Sections 4.2 and 4.3.
Main Eligibility Criteria
1) Male or female subjects who are ≥18 years of age, on the day 
of signing informed consent
2) Have a diagnosis of RA (2010 ACR/ EULAR criteria), and are 
ACR functional class I-III
3) Have ≥6 swollen joints (from a SJC66) and ≥6 tender joints 
(from a TJC68) at Screening and Day 1 
DAY 1 
WK24 
Primary Endpoint 
WK 52 
SCREENING~ 
RANDOM IZATION 
28 days prior 
2:1 :1 :2 
to Day 1 
(may be extended 
to 
42 days if 
repeat 
radiographs are 
required) 
WK 24: ;, Standard of care for all subjects with 
Subjects with 
protocol-defined inadequate response 
inadequate 
response will 
discontinue 
study drugs 

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4) Must meet at least one of the following parameters at 
Screening:

positivity for either  RF or anti-CCP Ab per central 
laboratory 
OR

Serum CRP ≥ 4 mg/L based on central laboratory value
OR

≥1 documented joint erosion on radiographs of the hands, 
wrists or feet by central reading
5) Limited or no prior treatment with MTX, ie, no more than 
3 doses of MTX ≤25 mg each in their lifetime for the treatment 
of RA, with last dose at least 28 days prior to Day 1, and are an 
appropriate candidate for MTX therapy, as per investigator 
judgment
Study Procedures/
Frequency:
The subjects will visit the clinical study center at Screening, 
Day 1, Weeks 2, 4, 8, 12, 16, 20, 24, 30, 36, 44, and 52 or ET. 
For those subjects not entering the LTE, a follow-up visit will be 
planned 4 weeks after the last dose of study drug (Post Treatment 
Week 4). Consequently, subjects are planned to be in the study for 
approximately 60 weeks. 
During the Screening period, the subject’s radiographs (hands, 
wrists, and feet) will be sent for blinded central scoring. In 
addition, information on demographics, medical 
history/concomitant diseases, prior and current RA medications
will be collected. A physical examination, a 12-lead 
electrocardiogram (ECG), and clinical laboratory assessments will 
be conducted to determine the subject’s eligibility for study 
participation. The screening window may be extended to up to 
42 days prior to the Day 1 visit for subjects who require repeat 
collection of radiographs only.
At Day 1, after the subject’s eligibility for the study has been 
confirmed, the subject will be randomized to receive one of 
4 dosing regimens: filgotinib 200 mg q.d. plus MTX up to 20 mg 
weekly, filgotinib 100 mg q.d. plus MTX up to 20 mg weekly,
filgotinib monotherapy 200 mg q.d. or MTX monotherapy up to 
20 mg weekly. 

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On-treatment assessments will include: adverse events (AEs), 
concomitant medications,  review of study medication compliance 
through drug accountability, SJC66, TJC68, Subject’s Global 
Assessment, Subject’s Pain Assessment, HAQ-DI, Functional 
Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), 
Short-Form Health Survey (SF-36), Work Productivity and 
Activity Impairment- Rheumatoid Arthritis (WPAI-RA), 
EuroQol 5 Dimensions (EQ-5D), 
 
Treatment Satisfaction Questionnaire for Medication 
(TSQM), Healthcare Resource Utilization, Physician’s Global 
Assessment, physical examination, weight, vital signs, serum CRP, 
blood and urine sampling for safety laboratory tests and 
biomarkers at selected visits, and urine pregnancy tests (females of 
child bearing potential only).
A resting 12-lead ECG should be performed at Screening, 
Weeks 12, 24, 36, and 52 or ET, and at the Post-treatment Week 4 
follow-up visit. ECGs should be interpreted by the investigator
(or qualified designee) for clinical significance. 
For all subjects, blood samples for PK analysis should be collected 
at least 30 minutes post study drug dose on Week 4, prior to study 
drug administration on Weeks 12 and 24,  and any time at the final 
assessment visit on Week 52 or ET. 
 
 
 
Blood samples for biomarker analysis should be collected at 
Day 1, Weeks 4, 8, 12, 24, 36, and Week 52 or ET and urine 
samples should be collected at Day 1, Weeks 12, 24, and Week 52 
or ET.
Radiographs of the bilateral hands, wrists, and feet should be taken 
at Screening, Week 24, and Week 52 or ET. However, if a subject 
prematurely discontinues study participation and has had X-rays 
performed within the previous 12 weeks, then X-rays do not need 
to be repeated at the ET visit. Radiographs performed after 
enrollment may be done +/-7 days of the scheduled visit.
Post treatment follow-up assessments include AEs, concomitant 
medications, physical examination, 12-lead ECG, weight, vital 
signs, blood and urine sampling for safety laboratory tests, and 
urine pregnancy tests (females of child bearing potential only).
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10) Superiority of filgotinib 100 mg in combination with MTX 
compared to MTX alone based on the change from Baseline in 
mTSS at Week 24
11) Superiority of filgotinib 200 mg alone compared to MTX alone 
based on the change from Baseline in mTSS atWeek 24
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.
Sample size is determined based on the superiority test of 
filgotinib 200 mg in combination with MTX compared to MTX 
alone based on the change from Baseline in mTSS at Week 24. 
When assuming a difference of 0.62 between the two groups and a 
common standard deviation of 2.7, 400 subjects in the filgotinib 
200 mg in combination with MTX group and 400 in the MTX 
alone group are required to obtain 90% power at a 2-sided 
0.05-level.
The total sample size will be 1200 (400 subjects for filgotinib 
200 mg in combination with MTX group, 200 subjects for 
filgotinib 100 mg in combination with MTX group, 200 subjects 
for filgotinib 200 mg alone group and 400 subjects for MTX alone 
group). This sample size will provide over 90% power to detect an 
increase in ACR20 response rate of 62% to 78% between the MTX 
alone group and each of the filgotinib groups respectively, using a 
2-sided 0.05-level test.
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
Ab
antibody
ACPA
anti-citrullinated protein antibody
ACR X
American College of Rheumatology X% improvement
AE
adverse event
ALT
alanine aminotransferase
ANA
anti-nuclear antibody
aPTT
activated partial thromboplastin time
ATP 
adenosine triphosphate
AST
aspartate aminotransferase
AUC0-Ʈ
area under the plasma drug concentration-time curve of a dosing interval
bDMARD(s)
biologic disease modifying antirheumatic drug(s)
b.i.d.
bis in die; twice daily
CƮ
trough plasma concentration (just before the next dosing ie, pre-dose sample)
CCP
cyclic citrullinated peptide
CD
Crohn’s Disease
CDAI
Clinical Diagnostic Activity Index
csDMARD(s)
conventional synthetic disease modifying antirheumatic drug(s)
CES
carboxylesterases
CIA
collagen-induced arthritis
Cmax
maximum observed plasma concentration
CMV
cytomegalovirus
CNS
central nervous system
CRO 
Contract Research Organization
CRP
C-reactive protein
CV-SEAC
Cardiovascular Safety Endpoint Adjudication Committee
CYP
Cytochrome 
DAS28
Disease Activity Score based on 28 joints
DBP
diastolic blood pressure
DMARD(s)
disease-modifying anti-rheumatic drugs
DMC/DSMB
data monitoring committee/data safety monitor board
dsDNA
double stranded deoxyribonucleic acid
DSS
dextran sulphate sodium
ECG
electrocardiogram
eCRF
electronic case report form
ET
early termination
EU
European Union
EULAR
European League Against Rheumatism
EQ-5D
EuroQol 5 Dimensions
FACIT-Fatigue
Functional Assessment of Chronic Illness Therapy-Fatigue
FAS
full analysis set
FDA
Food and Drug Administration

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FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GI
gastrointestinal 
GLP 
Galapagos 
HAQ-DI
Health Assessment Questionnaire – Disability Index
HCV
hepatitis C virus
HCG
human chorionic gonadotropin
HCQ
hydroxychloroquine
HDL
high density lipoprotein
hERG
human ether-a-gogo related gene
HIV
human immunodeficiency virus
HR
heart rate
IC50
half maximal inhibitory concentration
ICF
informed consent form
ICH
International Council for Harmonization
IEC
Independent Ethics Committee
Ig
immunoglobulin
IMP
investigational medicinal product
INR
international normalized ratio
IRB
Independent Review Board
ITT
Intent-to-treat
IV 
intravenous
IWRS
interactive web response system
JAK
janus kinase 
LCMS/MS
liquid chromatography mass spectrometry
LDL
low density lipoprotein
LH
luteinizing hormone
LTE
Long Term Extension
MAA
Marketing Authorization Application
MACE
Major adverse cardiovascular event
MCV
mean corpuscular volume
MRI
magnetic resonance imaging
MTX
methotrexate
IR
inadequate responders
mTSS
modified Total Sharp Score
NDA
New Drug Application
NSAIDs
nonsteroidal anti-inflammatory drugs
NYHA
New York Heart Association
OATs
organic anion transporters
PBMC
peripheral blood mononuclear cells
PD
pharmacodynamics

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PK
pharmacokinetics
PP
per-protocol
PT
prothrombin time
PTM 
placebo to match
q.d.
quaque die; once daily
RA
rheumatoid arthritis
RAMRIS
rheumatoid arthritis magnetic resonance imaging score
RF 
rheumatoid factor
SAE
serious adverse event
SAP
Statistical Analysis Plan 
SBP
systolic blood pressure
s.c.
subcutaneous
SD
standard deviation
SDAI
Simplified Diagnostic Activity Index
SF-36
short-form health survey, 36 questions
SI 
international system of units
SJC66
swollen joint count based on 66 joints
TB
tuberculosis
TEAEs
treatment emergent adverse events
TJC68
tender joint count based on 68 joints
tmax
the time of occurrence of maximum observed plasma concentration
TNFi
tumor necrosis factor inhibitors
TNFα
tumor necrosis factor α
TSQM
Treatment Satisfaction Questionnaire for Medication
UGTs
uridine 5’disphosphate glucuronosyltransferases
ULN
upper limit of normal
US
United States
vfPBMCs
viably frozen peripheral blood mononuclear cells
vs.
versus
WBC
white blood cell
WPAI-RA
Work Productivity and Activity Impairment for Rheumatoid Arthritis
Definition of Terms
QTcF
QT interval corrected for HR according to Fridericia’s formula: 
QTcF = QT/(RR)^(1/3), where RR = 60/HR
RR = RR interval in seconds
HR = heart rate in beats per minute

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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. While the cause of RA is still not completely understood, aberrant B-cell 
activation, T-cell co-stimulation, osteoclast differentiation, and cytokine release all have been 
implicated in its pathogenesis.
Treatment of RA is dependent on severity, the patient’s co–morbidities and initial response to 
therapy. Methotrexate is a conventional synthetic disease modifying anti-rheumatic drug 
(csDMARD) and continues to be the cornerstone of RA therapy {Singh et al 2012}. Patients 
with an inadequate response to csDMARD(s) are often treated with biologic therapies such as 
tumor necrosis factor inhibitors (TNFi) as an initial second line therapy. However, approximately 
28% to 58% of RA patients with inadequate response to MTX fail TNFi as reviewed in {Redlich 
et al 2003}. In this setting, treatment guidelines recommend either switching to another TNFi, 
alternate biologic, or to a small molecule drug {Singh et al 2012}. Despite significant advances 
in disease management in recent years, there remains a need for new treatments, since not all 
patients respond adequately to current therapies, have co-morbidities and some patients 
experience toxicities and/or intolerance that limit the use of approved therapies.
In November 2012, tofacitinib (Xeljanz®) became the first Janus kinase (JAK) inhibitor to 
receive Food and Drug Administration (FDA) approval for the treatment of adult patients with 
RA. Tofacitinib is a small molecule, has strong binding affinity for JAK1 and JAK3, and weaker 
affinity for JAK2. The extensive pre-clinical and clinical development programs demonstrated its 
mechanisms of action via anti-inflammatory and immunosuppressive effects. The drug proved to 
be efficacious in treating the signs and symptoms of RA. However, the observed side-effects and 
risk profile of tofacitinib are similar to those of several existing anti-rheumatic agents with 
cytopenias, elevated levels of liver function enzymes, increased total cholesterol levels, with 
increases in LDL typically exceeding those for HDL, and increased risk for infections including 
serious and opportunistic infections. At higher doses, tofacitinib treatment was associated with 
anemia, which is thought to be linked to inhibition of JAK2.
While the pan JAK inhibitor tofacitinib has shown an early onset of action and long-term 
efficacy in RA as mono therapy and in combination with background csDMARD therapy, dose 
levels were limited by side effects potentially mediated by its effect on JAK 2 and JAK 3. This 
highlights the need for more selective and targeted therapies with improved immunomodulatory 
and hematologic effects. JAK1 is thought to be an integral part of RA pathogenesis due its role in 
transmitting inflammatory cytokine signaling. Hence, targeted inhibition of JAK1 has great 
potential for the treatment of RA with an improved safety and side effect profile. 

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1.2.
Filgotinib
1.2.1.
General Information
Janus kinases are intracellular cytoplasmic tyrosine kinases (TYKs) that transduce cytokine 
signaling from membrane receptors through signal transducer and activator of transcription 
(STAT) to the nucleus of cells. JAK inhibitors block the signaling of various cytokines, growth 
factors, and hormones, including the pro-inflammatory cytokine interleukin (IL)-6. Four 
different types of JAKs are known, JAK1, JAK2, JAK3, and TYK2 which co-interact with 
different sets of membrane receptors. Inhibition of JAKs is a promising therapeutic option for a 
range of inflammatory conditions including RA and Crohn’s Disease (CD).
Filgotinib (GS-6034, formerly GLPG0634) is a potent and selective inhibitor of JAK1. The 
compound has shown good preliminary efficacy in RA and CD patients in Phase 2. No typical 
JAK2 side effects such as anemia were observed in clinical studies of up to 24 weeks duration. 
In humans, filgotinib is metabolized to form one major active metabolite, GS-829845
(formerly G254445). Though the potency of this metabolite is lower than the parent molecule, 
the overall exposure and peak plasma concentration in humans is higher than seen in all tested 
animal species. As a consequence, dedicated pharmacology and toxicology studies have been 
performed with GS-829845.  Results from pharmacodynamics (PD) testing in healthy volunteers 
suggest that the clinical activity of filgotinib could result from the combination of the parent 
molecule and the metabolite.
For further information on filgotinib, refer to the current investigator’s brochure.
1.2.2.
Nonclinical Pharmacology, Absorption, Distribution, Metabolism, and 
Excretion (ADME) and Toxicology
Filgotinib and its metabolite, GS-829845 have been extensively characterized in nonclinical 
studies. This program includes cellular assays demonstrating potency and selectivity of the 
compound against JAK1; efficacy studies in rats and mice; repeat dose toxicity studies (up to 
26 weeks in the rat and 39 weeks in the dog), in vitro and in vivo safety pharmacology and 
genetic toxicology studies, and reproductive toxicology studies in rats and rabbits. Additional 
toxicology studies conducted include phototoxicity studies and dose-range finding studies in 
support of a definitive rat juvenile toxicity study and a 6 month carcinogenicity study in 
transgenic (TgrasH2) mice. A 2 year rat oral carcinogenicity study is ongoing.
1.2.2.1.
Primary and Secondary Pharmacology
Filgotinib is an adenosine triphosphate (ATP)-competitive inhibitor of JAK1. It is highly 
selective for inhibition of JAK1 over 451 other kinases evaluated in vitro. In cellular assays, it 
inhibits JAK/STAT-driven processes with half maximal inhibitory concentration (IC50) values 
from 179 nM onwards.  In human whole blood, JAK1 is inhibited by filgotinib with an IC50 of 
629 nM and exhibits approximately 30-fold selectivity over JAK2. Filgotinib demonstrated 
significant efficacy in the rat collagen-induced arthritis (CIA) model as well as in the mouse 
dextran sulphate sodium (DSS)-induced colitis model.

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Metabolite GS-829845 exhibits a similar JAK1 selectivity profile but is approximately 
10 to 20-fold less potent than the parent filgotinib in in vitro assays. GS-829845 was as effective 
as filgotinib in the rat CIA model, but at doses that required a 10-fold higher exposure.
1.2.2.2.
Safety Pharmacology
Filgotinib and GS-829845 had no effects on the respiratory system and central nervous system 
(CNS) up to respectively 40- and 5-fold the exposure in RA subjects given filgotinib 200 mg q.d.
Filgotinib and GS-829845 had no relevant effects on cardiovascular parameters (human 
ether-a-gogo related gene [hERG] and dog telemetry studies), apart from a slight non-adverse 
increase in heart rate and arterial pressure with GS-829845 at exposures 7-fold that of the Cmax in 
subjects with RA treated with 200 mg q.d. filgotinib. There were no relevant effects on 
electrocardiogram (ECG) and QT.
1.2.2.3.
Nonclinical ADME
Filgotinib demonstrates good oral bioavailability in mice, rats, dogs, and minipigs but less in 
monkeys.  Plasma protein binding is low (< 70%) in all species, including humans.
The pharmacokinetics (PK) of filgotonib is generally dose proportional without gender 
differences.  No accumulation occurs with repeated dosing. The mean terminal half-life after oral 
administration is 4 and 5 hours (h) in rats and dogs, respectively.
In the rat, filgotinib showed a rapid and even distribution throughout the body.  High 
concentrations were observed only in the gastrointestinal (GI) tract and urinary bladder. 
Filgotinib does not penetrate into central nervous system (CNS) tissues.  The distribution of 
filgotinib indicates some affinity for melanin-containing tissues.
Excretion is nearly complete within 24 h (rat) and 48 h (dog) post-dosing.  In the rat, fecal and 
urinary excretion accounted for 40% and 53% of the administered dose, respectively, with a bile 
secretion of about 15%.  In the dog, fecal excretion was the primary route of excretion, 
accounting for 59% of the administered dose, with urinary excretion accounting for 25%.
In vitro metabolism studies in all species revealed one major metabolite (GS-829845). The 
formation of GS-829845 is mediated by carboxylesterases (CES) and is not dependent on 
cytochrome P450 (CYP).
In vitro experiments have shown that drug-drug interactions with filgotinib and GS-829845 are 
unlikely. There is no inhibition or induction of CYPs or uridine 5’disphosphate 
glucuronosyltransferases (UGTs), and no relevant inhibition of key drug transporters, including 
the organic anion transporters (OATs) involved in the renal elimination of MTX, by filgotinib or 
GS-829845.

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1.2.2.4.
Nonclinical Toxicology
In repeat oral dose toxicity studies in both rats and dogs, the primary target tissues identified for 
filgotinib were the lymphoid tissues, which are expected based on the pharmacology of JAK 
inhibition. Additional filgotinib-related findings were observed in the male reproductive organs 
of both species, and in the incisor teeth of rats only. Effects on the lymphoid system were fully 
reversible. Testicular toxicity demonstrated partial reversibility, however, sperm counts remained 
low. A dose of 200 mg/day of filgotinib results in an estimated mean clinical AUC of 
2.80 μg∙h/mL, which represents an exposure margin of 2.3, 1.8, and 3.4-fold when considering 
the mean AUC in male dogs at the no-observed-effect-levels (NOELs) in the 26 week and
39 week chronic toxicity studies, and the 39 week targeted exposure toxicity study, respectively.
GS-829845-related findings in general repeat dose toxicity studies were similar to those of the 
parent filgotinib, however no testicular toxicity was noted following administration of 
GS-829845.
Filgotinib and GS-829845 were non-genotoxic when evaluated in the bacterial mutagenicity 
assay, the in vitro mouse lymphoma mutagenicity assay, and the rat bone marrow micronucleus 
assay.
In embryofetal development studies, filgotinib and GS-829845 caused embryolethality and 
teratogenicity in rats and rabbits at exposures similar to the human exposure at 200 mg q.d. of 
filgotinib in subjects with RA. Administration of filgotinib did not affect female fertility but 
impaired fertility was observed in male rats at exposures approximately 15-fold the human 
exposure at 200 mg of filgotinib in subjects with RA. GS-829845 did not have any effects on 
fertility parameters in either male or female rats.
In an in vitro phototoxicity study in 3T3 cells, the metabolite GS-829845 was positive for 
phototoxic potential and results with filgotinib were equivocal. A follow-up in vivo rat 
phototoxicity assay revealed a lack of phototoxic potential for both compounds.
1.2.3.
Clinical Trials of Filgotinib
Comprehensive data from the Phase 1 and 2 programs are available to support development into 
Phase 3. As of January 2016, filgotinib has been administered to more than 150 healthy subjects, 
more than 1000 RA subjects, and more than 150 subjects with CD. A detailed description of all 
clinical studies can be found in the Investigator’s Brochure (IB). 
Phase 2b GLPG0634-CL-203, filgotinib with MTX in RA
In GLPG0634-CL-203, subjects with active RA on stable dose of MTX were randomized to
receive either placebo or one of three total daily doses of filgotinib (50 mg, 100 mg, or 200 mg)
on a once or twice daily schedule for 24 weeks. The primary objective of the study was to
evaluate the efficacy of different doses and dose regimens of filgotinib compared to placebo at 
Week 12.

Filgotinib 
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Final 
Amendment 1 
The percentage of American College ofRheumatology (ACR) 20 responders was statistically 
significantly higher in the 100 mg and 200 mg once daily, and 100 mg twice daily dose groups 
at Week 12 and in the 100 mg and 200 mg once da.ily, and 50 mg and 100 mg twice daily 
dose groups at Week 24. The percentage of ACR50 responders was statistically significantly 
higher compared with placebo across all filgotinib dose groups and regimens at both 
Weeks 12 and 24 (Table 1-1). The percentage of ACR70 responders was statistically 
significantly higher in the filgotinib 200 mg once daily and 100 mg twice daily dose groups 
compared with placebo at Week 12 and across all filgotinib dose groups and regimens at 
Week 24. A dose-response was observed for all three parameters. In addition, the ACR20 
response appeared to plateau at Week 8 in the majority of filgotinib treatment groups and was 
maintained up to Week 24. At Week 24, the ACR50 response was maintained and the ACR70 
response continued to increase compared with Week 12. 
Sta1ting at week 2 response was observed for ACR20 and ACR50. No statistically significant 
difference was found between the once and twice daily regimens. 
Table 1-1. 
Time 
Par-amete1· 
Point 
W12 
ACR20 
W24 
Wl2 
ACR50 
W24 
W12 
ACR70 
W24 
Summary and analysis of ACRl0/50/70 response at Weeks 12 and 24 
(NRI [ITT Population]), GLPG0634-CL-203 
Filgotinib once daily Dose Groups 
Filgotinib twice daily Dose Groups 
Placebo 
50mg 
100 mg 
200mg 
25 mg 
50mg 
100 mg 
N=86 
N=82 
N=85 
=86 
=86 
N=85 
N=84 
n(%) 
38 (44.2) 
46 (56.1) 
54 (63.5)"' 
59 (68.6)""" 
49 (57.0) 
51 (60.0) 
66 (78.6)"' 0 
36 (41.9) 
45 (54.9) 
52 (61.2)"' 
63 (73.3)"' 0 
48 (55.8) 
51 (60.0)'" 
67 (79.8)"' 0 
13 (15.1) 
27 (32.9)"' 
32 (37.6)0 
37 (43.o)"'*"' 
24 (27.9)"' 
29 (34.1/' 
46 (54.8)"'"'* 
14 (16.3) 
29 (35.4)0 
40 (47.1)*"'* 
43 (so.o)"'*"' 
30 (34.9)0 
30 (35.3)"'"' 
46 (54.8) 0 * 
7 (8.1) 
13 (15.9) 
18 (21.2) 
21 (24.4)"' 
12 (14.0) 
16 (18.8) 
26 (31.0)"'"' 
8 (9.3) 
18 (22.0/ 
28 (32.9)++ 
25 (29.1/"' 
18 (20.9)"' 
20 (23.5)+ 
33 (39.3)+++ 
Note 1: p-values were based on a pairwise comparisons of each group vs. the placebo group using a logistic regression model 
with factors treatment group, geographical region, and prior use of biologics; Honunel-con-ected p-value. Note 2: The 
denominator for the percentage calculations = the total number of subjects per group with a response (yes or no) at that time point 
Note 3: Subjects who switched treatment at Week 12 were handled as if they discontinued at Week 12. 
* p< 0.05; ** p< 0.01 ; **"' p < 0.001 
ACR=American College of Rhell1ll8tology; ITI=Intent-to-treat; NRI=non-responder imputation; W=week 
Source: GLPG0634-CL-203 
At Weeks 12 and 24 the mean decrease in DAS28(CRP) was statistically significantly 
greater across all filgotinib dose groups and regimens compared with placebo. A dose-response 
was observed. No statistically significant difference was apparent between the once and 
twice daily regimens. At Weeks 12 and 24, the mean decrease in Simplified Diagnostic 
Activity Index ( SDAI) and Clinical Disease Activity Index (CDAI) score was statistically 
significantly greater across all filgotinib dose groups and regimens compa1·ed with placebo 
(with the exception offilgotinib 50 mg once daily dose group at Week 12). In addition, the mean 
SDAI and CDAI scores were maintained after Week 12 in the 50 mg daily dose groups and 
continued to improve up to Week 24 in the 100 mg and 200 mg daily dose groups. 
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No unexpected safety findings were noted. Overall, no differences were observed in the 
incidence of treatment emergent adverse events (TEAEs) reported for subjects in any of the 
dosing groups, including placebo, for the duration of the study. TEAEs were reported for 51.2% 
of “All Placebo Exposed” subjects (ie, all subjects combined who received placebo during either 
the entire 24 weeks or only during the first 12 weeks) and 51.5% of “All filgotinib Exposed” 
subjects (ie, all subjects combined who received filgotinib during either the entire 24 weeks or 
only during the last 12 weeks, irrespective of dose).
A total of 15 subjects had ≥1 serious TEAE; 4 subjects in the placebo group (4.7%) and 
11 subjects (2.0%) in one of the filgotinib groups. One of these subjects with ≥1 serious TEAE, 
who received filgotinib 100 mg twice daily with concurrent MTX, died during the second 
12 weeks of the study period due to pneumonia and septic shock. Out of the 15 subjects with a 
serious TEAE, 11 subjects had a serious TEAE due to which the study medication was stopped 
and the subject discontinued the study. A total of 23 subjects had ≥1 AE leading to permanent 
discontinuation of the study medication and the study; 2 subjects (2.3%) in the placebo group 
and 21 subjects (3.9%) in one of the filgotinib groups (including a subject in the filgotinib 
100 mg q.d. group who had a pre-dosing AE which was ongoing throughout the study, for which 
the study medication was permanently discontinued). Most of the serious TEAEs and the AEs 
leading to discontinuation (by preferred term) were experienced by a single subject.
For the duration of the study, the most common (≥10%) TEAEs reported by SOC in subjects 
from both the placebo and filgotinib dosing groups were Infections and Infestations and 
Gastrointestinal disorders. There were no differences between subjects who received placebo or 
filgotinib in the severity of TEAEs (most TEAEs were mild or moderate; severe TEAEs were 
observed in 1.2% of “All Placebo Exposed” subjects and in 2.2% of “All filgotinib Exposed” 
subjects). Treatment-related TEAEs were generally reported more often for subjects in the 
filgotinib dosing groups than in the placebo group (9.3% with placebo and 20.3% with 
filgotinib); however, within the different filgotinib dosing groups, no clear dose relationships 
were observed.
Six serious infections were reported (1 in placebo arm, 5 in filgotinib arm). All 6 serious and one 
additional non-serious infection in the filgotinib group led to dosing discontinuation. Up to 
Week 24, herpes zoster infections were observed in 5 subjects (1 placebo treated patient and
4 filgotinib). No cases of tuberculosis, opportunistic infections, lymphoma, or cancer were 
reported throughout the 24-week dosing period.
Laboratory data were consistent with prior Phase 2 studies and no new safety findings were 
observed from laboratory data. A summary of laboratory findings of interest, including 
hemoglobin, neutrophil, lymphocyte, creatinine, lipid, and hormone data are summarized below. 
Up to Week 12, small increases were observed in mean hemoglobin concentrations in the 
filgotinib 200 mg daily dose groups (increase of 4.4 g/L from baseline in the filgotinib 100 mg 
b.i.d group). Thereafter, hemoglobin mean concentrations appeared to plateau and remained 
stable until Week 24 (increase of 4.9 g/L from baseline in the filgotinib 100 mg b.i.d group). 

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Up to Week 4, dose-dependent decreases were observed in mean absolute neutrophil counts in 
the filgotinib treatment groups. Mean absolute neutrophil counts appeared to plateau and 
remained stable until Week 24. No decreases in mean absolute lymphocyte counts were 
observed, including in lymphocyte subsets. 
Up to Week 4, dose-dependent decreases were observed in mean absolute platelet counts in the 
filgotinib treatment groups. Mean absolute platelet counts appeared to plateau and remained 
stable. Dose-dependent increases in the filgotinib groups were observed in mean creatinine 
concentrations during the first 4 weeks of the study for most filgotinib treatment groups (up to 
Week 8 for the filgotinib 100 mg b.i.d group) that subsequently plateaued and remained stable up 
to Week 24. 
Up to Week 4, dose-dependent increases were observed in mean concentrations of total 
cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides in all 
filgotinib treatment groups. All these lipid parameters further increased up to Week 8 in the 
filgotinib 200 mg daily dose groups. Thereafter, these increases appeared to plateau and 
maintained at stable mean concentrations up to Week 24. At Week 24, mean increases were 
observed of 0.7 mmol/L in total cholesterol, 0.3 mmol/L in LDL cholesterol, 0.3 mmol/L in HDL 
cholesterol, and 0.1 mmol/L in triglycerides in the filgotinib 100 mg b.i.d group.
In male subjects, small non dose-dependent increases were observed in total and free testosterone 
during the study (at Week 24, mean increases were 3.4 nmol/L for total and 51.7 pmol/L for free 
testosterone in the filgotinib 100 mg b.i.d group). For FSH, inhibin B, LH, and prolactin, small 
changes (both increases and decreases) were observed during the study, without any trends of 
larger changes in male subjects of one or more of the different treatment groups.
GLPG0634-CL-204, Filgotinib administered as monotherapy in RA Subjects
The primary objective of study GLPG0634-CL-204 was to evaluate the efficacy of three doses
of filgotinib q.d. compared to placebo at Week 12.
As shown in Table 1-2, the percentage of ACR20 and ACR50 responders at week 12 was
statistically significantly higher across all filgotinib dose groups compared with placebo. The
percentage of ACR70 responders in the filgotinib 100 mg and 200 mg once daily dose groups
was statistically significantly higher compared with placebo. At Week 24, the ACR50
response was maintained and the ACR70 response showed continued improvement. An early
onset of response was observed for ACR20 (from Week 1 in the filgotinib 200 mg once daily 
dose group and Week 4 across all other dose groups), ACR50 (from Week 2 in the filgotinib 
200 mg once daily dose group and Week 4 across all other filgotinib dose groups), and ACR70
(Week 4 in the filgotinib 200 mg once daily dose group). The time to ACR20/50/70 response
was shorter in all filgotinib dose groups compared with placebo.

Filgotinib 
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Table 1-2. 
Summary and analysis of ACR20/50/70 response at Weeks 12 and 
24 (NRI [ITT Population]); GLPG0634-0204 
Placebo 
Filgotinib once daily Dose GI'Oups 
50mg 
100mg 
200mg 
Time 
N=72 
N=72 
N=70 
N=69 
Paramete1· 
Point 
0(%) 
W12 
21 (29.2) 
48 (66.7)*** 
46 (65.7)*** 
50 (72.5)*** 
ACR20 
W24 
Not applicable 
41 (56.9) 
55 (78.6) 
46 (66.7) 
W12 
8 (11.1) 
25 (34.7)*** 
26 (37.1)*** 
30 (43.5)*** 
ACR50 
W24 
Not applicable 
24 (33.3) 
27 (38.6) 
31 (44.9) 
W12 
2 (2.8) 
6 (8.3) 
13 (18.6)** 
9 (13.0)* 
ACR70 
W24 
Not applicable 
14 (19.4) 
18 (25.7) 
17 (24.6) 
Note 1: p-values were based on a pairwise comparisons of each group vs. the placebo group using a logistic regression model 
with factors treatment group, geographical region, and prior use of biologics· Honunel-co11"ected p-value. 
Note 2: The denominator for the percentage calculations= the total number of subjects per group with a response (yes or no) at 
that time point 
Note 3: Subjects who switched treatment at Week 12 were handled as if they discontinued at Week 12. 
* p< 0.05; ** p< 0.01 · **• p < 0.001 
ITI=Intent-to-treat; NRI=non-responder imputation; W=week 
Source: GLPG0634-CL-204 
At Week 12, the mean decrease in DAS28(CRP) was statistically significantly greater across all 
filgotinib dose groups compmed with placebo. At Week 24, the mean decrease in 
DAS28(CRP) was maintained in the 50 mg once daily dose group and showed a small 
improvement in the highest dose groups. In addition, at Week 12 the percentage of subjects 
with DAS28(CRP) remission was higher across all filgotinib dose groups compared with 
placebo. Differences vs. placebo were not statistically significant for any of the filgotinib dose 
groups. The numbers of subjects with DAS28(CRP) < 2.6 and < 3.2 were higher acrnss all 
filgotinib dose groups compared with placebo at Week 12; differences vs. placebo were 
statistically significant for the filgotinib 200 mg once daily dose group. 
Safety data revealed no differences in the incidence of TEAEs reported for subjects in any of the 
treatment groups, including placebo, during both tl1e first 12 weeks of treatment and the full 
24 weeks of treatment. TEAEs were rep01ied for 38.9% of "All Placebo Exposed" subjects 
(ie, all subjects combined who received placebo during the first 12 weeks) and 41.3% of "All 
filgotinib Exposed" subjects (i.e., all subjects combined who received filgotinib during either the 
entire 24 weeks or only during the last 12 weeks, inespective of dose). 
No deaths were rep01ied and a total of 9 subjects had a serious TEAE; 1 subject (1.4%) during 
placebo dosing and 8 subjects (2.9%) during filgotinib dosing. No serious TEAE (by prefened 
te1m) was experienced by more than 1 subject, and all subjects recovered from their serious 
TEAEs. Out of the 9 subjects with a serious TEAE, 3 subjects had a serious TEAE for which the 
study medication was stopped and the subject discontinued the study. There were no differences 
in incidences of AEs leading to discontinuation among all the different dosing groups, including 
placebo. A total of 11 subjects had :::1 TEAE leading to discontinuation of the study medication; 
4 subjects (5.6%) during placebo dosing and 7 subjects (2.5%) during filgotinib dosing. 
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During the whole study, the most common TEAEs reported by System Organ Class in subjects 
from both the placebo and filgotinib treatment groups, were ‘Infections and Infestations’ and 
‘Gastrointestinal disorders’. There were no differences between subjects who received placebo or 
filgotinib in the severity of TEAEs (most TEAEs were mild or moderate; severe TEAEs were 
observed in 1.4% of “All Placebo Exposed” subjects and in 1.1% of “All filgotinib Exposed” 
subjects). Treatment-related TEAEs were generally reported more often for subjects in the 
filgotinib treatment groups than in the placebo group (9.7% with placebo and 16.7% with 
filgotinib); however, within the different filgotinib treatment group, no clear dose relationships 
were observed.
Low numbers of infections were reported as serious (4 subjects with filgotinib) or led to 
discontinuation of the study medication (2 serious infections; ie, cellulitis and pneumonia). Up to 
Week 24, 1 subject (filgotinib 50 mg q.d. group) had a herpes zoster infection. No cases of 
tuberculosis, opportunistic infections, lymphoma, or cancer were reported throughout the 
24-week dosing period.
Laboratory data were consistent with prior studies and no new safety findings were observed.
Please refer to the IB for additional data regarding efficacy and safety.
1.3.
Rationale for This Study
Over the last decade, changes in RA treatment strategies, accompanied by advances in drug 
development and the addition of targeted biological therapies, have greatly improved the 
outcomes for subjects with RA. Despite these developments, therapeutic challenges remain. The 
current conventional and biologic DMARDs may be ineffective or produce only partial 
responses in some subjects and may be associated with significant safety and tolerability 
concerns. There is a medical need for simple, orally administered therapies with novel and 
targeted mechanisms of action that can effectively improve the disease course while being safe 
and well-tolerated. MTX-naïve patients with RA have several medications to choose from, 
however, it is clear that as patients progress through the available therapies, they may be left with 
active disease and a need for additional options. Development of another drug for these patients 
is appropriate, since participation in this study will not preclude the use of approved RA 
therapies for these subjects in the future. Moreover, all subjects in this study will receive active 
drug: MTX, filgotinib, or a combination of the two, as well as frequent monitoring of their health 
and RA status. Any subjects considered to be non-responders at Week 24 and those with loss of 
response at 2 consecutive visits after week 30, will discontinue study drug and take standard of 
care medications.
Filgotinib is an orally administered, small molecule inhibitor of JAK1, an intracellular tyrosine 
kinase that is dysregulated in subjects with inflammatory disorders, including RA. Filgotinib has 
demonstrated clinical activity and a favorable safety and tolerability profile in Phase 2 studies in 
subjects with moderately to severely active RA.

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1.3.1.
Rationale for Study Design
The current study (GS-US-417-0303) is a Phase 3, randomized, double-blind, placebo and 
active-controlled study designed to evaluate the efficacy and safety of filgotinib in subjects with 
active RA who have limited or no prior exposure to MTX therapy. Study drugs will be 
administered for up to 52 weeks. The objectives of the study are to evaluate the efficacy of 
filgotinib as monotherapy, and in combination with MTX on the signs and symptoms of RA, to 
evaluate effects on physical function and radiographic progression, and to assess work 
productivity, fatigue, and quality of life. In addition, the safety, tolerability and pharmacokinetics 
(PK) of filgotinib will be assessed.
The active comparator in this study is oral MTX. Methotrexate is the most commonly 
prescribed first line csDMARD in the treatment of moderately to severely active RA and has 
been shown to reduce the signs and symptoms of disease as well as to inhibit radiographic 
progression {Lopez-Olivo et al 2014}. The inclusion of MTX will allow comparison of the 
efficacy and safety of filgotinib to an approved and frequently prescribed product indicated for 
use in treatment-naïve patients {Lopez-Olivo et al 2014}. In this study, MTX will be titrated up
to the maximal tolerated dose over a period of 8 weeks. Non-responders at Week 24 (as defined 
in Section 3.2) will discontinue investigational therapy but will continue with study visits and 
assessments per protocol. All subjects who discontinue from investigational therapy will receive 
standard of care treatment for their RA as determined by the investigator. 
Given that all subjects will receive at least one active drug in this study, determining non-
responder status at 24 weeks is considered both clinically and ethically appropriate and allows an 
acceptable time to assess initial response to therapy, especially since MTX will be titrated 
upward over an 8 week period. The study eligibility criteria are consistent with those of recent 
clinical trials evaluating novel investigational treatments for RA. Subjects should meet the 
2010 ACR/European League Against Rheumatism (EULAR) criteria for RA, and are required to 
have active disease, defined as ≥6 swollen and ≥6 tender joints at both Screening and Day 1, as 
well as one of the following: the presence of at least 1 joint erosion on radiographs of the hands, 
wrists, or feet, or a positive test for anti-citrullinated peptide antibody (anti-CCP Ab) or 
rheumatoid factor (RF), or an elevated CRP level. The study duration of up to 52 weeks allows 
sufficient time to evaluate safety, reduction in disease activity, and confirmation that clinical 
benefit is sustained over time.
1.3.2.
Rationale for the Outcome Measures
Safety and tolerability will be assessed by the evaluation of adverse events (AEs), selected 
clinical laboratory parameters, vital signs, physical examinations, and electrocardiograms 
(ECGs), all of which are standard safety evaluations in clinical trials of RA.
The ACR20, ACR50, and ACR70 responses and the DAS28 (CRP) are considered reliable 
measures of response to treatment and disease activity, respectively, in subjects with RA. 
Comparison between the treatment arms of the proportions of subjects achieving an ACR20 
response at Week 12 and the proportions of subjects achieving low disease activity in 
DAS28 (CRP) allows for interpretation of a clinically meaningful response and these measures 
have been shown to achieve high discriminatory capacity.

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Evaluation of continuous outcome measures of DAS28 (CRP) and American College of 
Rheumatology N (ACR-N) as secondary endpoints enables the demonstration of improvement 
and magnitude of benefit. The EULAR/ACR remission response criteria classify subjects as non, 
moderate-, or good responders depending on the extent of change and the level of disease 
activity reached. These response criteria are useful when describing clinically meaningful 
therapeutic results. The CDAI and the SDAI have been widely used in clinical studies to 
demonstrate the impact of a study drug on controlling disease activity in patients with RA.
Assessing quality of life (measured by the Functional Assessment of Chronic Illness 
Therapy-Fatigue [FACIT-Fatigue], 36-item short form health survey [SF-36], and EuroQol 
5-Dimension [EQ-5D]) at Day 1 and during the course of study treatment provides insight into 
the effects on modifying RA disease course and the impact on daily living. Treatment satification 
will be assessed by using the Treatment Satisfaction Questionnaire for Medication (TSQM) at 
Day 1 and during the course of the study. Assessing the change in economic impact 
(Work Productivity and Activity Impairment [WPAI] and Healthcare Resource Utilization) of 
RA over the course of the study provides insight into the subject’s ability to work and other daily 
activities as well as the impact on the burden of healthcare resources.
Radiographs have been widely used in assessing structural joint damage associated with RA and 
are therefore essential in evaluating the efficacy of a study drug. Reduction in radiographic 
evidence of structural damage progression is an important predictor of long-term benefits in 
delaying or preventing the progression to disability related to RA. While X-ray remains the 
widely accepted method for assessing progression of structural joint damage, evaluation by MRI 
may provide specific advantages
 
  Radiographic data using validated scoring methods will 
be used to demonstrate efficacy in this domain.
1.3.3.
Rationale for the Choice of Dose and Dosing Interval
Enrolled subjects will be randomized to receive filgotinib or active comparator MTX, or a 
combination thereof. The 100 mg and 200 mg q.d. dose regimens of filgotinib have been selected 
for Phase 3 evaluation based on non-clinical data and information concerning efficacy, 
tolerability, and safety data derived from the Phase 1 and Phase 2 studies, and are supported by 
non-clinical safety studies.
In seven Phase 1 studies conducted in healthy subjects (GPLG0634-CL-101, -102, −103, - 104, 
-105, -107, and -110), filgotinib administered at doses up to 450 mg q.d. for up to 10 days was 
safe and well tolerated.
In the 2 Phase 2a studies in subjects with RA (Study GLPG0634-CL-201 and -202), dosing with 
filgotinib was well tolerated and achieved a high level of efficacy at a 200 mg daily dose 
(ACR20 response of 75-92% at Week 4). Administration of a higher filgotinib dose (300 mg) did 
not demonstrate greater efficacy, therefore, the highest dose to be tested in this study will be 
200 mg q.d. 
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In two Phase 2b studies, filgotinib at doses of 50 mg, 100 mg, or 200 mg daily, administered in 
addition to a background therapy with  MTX (GLPG0634-CL-203) or as monotherapy 
(GLPG0634-CL-204) was shown to be safe and efficacious in subjects with moderately to 
severely active RA who had an inadequate response to MTX alone (Section 1.2.3). 
Exposure-response analysis based on data from all Phase 2 studies indicated a dose-dependent 
increase in efficacy (ACR20/50/70, DAS28[CRP]), with a plateau at/above the 200 mg total 
daily dose on the dose-response curve. Additionally, in Study GLPG0634-CL-203, no 
statistically significant difference in efficacy was observed at 200 mg daily dose, administered as 
200 mg q.d. or 100 mg b.i.d. These results are consistent with the relationship observed between 
filgotinib exposures and pSTAT1 activation (ex-vivo) following single and multiple filgotinib 
doses, where maximal inhibition of pSTAT1 (~78%) was achieved at or above 200 mg total 
daily dose and intermediate inhibition (~47%) at 100 mg {Namour et al 2015}. 
Overall, the 100 mg and 200 mg once-daily dose regimens have been proposed based on the 
safety and efficacy data from the Phase 2 studies in RA and the observed plateau in the pSTAT1 
response which indicates doses above 200 mg are unlikely to add additional benefit. Inclusion of 
two doses in the proposed Phase 3 trials will enable establishment of an appropriate nominal 
dose for the treatment of RA and determine the regimen with the most favorable risk:benefit 
profile in these populations.
Safety data collected across Phase 2 clinical studies showed no dose-dependent trends in the
incidence of AEs or SAEs, including infections, or laboratory abnormalities with the exception
of a numerical increase in select gastrointestinal AEs (eg, nausea, vomiting, abdominal pain, and 
upper abdominal pain). This numerical increase was observed in the 200 mg compared to the 
100 mg dose. However, the overall frequency was low and clinical relevance is unknown. 
Filgotinib, administered at a dose of 100 mg or 200 mg daily was found to be safe and well 
tolerated. The safety profile was consistent with that observed for an immunomodulatory 
compound administered to subjects with RA. 
Overall, the 100 mg and 200 mg once-daily dose regimens have been proposed based on the 
safety and efficacy data from the Phase 2 studies in RA and the observed plateau in the pSTAT1 
response which indicates doses above 200 mg are unlikely to add additional benefit. Inclusion of 
two doses in the proposed Phase 3 trials will enable establishment of an appropriate nominal 
dose for the treatment of RA and determine the regimen with the most favorable risk:benefit 
profile in these populations.
1.4.
Risk/Benefit Assessment for the Study
As of January 2016, Filgotinib has been administered to more than 150 healthy subjects as single 
doses ranging from 1 to 200 mg, and as multiple doses at 25 to 100 mg twice daily, and 200, 300, 
and 450 mg daily for 10 days. In addition, filgotinib has been administered to more than 1000
RA subjects and more than 150 subjects with Crohn’s Disease at daily doses ranging from 
50-200 mg. In general, filgotinib has been safe and well tolerated in all populations studied.

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Nonclinical studies in rats and dogs identified the testes and lymphoid tissue as target organs for 
filgotinib in long term repeat-dose toxicity studies. In both species, histopathological changes in 
the testes included germ cell depletion and degeneration, with reduced sperm content and 
increased cell debris in the epididymis and reduction in fertility in rats. The dog was determined 
to be the most sensitive species. A dose of 200 mg/day of filgotinib results in an estimated mean 
clinical AUC of 2.80 μg∙h/mL, which represents an exposure margin of 2.3, 1.8, and 3.4-fold 
when considering the mean AUC in male dogs at the no-observed-effect-levels (NOELs) in the 
26 week and 39 week chronic toxicity studies, and the 39 week targeted exposure toxicity study, 
respectively. Decreased lymphocytes observed in nonclinical studies have not been shown in 
clinical studies.
Filgotinib has shown an increased risk of embryofetal malformations at exposures similar to 
human doses; the use of highly effective contraception in the subject population will be 
implemented in the study to mitigate this risk.
No clinically relevant impact on cardiovascular parameters (including vital signs and ECG), 
respiratory or neurologic function has been observed in Phase 1 and 2 trials of filgotinib.  Across 
the phase 2 trials in RA, filgotinib was well-tolerated. In the RA studies (including the open label 
extension Darwin 3), infections were reported more commonly in the filgotinib groups, including 
serious infections leading to hospitalization, and even death. The most common system organ 
classes (SOC) with AEs were infections and infestations, and gastrointestional disorders. Dose 
dependent decreases in the phase 2b studies were observed in mean neutrophil counts and 
platelet counts (but mean changes in both remained within normal laboratory reference ranges), 
and there were no decreases in lymphocytes or lymphocyte subsets. Hemoglobin levels slightly 
improved (increased) with filgotinib treatment, confirming that no anemia was induced. Mild and 
clinically insignificant serum creatinine increases were noted in both Phase 2b studies, with 
stabilization by Week 24.  Neutrophil decreases (in the RA population) and a potential increased 
risk of infection may be considered risks consistent with the mechanism of JAK inhibition.  
Overall clinical findings and laboratory changes are consistent with selective JAK inhibition and 
based on Phase 2 data the expected benefit of using filgotinib as proposed in this study is 
considered to outweigh any associated risks.
An independent data monitoring committee (DMC) appointed to monitor the study (with an 
interim safety analysis after approximately 100 subjects complete Week 12) will provide an 
additional level of risk mitigation.
The overall risk:benefit balance of this study is considered favorable. For additional information
about the risks of filgotinib, reference is made to the IB.
1.5.
Compliance
This study is to be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.

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2.
OBJECTIVES
The primary objective of this study is as follows:

To evaluate the effects of filgotinib in combination with MTX versus MTX alone for the 
treatment of signs and symptoms of RA as measured by the proportion of subjects achieving 
ACR20 at Week 24
The secondary objectives of this study are as follows: 

To evaluate the effect of filgotinib in combination with MTX versus MTX alone on physical 
function as measured by change from Baseline in the Health Assessment Questionnaire 
Disability Index (HAQ-DI) score at Week 24 

To evaluate the effects of filgotinib in combination with MTX versus MTX alone for the 
treatment of signs and symptoms of RA as measured by the proportion of subjects achieving 
Disease Activity Score for 28 joint count using CRP (DAS28 [CRP])<2.6 at Week 24 

To evaluate the effects of filgotinib alone versus MTX alone for the treatment of signs and 
symptoms of RA as measured by the proportion of subjects achieving ACR20 at Week 24

To evaluate the effect of filgotinib alone versus MTX alone on physical function as measured 
by change from Baseline in HAQ-DI score at Week 24 

To evaluate the effects of filgotinib alone versus MTX alone for the treatment of signs and 
symptoms of RA as measured by the proportion of subjects achieving DAS28 (CRP)<2.6 at 
Week 24 

To evaluate the effects of filgotinib in combination with MTX versus MTX alone on 
preservation of joint structure as measured by change from Baseline in the mTSS at 
Week 24 and 52

To evaluate the effects of filgotinib alone versus MTX alone on preservation of joint 
structure as measured by change from Baseline in mTSS at Week 24 and 52

To evaluate the safety and tolerability of filgotinib alone and in combination with MTX 

To evaluate the effects of filgotinib alone and in combination with MTX on work 
productivity, fatigue, and general quality of life as measured by SF-36, FACIT-Fatigue, 
EQ-5D and WPAI-RA

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The exploratory objectives of this study are as follows:
 
 
CCII 
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Filgotinib 
Protocol GS-US-417-0303
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Amendment 1
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Subjects who have received at least one dose of study drug and choose to prematurely terminate 
study participation for any reason should complete an ET visit at the time of study 
discontinuation, as well as a post dosing visit four weeks after the last dose of study drug 
(post treatment Week 4) regardless of dosing duration.
At completion of the 52-week treatment period, subjects (who did not discontinue assigned study 
drug or have not met criteria for loss of therapeutic response) will be provided the option to enter 
a Long Term Extension (LTE) study (GS-US-417-0304).
For those subjects not entering the LTE, a follow-up visit will be planned at Post Treatment 
Week 4.
To enhance the safety monitoring during the study, a DMC consisting of independent experts 
will be convened to periodically review the accumulating safety data for the study. In addition, a 
cardiovascular safety endpoint adjudication committee (CV-SEAC) will be convened to 
periodically review and adjudicate all possible major cardiovascular events (MACE).
The assessments planned to be performed at each visit are detailed in the study procedures table 
(Appendix 2). A schedule of the study design is provided below.
Figure 3-1.
Study Design
3.3.
Study Treatments
Approximately 1200 subjects with active RA will be randomized in a 2:1:1:2 ratio to filgotinib
200 mg plus MTX, filgotinib 100 mg plus MTX, filgotinib 200 mg alone, or MTX alone, for up 
to 52 weeks: 

Filgotinib 200 mg + MTX group: Filgotinib (200 mg q.d.) + PTM filgotinib 100 mg 
(PTM q.d.) + MTX (once weekly up to 20 mg) (N=400)
DAY 1 
WK24 
Primary Endpoint 
WK 52 
SCREENING ~ 
RANDOM IZATION 
28 days prior 
2 :1 :1 :2 
to Day 1 
(may be extended 
to 
42 days if 
repeat 
radiographs are 
required) 
WK 24: ;, Standard of care for all subjects with 
Subjects with 
protocol-defined inadequate response 
inadequate 
response will 
discontinue 
study drugs 

Filgotinib 
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
Filgotinib 100 mg + MTX group: Filgotinib (100 mg q.d.) + PTM filgotinib 200 mg 
(PTM q.d.) + MTX (once weekly up to 20 mg) (N=200)

Filgotinib 200 mg monotherapy group: Filgotinib (200 mg q.d.) + PTM filgotinib 100 mg 
(PTM q.d.) + PTM MTX (PTM once weekly) (N=200)

MTX monotherapy group: PTM filgotinib 100 mg (PTM q.d.) + PTM filgotinib 200 mg 
(PTM q.d.) + MTX (once weekly up to 20 mg) (N=400)
NOTE: on study visit days, subjects should wait to take their regularly scheduled dose of study 
drug until instructed by site personnel, in case there are pre-dose blood draws or other pre-dose 
procedures required on that day.
3.4.
Duration of Treatment
Subjects are planned to participate in the study for approximately 60 weeks (from the Screening 
visit to Follow-up visit or entry into the LTE); the duration of dosing is up to 52 weeks.
3.5.
Criteria for Interruption or Discontinuation of Study Treatment
3.5.1.
Study drug interruption considerations:
The Gilead Medical Monitor should be consulted prior to study drug interruption when 
medically feasible. 
Study drug interruption should be considered in the following circumstances; prior to resumption 
of study drug, the investigator should discuss the case with the Gilead medical monitor:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree.   

Subject is scheduled for elective or emergency surgery (excluding minor skin procedures 
under local or no anesthesia); timing of study drug pausing should be determined in 
consultation with the Gilead medical monitor.   

Any subject who develops a new infection during the study should undergo prompt and 
complete diagnostic testing appropriate for an immuncompromised individual, and the 
subject should be closely monitored.
NOTE: During the time of study drug interruption for any of the above, the subject may
continue to have study visits and to take part in procedures and assessments, if deemed 
medically appropriate by the investigator.

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3.5.2.
Study drug discontinuation considerations:
The Gilead Medical Monitor should be consulted prior to study drug discontinuation when 
medically feasible. 
Study medication should be permanently discontinued in the following instances:

Any opportunistic infection

Any serious infection that requires antimicrobial therapy or hospitalization, or any infection 
that meets SAE reporting criteria. 

Complicated herpes zoster infection (with multi-dermatomal, disseminated, ophthalmic, or 
CNS involvement)

Evidence of active HCV during the study, as evidenced by HCV RNA positivity

Evidence of active HBV during the study, as evidenced by HBV DNA positivity

Unacceptable toxicity, or toxicity that, in the judgment of the investigator, compromises the 
subject’s ability to continue study-specific procedures or is considered to not be in the 
subject’s best interest

Non-responder at Week 14 OR at 2 consecutive visits after Week 30 as outlined in 
Section 3.2

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study (Section 7.7.2.1 and Appendix 5)

Discontinuation of the study at the request of Gilead, a regulatory agency or an institutional 
review board or independent ethics committee (IRB/IEC)

Subject use of prohibited concurrent therapy may trigger study drug discontinuation; 
consultation should be made with the Gilead medical monitor.

Laboratory criteria:
After becoming aware of any of the below described abnormal laboratory changes occurring at 
any one time, an unscheduled visit (ie sequential visit) should occur to retest within 3 to 7 days
(except creatinine, which should be retested 7-14 days apart). 
2 sequential neutrophil counts <750 neutrophils/mm3 (SI: <0.75x109 cells/L) after dose 
adjustment of MTX/PTM (Section 5.3.4)

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2 sequential platelet counts <75,000 platelets/mm3 (SI: <75.0x109 cells/L) after dose 
adjustment of MTX/PTM (Section 5.3.4)
2 sequential AST or ALT elevations >3xULN and ≥1 total bilirubin value >2xULN
or accompanied by symptoms consistent with hepatic injury1 after dose adjustment of 
MTX/PTM (Section 5.3.4)
2 sequential AST or ALT elevations >5xULN after dose adjustment of MTX/PTM
(Section 5.3.4)
2 sequential values for estimated creatinine clearance <35 mL/min based on the Cockroft 
Gault formula
Subjects who permanently discontinue study medication for any reason are to receive standard of
care treatment for their RA as determined by the investigator, and those subjects should be
encouraged to continue study visits and procedures, if deemed medically appropriate by the
investigator. Subjects who permanently discontinue study medication for pregnancy should not
continue in the study; if there are any questions regarding permanent discontinuation, these
should be discussed with the Sponsor.
Subjects withdrawing from the study should complete ET and Post Treatment Week 4 visits.
Subjects are free to withdraw from the study at any time without providing reason(s) for
withdrawal and without prejudice to further treatment. The reason(s) for withdrawal will be
documented in the electronic case report form (eCRF).
Reasonable efforts will be made to contact subjects who are lost to follow-up. These must be 
documented in the subject’s file. 
The sponsor has the right to terminate the study at any time in case of safety concerns or if 
special circumstances concerning the study medication or the company itself occur, making 
further treatment of subjects impossible. In this event, the investigator(s) and relevant authorities 
will be informed of the reason for study termination.
3.6.
End of Study
End of Study is defined as when the last subject has completed 52 weeks of dosing plus the
4 week post treatment visit or has entered the LTE. 
                                                  
1
In each case, there is a need for additional investigations, such as review of ethanol, recreational drug and 
dietary supplement consumption; testing for acute hepatitis A, B or C infection and biliary tract imaging should 
be promptly discussed with the study Medical Monitor

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3.7.
Post Study Care
All subjects who meet criteria for clinical response (per protocol), and who complete 52 weeks 
of study assessments will be offered an opportunity to participate in a LTE study 
(GS-US-417-0304). Subjects who discontinue early from the main study, or switch to standard of 
care treatment during the study, are not eligible for the LTE. The long term care of subjects who 
do not qualify for the LTE or choose not to participate in the LTE will remain the responsibility 
of their primary treating physician. 
3.8.
Biomarker Samples
3.8.1.
Biomarker Samples to Address the Study Objectives:
The following biological specimens will be collected in this study which may be used to evaluate 
the association of exploratory systemic and/or tissue specific biomarkers with study drug 
response, including efficacy and/or adverse events, and help inform the mechanism of action and 
mechanism of intrinsic and acquired resistance to filgotinib in RA. The specific samples to be 
collected from all subjects (unless otherwise stated) include the following:

Plasma, serum, and urine samples for potential analysis of circulating factors including but 
not limited to cytokines, metabolome, biomarkers of joint damage, and miRNA

Paxgene blood samples for potential gene expression analyses
 

Whole blood sample for potential B-/T-cell receptor sequencing

Viably frozen PBMCs (vfPBMCs) and Leukocyte subsets to profile immune cell subsets and 
inflammatory signaling pathways
The biomarker sample collection schedule is described in Study Procedures Table (Appendix 2). 
Since biomarker science is a rapidly evolving area of investigation, it is not possible to specify 
prospectively all tests that may be performed on the specimens collected.  The testing outlined 
above 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 parameters based 
upon the growing state of art knowledge. Any future testing of new tests not described above 
must be approved by local authorities as applicable according to specific local regulations.
The biomarker samples will be destroyed no later than 15 years after the end of study unless the
subject gives specific consent for the remainder of the samples to be stored for optional future
research. 
For sampling procedures, storage conditions, and shipment instructions, see the Sample Handling 
and Logistics Manual. 
CCII 

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Amendment 1
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3.8.2.
Biomarker Samples for Optional Future Research
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI-

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Protocol GS-US-417-0303
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Gilead Sciences, Inc. 
Amendment 1
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CCI
CCI

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Amendment 1
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
A sufficient number of subjects will be screened to ensure that approximately 1200 subjects with 
moderately to severely active RA will be randomized to one of 4 dosing groups.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Male or female subjects who are ≥18 years of age, on the day of signing informed consent. 
2) Have a diagnosis of RA (2010 ACR/EULAR criteria) (Appendix 8), and are ACR functional 
class I-III
3) Have ≥6 swollen joints (from a SJC66) and ≥6 tender joints (from a TJC68) at both 
Screening and Day 1 (need not be the same joints) (Appendix 7)
4) Must meet at least one of the following parameters at Screening:

≥1 documented joint erosion on radiographs of the hands, wrists or feet by central 
reading 
OR

positivity for either  RF or anti-CCP Ab (based on central laboratory)
OR

Serum CRP ≥ 4 mg/L (based on central laboratory)
5) Have limited or no prior treatment with MTX, ie, no more than 3 doses of MTX ≤25 mg each 
in the subject’s lifetime for the treatment of RA, with the last dose at least 28 daysprior to 
Day 1, and are an appropriate candidate for MTX therapy, as per investigator judgment 
6) Females of childbearing potential (as defined in Appendix 5) must have a negative pregnancy 
test at Screening and Day 1
7) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in 
Appendix 5
8) Lactating female subjects must agree to discontinue nursing from Screening through the end 
of their study participation. 

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9) Meet one of the following tuberculosis (TB) Screening criteria:
a) No evidence of active or latent TB:

A negative QuantiFERON® TB-Gold In-Tube test at Screening and 

A chest radiograph (views as per local guidelines)  taken at Screening or within the 
3 months prior to Screening (with the report or films available for investigator 
review) without evidence of active or latent TB infection and

No history of either untreated or inadequately treated latent or active TB infection
b) Previously treated for TB: ie, if a subject has previously received an adequate course of 
therapy as per local standard of care for either latent TB (9 months of isoniazid in a 
location where rates of primary multi-drug resistant TB infections are <5% or an 
acceptable alternative regimen) or active TB (acceptable multi-drug regimen). In these 
cases, no QuantiFERON® TB-Gold In-Tube test (or equivalent assay) need be obtained, 
but a chest radiograph must be obtained if not done so within 3 months prior to Screening
(with the report or films available for investigator review). It is the responsibility of the 
investigator to verify the adequacy of previous anti-tuberculosis treatment and provide 
appropriate documentation.
c) Newly identified latent TB during Screening: ie, a subject who has a newly identified 
positive diagnostic TB test result (defined as a positive QuantiFERON® TB Gold in Tube
test [or equivalent assay]) in which active TB has been ruled out and for which 
appropriate, ongoing, prophylactic treatment for latent tuberculosis has been initiated 
prior to the first administration of study medication. Adequate treatment for latent TB is 
defined according to local country guidelines for immunocompromised subjects.
Cases falling under category “b” and “c” need to be approved by the Sponsor prior to  
enrollment in the study. No subject with currently ACTIVE TB may be enrolled in the 
study, regardless of past or present anti-TB medication use.
10) Able and willing to sign the informed consent as approved by the IEC/IRB. Written consent 
must be provided before initiating any screening evaluations. Subjects must have read and 
understood the informed consent form (ICF), must fully understand the requirements of the 
trial, and must be willing to comply with all trial visits and assessments; subjects who cannot 
read or understand the ICF may not be enrolled by a guardian or any other individual.
11) Subjects receiving non-prohibited medication for any reason should be be on a stable dose 
(defined as no change in prescription) within 7 days or 5 half-lives (whichever is longer) 
prior to the first administration of study drug on Day 1.

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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) Prior treatments for RA as follows:
a) Alkylating agents, eg, chlorambucil or cyclophosphamide, at any time
b) Previous treatment with any JAK inhibitor 
c) Previous therapy with csDMARDs other than MTX or hydroxychloroquine 
(eg, gold salts, cyclosporine, leflunomide, azathioprine, sulfasalazine or any other 
immunosuppressive). 
NOTE: Subjects with prior exposure to csDMARD may be enrolled if the subject had 
limited exposure (less than 3 months of total exposure). Washout periods need to be 
satisfied per protocol (section 5.4).
d) Use of any licensed or investigational biologic DMARDs (eg, B-cell depleting agents,
tumor necrosis factor (TNF) alpha inhibitors, and/or interleukin (IL)-1, IL-6, IL-17, 
IL-12/23 inhibitors, including but not limited to abatacept, anakinra, certolizumab pegol, 
etanercept, golimumab, infliximab, rituximab, secukinumab, ustekinumab or tocilizumab 
2) Known hypersensitivity or allergy to study drug, its metabolites, or formulation excipients.
3) Known hypersensitivity or allergy to the MTX, its metabolites, or formulation excipients.
4) Oral steroids at a dose >10 mg/day of prednisone (or equivalent) or a prescription for oral 
steroids which has changed within 4 weeks of Day 1.
5) Receipt of an intra-articular or other injectable corticosteroid within 4 weeks prior to Day 1.
6) Use of nonsteroidal anti-inflammatory drugs (NSAIDs) which have not been at a stable dose 
(defined as no change in prescription) for at least 2 weeks prior to Day 1.  NOTE: subjects 
are permitted to take acetylsalicylic acid at a dose of ≤325mg daily for cardiac prophylaxis, 
or occasional NSAIDs for non-RA indications (eg, headache).  
7) Administration of a live/attenuated vaccine within 30 days from Day 1, or planned during the 
study.
8) Participation in any clinical study of an investigational drug/device within 4 weeks or 
5 half-lives prior to Screening, whichever is longer. Exposure to investigational biologics are 
excluded as outlined in 1d.
9) Have undergone surgical treatments for RA, including synovectomy or arthroplasty in 
>4 joints 

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10) Have any chronic, uncontrolled medical condition, which would put the subject at increased 
risk during 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 investigator.
11) Have a history of major surgery (requiring regional block or general anesthesia) within the 
last 3 months prior to Screening or planned major surgery during the study.
12) Have a moderately to severely active, generalized musculoskeletal disorder that would 
interfere with assessment of study parameters or increase risk to the subject by participating 
in the study, eg, generalized osteoarthritis, systemic inflammatory condition other than RA 
such as, but not limited to: ankylosing spondylitis, reactive arthritis, psoriatic arthritis, 
inflammatory bowel disease associated arthropathies, systemic lupus erythematosus, 
scleroderma, inflammatory myopathy, mixed connective tissue disease, overlap syndrome, or 
gout. Subjects with any history of Felty’s syndrome or juvenile idiopathic arthritis are 
excluded, regardless of the disease activity level at Screening. (NOTE: subjects with 
concurrent Sjogren's syndrome or limited cutaneous vasculitis associated with RA are not 
excluded, and may be enrolled, based on investigator judgment). 
13) Active autoimmune disease other than those listed above, that would interfere with 
assessment of study parameters or increase risk to the subject by participating in the study, 
eg, inflammatory bowel disease, uncontrolled thyroiditis, systemic vasculitis, transverse 
myelitis or uveitis.
14) Any known condition or contraindication as addressed in the local labeling or local clinical 
practice for MTX that would preclude the subject from participating in this study.
15) History of or current moderate to severe congestive heart failure (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 protocol.
16) History of malignancy within the past 5 years prior to Screening (except for adequately 
treated basal cell carcinoma or non-metastatic squamous cell carcinoma of the skin or 
cervical carcinoma in situ with no evidence of recurrence). 
17) History of lymphoproliferative disease or current lymphoproliferative disease.
18) History of gastrointestinal perforation.
19) History of organ or bone marrow transplant.
20) Positive serology for human immunodeficiency virus (HIV) 1 or 2. 

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21) Evidence of active Hepatitis C Virus (HCV) infection. Subjects with positive HCVAb at 
screening, require reflex testing for HCV RNA. Subjects with positive Hep C RNA viral load 
(VL) at screening will be excluded. Subjects with positive HCV Ab, but negative HCV RNA 
VL are eligible per investigator judgment, but require ongoing monitoring as outlined in the 
schedule of assessments. Subject with active HCV during the study, as evidenced by RNA 
positivity will be discontinued from study drug as outlined in the protocol. 
22) Evidence of active Hepatitis B Virus (HBV) infection. Subjects with positive HBV surface 
antigen (HBsAg) at screening are excluded from the study. Subjects with positive HBV core 
Ab and negative HBsAg, require reflex testing for HBV DNA. Subjects with positive HBV
DNA at screening will be excluded. Subjects with positive HBV core Ab, and negative HBV 
DNA are eligible per investigator judgment, but may require prophylactic treatment in 
accordance with HBV treatment guidelines/local standard of care and require ongoing
monitoring with blood tests for HBV DNA every 3 months, as outlined in the schedule of 
assessments. Subject with evidence of active Hepatitis B during the study, as evidenced by 
DNA positivity, will be discontinued from study drug as outlined in the protocol.
23) History of opportunistic infection or immunodeficiency syndrome which would put the 
subject at risk, as per investigator judgment.
24) Active infection that is clinically significant, as per judgment of the investigator, or any 
infection requiring hospitalization or treatment with intravenous anti-infectives within 
60 days of Screening; or any infection requiring oral anti-infective therapy within 30 days of 
Screening.
25) Currently on any therapy for chronic infection (such as pneumocystis, cytomegalovirus, 
herpes zoster, and atypical mycobacteria). Past history of disseminated staphylococcus 
aureus or disseminated Herpes simplex infection.
26) History of symptomatic herpes zoster within 12 weeks prior to Screening or have history of 
disseminated/complicated herpes zoster infection (multi dermatomal involvement, 
ophthalmic zoster, central nervous system involvement or postherpetic neuralgia)
27) History of an infected joint prosthesis or other implanted device with retention of the 
prosthesis or device in situ.
28) Current drug, tobacco or alcohol abuse, per investigator judgment.
29) 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.
30) Any condition or circumstances which in the opinion of the Investigator or Sponsor may 
make a subject unlikely or unable to complete the study or comply with study procedures and 
requirements.
31) Use of prohibited medication as outlined in section 5.4

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32) Significant blood loss (>450 mL) or transfusion of blood product within 12 weeks prior to 
Day 1.
33) Tests performed at the central laboratory at Screening that meet any of the criteria below
(out of range lab values may be rechecked one time, after consultation with the sponsor or 
it’s designee, before subject is considered a screen-failure):
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 creatinine clearance <40 mL/min based on the Cockroft-Gault formula.
 
 
 
 
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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
An Interactive Web Response System (IWRS) will be employed to manage subject 
randomization and treatment assignments. It is the responsibility of the investigator to ensure that 
the subject is eligible for the study prior to enrollment. Subjects will be assigned a Screening
number at the time of consent. 
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain individual subject treatment assignment directly from 
the IWRS system. 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 emergency medical care for the subject. The 
rationale for unblinding must be clearly explained in source documentation and on the electronic 
case report form (eCRF), along with the date on which the treatment assignment was
unblinded. 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 Phase 3 clinical trial and therefore, if 
a subject’s treatment assignment is disclosed to the investigator, the subject will have study drug
discontinued. 
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs) to Regulatory 
Authorities.
5.2.
Description and Handling of Filgotinib and PTM Filgotinib
5.2.1.
Formulation of Filgotinib and PTM Filgotinib
Filgotinib is provided as 100 mg and 200 mg strength tablets. Filgotinib tablets, 100 mg and 
200 mg tablets, are beige, capsule-shaped, debossed with "GSI" on one side and “100” or “200” 
on the other, biconvex, film-coated tablets for clinical use. Each tablet contains the equivalent of 
100 mg or 200 mg filgotinib free base in the form of filgotinib maleate. In addition to the active 
ingredient, filgotinib tablets contain the following inactive ingredients: microcrystalline 
cellulose, lactose monohydrate, fumaric acid, pregelatinized starch, silicon dioxide, magnesium 
stearate, macrogol/PEG 3350, polyvinyl alcohol, talc, titanium dioxide, iron oxide yellow, and 
iron oxide red.
Placebo to match filgotinib tablets, 100 mg and 200 mg, will be identical in appearance to the 
respective active tablets. Placebo to match filgotinib tablets contain the following inactive 
ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium 
stearate, macrogol/PEG 3350, polyvinyl alcohol, talc, titanium dioxide, iron oxide yellow, and 
iron oxide red.

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5.2.2.
Packaging and Labeling for Filgotinib and PTM Filgotinib
Filgotinib tablets, 100 mg and 200 mg, and PTM filgotinib tablets, 100 mg and 200 mg, are 
packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 30 tablets, 
silica gel desiccant and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child-resistant polypropylene screw cap fitted with an induction-sealed, 
aluminum-faced liner.
Study drugs to be distributed to participating centers, shall be labeled to meet applicable 
requirements of the United States Food and Drug Administration (FDA), the EU Guideline to
Good Manufacturing Practice - Annex 13 (Investigational Medicinal Products) and/or other local 
regulations, as applicable.
Sufficient quantities of filgotinib tablets, 100 mg and 200mg, and PTM filgotinib tablets to 
complete the entire study will be shipped to the investigator or qualified designee from the 
Gilead Supply Management Team (or its designee).
5.2.3.
Storage and Handling for Filgotinib and PTM Filgotinib
Filgotinib tablets, 100 mg and 200 mg, PTM filgotinib tablets should be stored at controlled 
room temperature of 25°C (77F); excursions are permitted between 15C and 30C 
(59F to 86F).
Until dispensed to the subjects, all drug products should be stored in a securely locked area, 
accessible only to authorized site personnel. To ensure the stability of the study drug and to 
ensure proper product identification, the drug product should not be stored in a container other 
than the container in which they are supplied. Consideration should be given to handling, 
preparation, and disposal through measures that minimize drug contact with the body. 
Appropriate precautions should be followed to avoid direct eye contact or exposure when 
handling.
5.2.4.
Dosage and Administration of Filgotinib
Filgotinib tablets, 100 mg and 200 mg, and PTM filgotinib will be administered once daily with 
or without food. Each subject should be given instructions to maintain approximately the same 
daily time of administration to ensure a similar dosing interval between study drug doses. 
For missed dose(s) of study medication, subjects should be instructed to take the missed dose(s) 
of study medication as soon as possible during the same day. If the missed dose is not taken on 
the original day, subjects should be cautioned not to double the next dose with the missed dose of 
study drug under any circumstances. In those cases, the missed dose should be returned to the 
study drug bottle.

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5.3.
Description and Handling of Methotrexate (MTX) and PTM MTX
5.3.1.
Formulation for MTX and PTM MTX
MTX is available as 2.5-mg strength capsules. MTX capsules are white opaque capsules. Each 
capsule contains one commercially sourced MTX tablet, 2.5 mg, and microcrystalline cellulose. 
Information regarding the formulation can be found in the current prescribing information.
Placebo to match MTX capsules is visually identical to the MTX capsule. Each PTM MTX 
capsule contains a placebo tablet and microcrystalline cellulose. The placebo tablet contains the 
inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, 
magnesium stearate, and iron oxide yellow.
5.3.2.
Packaging and Labeling for MTX and PTM MTX
Methotrexate and PTM methotrexate capsules are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 100 capsules and is enclosed with a white, continuous 
thread, child-resistant polypropylene screw cap fitted with an induction-sealed, aluminum-faced 
liner.
Study drugs to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), EU Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal 
Products) and/or other local regulations, as applicable.
5.3.3.
Storage and Handling for MTX and PTM MTX
Methotrexate and PTM methotrexate capsules should be stored at 25°C (77°F), until required for 
administration; excursions are permitted between 15 – 30°C (59 – 86°F). 
Storage conditions are specified on the label. Until dispensed to the subjects, all drug products 
should be stored in a securely locked area, accessible only to authorized site personnel. 
To ensure the stability of the study drug and to ensure proper product identification, the drug 
product should not be stored in a container other than the container in which they are supplied. 
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling.
5.3.4.
Dosage and Administration of MTX
The titration period for MTX will be 8 weeks.  Subjects will be started on 10 mg (4 capsules) of 
either MTX or PTM, in a blinded fashion. In the absence of any lack of tolerance as specified 
below, subjects will be advanced to 15 mg (6 capsules) of MTX or PTM at their 4 week visit and 
advanced to 20 mg (8 capsules) of MTX or PTM at their 8 week visit. Subjects should be on an 
adequate dose of folic acid (as per local practice) which should be confirmed or initiated at 
Day 1, and continued throughout the study. 

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All local standard-of-care practices for the administration of MTX, including follow-up care and 
contraindications should be performed according to local standards of care throughout the study. 
Events that might indicate a lack of tolerance may include, but are not limited to:

Moderate to severe headaches not responding to simple medical management;

Moderate to severe nausea not responding to simple medical management;

Moderate to severe fatigue;

Mucocutaneous problems: oral ulcers or stomatitis not responding to simple medical 
management;

Alopecia not responding to simple medical management;

Elevated transaminases, confirmed by two consecutive blood tests (3-7 days apart);

Cytopenia, on blood samples taken 3-7 days apart:
Thrombocytopenia, defined as two sequential platelet counts<100,000 platelets/mm3;
Neutropenia, defined as two sequential neutrophil counts <1.0 x 109/L;
Leukopenia, defined as two sequential white blood cell count <3.0 x 109/L;
Simple medical management of adverse events typical of suspected intolerance to MTX may
include allowed concomitant medications (e.g., anti-emetic medication), or replacing folic acid 
with up to 5 mg dose of leucovorin (folic acid) dosed 8 to 24 hours after the MTX weekly dose.
Single Dose Reduction of Methotrexate
After the first 4 weeks, a single dose reduction of MTX/PTM by 5 mg (2 capsules weekly) is 
allowed during the study, as long the patient remains on a dose of at least 4 capsules of 
MTX/PTM weekly. Lack of tolerance and dose reductions are to be documented by the 
investigator. Should significant laboratory abnormalities or symptoms persist after dose 
adjustment, please refer to the discontinuation guidelines as outlined in Section 3.5. If the subject 
cannot tolerate the MTX/PTM tablets within the first 4 weeks of the study, consideration should 
be given to discontinuing the subject from study drug dosing, as no dose reduction is permitted 
within the first 4 weeks.
5.4.
Prior and Concomitant Medications
Concomitant therapies taken for the treatment of pre-existing conditions can continue during the 
study provided they are in accordance with the inclusion and exclusion criteria 
(see Section 4.2 and 4.3). It is preferred that these medications be continued without variation of 

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dose or regimen during the study, as much as possible. All non-RA medication used within 
30 days of consent (including any changes) is to be documented in the eCRF. All prior 
medication used in the treatment for RA, are to be documented in the eCRF.
At each study visit, the site will capture any and all medications taken by the subject since the 
last visit or during the visit (as applicable). Concomitant medications include prescription, non-
prescription medications, therapies, dietary supplements, and minerals.
In case new (non-prohibited) therapies need to be administered during the study, the risk/benefit 
to the subject should be carefully assessed and consideration given to the timing of any necessary 
introduction of new medications.
Permitted concomitant medications should be kept stable for the study duration, as much as 
possible, and include: 

NSAIDs, at a stable dose and regimen, as much as possible; NSAID doses should be held 
starting 12 hours before a study visit until after all scheduled assessments have taken place, 
as much as possible

Anti-malarial DMARDs (hydroxychloroquine  ≤400mg/day or chloroquine ≤250mg/day) 
provided that the prescription has been stable for at least 4 weeks prior to Day 1

Oral prednisone ≤10 mg/day or equivalent, provided that the prescription has been stable for 
at least 28 days prior to Day 1. After Week 24, subject's steroid dose can be reduced or 
tapered based on investigator judgment (and may also be adjusted back up as needed), but 
should NOT exceed the stable dose identified at Baseline   

Analgesics, including opioids and other non-NSAID based therapies, at a stable dose and 
regimen, as much as possible; analgesic  doses should be held starting 12 hours before a 
study visit until after all scheduled assessments have taken place, as much as possible 

Dose adjustments for management of toxicity of the above medications are allowed and 
should be documented, along with documentation of the AE which led to the change in the 
medication
Female subjects of childbearing potential must agree to use highly effective birth-control 
methods as outlined in Appendix 5 and must agree to continue their use during the study and for 
at least 35 days after the last dose of study medication. The use of hormonal contraceptives will 
be recorded in the Concomitant Therapy section of the eCRF. Applicable procedures and 
treatment guidance based on package inserts will be respected. 
Hormone replacement therapy, thyroid replacement and other chronic therapies (such as those 
for well-controlled diabetes or hypertension) are permitted during the study, and should be kept 
at a stable dose and regimen, as much as possible.

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Vitamin, mineral or herbal supplementations are permitted during the study per judgment of 
investigator, and should be kept at a stable dose and regimen, as much as possible.
Prohibited concomitant medications (and their wash out period as applicable) while on study 
drugs include: 

Use of csDMARDs (other than the study-provided MTX/PTM or ongoing 
hydroxychloroquine  ≤400 mg/day or chloroquine ≤250 mg/day)

Use of any biologic DMARD

Any cytotoxic agent, including chlorambucil, cyclophosphamide, nitrogen mustard, and other 
alkylating agents.

Use of any other JAK inhibitor or other small molecule immunomodulator

Any injectable corticosteroids and receipt of an intra-articular or parenteral corticosteroid 
injection within 4 weeks prior to Day 1 is prohibited.

Potent Pg-p inducers (e.g. rifampin, phenytoin, carbamazepine, and St. John’s wort) within 
3 weeks prior to Day 1
Subjects with prior exposure to csDMARD other than HCQ or MTX may be enrolled if there is 
documented evidence of limited exposure (less than 3 months). Washout period of ≥8 weeks for 
leflunomide, or ≥4 weeks for all other csDMARD(s) prior to Day 1 need to be satisfied.
Any prior use of biologic DMARDs for RA is prohibited
Previous treatment at any time with a cytotoxic agent is prohibited. 
Previous use of JAK inhibitors is prohibited. For subjects who are treated with isoniazid, 
consideration should be given to supplementation with vitamin B6 (pyridoxine) to reduce the 
risk of peripheral neuropathy.
Vaccine Guidelines:

Prior to study participation, it is recommended that the subject’s vaccinations be brought up 
to date according to local vaccination standards.

Live or attenuated vaccines (including, but not limited to varicella and inhaled flu vaccine) 
are prohibited within 30 days of Day 1, throughout the study, and for 6 weeks after the last 
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
Subjects should be advised to avoid routine household contact with persons vaccinated with 
live/attenuated vaccine components. General guidelines suggest that a study subject’s 
exposure to household contacts should be avoided for the below stated time periods:
Varicella or attenuated typhoid fever vaccination – avoid contact for 4 weeks following 
vaccination
Oral polio vaccination -- avoid contact for 6 weeks following vaccination
Attenuated rotavirus vaccine -- avoid contact for 10 days following vaccination
Inhaled flu vaccine -- avoid contact for 1 week following vaccination

Inactivated vaccines (such as inactivated flu vaccines) should be administered according to 
local vaccination standards whenever medically appropriate; however, there are no available 
data on the concurrent use of filgotinib and its impact on immune responses following 
vaccination.
5.5.
Accountability for Study Drugs
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drugs. This includes acknowledgement of receipt of each shipment of study drugs (quantity and 
condition). All used and unused study drugs dispensed to subjects must be returned to the site.
Filgotinib and MTX accountability records will be provided to each study site to:

Record the date received and quantity of study drugs

Record the date, subject number, subject initials, the study drug number dispensed

Record the date, quantity of used and unused study drugs returned, along with the initials of 
the person recording the information.

Dispensing records will include the initials of the person dispensing the study drug or 
supplies.
5.5.1.
Investigational Medicinal Product Return or Disposal
At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead’s requirements. Study drug may be returned or destroyed on an ongoing basis during the 
study if appropriate. At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused investigational medicinal 
product supplies, including empty containers, according to these procedures. If the site cannot 
meet Gilead’s requirements for disposal, arrangements will be made between the site and 
Gilead’s or its representative for destruction or return of unused investigational medicinal 
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All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
For additional information about study drug accountability and return, refer to Section 9.1.7. 

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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled 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).
The study assessments as described below will be performed at the time points specified in the 
Study Procedures Table (Appendix 2). Visits are to be scheduled within a window as specified in 
the schedule of assessment and in such a way that the total study duration from Day 1 to last 
dosing does not exceed 52 weeks, as much as possible.
6.1.
Subject Enrollment and Treatment Assignment
Subject eligibility will be established at the conclusion of the screening evaluations. The 
screening number and subject ID will be assigned for each subject by IWRS. 
It is the responsibility of the investigator to ensure that each subject is eligible for the study 
before randomization. A subject will be considered enrolled once randomized.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened before randomization to determine eligibility for participation in the 
study. The screening window may be extended to up to 42 days prior to the Day 1 visit for 
subjects who require repeat collection of radiographs. Subject-reported outcomes, including
Global Assessment, HAQ-DI and Pain Scale are recommended to be done before any other study 
procedures. Invasive study procedures such as blood draws should be done at the end of a study 
visit, as much as possible. The following will be performed and documented at screening:

Obtain written informed consent

Obtain demographics and medical history  (including onset of RA, disease characteristics, 
smoking habits, average weekly alcohol consumption, and family history of coronary heart 
disease)

Complete physical examination including height

Weight

Vital Signs

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
Perform 66 swollen and 68 tender joint count assessment (SJC66/TJC68)

Physician’s global assessment

Subject’s global assessment

HAQ-DI and Pain Scale

Radiographs of hands, wrists, and feet to be sent to central review for confirmation of joint 
erosion(s)

12-Lead ECG

TB test and Chest X-ray (if applicable) 

Obtain blood samples for: 
Serology
Hematology and Chemistry
Serum CRP
Serum Pregnancy Test (if applicable)
Rheumatoid factor, anti-CCP Ab
Quantitative immunoglobulin (Ig)
FSH (for females only), TSH, Hemoglobin A1c

Urinalysis (including pregnancy test, if applicable)

Review of concomitant medications

Record any serious adverse events and all adverse events 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 after screening for randomization into the study.
Subjects who do not meet the eligibility criteria will be excluded from randomization; subjects
may be considered for rescreening one time for the study in consultation with the Sponsor or its 
designee.

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From the time of obtaining informed consent through the first administration of investigational 
medicinal product, the investigative site is to record all serious adverse events (SAEs), as well as 
any adverse events related to protocol-mandated procedures on the adverse events case report 
form (eCRF). All other untoward medical occurrences observed during the screening period, 
including exacerbation or changes in medical history are to be captured on the medical history 
eCRF.  See Section 7 Adverse Events and Toxicity Management for additional details.
6.2.2.
Day 1 Assessments
At Day 1, after the subject’s eligibility for the study has been confirmed, the subject will be 
randomized into the study to receive one of four study dosing regimens. 
Subject’s Global Assessment, HAQ-DI and Pain Scale, FACIT- Fatigue, and SF-36 are 
recommended to be done before any other study procedures. Invasive study procedures such as 
blood draws should be done at the end of a study visit. The following will be performed and 
documented at Day 1 prior to dosing:

Subject’s global assessment

HAQ-DI and Pain Scale FACIT-Fatigue and SF-36

WPAI-RA and EQ-5D, where available

TSQM , when and where available

Healthcare resource utilization questionnaire

Symptom-driven physical examination

Weight

Vital signs

SJC66/TJC68

Physician’s global assessment

Obtain blood samples for: 
Hematology and Serum Chemistry
Lipid profile (fasting)
Serum CRP
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Biomarker blood samples
Pre-dose vfPBMC and leukocyte subsets samples  (US and Canada only) 

Urinalysis (including pregnancy test, if applicable)

Urine stored for biomarker analysis

Review of concomitant medications

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form
 
6.3.
Randomization
Subjects will be randomly allocated to a dosing group according to a pre-specified randomization 
scheme prepared by an independent statistician. Upon qualification for the study, subjects will be 
randomized using a computerized IWRS system. Randomization will be stratified by geographic
region and presence of RF or anti-CCP Ab at Screening.
For each subject at each visit, the clinic will contact the IWRS system and for the appropriate kit 
number to be dispensed. The kit will contain the relevant study drugs for the period until the next 
dispensation visit.
 
6.4.
Week 2 through Week 44 Assessments 
The following assessments will be completed at each visit or as specified. All assessments are 
summarized in the Study Procedures Table (Appendix 2).
Subject’s Global Assessment, HAQ-DI and Pain Scale, FACIT- Fatigue, and SF-36 are
recommended to be done before any other study procedures. Invasive study procedures such as 
blood draws should be done at the end of a study visit. 

Subject’s global assessment

HAQ-DI and Pain Scale

FACIT-Fatigue and SF-36 at Weeks 4, 12, and 24
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
WPAI-RA and EQ-5D at Weeks 4, 12, and 24, where available

TSQM at Weeks 12, 24 and 36, when and where available

Healthcare resource utilization questionnaire at Weeks 12, 24 and 36

SJC66/TJC68

Vital signs

Weight

Complete physical examination at Week 24 (symptom-driven PE conducted at all other 
visits)

Physician’s global assessment

12-lead ECG at Weeks 12, 24, and 36

Assessment of serious AE(s), (S)AE(s) and concomitant medication

Obtain blood samples for:
Hematology and Serum Chemistry
Serum CRP
Pre-dose vfPBMC and leukocyte subset samples samples at Weeks 4, 8, 12, 24, and 
36 (US and Canada only)
Blood sampling for PK at Weeks 4, 12 and 24
Biomarker samples at Weeks 4, 8, 12, 24, and 36   
Lipid profile (fasting) at Weeks 12 and 24
Quantitative Ig at Week 24

Radiographs of hands, wrists, and feet at Week 24

Urinalysis at Week 24

Urine stored for biomarker analysis at Week 12 and Week 24
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
Urine pregnancy test (for women of childbearing potential, as defined per protocol). During
the periods where study visits are every 6-8 weeks, women should continue to have
pregnancy tests every 4 weeks, using home pregnancy urine tests, that will be provided to
them. The site will call the subject every 4 weeks to obtain results of these pregnancy tests
and will record the information in the source documents and CRF.
 
6.5.
Week 52/Early Termination (ET)
If a subject discontinues the study, every attempt should be made to perform the required 
study-related ET and Post Treatment Week 4 visits and procedures.
Subject’s Global Assessment, HAQ-DI and Pain Scale, FACIT- Fatigue, and SF-36 are
recommended to be done before any other study procedures. Invasive study procedures such as 
blood draws should be done at the end of a study visit. 

Subject’s global assessment

HAQ-DI and Pain Scale

FACIT-Fatigue and SF-36, 

WPAI-RA and EQ-5D, where available

TSQM, when and where available

Healthcare resource utilization questionnaire

Complete physical examination

Weight

Vital signs

SJC66/TJC68

Physician’s global assessment

12-Lead ECG

Radiographs of hands, wrists, and feet
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Obtain blood samples for: 
Hematology and Serum Chemistry
Lipid profile (fasting)
Serum CRP
Pregnancy test (serum required if subject is entering into LTE)
Blood sampling for PK 
Biomarker blood samples
Quantitative Ig
vfPBMC and leukocyte subset samples (US and Canada only)

Urinalysis (including pregnancy test if applicable)

Urine stored for biomarker analysis

Assessment of AE(s)/serious (S)AE(s) and concomitant medication

Review Entry criteria for LTE (if applicable)
6.6.
Post Treatment Week 4
The following procedures will be completed 4 weeks after the subject’s last dose of study 
treatment. This visit is not applicable if the subject is continuing onto the LTE study. 

Symptom-driven physical examination

Weight

Vital signs

Urinalysis (including pregnancy test if applicable)

12-lead ECG

Obtain blood samples for: 
Hematology and Serum Chemistry

Urinalysis

Assessment of AE(s)/SAE(s) and concomitant medication

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6.7.
Study Assessments
6.7.1.
Efficacy
Efficacy assessments will be carried out at Day 1 and at Weeks 2, 4, 8, 12, 16, 20, 24, 30, 36, 44, 
and 52, or at ET (if applicable). 
Assessments of RA will include the derived ACR (ACR20, 50, 70 as well as ACR-N and 
EULAR response criteria, DAS28 [CRP], CDAI, and SDAI as well as the individual components 
of the ACR response criteria [TJC68, SJC66], HAQ-DI, Physician’s Global assessment, 
Subject’s Global Assessment, Subject’s Assessment of Arthritis Pain and CRP]) and radiographs 
of hands, wrists and feet (mTSS and mTSS components of erosion score and joint space 
narrowing).
Additionally, subjects will be asked to complete questionnaires, including the FACIT-Fatigue
scale, SF-36, EQ-5D, TSQM, WPAI-RA at Day 1 and at Weeks 4, 12, 24, 36, and 52, or at ET
(if applicable). Healthcare resource utilization will be assessed at the Day 1 and at Weeks 12, 24,
36 and 52, or at ET (if applicable).
6.7.1.1.
Evaluation of Disease Activity: Tender and Swollen Joint Counts
Assessment of tender and swollen joints will take place at the time points indicated in the study 
procedures table (Appendix 2) and according to the assessments described in Section 6.4.
Each of 68 joints will be evaluated for tenderness and each of 66 joints will be evaluated for 
swelling (a list of joints to be evaluated is provided in Appendix 7). 
An independent joint assessor with adequate training and experience in performing joint 
assessments will be designated at each study site to perform all joint assessments, and should be 
blinded to the other study assessments performed on that day. The joint assessor should 
preferably be a rheumatologist; however, if a rheumatologist is not available, it should be a 
health care worker with experience in performing joint assessments. The assessor should remain 
the same throughout the study per subject, as much as possible. It is required that the designated 
joint assessor identify an appropriate back up assessor to provide coverage if the designated joint 
assessor is absent.
6.7.1.2.
Subject’s Global Assessment of Disease Activity
The Subject’s Global assessment of Disease Activity will be performed at the time points 
indicated in the study procedures table (Appendix 2). The Subject’s Global assessment of 
Disease Activity should be completed before any other study procedures.
The Subject’s Global Assessment of Disease Activity will be recorded on a 0-100 mm visual 
analog scale (VAS), with 0 indicating “no arthritis” and 100 indicating “severe arthritis”.

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6.7.1.3.
Physician’s Global Assessment of Disease Activity
The Physician’s Global assessment of Disease Activity will be performed at the time points 
indicated in the study procedures table (Appendix 2).
The Physician’s Global Assessment of Disease Activity will be recorded on a 0-100 mm VAS, 
with 0 indicating “no disease activity” and 100 indicating “maximum disease activity”. The 
evaluating physician and the subject should complete the global assessments independently of 
each other.
6.7.1.4.
Serum CRP
The subject’s serum CRP will be measured at the time points indicated in the study procedures 
table (Appendix 2).
6.7.1.5.
Health Assessment Questionnaire – Disability Index and Pain Scale
The functional status of the subject will be assessed using the HAQ-DI at the time points 
indicated in the study procedures table (Appendix 2) and should be completed before any other 
study procedures. The HAQ-DI is a 20-question instrument that assesses the degree of difficulty 
a person has in accomplishing tasks in 8 domains (dressing, arising, eating, walking, hygiene, 
reaching, gripping and errands/chores). Responses are scored on a 4-point Likert scale from 0, 
indicating no difficulty, to 3, indicating inability to perform a task in that area. The need for aids 
or help from another person will also be recorded. The HAQ-DI total score ranges from 
0 to 3 with higher scores indicating greater dysfunction.
As part of the HAQ-DI, subjects will be asked to assess their average pain during the last week 
on a 0-100 mm VAS, with 0 indicating “no pain” and 100 indicating “severe pain”. This 
assessment should be completed before the joint examination. This pain score will be used to 
drive the ACR20/50/70.
6.7.1.6.
FACIT - Fatigue Scale
The FACIT-Fatigue scale (version 4) will be completed at the time points indicated in the study 
procedures table (Appendix 2) and should be completed before any other study procedures where 
local language questionnaires are available.
The FACIT-Fatigue scale measures an individual’s level of fatigue during their usual daily 
activities over the past week. It consists of 13 questions with a 7-day recall period on a 5-point 
Likert scale, with 0 indicating “not at all” and 4 indicating “very much”. The total score ranges 
from 0 to 52. Higher scores indicate a better the quality of life.
6.7.1.7.
36-Item Short-form Health Survey 
The SF-36 (version 2) will be completed at the time points indicated in the study procedures 
table (Appendix 2) and should be done before any other study procedures.

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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).
The remaining item (health transition) is not part of the above domains but is kept separately. 
These scales will be rescaled from 0 to 100 (converting the lowest possible score to 0 and the 
highest possible score to 100), with higher scores indicating a better quality of life.
6.7.1.8.
EuroQol 5 Dimensions
The EQ-5D questionnaire will be completed at the time points indicated in the study procedures 
table (Appendix 2) and should be completed before any other study procedures where local 
language questionnaires are available.
The EQ-5D is a standard measure of health status developed by the EuroQol Group to provide 
a simple, generic measure of health for clinical and economical appraisal {The EuroQol Group 
1990}. The EQ-5D is not disease specific and has been validated in numerous health states.
The tool consists of the EQ-5D descriptive system and the EQ VAS. The descriptive part 
comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression). Each of these 5 dimensions has 3 levels (no problem, some problems, and 
severe problems). Results for each of the 5 dimensions are combined into a 5-digit number to 
describe the subject’s health state. The VAS records the subject’s health on a 0-100 mm VAS 
scale, with 0 indicating “the worst health you can imagine” and 100 indicating “the best health 
you can imagine”.
6.7.1.9.
Work Productivity and Activity Impairment 
The WPAI-RA is a questionnaire developed to measure impairments in work activities in 
subjects with RA {Zhang et al 2010} and will be completed at the time points indicated in the 
study procedures table (Appendix 2) and should be done before any other study procedures
where local language questionnaires are available.
The questionnaire consists of 6 questions (currently employed, work time missed due to RA, 
Work time missed due to other reasons, hours actually worked, degree RA affected productivity 
while working [0-10 VAS; with 0 indicating no effect and 10 indicating RA completely 
prevented the subject from working], and degree RA affected productivity in regular unpaid 
activities [0-10 VAS; with 0 indicating no effect and 10 indicating RA completely prevented the 
subject’s daily activities]). The recall period for questions 2 to 6 is 7 days.

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Four main outcomes (expressed in percentages) can be obtained from the WPAI-RA: percentage 
of work time missed due to RA, percentage of impairment due to RA, percentage of overall work 
impairment due to RA, percentage of activity impairment due to RA. Note that for subjects who 
did not work during the 7 days covered by the WPAI-RA, the percent overall work impairment 
will be equal to the percent of work time missed due to RA.
6.7.1.10.
Healthcare Resource Utilization
The Healthcare Resource Utilization Questionnaire is designed to assess healthcare usage during 
the previous three months across a number of direct medical cost domains. 
This questionnaire should be completed by the patient prior to any procedures being performed 
at the visit, if possible where local language questionnaires are available. 
6.7.1.11.
Hands, Wrists, and Feet Radiographs
Hands, wrists, and feet radiographs will be taken at the time points indicated in the study 
procedures table (Appendix 2). Note that if a subject discontinues the study early and has had 
X-rays performed in the <12 weeks prior to discontinuation, these do not need to be repeated at 
ET. Radiographs performed after enrollment may be done +/-7 days of the scheduled visit. 
All subjects who discontinue from investigational therapy but continue study visits and 
procedures, should continue to have radiographs performed as outlined in the study procedure 
table (Appendix 2). 
The radiographs will be evaluated through central review by 2 independent blinded assessors 
using the mTSS. 
6.7.1.12.
Exploratory Patient Reported Outcomes
 
 
6.7.1.13
Treatment Satisfaction Questionnaire for Medication (TSQM) 
The TSQM will assess the overall level of satisfaction or dissatisfaction with medication subjects 
are taking. Subjects will be asked to rate their treatment satisfaction at the time points indicated 
in the study procedures table (Appendix 2). The TSQM will implemented when and where local 
language TSQM  are available.
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6.7.2.
Safety and Tolerability
Adverse events, physical examinations, vital signs, ECG and laboratory assessments (standard 
hematology, serum/plasma chemistry, and urinalysis) will be collected.
6.7.3.
Clinical Laboratory Evaluations
The hematology and serum chemistry laboratory analyses will be performed at a central
laboratory. Reference ranges will be supplied by the central laboratory and will be used by the 
investigator to assess the laboratory data for clinical significance and pathological changes.
Blood samples will be collected by venipuncture 
 
 in the arm at the time points indicated in the study procedures 
table (Appendix 2) In addition, urine samples for the clinical laboratory assessments will be 
collected. Subjects only need to be fasted at days were lipid profiling is scheduled. 
Please refer to Appendix 6 for table of Clinical laboratory tests.
The laboratory values outside the normal range will be flagged and clinical relevance will be 
assessed by the investigator. More frequent sampling as well as additional tests may be 
performed as deemed necessary by the investigator as indicated. 
Note that in the case where clinically significant laboratory test results are a potential reason for 
discontinuation from the study drug and withdrawal from the study, retesting of the affected 
parameter(s) should be prompt (within 3 to 7 days) after the investigator has consulted with the 
medical monitor. A decision regarding subject discontinuation should be made after the results 
from the retest are available (see Section 3.5 for additional information).
The details of sample handling and shipment instructions will be provided in a separate 
laboratory manual.
6.7.4.
Vital Signs
Vital signs will be measured at the time points indicated in the study procedures table
(Appendix 2).
Vital signs should be taken after the subject has been resting for 5 min and will include heart 
rate, respiratory rate, SBP, DBP, and body temperature.
6.7.5.
Physical Examination
A physical examination should be performed at the time points indicated in the study procedures 
table (Appendix 2). 
Any changes from the Day 1 will be recorded. Height should be measured at Screening only. 
At Screening, Week 24 and Week 52 (or at ET), a complete physical examination should be 
performed. Symptom-driven physical exams should be performed at all other visits. Weight is 
measured at all visits.
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6.7.6.
Other Safety Assessments
6.7.6.1.
12-lead Electrocardiogram
A resting 12-lead ECG will be performed at the time points indicated in the study procedures 
table (Appendix 2). 
The ECG should be obtained after the subject has been resting in the supine position for 5 min 
and will include heart rate (HR), R-R interval, QRS, uncorrected QT, morphology, and rhythm 
analysis. QT interval corrected for HR according to Fridericia (QTcF) will be derived during the 
statistical analysis. ECGs will be interpreted by the investigator for clinical significance and 
results will be entered into the eCRF.
6.8.
Pharmacokinetics Assessments
For all subjects, blood samples for PK analysis will be collected at least 30 minutes post study 
drug dosing at Week 4, prior to study drug dose at Week 12 and Week 24, and at Week 52 or ET.
 
 
Plasma concentrations of filgotinib and GS-829845 will be analyzed.
Additional analyses (e.g., for MTX and its metabolites) may be performed.
6.9.
Biomarker Assessments
Blood and urine samples for biomarker analysis will be collected at Day 1, Weeks 4, 8, 12, 24, 
36, and Week 52 or ET for assessment of markers including but not limited to inflammation, 
immune status, joint damage, and the JAK-STAT pathway.
 
Specific 
information regarding the collection and processing of biomarker samples (if applicable) will be 
provide to each site in a separate laboratory manual.
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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 adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the 
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen.

Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.7.1)

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. It is 
considered to be pre-existing and should be documented on the medical history CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not to be recorded as AEs or SAEs. 
However, laboratory abnormalities (e.g., 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 (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 (e.g., anemia), not the 
laboratory result (i.e., decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to 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 (e.g., pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (e.g., invasive procedures such as venepuncture 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 modified 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 Table 7-1 and Appendix 4.
Table 7-1.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Grade 2
Moderate
Local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL
Grade 3
Severe
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL
Grade 4
Life-threatening
Urgent intervention indicated
Grade 5
Death
Death related AE
*
Activities of Daily Living (ADL) Instrumental ADL refer to opening preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
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 (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 30-days after last administration of study IMP must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
eCRF database and Gilead 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 30-days 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 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 as described above.
Gilead DSPH:
Fax:
E-mail: 

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.
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
All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form.
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 (eg, clinical chemistry, hematology, and urinalysis) independent of the 
underlying medical condition that require medical or surgical intervention or lead to 
investigational medicinal product interruption or discontinuation must be recorded as an AE, as 
well as an SAE, if applicable. In addition, laboratory or other abnormal assessments 
(eg, electrocardiogram, X-rays, vital signs) that are associated with signs and/or symptoms must 
be recorded as an AE or SAE if they meet the definition of an AE (or SAE) as described in 
Sections 7.1.1 and 7.1.2. If the laboratory abnormality is part of a syndrome, record the 
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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://www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-%20DMCC.pdf
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.
All clinical and clinically significant laboratory toxicities will be managed according to uniform 
guidelines detailed in Appendix 3 and as outlined below.
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue study drug at the discretion of the investigator.
7.5.2.
Grades 3 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.
7.5.3.
Grades 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.
Investigational medicinal product may be continued without dose interruption for a clinically 
non-significant Grade 4 laboratory abnormality (eg, Grade 4 CK after strenuous exercise or 
triglyceride elevation that is nonfasting or that can be medically managed) or a clinical event 
considered unrelated to investigational medicinal product.

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7.6.
Toxicity Management 
Treatment-emergent toxicities will be noted by the investigator and brought to the attention of 
the Gilead Sciences medical monitor, who will have a discussion with the investigator and 
decide the appropriate course of action. Whether or not considered treatment-related, all subjects 
experiencing AEs must be monitored periodically until symptoms subside, any abnormal 
laboratory values have resolved or returned to baseline levels or they are considered irreversible, 
or until there is a satisfactory explanation for the changes observed.
Grade 3 or 4 clinically significant laboratory abnormalities should be managed as outlined in 
Appendix 3 and Sections 7.5.2 and 7.5.3.
Any questions regarding toxicity management should be directed to the Gilead Sciences 
Medical Monitor.
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, 
pregnancy reports regardless of an associated AE and AE in an infant following exposure from 
breastfeeding.  
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively 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.  
Occupational exposure is defined as exposure to a medicinal product as a result of one's 
professional or non-professional occupation.  

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7.7.2.
Instructions for Reporting Special Situations
7.7.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to Gilead DSPH using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy. 
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
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: 
 and Fax: 
 
Pregnancies of female partners of male study subjects exposed to 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 
 or email 
 
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 or 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. 
PPD
PPD
PPD
PPD

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Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a non-
Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.

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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoint
8.1.1.
Analysis Objectives
The primary objective of this study is as follows:

To evaluate the effects of filgotinib in combination with MTX versus MTX alone for the 
treatment of signs and symptoms of RA as measured by the proportion of subjects achieving 
ACR20 at Week 24
The secondary objectives of this study are as follows: 

To evaluate the effect of filgotinib in combination with MTX versus MTX alone on physical 
function as measured by change from Baseline in the HAQ-DI score at Week 24 

To evaluate the effects of filgotinib in combination with MTX versus MTX alone for the 
treatment of signs and symptoms of RA as measured by the proportion of subjects achieving 
Disease Activity Score for 28 joint count using CRP (DAS28 [CRP])<2.6 at Week 24 

To evaluate the effect of filgotinib alone versus MTX alone for the treatment of signs and 
symptoms of RA as measured by the proportion of subjects achieving ACR20 at Week 24

To evaluate the effect of filgotinib in dose of 200 mg  q.d. alone versus MTX alone on 
physical function as measured by change from Baseline in HAQ-DI score at Week 24 

To evaluate the effect of filgotinib alone versus MTX alone for the treatment of signs and 
symptoms of RA as measured by the proportion of subjects achieving DAS28 (CRP)<2.6 at 
Week 24

To evaluate the effects of filgotinib in combination with MTX versus MTX alone on 
preservation of joint structure as measured by change from Baseline in the mTSS at Week 24 
and 52

To evaluate the effects of filgotinib versus MTX alone on preservation of joint structure as 
measured by change from Baseline in mTSS at Week 24 and 52

To evaluate the safety and tolerability of filgotinib alone and in combination with MTX 

To evaluate the effects of filgotinib alone and in combination with MTX on work 
productivity, fatigue, and general quality of life as measured by SF-36, FACIT-Fatigue, 
EQ-5D and WPAI-RA

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will be used for the hypothesis testing at the 2-sided 0.05-level. Subjects who do not have 
sufficient measurements to establish efficacy at Week 24 will be considered as failures 
(i.e. non-responder imputation [NRI]).  Sensitivity analyses will be conducted and described in 
the statistical analysis plan (SAP).
8.5.2.
Secondary Analyses
The following hypothesis testing will commence after the primary analysis reaches statistical 
significance, and will be tested according to the hierarchical testing principle at the 2-sided 
0.05 level. If a null hypothesis is not rejected, formal sequential testing will be stopped and only 
nominal significance will be reported for the remaining hypotheses.
1) Superiority of filgotinib 200 mg in combination with MTX compared to MTX alone based on 
the change from Baseline in HAQ-DI at Week 24. 
2) Superiority of filgotinib 200 mg in combination with MTX compared to MTX alone based on 
the response rate of DAS28 (CRP)<2.6 at Week 24.
3) Superiority of filgotinib 100 mg in combination with MTX compared to MTX alone based on 
ACR20 response rate at Week 24. 
4) Superiority of filgotinib 100 mg in combination with MTX compared to MTX alone based on 
the change from Baseline in HAQ-DI at Week 24. 
5) Superiority of filgotinib 100 mg in combination with MTX compared to MTX alone based on 
the response rate of DAS28 (CRP)<2.6 at Week 24.
6) Superiority of filgotinib 200 mg alone compared to MTX alone based on ACR20 response 
rate at Week 24.
7) Superiority of filgotinib 200 mg alone compared to MTX alone based on the change from 
Baseline in HAQ-DI to Week 24.
8) Superiority of filgotinib 200 mg alone compared to MTX alone based on the response rate of 
DAS28 (CRP)<2.6 at Week 24.
9) Superiority of filgotinib 200 mg in combination with MTX compared to MTX alone based on 
the change from Baseline in mTSS at Week 24.
10) Superiority of filgotinib 100 mg in combination with MTX compared to MTX alone based on 
the change from Baseline in mTSS at Week 24.
11) Superiority of filgotinib 200 mg alone compared to MTX alone based on the change from 
Baseline in mTSS at Week24.

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For categorical endpoints (the response rate of DAS28 [CRP]<2.6), the same CMH approach 
with NRI as in the primary analysis will be adopted.  For continuous endpoints (HAQ-DI and 
mTSS), mixed-effects model for repeated measures (MMRM) will be used to evaluate treatment 
effect on change from Baseline, with treatment, visit, stratification factors and baseline value 
included as fixed effects and subject being the random effect.  Missing change scores in HAQ-DI
and mTSS due to early withdrawal or treatment reassignment will not be otherwise imputed 
using the MMRM approach. Sensitivity analyses will be conducted by imputing missing data 
via, for example, last observation carried forward (LOCF) and multiple imputation (MI) 
methods.  More details will be specified in the SAP.
For other secondary endpoints listed under Section 8.1.3, summary statistics will be provided by 
treatment group. Differences across treatment groups will be summarized and treatment 
comparisons may be performed. Details on efficacy analyses will be described in the SAP. 
8.6.
Safety Analysis
All safety analyses will be performed using the safety analysis set.
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, vital 
signs measurements at various time points during the study, and by the documentation of AEs.
All safety data collected on or after the first dose of study drug administration up to 30 days after 
the last dose of study drug, unless specified otherwise will be summarized by treatment group 
according to the study drug received.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration page of the eCRF. Exposure data will be summarized by treatment group. 
Duration of exposure to study drug will be expressed as the number of weeks between the first 
and last dose of the study drug, inclusive, regardless of temporary interruptions in study drug 
administration and summarized by treatment group. 
8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Treatment-Emergent Adverse Events (TEAEs) are:

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 (Appendix 4).
8.7.
Pharmacokinetic Analysis
Plasma concentrations of filgotinib and its metabolite (GS-829845) will be listed and 
summarized for all subjects by treatment using descriptive statistics (eg, sample size, arithmetic 
mean, geometric mean, % coefficient of variation, standard deviation, median, minimum, and 
maximum).
 
 
Exposure-response analysis may be performed.
8.8.
Biomarker Analysis
Exploratory analyses may be performed to evaluate the association of each biomarker or 
combination of biomarkers with clinical outcomes, the modulation of biomarkers related to 
mechanism of action and disease progression, and biomarker or combination of biomarkers 
predictive of treatment response.
Exploratory biomarkers analyses that may enhance the understanding of the biological effects, 
the mechanism of action, or safety, may be performed. Biomarker objectives may be further 
described and updated based on evolving scientific knowledge of filgotinib. If an exploratory 
biomarker analysis is to be performed, biomarker analysis plan, with details on objectives and 
analysis methods, will be issued prior to the actual data analysis.
8.9.
Sample Size
Sample size is determined based on the superiority test of filgotinib 200 mg in combination with 
MTX compared to MTX alone based on the change from Baseline in mTSS at Week 24. When 
assuming a difference of 0.62 between the two groups and a common standard deviation of 2.7, 
400 subjects in the filgotinib 200 mg in combination with MTX group and 400 in the MTX alone 
group are required to obtain 90% power at a 2-sided 0.05-level.
CCI

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The total sample size will be 1200 (400 subjects for filgotinib 200 mg in combination with MTX 
group, 200 subjects for filgotinib 100 mg in combination with MTX, 200 subjects for filgotinib 
200 mg alone group and 400 subjects for MTX alone group). This sample size will provide over 
90% power to detect an increase in ACR20 response rate of 62% to 78% between the MTX 
alone group and each of the filgotinib groups respectively, using a 2-sided 0.05-level test.
8.10.
Data Monitoring Committee
An external multidisciplinary DMC will review the progress of the study and perform interim 
reviews of safety data 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 initial reviews will be conducted after approximately 100 subjects enrolled complete 
12 weeks treatment. 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.
8.11.
Cardiovascular Endpoint Adjudication Committee
A Cardiovascular Endpoint Adjudication Committee (CV-SEAC) consisting of at least 
2 cardiologists and governed by a Charter will be set up to perform adjudication of Major 
Adverse Cardiovascular Events occurring during the study. The adjudication of these events will 
be performed in a blinded fashion for the purposes of data analysis, and not for monitoring of
subject safety. 
8.12.
Analysis Schedule
The primary and secondary analyses will be conducted after all subjects either complete their 
Week 24 visit or prematurely discontinue from the study. The final analysis will be performed 
when all subjects complete the study or prematurely discontinue from 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 subinvestigators 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 subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (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. The investigator will not begin any study subject activities until 
approval from IRB/IEC has been documented and provided as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB/IEC –approved consent form for documenting written 

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informed consent. Each informed consent (or assent as applicable) 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 local requirements. The consent form will inform subjects about 
genomic testing and sample retention, and their right to receive clinically relevant genomic 
analysis results.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB/IEC, or laboratory. Laboratory 
specimens must be labeled in such a way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The 
investigator must keep a screening log showing codes, names, and addresses for all subjects 
screened and for all subjects enrolled in the trial. Subject data will be processed in accordance 
with all applicable regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, eCRF, the study drug, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following 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, i.e., 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 IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (i.e., 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 
eligibility have been received.  Subsequent to data entry, a study monitor will perform source 

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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 captures the data required per the protocol 
schedule of events and procedures. System-generated or manual queries will be issued to the 
investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, 
who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (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
Where possible, IMP should be destroyed at the site. At the start of the study, the study monitor 
will evaluate each study center’s IMP disposal procedures and provide appropriate instruction for 
disposal or return of unused IMP supplies. If the site has an appropriate standard operating 
procedure (SOP) for drug destruction as determined by Gilead Sciences, the site may destroy 
used (empty or partially empty) and unused IMP supplies as long as performed in accordance
with the site’s SOP. This can occur only after the study monitor has performed drug 
accountability during an on-site monitoring visit. 
A copy of the site’s IMP Disposal SOP or written procedure (signed and dated by the PI 
or designee) will be obtained for Gilead site files. If the site does not have acceptable 
procedures in place, arrangements will be made between the site and Gilead Sciences 
(or Gilead Sciences’ representative) for return of unused study drug supplies. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMPs 
destroyed. Upon study completion, copies of the IMP accountability records must be filed at the 
site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRB/IEC, 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/IEC in 
accordance with local requirements and receive documented IRB/IEC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to 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 (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, 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 
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests

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10.
REFERENCES
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, 3rd, et al. 2010 
Rheumatoid arthritis classification criteria: an American College of 
Rheumatology/European League Against Rheumatism collaborative initiative. 
Arthritis Rheum 2010;62 (9):2569-81.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College 
of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. 
Arthritis Rheum 1995;38 (6):727-35.
Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, et al. Estimates of the 
prevalence of arthritis and other rheumatic conditions in the United States. Part I. 
Arthritis Rheum 2008;58 (1):15-25.
Lopez-Olivo MA, Siddhanamatha HR, Shea B, Tugwell P, Wells GA, Suarez-Almazor ME. 
Methotrexate for treating rheumatoid arthritis. Cochrane Database Syst Rev 
2014;6:CD000957.
Namour F, Diderichsen PM, Cox E, Vayssiere B, Van der Aa A, Tasset C, et al. 
Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib 
(GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection. 
Clin Pharmacokinet 2015;54 (8):859-74.
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.
Redlich K, Schett G, Steiner G, Hayer S, Wagner EF, Smolen JS. Rheumatoid arthritis therapy 
after tumor necrosis factor and interleukin-1 blockade. Arthritis Rheum 2003;48 
(12):3308-19.
Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, et al. 2012 update of the 
2008 American College of Rheumatology recommendations for the use of 
disease-modifying antirheumatic drugs and biologic agents in the treatment of 
rheumatoid arthritis. Arthritis care & research 2012;64 (5):625-39.
The EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of 
life. . Health Policy 1990;16 (3):199-208.

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Zhang W, Bansback N, Boonen A, Young A, Singh A, Anis AH. Validity of the work 
productivity and activity impairment questionnaire--general health version in 
patients with rheumatoid arthritis. Arthritis research & therapy 2010;12 (5):R177.

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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
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 Methods
Appendix 6.
Laboratory Assessment Table
Appendix 7.
List of Joints to be Evaluated (66/68 Joint Count)
Appendix 8.
The 2010 American College of Rheumatology –European League Against 
Rheumatism Collaborative Initiative Classification Criteria for Rheumatoid 
Arthritis {Aletaha et al 2010}
Appendix 9.
American College of Rheumatology Response Evaluations/ Preliminary Definition 
of Improvement in Rheumatoid Arthritis {Felson et al 1995}
Appendix 10.
Disease Activity Score (DAS28) {Prevoo et al 1995}
Appendix 11.
Procedures and Specifications

PPD
PPD
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Gilead Sciences, Inc. 
Amendment l 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DR 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Randomized, Doub1e-blin~, Placebo- and Active-controlled, Multicenter, Phase 3 Study to 
Assess the Efficacy and Safety of Filgotinib Administered for 52 Weeks Alone and in 
Combination with Methotrexate (MTX) to Subjects with Moderately to Severely Active 
Rheumatoid Arthritis Who Are Na1ve to MTX Therapy 
GS-US-417-0303, Amendment 1 Protocol, 05 July 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Name (Printed) 
Author 
) d-O Ill 
Date UJ 
INVESTIGATOR ST A TEMENT 
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 umber 
CONFIDENTIAL 
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Appendix 2. 
Study Procedures Table 
EVENT 
T1·eatment Pe1iod 
Follow-Up4 
Post 
W52/ 
T1·eatmeot 
Visits 
Day lb 
W2 
W4 
W8 
W12 
W16 
W20 
W24 
W30 
W36 
W44 
ET' 
Week4 
(±3 
(±3 
(±3 
(±3 
(±3 
(±3 
(±3 
(±7 
(±7 
(±7 
(±7 
Visit window (Days) 
Screening" 
days) 
days) 
days) 
days) 
days) 
days) 
days) 
days) 
days) 
days) 
days) 
(±7 days) 
Infonm:d Consent 
X 
Inclusion/Exclusion Criteria 
X 
X" 
,,, -
Demographics and Baseline 
= 
X 
Disease Characteristics 
E 
,,, 
f!s 
RA diagnosis and Prior RA 
,.,, ,,, 
X 
< 
Treatment, Me.dical History f 
!:IJ) = 
·= Complete Physical Examination g 
X 
X 
X 
i.. 
rJ5 
TB test and Chest X-Ray h 
X 
RF/anti-CCP Ab 
X 
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I 
I 
I 
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EVENT 
Visits 
Visit window (Days) 
Subject's global assessment i 
,,, 
I-
HAQ-DI and Pain Scale i 
·; = 
= = 
.: 
FACIT-Fatigue, SF-36, WPAI-
"-' 
RAEQ-5D 1 
= 
0 ... = 
Healthcare Resource Utilization 
Questionnaire and TSQM i 
e,: 
=--
Physician's global assessment 
I-
Vital sigusi 
-~ = 
I-
Q., ,,, 
Symptom-driven physical 
-= examination 
= 
e,: E 
e 
e,: 
12-LeadECG 
io< 
,,, 
::: < 
= 
u 
SJC66/TJC68 
";j 
..... 
-= 
Q., 
Weight 
CONFIDENTIAL 
T1·eatment Period 
Day lb 
W2 
W4 
ws 
W12 
W16 
W20 
(±3 
(±3 
(±3 
(±3 
(±3 
(±3 
Screening" 
days) 
days) 
days) 
days) 
days) 
days) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
W24 
W30 
W36 
(±3 
(±7 
(±7 
days) 
days) 
days) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
W44 
(±7 
days) 
X 
X 
Final 
Amendment 1 
Follow-Upd 
Post 
W52/ 
T.-eatment 
ET< 
Week4 
(±7 
days) 
(±7 days) 
X 
X 
X 
X 
------------------------------------------
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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EVENT 
T1·eatment Period 
Follow-Upd 
Post 
W52/ 
T.-eatment 
Visits 
Day lb 
W2 
W4 
ws 
W12 
W16 
W20 
W24 
W30 
W36 
W44 
ET< 
Week4 
(±3 
(±3 
(±3 
(±3 
(±3 
(±3 
(±3 
(±7 
(±7 
(±7 
(±7 
Visit window (Days) 
Screening" 
days) 
days) 
days) 
days) 
days) 
days) 
days) 
days) 
days) 
days) 
days) 
(±7 days) 
Pregnancy test k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology and Chemistty 1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SenunCRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis and urine for 
X 
X 
X 
X 
X 
X 
biomarkers m 
Quantitative IG 
X 
X 
X 
= 
Endocrine: FSH, TSH, and 
X 
E 
HbAlc 
"' 
rr, 
Lipid profile (fasting) 1 
X 
X 
X 
X 
r.r, < 
C' 
0 ... 
'-
0 
,Q 
PK blood samples 0 
X 
X 
X 
X 
.J 
Biomarker Blood Samples: 
Plasma biomarker, semm 
X 
X 
X 
X 
X 
X 
X 
biomarker, trauscriptome, 
TCRIBCR repertoire P 
vfpBMC and Leukocyte subset q 
X 
X 
X 
X 
X 
X 
X 
Serology 
X' 
Viral Monitoring • 
X 
X 
X 
X 
CONFIDENTIAL 
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EVENT 
Visits 
Visit window (Days) 
Assessment of Adverse Events 
Concomitant Medications 
Randomization/reassignment 
Study Dmgs Dispensation x 
Review entry criteria for LTE (if 
applicable) 
Footnotes 
Screening" 
X 
X 
Day lb 
W2 
W4 
(±3 
(±3 
days) 
days) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
T1·eatment Period 
ws 
W12 
W16 
W20 
(±3 
(±3 
(±3 
(±3 
days) 
days) 
days) 
days) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
W24 
W30 
W36 
(±3 
(±7 
(±7 
days) 
days) 
days) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
W44 
(±7 
days) 
X 
X 
X"' 
X 
Final 
Amendment 1 
Follow-Upd 
Post 
W52/ 
T.-eatment 
ET< 
Week4 
(±7 
days) 
(±7 days) 
X 
X 
X 
X 
X 
a 
Screening ·window is 28 days prior to Day I, the window may be extended to up to 42 days prior to the Day I visit for subjects who require repeat collection of radio graphs 
b 
Subject w-i.11 begin study drugs on Day I, following baseline assessments and randomization. 
c 
Early Tennination Visit lo be performed if subject discontinues before Week 52 
d 
The follow-up visit will be performed only for subje.cts discontinuing preniaturely from the study and for those completing Week 52 but not entering the LTE. 
e 
Eligibility criteria check based on the laborat01y results from the Screening visit, TJC/SJC at screening and Day I and for female subjects of childbearing potential, the urine 
pregnancy test at Day I. 
f 
Medical History includes smoking status, average weekly alcohol consumption, family history of corona1y heart disease and any other chronic medical conditions or prior 
surgenes 
g 
At Screening, Week 24 and Week 52 (or at ET), a complete physical should be performed. Symptom driven exams should be pe1fom1ed at all other visits. Height will be 
measured at Screening only. 
h 
Chest X-ray for TB assessment should be pe1fonned unless pe1fonned in the previous 3 months, with results available at the site. 
Subject repo1ied outcomes are recolll11lende-d to be performed first at each visit prior to any other visit-related procedures ( other than signing of infonned consent), as much as 
possible. Questionnaire translations will be provided to subjects when and where available. 
J 
Vital signs are defined as heart rate, respirat01y rate, blood pressure (systolic and diastolic) and body temperature. 
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k
For female subjects of childbearing potential only. To be performed on serum sample at Screening and on urine samples for other visits.  For female subjects entering the 
LTE, at the Week 52 visit pregnancy test should be performed on serum. During the periods where visits are every 6-8 weeks, women should continue to have monthly home 
pregnancy tests performed at home. The site will call the subject every 4 weeks to obtain results of these pregnancy tests. If any pregnancy test is positive, study drug should 
be immediately interrupted and subject should come to the site for serum pregnancy test. 
l
Refer to list provided in Laboratory assessment table (Appendix 6).
m
Urine samples for biomarker analysis should be collected at Day 1, Weeks 12, 24, and Week 52 or ET
  
o
The PK sample at Week 4 should be collected at least 30 minutes post study drug dose in the clinic. PK samples at Week 12 and Week 24 should be collected prior to study 
drug dose (within 2 hours prior to dosing). The PK sample at Week 52 or ET can be collected at any time during the visit.
 
 
 
p
Details of biomarker collection are outlined in lab manual
q
Only for subjects in United States and Canada
r
Hepatitis B surface Ag and core Ab, reflex Hep B DNA, Hepatitis C Ab, reflex HCV RNA, HIV 1 and 2 at Screening.
s
Viral monitoring for HBV or HCV as applicable (see Exclusion criteria, Section 4.3).
t
Radiographs performed after enrollment may be done +/- 7 days of the scheduled visit. If subject discontinues study early and has had x-rays in the <12 weeks prior, x-rays do 
not need to be repeated at the ET visit.
v
Subjects failing to achieve at least a 20% improvement from Day 1 in TJC and SJC will discontinue study drugs, but will continue with study visits and assessments
w
Subjects failing to maintain at least a 20% improvement from Day 1 in TJC and SJC (confirmed at 2 consecutive visits) will discontinue study drugs, but will continue with 
study visits and assessments
x
Dispensation of study drugs according to IWRS manual.
CCI
CCI
CCI
I 
I 

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Appendix 3.
Management of Clinical and Laboratory Adverse Events 
Grade 1 
~--G-r-ad_e_2_-~I 
.... 
I ___ 
G_r_a-de_3_-~I 
.... 
I ____ 
G_r_a_d_e _4 ___ ___, 
May continue 
Repeat lab to 
dosing at the 
confirm toxicity 
discretion of the 
grade 
investigator 
" 
If confirmed and possibly and/or probably related to 
investigational medicinal products: 
1. 
Withhold investigational medicinal products until 
!S: Grade 2 
2. 
Restart all investiirntional medicinal oroducts at full dose 
l 
If Grade 3 or 4 recurrence that is confirmed and possibly or 
probably related to investigational medicinal products, 
discontinue all investigational medicinal products dosing 
oermanentlv 
l 
Repeat lab to 
confirm toxicity 
grade 
l 
If confirmed and 
possibly or probably 
Ifc onfirmed and unrelated to 
estigational medicinal 
---+ related to 
investigational 
medicinal products, 
discontinue 
investiga tional 
medicinal products 
dosing permanently 
and follow at 
periodic intervals at 
least weekly until a 
return to baseline or 
is otherwise 
explained 
inv 
pro 
the 
ducts, dosing may continue at 
discretion of the investigator 
If Grade 3 or 4 recurrence that is considered unrelated to 
investigational medicinal products, continue all 
investigational medicinal products at the same dose at the 
discretion of the investigator 

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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
The only modification to the CTCAE criteria is the addition of a Grade 1 upper respiratory 
infection as follows:
CTCAE 
v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.03 
AE Term 
Definition
Upper 
respiratory 
infection
Mild 
symptoms; 
symptomatic 
relief (eg, 
cough 
suppressant, 
decongestant)
Moderate 
symptoms; 
oral 
intervention 
indicated 
(eg, antibiotic, 
antifungal, 
antiviral)
IV antibiotic, 
antifungal, or 
antiviral 
intervention 
indicated; 
radiologic,
endoscopic, or 
operative 
intervention 
indicated
Life-
threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder 
characterized by 
an infectious 
process involving 
the upper 
respiratory tract 
(nose, paranasal 
sinuses, pharynx, 
larynx, or 
trachea).

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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Methods
The administration of filgotinib in embryo-fetal animal development studies resulted in 
decreased numbers of viable rat fetuses, increased resorptions, and visceral and skeletal 
malformations.  Similar effects were noted in the rabbit. A safety margin relative to human 
exposure has not been identified.  Pregnancy is contraindicated during use of filgotininb.
For participation in this study, all subjects of childbearing potential must agree to the use of 
highly effective contraception as outlined below.
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 > 12 months may also be considered 
postmenopausal if their FSH level is in the postmenopausal range at Screening 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 fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or has medical documentation of 
permanent male infertility.
2) Contraception for Female Subjects
a) Study Drug Effects on Pregnancy and Hormonal Contraception
Filgotinib is contraindicated in pregnancy as there is a possibility of human 
teratogenicity/fetotoxicity in early pregnancy based on non-clinical data. A dedicated study 
assessing the impact of filgotinib on the efficacy of hormonally-based contraceptives
(with ovulation inhibition as mechanism of action) has not yet been performed to fully verify the 
absence of any clinically significant interaction between filgotinib and oral contraceptives.  

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However, clinically relevant drug-drug interactions between hormonally-based contraceptives 
and filgotinib or its active metabolite GS-829845 are not expected. In vitro studies in HepaRG 
cells using reference substrates indicate that filgotinib and GS-829845 do not induce CYP1A2, 
CYP2B6, or CYP3A4, enzymes involved in metabolism of common hormonal contraceptives. 
Preliminary results using primary human hepatocytes also confirmed that filgotinib and 
GS-829845 did not induce mRNA expression of CYP1A2, CYP2B6, or CYP3A4. The lack of 
induction potential of filgotinib and GS-829845 on CYP3A4 was further confirmed in a clinical 
drug-drug interaction study, where multiple dose administration of 200 mg filgotinib did not 
affect the pharmacokinetics of midazolam (a prototypical in vivo probe CYP3A4 substrate). 
Additionally, clinically relevant inhibition of CYPs or UGTs during filgotinib treatment is 
unlikely, based on in vitro data.
Based on the totality of the in vitro and clinical data, clinically relevant drug interactions 
between filgotinib or GS-829845 with hormonal contraceptives are not expected. For female 
subjects, hormonal contraceptives will be permitted as a form of contraception when used in 
conjunction with a barrier method (preferably male condom). For male subjects, male condom 
should be used; for their female partners of childbearing potential, an accepted contraceptive 
method should also be considered. Details are outlined below.
Please refer to the latest version of the filgotinib investigator’s brochure for additional 
information.
b) Contraception for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures.  Women must have a negative serum pregnancy test at Screening and a 
negative urine pregnancy test on the Baseline/Day 1 visit prior to randomization.  Pregnancy 
tests will be performed at monthly intervals thereafter.  In the event of a delayed menstrual 
period (> one month between menstruations), a pregnancy test must be performed to rule out 
pregnancy.  This is true even for women of childbearing potential with infrequent or irregular 
periods. Female subjects must agree to use one of the following methods from Screening until 
35 days following the last dose of study drug. 

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below. 
Intrauterine device (IUD) with a failure rate of <1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)

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Vasectomy in the male partner (provided that the partner is the sole sexual partner and
had confirmation of surgical success at least 3 months after procedure, with 
documentation of sperm-free ejaculate)
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 agree to 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 three months prior to study dosing.
Hormonally-based contraceptives and barrier methods permitted for use in this protocol are as 
follows:

Hormonal methods (subject must agree to use with a barrier method, preferably, with a male 
condom)
Oral contraceptives (either combined estrogen/progestin or progesterone only)
Injectable progesterone
Implants of levonorgestrel
Transdermal contraceptive patch
Contraceptive vaginal ring

Barrier methods (subject must agree to use with a hormonal method)
Male or female condom, with or without spermicide
Diaphragm with spermicide
Cervical cap with spermicide
Sponge with spermicide
All female subjects must also agree to refrain from egg donation and in vitro fertilization during 
study participation and for at least 35 days after the last study drug dose.
3) Contraception for Male Subjects
It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure to the male subject’s seminal fluid.  Therefore, male subjects with female 
partners of childbearing potential must agree to use condoms during study participation and for 
90 days after the last study drug dose.  Female partners of male study subjects should consider 
using one of the above methods of contraception as well. Male subjects must also agree to refrain 
from sperm donation during treatment and until at least 90 days after the end of dosing.

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4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e,g, calendar, ovulation, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM).  Female condom and male condom should not be used 
together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 35 days of last study drug dose.  Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study are to report the information to 
the investigator.
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 7.7.2.1.
Pregnancy Testing 
All females of childbearing potential will have urine pregnancy testing every 4 weeks during the 
dosing period through 35 days after their last dose of study drug. During the dosing period when 
study visits are every 6-8 weeks, the subject will be provided with home urine pregnancy tests, 
and will be contacted every 4 weeks to report results of the urine pregnancy tests. If a positive 
urine pregnancy test is reported, the subject will be asked to return to the clinic for a 
confirmatory serum pregnancy test.

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Appendix 6.
Laboratory Assessment Table
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Hemoglobin
Platelet count
Red blood cell (RBC) 
count
Red blood cell indices
White blood cell (WBC) 
count
Differentials (absolute 
and percentage), 
including:
Leukocytes
Monocytes
Neutrophils
Eosinophils
Basophils
Mean corpuscular 
volume (MCV)
Alkaline phosphatase
Aspartate aminotransferase 
(AST)
Alanine aminotransferase 
(ALT)
Gamma-glutamyl 
transpeptidase (GGT)
Total bilirubin
Direct and indirect 
bilirubin
Total protein
Albumin
Bicarbonate
Blood urea nitrogen 
(BUN)
Calcium
Chloride
CPK
Serum creatinine
Glucose
Phosphorus
Magnesium
Potassium
Sodium
Amylase
Lipase
Uric Acid (screening)
Lipid profile (fasting): 
Triglycerides
Cholesterol and its 
subfractions (high-density 
lipoprotein [HDL] and 
low-density lipoprotein 
[LDL])
Appearance
Blood
Color
Glucose
Leukocyte esterase
Nitrites
pH
Protein
Specific gravity
Urobilinogen
Reflex to microscopic 
urinalysis if dipstick result 
is abnormal.
Urine drug screen for:
Amphetamines
Cocaine
Methadone
Opiates
vfPBMC*
Leucocyte subsets*
C-reactive protein (hsCRP)
Rheumatoid factor and anti-
cyclic citrullinated peptide 
(RF/ Anti-CCP)
QuantiFERON- TB GOLD 
Quantitative Ig subclasses at 
Screening, Week 24 and Week 
52
Endocrine (At 
Screening Only)
Serology
Pregnancy
Hemoglobin A1c
TSH
FSH (for women only)
Hepatitis BsAg and core 
Ab (if positive core Ab, 
then reflex Hep B DNA)
Hepatitis C Ab (if positive 
then reflex HCV RNA)
HIV
In females of childbearing 
potential:
Serum β-hCG (Screening and 
if positive urine β-hCG)
Urine β-hCG (all other 
visits)†
*    vfPBMC and Leukocyte subsets US and Canada only.
†    During the periods where visits are every 6-8 weeks, women should continue to have monthly home pregnancy tests
performed at home. The site will call the subject every 4 weeks to obtain results of these pregnancy tests.

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Appendix 7.
List of Joints to be Evaluated (66/68 Joint Count)
An overview of the joints assessed is provided below (left and right):

Temporomandibular 

Sternoclavicular 

Acromioclavicular 

Shoulder 

Elbow

Wrist

Metacarpophalangeal: first, second, third, fourth, fifth 

Proximal interphalangeal: first, second, third, fourth, fifth

Distal interphalangeal: second, third, fourth, fifth

Hip2

Knee 

Ankle 

Tarsus 

Metatarsophalangeal: first, second, third, fourth, fifth 

Proximal interphalangeal (toe) : first, second, third, fourth, fifth
Replaced (or otherwise not assessable) joints should be documented at screening and omitted 
from further evaluation during the study.
                                                  
2
Assessed for tenderness only

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Appendix 8.
The 2010 American College of Rheumatology –European League 
Against Rheumatism Collaborative Initiative Classification Criteria 
for Rheumatoid Arthritis {Aletaha et al 2010}
Target population (Who should be tested?): Patients who have at least 1 joint with definite 
clinical synovitis (swelling)a with the synovitis not better explained by another diseaseb
Classification criteria for RA (score-based algorithm: add score of categories A - D;
a score of ≥ 6/10 is needed for classification of a patient as having definite RA)c
A. Joint involvementd
1 large jointe
0
2-10 large joints
1
1-3 small joints (with or without involvement of large joints)f
2
4-10 small joints (with or without involvement of large joints)
3
>10 joints (at least 1 small joint)g
5
B. Serology (at least 1 test result is needed for classification)h
Negative RF and negative ACPA
0
Low-positive RF or low-positive ACPA
2
High-positive RF or high-positive ACPA
3
C. Acute-phase reactants (at least 1 test result is needed for classification)i
Normal CRP and normal ESR
0
Abnormal CRP or abnormal ESR
1
D. Duration of symptomsj
<6 weeks
0
≥6 weeks
1
a
The criteria are aimed at classification of newly presenting patients. In addition, patients with erosive disease typical of 
rheumatoid arthritis (RA) with a history compatible with prior fulfillment of the 2010 criteria should be classified as having 
RA. Patients with longstanding disease, including those whose disease is inactive (with or without treatment) who, based on 
retrospectively available data, have previously fulfilled the 2010 criteria should be classified as having RA.
b
Differential diagnoses vary among patients with different presentations, but may include conditions such as systemic lupus 
erythematosus, psoriatic arthritis, and gout. If it is unclear about the relevant differential diagnoses to consider, an expert 
rheumatologist should be consulted.
c
Although patients with a score of <6/10 are not classifiable as having RA, their status can be reassessed and the criteria 
might be fulfilled cumulatively over time.
d
Joint involvement refers to any swollen or tender joint on examination, which may be confirmed by imaging evidence of 
synovitis. Distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints are excluded from
assessment. Categories of joint distribution are classified according to the location and number of involved joints, with 
placement into the highest category possible based on the pattern of joint involvement.
e
"Large joints" refers to shoulders, elbows, hips, knees, and ankles.
f
"Small joints" refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through 
fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists.
g
In this category, at least 1 of the involved joints must be a small joint; the other joints can include any combination of large 
and additional small joints, as well as other joints not specifically listed elsewhere (eg, temporomandibular, 
acromioclavicular, sternoclavicular).

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h
Negative refers to IU values that are less than or equal to the 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 9.
American College of Rheumatology Response Evaluations/ 
Preliminary Definition of Improvement in Rheumatoid Arthritis 
{Felson et al 1995}
ACR 20 Required
≥20% improvement in tender joint count,  AND
≥ 20% improvement in swollen joint count, AND
≥ 20% improvement in at least 3 of the following 5 items:
Patient pain assessment
Patient global assessment of disease activity
Physician global assessment of disease activity

Patient’s assessment of physical function (HAQ-DI)
Acute-phase reactant (CRP)
The following lists the disease activity measure followed by the method of assessment
1. Tender joint count
ACR tender joint count is an assessment of 68 total joints. The joint count should be done by 
scoring several different aspects of tenderness, as assessed by pressure and joint manipulation on 
physical examination. The information on various types of tenderness should then be collapsed 
into a single tender-versus-nontender dichotomy.
2. Swollen joint count
ACR swollen joint count is an assessment of 66 total joints. Joints are classified as either swollen 
or not swollen
3. Patient’s assessment of pain
The pain score from the HAQ-DI will be used to calculate ACR response.

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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 rheumatoid 
arthritis disease activity:
   No arthritis
Severe 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 RA 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 as measured at the central laboratory

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Appendix 10.
Disease Activity Score (DAS28) {Prevoo et al 1995}
Assessments of RA in patients by the Disease Activity Score (modified to include the 28 joint 
counts according to Smolen* 1995) will be conducted at the measured timepoints. The DAS28 
consists of a composite score of the following variables: tender joint count, swollen joint count, 
CRP, and patient global score. The following equation will be used to calculate the DAS28-CRP

DAS28-CRP 0.56 √TJC28 0.28√SJC28 0.36ln(CRP 1) 0.014(patients global VAS) 
0.96

TJC28 = number of joints tender out of 28

SJC28 = number of joints swollen out of 28

CRP = C-reactive protein

Patient global VAS as defined in  Appendix 9

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Appendix 11.
Procedures and Specifications
Complete Physical Examination
A complete physical examination should include source documentation of general appearance, 
and the following body systems: Head, neck and thyroid; eyes, ears, nose, throat, mouth and 
tongue; chest (excluding breasts); respiratory; cardiovascular; lymph nodes, abdomen; skin, hair, 
nails; musculoskeletal; and neurological. . 
Blood Pressure
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature.
Blood pressure will be measured using the following standardized process:

Subject should be resting for 5 minutes with feet flat on the floor and measurement arm 
supported so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.
Creatinine Clearance 
Creatinine clearance is calculated by the Cockcroft-Gault equation {Cockcroft et al 1976} using 
actual body weight (BW). 
Male:
CLcr (mL/min) = [140 - age (years)] BW(kg)
72 Scr
Female:
CLcr (mL/min) = [140 - age (years)] BW(kg) 0.85
72 Scr
Scr = serum creatinine (mg/dL)
12-Lead ECG
Subjects should be resting 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 
Screening as part of routine safety monitoring.