Clinical trial NCT02873936
Conditions: Rheumatoid Arthritis
Sponsor: Gilead Sciences
Start date: 2016-07-27; Completion date: 2018-06-26
Enrollment: 449 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the effects of filgotinib versus placebo for the treatment of signs and symptoms of rheumatoid arthritis (RA) as measured by the percentage of participants achieving an American College of Rheumatology 20% improvement response (ACR20) at Week 12.

Detailed description:

Arms: arm 1: Filgotinib 200 mg + placebo to match filgotinib 100 mg + stable dose of permitted csDMARD(s) arm 2: Filgotinib 100 mg + placebo to match filgotinib 200 mg + stable dose of permitted csDMARD(s) arm 3: Placebo to match filgotinib 200 mg + placebo to match filgotinib 100 mg + stable dose of permitted csDMARD(s)
Interventions: intervention 1: Filgotinib intervention 2: Placebo to match filgotinib intervention 3: csDMARDs
Intervention descriptions: intervention 1: Tablet(s) administered orally once daily intervention 2: Tablet(s) administered orally once daily intervention 3: csDMARDs may include one or two of the following: methotrexate (MTX), hydroxychloroquine or chloroquine, sulfasalazine, and/or leflunomide (combination of leflunomide and MTX is not allowed)

Protocol documents:
Prot_000.pdf: 
    
CLINICAL STUDY PROTOCOL
Study Title:
A Randomized, Double-blind, Placebo-controlled, Multicenter, Phase 
3 Study to Assess the Efficacy and Safety of Filgotinib Administered 
for 24 weeks in Combination with Conventional Synthetic
Disease-modifying Anti-rheumatic Drug(s) (csDMARDs) to Subjects 
with Moderately to Severely Active Rheumatoid Arthritis Who Have 
an Inadequate Response to Biologic DMARD(s) Treatment
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
115,510
2016-000569-21
TBD
Indication:
Rheumatoid Arthritis 
Protocol ID:
GS-US-417-0302
Gilead Clinical 
Program Manager:
Name:
Rebecca Pyle
Telephone:
Gilead Medical 
Monitor:
Name:
Franziska Matzkies
Telephone:
Fax:
Pager:
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The information contained in this document, particularly unpublished data, is the property or 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.
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................14
1.
INTRODUCTION ..............................................................................................................................................17
1.1.
Background ............................................................................................................................................17
1.2.
Filgotinib................................................................................................................................................18
1.2.1.
General Information .............................................................................................................18
1.2.2.
Nonclinical Pharmacology, Absorption, Distribution, Metabolism, and 
Excretion (ADME) and Toxicology.....................................................................................18
1.2.3.
Clinical Trials of Filgotinib..................................................................................................20
1.3.
Rationale for This Study ........................................................................................................................25
1.3.1.
Rationale for Study Design ..................................................................................................25
1.3.2.
Rationale for the Outcome Measures ...................................................................................26
1.3.3.
Rationale for the Choice of Dose and Dosing Interval.........................................................27
1.4.
Risk/Benefit Assessment for the Study..................................................................................................28
1.5.
Compliance ............................................................................................................................................29
2.
OBJECTIVES.....................................................................................................................................................30
3.
STUDY DESIGN................................................................................................................................................31
3.1.
Endpoints ...............................................................................................................................................31
3.2.
Study Design..........................................................................................................................................32
3.3.
Study Treatments ...................................................................................................................................33
3.4.
Duration of Treatment............................................................................................................................33
3.5.
Criteria for Interruption or Discontinuation of Study Treatment ...........................................................34
3.5.1.
Study Drug Interruption Considerations...............................................................................34
3.5.2.
Study Drug Discontinuation Considerations ........................................................................34
3.6.
End of Study...........................................................................................................................................36
3.7.
Post Study Care......................................................................................................................................36
3.8.
Biomarker Samples ................................................................................................................................36
3.8.1.
Biomarker Samples to Address the Study Objectives ..........................................................36
3.8.2.
Biomarker Samples for Optional Future Research...............................................................37
3.8.3.
Biomarker Samples for Optional Genomic Research...........................................................38
3.9.
SUBSTUDY: 
.39
4.
SUBJECT POPULATION..................................................................................................................................40
4.1.
Number of Subjects and Subject Selection ............................................................................................40
4.2.
Inclusion Criteria....................................................................................................................................40
4.3.
Exclusion Criteria...................................................................................................................................42
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................46
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................46
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................46
5.2.
Description and Handling of Filgotinib and PTM Filgotinib .................................................................46
5.2.1.
Formulation of Filgotinib and PTM Filgotinib.....................................................................46
5.2.2.
Packaging and Labeling .......................................................................................................47
5.2.3.
Storage and Handling...........................................................................................................47
5.2.4.
Dosage and Administration..................................................................................................47
5.3.
Prior and Concomitant Medications.......................................................................................................48
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5.4.
Accountability for Study Drugs .............................................................................................................50
5.4.1.
Investigational Medicinal Product Return or Disposal.........................................................51
6.
STUDY PROCEDURES ....................................................................................................................................52
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................52
6.2.
Pretreatment Assessments......................................................................................................................52
6.2.1.
Screening Visit .....................................................................................................................52
6.2.2.
Day 1 Assessments...............................................................................................................54
6.3.
Randomization .......................................................................................................................................55
6.4.
Week 2 through Week 20 Assessments .................................................................................................55
6.5.
Week 24/Early Termination...................................................................................................................56
6.6.
Post-treatment Week 4 Assessments......................................................................................................58
6.7.
Study Assessments.................................................................................................................................58
6.7.1.
Efficacy ................................................................................................................................58
6.7.2.
Safety and Tolerability.........................................................................................................62
6.7.3.
Clinical Laboratory Evaluations...........................................................................................62
6.7.4.
Vital Signs............................................................................................................................62
6.7.5.
Physical Examination...........................................................................................................63
6.7.6.
Other Safety Assessments ....................................................................................................63
6.8.
Pharmacokinetics Assessments..............................................................................................................63
6.9.
Biomarker Assessments .........................................................................................................................63
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................64
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................64
7.1.1.
Adverse Events.....................................................................................................................64
7.1.2.
Serious Adverse Events........................................................................................................64
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................65
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................65
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................65
7.2.2.
Assessment of Severity ........................................................................................................66
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................66
7.4.
Gilead Reporting Requirements.............................................................................................................68
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................68
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................69
7.5.2.
Grades 3 Laboratory Abnormality or Clinical Event ...........................................................69
7.5.3.
Grades 4 Laboratory Abnormality or Clinical Event ...........................................................69
7.6.
Toxicity Management ............................................................................................................................70
7.7.
Special Situations Reports......................................................................................................................70
7.7.1.
Definitions of Special Situations..........................................................................................70
7.7.2.
Instructions for Reporting Special Situations.......................................................................71
8.
STATISTICAL CONSIDERATIONS................................................................................................................73
8.1.
Analysis Objectives and Endpoints........................................................................................................73
8.1.1.
Analysis Objectives..............................................................................................................73
8.1.2.
Primary Endpoint .................................................................................................................73
8.1.3.
Secondary Endpoints............................................................................................................74
8.2.
Analysis Conventions.............................................................................................................................75
8.2.1.
Analysis Sets ........................................................................................................................75
8.3.
Data Handling Conventions ...................................................................................................................75
8.4.
Demographic Data and Baseline Characteristics ...................................................................................76
8.5.
Efficacy Analysis ...................................................................................................................................76


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8.5.1.
Primary Analysis..................................................................................................................76
8.5.2.
Secondary Analyses .............................................................................................................76
8.6.
Safety Analysis.......................................................................................................................................77
8.6.1.
Extent of Exposure...............................................................................................................77
8.6.2.
Adverse Events.....................................................................................................................77
8.6.3.
Laboratory Evaluations ........................................................................................................78
8.7.
Pharmacokinetic Analysis......................................................................................................................78
8.8.
Biomarker Analysis................................................................................................................................78
8.9.
Sample Size............................................................................................................................................78
8.10.
Data Monitoring Committee ..................................................................................................................79
8.11.
Cardiovascular Endpoint Adjudication Committee................................................................................79
9.
RESPONSIBILITIES..........................................................................................................................................80
9.1.
Investigator Responsibilities ..................................................................................................................80
9.1.1.
Good Clinical Practice..........................................................................................................80
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................80
9.1.3.
Informed Consent.................................................................................................................80
9.1.4.
Confidentiality......................................................................................................................81
9.1.5.
Study Files and Retention of Records ..................................................................................81
9.1.6.
Case Report Forms...............................................................................................................82
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................83
9.1.8.
Inspections............................................................................................................................83
9.1.9.
Protocol Compliance............................................................................................................83
9.2.
Sponsor Responsibilities ........................................................................................................................84
9.2.1.
Protocol Modifications.........................................................................................................84
9.2.2.
Study Report and Publications .............................................................................................84
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................84
9.3.1.
Payment Reporting...............................................................................................................84
9.3.2.
Access to Information for Monitoring..................................................................................85
9.3.3.
Access to Information for Auditing or Inspections ..............................................................85
9.3.4.
Study Discontinuation..........................................................................................................85
10.
REFERENCES ...................................................................................................................................................86
11.
APPENDICES ....................................................................................................................................................88
Appendix 1.
Investigator Signature Page....................................................................................................89
Appendix 2.
Study Procedures Table..........................................................................................................90
Appendix 3.
Management of Clinical and Laboratory Adverse Events......................................................95
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03....................................96
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Methods...........................................................................................................97
Appendix 6.
Laboratory Assessment Table ..............................................................................................101
Appendix 7.
List of Joints to be Evaluated (66/68 Joint Count) ...............................................................102
Appendix 8.
The 2010 American College of Rheumatology –European League Against 
Rheumatism Collaborative Initiative Classification Criteria for Rheumatoid 
Arthritis {Aletaha et al 2010},..............................................................................................103
Appendix 9.
American College of Rheumatology Response Evaluations/ Preliminary Definition 
of Improvement in Rheumatoid Arthritis {Felson et al 1995} .............................................105
Appendix 10.
Disease Activity Score (DAS28) {Prevoo et al 1995} .........................................................107
Appendix 11.
Procedures and Specifications..............................................................................................108


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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..........................................................................................21
Table 1-2.
Summary and analysis of ACR20/50/70 response at Weeks 12 and 24 (NRI [ITT 
Population]); GLPG0634-0204 ..............................................................................................24
Table 7-1.
Grading of Adverse Event Severity........................................................................................66
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Design ..........................................................................................................................33


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
Study Title: 
A Randomized, Double-blind, Placebo-controlled, Multicenter, Phase 
3 Study to Assess the Efficacy and Safety of Filgotinib Administered 
for 24 weeks in Combination with Conventional Synthetic 
Disease-modifying Anti-rheumatic Drug(s) (csDMARDs) to Subjects 
with Moderately to Severely Active Rheumatoid Arthritis Who Have 
an Inadequate Response to Biologic DMARD(s) Treatment
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
115510
2016-000569-21
TBD
Study Centers 
Planned:
Approximately 80-120 centers worldwide
Objectives:
The primary objective of this study is:

To evaluate the effects of filgotinib versus placebo 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 12 
The secondary objectives of this study are: 

To evaluate the effects of filgotinib versus placebo 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])≤3.2 at 
Week 12

To evaluate the effect of filgotinib versus placebo on physical 
function as measured by change from Baseline in the Health 
Assessment Questionaire Disability Index (HAQ-DI) at Week 12

To evaluate the safety and tolerability of filgotinib

To evaluate the effects of filgotinib on work productivity, fatigue, 
and general quality of life as measured by SF-36, FACIT-Fatigue,
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The exploratory objective of this study is as follows: 
 
 
 
Study Design:
This is a randomized, double-blind, placebo-controlled, add-on,
Phase 3 study in adult male and female subjects with active RA 
despite csDMARD(s) therapy (ie, MTX, hydroxychloroquine, 
sulfasalazine, leflunomide) who have had an inadequate response or 
are intolerant to at least one biologic DMARD (bDMARD). 
Approximately 423 subjects will be randomized in a 1:1:1 ratio to 
filgotinib 200 mg, filgotinib 100 mg, or placebo to match (PTM) 
administered for up to 24 weeks, all in the context of a stable dose of 
permitted csDMARD(s):

Filgotinib 200 mg group: filgotinib (200 mg once daily [q.d.]) +  
PTM filgotinib 100 mg (PTM q.d.) (N=141) 

Filgotinib 100 mg group: filgotinib (100 mg q.d.) + PTM filgotinib 
200 mg (PTM q.d.) (N=141)

Placebo control group: PTM filgotinib 200 mg (PTM q.d.) and 
PTM filgotinib 100 mg (PTM q.d.) (N=141) 
Randomization will be stratified by geographic region, prior exposure 
to number of bDMARDs (<3 or >=3 bDMARDs) and presence of
rheumatoid factor (RF) or anti-CCP (cyclic citrullinated peptide)
antibody (Ab)) at screening.
At Week 14, subjects who have not achieved at least 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. 
All subjects who attain responder status at Week 14 will continue on 
their assigned study drug, in a blinded fashion through Week 24. 
Placebo-responders at Week 14 will continue on placebo in a blinded 
fashion through Week 24.
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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 follow up visit four weeks after 
the last dose of study drug (Post Treatment visit Week 4), regardless 
of dosing duration.
At completion of the 24-week dosing period all subjects, regardless of 
response, who have not discontinued the study due to toxicity, 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 423 subjects 
Target Population:
Male or female subjects  ≥18 years of age with a diagnosis of  RA 
meeting the 2010 ACR/ European League Against Rheumatism
(EULAR) criteria, who have active RA despite treatment with 
csDMARD(s) and have failed or are intolerant to at least one 
bDMARD
Duration of 
Treatment:
Up to 24 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.


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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 for RA), 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
4) Have serum CRP ≥ 4 mg/L based on central laboratory analysis at 
Screening
5) Ongoing treatment with a stable prescription of 1 or
2 csDMARD(s) as follows: 
Permitted csDMARDs
a)
Use of MTX for at least 12 weeks prior to Day 1. Subject is on 
a stably prescribed dose and route of administration of 7.5-
25 mg/weekly for at least 4 weeks prior to Day 1. Stable 
weekly doses <7.5 mg are allowed only in the presence of 
intolerance to or toxicity from higher doses or where higher 
doses are prohibited by the local label or local clinical 
practice. Doses >25 mg weekly are not permitted. 
b)
Subjects on MTX should be receiving an adequate and stable 
dose of folic acid (≥5 mg/week total dose or as per local 
clinical practice) which should be confirmed or initiated at 
Screening, and continued throughout the study. 
MTX is not permitted to be used in combination with leflunomide.
c)
Oral hydroxychloroquine ≤400 mg/day or chloroquine 
≤250 mg/day with prescription having been stable for at least 
4 weeks prior to Day 1
d)
Oral sulfasalazine 1 g to 3 g/day with prescription having been 
stable for at least 4 weeks prior to Day 1
e)
Oral leflunomide 10-20 mg/day, with prescription having been 
stable for at least 4 weeks prior to Day 1  
The treatment with csDMARD should be continued at a stable dose 
until the end of the study. Dose adjustments are only permitted for 
the management of toxicity. Prior treatment with additional 
csDMARDs is allowed, however, subject may only be on 1 or 
2 csDMARDs at Day 1 and appropriate wash out needs to be 
satisfied according protocol (Section 5.3), in order to be eligible for 
the study.


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6) Have received at least one bDMARD for the treatment of RA to 
which they have had an inadequate response or intolerance. An 
inadequate response is defined as documented continued or 
recurrent disease activity after at least 12 weeks of treatment with 
any investigational or licensed bDMARD, including biosimilars, 
for the treatment of  RA. Intolerance is defined as treatment 
discontinuation due to any documented adverse effect associated 
with a bDMARD used according to its respective label. There is 
no limit to the prior number of bDMARDs that may have been 
used by the subject, however the subject may not be on a 
bDMARD at Day 1 or during the study.
Study Procedures/
Frequency:
Participating subjects will visit the clinical study center at Screening, 
Day 1, Weeks 2, 4, 8, 12, 14, 16, 20, and Week 24 or at 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 32 weeks
During the screening period, information on demographics, medical 
history/concomitant diseases (including onset of RA, drug and alcohol 
use, and smoking habits), and prior RA medication will be collected. 
A physical examination, vital signs, 12-lead electrocardiogram (ECG), 
and clinical laboratory assessments will be conducted to determine the 
subject’s eligibility for study participation. 
At Day 1, after the subject’s eligibility for the study has been 
confirmed, the subject will be randomized into the study to receive 
treatment with filgotinib 200 mg q.d., filgotinib 100 mg q.d, or 
placebo control  in addition to background therapy with 
csDMARD(s). 
On-treatment assessments include adverse events (AEs), concomitant 
medication, review of study medication compliance through study 
drug accountability, SJC66/TJC68, Physician’s Global Assessment, 
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, physical examination, 
weight, vital signs, blood sampling for safety laboratory tests, and 
urine pregnancy tests (for females of child bearing potential only).
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A resting 12-lead ECG should be performed at Screening, Week 12, 
Week 24, or ET, and at the post dosing Week 4 follow-up visit, as 
applicable. 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 anytime on Week 16 or  ET. 
 
 
Blood samples for biomarker analysis should be collected at Day 1, 
Week 4, Week 8, Week 12, Week 24 or ET and urine samples should 
be collected at Day 1, Weeks 12, and Week 24 or ET.
Post treatment follow-up assessments include AEs, concomitant 
medications, physical examinations, 12-lead ECGs, weight, vital 
signs, blood and urine sampling for safety laboratory tests, and 
pregnancy tests (females of child bearing potential only).
Test Product, Dose, 
and Mode of 
Administration:
200 mg filgotinib orally q.d.
100 mg filgotinib orally q.d.
Reference Therapy, 
Dose, and Mode of 
Administration:
PTM filgotinib 200 mg orally q.d. 
PTM filgotinib 100 mg orally q.d.
Required Backgound 
therapy
Permitted csDMARD(s) as described in protocol and administered 
according to the local product label/standard of care.
Criteria for 
Evaluation:
Safety:
Safety will be assessed by the documentation of AEs, clinical 
laboratory tests, physical examination, vital signs, and 12-lead ECGs 
during the study. 
Efficacy:
The primary endpoint is the proportion of subjects who achieve an 
ACR20 response at Week 12.
The key secondary endpoints are:
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The proportion of subjects who achieve DAS28 (CRP) ≤3.2 at 
Week 12
Change from baseline in the HAQ-DI score at Week 12
Pharmacokinetics:
Plasma concentrations of filgotinib and its active metabolite 
(GS-829845) will be analyzed. 
Statistical Methods:
The primary analysis set for efficacy analyses will be the Full 
Analysis Set (FAS), which includes all randomized subjects who
received at least one dose of study drug.
The primary endpoint is the proportion of subjects who achieve an 
ACR20 response at Week 12. The primary analysis will consist of a 
superiority test of filgotinib 200 mg compared to placebo based on the 
ACR20 response rate at Week 12. Cochran-Mantel-Haenszel approach 
adjusting for the randomization stratification factors will be used for 
the hypothesis testing at the 2-sided 0.05-level. 
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 compared to placebo based on 
the response rate of DAS28 (CRP)≤3.2 at Week 12 
2)
Superiority of filgotinib 200 mg compared to placebo based on 
the change from Baseline in HAQ-DI at Week 12
3)
Superiority of filgotinib 100 mg compared to placebo based on 
the ACR20 response rate at Week 12 
4)
Superiority of filgotinib 100 mg compared to placebo based on 
the response rate of DAS28 (CRP)≤3.2 at Week 12 
5)
Superiority of filgotinib 100 mg compared to placebo based on 
the change from Baseline in HAQ-DI at Week 12
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.


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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 
groups compared to placebo on the change from Baseline in HAQ-DI 
at Week 12. When assuming a difference of 0.25 between the two 
groups and a common standard deviation of 0.645, 141 subjects in 
each of the filgotinib groups and placebo control group are required to 
obtain 90% power at a 2-sided 0.05-level. 
A sample size of 141 subjects in each of the filgotinib groups and 
placebo control group will also provide over 90% power to detect an 
increase in ACR20 response rate of 25% to 45% between the placebo 
control group and the filgotinib groups respectively, using a 2-sided 
0.05-level test.
In summary, the total sample size will be 423 (141 per group).
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
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 predose sample)
CCP
cyclic citrullinated peptide
CD
Crohn’s disease
CDAI
Clinical Diagnostic Activity Index
csDMARD(s)
Conventional 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 P450
DAS28
Disease Activity Score based on 28 joints
DBP
diastolic blood pressure
DMARD(s)
disease-modifying antirheumatic drug(s)
DMC
data monitoring committee
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-Fatique


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FAS
Full Analysis Set
FDA
Food and Drug Administration
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
IWRS
Interactive web response system
JAK
janus kinase inhibitor
LCMS/MS
liquid chromatography mass spectrometry
LDL
low density lipoprotein
LH
luteinizing hormone
LTE
Long Term Extension
MACE
major adverse cardiovascular event
MCV
mean corpuscular volume
MTX
methotrexate
MTX-IR
inadequate response to Methotrexate
NSAIDs
nonsteroidal anti-inflammatory drugs
NOEL
no-observed-effect-level
NYHA
New York Heart Association
OATs
organic anion transporters
PK
pharmacokinetics


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PP
per-protocol
PT
prothrombin time
PTM
Placebo to match
q.d.
quaque die; once daily
RA
rheumatoid arthritis
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
SI 
international system of units
SJC66
swollen joint count based on 66 joints
SOC
Symptom Organ Class
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
TNFα
tumor necrosis factor alpha
TSQM
Treatment Satisfaction Questionnaire for Medication
UGTs
uridine disphosphate glucuronosyltransferases
ULN
upper limit of normal
US
United States
vs.
versus
WBC
white blood cell
WPAI-RA
Work Productivity and Activity Impairment- 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 = R-R 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 (MTX) is a conventional disease modifying anti-rheumatic drug 
(DMARD) and continues to be the cornerstone of RA therapy {Singh et al 2012}. Patients with 
an inadequate response to conventional DMARD(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 monotherapy and in combination with background conventional disease 
modifying anti-rheumatic drugs (csDMARDs) 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. 


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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. 
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.


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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.
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).


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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 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 .
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 is 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 resulted 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 toxicology 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). 


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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.
The percentage of American College of Rheumatology (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 daily, 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 increases
compared with Week 12.
Starting 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.
Summary and analysis of ACR20/50/70 response at Weeks 12 and 
24 (NRI [ITT Population]), GLPG0634-CL-203
Parameter
Time
Point
Placebo
N=86
Filgotinib once daily Dose Groups
Filgotinib twice daily Dose Groups
50 mg
N=82
100 mg
N=85
200 mg
N=86
25 mg
N=86
50 mg
N=85
100 mg
N=84
n (%)
ACR20
W12
38 (44.2)
46 (56.1)
54 (63.5)*
59 (68.6)**
49 (57.0)
51 (60.0)
66 (78.6)***
W24
36 (41.9)
45 (54.9)
52 (61.2)*
63 (73.3)***
48 (55.8)
51 (60.0)*
67 (79.8) ***
ACR50
W12
13 (15.1)
27 (32.9)*
32 (37.6)**
37 (43.0)***
24 (27.9)*
29 (34.1)*
46 (54.8)***
W24
14 (16.3)
29 (35.4)**
40 (47.1)*** 43 (50.0)***
30 (34.9)**
30 (35.3)**
46 (54.8)***
ACR70
W12
7 (8.1)
13 (15.9)
18 (21.2)
21 (24.4)*
12 (14.0)
16 (18.8)
26 (31.0)**
W24
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; Hommel-corrected 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 Rheumatology; ITT=Intent-to-treat; NRI=non-responder imputation; W=week
Source: GLPG0634-CL-203


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At both Weeks 12 and 24 the mean decrease in DAS28(CRP) (Appendix 10) was
statistically significantly greater across all filgotinib dose groups compared with placebo. A
dose-response was observed. No statistically significant difference was apparent between the 
once and twice daily regimens. At both Weeks 12 and 24, the mean decrease in Simplified 
Diagnostic Activity Index ( SDAI) a n d  Clinical Diagnostic Activity Index (CDAI) score was
statistically significantly greater across all filgotinib dose groups and regimens compared with
placebo(with the exception of filgotinib 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.
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 subject of these subjects with ≥1 serious 
TEAE, who received filgotinib 100 mg bid twice daily with concurrent MTX, died during the 
second 12 weeks of the treatment 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-doisng 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 treatment 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). All 6 serious and 
one additional non-serious infection in the filgotinib group led todosing discontinuation. Up to 
Week 24, herpes zoster infections were observed in 5 subjects (1 placebo treated patient and 
4 filigotnib ). No cases of tuberculosis, opportunistic infections, lymphoma, or cancer were 
reported throughout the 24-week dosing period.


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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 
bid 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 bid group). 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 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 bid 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 bid group.
In male subjects, small non dose-dependent increases were observed in totaland free testosterone 
during the study (at Week 24, mean increases were 3.4 nmol/L for testosterone and 51.7 pmol/L 
for free testosterone in the filgotinib 100 mg bid 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


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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
Parameter
Time
Point
Placebo
Filgotinib once daily Dose Groups
N=72
50 mg
N=72
100 mg
N=70
200 mg
N=69
n (%)
ACR20
W12
21 (29.2)
48 (66.7)***
46 (65.7)***
50 (72.5)***
W24
Not applicable
41 (56.9)
55 (78.6)
46 (66.7)
ACR50
W12
8 (11.1)
25 (34.7)***
26 (37.1)***
30 (43.5)***
W24
Not applicable
24 (33.3)
27 (38.6)
31 (44.9)
ACR70
W12
2 (2.8)
6 (8.3)
13 (18.6)**
9 (13.0)*
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; Hommel-corrected 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
ITT=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 compared with placebo . 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 at Week 12.
Differences vs. placebo were not statistically significant for any of the filgotinib dose groups.
The number of subjects with DAS28(CRP) <2.6 and <3.2 were higher across 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 the first 12 weeks of treatment and the full 
24 weeks of treatment. TEAEs were reported 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 (ie, all subjects combined who received filgotinib during either the 
entire 24 weeks or only during the last 12 weeks, irrespective of dose).
No deaths were reported 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 preferred
term) 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 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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Throughout the 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) were 
observed during the study. 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 treatment period.
Laboratory data were consistent with prior studies and no new safety findings were observed.
Please refer to the IB for additional data for efficacy endpoints 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. This need is especially pronounced for subjects that have had an inadequate 
response or are intolerant to bDMARDs, as they may have limited options remaining for further 
treatment. 
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.
1.3.1.
Rationale for Study Design
GS-US-417-0302 is a Phase 3 randomized, double-blind, placebo-controlled study designed to 
evaluate the efficacy and safety of filgotinib in subjects with active RA despite csDMARD(s)
therapy who have failed treatment with or had intolerance to at least one bDMARD. The 
objectives of the study are to evaluate the efficacy of filgotinib on the signs and symptoms of 
RA, to evaluate its effect on physical function, work productivity, fatigue, and quality of life. In 
addition, the safety, tolerability, and pharmacokinetics (PK), will be assessed.


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All subjects in this study are required to maintain therapy with background csDMARD(s). 
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 placebo 
control used in this study will allow assessment of the filgotinib safety and tolerability profile 
and establish the efficacy contribution that filgotinib may provide in combination with
csDMARD(s). Duration of placebo will be limited in inadequate responders who will 
discontinue investigational therapy at Week 14 but will continue with study visits and 
assessments per protocol. All subjects who discontinue from investigational therapy, are to 
receive standart of care treatment for their RA as determined by the investigator. Inclusion of a
placebo arm in addition to background therapy will enable discernment of the true added effect 
of filgotinib. Given the slowly progressive nature of RA, 14 weeks of placebo in Non-responders 
on accepted background therapy is considered both clinically and ethically appropriate and 
allows an acceptable time to assess initial response to therapy. The use of placebo is additionally 
critical when evaluating patient reported and subjective outcomes, which can be highly variable 
and influenced by placebo therapy. The placebo effect is well established in RA therapy and 
inclusion of the placebo arm is critical in evaluating the overall risk:benefit balance of added 
filgotinib therapy. Finally, the provision of best supportive care in the context of the trial, as well 
as the limited duration and eventual opportunity for subjects to enterthe LTE filgotinib, make the 
use of placebo ethically acceptable for the duration noted, especially in patients who have 
already failed multiple lines of therapy and for whom no single standard of care is accepted.
The study eligibility criteria are consistent with those of recent clinical trials evaluating novel 
investigational treatments for RA. Subjects will meet the 2010 ACR/ European League Against 
Rheumatism (EULAR) diagnostic criteria for RA. In addition, subjects are required to have 
active disease defined as ≥6 swollen and ≥6 tender joints at both Screening and Day 1.
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 ECGs, all of which are 
standard safety evaluations in clinical research studies.
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 groups of the proportions of subjects achieving an ACR20 
response at Week 12 and the proportions of subjects achieving DAS28 (CRP) ≤3.2allows for 
straightforward interpretation of a clinically meaningful response and these measures have been 
shown to achieve high discriminatory capacity.
Evaluation of continuous outcome measures of DAS28 and ACR-N as secondary endpoints 
enables the demonstration of improvement and magnitude of benefit. The EULAR 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 Clinical Diagnostic Activity Index 
(CDAI) and the Simplified Diagnostic Activity Indes (SDAI) have been widely used in clinical 
studies to demonstrate the impact of a study drug on controlling disease activity.


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Assessing quality of life (measured by the Functional Assessment of Chronic Illness Therapy 
[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 disease course and impact on daily life. Treatment satisfaction 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.
1.3.3.
Rationale for the Choice of Dose and Dosing Interval
Enrolled subjects will be randomized to receive filgotinib or placebo. The 100 mg q.d. and 
200 mg q.d. dose of filgotinib are based on efficacy, tolerability, and safety data derived from 
the Phase 1 and Phase 2 studies.
In seven Phase 1 studies conducted in healthy subjects (GLPG0634-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 two 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.
In two Phase 2b studies, filgotinib at total daily doses of 50 mg, 100 mg, or 200 mg, 
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 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 q.d. daily dose, administered as 
200 mg q.d. or 100 mg bid. 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}. 
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 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. 


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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 
multiple 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.
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 resulted 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 NOEL 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 is expected 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 filigotinib 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.  


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Overall clinical findings and laboratory changes are consistent with selective JAK1 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 the first 100 subjects complete 12 weeks of treatment) 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 will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES
The primary objective of this study is:

To evaluate the effects of filgotinib versus placebo 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 12 
The secondary objectives of this study are: 

To evaluate the effects of filgotinib versus placebo 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])≤3.2 at Week 12

To evaluate the effect of filgotinib versus placebo on physical function as measured by
change from Baseline in the Health Assessment Questionaire Disability Index (HAQ-DI) at 
Week 12

To evaluate the safety and tolerability of filgotinib

To evaluate the effects of filgotinib on work productivity, fatigue, and general quality of life 
as measured by SF-36, FACIT-Fatigue, EQ-5 and WPAI-RA.
The exploratory objective of this study is as follows: 
 
 
 
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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoint is:

The proportion of subjects who achieve an ACR20 response at Week 12.
The key secondary endpoints are:

The proportion of subjects who achieve DAS28 (CRP)≤3.2 at Week 12

Change from Baseline in the HAQ-DI score at Week 12
Other secondary endpoints are:

The proportion of subjects who achieve ACR50 and ACR70 at Weeks 4, 12 and 24, ACR20 
at Weeks 4 and 24, and ACR20/50/70 over time from Day 1 through Week 24

Change from Baseline in individual components of the ACR response at Weeks 4, 12, and
24 and over time from Day 1 through Week 24 

The proportion of subjects who achieve change in HAQ-DI of ≥0.22 at Weeks 4, 12, and 24, 
and over time from Day 1 through Week 24

Change from Baseline in DAS28 (CRP) at Weeks 4, 12, 24 and over time from Day 1
through Week 24

The proportion of subjects who achieve DAS28 (CRP)≤3.2 at Weeks 4 and 24, and over time 
from Day 1 through Week 24

The proportion of subjects who achieve DAS28 (CRP)<2.6 at Weeks 4, 12, and 24, and over 
time from Day 1 through Week 24

ACR-N and EULAR  response at Weeks 4, 12, and 24, and over time from Day 1 through 
Week 24 

Change from Baseline in CDAI at Weeks 4, 12, and 24, and over time from Day 1 through 
Week 24 

Change from Baseline in SDAI at Weeks 4, 12, and 24, and over time from Day 1 through 
Week 24 

Absolute value and change from Baseline in SF-36, FACIT-Fatigue, and the EQ-5D over 
time at Weeks 4, 12 and 24, and over time from Day 1 through Week 24

Absolute value and change from Baseline in WPAI-RA at Weeks 4, 12, and 24, and over 
time from Day 1 through Week 24 


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3.2.
Study Design
This is a randomized double-blind, placebo-controlled add-on Phase 3 study in adult male and 
female subjects with moderately to severly active RA despite ongoing therapy with 1 or 
2 csDMARD(s) (ie, MTX, hydroxychloroquine, sulfasalazine, leflunomide) who have had an 
inadequate response or are intolerant to at least one biologic DMARD. The study is designed to 
evaluate the efficacy, safety and tolerability of filgotinib as well as its effect on patient-reported 
outcomes, including work productivity, fatigue, and quality of life. In addition, PK will be 
assessed.
Adult male and female subjects with moderately to severly active RA will be screened to 
determine eligibility as per the inclusion and exclusion criteria (see Section 4.2 and 4.3, 
respectively). The Screening period will be up to 28 days.
Written informed consent must be obtained before any study-related procedures take place. 
Subjects will be randomized in a 1:1:1 ratio to filgotinib 200 mg, filgotinib 100 mg, or matching 
placebo controls for up to 24 weeks in a double-blind fashion.
At Week 14, subjects who have not achieved a 20% improvement from Day 1 in both swollen 
joint count (SJC) and tender joint count (TJC) will discontinue investigational therapy but will 
continue with study visits and assessments per protocol. All subjects who discontinue from 
investigational therapy, are to receive standard of care treatment for their RA as determined by 
the investigator. At Week 14, all subjects who achieve a 20% improvement from Day 1 in both 
SJC and TJC will remain on assigned therapy through treatment Week 24.
At completion of the 24-week treatment period, all subjects, regardless of response,will be 
offered the option to screen for a Long Term Extension (LTE) study (GS-US-417-0304).
For those subjects not entering the LTE, a follow-up visit will be completed at Post Treatment 
Week 4. 
To enhance the safety monitoring during the study, a data monitoring committee (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.


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Figure 3-1.
Study Design
3.3.
Study Treatments
Approximately 423 subjects will be randomized in a 1:1:1 ratio to filgotinib 200 mg q.d.,  
filgotinib 100 mg q.d., or placebo control group for up to 24 weeks as follows, all subjects will 
be on a stable dose of permitted csDMARD(s): 

Filgotinib 200 mg group: filgotinib (200 mg once daily [q.d.]) +  placebo to match filgotinib 
100 mg (PTM q.d.).) (N=141) 

Filgotinib 100 mg group: filgotinib (100 mg q.d.) + placebo to match filgotinib 200 mg 
(PTM q.d.) (N=141) 

Placebo control group: placebo to match filgotinib 200 mg  and placebo to match filgotinib 
100mg (PTM q.d.) (N=141) 
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 32 weeks (from Screening visit 
to Follow-up visit or entry into the LTE); the duration of dosing is up to 24 weeks.


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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.
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


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
Non-responder at Week 14 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) 
2 sequential platelet counts <75,000 platelets/mm3 (SI: <75.0x109 cells/L)
2 sequential AST or ALT elevations >3xULN and ≥1 total bilirubin value >2xULN or
accompanied by symptoms consistent with hepatic injury.1
2 sequential AST or ALT elevations >5xULN
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.
                                                
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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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. All contacts and 
contact attempts 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 24 weeks of dosing plus the
4 week post treatment or has entered the LTE. 
3.7.
Post Study Care
All subjects, regardless of respose who complete 24 weeks of study assessments will be offered 
an opportunity to participate in an LTE study (GS-US-417-0304). Subjects who discontinue 
early from the main study, or discontinue from study treatment due to toxicity are not eligible for 
the LTE study, and should have a Post-Dosing Visit, 4 weeks after the last dose of study drug. 
The long term care of subjects who do not qualify 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
 
 
 
 
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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.
 
 
 
For sampling procedures, storage conditions, and shipment instructions, see the Sample Handling 
and Logistics Manual. 
3.8.2.
Biomarker Samples for Optional Future Research
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.8.3.
Biomarker Samples for Optional Genomic Research
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.9.
SUBSTUDY: 
 
 
 
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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 423 subjects with 
moderately to severely active RA are randomized to 1 of 3 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 for RA) (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) Have serum CRP ≥4 mg/L.
5) Ongoing treatment with a stable presecription of 1 or 2 csDMARD(s) as follows: 
Permitted csDMARD(s)
a) Use of MTX for at least 12 weeks prior to Day 1. Subject is on a stably prescribed dose 
and route of administration of 7.5-25 mg/weekly for at least 4 weeks prior to Day 1. 
Stable weekly doses <7.5 mg are allowed only in the presence of intolerance to or 
toxicity from higher doses or where higher doses are prohibited by the local label or local 
clinical practice. Doses >25 mg weekly are not permitted.  
b) Subjects on MTX should be receiving an adequate and prescribed stable dose of folic 
acid (≥5 mg/week total dose or as per local clinical practice) which should be confirmed 
or initiated at Screening, and continued throughout the study. 
MTX is not permitted to be used in combination with leflunomide
c) Oral hydroxychloroquine ≤400 mg/day or chloroquine ≤250 mg/day with prescription
having been stable for at least 4 weeks prior to Day 1
d) Oral sulfasalazine 1 g to 3 g/day with prescription having been stable for at least 4 weeks 
prior to Day 1
e) Oral leflunomide 10-20 mg/day with prescription having been stable for at least 4 weeks 
prior to Day 1  


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The treatment with csDMARD(s) should be continued at a stable dose until the end of the 
study. Dose adjustments are only permitted for the management of toxicity. Prior treatment 
with additional csDMARDs is allowed, however, subject may only be on 1 or 2 csDMARDs 
at Day 1 and appropriate wash out needs to be satisfied according protocol (Section 5.3), in 
order to be eligible for the study.
6) Have received at least one bDMARD for the treatment of RA to which they have had an 
inadequate response or intolerance. An inadequate response is defined as documented 
continued or recurrent disease activity after at least 12 weeks of treatment with any 
investigational or licensed bDMARD, including biosimilars, for the treatment of  RA.
Intolerance is defined as any documented adverse effect associated with a  bDMARD used 
according to its respective label. There is no limit to the prior number of bDMARDs that may 
have been used by the subject, however, the subject must not be on a bDMARD at Day 1 
(appropriate wash out needs to be satisfied according to the protocol) or during the study.
7) Females of childbearing potential (defined in Appendix 5) must have a negative pregnancy 
test at screening and Day 1 
8) 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
9) Lactating female subjects must agree to discontinue nursing from Screening through the end
of their study participation
10) 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 
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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 TB 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.
11) Able and willing to sign the informed consent as approved by the IRB/IEC. Written consent 
must be provided before initiating any screening evaluations. Subjects must have read and 
understood the ICF, must fully understand the requirements of the study, and must be 
willing to comply with all study visits and assessments subjects who cannot read or
understand the ICF may not be enrolled by a guardian or any other individual.
12) Subjects receiving non-prohibited medication for any reason should 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.
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, ie, chlorambucil or cyclophosphamide, at any time
b) Previous treatment with JAK inhibitor 
c) Leflunomide use within 8 weeks prior to Day 1 or in the case of cholestyramine washout, 
within 4 weeks prior to Day 1
d) Discontinuation of hydroxyxhloroquine or chloroquine less than 4 weeks prior to Day 1.
e) Cyclosporine, other calcineurin inhibitors, gold therapy, mycophenolate, or azathioprine 
within 4 weeks prior to Day 1
f)
B-cell depleting agents (ie, rituximab) within 6 months prior to Day 1.Documented return 
of CD19 cells required for subjects who have received B-cell depleting agent(s). 
g) Use of non-cell depleting bDMARDs, including: abatacept, adalimumab, certolizumab 
pegol, golimumab, infliximab, tocilizumab, anakinra or etanercept (including biosimilars) 
within 4 weeks prior to Day 1.


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2) Known hypersensitivity or allergy to the study drug, its metabolites, or formulation 
excipients.
3) Oral steroids at a dose >10 mg/day of prednisone equivalent or a prescription for oral steroids 
which has changed within 4 weeks of Day 1.
4) Receipt of an intra-articular or parenteral corticosteroid injection within 4 weeks prior to 
Day 1.
5) Use of nonsteroidal anti-inflammatory drugs (NSAID(s) 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 ≤325 mg daily for cardiac prophylaxis, or 
occasional NSAIDs for non-RA indications (eg. headache).
6) Administration of a live/ attenuated vaccine within 30 days prior to Day 1, or planned during 
the study.
7) 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 
should be discussed with the sponsor.
8) Have undergone surgical treatments for RA including synovectomy or arthroplasty in 
>4 joints and/or within the last 12 weeks prior to Screening 
9) 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
10) Have a history of major surgery (requiring regional block or general anesthesia) within the 
last 12 weeks prior to Screening or planned major surgery during the study.
11) 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).
12) 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.


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13) History of or current moderate to severe congestive heart failure (New York Heart 
Association [NYHA] class III or IV), or within the last 6 months, a cerebrovascular accident, 
myocardial infarction, unstable angina, unstable arrhythmia or new or significant ECG 
finding at Screening, or any other cardiovascular condition which, in the opinion of the 
investigator, would put the subject at risk by participation in the study.
14) 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).
15) History of lymphoproliferative disease or current lymphoproliferative disease. 
16) History of gastrointestinal perforation.
17) History of organ or bone marrow transplant.
18) Positive serology for human immunodeficiency virus (HIV) 1 or 2
19) 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[NM1] . Subject with  active HCV during the study, as 
evidenced by RNA positivity, will be discontinued from study drug as outlined in the 
protocol.
20) 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 .
21) History of opportunistic infection or immunodeficiency syndrome which would put the 
subject at risk, as per investigator judgment.
22) 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.


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23) 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. 
24) History of symptomatic herpes zoster infection within 12 weeks prior to Screening or have 
history of disseminated/complicated herpes zoster infection (multi-dermatomal involvement, 
ophthalmic zoster, central nervous system involvement or postherpetic neuralgia).
25) History of an infected joint prosthesis or other implanted device with retention of the 
prosthesis or device in situ.
26) Current drug, tobacco or alcohol abuse per investigator judgment.
27) Any condition including active fibromyalgia that based on the investigator’s opinion would 
make it difficult to appropriately assess RA activity for the purposes of this study. 
28) Any 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.
29) Significant blood loss (>450 mL) or transfusion of any blood product within 12 weeks prior 
to Day 1.
30) Use of prohibited medication as outlined in Section 5.3
31) 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) ≥1.5 x ULN;
g) Total bilirubin level ≥2 x 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 the 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 assignments 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 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, debossed with “GSI” on one side and “100” or “200” on the other, 
capsule-shaped, 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, are 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
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 and 
aluminum-faced liner. 
Sufficient quantities of filgotinib tablets, 100 mg and 200 mg, and PTM filgotinib tablets, 
100 mg and 200 mg, to complete the entire study will be shipped to the investigator or qualified 
designee from the Gilead Supply Management Team (or its designee).
Study drugs to be distributed to participating centers in the US and other participating countries
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. 
5.2.3.
Storage and Handling
Filgotinib tablets and PTM filgotinib tablets should be stored at controlled room of 25°C (77F); 
excursions are permitted between 15C and 30C (59F to 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.
5.2.4.
Dosage and Administration 
Filgotinib tablets, 100 mg and 200 mg, and PTM filgotnib tablets, 100 mg and 200 mg, 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 similar dosing interval is 
maintained 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.
Prior and Concomitant Medications
Concomitant therapies taken for 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 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 for
treatment of 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. 
As specified in the inclusion criteria, eligible subjects must be on a stable dose of 1 to 
2 csDMARD(s) and should remain on that stable dose until the end of the study:

MTX on a continuous basis for ≥12 weeks prior to Day 1 and on a stably prescribed dose and 
route of administration between 7.5 and 25 mg/weekly for at least 4 weeks prior to Day 1. 
Stable weekly doses <7.5 mg are allowed only in the presence of intolerance to or toxicity 
from higher doses or where higher doses are prohibited by the local label or local clinical 
practices.  Doses >25 mg weekly are not permitted.  Subjects on MTX should be receiving an 
adequate and stable dose of folic acid (≥5 mg/week total dose or as per local clinical practice) 
which should be confirmed or initiated at Screening, and continued throughout the study.  

Oral hydroxychloroquine ≤400 mg/day or chloroquine ≤250 mg/day with prescription having 
been stable for at least 4 weeks prior to Day 1

Oral sulfasalazine 1g to 3 g/day with prescription having been stable for at least 4 weeks 
prior to Day 1

Oral leflunomide 10-20 mg/day with prescription having been stable for at least 12 weeks 
prior to Day 1  
Note that MTX is not permitted to be used in combination with leflunomide.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

Oral steroids ≤10 mg/day prednisone or equivalent, provided that the prescription has been 
stable for at least 28 days prior to Day 1 


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
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 followed. 
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.
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: 

Any DMARDs, other than the ones specified above,

Oral or injectable gold within 4 weeks prior to Day 1

Azathioprine within 4 weeks prior to Day 1

D penicillamine within 4 weeks prior to Day 1

Cyclosporine within 8 weeks prior to Day 1

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 cortcosteriod 
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


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Previous treatment at any time with a cytotoxic agent, other than MTX, before Screening is 
prohibited. 
Previous use of JAK inhibitors is prohibited.
Receipt of an intra-articular or parenteral corticosteroid injection within 4 weeks prior to Day 1
and for the duration of the study 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 
dose of study drug.

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.
5.4.
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 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


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
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.
5.4.1.
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 
product supplies.
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 and Appendix 11.
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 Study Procedures Table and in such a way that the total study duration from Day 1 to last 
dosing does not exceed 24 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 before randomization. A subject will be considered enrolled once randomized.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 28 days before randomization to determine eligibility for 
participation in the study. 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

Subject global assessment

HAQ-DI and Pain Scale

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, includingheight

Weight


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
Vital Signs

Perform SJC66/TJC68

12-Lead ECG

Physician’s global assessment

Obtain blood samples for :
Serology
Hematology and Serum Chemistry
Serum CRP
Serum pregnancy test (if applicable)
Rheumatoid factor, anti-CCP Ab
FSH (females only), TSH, HbA1c
Quantitative immunoglobulin (Ig)

UrinalysisTB test and Chest X-ray (if applicable)

Review and collection 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 and may be 
considered for rescreening one time for the study in consultation with the Sponsor or its 
designee.
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 (CRF/eCRF).  All other untoward medical occurrences observed during the screening 
period, including exacerbation or changes in medical history are to be captured on the medical 
history CRF/eCRF.  See Section 7 Adverse Events and Toxicity Management for additional 
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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 three dosing regimens.
Subject’s Global Assessment, HAQ-DI and Pain Scale, FACIT-Fatigue, SF-36 are recommended 
to be completed 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 global assessment

HAQ-DI and Pain Scale

FACIT-Fatigue, SF-36

WPAI-RA, EQ-5D, where available


TSQM, when and where available

Healthcare resource utilization questionnaire

Symptom-directed physical examination

Weight

Vital signs

Perform SJC66/TJC68

Physician’s global assessment

Obtain blood samples for :
Hematology and Serum Chemistry
Lipid profile (fasting)
Serum CRP

Biomarker blood samples
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
 

Carotid artery ultrasounds, at selected sites only, when available

Urine stored for potential biomarker analysis

Urinalysis (including urine pregnancy test for females of childbearing potential, as defined 
per protocol)

Review and collection 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 treatment 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, prior exposure to number of bDMARDs (<3 or >=3 bDMARDs), 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 medication for the period until 
the next visit.
6.4.
Week 2 through Week 20 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 completed before any other study procedures. Invasive study procedures 
such as blood draws should be done at the end of a study visit. 

Subject global assessment

Subject’s pain assessment

HAQ-DI and pain scale

FACIT-Fatigue, SF-36 at Weeks 4 and 12 

WPAI-RA, EQ-5D at Weeks 4 and 12, where available
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

TSQM at Week 12, when and where available

Healthcare resource utilization questionnaire at Week 12 

Symptom-directed physical examination

Weight

Vital signs

Physician’s global assessment

Perform SJC66/TJC68

12-Lead ECG at Week 12 

Obtain blood samples for:
Hematology and Serum chemistry
Lipid profile (fasting) at Week 12 
Serum CRP
Pharmacokinetic (PK: Weeks 4, 12, and 16)
Biomarker blood samples at Weeks 4, 8, and 12

Urine pregnancy test (for females of childbearing potential, as defined per protocol)

Urine biomarker sample at Week 12
6.5.
Week 24/Early Termination
If a subject discontinues the study dosing (for example, as a result of an AE), every attempt 
should be made perform the required study-related ET visit and post treatment week 4 visist (see 
Section 3.5, Criteria for Discontinuation of Study Treatment).
Subject’s Global Assessment, HAQ-DI and Pain Scale, FACIT-Fatigue, and SF-36 are 
recommended to be completed before any other study procedures. Invasive study procedures 
such as blood draws should be done at the end of a study visit. 

Subject global assessment

Subject’s pain assessment
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
HAQ-DI and Pain Scale

FACIT-Fatigue, SF-36 

WPAI-RA, EQ-5D, where available 


TSQM, when and where available

Healthcare resource utilization questionnaire

Perform SJC66/TJC68

Vital signs

Complete Physical examination

Weight

Physician’s global assessment

12-Lead ECG

Obtain blood samples for :
Hematology Serum chemistry
Lipid profile (fasting)
Serum CRP
Pregnancy test (serum required if subject is entering into LTE)
Pharmacokinetic (PK)
Biomarker blood samples
Quantitative Ig

 

Urinalysis (including urine pregnancy test for females of childbearing potential, as defined 
per protocol)

Urine stored for biomarker analysis

Assessment of serious AE(s)/(S)AE(s) and concomitant medication
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
Carotid artery ultrasounds at Week 24, at selected sites only and when available

Review Entry criteria for LTE (if applicable)
6.6.
Post-treatment Week 4 Assessments
The following procedures will be completed 4 Weeks after the subject’s last dose of study 
treatment. This visit is not applicable if subject is continuing onto the LTE study.

Symptom Directed Physical examination

Vital signs

Weight

12-lead ECG

Urine pregnancy test ( for females of childbearing potential, as defined per protocol)

Urinalysis

Obtain blood samples for :
Hematology and Serum chemistry
6.7.
Study Assessments
6.7.1.
Efficacy
Efficacy assessments will be carried out at Day 1 and at Weeks 2, 4, 8, 12, 14, 16, 20 and 24, 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].
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, or at ET (if 
applicable). Healthcare resource utilization will be assessed at the same time points.
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).
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). 


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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 the 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”.
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.


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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  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 completed before any other study procedures.
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. The SF-36 
is not disease specific and has been validated in numerous health states.
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 done 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 


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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 for Rheumatoid Arthritis
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.
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.
Exploratory patient reported outcomes
 
 
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6.7.1.12.
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.
6.7.2.
Safety and Tolerability
Adverse events (AEs), physical examinations, vital signs, 12-lead electrocardiograms (ECG) and 
laboratory assessments (standard hematology, serum/plasma chemistry,  and urinalysis).
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 (or optional indwelling catheter for 
pharmacokinetic sampling days) 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.


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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 Baseline will be recorded. Height should be measured at Screening only.
At Screening, and Week 24 (or at ET), a complete physical examination including weight should 
be performed. Symptom-directed physical examinations should be performed at all other visits.
Weight is measured at all visits.
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), respiratory rate (RR), 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 should bebe collected at least 30 minutes post 
study drug dosing at Week 4, prior to study drug administration at Week 12 and Week 24, and 
anytime at Week 16 or ET. 
 
 
Plasma concentrations of filgotinib and its metabolite GS-829845 will be analyzed. Additional 
analyses (ie, for MTX and its metabolites) may be performed.
6.9.
Biomarker Assessments
Blood and urine samples will be collected at Day1, Weeks 4, 8, 12, and week 24 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 (if applicable) will be provided 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 (ie, hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.7.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
7.1.2.
Serious Adverse Events
A 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.)

In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity


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
A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to study 
drug therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study drug. For 
SAEs, an alternative causality must be provided (eg, pre-existing condition, underlying 
disease, intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.


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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)
7.2.2.
Assessment of Severity
The severity 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. 
**  Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.


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Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30-days after last administration of study drug must be reported to the CRF/eCRF database 
as instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30-days of the 
last dose of study drug, regardless of causality, should also be reported. Investigators are not 
obligated to actively seek SAEs after the protocol defined follow up periodhowever, if the 
investigator learns of any SAEs that occur after study participation has concluded and the event 
is deemed relevant to the use of study drug, he/she should promptly document and report the 
event to Gilead DSPH.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.
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:
1-650-522-5477
E-mail: Safety_FC@gilead.com

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.


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
If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the
eCRF completion guideline

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
form.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
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 drug. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (eg, clinical chemistry, hematology, and urinalysis) independent of the 
underlying medical condition that require medical or surgical intervention or lead to 
investigational medicinal product interruption or discontinuation must be recorded as an AE, as 
well as an SAE, if applicable. In addition, laboratory or other abnormal assessments 
(eg, electrocardiogram, X-rays, vital signs) that are associated with signs and/or symptoms must 


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be recorded as an AE or SAE if they meet the definition of an AE (or SAE) as described in 
Sections 7.1.1 and 7.1.2.  If the laboratory abnormality is part of a syndrome, record the 
syndrome or diagnosis (ie, anemia) not the laboratory result (ie, decreased hemoglobin).
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.


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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
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 Day 1 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 
Section 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.


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Occupational exposure is defined as exposure to a medicinal product as a result of one's 
professional or non-professional occupation. 
7.7.2.
Instructions for Reporting Special Situations
7.7.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to Gilead DSPH using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy. 
Refer to Section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead DSPH. Gilead DSPH contact information is as follows:
Email: Safety_FC@gilead.com and Fax: +1 (650) 522-5477.
Pregnancies of female partners of male study subjects exposed to study drugs must also be 
reported and relevant information should be submitted to Gilead DSPH using the pregnancy and 
pregnancy outcome forms within 24 hours. Monitoring of the subject should continue until the 
conclusion of the pregnancy. If the end of the pregnancy occurs after the study has been 
completed, the outcome should be reported directly to Gilead DSPH,
fax number +1 650 522-5477 or email Safety_FC@gilead.com. 
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.7.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 


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


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of this study is:

To evaluate the effects of filgotinib versus placebo 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 12 
The secondary objectives of this study are: 

To evaluate the effects of filgotinib versus placebo 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]) ≤3.2 at Week 12

To evaluate the effect of filgotinib versus placebo on physical function as measured by 
change from Baseline in the Health Assessment Questionaire Disability Index (HAQ-DI) at 
Week 12

To evaluate the safety and tolerability of filgotinib

To evaluate the effects of filgotinib on work productivity, fatigue, and general quality of life 
as measured by SF-36, FACIT-Fatigue, EQ-5 and WPAI-RA.

The exploratory objective of this study is as follows: 
 
 
 
8.1.2.
Primary Endpoint
The primary endpoint is the proportion of subjects who achieve an ACR20 response at Week 12.
PPD


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8.1.3.
Secondary Endpoints
The key secondary endpoints are:

The proportion of subjects who achieve DAS28 (CRP)≤3.2 at Week 12

Change from Baseline in the HAQ-DI score at Week 12
Other secondary endpoints include:

The proportion of subjects who achieve ACR50 and ACR70 at Weeks 4, 12 and 24, ACR20 
at Weeks 4 and 24, and ACR20/50/70 over time from Day 1 through Week 24

Change from Baseline in individual components of the ACR response at Weeks 4, 12, and 24 
and over time from Day 1 through Week 24 

The proportion of subjects who achieve change in HAQ-DI of ≥0.22 at Weeks 4, 12, and 24, 
and over time from Day 1 through Week 24

Change from Baseline in DAS28 (CRP) at Weeks 4, 12, 24 and over time from Day 1
through Week 24

The proportion of subjects who achieve DAS28 (CRP)≤3.2 at Weeks 4 and 24, and over time 
from Day 1 through Week 24

The proportion of subjects who achieve DAS28 (CRP)<2.6 at Weeks 4, 12, and 24, and over 
time from Day 1 through Week 24

ACR-N and EULAR  response at Weeks 4, 12, and 24, and over time from Day 1 through 
Week 24 

Change from Baseline in CDAI at Weeks 4, 12, and 24, and over time from Day 1 through 
Week 24 

Change from Baseline in SDAI at Weeks 4, 12, and 24, and over time from Day 1 through 
Week 24 Absolute value and change from Baseline in SF-36, FACIT-Fatigue, and the 
EQ-5D over time at Weeks 4, 12 and 24, and over time from Day 1 through Week 24

Absolute value and change from Baseline in WPAI-RA at Weeks 4, 12, 24, and over time 
from Day 1 through Week 24 


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8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
All Randomized
The all randomized analysis set includes all subjects who are randomized in the study. This is the 
primary analysis set for by-subject listings.
8.2.1.2.
Efficacy
8.2.1.2.1.
Full Analysis Set (FAS)
The primary analysis set for efficacy analyses will be the Full Analysis Set (FAS), which 
includes all randomized subjects who received at least one dose of study drug.
8.2.1.2.2.
Per-Protocol (PP) Analysis Set
The secondary analysis set for efficacy analyses will be the Per-Protocol (PP) Analysis set, 
which includes all subjects in the Full Analysis Set who have not committed any major protocol 
violation, including the violation of key entry criteria. 
8.2.1.3.
Safety
The primary analysis set for safety analyses will be the Safety Analysis Set, which includes all 
subjects who received at least one dose of study drug.
8.2.1.4.
Pharmacokinetic 
8.2.1.4.1.
Pharmacokinetic (PK) Substudy Analysis Set
 
 
8.2.1.4.2.
Pharmacokinetic (PK) Analysis Set
The primary analysis set for general PK analyses will be the PK analysis set, which includes all 
subjects in the Safety Analysis Set who have at least 1 nonmissing concentration data for 
filgotinib and/or its metabolite GS-829845 .
8.3.
Data Handling Conventions
PK concentration values and PK parameter values below the limit of quantitation (BLQ) will be
presented as “BLQ” in the data listings. BLQ values that occur prior to the first dose will be
treated as 0, BLQ values at all other time points will be treated as 1/2 of the lower limit of
quantitation (LLOQ).
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Laboratory data that are continuous in nature but are less than the lower limit of quantitation or
above the upper limit of quantitation will be imputed to the value of the lower or upper limit
minus or plus one significant digit, respectively (eg, if the result of a continuous laboratory test is
< 20, a value of 19 will be assigned; if the result of a continuous laboratory test is < 20.0, a value 
of 19.9 will be assigned).
8.4.
Demographic Data and Baseline Characteristics
Demographic and Baseline characteristics will be summarized by treatment group using standard 
descriptive statistics including sample size, mean, SD, median, Q1, Q3, minimum, and maximum 
for continuous variables and numbers and percentages of subjects for categorical variables.
Demographic data will include sex, race, ethnicity, and age.
Baseline characteristics may include number of prior bDMARD exposure, RF status, anti-CCP 
status, DAS28(CRP), HAQ-DI, SDAI, CDAI, and other variables of interest.
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary endpoint for the study is the proportion of subjects who achieve an ACR20 response 
at Week 12. The primary analyses will consist of a superiority test of filgotinib 200 mg 
compared to placebo based on the ACR20 response rate at Week 12. Cochran-Mantel-Haenszel
(CMH) approach adjusting for the randomization stratification factors 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 12 will be considered failures (i.e. non-responder imputation [NRI]).  
Sensitivity analyses will be 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 compared to placebo based on the response rate of DAS28 
(CRP)≤3.2 at Week 12. 
2) Superiority of filgotinib 200 mg compared to placebo based on the change from Baseline in 
HAQ-DI at Week 12. 
3) Superiority of filgotinib 100 mg compared to placebo based on ACR20 response rate at 
Week 12. 
4) Superiority of filgotinib 100 mg compared to placebo based on the response rate of DAS28 
(CRP)≤3.2 at Week 12. 
5) Superiority of filgotinib 100 mg compared to placebo based on the change from Baseline in 
HAQ-DI at Week 12. 


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For categorical endpoints (ACR20 and response rate of DAS28 (CRP)≤3.2), the same CMH
approach with NRI as used for the primary analysis will be adopted. For continuous endpoint 
(HAQ-DI), mixed-effects model for repeated measures (MMRM) will be used to evaluate 
treatment effect on change from baseline. Treatment, visit, treatment-by-visit interaction, 
stratification factors and baseline value may be included in the model as fixed effects, with 
subject being a radom effect.
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.
Summaries (number and percentage of subjects) of TEAEs by SOC and PT will be provided by 
treatment group. TEAEs will also be summarized by relationshiop to study drug and severity. In 
addition, TEAEs leading to premature discontinuation of study drug will be summarized and 
listed.


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8.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum, and
maximum) by treatment group and study visit along with corresponding change from Baseline. 
The incidence of treatment-emergent graded laboratory abnormalities will be summarized 
similarly.
Graded laboratory abnormalities will be defined using CTCAE 4.03 grading scale.
8.7.
Pharmacokinetic Analysis
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
 
 
 
 
8.9.
Sample Size
Sample size is determined based on the superiority test of filgotinib compared to placebo on the 
change from Baseline in HAQ-DI at Week 12. When assuming a difference of 0.25 between the 
two groups and a common standard deviation of 0.645, 141 subjects in each of the filgotinib 
groups and placebo control group are required to obtain 90% power at a 2-sided 0.05-level. 
A sample size of 141 subjects in each of the filgotinib groups and placebo control group will 
also provide over 90% power to detect an increase in ACR20 response rate of 25% to 45% 
between the placebo control group and the filgotinib groups respectively, using a 2-sided 
0.05-level test.
PPD
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In summary, the total sample size will be 423 (141 per group).
8.10.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (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 through 
12 weeks of 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. 


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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 IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 


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investigator must use the most current IRB/IEC-approved consent form for documenting written 
informed consent. Each informed consent (or assent as applicable) will be appropriately signed 
and dated by the subject and the person conducting the consent discussion, and also by an 
impartial witness if required by IRB/IEC or local requirements. The consent form will inform 
subjects about 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 as way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The 
investigator must keep a screening log showing codes, names, and addresses for all subjects 
screened and for all subjects enrolled in the trial. Subject data will be processed in accordance 
with all applicable regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/eCRF, thestudy 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, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);


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


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eligibility have been received.  Subsequent to data entry, a study monitor will perform source 
data verification within the EDC system. Original entries as well as any changes to data fields 
will be stored in the audit trail of the system.  Prior to database lock (or any interim time points 
as described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 
the information in the source documents. The eCRF capture the data required per the protocol 
schedule of events and procedures. System-generated or manual queries will be issued to the 
investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, 
who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (ie 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, study drug should be destroyed at the site. At the start of the study, the study 
monitor will evaluate each study center’s study drug disposal procedures and provide appropriate 
instruction for disposal or return of unused study drugsupplies. 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 study drug 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 Study Drug 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 study drug is destroyed on site, the investigator must maintain accurate records for all study 
drugs destroyed. Upon study completion, copies of the study drug accountability records must be 
filed at the site. Another copy will be returned to Gilead.
The study monitor will review study drug supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs/IECs, 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/IECapproval 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(ies). Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases. 
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, ie attendance at Investigator's Meetings.  If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.


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9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of  monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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10.
REFERENCES
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, 3rd, et al. 2010 
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


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Amendment 1 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404, USA 
STUDY ACKNOWLEDGE:MENT 
A Randomized, Double-blind, Placebo-controlled, Multicenter, Phase 3 Study to Assess the 
Efficacy and Safety of Filgotinib Administered for 24 weeks in Combination with Conventional 
Disease-modifying Anti-rheumatic Drug(s) (DMARDs) to Subjects with Moderately to Severely 
Active Rheumatoid Arthritis Who Have an Inadequate Response to Biologic DMARD(s) 
Treatment 
GS-US-417-417-0302, Amendment 1, 05 July 2016 
This protocol has been approved by Gilead Scienc;es~,~In~c
::::_·...::T~h:.:::e~~~~~=~d::o~cum
=::::en~ts
::......., 
this approval. 
+eALJZiUA Ht\12\e\ £5. 1 ho 
Name (Printed) 
Author 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains alJ necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and wilJ 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 tllls material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator N arne (Printed) 
Signature 
Date 
Site Number 
CONHDENTIAL 
Page 89 
05 July 2016 


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Amendment 1 
Appendix 2. 
Study Procedures Table 
Follow 
EVENT 
Treatment Period 
up• 
W24/ 
Post-
W2 
W4 
ws 
W12 
W14 
W16 
W20 
ET C 
Treatment 
SCl'eening 
Day 1 b 
(±3 
(±3 
(± 3 
(±3 
(±3 
(±3 
(±5 
(±5 
Week4 
Study days /weeks (W) 
(-28 Days) 
days) 
days) 
days) 
days) 
days) 
days) 
days) 
days) 
(± 5 days) 
hlfonned consent 
X 
Inclusion/exclusion criteria 
X 
xd 
Demographics and Baseline disease 
X 
characteristics 
~ 
~ 
RA Diagnosis and Prior Treatment, Medical 
e 
X 
~ 
history• 
"' , 
< 
Complete Physical Examination f 
X 
X 
Cl) = 
·= ... 
CD19 connt (for subjects with prior rituxin1ab 
... 
X 
... 
" 
therapy) 
fJ) 
TB test and Chest X-ray g 
X 
Serologyh 
X 
Endocrine: FSH, TSH, and HbAlc 
X 
CONFIDENTIAL 
Page 90 
05 July 2016 


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Protocol GS-US-417-0302 
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EVENT 
Study days /weeks (W) 
Subject's global assessment i 
~ 
HAQ-DI and Pain Scale i 
... 
·; = 
= 
0 
F ACIT -Fatigue, SF-36 questionnaire, EQ-5D, 
·.:: 
"' 
WPAI-RA 
1 
... = 
Cl 
.... 
Healthcare resource utilization questi01maire 
= 
... 
<= 
andTSQM' 
= 
~ 
... 
Physician's global assessment 
... 
~ 
·;; 
Vital signs i 
0 ... 
C:...!l 
~ :il MeastU'ement of weight and Symptom driven 
s a 
.. "' physical examination 
>< ... 
r.J 
~ 
- < 
5 
12-LeadECG 
·;; 
>. 
-= 
c:... 
SJC 66/TJC 68 
CONFIDENTIAL 
W2 
W4 
Sct•eening 
Dayl b 
(±3 
(±3 
(-28 Days) 
days) 
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 
Page 91 
Treatment Period 
ws 
W12 
W14 
W16 
(±3 
(±3 
(±3 
(±3 
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 
X 
X 
X 
X 
X 
X 
W24/ 
W20 
ETC 
(± 5 
(±5 
days) 
days) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Final 
Amendment 1 
Follow 
up • 
Post-
Treatment 
Week4 
(± 5 days) 
X 
X 
X 
05 July 2016 
1 


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Protocol GS-US-417-0302 
Gilead Sciences, Inc. 
EVENT 
Study days /weeks (W) 
Hematology and chemistty k 
Rhemnatoid factor, anti-CCP Ab 
Urinalysis 
Urine Biomarker Sample 1 
Lipid profile (fasting) 
"' 
.... = 
"' s 
"' 
PK blood samples n 
~ 
"' 
-< 
t 
Plasma biomarker sample, Senun biomarker 
s = 
sample, Blood transcriptome sample, Blood 
... 
0 
TCRIBCR repertoire sample 
0 
.1:> = 
;..l 
Pregnancy test P 
SenunCRP 
Viral Monitoring q 
Explorat01y Lab Panel: Leptin, LDL particle, 
Homocystein, Apo A liB, HbAlc r 
Quantitative Ig 
CONFIDENTIAL 
W2 
W4 
Sct•eening 
Day l b 
(±3 
(±3 
(-28 Days) 
days) 
days) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 92 
Treatment Period 
ws 
W12 
W14 
W16 
(±3 
(±3 
(±3 
(±3 
days) 
days) 
days) 
days) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
W24/ 
W20 
ET C 
(± 5 
(±5 
days) 
days) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Final 
Amendment 1 
Follow 
up• 
Post-
Treatment 
Week4 
(± 5 days) 
X 
X 
I 
X 
05 July 2016 


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EVENT
Treatment Period
Follow
Up a
Study days /weeks (W)
Screening
(-28 Days)
Day 1 b
W2 
(± 3 
days)
W4 
(± 3 
days)
W8 
(± 3 
days)
W12 
(± 3 
days)
W14 
(± 3 
days)
W16 
(± 3 
days)
W20 
(± 5 
days)
W24/
ET c
(± 5 
days)
Post-
Treatment 
Week 4
(± 5 days)
Carotid Artery Ultrasound s
X
X
AE assessment
X
X
X
X
X
X
X
X
X
X
X
Review Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Randomization/reassignment
Xt
Xu
Study Drug Dispensation v
X
X
X
X
X
X
Review Entry criteria for LTE (if applicable)
X
a
The follow-up visit will be performed only for subjects discontinuing prematurely from the study and for those completing week 24, but not entering the LTE.
b
Subject will begin medication on Day 1, following baseline assessments and randomization.
c
Early Termination Visit to be performed if subject discontinues before Week 24.
d
Eligibility criteria check based on the laboratory results from the Screening visit, TJC/SJC at screening and day 1, and for female subjects of childbearing potential, the urine 
pregnancy test is performed at Day 1.
e
Medical History includes smoking status, average weekly alcohol consumption, family history of coronary heart disease (CHD) any other chronic medical conditions or prior 
surgeries.
f
At Screening and Week 24 (or at ET), a complete physical examination, including weight should be performed. Symptom-directed exams should be performed at all other 
visits. Height will be measured at Screening only.
g
Chest X-ray for TB should be performed if not performed in the previous 3 months, and results are available at the site. 
h
Hepatitis B surface Ag and core Ab, reflex Hep B DNA, Hepatitis C Ab, reflex HCV RNA, HIV 1 and 2 at Screening.
i
 
j
Vital signs include heart rate, respiratory rate, blood pressure (systolic and diastolic) and temperature.
k
Refer to list provided in Laboratory assessment table (Appendix 6). Hemoglobin A1c and TSH will be measured at Screening only. 
l
Urine biomarker sample collected on Day 1 and Week 24/ET only. 
m
  
n
One blood sample will be collected for analysis of filgotinib and its active metabolite (GS-829845 ) in plasma. The PK sample at Week 4 should be collected at least 
30 minutes post study drug dose. PK samples at Week 12 and Week 24 visit should be collected prior to study drug dose (within 2 hours prior to dosing) at the visit. PK 
samples at week 16 or ET can be collected anytime during the visit. 
 
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o
Details of biomarker collection are outlined in lab manual.
p
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 24 visit, pregnancy test should be performed on serum. f any pregnancy test is positive, study drug should be immediately interrupted and the subject should 
come to the site for serum pregnancy test.
q
Viral monitoring for HBV or HCV as applicable (See exclusion criteria Section 4.3)
r
Sites participating in the Coratic Artery Ultrasound study: Leptin, LDL particle, Homocystein, Apo A1/B, HbA1c will be performed at Screening and Week 24.
s
Carotid artery ultrasounds will be performed when available at selected sites, at Day 1 (+ 7 window) and Week 24 (± 7 day window).
t
Upon qualification for the study.
u
At Week 14, subjects who failed to achieve both a TJC and SJC improvement of ≥20% will be treated as inadequate responders.
v
Dispensation of study drugs according to IWRS manual.
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Appendix 3.
Management of Clinical and Laboratory Adverse Events
Grade I 
L_ ____ G_r_a_de-2----~~· ~ -----G-r-a-de-3----~~ 
Ll --------G-r-a-de-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: 
I. Withhold investigational medicinal products until 
:S Grade 2 
2. 
Restart all investieational medicinal oroducts at fu ll dose 
1 
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 
1 
Repeat lab to 
confirm toxicity 
grade 
1 
lfc onfirmed and unrelated to 
estigational medicinal 
inv 
pro 
the 
ducts, dosing may continue at 
discretion of the investigator 
If confirmed and 
possibly or probably 
---+ related to 
investigational 
medicinal products, 
discontinue 
investigational 
medicinal products 
dosing permanently 
and follow at 
periodic intervals at 
least weekly until a 
return to baseline or 
is otherwise 
explained 
If Grade 3 or 4 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.  
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, 


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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.


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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:
Leucocytes
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
Lipid profile: 
Triglycerides
Cholesterol and its 
subfractions (high-density 
lipoprotein [HDL] and low-
density lipoprotein [LDL])
Appearance
Blood
Color
Glucose
Specific gravity
Nitrites
Leukocyte esterase
pH
Protein
Urobilinogen
Reflex to microscopic 
urinalysis if dipstick result 
is abnormal.
Urine drug screen for:
Amphetamines
Cocaine
Methadone
Opiates
C-reactive protein (hsCRP)
Rheumatoid factor and anti 
cyclic citrullinated peptide 
antibody (RF/ Anti-CCP)
QuantiFERON- TB GOLD 
Quantitative Ig subclasses at 
Screening and Week 24 
In the carotic imaging study 
at selected sites and where 
available at Screening and 
Week 24: 
Leptin 
LDL particle
Homocystein
Apo A1/B
HbA1c
Endocrine (At 
Screening Only)
Serology
Pregnancy
Hemoglobin A1c
TSH
FSH
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)


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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 assessment of physical function (HAQ-DI) 
Acute-phase reactant (CRP)
The following lists the disease activity measure followed by the method of assessment
1.
Tender joint count
ACR tender joint count is an assessment of 68. The joint count should be done by scoring several 
different aspects of tenderness, as assessed by pressure and joint manipulation on physical 
examination. The information on various types of tenderness should then be collapsed into a 
single tender-versus-nontender dichotomy.
2.
Swollen joint count
ACR swollen joint count is an assessment of 66. Joints are classified as either swollen or not 
swollen.
3.
Patient’s assessment of pain
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 = patient global assessment 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; neurological (must be performed at Screening). 
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 ECG as part of routine safety monitoring.  

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Randomized, Double-blind, Placebo-controlled, Multicenter, 
Phase 3 Study to Assess the Efficacy and Safety of Filgotinib
Administered for 24 weeks in Combination with Conventional 
Synthetic Disease-modifying Anti-rheumatic Drug(s) 
(csDMARDs) to Subjects with Moderately to Severely Active 
Rheumatoid Arthritis Who Have an Inadequate Response to 
Biologic DMARD(s) Treatment
Name of Test Drug:
Filgotinib
Study Number:
GS-US-417-0302
Protocol Version (Date):
Amendment 1 (05 July 2016)
Analysis Type:
Final Analysis
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
23 August 2018
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
LIST OF IN-TEXT FIGURES ......................................................................................................................................4
LIST OF ABBREVIATIONS........................................................................................................................................5
PHARMACOKINETIC ABBREVIATIONS................................................................................................................8
1.
INTRODUCTION ................................................................................................................................................9
1.1.
Study Objectives ......................................................................................................................................9
1.2.
Study Design..........................................................................................................................................10
1.3.
Sample Size and Power..........................................................................................................................11
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................12
2.1.
Data Monitoring Committee Analyses...................................................................................................12
2.2.
Final Analysis ........................................................................................................................................12
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................13
3.1.
Analysis Sets..........................................................................................................................................13
3.1.1.
All Randomized Analysis Set...............................................................................................13
3.1.2.
Full Analysis Set ..................................................................................................................13
3.1.3.
Per-Protocol Analysis Set.....................................................................................................13
3.1.4.
Safety Analysis Set...............................................................................................................14
3.1.5.
Pharmacokinetic Analysis Set..............................................................................................14
3.1.6.
Pharmacokinetic Substudy Analysis Set ..............................................................................15
3.2.
Subject Grouping ...................................................................................................................................15
3.3.
Strata and Covariates..............................................................................................................................15
3.4.
Examination of Subject Subgroups........................................................................................................16
3.5.
Multiple Comparisons............................................................................................................................16
3.6.
Missing Data and Outliers......................................................................................................................17
3.6.1.
Missing Data ........................................................................................................................17
3.6.2.
Outliers.................................................................................................................................18
3.7.
Data Handling Conventions and Transformations .................................................................................18
3.8.
Analysis Visit Windows.........................................................................................................................19
3.8.1.
Definition of Study Day .......................................................................................................19
3.8.2.
Analysis Visit Windows.......................................................................................................19
3.8.3.
Selection of Non-Efficacy Data in the Event of Multiple Records in an 
Analysis Visit Window ........................................................................................................21
4.
SUBJECT DISPOSITION ..................................................................................................................................23
4.1.
Subject Enrollment and Disposition.......................................................................................................23
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................24
4.2.1.
Duration of Exposure to Study Drug....................................................................................24
4.2.2.
Adherence to Study Drug.....................................................................................................25
4.3.
Protocol Deviations................................................................................................................................26
5.
BASELINE CHARACTERISTICS....................................................................................................................27
5.1.
Demographics and Other Baseline Characteristics ................................................................................27
5.2.
Baseline Disease Characteristics............................................................................................................27
5.3.
Medical History......................................................................................................................................30
6.
EFFICACY ANALYSES ...................................................................................................................................31


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6.1.
General Considerations ..........................................................................................................................31
6.1.1.
Tender/Swollen Joint Counts (TJC/SJC)..............................................................................32
6.1.2.
Global Assessment of Disease Activity................................................................................33
6.1.3.
Health Assessment Questionnaire Disability Index (HAQ-DI)............................................34
6.2.
Primary Efficacy Endpoint.....................................................................................................................34
6.2.1.
Definition of the Primary Efficacy Endpoint .......................................................................34
6.2.2.
Statistical Hypothesis for the Primary Efficacy Endpoint....................................................35
6.2.3.
Primary Analysis of the Primary Efficacy Endpoint ............................................................35
6.2.4.
Sensitivity Analysis of the Primary Endpoint ......................................................................36
6.2.5.
Subgroup Analysis of the Primary Endpoint........................................................................37
6.3.
Key Secondary Efficacy Endpoints........................................................................................................37
6.3.1.
Definition of Key Secondary Efficacy Endpoints ................................................................37
6.3.2.
Analysis Methods for Key Secondary Efficacy Endpoints ..................................................38
6.3.3.
Sensitivity Analysis for Key Secondary Efficacy Endpoints ...............................................39
6.3.4.
Subgroup Analysis of Key Secondary Endpoints.................................................................41
6.4.
Other Secondary Efficacy Endpoints .....................................................................................................41
6.4.1.
Definition of Other Secondary Efficacy Endpoints..............................................................42
6.4.2.
Analysis Methods for Other Secondary Efficacy Endpoints................................................45
6.5.
Changes From Protocol-Specified Efficacy Analyses............................................................................48
7.
SAFETY ANALYSES........................................................................................................................................49
7.1.
Adverse Events and Deaths....................................................................................................................49
7.1.1.
Adverse Event Dictionary ....................................................................................................49
7.1.2.
Adverse Event Severity........................................................................................................49
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................49
7.1.4.
Serious Adverse Events........................................................................................................49
7.1.5.
Treatment-Emergent Adverse Events...................................................................................49
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................50
7.1.7.
Adverse Events of Special Interest.......................................................................................51
7.2.
Laboratory Evaluations ..........................................................................................................................53
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................53
7.2.2.
Graded Laboratory Value.....................................................................................................55
7.2.3.
Laboratory Evaluations of Special Interest ..........................................................................56
7.3.
Body Weight and Vital Signs.................................................................................................................57
7.4.
Prior and Concomitant Medications.......................................................................................................58
7.4.1.
Prior Medications .................................................................................................................58
7.4.2.
Concomitant Medications.....................................................................................................58
7.5.
Electrocardiogram Results .....................................................................................................................59
7.5.1.
Investigator Electrocardiogram Assessment ........................................................................59
7.6.
Other Safety Measures ...........................................................................................................................59
7.7.
Changes From Protocol-Specified Safety Analyses...............................................................................59
8.
PHARMACOKINETIC ANALYSES ................................................................................................................60
8.1.
PK Analyses Related to Intensive PK Sampling....................................................................................60
8.1.1.
Estimation of Pharmacokinetic Parameters..........................................................................60
8.1.2.
Pharmacokinetic Parameters ................................................................................................60
8.1.3.
Statistical Analysis Methods ................................................................................................61
9.
BIOMARKER ANALYSIS................................................................................................................................63
10.
REFERENCES ...................................................................................................................................................64
11.
SOFTWARE.......................................................................................................................................................65
12.
SAP REVISION..................................................................................................................................................66


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13.
APPENDICES ....................................................................................................................................................67
Appendix 1.
Lists of RA Medications.........................................................................................................68
Appendix 2.
Health Assessment Questionnaire Disability Index (HAQ-DI)..............................................70
Appendix 3.
Treatment Satisfaction Questionnaire for Medication (TSQM) .............................................72
Appendix 4.
Cortocosteroids.......................................................................................................................73
Appendix 5.
SAS Programming for Tipping Point Analysis for Binary Endpoint .....................................74
Appendix 6.
SAS Programming for Tipping Point Analysis for Continuous .............................................76
LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Visit Windows for On-Treatment Joint Count Assessment, HAQ-DI, SGA, 
PGA, CRP, Exploratory PRO, and Vital Signs, Weight, and Safety Laboratory Data 
(Lipid Data Excluded)............................................................................................................20
Table 3-2.
Analysis Visit Windows for On-Treatment Lipid and ECG Data ..........................................20
Table 3-3.
Analysis Visit Windows for On-Treatment SF-36, FACIT-Fatigue, EQ-5D, and 
WPAI-RA...............................................................................................................................20
Table 3-4.
Analysis Visit Windows for On-Treatment HRUQ and TSQM.............................................21
Table 6-1.
Composition of the 28 Joints..................................................................................................33
Table 6-2.
EULAR Response Criteria .....................................................................................................43
Table 8-1.
Study Treatments and Associated Analytes ...........................................................................60
Table 8-2.
Pharmacokinetic Parameters for Each Analyte ......................................................................61
LIST OF IN-TEXT FIGURES
Figure 1-1.
Study Design ..........................................................................................................................10


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LIST OF ABBREVIATIONS
Ab
Antibody
ACR
American College of Rheumatology
ACR20/50/70
American College of Rheumatology 20/50/70% improvement
AE
adverse event
AESIs
adverse events of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
ATC
anatomical therapeutic chemical drug class
bDMARD
biological disease modifying anti-rheumatic drug
BLQ
below the limit of quantitation
BMI
body mass index
CBC
complete blood count
CCP
cyclic citrullinated peptide
CDAI
clinical disease activity index
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CPK
creatine phosphokinase
CRF
case report form
CSR
clinical study report
CTCAE
Common Toxicity Criteria for Adverse Events
DAS28
disease activity score for 28 joint count
DMC
data monitoring committee
ECG
electrocardiogram
EQ-5D
EuroQoL 5 Dimensions 
ET
early termination
EULAR
European League Against Rheumatism
FACIT-Fatigue
Functional Assessment of Chronic Illness Therapy-Fatigue
FAS
full analysis set
Gilead
Gilead Sciences
HAQ-DI
health assessment questionnaire-disability index
HLGT
high-level group term
HLT
high-level term
HRQoL
health-related quality of life
HRUQ
healthcare resource utilization questionnaire
hsCRP
High-sensitivity C-reactive Protein
IAC
independent adjudication committee


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ID
identification
IWRS
interactive web response system
LLOQ
lower limit of quantitation
LLT
lower-level term
LOCF
last observation carried forward
LOQ
limit of quantitation
LS
least squares
LTE
long-term extension
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
MMRM
mixed model repeated measures
MNAR
missing not at random
MST
MedDRA search listing
MTX
methotrexate
NRI
non-responder imputation
OC
observed case
PD
pharmacodynamics 
PGA
physician’s global assessment 
PK
pharmacokinetic
PP
per-protocol
PT
preferred term
PTM
placebo to match
Q1, Q3
first quartile, third quartile
QD
quaque die (each day)
RA
rheumatoid arthritis
RF
rheumatoid factor
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SDAI
simplified disease activity index
SE
standard error
SF-36
36-item short form survey
SGA
subject's global assessment 
SJC
swollen joint count
SMQ
standardized MedDRA query
SOC
system organ class
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
TNFα
tumor necrosis factor-alpha
TJC
tender joint count


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TSQM
treatment satisfaction questionnaire for medication
ULN
upper limit of normal
VAS
visual analog scale
VR
ventricular rate
WBC
white blood cell
WHO
World Health Organization
WPAI
Work Productivity and Activity Impairment 


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PHARMACOKINETIC ABBREVIATIONS
AUClast
area under the concentration versus time curve from time zero to the last quantifiable 
concentration
AUCtau
area under the concentration versus time curve over the dosing interval
Clast
last observed quantifiable concentration of the drug 
Cmax
maximum observed concentration of drug 
Ctau
observed drug concentration at the end of the dosing interval
CLss/F
apparent oral clearance after administration of the drug:
at steady state: CLss/F = Dose/AUCtau , where “Dose” is the dose of the drug
t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the natural 
log of 2 by the terminal elimination rate constant (z)
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
Vz/F
apparent volume of distribution of the drug
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination 
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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study GS-US-417-0302. This SAP is based on the study protocol amendment 1 dated 
05 July 2016 and the electronic case report form (eCRF). The SAP will be finalized before 
database finalization. Any changes made after the finalization of the SAP will be documented in 
the CSR.
1.1.
Study Objectives
The primary objective of this study is as follows:

To evaluate the effects of filgotinib versus placebo 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 12
The secondary objectives of this study are as follows:

To evaluate the effects of filgotinib versus placebo 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)) ≤ 3.2 at Week 12

To evaluate the effect of filgotinib versus placebo on physical function as measured by 
change from Baseline in the Health Assessment Questionaire Disability Index (HAQ-DI) at 
Week 12

To evaluate the safety and tolerability of filgotinib

To evaluate the effects of filgotinib on work productivity, fatigue, and general quality of life
as measured by 36-Item Short Form Survey (SF-36), Functional Assessment of Chronic 
Illness Therapy-Fatigue (FACIT-Fatigue), EuroQol 5 Dimensions (EQ-5D) and Work 
Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA).
The exploratory objectives of this study are as follows:
 
 
 
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1.2.
Study Design
This is a randomized, double-blind, placebo-controlled, add-on, Phase 3 study in adult male and 
female subjects with active RA despite conventional synthetic Disease-modifying 
Anti-rheumatic Drug(s) (csDMARD[s]) therapy (ie, methotrexate [MTX], hydroxychloroquine, 
sulfasalazine, leflunomide) who have had an inadequate response or are intolerant to at least one 
biologic DMARD (bDMARD). 
Approximately 423 subjects will be randomized in a 1:1:1 ratio to filgotinib 200 mg, filgotinib 
100 mg, or placebo to match (PTM) administered for up to 24 weeks, all in the context of a 
stable dose of permitted csDMARD(s):

Filgotinib 200 mg group: filgotinib (200 mg once daily [q.d.]) + PTM filgotinib 100 mg 
(PTM q.d.) (N=141) 

Filgotinib 100 mg group: filgotinib (100 mg q.d.) + PTM filgotinib 200 mg (PTM q.d.)
(N=141) 

Placebo control group: PTM filgotinib 200 mg (PTM q.d.) and PTM filgotinib 100 mg 
(PTM q.d.) (N=141) 
Randomization will be stratified by geographic region, prior exposure to number of bDMARDs 
(< 3 or ≥3 bDMARDs) and presence of rheumatoid factor (RF) or anti-CCP (cyclic citrullinated 
peptide) antibody (Ab) at screening.
Figure 1-1.
Study Design


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At Week 14, subjects who have not achieved at least 20% improvement from Baseline 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.
All subjects who attain responder status at Week 14 will continue on their assigned study drug, 
in a blinded fashion through Week 24. Placebo-responders at Week 14 will continue on placebo 
in a blinded fashion through Week 24.
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 follow up 
visit four weeks after the last dose of study drug (Post Treatment visit Week 4), regardless of 
dosing duration.
At completion of the 24-week dosing period all subjects, regardless of response, who have not 
discontinued the study due to toxicity, will be provided the option to enroll into a separate Long 
Term Extension (LTE) study (GS-US-417-0304).
1.3.
Sample Size and Power
Sample size is determined based on the superiority test of filgotinib compared to placebo on the 
change from Baseline in HAQ-DI at Week 12. When assuming a difference of 0.25 between the 
two groups and a common standard deviation of 0.645, 141 subjects in each of the filgotinib 
groups and placebo control group are required to obtain 90% power at a 2-sided 0.05-level. 
A sample size of 141 subjects in each of the filgotinib groups and placebo control group will also 
provide over 90% power to detect an increase in ACR20 response rate of 25% to 45% between 
the placebo control group and the filgotinib groups respectively, using a 2-sided 0.05-level test.
In summary, the total planned sample size will be 423 (141 per group).


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Data Monitoring Committee Analyses
An external multidisciplinary Data Monitoring Committee (DMC) will review the progress of 
the study and perform interim reviews of safety data in order to protect subject welfare and 
preserve study integrity. To ensure the best interests of the participants, the DMC will 
recommend to the sponsor if the nature, frequency, and severity of adverse effects associated 
with the study treatment warrant the early termination of the study, the continuation of the study, 
or the continuation of the study with modifications.
The initial review was conducted after approximately 100 subjects completed at least 12 weeks 
of dosing in any one of the three RA phase 3 studies (GS-US-417-0301, GS-US-417-0302, and 
GS-US-417-0303). Regular DMC review of safety data will be scheduled approximately every 
6 months following the initial data review meeting including all 3 RA phase 3 studies and a long-
term extension study (GS-US-417-0304).
The DMC’s role and responsibilities and the scope of analysis to be provided to the DMC are 
provided in a mutually agreed upon charter, which defines the DMC membership, meeting 
logistics, and meeting frequency.
2.2.
Final Analysis
After all subjects have completed the study, outstanding data queries have been resolved or 
adjudicated as unresolvable, and the data have been cleaned and finalized, the study blind will be 
broken and the final analysis of the data will be performed.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, 
the number and percentage of subjects in each category will be presented; for continuous 
variables, the number of subjects (n), mean, standard deviation (SD) or standard error (SE), 
median, first quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
All statistical tests will be 2-sided and performed at the 5% significance level unless otherwise 
specified.
By-subject listings will be presented for all subjects in the All Randomized Analysis Set and 
sorted by subject identification (ID) number, visit date, and time (if applicable). Data collected 
on log forms, such as AEs, will be presented in chronological order within the subject. The 
treatment group to which subjects were randomized will be included in the listings, as well as 
age, sex at birth, race, and ethnicity.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The analysis set will be identified and included as a subtitle of each 
TFL.
For each analysis set, the number and percentage of subjects eligible for inclusion, as well as the 
number and percentage of subjects who were excluded and the reasons for their exclusion, 
will be summarized by treatment group.
A listing of reasons for exclusion from analysis sets will be provided by subject.
3.1.1.
All Randomized Analysis Set
All Randomized Analysis Set includes all subjects who are randomized in the study. This is the 
primary analysis set for by-subject listings.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all randomized subjects who received at least 1 dose of 
study drug. The study drugs in this study are filgotinib 200 mg, filgotinib 100 mg and PTMs. 
This is the primary analysis set for efficacy analyses.
3.1.3.
Per-Protocol Analysis Set
The Per-Protocol (PP) Analysis Set includes subjects in the FAS who did not have major 
protocol deviations occurring prior to or at Week 12 which will affect the efficacy analysis, and 
were compliant (with on-treatment adherence ≥ 80% in the first 12-week period) to study 
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Major protocol deviations include the following:

Violated at least one of the following key eligibility criteria
1) Have a diagnosis of RA (2010 ACR/EULAR criteria for RA), and are ACR functional 
class I-III
2) Have ≥ 6 swollen joints (from swollen joint count based on 66 joints [SJC66]) and 
≥6 tender joints (from tender joint count based on 68 joints [TJC68]) at both screening 
and Day 1 (need not be the same joints)
3) Have serum CRP ≥ 4 mg/L
4) Ongoing treatment with a stable prescription of 1 or 2 permitted csDMARD(s) as 
described per protocol. 
5) Have received at least one bDMARD for the treatment of RA to which they have had an 
inadequate response or intolerance as defined by the protocol
6) Did not receive protocol prohibited medications

Received prohibited concomitant medications

Background medications were changed in violation of protocol

Improper study medication administration and unintended medication overdose

Data were questionable because of significant site quality or compliance issues
Qualifications and identification of the specific major protocol deviations that result in exclusion 
from the PP Analysis Set will be determined while the study remains blinded, prior to database 
finalization.
The PP Analysis Set is the secondary analysis set for efficacy analyses. Statistical analyses using 
PP Analysis Set are specified in Section 6.
3.1.4.
Safety Analysis Set
The Safety Analysis Set includes all subjects who received at least 1 dose of study drug. This is 
the primary analysis set for safety analyses.
3.1.5.
Pharmacokinetic Analysis Set
The Pharmacokinetic (PK) Analysis Set includes all subjects in the Safety Analysis Set who have 
at least 1 nonmissing plasma concentration data for filgotinib and/or its metabolite GS-829845. 
This is the primary analysis set for general PK analyses.


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3.1.6.
Pharmacokinetic Substudy Analysis Set
 
 
3.2.
Subject Grouping
For analyses based on the All Randomized Analysis Set and FAS, subjects will be grouped 
according to the treatment to which they were randomized. For analyses based on the Safety 
Analysis Set and PP Analysis Set, subjects will be grouped according to actual treatment 
received. The actual treatment received will differ from the randomized treatment only when 
their actual treatment differs from randomized treatment for the entire treatment duration. 
For the PK Analysis Set, subjects will be grouped according to the actual treatment they 
received.
3.3.
Strata and Covariates
Subjects will be randomly assigned to treatment groups via the interactive web response system 
(IWRS) in a 1:1:1 ratio using a stratified randomization schedule. Stratification will be based on 
the following variables:

Geographic region (Group A includes the following countries: Australia, Belgium, France, 
Germany, Israel, Italy, Netherlands, South Korea, Spain, Switzerland, United Kingdom, and 
USA; Group B includes the following countries: Hungary, Czech Republic and Poland; 
Group C includes the following countries: Argentina, Puerto Rico and Mexico; Group E:
Japan; Group D: China, originally planned but no subjects screened or enrolled from this 
country)

Prior exposure to number of bDMARDs (< 3 or ≥ 3 bDMARDs))

Presence of RF or anti-CCP Ab (Yes or No) (Presence of RF = No if RF < 15 IU/mL; 
Presence of anti-CCP Ab = No if anti-CCP Quant < 17 U/mL)
If there are discrepancies in stratification factor values between the IWRS and the clinical 
database, the values recorded in the clinical database will be used for analyses. 
For efficacy endpoints, stratification factors and the baseline value of the efficacy variable(s) will 
be included as covariates in the efficacy analysis model, as specified in Section 6.
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3.4.
Examination of Subject Subgroups
The primary and key secondary efficacy endpoints will be examined using the following 
subgroups (but not limited to the ones listed below):

Age (on the first dosing date of any study drug, < 65 or ≥ 65)

Sex at birth (male or female)

Race

Baseline weight (< 60 kg, ≥ 60 to < 100 kg, ≥ 100 kg)

Geographic region (A, B, C, or E)

Presence of RF or anti-CCP Ab (Yes or No)

Duration of RA diagnosis on the first dosing date of study drug (< 5 years, ≥5 to < 10 years, 
≥ 10 years)

Number of prior bDMARDs exposure (< 3 or ≥ 3)

Number of prior bDMARDs exposure (≤ 1 or > 1)

Disease activity at Baseline (DAS28(CRP) ≤ 5.1 or DAS28(CRP) > 5.1)

Concurrent use of MTX on the first dosing date of study drug (Yes or No) 

Number of concurrent csDMARDs use on the first dosing date of study drug (0-1 or ≥ 2)

Concurrent use of oral corticosteroids on the first dosing date of study drug (Yes or No)

High-Sensitivity C-reactive Protein (hsCRP) at Baseline (≥ 4 mg/L or < 4 mg/L) 
Lists of csDMARDs, bDMARDs, and oral corticosteroids are provided in Appendix 1.
3.5.
Multiple Comparisons
The primary endpoint for the study is the proportion of subjects who achieve ACR20 response at 
Week 12. The primary analyses will consist of a superiority test of filgotinib 200 mg compared 
to placebo based on the ACR20 response rate at Week 12. 
The following hypothesis testing for secondary analyses 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:


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1) Superiority of filgotinib 100 mg compared to placebo based on ACR20 response rate at 
Week 12.
2) Superiority of filgotinib 200 mg compared to placebo based on the change from Baseline in 
HAQ-DI at Week 12.
3) Superiority of filgotinib 100 mg compared to placebo based on the change from Baseline in 
HAQ-DI at Week 12.
4) Superiority of filgotinib 200 mg compared to placebo based on the proportion of subjects 
with DAS28(CRP) ≤ 3.2 at Week 12.
5) Superiority of filgotinib 100 mg compared to placebo based on proportion of subjects with 
DAS28(CRP) ≤ 3.2 at Week 12.
6) Superiority of filgotinib 200 mg compared to placebo based on the change from Baseline in 
SF-36 PCS at Week 12.
7) Superiority of filgotinib 100 mg compared to placebo based on the change from Baseline in 
SF-36 PCS at Week 12.
8) Superiority of filgotinib 200 mg compared to placebo based on the proportion of subjects 
with DAS28(CRP) < 2.6 at Week 24.
9) Superiority of filgotinib 100 mg compared to placebo based on the proportion of subjects 
with DAS28(CRP) < 2.6 at Week 24.
10) Superiority of filgotinib 200 mg compared to placebo based on the change from Baseline in 
FACIT-Fatigue at Week 12.
11) Superiority of filgotinib 100 mg compared to placebo based on the change from Baseline in 
FACIT-Fatigue at Week 12.
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.
For missing last dosing date of study drug, imputation rules are described in Section 4.2.1. For 
partial date of initial RA diagnosis, imputation rules are described in Section 5.2. The handling 
of missing or incomplete dates for AE onset is described in Section 7.1.5.2, and for prior and 
concomitant medications in Section 7.4. Imputation rules adopted in the efficacy analyses are 
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3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analyses.
3.7.
Data Handling Conventions and Transformations
In general, age (in years) on the date of the first dose of study drug will be used for analyses and 
presentation in listings. If an enrolled subject was not dosed with any study drug, the 
randomization date will be used instead of the first dosing date of study drug. For screen failures, 
the date the last informed consent was signed will be used for age calculation. If only birth year 
is collected on the CRF, “01 July” will be used for the unknown birth day and month for the 
purpose of age calculation. If only birth year and month are collected, “01” will be used for the 
unknown birth day.
Non-PK Data that are continuous in nature but are less than the lower limit of quantitation 
(LOQ) or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used to calculate descriptive statistics if the
datum is reported in the form of “x” (where x is considered the LOQ). For example, if the 
values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to 
calculate summary statistics. An exception to this rule is any value reported as < 1 or < 0.1, 
etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used for 
calculate summary statistics.

A value that is 1 unit above the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “> x” (where x is considered the LOQ). Values with decimal 
points will follow the same logic as above.

The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of 
“≤ x” or “≥ x” (where x is considered the LOQ).
Natural logarithm transformation will be used for plasma/blood concentrations and analysis of 
PK parameters. Plasma concentration values that are below the limit of quantitation (BLQ) will 
be presented as “BLQ” in the concentration data listing. Values that are BLQ will be treated as 
0 at predose time points, and one-half the value of the LOQ at postbaseline time points.
The following conventions will be used for the presentation of summary and order statistics: 

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as “BLQ.”

If more than 25% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ.”

If more than 50% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ.”


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
If more than 75% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.”

If all subjects have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”
PK parameters that are BLQ will be imputed as one-half LOQ before log transformation or 
statistical model fitting.
3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
The first dose date of individual study drug will be calculated separately for each study drug 
(ie, filgotinib 200 mg, filgotinib 100 mg and PTMs) in a treatment group. Study Day 1 is defined 
as the first dose date of any study drug, which is the minimum of the first dose dates of 
individual study drugs in a treatment group.
The last dose date of individual study drug will be calculated separately for each study drug in a 
treatment group. The last dose date for an individual study drug will be the end date on study 
drug administration CRF for the record where the “study drug was permanently withdrawn” flag 
is “Yes”. The last dose date of any study drug will be defined as the maximum of the last dose 
dates of individual study drugs in a treatment group.
Study Day will be calculated from the Study Day 1 and derived as follows:

For postdose study days: Assessment Date – Study Day 1 + 1

For days prior to the first dose: Assessment Date – Study Day 1
3.8.2.
Analysis Visit Windows
Subject visits may not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows.
In general, the baseline value will be the last nonmissing value on or prior to the first dose date 
of study drug.
For efficacy endpoints, vital signs, ECGs, weight, lipids and safety laboratory data, the analysis 
visit windows will be applied to data collected during the ‘on-treatment’ period. The 
‘on-treatment’ period is defined as the last dose date of any study drug + 5 days. 
The analysis windows for on-treatment efficacy endpoints including joint count assessment, 
HAQ-DI (including subject’s pain assessment), subject’s global assessment (SGA), physician’s 
global assessment (PGA), serum CRP, 
 and vital 
signs, weight, and safety laboratory data (lipid data excluded) are provided in Table 3-1. 
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Table 3-1.
Analysis Visit Windows for On-Treatment Joint Count Assessment, 
HAQ-DI, SGA, PGA, CRP, 
 and Vital Signs, 
Weight, and Safety Laboratory Data (Lipid Data Excluded)
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 2
15
2
22
Week 4
29
23
43
Week 8
57
44
71
Week 12
85
72
92
Week 14
99
93
106
Week 16
113
107
127
Week 20
141
128
155
Week 24
169
156
≥ 169
The analysis windows for on-treatment lipid and electrocardiogram (ECG) data are provided in 
Table 3-2. 
Table 3-2.
Analysis Visit Windows for On-Treatment Lipid and ECG Data
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 12
85
2
127
Week 24
169
128
≥ 169
The analysis windows for on-treatment SF-36, FACIT-Fatigue, EQ-5D and WPAI-RA are 
provided in Table 3-3. The analysis windows for on-treatment Healthcare Resource Utilization 
Questionnaire (HRUQ) and Treatment Satisfaction Questionnaire for Medication (TSQM) are 
provided in Table 3-4. 
Table 3-3.
Analysis Visit Windows for On-Treatment SF-36, FACIT-Fatigue, 
EQ-5D, and WPAI-RA
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 4
29
2
57
Week 12
85
58
127
Week 24
169
128
≥ 169
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Table 3-4.
Analysis Visit Windows for On-Treatment HRUQ and TSQM
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 12
85
2
127
Week 24
169
128
≥ 169
Vital signs, weight, ECGs, lipids and safety laboratory data collected in the post-treatment 
follow-up period will also be summarized. The analysis window for the post-treatment follow-up 
period is defined as from (the last dose date of any study drug + 6 days) to (the last dose date of 
any study drug + 30 days). If multiple valid, nonmissing measurements exist in the 
post-treatment follow-up visit window, then the latest record will be selected for analysis. If the 
chronological order cannot be determined (eg, more than 1 record on the same day with time 
missing), for any given subject, the value with the worst severity will be selected for categorical 
variable, and the average will be taken for continuous variable. Data obtained after last dose date 
plus 30 days will be excluded from the summaries, but will be included in the listings.
For efficacy endpoints, the same analysis visit windows will be applied to all available data 
collected during standard of care. 
3.8.3.
Selection of Non-Efficacy Data in the Event of Multiple Records in an 
Analysis Visit Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window.
If multiple valid, nonmissing, continuous measurements exist in an analysis window, 
records will be chosen based on the following rules if a single value is needed:

In general, the baseline value will be the last nonmissing value on or prior to the first dose 
date of study drug, unless otherwise specified. If multiple measurements occur on the same 
day, the last nonmissing value prior to the time of first dose of study drug will be considered 
as the baseline value. If these multiple measurements occur at the same time or the time is 
not available, the average of these measurements (for continuous data) will be considered the 
baseline value.

For postbaseline visits:
The record closest to the nominal day for that visit will be selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken, 
unless otherwise specified.


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If multiple valid, nonmissing, categorical measurements exist in an analysis window, records 
will be chosen based on the following rules if a single value is needed:

For baseline, the last available record on or prior to the date of the first dose of study drug 
will be selected. If there are multiple records with the same time or no time recorded on the 
same day, the value with the lowest severity will be selected (eg, normal will be selected over 
abnormal for safety ECG findings).

For postbaseline visits:
The record closest to the nominal day for that visit will be selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the value with the worst severity will 
be selected (eg, abnormal will be selected over normal for safety ECG findings), unless 
otherwise specified.
The rules for selecting efficacy data in the event of multiple records in an analysis visit window 
are specified in Section 6.1.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided by treatment group for each country within 
each geographic region and investigator within a country. The summary will present the number 
and percentage of subjects enrolled. For each column, the denominator for the percentage 
calculation will be the total number of subjects analyzed for that column.
A similar enrollment table will be provided by stratification factor stratum. The denominator for 
the percentage of subjects in the stratum will be the total number of enrolled subjects. If there are 
discrepancies in the value used for stratification assignment between the IWRS and the clinical 
database, the value collected in the clinical database will be used for the summary. A listing of 
subjects with discrepancies in the value used for stratification assignment between the IWRS and 
the clinical database at the time of data finalization will be provided.
The randomization schedule used for the study will be provided in a listing and as an appendix to 
the CSR.
A summary of subject disposition will be provided by treatment group. This summary will 
present the number of subjects screened, the number of subjects not randomized, the number of 
subjects who met all eligibility criteria but were not randomized with reasons subjects were not 
randomized, the number of subjects randomized, and the number of subjects in each of the 
categories listed below:

Safety Analysis Set

Full Analysis Set

Per-Protocol Analysis Set

PK Analysis Set

Completed study drug 

Did not complete study drug with reasons for premature discontinuation of study drug

Completed study 

Did not complete study with reasons for premature discontinuation from the study
For the status of study drug and study completion, and reasons for premature discontinuation, the 
number and percentage of subjects in each category will be provided. The denominator for the 
percentage calculation will be the total number of subjects in the Safety Analysis Set 
corresponding to that column. 
PPD


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The following by-subject listings will be provided by subject ID number in ascending order to 
support the above summary tables:

Reasons for premature study drug or study discontinuation

Reasons for screen failure (will be provided by screening ID number in ascending order)

Lot number and kit ID of assigned study drugs
4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug and the level of adherence to the study drug specified in the protocol.
4.2.1.
Duration of Exposure to Study Drug
Total duration of exposure to any study drug will be defined as (last dose date of any study drug -
first dose date of any study drug + 1), regardless of any temporary interruptions in study drug 
administration and will be expressed in weeks using up to 1 decimal place (eg, 4.5 weeks). 
Total duration of exposure to individual study drug will be defined as (last dose date of 
individual study drug – first dose date of individual study drug + 1), regardless of any temporary 
interruptions in study drug administration and will be expressed in weeks using up to 1 decimal 
place.
For subjects with a partial last dosing date (ie, month and year of last dose are known), the latest 
of the dispensing dates of study drug bottles, study drug start dates and end dates, and the 
imputed last dose date [day imputed as 15] will be used as the final imputed last dose date. If the 
subject died and the death date is complete (ie, not partial date) and before the imputed last dose 
date, the complete death date will be used as the imputed last dose date.
If only year is recorded (ie, month and day of last dose are missing), the latest of the dispensing 
month of study drug bottles, study drug start month, and study drug end month will be used to 
impute the unknown last dose month. If the subject died and the death date has month and year 
available and before the imputed last dose month, then the month of death will be used instead. 
With the month imputed, the aforementioned method will be used to impute the last dose date.
The total duration of exposure to any study drug and total duration of exposure to each individual 
study drug will be summarized using descriptive statistics and using the number (ie, cumulative 
counts) and percentage of subjects exposed through the following time periods: Baseline 
(Day 1), Week 2 (Day 15), Week 4 (Day 29), Week 8 (Day 57), Week 12 (Day 85), Week 14 
(Day 99), Week 16 (Day 113), Week 20 (Day 141), Week 24 (Day 169). 
Summaries will be provided by treatment group for the Safety Analysis Set. No formal statistical 
testing is planned.


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4.2.2.
Adherence to Study Drug
Adherence will be calculated separately for filgotinib 200 mg/PTM (tablets) and filgotinib 
100 mg/PTM (tablets).
The total number of tablets administered will be summarized using descriptive statistics. 
The presumed total number of tablets administered to a subject will be determined by the data 
collected on the drug accountability CRF using the following formula:
Total Number of Tablets Administered = 
(Σ No. of Tablets Dispensed) - (Σ No. of Tablets Returned)
If a bottle is dispensed and the bottle is returned empty, then the number of tablets returned will 
be entered as zero. If a bottle is dispensed but not returned (missing), then the number of tablets 
returned will be entered as zero.
4.2.2.1.
On-Treatment Adherence
The level of on-treatment adherence to the study drug will be determined by the total amount of 
study drug administered relative to the total amount of study drug expected to be administered 
during a subject’s actual on-treatment period based on the study drug regimen.
The level of on-treatment adherence will be expressed as a percentage using the following 
formula:
Total Amount of Study Drug Administered
On-Treatment Adherence (%) = 
 x 100
Study Drug Expected to be Administered on Treatment






Note: If calculated adherence is greater than 100%, the result will be set to 100%.
Study drug expected to be administered for filgotinib 200 mg/PTM (tablets) = 1× total duration 
of exposure to any study drug (days).
Study drug expected to be administered for filgotinib 100 mg/PTM (tablets) = 1× total duration 
of exposure to any study drug (days).
Descriptive statistics for the level of on-treatment adherence with the number and percentage of 
subjects belonging to adherence categories (eg, < 80%, ≥ 80% to < 90%, ≥ 90%) will be 
provided by treatment group for the Safety Analysis Set. 
No formal statistical testing is planned.


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A by-subject listing of study drug administration and drug accountability will be provided 
separately by subject ID number (in ascending order) and visit (in chronological order).
4.3.
Protocol Deviations
Subjects who did not meet the eligibility criteria for study entry, but enrolled in the study will be 
summarized regardless of whether they were exempted by the sponsor or not. The summary will 
present the number and percentage of subjects who did not meet at least 1 eligibility criterion and 
the number of subjects who did not meet specific criteria by treatment group based on the All 
Randomized Analysis Set. A by-subject listing will be provided for those subjects who did not 
meet at least 1 eligibility (inclusion or exclusion) criterion. The listing will present the eligibility 
criterion (or criteria if more than 1 deviation) that subjects did not meet and related comments, if 
collected.
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. The number and percentage of subjects with important protocol deviations by 
deviation reason (eg, nonadherence to study drug, violation of select inclusion/exclusion criteria) 
will be summarized by treatment group for the All Randomized Analysis Set. A by-subject 
listing will be provided for those subjects with important protocol deviation.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Other Baseline Characteristics
Subject demographic variables will be summarized by treatment group and overall using 
descriptive statistics for continuous variables, and using number and percentage of subjects for 
categorical variables. The summary of demographic data will be provided for the Safety Analysis 
Set for the following:

Age (on the first dose date of any study drug) 

Age group (< 65 years, ≥ 65 years)

Sex at birth (male, female)

Race 

Ethnicity (Hispanic or Latino, not Hispanic or Latino)

Geographic region and country

Weight

Height

Body mass index (BMI; in kg/m2)

Smoking status
A by-subject demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order.
5.2.
Baseline Disease Characteristics
Baseline disease characteristics include:

Duration of RA from diagnosis (years)
Calculated as ((first dose date) – (date of initial diagnosis) + 1 day) / 365.25. If the date of 
initial diagnosis is incomplete, then the following rules will be applied: 
missing day: use the first of the month
missing month: use January

Presence of RF (Yes/No)


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
Presence of anti-CCP Ab (Yes/No)

Presence of both RF and anti-CCP Ab (Yes/No)

Number of prior bDMARDs exposure: n (%) 
< 3 
≥ 3 

Number of prior bDMARDs exposure: n (%)
1
2
3
4
≥ 5

Prior exposure to TNF bDMARDs (Yes/No): n (%)
Etanercept: n (%)
Adalimumab: n (%)
Infliximab: n (%)
Golimumab: n (%)
Certolizumab: n (%)

Prior exposure to non-TNF bDMARDs (Yes/No): n (%)
Abatacept: n (%)
Tocilizumab: n (%)
Rituximab: n (%)
Anakinra: n (%)

Concurrent oral corticosteroids use on the first dosing date (Yes/No): n (%)
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
Concurrent MTX use on the first dosing date (Yes/No): n (%)
MTX dose, mg/week, mean (SD)

Number of concurrent csDMARDs use on the first dosing date: n (%)
1
2
≥ 3

Swollen joint count based on 66 joints (SJC66) 

Tender joint count based on 68 joints (TJC68)

Swollen joint count based on 28 joints (SJC28) 

Tender joint count based on 28 joints (TJC28)

HAQ-DI total score

DAS28(CRP)

SF-36 PCS score

SF-36 MCS score

FACIT-Fatigue

Subject’s pain assessment (by visual analog scale [VAS] in mm)

Subject’s global assessment of disease activity [SGA] (by VAS in mm)

Physician’s global assessment of disease activity [PGA] (by VAS in mm)

Simplified Disease Activity Index (SDAI) 

Clinical Disease Activity Index (CDAI)

hsCRP (mg/L)
These baseline characteristics will be summarized by treatment group and overall using 
descriptive statistics for continuous variables and using number and percentage of subjects for 
categorical variables. The summary of baseline characteristics will be provided for the Safety 
Analysis Set. 


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A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.
5.3.
Medical History
Medical history collected at screening will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) 21.0. 
Medical history will be summarized by system organ class (SOC), preferred term (PT), treatment 
group, and overall. Subjects who report 2 or more medical history items that are coded to the 
same SOC and/or PT will be counted only once by the unique coded term in the summary. 
In addition, numbers and percentages of subjects who have any first degree relatives that had 
experienced myocardial infarction or stroke before the age of 50 years, experienced myocardial 
infarction or stroke before the age of 50 years, or have diabetes (type I or II) will be summarized. 
The summary will be provided for the Safety Analysis Set. No formal statistical testing is 
planned.
A by-subject listing of medical history will be provided by subject ID number. 


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6.
EFFICACY ANALYSES
6.1.
General Considerations
The primary analysis set for efficacy analyses will be the FAS, defined in Section 3.1.2.
Efficacy analysis will generally be conducted on the following 2 datasets:
1) On-treatment data as specified in Section 3.8.2 with exclusion of the observations described 
as the following. This is the primary analysis dataset for efficacy analysis. 
For subjects who continued study drug BUT did not achieve at least 20% improvement from 
Baseline in both SJC66 and TJC68 at
Nominal Week 14 visit, then efficacy data collected after nominal Week 14 visit will be 
excluded from the primary analysis, OR
Nominal Week 12 visit if subjects missed Week 14 visit or the response status cannot be 
determined due to missing SJC66 or TJC68 value at Week 14, then efficacy data 
collected after nominal Week 16 visit will be excluded from the primary analysis, OR 
Nominal Week 16 visit if subjects missed both Week 12 and Week 14 visits or the 
response status cannot be determined due to missing SJC66 or TJC68 value at both 
Week 12 and Week 14 visits, then efficacy data collected after nominal Week 16 visit 
will be excluded from the primary analysis
If subjects missed all three visits (Week 12, Week 14 and Week 16) or the response status 
cannot be determined at all of these three visits, all the efficacy data collected will be 
included for analysis. 
2) All available data (including data collected under standard of care).
Selection of Efficacy Data in the Event of Multiple Records in an Analysis Visit Window
If multiple valid, nonmissing efficacy measurements exist in an analysis window, records will be 
chosen based on the following rules if a single value is needed:

The record closest to the nominal day for that visit will be selected

If there are 2 records that are equidistant from the nominal day, or more than 1 record (with 
time known) on the selected day, the latest record will be taken

If chronological order cannot be determined (eg, more than 1 record on the same day with 
time missing), for any given subject, the worst outcome will be selected.
Calculation of Composite Endpoints
For the calculation of composite endpoints including DAS28(CRP), ACR20/50/70, ACR-N, 
SDAI, and CDAI, we use the following steps unless otherwise specified:


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
Step 1: Assign individual components to analysis visit windows defined in Section 3.8.2

Step 2: Within each analysis visit window, select the component-level data based on the rules 
for selecting efficacy data as above

Step 3: Calculate the composite endpoint based on the selected component-level data in Step 2.
Missing Data Imputation
Below are the descriptions for the imputation methods that will be used throughout the efficacy 
analyses:

Observed case (OC): Missing values remain missing. For the categorical composite 
endpoints, in the case that some components are missing, the composite endpoint assessment 
will be derived based on the non-missing components. If non-missing components are not 
sufficient to determine final composite endpoint, then the composite endpoint will be set as 
missing. For continuous composite endpoints (including ACR-N), if any components are 
missing, the composite endpoints will be set as missing.

Last observation carried forward (LOCF): Baseline measurements will not be carried forward 
to postbaseline. Only postbaseline measurements will be LOCF. For the composite 
endpoints, the last nonmissing postbaseline observation will be carried forward to subsequent 
visits for each individual component first, and then calculate the composite endpoints using 
individual components imputed by LOCF as described above. If a subject does not have a 
nonmissing observed record for a postbaseline visit, the last postbaseline record prior to the 
missed visit will be used for this postbaseline visit. If the last nonmissing observation prior to 
the missing visits cannot be determined due to multiple measurements occurring at the same 
time or the time not available within the same day, the worst outcome will be used for LOCF. 
If missing components still exist after LOCF, the composite endpoints will be calculated 
using the same rules as described in OC.

Non-responder imputation (NRI): For all binary response measurements, starting from OC, 
all missings will be set as non-responders.
If subject only had baseline measurements, LOCF and OC analyses will not include this subject. 
But this subject will be treated as non-responder in NRI analyses.
6.1.1.
Tender/Swollen Joint Counts (TJC/SJC)
Tender joint count based on 68 joints (TJC68) and swollen joint count based on 66 joints 
(SJC66) will be collected during the course of the study. The assessment for each joint will be 
from the following selections: Tender Only, Swollen Only, Tender and Swollen, Joint 
Non-Evaluable or Missing, or Not Tender or Swollen.
Individual joint with missing assessment will not be imputed. If at least half of the joints are 
assessed at a given visit, the prorated tender and swollen joint counts will be calculated using the 
following formula: 


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68 =

  
  

68 −( 
 
 
  
 
 
 68 
) × 68
 66 =

  
 !
 

66 −( 
 
 
  
 
 
 66 
) × 66
If less than half of joints are assessed at a given visit, joint counts are treated as missing for that 
visit.
A more abbreviated assessment considering 28 joints as listed in Table 6-1 for both tenderness 
and swelling will also be conducted (as part of the TJC68 and SJC66 assessment), denoted as 
TJC28 and SJC28, respectively.
Table 6-1.
Composition of the 28 Joints
Joints 
Number
Shoulder Joints (Left and Right)
2
Elbow Joints (Left and Right)
2
Wrist Joints (Left and Right)
2
Metacarpophalangeal Joints I-V (Left and Right) – hands only
10
Proximal Interphalangeal Joints I-V (Left and Right) – hands only
10
Knee Joints (Left and Right)
2
If there exist non-evaluable or missing joints among the 28 joints, similar prorated tender and 
swollen joint counts will be calculated as follows:
28 =

  
  

28 −( 
 
 
  
 
 
 28 
) × 28
 28 =

  
 !
 

28 −( 
 
 
  
 
 
 28 
) × 28
If less than half of the 28 joints are assessed at a given visit, TJC28 and SJC28 are treated as 
missing for that visit.
6.1.2.
Global Assessment of Disease Activity
Subject’s Global Assessment of Disease Activity (SGA) and Physician’s Global Assessment of 
Disease Activity (PGA) based on a 0-100 visual analog scale (VAS) will be recorded during the 
study, with 0 indicating “no disease activity” and 100 indicating “maximum disease activity” 
(or similar description of disease severity). 


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6.1.3.
Health Assessment Questionnaire Disability Index (HAQ-DI)
The HAQ-DI score is defined as the average of the scores of eight functional categories (dressing 
and grooming, arising, eating, walking, hygiene, reach, grip, and other activities), administered 
by the patient. Responses in each functional category are collected as: without any difficulty; 
with some difficulty; with much difficulty; unable to do a task in that area and with or without 
aids or devices. The HAQ-DI score ranges from 0 (no disability) to 3 (completely disabled), 
when 6 or more categories are non-missing. Detailed algorithm for calculating HAQ-DI score is 
described in Appendix 2.
HAQ-DI also includes a separate pain assessment and subject will be requested to mark the 
severity of the pain in the past week on a 0-100 VAS, with 0 indicating “no pain” and 
100 indicating “severe pain”.
6.2.
Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of subjects who achieve ACR20 response at 
Week 12.
6.2.1.
Definition of the Primary Efficacy Endpoint
A subject achieves ACR20 response when this subject has

≥ 20% improvement from baseline in TJC68, AND

≥20% improvement from baseline in SJC66, AND

≥ 20% improvement from baseline in at least 3 of the following 5 items:
1) PGA
2) SGA
3) Subject’s pain assessment
4) HAQ-DI score
5) hsCRP
Percent improvement from baseline at a postbaseline visit is calculated as follows for all 
7 components mentioned above:
% improvement = baseline value - postbaseline value
baseline value
× 100
If the baseline value is 0 then the percent improvement from baseline is set to missing. 


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In the case that some ACR20 individual components are missing other than TJC68 or SJC66, the 
ACR20 assessment will be based on the non-missing components. If non-missing components 
are not sufficient to determine ACR20 response, then the ACR20 response will be considered as 
missing.
6.2.2.
Statistical Hypothesis for the Primary Efficacy Endpoint
In the primary analysis, the ACR20 response rate at Week 12 in the filgotinib 200 mg group will 
be compared to placebo control group for a superiority test at the 2-sided 0.05-level. If we denote 
the ACR20 response rate at Week 12 in the filgotinib 200 mg group and placebo control group as 
P1 and P2, respectively, the null and alternative hypotheses for the superiority test on the primary 
efficacy endpoint are as follows:
H0: P1 = P2;
vs
H1: P1 ≠ P2.
6.2.3.
Primary Analysis of the Primary Efficacy Endpoint
To test for superiority of filgotinib 200 mg group versus placebo control group in proportion of 
subjects who achieve ACR20 at Week 12, a logistic regression analysis with treatment groups 
and stratification factors in the model will be used. Subjects who do not have sufficient 
measurements to establish efficacy at Week 12 will be considered as failures (ie, NRI). The 
p-value from the logistic regression model for testing the superiority of filgotinib 200 mg as 
compared to placebo will be provided. The 2-sided 95% confidence interval (CI) of the ACR20 
response rate at Week 12 based on normal approximation will be provided for each treatment 
group. In addition, non-stratified ACR20 response rate difference along with its 95% CI 
calculated based on the normal approximation method will be provided.
The comparisons of filgotinib 100 mg groups versus placebo group in proportion of subjects 
achieving ACR20 at Week 12 will also be conducted with the similar logistic regression model 
with NRI.
The number and percentage of ACR20 non-responders observed and non-responders due to 
missing at Week 12 will also be summarized respectively by treatment.
For subjects with observed ACR20 outcomes (ie, responders and observed non-responders) at 
Week 12, actual values and change from Baseline at Week 12 in individual components, 
including TJC68, SJC66, SGA, PGA, Subject’s pain assessment, hsCRP, will be summarized 
using descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) 
by treatment.
The proportions of subjects achieving ACR20 (using NRI) will be plotted over time from 
Baseline through Week 24 by treatment and by visit. 


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6.2.4.
Sensitivity Analysis of the Primary Endpoint
Sensitivity analyses of the primary efficacy endpoint will be performed.
6.2.4.1.
Per-Protocol Analysis
To evaluate the impact of study conduct on the primary analysis, the proportion of subjects who 
achieve ACR20 at Week 12 will be analyzed based on the PP Analysis Set as defined in 
Section 3.1.3 using the logistic regression analysis with NRI for the comparisons of each 
filgotinib group versus the placebo group. The p-value from the logistic regression model will be 
provided. The non-stratified ACR20 response rate difference along with its 95% CI calculated 
based on the normal approximation method will also be provided.
6.2.4.2.
Missing Data Imputation Analyses
To evaluate the impact of missing data on the ACR20 response rate at Week 12, the following 
missing value imputation methods will be used:

The analysis specified in Section 6.2.3 will be performed by using OC and LOCF methods as 
described in Section 6.1.

Multiple Imputation: The MI procedure replaces each missing binary ACR20 value with a set 
of plausible values that represent the uncertainty about the right value to impute. Fifty
imputed datasets will be generated based on logistic regression models. These multiple 
imputed data sets are then analyzed by using the same method for the primary analysis for 
complete data as specified in Section 6.2.3. The results from each set of imputed data sets 
will then be combined using Rubin’s rule {Rubin 1987}. The stratification factors will be 
included in the imputation model as covariates, and all available data at post-baseline visits 
up to the time point of interest will be included in the longitudinal model.

Tipping point analysis: To assess the robustness of analysis results under MNAR (missing 
not at random) assumption, a delta-adjusting pattern-mixture approach for tipping point 
analysis {Ratitch 2013} will be conducted for the primary efficacy endpoint. The impact 
from missing data on the comparisons in proportion of subjects achieving ACR20 at 
Week 12 between filgotinib groups and placebo control group will be examined, by adjusting 
for stratification factors. Specifically, the proposed method will perform a series of analyses 
with a range of different values of the shift parameter δ applied to the imputed datasets at 
which the conclusion about the statistical significance of the estimated treatment effect will 
be altered. Each δ value is classified as either ‘altering the study’s conclusion’ or tips, 
‘keeping the study’s conclusion unchanged’. The tipping points that alter the statistical 
conclusion will be provided. For each δ value, multiple imputed data sets will be generated. 
The same analysis method for the primary analysis as specified in Section 6.2.3 will be 
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6.2.5.
Subgroup Analysis of the Primary Endpoint
Subgroup analyses comparing each filgotinib dose group to the placebo group will be performed 
for the primary endpoint, for the subgroups specified in Section 3.4. 
The proportion of subjects who achieve ACR20 will be analyzed using the Fisher’s exact test 
based on the NRI method for treatment group comparison. The number and percentage of 
subjects with ACR20 will also be provided for each treatment group within the subgroups.
6.3.
Key Secondary Efficacy Endpoints
The key secondary efficacy endpoints are:

Change from Baseline in the HAQ-DI score at Week 12

The proportion of subjects who achieve DAS28(CRP) ≤ 3.2 at Week 12

Change from Baseline in SF-36 physical component score (PCS) at Week 12

The proportion of subjects who achieve DAS28(CRP) < 2.6 at Week 24

Change from Baseline in FACIT-Fatigue at Week 12
6.3.1.
Definition of Key Secondary Efficacy Endpoints
6.3.1.1.
Disease Activity Score for 28 Joint Count using CRP
The DAS28(CRP) score is calculated as follows:
DAS28(CRP) = 0.56-TJC28 + 0.28-SJC28 + 0.36 ln(CRP + 1) + 0.014 × SGA + 0.96,
where 
CRP = hsCRP measurement (mg/L)
SGA = subject’s global assessment of disease activity on a 0-100mm VAS
Higher DAS28(CRP) value indicates more severe disease activity.
No component-level imputation will be performed for the calculation of DAS28(CRP) for the 
primary analyses. If any components are missing, the DAS28(CRP) will be set as missing. 
6.3.1.2.
36-Item Short-form Health Survey
The SF-36 Version 2 is a 36-item, self-reported, generic, comprehensive, and health-related 
quality of life questionnaire that yields an 8 health domains (physical functioning, role-physical, 
bodily pain, general health, vitality, social functioning, role-emotional, and mental health). Each 
domain is scored by summing the individual items and transforming the scores into a 0 to 


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100 scale with higher scores indicting better health status or functioning. In addition, 2 summary 
scores, the physical component score (PCS) and the mental component score (MCS) will be 
evaluated based on the 8 SF-36 domains.
6.3.1.3.
FACIT-Fatigue
The FACIT-Fatigue scale is a brief, 13-item, symptom-specific questionnaire that specifically 
assesses the self-reported severity of fatigue and its impact upon daily activities and functioning 
in the past 7 days. The FACIT-Fatigue uses 0 (“not at all”) to 4 (“very much”) numeric rating 
scales. Negatively stated items are reversed by subtracting the response from “4” before being 
added to obtain a total score. Scores range from 0 to 52 with higher scores indicating less fatigue. 
In the case of missing response for some items in the questionnaire, if at least half of the items 
(ie, ≥ 7 of 13 items) were answered at a given visit, the prorated score will be calculated and 
used in the analysis.
6.3.2.
Analysis Methods for Key Secondary Efficacy Endpoints
Hypothesis testing on the key secondary efficacy endpoints will commerce after the testing on 
the primary efficacy endpoint reaches statistical significance, and will be performed according to 
the hierarchical testing principle at the 2-sided 0.05 level as described in Section 3.5. If a null 
hypothesis is not rejected, formal sequential testing will be stopped and only nominal 
significance will be reported for the remaining hypotheses. 
For proportion of subjects who achieve DAS28(CRP) ≤ 3.2 at Week 12, the similar logistic 
regression analysis with the same model specification as the primary endpoint analysis described 
in Section 6.2.3 will be adopted for the treatment comparisons. The NRI method will be used to 
impute missing values. Comparison will be made between each filgotinib dose group and 
placebo. The p-value from the logistic regression model will be reported for statistical inference. 
The 2-sided 95% CI of the response rate of DAS28(CRP) ≤ 3.2 at Week 12 based on normal 
approximation will be provided for each treatment group. In addition, non-stratified response rate 
difference along with its 95% CI calculated based on the normal approximation method will be 
provided. The proportion of subjects who achieve DAS28(CRP) < 2.6 at Week 24 will be 
analyzed similarly.
The change from Baseline in HAQ-DI at Week 12 will be analyzed using the mixed-effects 
model for repeated measures (MMRM) that include all available data at post-baseline visits. 
Subjects that have a baseline value and at least 1 postbaseline value are included in the analysis. 
The MMRM models will be used to evaluate treatment effect on change score from Baseline, 
with baseline value, stratification factors, treatment, visit, and treatment by visit interaction, 
included as fixed effects and subject being the random effect. An unstructured 
variance-covariance matrix will be used. The Kenward-Roger method will be used to estimate 
the degrees of freedom. Missing change scores due to missing study visits or early withdrawal 
will not be otherwise imputed using the MMRM approach. The least squares (LS) means along 
with 95% CIs and the p-value for the difference in mean change from Baseline in HAQ-DI at 
Week12 between each filgotinib dose group and placebo control group from MMRM will be 
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The change from Baseline in SF-36 PCS score and FACIT-Fatigue scale score at Week 12 will 
be analyzed using the similar MMRM method as change from Baseline in HAQ-DI, by including 
all available data at post-baseline visits. To test for a treatment difference between each filgotinib 
dose group and placebo, LS mean difference along with 95% CI and p-values from the MMRM 
model will be presented. 
The proportion of subjects achieving DAS28(CRP) ≤ 3.2 (using NRI) and proportion of subjects 
achieving DAS28(CRP) <2.6 (using NRI) will be plotted over time by treatment and by visit. 
Plots of mean ± SD of changes from Baseline in HAQ-DI, SF-36 PCS score and FACIT-Fatigue 
scale score over time will be presented respectively. 
6.3.3.
Sensitivity Analysis for Key Secondary Efficacy Endpoints
6.3.3.1.
Per-Protocol Analysis
The analyses for change from Baseline in HAQ-DI, SF-36 PCS and FACIT-Fatigue scale score 
at Week 12, and proportions of subjects achieving DAS28(CRP) ≤ 3.2 at Week 12 will be 
repeated using the PP Analysis Set specified in Section 3.1.3.
6.3.3.2.
Missing Data Imputation Analyses
The following imputation methods will be explored:

Proportion of subjects who achieve DAS28(CRP) ≤ 3.2 at Week 12
1) The analysis using the same logistic regression model specified above will be performed 
by using OC and LOCF methods as described in Section 6.1.
2) MI: All subjects with baseline measurement will be included. The MI procedure replaces 
each missing composite DAS28(CRP) value with a set of plausible values that represent 
the uncertainty about the right value to impute. Baseline value and stratification factors 
will be included in the imputation model as covariates, and all available data at baseline 
and post-baseline visits up to the time point of interest will be included in the longitudinal 
model. The 50 imputed datasets will be generated. These multiple imputed data sets are 
then used to identify subjects with DAS28(CRP) ≤ 3.2 at Week 12, and analyzed by 
using the analysis method specified in Section 6.3.2 for complete data. The results from 
each set of imputed data sets will then be combined using Rubin’s rule {Rubin 1987}.
3) Tipping point analysis: Similar modified tipping point method as described in 
Section 6.2.4.2 will be applied to DAS28(CRP) ≤ 3.2 response rate at Week 12.

Change from Baseline in the HAQ-DI score at Week 12
1) MI: All subjects with baseline measurement will be included. The MI procedure replaces 
each missing value with a set of plausible values that represent the uncertainty about the 
right value to impute. The multiple imputed datasets will be generated based on linear 
regression models on observed HAQ-DI scores. These multiple imputed data sets are 


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then analyzed by using the analysis method specified in Section 6.3.2 for complete data. 
The results from each set of imputed data sets will then be combined using Rubin’s rule 
{Rubin 1987}. Stratification factors and baseline values will be included in the 
imputation model as covariates, and all available data at baseline and post-baseline visits 
up to the time point of interest will be included in the longitudinal model. 
2) Tipping point analysis: All subjects with baseline measurement will be included. To 
access the robustness of analysis results for change from Baseline in HAQ-DI at Week 12 
under MNAR assumption, a set of the shift parameters that adjust the imputed values will 
be examined {Yuan 2014}. The shift parameter that alters the study conclusion for the 
hypothesis testing for change from Baseline in HAQ-DI at Week 12 under the MAR 
assumption will be reported as the tipping point and provided. The tipping point analysis 
will be conducted by iteratively assigning plausible outcomes to missing values for 
subjects in different treatment group independently until the conclusion is reversed (eg, 
analyses are no longer statistically significant). The same analysis method for the primary 
analysis as specified in Section 6.3.2 will be applied when analyzing adjusted data 
generated under each plausible shift parameter.

Change from Baseline in SF-36 physical component score (PCS) at Week 12
1) MI: Similar MI procedure used for analyzing the change from baseline in the HAQ-DI 
score at Week 12 will be performed. 
2) Tipping point analysis: Similar tipping point analysis method used for analyzing the 
change from Baseline in the HAQ-DI score at Week 12 will be performed.

Change from Baseline in FACIT-Fatigue at Week 12
1) MI: Similar MI procedure used for analyzing the change from baseline in the HAQ-DI 
score at Week 12 will be performed.
2) Tipping point analysis: Similar tipping point analysis method used for analyzing the 
change from Baseline in the HAQ-DI score at Week 12 will be performed.

Proportion of subjects who achieve DAS28(CRP) < 2.6 at Week 24
1) The analysis using the same logistic regression model specified in Section 6.2.3 will be 
performed by using OC and LOCF methods as described in Section 6.1.
2) MI: Similar MI procedure used for analyzing the proportion of subjects who achieve 
DAS28(CRP) ≤ 3.2 at Week 12 will be performed. 
3) Tipping point analysis: Similar modified tipping point method as described in 
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6.3.4.
Subgroup Analysis of Key Secondary Endpoints
Subgroup analyses comparing each filgotinib dose group to the placebo group will be performed 
for the key secondary efficacy endpoints, for the subgroups specified in Section 3.4. 
The subgroup analysis for the proportion of subjects with DAS28(CRP) ≤ 3.2 and the proportion 
of subjects with DAS28(CRP) < 2.6 will be performed using the Fisher’s exact test based on the 
NRI method. The number and percentage of subjects with DAS28(CRP) ≤ 3.2 will also be 
provided for each treatment group within the subgroups.
The change from Baseline in HAQ-DI will be analyzed using the MMRM method with baseline 
value, treatment, visit, and treatment by visit interaction included as fixed effects and subjects 
being the random effect. The LS mean, LS mean difference, SE and 95% CI will be presented. 
The change from Baseline in SF-36 PCS, and change from Baseline in FACIT-Fatigue will be 
analyzed similarly using the MMRM model respectively. Descriptive statistics for actual values 
and change from Baseline in HAQ-DI, SF-36 PCS and FACIT-Fatigue will also be presented for 
each treatment group within the subgroups.
6.4.
Other Secondary Efficacy Endpoints
Other secondary efficacy endpoints include:

The proportion of subjects who achieve ACR50 at Weeks 4 and 24, and ACR70 at Weeks 4, 
and 12 , ACR20 at Weeks 4 and 24, and ACR20/50/70 over time from Day 1 through 
Week 24

Change from Baseline in individual components of the ACR response at Weeks 4, 12 and 24,  
and over time from Day 1 through Week 24 

The proportion of subjects who achieve a decrease in HAQ-DI of  ≥ 0.22 at Weeks 4, 12 
and 24,  and over time from Day 1 through Week 24 

Change from Baseline in DAS28(CRP) at Weeks 4, 12 and 24,  and over time from Day 1 
through Week 24 

The proportion of subjects who achieve DAS28(CRP) ≤ 3.2 at Weeks 4 and 24,  and over 
time from Day 1 through Week 24 

The proportion of subjects who achieve DAS28(CRP) < 2.6 at Weeks 4, and 12, and over 
time from Day 1 through Week 24

ACR-N and European League Against Rheumatism (EULAR) response at Weeks 4, 12 
and 24,  and over time from Day 1 through Week 24 

Change from Baseline in CDAI at Weeks 4, 12 and 24,  and over time from Day 1 through 
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
Change from Baseline in SDAI at Weeks 4, 12 and 24,  and over time from Day 1 through 
Week 24 

Absolute value and change from Baseline in SF-36, FACIT-Fatigue, and the EQ-5D over 
time at Weeks 4, 12 and 24 (except for SF-36 PCS and FACIT-Fatique), and over time from 
Day 1 through Week 24 

Absolute value and change from Baseline in WPAI-RA at Weeks 4, 12 and 24,  and over 
time from Day 1 through Week 24
6.4.1.
Definition of Other Secondary Efficacy Endpoints
6.4.1.1.
ACR50 and ACR70
ACR50 and ACR70 are similarly defined as ACR20 (see Section 6.2.1), except the improvement 
threshold from Baseline is 50% and 70%, respectively.
6.4.1.2.
SDAI and CDAI
Simplified Disease Activity Index (SDAI) is a composite measure that sums the TJC28, SJC28, 
the SGA on a 0-10 scale, the PGA on a 0-10 scale, and the hsCRP (in mg/dL). SDAI is scored as 
follows {Aletaha 2005}:
SDAI = TJC28 + SJC28 + SGA + PGA + CRP 
Higher SDAI score indicates more severe disease activity status.
Clinical Disease Activity Index (CDAI) is a further simplification of the SDAI that excludes the 
CRP, which is calculated using the following formula {Aletaha 2005}:
CDAI = TJC28 + SJC28 + SGA + PGA 
CDAI can range from 0 to 76, with higher score indicating more severe disease activity status.
No component-level imputation will be performed for the calculation of both SDAI and CDAI. 
If any components are missing, the SDAI and CDAI will be set as missing.
6.4.1.3.
ACR-N
ACR-N is defined as the smallest percentage improvement from baseline in swollen joints, 
tender joints and the median of the following 5 items (PGA, SGA, subject’s pain assessment, 
HAQ-DI and CRP). It has a range between 0 and 100%. In particular,
ACR-N = min { improvement in TJC68 (%), improvement in SJC66 (%), median [ improvement 
in SGA (%), improvement in PGA (%), improvement in pain assessment (%), improvement in 
HAQ-DI (%), improvement in hsCRP (%)] }. 


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If this calculation results in a negative value, then the ACR-N is set to 0. If any components are 
missing, the ACR-N will be set as missing.
6.4.1.4.
EULAR Response
Subject’s response will be categorized according to the following table based on the 
DAS28(CRP).
Table 6-2.
EULAR Response Criteria
DAS28(CRP) at Visit
DAS28(CRP) Improvement from Baseline
> 1.2
> 0.6 and ≤ 1.2
≤ 0.6
≤ 3.2
Good Response
Moderate Response
No Response
> 3.2 and ≤ 5.1
Moderate Response
Moderate Response
No Response
> 5.1
Moderate Response
No Response
No Response
6.4.1.5.
European Quality of Life 5 Dimensions – 5 Levels (EQ-5D-5L)
The EQ-5D-5L is a standardized measure of health status of the subject at the visit (same day) 
that provides a simple, generic measure of health for clinical and economic appraisal. The 
EQ-5D-5L consists of 2 components: a descriptive system of the subject’s health and a rating of 
his or her current health state using a 0 to 100 VAS. The descriptive system comprises the 
following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate 
problems, severe problems, and extreme problems. The subject is asked to indicate his/her health 
state by ticking (or placing a cross) in the box associated with the most appropriate statement in 
each of the 5 dimensions. The VAS records the subject’s self-rated health on a vertical VAS in 
which the endpoints are labeled “best imaginable health state” on the top and “worst imaginable 
health state” on the bottom. Higher EQ VAS indicates better health. The EQ-5D-5L will be 
scored according to the developer’s instructions (scoring guidelines).
6.4.1.6.
Work Productivity and Activity Impairment questionnaire (WPAI) – RA
The WPAI is a questionnaire developed to measure impairments in work activities in subjects 
with RA. The questionnaire consists of 6 questions:
Q1:
currently employed,
Q2:
work time missed due to RA,
Q3:
work time missed due to other reasons,
Q4:
hours actually worked,


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Q5:
degree RA affected productivity while working (0-10 VAS; with 0 indicating no effect 
and 10 indicating RA completely prevented the subject from working),
Q6:
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. WPAI-RA outcomes are expressed as 
impairment percentages, with higher numbers indicating greater impairment and less 
productivity, that is, worse outcomes, as follows:

Absenteeism (work time missed) due to RA: 100× {Q2/(Q2+Q4)}

Presenteeism ( impairment while working) due to RA: 100× {Q5/10}

Work productivity loss (overall work impairment) due to RA: 100× {Q2/(Q2+Q4) + 
[(1-Q2/(Q2+Q4) ) × (Q5/10) ]}

Activity impairment due to RA: 100× {Q6/10}.
If Question 1 (Are you currently employed?) is ‘NO’, then only the activity impairment score 
can be determined.
6.4.1.7.
Healthcare Resource Utilization Questionnaire 
The Healthcare Resource Utilization Questionnaire (HRUQ) is designed to assess healthcare 
usage during the previous three months across a number of direct medical cost domains.
6.4.1.8.
Treatment Satisfaction Questionnaire for Medication (TSQM)
TSQM Scale scores are computed by adding the items loading on each factor. The lowest 
possible score is subtracted from this composite score and divided by the greatest possible score 
minus the lowest possible score. This provides a transformed score between 0 and 1 that should 
be multiplied by 100. Note that only one item may be missing from each scale before the 
subscale should be considered invalid for that respondent. Detailed scoring method is available 
in the Quintiles TSQM Scoring Manual v1.4. 
6.4.1.9.
Exploratory PRO
 
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6.4.2.
Analysis Methods for Other Secondary Efficacy Endpoints
The FAS will be used for all summaries and analyses of other secondary efficacy endpoints.
Nominal p-values will be presented, if applicable.
The proportion of subjects who achieve ACR20/50/70, and proportion of subjects with change in 
HAQ-DI ≥ 0.22 (ie, reduction in HAQ-DI ≥ 0.22), DAS28(CRP) ≤ 3.2 and DAS28(CRP) < 2.6 
at each postbaseline visit through Week 24, will be analyzed using the same logistic regression 
method with NRI as the primary endpoint analysis described in Section 6.2.3. Comparison will 
be made between each filgotinib dose group and placebo through Week 24. The 2-sided 95% CIs 
for the proportion based on normal approximation will be provided for each treatment group. 
The observed values and LOCF values will be analyzed as a sensitivity approach to the primary 
method that uses NRI.
The change from Baseline in DAS28(CRP), CDAI and SDAI will be analyzed using MMRM 
method that include all available data at post-baseline visits through Week 24. The MMRM 
models will include baseline value, stratification factors, treatment, visit, and treatment by visit 
interaction as fixed effects and subject being the random effect. An unstructured variance-
covariance matrix will be used. The Kenward-Roger method will be used to estimate the degrees 
of freedom. Missing change scores due to missing study visits or early withdrawal will not be 
otherwise imputed using the MMRM approach. The LS means and 95% CI of the difference in 
mean change scores from Baseline between each filgotinib dose group and placebo control group 
from the MMRM model will be provided for each postbaseline visit. Descriptive statistics of 
actual and change in DAS28(CRP), CDAI and SDAI from baseline to postbaseline visits will 
also be performed by treatment and visit.
Actual values and change from Baseline in individual components of the ACR response 
(including TJC68, SJC66, SGA, PGA, Subject’s pain assessment, hsCRP), TJC28, and SJC28, 
will by summarize using descriptive statistics (sample size, mean, SD, median, Q1, Q3, 
minimum, and maximum) by treatment and visit. In addition, the MMRM model with baseline 
value, stratification factors, treatment, visit and treatment and visit interaction as fixed effects 
and subject being the random effect will be performed to compare each filgotinib dose group to
placebo control group. The LS means and 95% CI of the difference between each filgotinib dose 
group and placebo control group will be provided.
Actual values and change from Baseline in ACR-N, will by summarize using descriptive 
statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) by treatment and 
visit.
Number and percentage of subjects for EULAR responses will be presented for each visit 
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For HRQoL endpoints, the analysis methods are detailed below:

SF-36
The transformed scores and change from baseline in the 8 domains and 2 summary 
component scores (PCS and MCS) of the SF-36 will be summarized at each visits through 
Week 24 by treatment group using descriptive statistics (sample size, mean, SD, median, Q1,
Q3, minimum and maximum). 
The change from Baseline in PCS and MCS at each postbaseline visit through Week 24 will 
be analyzed using MMRM method that includes all available data at post-baseline visits, 
without imputation for missing data. The MMRM models will be used to evaluate treatment 
effect on change score from Baseline, with baseline value, stratification factors, treatment, 
visit, and treatment by visit interaction included as fixed effects and subject being the random 
effect. An unstructured variance-covariance matrix will be used. The Kenward-Roger method 
will be used to estimate the degrees of freedom. To test for a treatment difference between 
each filgotinib dose group and placebo, the LS means along with the 95% CIs of the 
difference from MMRM, and p-value will be provided for each postbaseline visit. 

FACIT-Fatigue
The change from baseline in FACIT-Fatigue scale score at each postbaseline visit through 
Week 24 will be analyzed using similar MMRM models as for SF-36. To test for a treatment 
difference between each filgotinib dose group and placebo, LS mean difference along with 
95% CI and p-values will be presented for each postbaseline visit. Missing change scores due 
to missing study visits or early withdrawal will not be otherwise imputed using the MMRM 
approach. Summary statistics of the actual score and change from baseline in FACIT-Fatigue 
scale score will also be displayed by treatment and visit. 

EQ-5D-5L
Summary statistics of two outcomes of the EQ-5D-5L described as the following will be 
provided:
A health profile: the number and percentage of subjects at each categorical response for 
the 5 dimensions (mobility, self-care, usual activity, pain/discomfort, and 
anxiety/depression) will be provided by treatment and visit.
A self-perceived current health score: calculated from patient level EQ VAS responses 
(continuous variable). Descriptive statistics (sample size, mean, SD, min, median, and 
max) will be provided by treatment and visit.
The change from baseline in EQ VAS score through Week 24 will be analyzed using similar 
MMRM models as for SF-36. To test for a treatment difference between each filgotinib dose 
group and placebo, LS mean difference, 95% CI and p-values will be presented. Missing 
change scores due to missing study visits or early withdrawal will not be otherwise imputed 
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
WPAI – RA
Summary statistics of the actual scores and change from baseline in each of the four types of 
scores of WPAI-RA (absenteeism, presenteeism, work productivity loss, and activity
impairment) will be summarized by treatment and visit using descriptive statistics (sample 
size, mean, SD, median, Q1, Q3, minimum and maximum). 
The analyses of absenteeism, presenteeism, and work productivity loss will be based on 
subjects employed at both baseline and postbaseline visits.

HRUQ
Summary statistics will be provided for all the following parameters by treatment group and 
visit.
Healthcare resource utilization – Outpatient visits: 
Number and percentage of subjects with any medical visits, and the number of visits 
related to RA will be provided for the categories:
■
Outpatient Healthcare Provider
■
Emergency Room
■
Chiropractor, Physical or Occupational Therapist
Healthcare resource utilization – Inpatient hospitalization:
Number and percentage of subject with hospital stays, and number of stays related to RA 
Descriptive statistics for the total number of days in hospital related to RA
Number and percentage of subject with nursing home or rehabilitation center stays, and 
number of stays related to RA
Descriptive statistics for the total number of days in nursing home or rehabilitation center 
related to RA

TSQM
Descriptive statistics of the scores from each of the 4 domains (Effectiveness, Side-Effects, 
Convenience, and Global Satisfaction) will be presented by treatment group and by visit.
 
 
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Plots of proportions of subjects for categorical endpoints and mean ± SD for continuous 
endpoints (including each individual component of the ACR response) will be presented over 
time by treatment.
In addition, all available data including those collected under the standard of care will be 
summarized by treatment group for the proportion of subjects who achieve ACR20, 
DAS28(CRP) ≤ 3.2, and DAS28(CRP) < 2.6, and the actual value and change from Baseline in 
HAQ-DI, SF-36 PCS score and FACIT-Fatigue score. The observed values will be analyzed, and 
no formal statistical testing will be performed.
For the subgroups specified in Section 3.4, subgroup analyses comparing each filgotinib dose 
group to the placebo group will be performed for the proportion of subjects who achieve ACR20, 
DAS28(CRP) ≤ 3.2, and the actual value and change from Baseline in HAQ-DI, SF-36 PCS 
score and FACIT-Fatigue score at Week 24. Additionally, subgroup analyses comparing each 
filgotinib dose group to the placebo group will be performed for the proportion of subjects who 
achieve DAS28(CRP) < 2.6 at Week 12.
6.5.
Changes From Protocol-Specified Efficacy Analyses
The following changes were made from the protocol-specified efficacy analyses:

It has been observed from the blinded data that the enrollment rate is low in some 
combinations of stratification factors, which will result in the small cell counts for the 
stratified Cochran-Mantel-Haenszel (CMH) test adjusted for the stratification factors. The 
logistic regression analysis with treatment and stratification factors in the model will be used 
instead to analyze binary endpoints.

The following endpoints have been updated as key secondary efficacy endpoints in 
Section 6.3 and included in the hierarchy testing in Section 3.5, in order to support inclusion 
in the label.
Change from baseline in SF-36 physical component score (PCS) at Week 12
The proportion of subjects who achieve DAS28(CRP) < 2.6 at Week 24
Change from baseline in FACIT-Fatigue at Week 12

Given the importance of determining the lowest effective dose for filgotinib in RA, the 
hierarchical ordering has been updated in Section 3.5 to test filgotinib 100 mg immediately 
after each test for filgotinib 200 mg (including the primary endpoint and each of the key 
secondary endpoints). In addition, the testing for ACR20 and HAQ-DI is moved up earlier in 
the list to accommodate the changes aforementioned as well as because of the importance of 
these endpoints in determining drug efficacy in RA. These changes together caused a relative 
move down for testing of DAS28(CRP) ≤ 3.2.


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the MedDRA 21.0. System 
organ class (SOC), high-level group term (HLGT), high-level term (HLT), preferred term (PT), 
and lower-level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, 4, or 5 according to toxicity 
criteria specified in the protocol. The severity grade of events for which the investigator did not 
record severity will be categorized as “missing” for tabular summaries and data listings. The 
missing category will be listed last in summary presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the investigator’s 
choice, not that of the Medical Monitor. Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs met the definitions 
of SAE that were specified in the study protocol. SAEs captured and stored in the clinical 
database will be reconciled with the SAE database from the Gilead Pharmacovigilance & 
Epidemiology Department before data finalization.
7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as one or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug

Any AEs leading to premature discontinuation of study drug


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7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met:

The AE onset is the same as or after the month and year (or year) of the first dosing date of 
study drug, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after the date of the last dose of study drug 
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of study drug, will be considered to be treatment emergent. In 
addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of study drug will 
be considered treatment emergent.
7.1.6.
Summaries of Adverse Events and Deaths
Treatment-emergent AEs will be summarized based on the Safety Analysis Set.
7.1.6.1.
Summaries of AE Incidence in Combined Severity Grade Subsets
The number and percentage of subjects who experienced at least 1 TEAE will be provided and 
summarized by SOC, HLT, PT, and treatment group. For other AEs described below, summaries 
will be provided by SOC, PT, and treatment group:

TEAEs of Grade 3 or higher (by maximum severity)

TEAEs of Grade 2 or higher

All TE treatment-related AEs

TE Treatment-related AEs of Grade 3 or higher (by maximum severity)

TE Treatment-related AEs of Grade 2 or higher

All TE SAEs

All TE treatment-related SAEs 

All TEAEs leading to premature discontinuation of any study drug

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
All TE SAEs leading to death (ie, outcome of death)

All TEAEs leading to temporary interruption of any study drug
A brief, high-level summary of AEs described above will be provided by treatment group and by 
the number and percentage of subjects who experienced the above AEs. All deaths observed in 
the study will be also included in this summary.
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetic order of SOC and HLT within each SOC (if applicable), 
and then by PT in descending order of total frequency within each SOC. For summaries by 
severity grade, the most severe grade will be used for those AEs that occurred more than once in 
an individual subject during the study. 
In addition to the above summary tables, all TEAEs and TE treatment-related AEs will be 
summarized by PT only, in descending order of total frequency.
In addition, data listings will be provided for the following:

All AEs, indicating whether the event is treatment emergent

All AEs of Grade 3 or higher

All AEs of Grade 2 or higher

SAEs

Deaths

All SAEs leading to death (ie, outcome of death)

AEs leading to premature discontinuation of any study drug

AEs leading to premature discontinuation of study

AEs leading to temporary interruption of any study drug
7.1.7.
Adverse Events of Special Interest
Events of interest will be identified by the use of either SMQs or MSTs. However, should 
additional cases not detected by the predefined search term listings be identified during the 
clinical review process, these cases will also be reported by respective category.
7.1.7.1.
Adjudication Committee for MACE
An independent cardiovascular safety endpoint adjudication committee (CVEAC) will be formed 
to periodically review and adjudicate all potential major cardiovascular adverse events (MACE). 
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To identify the MACE, the following potential cases identified using MedDRA search listing 
(MST) searches will be adjudicated:

All deaths

Cardiovascular events (meeting serious criteria)

Myocardial infarction (Narrow)

Hospitalization for unstable angina

Transient ischemic attack

Stroke

Hospitalization for cardiac failure

Percutaneous coronary intervention
The CVEAC will review those potential MACE and related clinical data to determine whether a 
MACE has developed. The CVEAC’s role and responsibilities and the data to be provided to the 
CVEAC are described in a mutually agreed upon CVEAC charter. The CVEAC charter defines 
the CVEAC membership, adjudication process, meeting logistics, and meeting frequency. The 
number and percentage of subjects with positively adjudicated MACE will be summarized by 
treatment group using the PT term.
A by-subject listing for all patients who have potential MACE events, and have a positively 
adjudicated MACE event at any time will be provided.
7.1.7.2.
Other Adverse Events of Special Interest
In addition to general safety parameters and MACE, safety information on other adverse events 
of special interest (AESIs) will also be analyzed. AESIs will be identified by either laboratory 
results, standardized MedDRA queries (SMQs), or sponsor defined MSTs, or a combination of 
these methods as indicated below.

All infections (defined as all PTs in the Infections and Infestations SOC)

Serious infections (defined as all PTs in the Infections and Infestations SOC that are SAEs)

Infections of special interest as defined below
a) Herpes zoster
b) Active tuberculosis 
c) Opportunistic infections 
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
Deep vein thrombosis (DVT) and pulmonary embolism (PE) 

Malignancy (including lymphoma; not including nonmelanoma skin cancer) 

Nonmelanoma skin cancer 

GI (Gastrointestinal) perforations 
The number and percentage of patients with aforementioned events of special interest will be 
provided by the PT term for each AE of special interests.
A by-subject listing for all patients having AE of special interests at any time will be provided 
for each AE of special interest.
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of any study drug plus 
30 days for subjects who have permanently discontinued study drug, or all available data at the 
time of the database snapshot for subjects who were ongoing at the time of an interim analysis. 
The analysis will be based on values reported in conventional units. When values are below the 
LOQ, they will be listed as such, and the closest imputed value will be used for the purpose of 
calculating summary statistics as specified in Section 3.7. 
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, and urinalysis separately. Values falling 
outside of the relevant reference range and/or having a severity grade of 1 or higher on the 
CTCAE severity grade will be flagged in the data listings, as appropriate.
No formal statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics of Baseline values, values at each postbaseline visit and change from 
Baseline at each postbaseline visit will be provided by treatment group for the following 
laboratory tests:

Hematology
Hematocrit
Hemoglobin
Platelet count
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Mean corpuscular volume
White blood cell (WBC) count
Lymphocytes
Monocytes
Neutrophils
Eosinophils
Basophils

Chemistry
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Alkaline phosphatase (ALP)
Total bilirubin
Serum creatinine
Creatinine clearance by Cockcroft-Gault formula
Creatinine phosphokinase (CPK)
Glucose

Lipid
Triglycerides
Total cholesterol
HDL
LDL
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A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date/time of first dose of any study drug. Change from baseline to a postbaseline visit will be 
defined as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and 
maximum values will be displayed to the reported number of digits; SD values will be displayed 
to the reported number of digits plus 1.
Median (Q1, Q3) of the observed values for the laboratory tests specified above will be plotted 
using a line plot by treatment group and visit.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3.
7.2.2.
Graded Laboratory Value
The CTCAE Version 4.03 (with one modification specified in protocol) will be used to assign 
toxicity grades (0 to 4) to laboratory results for analysis. Grade 0 includes all values that do not 
meet the criteria for an abnormality of at least Grade 1. For laboratory tests with criteria for both 
increased and decreased levels, analyses for each direction (ie, increased, decreased) will be 
presented separately. 
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last 
dose of any study drug plus 30 days for subjects who permanently discontinued study drug, or 
the last available date in the database snapshot for subjects who were still on treatment at the 
time of an interim analysis. 
If the relevant baseline laboratory value is missing, any abnormality of at least Grade 1 observed 
within the time frame specified above will be considered treatment emergent.
7.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities
Treatment-emergent marked laboratory abnormalities are defined as values that increase from 
baseline by at least 3 toxicity grades at any postbaseline time point, up to and including the date 
of the last dose of any study drug plus 30 days for subjects who permanently discontinued study 
drug or the last available date in the database snapshot for subjects who were still on treatment at 
the time of an interim analysis.
If the relevant baseline laboratory value is missing, any Grade 3 or higher values observed within 
the timeframe specified above will be considered treatment-emergent marked abnormalities.


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7.2.2.3.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at baseline and each scheduled postbaseline visit.
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by laboratory test and treatment group; subjects will be 
categorized according to the most severe postbaseline abnormality grade for a given laboratory 
test:

Graded laboratory abnormalities

Grade 3 or higher laboratory abnormalities

Marked laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 30 days after last dosing date.
A by-subject listing of treatment-emergent Grade 3 or higher laboratory abnormalities and 
marked laboratory abnormalities will be provided separately by subject ID number and visit in 
chronological order. These listings will include all test results that were collected throughout the 
study for the laboratory test of interest, with all applicable severity grades or abnormal flags
displayed.
7.2.3.
Laboratory Evaluations of Special Interest
7.2.3.1.
Liver-Related Laboratory Evaluations
Liver-related abnormalities after initial study drug dosing will be examined and summarized 
using the number and percentage of subjects who were reported to have the following laboratory 
test values for postbaseline measurements:

AST: (a) > 3 times of the upper limit of reference range (ULN); (b) > 5 x ULN; 
(c) > 10 x ULN; (d) > 20 x ULN

ALT: (a) > 3 x ULN; (b) > 5 x ULN; (c) > 10 x ULN; (d) > 20 x ULN

AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
The summary will include data from all postbaseline visits up to 30 days after the last dose of 
any study drug. For individual laboratory tests, subjects will be counted once based on the most 
severe postbaseline values. For both the composite endpoints of AST or ALT and total bilirubin, 
subjects will be counted once when the criteria are met at the same postbaseline visit date. The 
denominator is the number of subjects in the Safety Analysis Set who have nonmissing 
postbaseline values of all relevant tests at the same postbaseline visit date. A listing of subjects 
who met at least 1 of the above criteria will be provided.


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7.2.3.2.
Complete Blood Count-Related Laboratory Evaluations
Complete blood count (CBC)-related abnormalities such as anemia, leucopenia, neutropenia, 
lymphopenia, and thrombocytopenia after initial study drug dosing will be examined and 
summarized using the number and percentage of subjects who were reported to have the 
following laboratory test values for postbaseline measurements:

Hemoglobin: (a) any postbaseline worsening CTCAE grade from baseline; (b) baseline value 
of less than Grade 3 and increase to Grade 3 or higher at worst postbaseline; (c) baseline 
value of less than Grade 3 and increase to Grade 4 or higher at worst postbaseline

WBC count: (a) any postbaseline worsening CTCAE grade from baseline; (b) baseline value 
of less than Grade 3 and increase to Grade 3 or higher at worst postbaseline; (c) baseline 
value of less than Grade 3 and increase to Grade 4 or higher at worst postbaseline

Absolute neutrophil count: (a) any postbaseline worsening CTCAE grade from baseline; 
(b) baseline value of less than Grade 3 and increase to Grade 3 or higher at worst 
postbaseline; (c) baseline value of less than Grade 3 and increase to Grade 4 or higher at
worst postbaseline

Lymphocyte count: (a) any postbaseline worsening CTCAE grade from baseline; (b) baseline 
value of less than Grade 3 and increase to Grade 3 or higher at worst postbaseline; 
(c) baseline value of less than Grade 3 and increase to Grade 4 or higher at worst 
postbaseline

Platelet count: (a) any postbaseline worsening CTCAE grade from baseline; (b) baseline 
value of less than Grade 3 and increase to Grade 3 or higher at worst postbaseline; 
(c) baseline value of less than Grade 3 and increase to Grade 4 or higher at worst 
postbaseline
The summary will include data from all postbaseline visits up to 30 days after the last dose of 
any study drug.
7.3.
Body Weight and Vital Signs
Descriptive statistics will be provided by treatment group for body weight, BMI and vital signs 
(systolic and diastolic blood pressures [mmHg], pulse [beats/min]) as follows:

Baseline value

Values at each postbaseline visit 

Change from baseline at each postbaseline visit 


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A baseline value will be defined as the last available value collected on or prior to the date/time 
of first dose of any study drug. Change from baseline to a postbaseline visit will be defined as 
the postbaseline value minus the baseline value. Body weight and vital signs measured at 
unscheduled visits will be included for the baseline value selection.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. No formal statistical testing is planned.
A by-subject listing of vital signs (systolic and diastolic blood pressure [mmHg], pulse 
[beats/min], respiration [breaths/min], and body temperature [°C]) will be provided by subject ID 
number and visit in chronological order. In the same manner, a by-subject listing of body weight, 
height, and BMI will be provided separately.
7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the World Health 
Organization (WHO) Drug dictionary version BSEP17.
All the analyses in this section will be performed for general prior /concomitant medications and 
RA-specific prior/concomitant medications separately, unless otherwise specified.
7.4.1.
Prior Medications
Prior medications are defined as any medication taken before a subject took the first study drug.
Prior medications will be summarized by Anatomical Therapeutic Chemical (ATC) drug class 
preferred name using the number and percentage of subjects for each treatment group and 
overall. A subject reporting the same medication more than once will be counted only once when 
calculating the number and percentage of subjects who received that medication. The summary 
will be provided by preferred name in order of descending overall frequency. For drugs with the 
same frequency, sorting will be done alphabetically.
For the purposes of analysis, any medication with a start date prior to the first dosing date of any 
study drug will be included in the prior medication summary regardless of when the stop date is. 
If a partial start date is entered the medication will be considered prior unless the month and year 
(if day is missing) or year (if day and month are missing) of the start date are after the 
first dosing date. Medications with a completely missing start date will be included in the prior 
medication summary, unless otherwise specified.
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned.
7.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a subject took study drug. Use 
of concomitant medications will be summarized by ATC drug class preferred name using the 
number and percentage of subjects for each treatment group. A subject reporting the same
medication more than once will be counted only once when calculating the number and 


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percentage of subjects who received that medication. The summary will be provided by preferred 
term in descending overall frequency. For drugs with the same frequency, sorting will be done 
alphabetically.
For the purposes of analysis, any medication with a start date prior to or on the first dosing date 
of any study drug and continued to take after the first dosing date, or started after the first dosing 
date but prior to or on the last dosing date of study drug will be considered concomitant 
medications. Medications started and stopped on the same day as the first dosing date or the last 
dosing date of any study drug will also be considered concomitant. Medications stopped on the 
same day as the first dosing date will be considered concomitant. Medications with a stop date 
prior to the date of first dosing date of any study drug or a start date after the last dosing date of 
any study drug will be excluded from the concomitant medication summary. If a partial stop date 
is entered, any medication with the month and year (if day is missing) or year (if day and month 
are missing) prior to the date of first study drug administration will be excluded from the 
concomitant medication summary. If a partial start date is entered, any medication with the 
month and year (if day is missing) or year (if day and month are missing) after the study drug 
stop date will be excluded from the concomitant medication summary. Medications with 
completely missing start and stop dates will be included in the concomitant medication summary, 
unless otherwise specified. 
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned.
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.
7.5.
Electrocardiogram Results
7.5.1.
Investigator Electrocardiogram Assessment
A shift table of the investigators’ assessment of ECG results at each visit compared with baseline 
values will be presented by treatment group using the following categories: normal; abnormal 
(not clinically significant); abnormal (clinically significant); or missing. The number and 
percentage of subjects in each cross-classification group of the shift table will be presented. 
Subjects with a missing value at baseline or postbaseline will not be included in the denominator 
for percentage calculation. 
No formal statistical testing is planned.
A by-subject listing for ECG assessment results will be provided by subject ID number and visit 
in chronological order.
7.6.
Other Safety Measures
A data listing will be provided for subjects who become pregnant during the study.
7.7.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC ANALYSES
Concentrations of filgotinib and its metabolite GS-829845 in plasma will be determined using 
validated bioanalytical assays. Plasma PK of filgotinib and GS-829845 will be evaluated.
8.1.
PK Analyses Related to Intensive PK Sampling
 
8.1.1.
Estimation of Pharmacokinetic Parameters
PK parameters will be estimated using Phoenix WinNonlin® software using standard
noncompartmental methods. The linear/log trapezoidal rule will be used in conjunction with the 
appropriate noncompartmental model, with input values for dose level, dosing time, plasma 
concentration, and corresponding real-time values, based on drug dosing times whenever possible.
All predose sample times before time-zero will be converted to 0. Predose samples may also 
serve as the 24-hr post dose sample if appropriate.
For area under the curve (AUC), samples BLQ of the bioanalytical assays occurring prior to the 
achievement of the first quantifiable concentration will be assigned a concentration value of 0 to 
prevent overestimation of the initial AUC. Samples that are BLQ at all other time points will be 
treated as missing data in WinNonlin. The nominal time point for a key event or dosing interval 
(τ) may be used to permit direct calculation of AUC over specific time intervals. The 
appropriateness of this approach will be assessed by the PK scientist on a profile-by-profile 
basis.
Pharmacokinetic parameters such as AUCtau, λz and t1/2 are dependent on an accurate estimation 
of the terminal elimination phase of drug. The appropriateness of calculating these parameters 
will be evaluated upon inspection of PK data on a profile-by-profile basis by the PK scientist.
8.1.2.
Pharmacokinetic Parameters
PPD
PPD


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The analytes and parameters presented in Table 8-2 will be used to evaluate the PK objectives of 
the study. The PK parameters to be estimated in this study are listed and defined in the 
Pharmacokinetic Abbreviations section.
Table 8-2.
Pharmacokinetic Parameters for Each Analyte
Analyte
Parameters
Filgotinib
AUClast, AUCtau, Ctau, Cmax, Tmax, Clast, Tlast, λz, CLss/F, Vz/F, and t1/2, if appropriate
GS-829845
AUClast, AUCtau, Ctau, Cmax, Tmax, Clast, Tlast, λz, and t1/2, if appropriate
8.1.3.
Statistical Analysis Methods
Individual subject concentration data and individual subject PK parameters for filgotinib and 
GS-829845 will be listed and summarized using descriptive statistics by treatment. Summary 
statistics (number of subjects [n], mean, SD, coefficient of variation [%CV], median, minimum, 
maximum, Q1, and Q3) will be presented for both individual subject concentration data by time 
point and treatment; and individual subject PK parameters by treatment. Moreover, the geometric 
mean, 95% CI, and the mean and SD of the natural log-transformed values will be presented for 
individual subject PK parameter data. 
Individual concentration data listings and summaries will include all subjects with concentration 
data. The sample size for each time point will be based on the number of subjects with 
nonmissing concentration data at that time point. The number of subjects with concentration 
BLQ will be presented for each time point. For summary statistics, BLQ values will be treated as 
0 at predose and one-half of the lower limits of quantitation (LLOQ) for postdose time points. 
Individual PK parameter data listings and summaries will include all subjects for whom PK 
parameter(s) can be derived. The sample size for each PK parameter will be based on the number 
of subjects with nonmissing data for that PK parameter.
The following tables may be provided for each analyte by treatment:

Individual subject concentration data and summary statistics

Individual subject plasma PK parameters and summary statistics.
 
PPD


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The following listings may be provided:

PK sampling details (and PK concentrations) by subject, including procedures, differences in 
scheduled and actual draw times, and sample age.

Individual data on determination of plasma half-life and corresponding regression correlation 
coefficient.


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9.
BIOMARKER ANALYSIS
A separate biomarker analysis plan (BAP) will document methods to analyze biomarker 
assessments.


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10.
REFERENCES
Aletaha D, Nell VP, Stamm T, Uffmann M, Pflugbeil S, Machold K, et al. Acute phase reactants 
add little to composite disease activity indices for rheumatoid arthritis: validation 
of a clinical activity score. Arthritis research & therapy 2005;7 (4):R796-806.
Ratitch B, O'Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharm Stat 2013;12 (6):337-47.
Rubin DB. Multiple Imputation for Nonresponse in Surveys.  New York, NY: John Wiley & 
Sons, Inc, 1987:
Yuan Y. Sensitivity Analysis in Multiple Imputation for Missing Data.  2014:


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11.
SOFTWARE
SAS® Software Version 9.X. SAS Institute Inc., Cary, NC, USA.
nQuery Advisor(R) Version X.0. Statistical Solutions, Cork, Ireland.


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12.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision
23 August 2018
Throughout the 
document
Minor editorial changes 
Administrative changes for 
clarification
23 August 2018
Section 4.2.2
Updating details to adherence 
calculation when bottles were 
not return
Align with clinical practice


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13.
APPENDICES
Appendix 1.
Lists of RA Medications
Appendix 2.
Health Assessment Questionnaire Disability Index (HAQ-DI)
Appendix 3.
Treatment Satisfaction Questionnaire for Medication (TSQM)
Appendix 4.
Cortocosteroids
Appendix 5.
SAS Programming for Tipping Point Analysis for Binary Endpoint
Appendix 6.
SAS Programming for Tipping Point Analysis for Continuous


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Appendix 1.
Lists of RA Medications
1) List of bDMARDs and Investigational bDMARDs (WHO Preferred Terms)

ABATACEPT

ADALIMUMAB

ANAKINRA

BAMINERCEPT

BELIMUMAB

BIMEKIZUMAB

CABIRALIZUMAB

CERTOLIZUMAB

CERTOLIZUMAB PEGOL

CLAZAKIZUMAB

DENOSUMAB

EPRATUZUMAB

ETANERCEPT

GOLIMUMAB

INFLIXIMAB

INTERLEUKIN-2

OCRELIZUMAB

REMTOLUMAB

RITUXIMAB

SARILUMAB

SECUKINUMAB

SIRUKUMAB

TABALUMAB


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
TILDRAKIZUMAB

TOCILIZUMAB

TREGALIZUMAB

Other investigational bDMARDs 
2) List of csDMARDs (WHO Preferred Terms)

BUCILLAMINE

CHLOROQUINE

CHLOROQUINE PHOSPHATE

CICLOSPORIN

HYDROXYCHLOROQUINE

HYDROXYCHLOROQUINE SULFATE

LEFLUNOMIDE

METHOTREXATE

METHOTREXATE SODIUM

PENICILLAMINE

SULFASALAZINE
3) List of Oral Corticosteroids (WHO Preferred Terms)

MEPREDNISONE

METHYLPREDNISOLONE

METHYLPREDNISOLONE ACETATE

METHYLPREDNISOLONE SODIUM SUCCINATE

PREDNISOLONE

PREDNISONE


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Appendix 2.
Health Assessment Questionnaire Disability Index (HAQ-DI)
The HAQ-DI score is defined as the average of the scores of eight functional categories (dressing 
and grooming, arising, eating, walking, hygiene, reach, grip, and other activities), usually 
administered by the patient. Responses in each functional category are collected as 0 (without 
any difficulty) to 3 (unable to do a task in that area), with or without aids or devices. 
The highest score for questions in each category (range 0 to 3) determines the score for the 
category, unless aids or devices are required. Dependence on equipment or physical assistance 
increases a lower score (ie, scores of 0 or 1) to the level of 2 to more accurately represent 
underlying disability. The eight category scores are averaged into an overall HAQ-DI score on a 
scale from 0 (no disability) to 3 (completely disabled) when 6 or more categories are 
non-missing. If more than 2 categories are missing, the HAQ-DI score is set to missing. The 
HAQ-DI can be treated as a continuous measure. 
The HAQ-DI score using aids (and/or devices) is computed by taking the maximum score of the 
questions in each category (range: [0, 3]) and whether or not aids/devices are used (0 or 1):
A = max(dressing & grooming category questions, 2*aids indicator) +
max(rising category questions, 2*aids indicator) +
max(eating category questions, 2*aids indicator) +
max(walking category questions, 2*aids indicator) +
max(hygiene category questions, 2*aids indicator) +
max(reach category questions, 2*aids indicator) +
max(grip category questions, 2*aids indicator) +
max(usual activities category questions, 2*aids indicator)
HAQ-DI = A/(total number of categories with at least 6 non-missing)
The following table shows the contribution of the 43 questions used to calculate the HAQ-DI:


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HAQ-DI Category:
Category questions:
At least 6 categories must have scores to compute 
the HAQ-DI.
HAQ-DI Category Score with 
Aids/Devices Calculation:
Category Questions
Aids/Devices Indicators
Dressing / Grooming
HAQ0101, HAQ0102
(DRESS, HAIR)
HAQ0114, HAQ0119
(DRSG, GROOM)
Using each question with a scale 
of 0-3, calculate the category 
score as the maximum of the 
category questions.
If the Aids/Devices indicator is 
“No”, no need to adjust the 
category score.
If the Aids/Devices indicator is 
“Yes” and the category score is 
<2, then the category score with 
the Aids/Devices is set to 2.
If the Aids/Devices indicator is 
“Yes” and the category score is 
≥2, then the category score with 
Aids/Devices is the calculated 
category score without 
adjustment.
For example:
The Dressing/Grooming category 
score is 2 if subject answered 1 for 
both questions 1 and 2 and “Yes” 
for both question 14 and 18.
In the HAQ-DI score calculation, 
questions on other device/aids 
will not be used.
Arising
HAQ0103, HAQ0104
(STAND, BED)
HAQ0116, HAQ0120
(CHAIR, ARISING)
Eating
HAQ0105,HAQ0106, 
HAQ0107
(MEAT, LIFT,MILK)
HAQ0115, HAQ0121
(UTENSIL, EAT)
Walking
HAQ0108, HAQ0109
(WALK, STEPS)
HAQ0110, HAQ0111, 
HAQ0112, HAQ0113, 
HAQ0122
(CANE, WALKER, 
CRUTCH, WHEEL, 
WALKING)
Hygiene
HAQ0123, HAQ0124, 
HAQ0125
(WASH, BATH, TOILET)
HAQ0134, HAQ0135, 
HAQ0137, HAQ0139, 
HAQ0142
(RAISEAT, BATHBAR, 
BATHSEAT, 
LONGBATH, HYGIENE)
Reach
HAQ0126, HAQ0127
(REACH, BEND)
HAQ0138, HAQ0143
(LONGRCH, REACH)
Grip
HAQ0128, HAQ0129, 
HAQ0130
(OPENCAR, JAR, 
FAUCET)
HAQ0136, HAQ0144
(JAROPEN, GRIP)
Activity
HAQ0131, HAQ0132, 
HAQ0133
(SHOP, INCAR, 
CHORES)
HAQ0145
(ERRAND)
Handling Missing Data: If no more than 2 categories have missing category scores, then the 
HAQ-DI is the mean of the non-missing category scores. Otherwise, the HAQ-DI score is set to 
missing.
If any of the category questions are missing, but the aids/device indicator is non-missing, the 
category score can still be computed. However, if all category questions and its aids/device 
indicators are missing, then the category score is considered missing. 


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Appendix 3.
Treatment Satisfaction Questionnaire for Medication (TSQM)
TSQM scale scores are computed by adding the items loading on each factor. The lowest 
possible score is subtracted from this composite score and divided by the greatest possible score 
minus the lowest possible score. This provides a transformed score between 0 and 1 that should 
be multiplied by 100. Note that only one item may be missing from each scale before the 
subscale should be considered invalid for that respondent.
EFFECTIVENESS:
([Sum(Item 1 + Item 2 + Item 3) – 3] divided by 18) * 100
If one item is missing
([Sum(Item 1? + Item 2? + Item 3?) – 2] divided by 12) * 100
SIDE-EFFECTS:
If Question 4 is answered ‘No’, then score = 100
Else,
([Sum(Item 5 to Item 8) – 4] divided by 16) * 100
If one item is missing
([Sum(Item 5? to Item 8?) – 3] divided by 12) * 100
CONVENIENCE:
([Sum(Item 9 to Item 11) – 3] divided by 18) * 100
If one item is missing
([Sum(Item 9? to Item 11?) – 2] divided by 12) * 100
GLOBAL SATISFACTION:
([Sum(Item 12 to Item 14) – 3] divided by 14) * 100
If either Item 12 or 13 is missing
([Sum(Item 12? to Item 14?) – 2] divided by 10) * 100
If Item 14 is missing
([Sum(Item 12 and Item 13) – 2] divided by 8) * 100


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Appendix 4.
Cortocosteroids
The following table will be used for converting non-prednisone medications to prednisone 
equivalent:
Example: Patient is taking 8 mg of Methylprednisolone orally daily. To get the equivalent dose 
of prednisone: 8 mg Methylprednisolone = (5*8)/ 4 = 10 mg prednisone. 
Corticosteroids Name
Equivalent Dose (mg) to 5 mg Prednisone
Betamethasone 
0.75
Betamethasone Dipropionate
0.75
Betamethasone Sodium Phosphate
0.75
Cortisone
20
Dexamethasone 
0.75
Dexamethasone Palmitate
0.75
Dexamethasone Phosphate
0.75
Dexamethasone Sodium Phosphate
0.75
Hydrocortisone 
20
Meprednisone
4
Methylprednisolone 
4
Methylprednisolone Acetate
4
Methylprednisolone Sodium Succinate
4
Prednisone 
5
Prednisolone 
5
Prednisolone Farnesylate
5
Prednisolone Sodium Succinate
5
Triamcinolone 
4


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Appendix 5.
SAS Programming for Tipping Point Analysis for Binary Endpoint
The following %tp_binary macro generates multiple imputed data and a set of the shift 
parameters that adjust the imputed values will be examined.
/*----------------------------------------------------------------------------------------------------------------------*/
/*--- Delta-Adjusting Method for Tipping Point Analysis for Binary Endpoint                              ---*/
/*---                                                                                                                                                    ---*/
/*--- Generate imputed data set for specified shift parameters                                                          ---*/
/*--- data= input data set                                                                                                                    ---*/
/*--- smin= min shift parameter for active drug                                                                                ---*/
/*--- smax= max shift parameter for active drug                                                                               ---*/
/*--- sinc= increment of the shift parameter for active drug                                                             ---*/
/*--- pmin= min shift parameter for placebo drug                                                                            ---*/
/*--- pmax= max shift parameter for placebo drug                                                                          ---*/
/*--- pinc= increment of the shift parameter for placebo drug                                                         ---*/
/*--- trt= treatment group indicator                                                                                                  ---*/
/*--- out= output imputed data set                                                                                                   ---*/
/*--------------------------------------------------------------------------------------------------------------------*/
%macro tp_binary( data=, smin=, smax=, sinc=, pmin=, pmax=, pinc=, trt=, out=);
data &out;
set _null_;
run;
/*------------ # of shift values ------------*/
%let ncase_pbo = %sysevalf( (&pmax-&pmin)/&pinc, ceil );
%do pc=0 %to &ncase_pbo;
%let pj= %sysevalf( &pmin + &pc * &pinc);
/*------------ # of shift values ------------*/
%let ncase= %sysevalf( (&smax-&smin)/&sinc, ceil );
/*------- Imputed data for each shift -------*/
%do jc=0 %to &ncase;
%let sj= %sysevalf( &smin + &jc * &sinc);
proc mi data=&data seed=14823 nimpute=20 out=outmi;
var trt01pn strat1V strat2V strat3V das28n;
class trt01pn strat1V strat2V strat3V das28n;
monotone logistic (das28n / link=glogit);
mnar adjust( das28n(event='1') / adjustobs=(trt01pn="&trt") shift= &sj)
adjust( das28n(event='1') / adjustobs=(trt01pn='3') shift= &pj);
run;
data outmi;
    set outmi;
   
Shift_Trt= &sj;
    
Shift_Pbo= &pj;
run;
data &out;


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set &out outmi;
run;
%end;
%end;
%mend tp_binary;


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Appendix 6.
SAS Programming for Tipping Point Analysis for Continuous
Endpoint
The following %tp_conti macro generates multiple imputed data sets and a set of the shift
parameters that adjust the imputed values will be examined.
/**************************************************************************************/
/*--- Modified Tipping Point Analysis from Yuan's method                                                                         ---*/
/*---                                                                                                                                                                ---*/
/*--- Generate imputed data set for specified shift parameters                                                                     ---*/
/*--- data= input data set                                                                                                                               ---*/
/*--- smin= min shift parameter for active drug                                                                                           ---*/
/*--- smax= max shift parameter for active drug                                                                                         ---*/
/*--- sinc= increment of the shift parameter for active drug                                                                        ---*/
/*--- pmin= min shift parameter for placebo drug                                                                                       ---*/
/*--- pmax= max shift parameter for placebo drug                                                                                      ---*/
/*--- pinc= increment of the shift parameter for placebo drug                                                                     ---*/
/*--- trt= treatment group indicator (eg, 1= filgotinib 200 mg)                                                                   ---*/
/*--- out= output imputed data set                                                                                                                ---*/
/**************************************************************************************/
%macro tp_conti( data=, smin=, smax=, sinc=, pmin=, pmax=, pinc=, trt=, out=);
data &out;
set _null_;
run;
%let ncase_pbo = %sysevalf( (&pmax-&pmin)/&pinc, ceil );
    %do pc=0 %to &ncase_pbo;
%let pj= %sysevalf( &pmin + &pc * &pinc);
/*------------ # of shift values ------------*/
%let ncase= %sysevalf( (&smax-&smin)/&sinc, ceil );
/*------- Imputed data for each shift -------*/
%do jc=0 %to &ncase;
%let sj= %sysevalf( &smin + &jc * &sinc);
proc mi data=&data out=all mono nimpute=15 seed=123;
var  v_1 v_2 v_3 v_4 v_5 v_6 v_7 v_8 v_9 ;
mcmc chain=multiple impute=monotone;
run;
proc sort data=all_mono; by _Imputation_ trt01pn; run;
proc mi data=all_mono out=outmi seed=465 nimpute=1;
by Imputation ;
var trt01pn strat1V strat2V strat3V v_1 v_2 v_3 v_4 v_5 v_6 v_7 v_8 v_9;
class trt01pn strat1V strat2V strat3V;
monotone regression;


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mnar adjust( v_5 / adjustobs=(trt01pn="&trt") shift=&sj)
adjust( v_5 / adjustobs=(trt01pn='3') shift= &pj);
run;
data outmi;
set outmi;
Shift_Trt= &sj;
Shift_Pbo= &pj;
run;
data &out;
set &out outmi;
run;
%end;
  %end;
%mend tp_conti;