Conditions: Sjogren's Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 152
Healthy volunteers: no

Brief summary:
The primary objective of this study is to assess the efficacy of filgotinib, lanraplenib, and tirabrutinib in adults with active Sjogren's Syndrome (SjS).

Detailed description:

Arms:
arm 1: Lanraplenib + filgotinib placebo + tirabrutinib placebo for up to 49.4 weeks. arm 2: Filgotinib + lanraplenib placebo + tirabrutinib placebo for up to 50.4 weeks. arm 3: Tirabrutinib + filgotinib placebo + lanraplenib placebo for up to 50.3 weeks. arm 4: Filgotinib placebo + lanraplenib placebo + tirabrutinib placebo for 24 weeks. Following completion of the Week 24 assessments and procedures, participants will be rerandomized 1:1:1, in a blinded fashion and receive either of the following study drugs through Week 48:

* filgotinib + lanraplenib placebo + tirabrutinib placebo
* lanraplenib + filgotinib placebo + tirabrutinib placebo
* tirabrutinib + filgotinib placebo + lanraplenib placebo

Interventions: intervention 1: Lanraplenib intervention 2: Filgotinib intervention 3: Tirabrutinib intervention 4: Lanraplenib placebo intervention 5: Filgotinib placebo intervention 6: Tirabrutinib placebo
Intervention descriptions: intervention 1: 1 x 30 mg tablet administered orally once daily intervention 2: 1 x 200 mg tablet administered orally once daily intervention 3: 1 x 40 mg tablet administered orally once daily intervention 4: 1 x tablet administered orally once daily intervention 5: 1 x tablet administered orally once daily intervention 6: 1 x tablet administered orally once daily

Protocol document:
Prot_000.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Randomized, Phase 2, Double-blind, Placebo-controlled Study to 
Assess the Safety and Efficacy of Filgotinib, GS-9876 and GS-4059 
in Adult Subjects with Active Sjogren's Syndrome 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
USA 
123903 
2016-003558-34 
NCT03100942 
Sjogren's Syndrome 
GS-US-445-4189 
Gilead Clinical 
Name: 
PD 
PD 
Program Manager: 
Telephone: 
Gilead Medical 
Name: 
Monitor: 
Telephone: 
Fax: 
Mobile: 
Protocol Version/Date: 
Original: 
Amendment 1: 
PD 
PD 
PD 
PD 
09 November 2016 
12 July 2018 
CONFIDENTIALITY STATEMENT 
The info1mation contained in this document, paiiicularly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessa1y to obtain infonned consent from those 
persons to whom the dmg may be administered. 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................12
1.
INTRODUCTION ..............................................................................................................................................16
1.1.
Background ............................................................................................................................................16
1.2.
Filgotinib................................................................................................................................................17
1.2.1.
Nonclinical Pharmacology and Toxicology .........................................................................17
1.2.2.
Clinical Trials of Filgotinib..................................................................................................18
1.3.
GS-9876 .................................................................................................................................................18
1.3.1.
Nonclinical Pharmacology and Toxicology .........................................................................18
1.3.2.
Clinical Trials of GS-9876 ...................................................................................................20
1.4.
GS-4059 .................................................................................................................................................21
1.4.1.
Nonclinical Pharmacology and Toxicology .........................................................................21
1.4.2.
Clinical Trials of GS-4059 ...................................................................................................23
1.5.
Rationale for Current Study ...................................................................................................................23
1.6.
Rationale for Dose Selection..................................................................................................................25
1.7.
Risk/Benefit Assessment for the Study..................................................................................................25
1.8.
Compliance ............................................................................................................................................27
2.
OBJECTIVES AND ENDPOINTS ....................................................................................................................28
3.
STUDY DESIGN................................................................................................................................................30
3.1.
Study Design..........................................................................................................................................30
3.2.
Study Treatments ...................................................................................................................................31
3.3.
Duration of Treatment............................................................................................................................31
3.4.
Criteria for Interruption and Discontinuation Criteria............................................................................31
3.4.1.
Study Drug Interruption Considerations...............................................................................32
3.4.2.
Study Drug Discontinuation Considerations ........................................................................32
3.5.
End of Study...........................................................................................................................................34
3.6.
Post Study Care......................................................................................................................................34
3.7.
Biomarker Testing..................................................................................................................................34
3.7.1.
Biomarker Samples to Address the Study Objectives:.........................................................35
3.7.2.
Biomarker Samples for Optional Future Research...............................................................36
3.7.3.
Biomarker Samples for Optional Genomic Research...........................................................36
4.
SUBJECT POPULATION..................................................................................................................................37
4.1.
Number of Subjects and Subject Selection ............................................................................................37
4.2.
Inclusion Criteria....................................................................................................................................37
4.3.
Exclusion Criteria...................................................................................................................................38
4.4.
Screen Failure ........................................................................................................................................41
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................42
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................42
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................42
5.2.
Description of Filgotinib and PTM Filgotinib........................................................................................42
5.3.
Description of GS-9876 and PTM GS-9876 ..........................................................................................43
5.4.
Description of GS-4059 and PTM GS-4059 ..........................................................................................43


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5.5.
Packaging and Labeling of All Study Drugs for this Protocol...............................................................43
5.6.
Storage and Handling of Study Drugs....................................................................................................44
5.7.
Dosage and Administration of Investigational Medicinal Products.......................................................44
5.8.
Prior and Concomitant Medications.......................................................................................................45
5.9.
Vaccine Guidelines ................................................................................................................................47
5.10.
Investigational Medicinal Product Accountability and Disposal or Return ...........................................48
6.
STUDY PROCEDURES ....................................................................................................................................49
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................49
6.2.
Pretreatment Assessments......................................................................................................................49
6.2.1.
Screening Visit .....................................................................................................................49
6.2.2.
Day 1 Assessments...............................................................................................................51
6.3.
Randomization .......................................................................................................................................53
6.4.
Week 2 and Week 26 .............................................................................................................................53
6.5.
Week 4 ...................................................................................................................................................54
6.6.
Week 8 ...................................................................................................................................................56
6.7.
Week 12 .................................................................................................................................................57
6.8.
Week 18 .................................................................................................................................................59
6.9.
Week 24 .................................................................................................................................................61
6.10.
Week 28 .................................................................................................................................................63
6.11.
Week 32 .................................................................................................................................................64
6.12.
Week 36 .................................................................................................................................................65
6.13.
Week 42 .................................................................................................................................................67
6.14.
Week 48/Early Termination (ET)...........................................................................................................68
6.15.
Follow-up Visit ......................................................................................................................................70
6.16.
Study Assessments.................................................................................................................................70
6.16.1.
Patient Reported Outcomes: Visual Analogue Scales and Questionnaires ..........................71
6.16.2.
Physician Reported Outcomes: Visual Analogue Scales, Joint Exam and 
Disease Activity Index .........................................................................................................73
6.16.3.
Pulmonary Function Testing ................................................................................................74
6.16.4.
Clinical Laboratory Evaluations...........................................................................................74
6.16.5.
Salivary Flow Measurements ...............................................................................................75
6.16.6.
Tear Production....................................................................................................................75
6.16.7.
Parotid Gland Ultrasound.....................................................................................................75
6.16.8.
Vital Signs............................................................................................................................76
6.16.9.
Cognitive Test ......................................................................................................................76
6.16.10.
Physical Examination...........................................................................................................76
6.16.11.
Other Assessments ...............................................................................................................76
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................78
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................78
7.1.1.
Adverse Events.....................................................................................................................78
7.1.2.
Serious Adverse Events........................................................................................................78
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................79
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................79
7.2.2.
Assessment of Severity ........................................................................................................80
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................80
7.4.
Gilead Reporting Requirements.............................................................................................................82
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments..................................................82
7.6.
Toxicity Management ............................................................................................................................83
7.7.
Special Situations Reports......................................................................................................................83
7.7.1.
Definitions of Special Situations..........................................................................................83
7.7.2.
Instructions for Reporting Special Situations.......................................................................84


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8.
STATISTICAL CONSIDERATIONS................................................................................................................86
8.1.
Analysis Objectives and Endpoints........................................................................................................86
8.1.1.
Analysis Objectives..............................................................................................................86
8.1.2.
Primary Endpoint .................................................................................................................86
8.1.3.
Secondary Endpoint .............................................................................................................86
8.1.4.
Exploratory Endpoints..........................................................................................................87
8.2.
Analysis Conventions.............................................................................................................................88
8.2.1.
Analysis Sets ........................................................................................................................88
8.3.
Data Handling Conventions ...................................................................................................................89
8.4.
Demographic Data and Baseline Characteristics ...................................................................................89
8.5.
Efficacy Analysis ...................................................................................................................................89
8.5.1.
Primary Analysis..................................................................................................................89
8.5.2.
Secondary and Exploratory Analyses...................................................................................89
8.6.
Safety Analysis.......................................................................................................................................89
8.6.1.
Extent of Exposure...............................................................................................................90
8.6.2.
Adverse Events.....................................................................................................................90
8.6.3.
Laboratory Evaluations ........................................................................................................90
8.7.
Pharmacokinetic Analysis......................................................................................................................91
8.8.
Biomarker Analysis................................................................................................................................91
8.9.
Sample Size............................................................................................................................................92
8.10.
Analysis Schedule ..................................................................................................................................92
9.
RESPONSIBILITIES..........................................................................................................................................93
9.1.
Investigator Responsibilities ..................................................................................................................93
9.1.1.
Good Clinical Practice..........................................................................................................93
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................93
9.1.3.
Informed Consent.................................................................................................................94
9.1.4.
Confidentiality......................................................................................................................94
9.1.5.
Study Files and Retention of Records ..................................................................................94
9.1.6.
Case Report Forms...............................................................................................................96
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................96
9.1.8.
Inspections............................................................................................................................97
9.1.9.
Protocol Compliance............................................................................................................97
9.2.
Sponsor Responsibilities ........................................................................................................................97
9.2.1.
Protocol Modifications.........................................................................................................97
9.2.2.
Study Report and Publications .............................................................................................97
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................98
9.3.1.
Payment Reporting...............................................................................................................98
9.3.2.
Access to Information for Monitoring..................................................................................98
9.3.3.
Access to Information for Auditing or Inspections ..............................................................98
9.3.4.
Study Discontinuation..........................................................................................................98
10.
REFERENCES ...................................................................................................................................................99
11.
APPENDICES ..................................................................................................................................................102
Appendix 1.
Investigator Signature Page..................................................................................................103
Appendix 2.
Schedule of Assessments Table............................................................................................104
Appendix 3.
Management of Clinical and Laboratory Adverse Events....................................................109
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03..................................110
Appendix 5.
Pregnancy Precautions, Definition of Female of Childbearing Potential, and 
Contraceptive Measures .......................................................................................................111


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Appendix 6.
Laboratory Assessment Table ..............................................................................................114
Appendix 7.
American European Consensus Group (AECG) ..................................................................115
Appendix 8.
EULAR Sjogren’s Syndrome Disease Activity Index (ESSDAI) ........................................117
LIST OF IN-TEXT TABLES
Table 1-1.
Margins for GS-9876 Based on Systemic Exposure Relative to the Observed 
Human Exposure at 30 mg once daily (AUC)........................................................................20
Table 1-2.
Margins for GS-4059 Based on Systemic Exposure Relative to the Observed 
Human Exposure at 40 mg once daily (AUC)........................................................................23
Table 3-1.
List of Exploratory Biomarker Samples.................................................................................35
Table 7-1.
Grading of Adverse Event Severity........................................................................................80
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Design Schematic.........................................................................................................30


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
Study Title: 
A Randomized, Phase 2, Double-blind, Placebo-controlled Study 
to Assess the Safety and Efficacy of Filgotinib, GS-9876 and GS-
4059 in Adult Subjects with Active Sjogren’s Syndrome
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
123903
2016-003558-34
NCT03100942
Study Centers Planned:
Approximately 60-80 centers globally
Objectives:
The primary objective of this study is:

To assess the efficacy of filgotinib, GS-9876, and GS-4059 in
adult subjects with active Sjogren’s Syndrome (SjS)
The secondary objectives of this study are:

To assess the safety and tolerability of filgotinib, GS-9876,
and GS-4059 in active SjS

To assess the effect of filgotinib, GS-9876 and GS-4059 on 
patient reported outcomes in active SjS
The exploratory objectives of this study are:
CCI


Filgotinib, GS-9876 and GS-4059 
Protocol GS-US-445-4189 
Final 
Gilead Sciences, Inc. 
Amendment 1 
Study Design: 
This will be a multicenter, randomized, double-blind, 
placebo-controlled study to evaluate the safety and efficacy of 
filgotinib, GS-9876, and GS-4059 in adult male and female 
subjects with active SjS. Eligible subjects will be randomized 
Number of Subjects 
Plalllled: 
CONFIDENTIAL 
1: 1: 1: 1 to daily oral filgotinib (200 mg), or GS-987 6 (30 mg), or 
GS-4059 ( 40 mg) or placebo to match (PTM). Randomization will 
be stratified by: use of concunent immunomodulato1y drngs at 
baseline (YIN: conventional synthetic disease modifying 
anti.rheumatic drugs ( csDMARD[ s]) or corticosteroids), and the 
hematologic + biological component scores of the EULAR 
Sjogren's syndrome disease activity index (ESSDAI) obtained at 
screening ( combined score of <2 or~ 2). Stable medications at 
Day 1 should be continued during the study dosing period. Dose 
adjustments for toxicities and dose adjustment of corticosteroids 
after Week 12 a.re outlined in Section 5.8. 
At the Week 24 visit, subjects on placebo will be re-randomized 
1: 1: 1, in a blinded fashion, to daily oral filgotinib (200 mg), 
GS-9876 (30 mg), or GS-4059 (40 mg) without fmiher 
stratification. Dosing and assessments for all subjects will continue 
through Week 48. 
Subjects who intenupt or pennanently discontinue study drng 
dosing will continue the study visits, procedures, and assessments, 
if deemed medically a 'ppropriate by the investigator. 
Screening 
28 days 
Day l 
Placebo 
Week24 
Filgotinib 
200mgQD 
GS-9876 
30mgQD 
GS-4059 
40mgQD 
Filgotinib 200 mg QD 
GS-9876 30 mg QD 
GS-4059 40 mg QD 
Approximately 140 adult subjects with active SjS 
Page 7 
Week48 
FU visit 
4we-eks 
aftH 
dose- of 
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Target Population:
Male and female subjects with active SjS between 18 and 75 years 
of age (inclusive) at the time of consent 
Duration of Treatment:
Up to 48 weeks of dosing
Diagnosis and Main 
Eligibility Criteria:
Subjects must meet the all eligibility criteria participate in this 
study. For a complete list of study inclusion and exclusion criteria, 
please refer to Sections 4.2 and 4.3, respectively.

Male or female subjects between 18 and 75 years of age
(inclusive)

Diagnosed with SjS according to American European 
Consensus Group (AECG) classification

Active SjS as defined by an ESSDAI ≥5

Seropositivity for antibodies to SjS-associated antigens A and 
B (anti-SSA or anti-SSB)

No concurrent treatment with any bDMARD (washout as 
per protocol Section 5.8)
Study Procedures/
Frequency:
Participating subjects will visit the clinical study center at 
Screening, Day 1, Weeks 2, 4, 8, 12, 18, 24, 26, 28, 32, 36, 42 and
48 or early termination (ET) plus follow up visit.
At Day 1, after the subject’s eligibility for the study has been 
confirmed, the subject will be randomized into the study to receive 
filgotinib (200 mg), GS-9876 (30 mg), GS-4059 (40 mg), or PTM.
Screening and on-treatment assessments will include: Vital Signs, 
Physical Examination (PE), 28 Swollen and Tender Joint count, 
Investigator’s Assessment of SjS disease activity, Investigator’s 
global assessment of concomitant Rheumatoid Arthritis (RA) or 
Systemic Lupus Erythematosus (SLE) disease activity (as
applicable), ESSDAI, urine drug screen, pregnancy test (as
applicable),
, TB testing, 
chest X-ray (CXR as applicable), CD19+ B cell count (as 
applicable), HbA1c, Thyroid-Stimulating Hormone (TSH), 
hematology, Erythrocyte Sedimentation Rate (ESR) as available, 
chemistry and hsCRP, viral serology and viral monitoring (as 
applicable), autoantibodies, complement, immunoglobulins, fasting 
lipid profile, 
, Patient Reported Outcome (PRO) 
questionnaires and Visual Analogue Scales (VAS), Pulmonary 
Function Test (PFT as available), 
 
s test, concomitant medications, Adverse 
Events (AEs), and at available sites: m
 
CCI
CCI
CCI
CCI


Filgotinib, GS-9876 and GS-4059 
Protocol GS-US-445-4189 
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Test Product, Dose, and 
Mode of Administration: 
Reference Therapy, Dose, 
and Mode of 
Administration: 
Criteria for Evaluation: 
Safety: 
Efficacy: 
CONFIDENTIAL 
Final 
Amendment 1 
A resting 12-lead ECG should be perfonned at Screening, Day 1, 
Weeks 2, 8, 12, 24, 26, 32, 36 and 48 or ET. ECGs should be 
inte1preted by the investigator ( or qualified designee) for clinical 
significance. 
Post treatment follow-up assessments include AEs, concomitant 
medications, physical examination, 12-lead ECG, vital signs, 
blood and urine sampling for safety laborat01y tests, and urine 
pregnancy tests (if applicable). 
Filgotinib 200 mg (1 x 200 mg tablet), administered orally 
once daily 
GS-9876 30 mg (1 x 30 mg tablet), administered orally once daily 
GS-4059 40 mg (1 x 40 mg tablet), administered orally once daily 
PTM filgotinib (1 x placebo tablet), administered orally once daily 
PTM GS-9876 (1 x placebo tablet), administered orally once daily 
PTM GS-4059 (1 x placebo tablet), administered orally once daily 
Safety will be assessed through the repo1iing of AEs, clinical 
laborato1y tests, PEs, vital sign assessments, and ECGs at various 
time points during the study. 
The primaiy endpoint is the propo1iion of subjects fulfilling 
protocol-specified response criteria at Week 12, as compared to 
baseline. 
Response is defined as follows: 
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
For subjects with elevated hsCRP (defined as ≥1.5 upper limit 
of normal (ULN) of hsCRP) at Day 1, subjects are considered 
to be a responder if they achieve all of the following :
-
≥ 20% improvement in hsCRP
-
≥20% improvement in at least 3 out of 5 subject reported, 
SjS related visual analog scales (VAS; subject’s assessment 
of global disease, pain, oral dryness, ocular dryness and 
fatigue)
-
no worsening (defined as > 30 mm increase from baseline) 
in any of the above VAS

For subjects without elevated hsCRP (< 1.5 ULN of hsCRP) 
at Day 1, subjects are considered to be a responder if achieve 
all of the following:
-
no increase ≥ 1.5 ULN of hsCRP
-
≥20% improvement in at least 3 out of 5 subject reported, 
SjS related VAS (subject’s assessment of global disease, 
pain, oral dryness, ocular dryness and fatigue)
-
no worsening (defined as > 30 mm increase from baseline) 
in any of the above VAS
Secondary endpoints include: the change in ESSDAI and in
ESSPRI from baseline to Week 12 and 24
Pharmacokinetics:
Plasma concentrations of filgotinib (and its metabolite 
GS-829845), GS-9876, and GS-4059 will be listed and 
summarized using descriptive statistics.
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 fulfilling 
response criteria as outlined above. The primary analysis will 
consist of a superiority test of each of filgotinib, GS-9876 or GS-
4059 compared to placebo, respectively. Cochran Mantel Haenszel 
(CMH) approach adjusted for the randomization stratification 
factors will be used for the hypothesis testing at the 2-sided 0.05-
level.
Based on results of prior SjS studies, assuming a response rate of 
70% for the active arm and 30% for the placebo arm at Week 12, 
at least 35 evaluable subjects will be needed in each arm to achieve 
85% power to detect a significant difference at a 2-sided, 
0.05-level. Therefore, a total of approximately 140 subjects are 
planned to be enrolled in the study.


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All continuous endpoints will be summarized using an 8-number 
summary (n, mean, standard deviation [SD], median, 1st quartile 
[Q1], 3rd quartile [Q3], minimum, maximum) by treatment group 
and by study part. All categorical endpoints will be summarized by 
the number and percentage of subjects who meet the endpoint 
definition.
Safety endpoints will be analyzed by the number and percent of 
subjects with events or abnormalities for categorical values or 
8-number summary (n, mean, SD, median, Q1, Q3, minimum, 
maximum) for continuous data by treatment group and by study 
part.
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
ADL
Activities of Daily Living
AE(s)
Adverse Event(s)
AECG
American European Consensus Group
ALT
Alanine Aminotransferase
Anti-SSA
Anti-Sjogren’s-syndrome-related antigen A
Anti-SSB
Anti-Sjogren’s-syndrome-related antigen B
ATP
adenosine triphosphate
AST
Aspartate Aminotransferase
AUC0-Ʈ
Area under the plasma drug concentration-time curve of a dosing interval
AUROC
Area Under Receiver Operating Characteristic
BCR
B-cell receptor
bDMARD(s)
Biologic Disease Modifying Antirheumatic Drug(s)
BLQ
Below the Limit of Quantitation
BTK
Bruton’s tyrosine kinase
CƮ
Trough plasma concentration (just before the next dosing ie pre-dose sample)
Cave
Average observed concentration
CCP
Cyclic citrullinated peptide
csDMARD(s)
Conventional synthetic disease modifying antirheumatic drugs
CFR
Code of Federal Regulations
CIA
Collagen-Induced Arthritis
Cmax
Maximum observed plasma concentration
CLE
cutaneous lupus erythematosus
CMH
Cochran Mantel Haenszel
CNS
central nervous system
CRO
Contract Research Organization
hsCRP
High sensitivity C-Reactive Protein
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DAS28
Disease Activity Score based on 28 joints
DMARD(s)
Disease-Modifying Antirheumatic Drugs
DNA
Deoxyribonucleic acid
EC50
Half maximal effective concentration
ECG
electrocardiogram
eCRF
electronic Case Report Form
ESSDAI
EULAR Sjogren's syndrome disease activity index
ESSPRI
EULAR Sjogren's Syndrome Patient Reported Index
ET
Early Termination
EU
European Union


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EULAR
European League Against Rheumatism
FACIT-Fatigue
Functional Assessment of Chronic Illness Therapy-Fatigue
FDA
Food and Drug Administration
FEF
Forced expiratory flow
FEV
Forced expiratory volume
FSH
Follicle Stimulating Hormone
FVC
Forced vital capacity
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GGT
Gamma Glutamyl Transferase
HBsAg
Hepatitis B virus surface antigen
HBV
Hepatitis B virus
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
HLGT
High Level Group Term
HLT
High Level Term
HR
Heart Rate
IC50
Half maximal inhibitory concentration
ICF
Informed Consent Form
ICH
International Council for Harmonization
IDEEL
Impact of Dry Eye on Everyday Life
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IRB
Independent Review Board
IWRS
Interactive Web Response System
JAK
Janus kinase
LDL
Low Density Lipoprotein
LLOQ
Lower Limit Of Quantitation
LLT
Lower-Level Term
LMN
Lupus Membranous Nephropathy
MAD
Multiple Ascending Dose
MATE1
Multidrug and toxin extrusion protein 1
MCV
Mean Corpuscular Volume
MTX
Methotrexate
NOAEL
No-observed-adverse-effect-level


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NOEL
No-observed-effect-level
NSAIDs
Nonsteroidal anti-inflammatory drugs
OATP
Organic anion transporter polypeptide
OCT1
Organic cation transporter 1
OHIP- 14
Oral Health Impact Profile-14
PBMC
Peripheral blood mononuclear cells
PD
Pharmacodynamics
PE
Physical examination
PFT
Pulmonary Function Test
P-gp
P-glycoprotein
PK
Pharmacokinetics
PRO
Patient Reported Outcome
PROFAD-SSI- SF
Profile of Fatigue and Discomfort-Sicca Symptoms Inventory
PT
Preferred Term
PTM
Placebo To Match
PVE
Pharmacovigilance and Epidemiology
QD
quaque die; once daily
QTc interval
Corrected QT interval
RA
Rheumatoid Arthritis
ROC
Receiver Operating Characteristic
SAE(s)
Serious Adverse Event(s)
SAP
Statistical Analysis Plan
SF-36
Short-form health survey
SI
International system of units
SjS
Sjogren’s Syndrome
SLE
Systemic Lupus Erythematosus
SOC
System Organ Class
STAT
Signal Transducer and Activator of Transcription
SYK
Spleen tyrosine kinase 
TB
Tuberculosis
TBNK
T-cells, B-cells and NK cells
TEAEs
Treatment emergent adverse events
TFH
Follicular B T helper cells
tmax
Time of occurrence of maximum observed plasma concentration
TSH
Thyroid-Stimulating Hormone
TSQM
Treatment Satisfaction Questionnaire for Medication
UGT
Uridine 5’-disphosphate glucuronosyltransferase
ULN
Upper Limit of Normal
U/S
Ultrasound
VAS
Visual analog scale


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VC
Vital Capacity
VL
Viral Load
vs.
Versus
WBC
White Blood Cell


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1.
INTRODUCTION
1.1.
Background
Sjogren’s Syndrome (SjS) is estimated to affect approximately 1% of the population worldwide 
{Patel 2014}; it is a systemic autoimmune disease that is primarily diagnosed in women 40 to
60 years of age, but can occur at any age. About half of all patients with SjS also have another 
concurrent autoimmune disease, most often, RA or SLE. Although prior convention was to label
these patients as “secondary” SjS, the distinction is arbitrary and the designations of “primary” 
and “secondary” have fallen out of favor {The Sjogren's Syndrome Foundation 2016}.
The features of SjS include the classic symptoms of dry eyes and dry mouth, but also generalized 
fatigue with myalgias and arthralgias. Many patients with SjS also suffer from cognitive 
difficulties, and find it increasingly difficult to perform their occupation. Due to the nonspecific 
nature of the disease, it is often undiagnosed or misdiagnosed. Therefore, patients remain 
generally untreated, unless they have another autoimmune syndrome (eg, RA or SLE) for which 
they are receiving care. Immune dysfunction and autoimmunity are evident by the presence of 
antibodies to SjS-associated antigens A and B (SSA and SSB), and the abnormal histology of 
exocrine glands, with ectopic germinal center formation {Fox 2005}. Although the perception is 
that this disease is generally benign, there may be serious multiorgan consequences, including 
early cerebro-cardiovascular disease, pulmonary and renal disease {Fox 2005}. An increased risk 
of lymphoma has also been demonstrated for patients with SjS {Fox 2005}.
Therapeutic options for SjS are few. There are no approved disease-modifying, anti-rheumatic 
drugs (DMARDs) for SjS, and only limited clinical trial data in SjS for the various newer 
biologic and synthetic DMARDs approved for other indications. Milder SjS is often treated with 
oral and ocular hydration, non-steroidal anti-inflammatory drugs (NSAIDs), hydroxychloroquine
(HCQ) and/or low dose oral steroids. Although treatment with methotrexate (MTX) and other 
conventional synthetic immunomodulators has been attempted, there are no strong data 
demonstrating amelioration of disease or its long-term effects. Thus, a need exists for new 
therapies with proven benefit in this disease.
Filgotinib (GS-6034, formerly GLPG0634) is a potent and selective oral inhibitor of JAK1 being 
developed by Gilead Sciences, Inc. (Gilead) and Galapagos NV for the treatment of 
inflammatory diseases. JAK1 is believed to play an integral part in the pathogenesis of various 
autoimmune diseases, due to its role in inflammatory cytokine signaling.
GS-9876 is a potent and selective oral inhibitor of SYK being developed by Gilead for the 
treatment of inflammatory diseases. SYK is a cytoplasmic tyrosine kinase primarily expressed in 
cells of hematopoietic lineage, where it functions as a key signaling molecule mediating 
immunoreceptor signaling in a range of cells involved in inflammatory diseases.


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GS-4059, also named tirabmtinib, is a potent and selective oral inhibitor of BTK being 
developed by Gilead and Ono Phannaceutical Co, Ltd. (Ono) for the ti·eatment ofB-cell 
malignancies and inflammato1y diseases. BTK is an intracellular tyrosine kinase primarily 
expressed in hematopoietic cell lineages { Genevier 1994}, { de Weers 1993}, { Smith 1994}, and 
mediates immunoreceptor signaling in B lymphocytes, antigen-presenting cells , and mast cells, 
basophils, and osteoclasts. In addition, BTK is involved in integrin receptor and adaptor protein 
signaling, through which it plays a role in cell adhesion { de Rooij 2012} and osteoclast 
differentiation {Lee 2008}, {Shinohara 2008}, {Tai 2012}. 
Given the important roles of these proteins (JAKl, SYK, and BTK) in immune cell signaling, 
inhibition of these targets is expected to ameliorate autoimmune disease, via pleioti·opic 
anti-inflammato1y effects. 
1.2. 
Filgotinib 
1.2.1. 
Nonclinical Pharmacology and Toxicology 
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1.2.2. 
Clinical Trials of Filgotinib 
1.3. 
GS-9876 
1.3.1. 
1.3.1.1. 
Nonclinical Pharmacology and Toxicology 
Nonclinical Phaim acology and Safety Phaim acology 
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1.4. 
GS-4059 
1.4.1. 
Nonclinical Pharmacology and Toxicology 
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1.4.2. 
Clinical Trials of GS-4059 
1.5. 
Rationale for Current Study 
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Therapeutic options for SjS are few. There are no approved DMARDs for the ti·eatment of SjS, 
and there are only limited clinical ti·ial data in SjS using newer biologic and synthetic DMARDs 
approved for other indications. Milder SjS is often ti·eated with oral and ocular hydration, 
NSAIDS, HCQ and/or low dose oral steroids; highly active disease is ti·eated off-label with 
significant immunosuppression. Although u-eatment with MTX and other conventional synthetic 
immunomodulators has been attempted in SjS, there are no sti·ong data showing amelioration of 
the disease or its sequelae. {Kruszka 2009}, {Ramos-Casals 2005}, {Mariette 2015}. For the chy 
eyes and chy mouth associated with SjS (keratoconjunctivitis sicca and xerostomia), 
topical aiiificial tear solutions or muscarinic agonists such as pilocarpine and cevimeline {Rising 
Phaimaceuticals Inc }, {Pfizer 2014} are used for symptomatic conu-ol {Kruszka 2009}, {Wu 
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1.6.
Rationale for Dose Selection
Filgotinib: Results from Phase 2a studies (GLPG0634-CL-201 and GLPG0634-CL-202) and 
Phase 2b studies (GLPG0634-CL-203 and GLPG0634-CL-204) showed that 200 mg once daily 
filgotinib was well tolerated and demonstrated clinical efficacy (ACR20/50/70 and 
DAS28[CRP]) in subjects with RA. Exposure-response analysis of data from Phase 2 studies 
indicated a dose-dependent increase in efficacy, with a plateau at the 200 mg total daily dose on 
the dose-response curve. 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 the 200 mg total 
daily dose {Namour 2015}. Filgotinib 200 mg is one of the doses currently investigated in a 
phase 3 program for RA. Based on the overall risk-benefit ratio observed in Phase 2b studies, as 
well as the clinical overlap of RA and SjS, 200 mg once daily filgotinib is expected to be safe 
and to have the potential to be efficacious in SjS.
GS-9876: In the multiple ascending dose (MAD) study (GS-US-379-1900), doses of up to 50 mg
once daily GS-9876 for 7 days were well tolerated in healthy volunteers. The 30-mg once daily
dose of GS-9876 was the highest dose administered in Study GS-US-379-1582 in subjects with 
RA and was well-tolerated. Based on the similarity for risk-benefit between RA and SjS, 
30 mg once daily GS-9876 is expected to be safe and to have the potential to show clinical 
activity in SjS.
GS-4059: A dose of 40 mg once daily GS-4059 was selected for this study based on available 
PK, PD, and safety data, guided by the goal of maximizing target occupancy. Based on a PK/PD 
analysis from two Phase 1 studies in healthy volunteers and subjects with RA (GS-US-401-1765 
and GS-US-407-1833), a dose of 40 mg once daily GS-4059 is expected to provide near maximal 
BTK occupancy over the dosing interval (median >90% occupancy). In addition, the selection of 
40 mg once daily GS-4059 for this study is supported by the current overall safety and 
tolerability profile of GS-4059. Preliminary results from Study GS-US-407-1833 demonstrate 
that a total daily dose of 20 mg GS-4059 was well tolerated during a 4-week treatment period in 
subjects with RA (N=21). The maximum tolerated dose (MTD) of GS-4059 was 480 mg once 
daily in subjects with non-Hodgkin’s lymphoma, with dose limiting toxicity events of rash and 
non-immune reaction at the 600 mg once daily dose; no MTD was identified in subjects with 
chronic lymphocytic leukemia at doses up to 600 mg once daily. Therefore, 40 mg once daily 
GS-4059 is expected to be well tolerated and to have the potential to show clinical activity in 
subjects with SjS.
1.7.
Risk/Benefit Assessment for the Study
Sjogren’s Syndrome is a chronic, systemic inflammatory disease that affects approximately 
1% of the population. Currently, there are no DMARDs approved for the treatment of SjS. 
The need for new, therapeutic options with a favorable efficacy and safety profile has prompted 
efforts to evaluate orally administered, small molecules in this disease setting.
Please refer to respective Investigator’s Brochures (IB) for updated safety information and 
risk/benefit assessment.


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Filgotinib, a once-daily, oral, and potent JAK-1 inhibitor, is being developed for the treatment of 
RA and other autoimmune diseases.In the ongoing and concluded studies, filgotinib has been 
generally safe and well tolerated The primary endpoint was achieved in two large dose ranging 
studies (GLPG-CL-203 and GLPG-CL-204) evaluating the effect of filgotinib on RA disease 
activity. However, a potential increased risk of infection may be considered consistent with the 
mechanism of JAK inhibition. In the filgotinib RA program, deaths were reported due to 
infectious etiologies. 
Nonclinical studies in rats and dogs identified lymphoid tissues and testes as target organs for 
filgotinib; microscopic findings in the testes included germ cell depletion and degeneration in 
both species, with reduced sperm content and reduced fertility in male rats. The clinical 
relevance of nonclinical testicular findings in rats and dogs is unknown. A male safety study is
ongoing to assess the effects, if any, of filgotinib on semen parameters in males with 
inflammatory diseases. Until the definite results of this study are available, all males will be 
informed about this potential toxicity in the informed consent form and only men understanding 
and accepting the potential risk for loss of fertility will be enrolled. In addition SjS is a disease of 
female predominance and depending on the study population the incidence of SjS in females is 
reported to be 10 to 20 fold higher in females than males{Patel 2014}.
GS-9876 is a highly selective SYK inhibitor. SYK is a key signaling molecule involved in innate 
and adaptive immune system responses and is important in various cell types, including platelets, 
phagocytes, fibroblasts, and osteoclasts, and in the generation of the inflammasome. 
Nonclinical studies show that SYK inhibition may have therapeutic value in the treatment of 
allergic and autoimmune diseases. Clinical trials with fostamatinib (an experimental SYK 
inhibitor) have demonstrated responses in RA and in idiopathic thrombocytopenic purpura.
In non-clinical studies of GS-9876 in rats and in cynomolgus monkeys, the primary observed 
effects were reversible, dose-dependent decreases in circulating lymphocytes and lymphocytes in 
various tissues (spleen, lymph nodes, thymus, and/or bone marrow), consistent with the expected 
pharmacology of SYK inhibition {Barr 2012}. Additionally, effects on erythrocyte turnover were 
seen in rats, and effects on hemostasis (hemorrhage and thrombosis) were seen in monkeys. In 
the ongoing and concluded clinical studies, GS-9876 generally has been well tolerated.
GS-4059 is a highly selective BTK inhibitor. BTK is primarily expressed in cells of the 
hematopoietic lineage. It is a key mediator in coupling activated immunoreceptors to 
downstream signaling events that affect diverse biological functions, from cellular proliferation, 
differentiation and adhesion to innate and adaptive immune responses. As such, pharmacological 
inhibitors of BTK are being actively pursued as potential immunomodulatory agents for the 
treatment of autoimmune and inflammatory disorders.


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In non-clinical studies of GS-4059 in rats and in monkeys, the primary effects were generally 
minor, reversible, dose-dependent decreases in lymphocytes in various tissues (spleen, lymph 
nodes, and/or thymus) consistent with expected pharmacologic effects of BTK inhibition. 
Additionally, minor, reversible effects on erythrocytes were seen in rats and monkeys. Effects on 
the pancreas, adrenal and thyroid glands, liver and kidney in rats were considered to be 
species-specific and of limited to no relevance to humans. In clinical studies of GS-4059 in 
healthy volunteers and subjects with RA, a 20 mg daily dose of GS-4059 was generally well 
tolerated. Further, doses up to 600 mg of GS-4059 have been administered to patients with 
hematologic malignancies with an acceptable safety profile for the population studied.
Based on available non-clinical findings, GS-9876 is not contraindicated in pregnancy, although 
pregnancy in GS-9876 trials should be avoided. However, filgotinib and GS-4059 are 
contraindicated in pregnancy; highly effective contraception is to be used across all clinical 
studies to mitigate this risk. Measures to minimize other potential risks to subjects will include 
site/investigator training regarding monitoring for infection, and collection of AEs of special 
interest, including major adverse cardiac events, malignancies, infections, and specific laboratory 
abnormalities.
Preclinical and clinical data for filgotinib, GS-9876, and GS-4059 indicate that these novel 
agents have potential to offer therapeutic benefit in autoimmune and inflammatory diseases
including SjS. These drugs have an acceptable level of risk that is consistent with that of other 
immunomodulatory agents in patient populations with autoimmune diseases. Given the clinical
and nonclinical data available to date for these 3 drugs, and their overall safety, tolerability, and 
PK characteristics, there is a favorable benefit: risk profile for development of these agents in 
SjS. This study will help to determine the potential of filgotinib, GS-9876, or GS-4059 as much 
needed alternatives to existing treatment options for SjS and related diseases.
1.8.
Compliance
This study will be conducted in compliance with this protocol, GCP, and all applicable 
regulatory requirements.


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2.
OBJECTIVES AND ENDPOINTS
Study Objectives
Study Endpoints
Primary objective:

To assess the efficacy of filgotinib, GS-9876, and 
GS-4059 in adult subjects with active SjS
Primary endpoint:
The primary endpoint is the proportion of subjects 
fulfilling protocol-specified response criteria at 
Week 12, as compared to baseline.
Response is defined as follows:

For subjects with elevated hsCRP (defined as ≥ 1.5 
upper limit of normal (ULN) of hsCRP) at Day 1, 
subjects are considered to be a responder if they 
achieve all of the following :
-
≥ 20% improvement in hsCRP
-
≥20% improvement in at least 3 out of 5 
subject reported, SjS related visual analog 
scales (VAS; subject’s assessment of global 
disease, pain, oral dryness, ocular dryness and 
fatigue)
-
no worsening (defined as > 30 mm increase 
from baseline) in any of the above VAS

For subjects without elevated hsCRP (< 1.5 ULN of 
hsCRP) at Day 1, subjects are considered to be a 
responder if achieve all of the following:
-
no increase ≥ 1.5 ULN of hsCRP
-
≥20% improvement in at least 3 out of 5 
subject reported, SjS related VAS (subject’s 
assessment of global disease, pain, oral 
dryness, ocular dryness and fatigue)
-
no worsening (defined as > 30 mm increase 
from baseline) in any of the above VAS
Secondary objectives:

To assess the safety and tolerability of filgotinib, 
GS-9876, and GS-4059 in adult subjects with active 
SjS

To assess the effect of filgotinib, GS-9876, and GS-
4059 on patient reported outcomes in active SjS, 
including fatigue, disability, and quality of life
Secondary endpoints:

Change from baseline in ESSDAI and ESSPRI at 
Weeks 12 and 24.


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Study Objectives
Study Endpoints
The exploratory objectives of this study are:
The exploratory endpoints of this study are:
CCI CCI


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3. 
STUDY DESIGN 
3.1. 
Study Design 
Final 
Amendment 1 
Adult male and female subjects who provide written, info1med consent will enter a Screening 
period (28 days) during which they will be evaluated for eligibility, based on the 
Inclusion/Exclusion criteria. 
At Day 1, eligible subjects will be randomized to study dmg (see Section 3.2). Subjects will 
return to the study site for scheduled study visits at Weeks 2, 4, 8, 12, 18, 24, 26, 28, 32, 36, 42 
and 48. After completion of the Week 24 assessments and procedures, subjects on placebo will 
be re-randomized 1: 1: 1 to filgotinib, or GS-987 6, or GS-4059, in a blinded fashion. Dosing will 
continue through Week 48. 
Subjects who discontinue study drng for any reason ( other than noncompliance) may continue to 
pa1iicipate in scheduled study visits and procedures, as long as deemed medically appropriate by 
the investigator. Subjects who discontinue all study participation will have an early te1mination 
(ET) visit; these subjects, and those who complete the study, should return to the study site for a 
follow-up visit, 4 weeks after the last dose of study dmg (subjects who have discontinued study 
dmg 
4 weeks prior to the ET/Week 48 visit, do not need a follow up visit). 
Figure 3-1. 
Screening 
28 days 
Study Design Schematic 
Dayl 
Placebo 
Week24 
Filgotioib 
200mgQD 
GS-9876 
30mgQD 
GS-4059 
40 mgQD 
Filgotinib 200 mg QD 
GS-9876 30 mg QD 
GS-4059 40 mg QD 
For details regarding dosing and blinding, see Section 5.7. 
Week48 
FU visit 
4week.5 
aft.et· last 
dose of 
study 
drug 
For details regarding concomitant and excluded medications, see Section 5.8. 
For study visit schedule and procedures, including clinical laborato1y tests and 
see Schedule of Activities in Section 6 and Appendix 2. 
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3.2. 
Study Treatments 
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Following completion of screening assessments, eligible subjects will be randomized 1: 1: 1: 1 in a 
blinded fashion to active investigational product or PTM: 
• 
Filgotinib 200 mg arm (n=35): filgotinib (1 x 200 mg tablet once daily) + PTM GS-9876 
(1 x tablet once daily) + PTM GS-4059 (1 x tablet once daily) 
• 
GS-9876 30 mg arm (n=35): PTM filgotinib (1 x tablet once daily) + GS-9876 (1 x 30 mg 
tablet once daily) + PTM GS-4059 (1 x tablets once daily) 
• 
GS-4059 40 mg arm (n=35): PTM filgotinib (1 x tablet once daily)+ PTM GS-9876 
(1 x tablet once daily) + GS-4059 (1 x 40 mg tablet once daily) 
• 
Placebo arm (n=35): PTM filgotinib (1 x tablet once daily) + PTM GS-9876 (1 x tablet 
once daily) + PTM GS-4059 (1 x tablet once daily) 
Randomization will be stratified by use of concmTent immunomodulato1y drngs at baseline 
(YIN: csDMARDs or corticosteroids), and the hematologic + biological component scores of the 
ESSDAI obtained at screening (combined score of <2 or ~ 2). 
3.3. 
Duration of Treatment 
Subjects will be dosed for up to 48 weeks and will retmn for a Follow-Up Visit, 4 weeks after 
their last visit (Week 48 or ET); the Follow-Up Visit will not be perfonned if the subject has 
discontinued study drng 
4 weeks prior to their final study visit. 
3.4. 
Criteria for Interruption and Discontinuation Criteria 
If a subject discontinues study dosing (for example, as a result of an AE), eve1y attempt should 
be made to keep the subject in the study and continue to perfonn the required study-related 
follow-up and procedm es. If this is not possible or acceptable to the subject or investigator, 
the subject may be withdrawn from the study. In these cases, an Early Termination visit should 
be perfonned as soon as possible. 
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3.4.1.
Study Drug Interruption Considerations
The 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 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.

If the subject has any signs or symptoms suggestive of infection (regardless of severity), 
study drug dosing should be immediately interrupted, and the medical monitor notified. 
Any subject who develops a new infection during the study should undergo prompt and 
complete diagnostic testing appropriate for an immunocompromised individual, and the 
subject should be closely monitored. Study treatment should not be resumed until the 
subject’s event has resolved, per judgment of the investigator.
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.
3.4.2.
Study Drug Discontinuation Considerations
The Medical Monitor should be consulted prior to study drug discontinuation whenever 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)

Unacceptable toxicity, or toxicity that, in the judgment of the investigator, compromises the 
subject’s ability to continue study-specific procedures or is not considered to be in the 
subject’s best interest

Need for prohibited concomitant medication (see Section 5.8)


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
Subject request to discontinue for any reason

Subject noncompliance, as per judgment of investigator

Request from Gilead, a regulatory agency or an IRB or IEC

Female subject becomes pregnant during the study; refer to Section 7.7.2.1

Positive HCV VL

Investigator discretion

Laboratory criteria:
After becoming aware of any of the below described abnormal laboratory values at any time, 
an unscheduled visit should occur within 3 to 7 days, with the exception of creatinine 
clearance which should be retested within 7 to 14 days. Retest may be obtained sooner if 
medically indicated per investigator judgment. If the laboratory abnormality is confirmed by 
the retest, then study medication should be discontinued and further care of the subject 
should be directed per the investigator.
total white blood cell (WBC) count < 2000 cells/mm3 (SI: < 2.0x109 cells/L)
neutrophil count < 1000 neutrophils/mm3 (SI: < 1.0x109 cells/L)
hemoglobin < 8.0 g/dL (SI: < 80 g/L)
platelet count < 75,000 platelets/mm3 (SI: < 75.0x109 cells/L)
AST or ALT elevation:
■
> 3xULN with at least 1 total bilirubin value >2xULN
■
> 3xULN with elevated international normalized ratio (INR)
■
> 5xULN, regardless of total bilirubin or accompanying symptoms
Note: For the above described AST or ALT elevations, additional investigations (such as:
review of ethanol, recreational drug use, dietary supplement consumption; testing for 
acute hepatitis A, B or C infection and biliary tract imaging) should be promptly
considered by the investigator; these subjects should be discussed with the study Medical 
Monitor.
estimated creatinine clearance < 40 mL/min based on the Cockroft-Gault formula


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Subjects who stop study chugs for any reason will not be replaced. Subjects withdrawing from 
the study should complete the ET and 4 week Follow Up visits, as applicable. Subjects may 
withch·aw from the study at any time without providing reason(s) for withch·awal and without 
prejudice to fmther ti·eatment. The reason(s) for withch·awal will be documented in the somce 
documents and in the electi·onic case repo1i f01m (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. 
3.5. 
End of Study 
The end of study is defined as when the last subject has completed their final study visit 
(Week 48 or ET) plus the 4 week post ti·eatment visit (Follow-Up Visit - if applicable). 
3.6. 
Post Study Care 
The long tenn care of subjects will remain the responsibility of their prima1y ti·eating physician. 
3.7. 
Bio marker Testing 
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Table 3-1.
List of Exploratory Biomarker Samples
3.7.1.
Biomarker Samples to Address the Study Objectives:
The following biologic specimens will be collected in this study in order to evaluate the 
association of exploratory systemic and/or tissue specific biomarkers with study drug response, 
including efficacy and/or adverse events, and to increase knowledge and understanding of SjS
and related diseases, the development of a companion diagnostic, and/or to help inform how 
inhibition of JAK1, SYK, or BTK affect downstream markers. Because biomarker science is a 
rapidly evolving area of investigation, it is not possible to specify prospectively all tests that will 
be done on the specimens provided. The testing proposed in Table 3-1 based upon the current
state of scientific knowledge. It may be modified during or after the end of the study to remove 
tests and/or to add new tests based upon the growing state of knowledge. The biomarker sample 
collection schedule is described in the Schedule of Assessments Table (Appendix 2).
CCI


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3.7.2. 
Biomarker Samples for Optional Future Research 
3.7.3. 
Biomarker Samples for Optional Genomic Research 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 140 subjects will be enrolled in this study.
4.2.
Inclusion Criteria
Subjects must meet all of the following criteria to be eligible for participation in this study.
Retesting of screening laboratory tests may be performed one time prior to screen-failing the 
subject, if the investigator deems that the initial value was inconsistent with the subject’s 
previous results; due either to error (eg, a mishandled/hemolyzed sample), or to an extenuating 
circumstance which has since resolved.
1) Male or female 18 to 75 years of age (inclusive) at the time of signing initial consent, 
with all of the following at Screening:
a.
Diagnosis of SjS based on AECG classification (Appendix 7)
b. Active SjS, with ESSDAI ≥5
c.
Seropositivity for anti-SSA or anti-SSB, per central laboratory
2) A negative serum pregnancy test at Screening and a negative urine pregnancy test at 
Day 1 are required for female subjects of child-bearing potential (as defined in
Appendix 5)
3) Starting at the time of written consent, through the study, and for 90 days (male) 
and 36 days (female) following their last dose of study drug:
a.
Male 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,
b. Male subjects must agree to refrain from sperm donation
c.
Female subjects must agree not to breastfeed or to donate/harvest eggs for the 
purpose of fertilization,
4) Subjects with prior exposure to a B-cell depleting bDMARD (at any time) must have a 
documented return of CD19+ B cells at Screening.
5) Stable dose (defined as no change in prescription for at least 4 weeks prior to Day 1) of
NSAIDs, HCQ, MTX and/or oral corticosteroids is permitted during the study, but not 
required (see protocol Section 5.8 for definitions, full list of allowed prior and 
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6) Meet one of the following (a or b) tuberculosis (TB) Screening criteria:
a.
No evidence of active or latent TB:

Negative history of TB infection and

Negative QuantiFERON® TB-Gold In-Tube test and
Note: QuantiFERON® tests with inconclusive results may be repeated one time. 
If the repeat result is also inconclusive, the subject is excluded from the study.

Negative chest X-ray results (radiographs taken at Screening or within 
90 days prior to Screening with films or report available for investigator 
review).
b. Subjects with prior latent TB who have been treated with a full course of 
prophylaxis as per local guidelines.
Note:
Appropriate documentation of previous treatment is required.
In these cases, a QuantiFERON® TB-Gold In-Tube test is not needed, but a chest 
radiograph must be obtained within 3 months prior to Screening (report or films 
must be available).
In addition, these cases must be approved by the Medical Monitor prior to 
enrollment.
Subjects with a new diagnosis of latent TB or prior untreated/partially treated 
latent TB are NOT allowed (ie, subjects who require prophylactic therapy for TB 
during the study). Subjects with any prior active TB are excluded regardless of 
treatment.
7) Are willing and able to sign the informed consent form and comply with study 
requirements, procedures, and scheduled visits.
Note:
Subjects who cannot read or understand the ICF may not be enrolled by a guardian, 
representative, or any other individual
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria must not be enrolled in this study.
1) Concurrent treatment at Screening with any bDMARD (prior bDMARD treatment 
allowed with appropriate washout as defined in Section 5.8)
2) Any prior use of cyclophosphamide
3) Use of cyclosporine within 4 weeks prior to the first dose of study drug (Day 1) or 
anticipated chronic use while on study (other than ophthalmic cyclosporine as described 
as per Section 5.8)


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4) Clinically significant abnormalities on 12-lead ECG as judged by the investigator.
5) Treatment with moderate or strong CYP3A inducers or inhibitors within 2 weeks, or 
strong P-gp inducers within 3 weeks prior to the first dose of study drug (Day 1) or 
anticipated chronic use while on study (see Section 5.8)
6) Participation in any clinical study of an investigational drug within 4 weeks or 5 drug 
half-lives prior to Screening, whichever is longer. Washout duration for exposure to 
investigational biologics should be discussed with the sponsor
7) Treatment with any commercially available or investigational drug listed below within 
3 months of Screening:
a.
BTK inhibitor, such as ibrutinib, or
b. SYK inhibitor, such as fostamatinib, or
c.
JAK inhibitor, such as tofacitinib or baricitinib
8) History of opportunistic infection or immunodeficiency syndrome which would put the
subject at risk, as per investigator judgment
9) History of symptomatic Herpes zoster or Herpes simplex infection within 12 weeks prior 
to Screening or history of disseminated/complicated Herpes zoster infection 
(multi-dermatomal involvement, ophthalmic zoster, CNS involvement or postherpetic 
neuralgia) at any time
10) Known hypersensitivity to the study drug, its metabolites, or any of the excipients,
or previous clinically significant allergic reaction to any drug, per judgment of the 
investigator
11) Another highly active inflammatory/autoimmune/rheumatic disease (such as highly 
active RA, highly active SLE, highly active nephritis or CNS inflammation) which would 
compromise subject safety or interfere with the conduct of the study.
Note:
Subjects with stable autoimmune disease, (eg, RA, SLE, or thyroiditis) not requiring 
prohibited medications are permitted
12) History of head/neck irradiation, sarcoidosis, graft v host disease, or IgG4 related disease
{Stone 2012}, {Umehara 2012}
13) Female subjects who are pregnant, breastfeeding, or planning to become pregnant or 
breastfeed during the study up to 36 days after the last dose of study drug or males who 
are planning to father a child during the study up to 90 days after the last dose of study 
drug (as per Appendix 5)


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14) Major surgery (requiring regional block or general anesthesia) within 30 days prior to 
Screening, or planned during the study
15) History of live or attenuated vaccines within 30 days of Day 1, or planned during the 
study period or for 12 weeks after the subject's last dose of study drug. Refer to 
Section 5.9
16) History of malignancy within the past 5 years prior to Screening (except for adequately 
treated basal cell carcinoma or non-metastatic squamous cell carcinoma of the skin or 
cervical carcinoma in situ, with no evidence of recurrence). 
17) Positive serology for human immunodeficiency virus (HIV) 1 or 2 at Screening,
18) Hepatitis B virus (HBV) surface antigen (HBsAg) or positive HBV core antibodies at 
Screening
19)Hepatitis C virus (HCV) antibodies and positive HCV RNA viral load (VL).
Note:
Subjects with positive HCV Ab, but negative HCV RNA VL are eligible per 
investigator judgment, but require monitoring as outlined in Appendix 2.
Subject with active HCV during the study as evidenced by RNA positivity will be 
discontinued from study drug as outlined in Section 3.4.
20) Serious active infection of any kind at Screening or Day 1
21) Blood loss (> 500 mL) or blood product transfusion within 12 weeks of Day 1
22) Known bleeding disorder or hypercoagulable state; antiphospholipid antibody syndrome 
with prior clinically significant event (per judgment of investigator); or on chronic 
anticoagulation or anti-platelet therapy
Note:
Aspirin therapy ≤325 mg/day for cardiovascular prophylaxis is permitted
23) Current drug or alcohol abuse, or heavy tobacco use, as per judgment of investigator
24) Clinically significant laboratory values at Screening, including the following:
a.
Hemoglobin <9 g/dL (International System of Units [SI]: <90 g/L)
b. Neutrophil count <1.5 x 109/L (SI: <1.5 x 109 cells/L)
c.
Platelets <100 x 103 cells/mm3 (SI: <100 x 109 cells/L);
d. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥1.5x upper 
limit of normal (ULN)


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e.
Total bilirubin level ≥2x ULN unless the subject has been diagnosed with 
Gilbert’s disease and this is clearly documented
f.
Estimated creatinine clearance <60 mL/min per Cockcroft-Gault equation
Note:
Abnormal values may be rechecked one time, at discretion of the investigator if 
an error is suspected
4.4.
Screen Failure
Subjects who do not meet the Inclusion/Exclusion criteria for entry into the study 
(“screen failures”) may be rescreened one time in selected cases with written permission from 
the Sponsor; for example, to meet a drug washout period.
Subjects who do not enter the study due to administrative reasons (for example, exceeding the 
screening window due to issues with appointment scheduling or obtaining results of laboratory 
data) may be rescreened one time with written permission from the Sponsor; this rescreening 
option is in addition to the rescreening permitted above.
Neither of the rescreening options is to be used to recheck a subject who is likely unsuitable for 
the study, for example, to check whether their chronically abnormal laboratory test is closer to 
normal range.
Subjects who are permitted to rescreen must repeat the informed consent process and sign a new 
consent form; they will receive a new subject number. In these cases, lab screening tests do not 
need to be repeated if they were performed within 28 days of randomization, and within 90 days 
for Quantiferon and/or Chest X-ray, if needed.


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5. 
INVESTIGATION AL MEDICINAL PRODUCTS 
5.1. 
Randomization, Blinding and Treatment Codes 
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An Interactive Web and Mobile Response System (IWRS) will be employed to manage subject 
randomization and ti·eatment assignments. It is the responsibility of the investigator to ensure that 
the subject is eligible for the study prior to emollment. 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 ti·eatment 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 necessaiy to detennine emergency medical cai·e for the subject. 
The rationale for unblinding must be clearly explained in source documentation and on the 
elecu-onic case repo1i fonn (eCRF), along with the date on which the ti·eatment assignment was 
unblinded. The investigator is requested to contact the Gilead Medical Monitor promptly in case 
of any ti·eatment unblinding. 
Blinding of study ti·eatment is critical to the integrity of this Phase 2 clinical ti·ial and therefore, 
if a subject's u-eatment assignment is disclosed to the investigator, the subject will be 
discontinued from the u-ial. 
Gilead Phaim acovigilance and Epidemiology (PVE) may independently unblind cases for 
expedited repo1i ing of suspected unexpected serious adverse reactions (SUSARs) to Regulato1y 
Authorities. 
5.2. 
Description of Filgotinib and PTM Filgotinib 
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5.3. 
Description of GS-9876 and PTM GS-9876 
5.4. 
Description of GS-4059 and PTM GS-4059 
5.5. 
Packaging and Labeling of All Study Drugs for this Protocol 
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Filgotinib 200 mg tablets, PTM filgotinib 200 mg tablets, GS-9876 30 mg tablets, PTM GS-9876 
30 mg tablets, GS-4059 40 mg tablets, and PTM GS-4059 40 mg tablets for each drng are 
packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 30 tablets, 
silica gel desiccant and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child-resistant polypropylene screw cap with an induction-sealed and 
aluminum-faced liner. 
All study chug( s) to be disti·ibuted to centers in the US and other paiiicipating counti·ies shall be 
labeled to meet applicable requirements of the United States Food and Drng Adminisu-ation 
(FDA), the European Union (EU) Guideline to Good Manufacturing Practice-Annex 13 
(Investigational Medicinal Products), and/or other local regulations, as applicable. 
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5.6.
Storage and Handling of Study Drugs
Study drugs (filgotinib, GS-9876, GS-4059, and PTM tablets for each) should be stored at 
controlled room temperature of 25°C (77°F); excursions are permitted between 15°C and 30°C 
(59°F and 86°F). Storage conditions are specified on the label. Until dispensed to the subjects, 
all bottles of study drugs should be stored in a securely locked area, accessible only to authorized 
site personnel.
To ensure the stability and proper identification, study drug(s) should not be stored in a container 
other than the container in which they were supplied.
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling.
5.7.
Dosage and Administration of Investigational Medicinal Products
Subjects will receive study drugs according to their randomization arm as described in 
Section 3.2.
The study drugs should be administered orally once daily with water, with or without food. 
The study drugs should be swallowed whole and all 3 tablets administered at the same time. 
Subjects should be instructed to take study drugs at approximately the same time each morning.
On study visit days, subjects should not take their study drugs at home, but should bring them to 
the clinic and take them as instructed by site staff (in order to enable timing of PK blood draws 
and/or other procedures).
On Day 1, subjects will be instructed to take their dose in clinic as the last in-clinic study 
procedure (after all other procedures for that visit have been completed).
At Weeks 4, 8, 12, 24, 36 and 48/ET, subjects will be instructed to take their dose after 
PK assessments have been completed.
At Week 18, subjects will be instructed to take their dose in clinic in order to have a pre-dose 
biomarker blood draw, and a post-dose PK and biomarker blood draw approximately 2 hours 
after study drug administration.
For a missed dose of study medication, subjects should be instructed to take the missed dose of 
study medication as soon as possible during the same day. If more than 12 hours have elapsed 
since the scheduled time of the missed dose, the subject should be instructed to return the missed 
unused tablets to the study drug bottles and take the next dose at the regularly scheduled time. 
Subjects should be reminded never to double the missed dose of study drug with their next dose, 
under any circumstances.


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5.8.
Prior and Concomitant Medications

Prior medications that are allowed in this study:
See I/E criteria

Prior medications that are prohibited in this study:
See I/E criteria

Concomitant medications allowed in this study:
Doses of concomitant chronic medications should be stable (defined as no change in 
prescription for at least 28 days prior to Day 1) and should be continued at the stable dose 
throughout at least the first 12 weeks of the study. However, dose adjustments for toxicities 
are allowed, and should be recorded in the eCRF, along with documentation of the AE 
requiring the dose change.
Cevilimine or pilocarpine, as prescribed by investigator.
Ophthalmic cyclosporine, as prescribed by investigator.
Oral NSAIDs, as prescribed by investigator.
Oral or injectable MTX ≤ 20 mg per week (subjects on MTX should also be on chronic 
folic acid supplementation [or equivalent], as per local standard of care).
All local standard of care practices for the administration of MTX, including laboratory 
testing, follow-up care, and contraindications should be performed throughout the study. 
The concomitant use of medicines which may increase the risk of hepatotoxicity and/or 
nephrotoxicity with MTX (such as NSAIDs, salicylates, leflunomide, or other folate 
antagonists) should be avoided, as much as possible, in accordance with clinical practice.
Chloroquine ≤250 mg/day or HCQ ≤400 mg/day.
Oral leflunomide ≤ 20 mg/day (Leflunomide in combination with MTX is not allowed)
Azathioprine up to maximum of 2 mg/kg or 300 mg, whichever is lower
Vitamins, minerals, or herbal supplements, as per judgment of the investigator.
Note: after completion of the Week 12 visit, the dose of any of the above medications 
may be reduced, and subsequently increased, as often as needed, per judgment of the 
investigator; however, the highest dose prescribed should not exceed the subject’s 
Baseline dose. Subjects requiring a dose higher than their Baseline dose for more than 
14 consecutive days should be withdrawn from study drug, but may continue with study 
visits.


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Oral corticosteroids ≤10 mg prednisone (or equivalent) per day.
Note: after completion of the Week 12 visit, the dose of corticosteroids may be reduced,
and subsequently increased, as often as needed, per investigator judgment; however, the 
dose should not exceed the subject’s Baseline dose. Subjects requiring oral 
corticosteroids > 10 mg prednisone/day should be withdrawn from study drug, but may 
continue with study visits.
Other chronic therapies at stable doses (eg, antihypertensives, female hormone
replacement therapy, thyroid replacement therapy, anti-depressants), as per judgment of 
the investigator.

Concomitant medications that are not allowed in this study:
Cyclophosphamide
Cyclosporine (other than ophthalmic cyclosporine, as described above)
Moderate or strong CYP3A inhibitors or inducers are prohibited within 2 weeks prior to 
the first dose of study drug and throughout the study. Strong P-gp inducers are prohibited 
within 3 weeks prior to the first dose of study drug and throughout the study.
Examples of these medicines are provided below.
This list does not include medications such as anti-HIV agents that would be contraindicated 
based on other exclusion criteria (questions regarding these medications should be discussed 
with the Medical Monitor):
Drug Class
Agents Disallowed
Strong CYP3A Inhibitorsa
clarithromycin, conivaptan, itraconazole, ketoconazole, nefazodone, posaconazole, 
telithromycin, voriconazole, telaprevir, boceprevir, grapefruit juice, idelalisib,
Viekira Pak (ombitasvir, paritaprevir, ritonavir, dasabuvir), troleandomycin, 
mibefradil
Strong CYP3A Inducersa, b
Carbamazepine, phenytoin, rifampin, fosphenytoin, pentobarbital, primidone, 
rifabutin, rifapentine, phenobarbital, mitotane, avasimibe, St. John’s Wort, 
enzalutamide
Strong P-gp inducersc
Phenobarbital, phenytoin, carbamazepine, rifabutin, rifapentine, rifampin, St. 
John’s wort, danshen (salvia miltiorrhiza)
Moderate CYP3A Inhibitorsa,
fluconazole, erythromycin, diltiazem, dronedarone, aprepitant, casopitant, imatinib, 
verapamil, tofisopam, ciprofloxacin, cimetidine, cyclosporine, Schisandra 
sphenanthera, crizotinib, netupitant, nilotinib, isavuconazole
Moderate CYP3A Inducersa
bosentan, thioridazine, nafcillin, modafinil, semagacestat, genistein
a In vitro data indicated GS-9876 is a substrate of CYP3A4. Co-administration of CYP3A inhibitors may increase GS-9876 
exposure and coadministration of CYP3A inducers may decrease GS-9876 exposure.
b GS-4059 is a substrate of CYP3A and P-gp. Coadministration of strong CYP3A/P-gp inducers may decrease GS-4059
exposure.
c Filgotinib is a P-gp substrate. Coadministration of strong P-gp inducers may decrease filgotinib exposure.


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GS-4059 has the potential to inhibit P-gp, which may affect the plasma concentrations of 
its substrates. Caution should be exercised when co-administering medicines that are
P-gp substrates with narrow therapeutic windows, such as digoxin, dabigatran etexilate, 
ranolazine and aliskiren
The following medications are prohibited within 4 weeks prior to the first dose of study 
drug and throughout the study: gold salts, minocycline, penicilamine, sulfasalazine, 
tacrolimus, sirolimus, everolimus, mycophenolate mofetil, etanercept, adalimumab, 
anakinra, or biosimilar versions of these drugs, where applicable
The following medications are prohibited within 10 weeks prior to the first dose of study 
drug and throughout the study: infliximab, golimumab, certolizumab pegol, abatacept, 
tocilizumab, or biosimilar versions of these drugs, where applicable
Parenteral corticosteroids are prohibited during the first 24 weeks of the study (except for 
one joint injection, at a maximum dose of 40 mg triamcinolone, or equivalent; the injected
joint should be marked as “non-assessible” for the remainder of the study
Concurrent therapy with any anti-coagulant (eg, coumadin [warfarin], any Vitamin K 
antagonist, any novel oral anticoagulant, heparins or low molecular heparins, any 
inhibitors of factor Xa) or any anti-platelet therapy (eg, adenosine diphosphate [ADP] 
receptor inhibitors, phosphodiesterase inhibitors, Protease-activated receptor 1 (PAR-1)
antagonists, Glycoprotein 2b/3a inhibitors). NOTE: aspirin therapy ≤325 mg/day for 
cardiac prophylaxis is allowed.
5.9.
Vaccine Guidelines

Prior to study participation, it is recommended that the subject’s vaccinations be brought up 
to date according to local vaccination standards, as much as possible.

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 12 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 with vaccinated person 
for 4 weeks following vaccination
Oral polio vaccination – avoid contact with vaccinated person for 6 weeks following 
vaccination
Attenuated rotavirus vaccine – avoid contact with vaccinated person for 10 days 
following vaccination


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Inhaled flu vaccine – avoid contact with vaccinated person for 1 week following 
vaccination

Inactivated vaccines (such as non-live flu vaccines) should be administered according to 
local vaccination standards whenever deemed medically appropriate by the investigator; 
however, there are no available data on the concurrent use of filgotinib, GS-9876,
or GS-4059 and their respective impacts (if any) on immune responses following 
vaccination.
5.10.
Investigational Medicinal Product Accountability and Disposal or Return
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drugs. This includes acknowledgement of receipt of each shipment of IMP (quantity and 
condition). All partially used or unused study drugs dispensed to subjects must be returned to the 
site.
Study drug accountability records will be provided to each study site to:

Record the date received and quantity of study drugs

Record the date, subject number, subject initials, the study drug numbers dispensed

Record the date, quantity of used and unused study drugs returned, along with the initials of 
the person recording the information.

For additional information about study drug accountability and return, refer to Section 9.1.7.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. Additional information is 
provided in the site operations manual.
The investigator should document any deviation from protocol procedures and notify the sponsor 
or its designee.
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that subjects are eligible to participate in the 
study prior to randomization/enrollment and throughout the study.
Once consent has been obtained, all screening tests and procedures have been assessed, 
and study eligibility has been confirmed, eligible subjects will be randomized to study treatment 
as described in Section 3.2.
The study center will not be activated and allowed to screen patients until:

The IRB or IEC have reviewed and approved the study and the informed consent document

All required regulatory documents have been submitted to and approved by Gilead or its 
designee

A master services agreement and/or study agreement is executed

The site initiation meeting has been conducted by Gilead or its designee. The initiation 
meeting will include, but is not limited to, a review of the protocol, the IB, and the 
Investigator’s responsibilities.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened before randomization to determine eligibility for participation in the 
study. The screening window may be extended to up to 28 days prior to the Day 1 visit. 
Subject-reported outcomes, including Global Assessment, VAS assessments 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, as much as possible. The following will be performed 
and documented at screening:

Obtain written Informed Consent

Obtain non-SjS and SjS medical/surgical history, including diagnosis and prior treatments


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
Vital Signs, including weight and height

Complete Physical Examination

ESSDAI

PE for domains of ESSDAI, (including glandular exam, lymph nodes, general skin, 
neurologic exam for peripheral neuropathy, pulmonary exam)

28 Swollen and Tender Joint count

Physician’s Global Assessment of SjS disease activity

Physician’s Global Assessment of concomitant RA or SLE disease activity as applicable

Obtain urine sample for:
Urine drug screen (amphetamines cocaine, methadone opiates)
Urinalysis with spot protein/microalbumin/creatinine

Obtain blood samples for:
Serum Pregnancy Test (female subjects of child bearing potential) or follicle stimulating 
hormone (FSH, as applicable)
TB testing (Quantiferon gold)
CD19+ B cell count (as applicable)
HbA1c, TSH
Hematology, ESR as applicable, chemistry and hsCRP
Viral Screening and Reflex PCR
Autoantibodies: anti-SSA or anti-SSB
Complement (C3, C4, CH50), and CK
Cryoglobulins, total Ig, quant IgG, IgA, and IgM, serum and urine immunofixation
Biomarker samples

Chest X-ray (for subject who had no previous chest X-ray available for review by the 
investigator within the last 3 months)


Filgotinib, GS-9876 and GS-4059
Protocol GS-US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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12 July 2018

VAS

12‑Lead ECG

PFTs (as applicable at selected sites)



Adverse Events

Concomitant medications (All non‑SjS medication used within 30 days of consent (including 
any changes) are to be documented in the eCRF. All prior medication(s) used in the treatment 
for SjS or any other autoimmune disease, are to be documented in the eCRF)
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 
details.
6.2.2.
Day 1 Assessments
At Day 1, after the subject’s eligibility for the study has been confirmed, the subject will be 
randomized into the study to receive one of four study dosing regimens.
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to D1 visit to ensure an approximate 
8-hour fast prior to the blood sample collection under fasting condition the next morning.
VAS and subject reported QOLs assessments 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:

Randomization

Vital Signs, including weight
CCI
CCI


Filgotinib, GS-9876 and GS-4059 
Protocol GS-US-445-4189 
Gilead Sciences, Inc. 
• 
Symptom-directed PE 
• 
ESSDAI (lab results and PFTs as applicable from screening will be used) 
• 
PE for domains of ESSDAI 
• 
28 Swollen and Tender Joint count 
• 
Physician's Global Assessment of SjS disease activity 
Final 
Amendment 1 
• 
Physician's Global Assessment of concomitant RA or SLE disease activity as applicable 
• 
Obtain urine sample for: 
-
Urinalysis with spot protein/microalbumin/creatinine 
-
Urine Pregnancy Test (female subjects of child bearing potential only) 
-
Fasting urine for biomarker 
• 
Obtain blood samples for: 
-
Hematology, ESR as applicable, chemistry and hsCRP 
-
Complement (C3, C4, CH50), and CK 
-
Fasting lipid profile, as outlined in Appendix 6 
-
Biomarker samples 
-
Autoantibodies: deamidated gliadin peptide antibodies (anti DGP lgA or lgG); Anti 
endomysial antibodies (EMA), RF, CCP ( cyclic citiullinated peptide), dsDNA, ANA, 
lgA anti tTA (tissue h'ansglutaminase antibodies) 
• 
VAS 
• 
Subject repo1ted QOLs 
• 
Other questionnaires addressing disease, activity and fatigue may be provided when and 
where available. 
• 
Treatment Satisfaction Questionnaire for Medication (TSQM) 
CONFIDENTIAL 
Page 52 
12 July2018 


Filgotinib, GS-9876 and GS-4059 
Protocol GS-US-445-4189 
Gilead Sciences, Inc. 
• 
• 
12-Lead ECG 
• 
• 
• 
• 
• 
• 
• 
Dmg dispensing 
• 
Adverse Events 
• 
Concomitant medications 
6.3. 
Randomization 
Final 
Amendment 1 
Subjects will be randomly allocated to a dosing group according to a pre-specified randomization 
scheme prepared by an independent statistician. Upon qualification for the study, subjects will be 
randomized using a computerized IWRS system. 
The clinic will contact the IWRS system and for the appropriate kit number to be dispensed as 
directed by the IWRS. The kit will contain the relevant study chu gs for the period until the next 
dispensation visit. 
At Week 24 subjects originally randomized to placebo will be re-randomized to either filgotinib, 
GS-9876 or GS-4059. Sites and subjects will continue to remain blinded throughout the study. 
6.4. 
Week 2 and Week 26 
Subject should be instmcted to hold their dose of study drugs in the morning of the visit. The 
dose should be taken at the clinic. 
The following assessments will be completed at each visit or as specified in the Schedule of 
Assessments in Appendix 2. 
Note: VAS and Subject reported QOLs assessments are recommended to be completed before 
any other study procedures. Invasive study procedures such as blood ch·aws should be done at the 
end of a study visit. 
CONFIDENTIAL 
Page 53 
12 July 2018 


Filgotinib, GS-9876 and GS-4059 
Protocol GS-US-445-4189 
Gilead Sciences, Inc. 
• 
Vital Signs, including weight 
• 
Symptom-directed PE 
• 
28 Swollen and Tender Joint count 
• 
Physician's Global Assessment of SjS disease activity 
Final 
Amendment 1 
• 
Physician's Global Assessment of concomitant RA or SLE disease activity as applicable 
• 
Obtain urine sample for: 
-
Urinalysis with spot protein/ microalbumin/creatinine 
-
Urine Pregnancy Test (female subjects of child bearing potential only) 
• 
Obtain blood samples for: 
-
Hematology, ESR as applicable, chemistry and hsCRP 
-
Complement (C3, C4, CH50), and CK 
-
Biomarker samples 
• 
VAS 
• 
12-Lead ECG 
• 
• 
• 
Dmg accountability 
• 
Adverse Events 
• 
Concomitant medications 
6.5. 
Week4 
Subject should be insti11cted to hold their dose of study drugs in the morning of the visit. The 
dose should be taken at the clinic after the pre-dose PK assessment is completed. 
CONFIDENTIAL 
Page 54 
12 July2018 


Filgotinib, GS-9876 and GS-4059 
Protocol GS-US-445-4189 
Gilead Sciences, Inc. 
Final 
Amendment 1 
The following assessments will be completed at each visit or as specified in the Schedule of 
Assessments in Appendix 2. 
Note: VAS and Subject repo1ted QOLs assessments 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. 
• 
Vital Signs, including weight 
• 
Symptom-directed PE 
• 
ESSDAI 
• 
PE for domains of ESSDAI 
• 
28 Swollen and Tender Joint count 
• 
Physician's Global Assessment of SjS disease activity 
• 
Physician's Global Assessment of concomitant RA or SLE disease activity as applicable 
• 
Obtain urine sample for: 
-
Urinalysis with spot protein/ microalbumin/creatinine 
-
Urine Pregnancy Test (female subjects of child bearing potential only) 
• 
Obtain blood samples for: 
-
Hematology, ESR as applicable, chemistry and hsCRP 
-
Complement (C3, C4, CH50), and CK 
-
C1yoglobulins, total lg, quant lgG, lgA, and lgM, sernm and urine immunofixation 
-
PK samples, collected prior to study diug adininish'ation (pre-dose) 
-
Biomarker samples 
• 
VAS 
• 
Subject repo1ted QOLs 
CONFIDENTIAL 
Page 55 
12 July2018 


Filgotinib, GS-9876 and GS-4059
Protocol GS-US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 56
12 July 2018





Drug dispensing

Drug accountability

Adverse Events

Concomitant medications
6.6.
Week 8
Subject should be instructed to hold their dose of study drugs in the morning of the visit. The 
dose should be taken at the clinic after the pre-dose PK assessment is completed.
The following assessments will be completed at each visit or as specified in the Schedule of 
Assessments in Appendix 2.
Note: VAS and Subject reported QOLs assessments 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.

Vital Signs, including weight

Symptom‑directed PE

ESSDAI

PE for domains of ESSDAI

28 Swollen and Tender Joint count

Physician’s Global Assessment of SjS disease activity

Physician’s Global Assessment of concomitant RA or SLE disease activity as applicable

Obtain urine sample for:
Urinalysis with spot protein/ microalbumin/creatinine
Urine Pregnancy Test (female subjects of child bearing potential only)
CCI
CCI
CCI
CCI


Filgotinib, GS-9876 and GS-4059 
Protocol GS-US-445-4189 
Gilead Sciences, Inc. 
• 
Obtain blood samples for: 
-
Hematology, ESR as applicable, chemistiy and hsCRP 
-
Complement (C3, C4, CH50), and CK 
-
PK samples, collected prior to study chug adminish'ation (pre-dose) 
-
Biomarker samples 
• 
VAS 
• 
Subject repo1ied QOLs 
• 
• 
12-LeadECG 
• 
• 
• 
Dmg dispensing 
• 
Dmg accountability 
• 
Adverse Events 
• 
Concomitant medications 
6.7. 
Week12 
Final 
Amendment 1 
Subject should be insti11cted to hold their dose of study drugs in the morning of the visit. The 
dose should be taken at the clinic after the pre-dose PK assessment is completed. 
Subjects should be instiucted to fast (no food or ch·ink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to Week 12 visit to ensure an approximate 
8-hour fast prior to the blood sample collection under fasting condition the next morning. 
The following assessments will be completed at each visit or as specified in the Schedule of 
Assessments in Appendix 2. 
CONFIDENTIAL 
Page 57 
12 July2018 


Filgotinib, GS-9876 and GS-4059
Protocol GS-US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 58
12 July 2018
Note: VAS and Subject reported QOL assessments 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.

Vital Signs, including weight

Symptom‑directed PE

ESSDAI

PE for domains of ESSDAI

28 Swollen and Tender Joint count

Physician’s Global Assessment of SjS disease activity

Physician’s Global Assessment of concomitant RA or SLE disease activity as applicable

Obtain urine sample for:
Urinalysis with spot protein/ microalbumin/creatinine
Urine Pregnancy Test (female subjects of child bearing potential only)
Fasting urine for biomarker

Obtain blood samples for:
Hematology, ESR as applicable, chemistry and hsCRP
Viral Monitoring for HCV as applicable (see Exclusion criteria, Section 4.3)
Autoantibodies: deamidated gliadin peptide antibodies (anti DGP IgA or IgG); Anti 
endomysial antibodies (EMA), RF, CCP, dsDNA, ANA, SSA, SSB, IgA anti tTA (tissue 
transglutaminase antibodies)
Complement (C3, C4, CH50), and CK
Cryoglobulins, total Ig, quant IgG, IgA, and IgM, serum and urine immunofixation
Fasting lipid profile
PK samples, collected prior to study drug administration (pre-dose)
Biomarker samples


Filgotinib, GS-9876 and GS-4059
Protocol GS-US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 59
12 July 2018

VAS

Subject reported QOLs

TSQM


12‑Lead ECG

PFTs (at selected sites)







Drug dispensing

Drug accountability

Adverse Events

Concomitant medications
6.8.
Week 18
Subject should be instructed to hold their dose of study drugs in the morning of the visit. The 
dose should be taken at the clinic as soon as possible after the pre-dose biomarker blood draw is 
completed, so PK samples and post-dose biomarker samples can be drawn approximately 2 hours 
after dose.
The following assessments will be completed at each visit or as specified in the Schedule of 
Assessments in Appendix 2.
Note: VAS and outcomes assessments are recommended to be completed before any other study 
procedures. Invasive study procedures such as blood draws should be done after VAS and 
outcome assessments.
CCI
CCI
CCI
CCI
CCI
CCI
CCI


Filgotinib, GS-9876 and GS-4059
Protocol GS-US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 60
12 July 2018

Vital Signs, including weight

Symptom‑directed PE

ESSDAI

PE for domains of ESSDAI

28 Swollen and Tender Joint count

Physician’s Global Assessment of SjS disease activity

Physician’s Global Assessment of concomitant RA or SLE disease activity as applicable

Obtain urine sample for:
Urinalysis with spot protein/ microalbumin/creatinine
Urine Pregnancy Test (female subjects of child bearing potential only)

Obtain blood samples for:
Hematology, ESR as applicable, chemistry and hsCRP
Complement (C3, C4, CH50), and CK
PK samples will be collected approximately 2 hours post dose
Biomarker samples

VAS

Subject reported QOLs


Drug dispensing

Drug accountability

Adverse Events

Concomitant medications
CCI


Filgotinib, GS-9876 and GS-4059
Protocol GS-US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 61
12 July 2018
6.9.
Week 24
Subject should be instructed to hold their dose of study drugs in the morning of the visit. The
dose should be taken at the clinic after the pre-dose PK assessment is completed.
Subjects should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to Week 24 visit to ensure an approximate 
8-hour fast prior to the blood sample collection under fasting condition the next morning.
The following assessments will be completed at each visit or as specified in the Schedule of 
Assessments in Appendix 2.
Note: VAS and outcomes assessments 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.

Randomization, subjects on placebo will be re‑randomized 1:1:1 to either filgotinib, or 
GS-9876 or GS-4059

Vital Signs, including weight

Complete Physical Examination

ESSDAI

PE for domains of ESSDAI

28 Swollen and Tender Joint count

Physician’s Global Assessment of SjS disease activity

Physician’s Global Assessment of concomitant RA or SLE disease activity as applicable

Obtain urine sample for:
Urinalysis with spot protein/ microalbumin/creatinine
Urine Pregnancy Test (female subjects of child bearing potential only)
Fasting urine for biomarker

Obtain blood samples for:
Hematology, ESR as applicable, chemistry and hsCRP
Viral Monitoring


Filgotinib, GS-9876 and GS-4059
Protocol GS-US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 62
12 July 2018
Autoantibodies: deamidated gliadin peptide antibodies (anti DGP IgA or IgG); Anti 
endomysial antibodies (EMA), RF, CCP, dsDNA, ANA, SSA, SSB, IgA anti tTA (tissue 
transglutaminase antibodies)
Complement (C3, C4, CH50), and CK
Cryoglobulins, total Ig, quant IgG, IgA, and IgM, serum and urine immunofixation
Fasting lipid profile
PK samples, collected prior to study drug administration (pre-dose)
Biomarker samples

VAS

Subject reported QOLs

TSQM


12‑Lead ECG

PFTs (if available, at selected sites)






Drug dispensing

Drug accountability

Adverse Events

Concomitant medications
CCI
CCI
CCI
CCI
CCI
CCI


Filgotinib, GS-9876 and GS-4059
Protocol GS-US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 63
12 July 2018
6.10.
Week 28
Subject should be instructed to hold their dose of study drugs in the morning of the visit. The 
dose should be taken at the clinic.
The following assessments will be completed at each visit or as specified in the Schedule of 
Assessments in Appendix 2.
Note: VAS and outcomes assessments 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.

Vital Signs, including weight

Symptom‑directed PE

ESSDAI

PE for domains of ESSDAI

28 Swollen and Tender Joint count

Physician’s Global Assessment of SjS disease activity

Physician’s Global Assessment of concomitant RA or SLE disease activity as applicable

Obtain urine sample for:
Urinalysis with spot protein/ microalbumin/creatinine
Urine Pregnancy Test (female subjects of child bearing potential only)

Obtain blood samples for:
Hematology, ESR as applicable, chemistry and hsCRP
Complement (C3, C4, CH50), and CK
Cryoglobulins, total Ig, quant IgG, IgA, and IgM,serum and urine immunofixation
Biomarker samples

VAS

Subject reported QOLs


Filgotinib, GS-9876 and GS-4059
Protocol GS-US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 64
12 July 2018




Drug dispensing

Drug accountability

Adverse Events

Concomitant medications
6.11.
Week 32
Subject should be instructed to hold their dose of study drugs in the morning of the visit. The 
dose should be taken at the clinic.
The following assessments will be completed at each visit or as specified in the Schedule of 
Assessments in Appendix 2.
Note: VAS and Subject reported QOL assessments 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.

Vital Signs, including weight

Symptom‑directed PE

ESSDAI

PE for domains of ESSDAI

28 Swollen and Tender Joint count

Physician’s Global Assessment of SjS disease activity

Physician’s Global Assessment of concomitant RA or SLE disease activity as applicable

Obtain urine sample for:
Urinalysis with spot protein/ microalbumin/creatinine
Urine Pregnancy Test (female subjects of child bearing potential only)
CCI
CCI
CCI


Filgotinib, GS-9876 and GS-4059
Protocol GS-US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 65
12 July 2018

Obtain blood samples for:
Hematology, ESR as applicable, chemistry and hsCRP
Complement (C3, C4, CH50), and CK
Biomarker samples

VAS

Subject reported QOLs




Drug dispensing

Drug accountability

Adverse Events

Concomitant medications

12‑Lead ECG
6.12.
Week 36
Subject should be instructed to hold their dose of study drugs in the morning of the visit. The 
dose should be taken at the clinic after the pre-dose PK assessment is completed.
The following assessments will be completed at each visit or as specified in the Schedule of 
Assessments in Appendix 2.
Note: VAS and outcomes assessments 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.

Vital Signs, including weight

Symptom‑directed PE

ESSDAI
CCI
CCI
CCI


Filgotinib, GS-9876 and GS-4059
Protocol GS-US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 66
12 July 2018

PE for domains of ESSDAI

28 Swollen and Tender Joint count

Physician’s Global Assessment of SjS disease activity

Physician’s Global Assessment of concomitant RA or SLE disease activity as applicable

Obtain urine sample for:
Urinalysis with spot protein/ microalbumin/creatinine
Urine Pregnancy Test (female subjects of child bearing potential only)

Obtain blood samples for:
Hematology, ESR as applicable, chemistry and hsCRP
Viral Monitoring
Complement (C3, C4, CH50), and CK
Cryoglobulins, total Ig, quant IgG, IgA, and IgM, serum and urine immunofixation



VAS

Subject reported QOLs

TSQM


12‑Lead ECG




Drug dispensing
CCI
CCI
CCI
CCI
CCI
CCI


Filgotinib, GS-9876 and GS-4059
Protocol GS-US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 67
12 July 2018

Drug accountability

Adverse Events

Concomitant medications
6.13.
Week 42
Subject should be instructed to hold their dose of study drugs in the morning of the visit. The 
dose should be taken at the clinic.
The following assessments will be completed at each visit or as specified in the Schedule of 
Assessments in Appendix 2.
Note: VAS and Subject reported QOL assessments 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.

Vital Signs, including weight

Symptom‑directed PE

ESSDAI

PE for domains of ESSDAI

28 Swollen and Tender Joint count

Physician’s Global Assessment of SjS disease activity

Physician’s Global Assessment of concomitant RA or SLE disease activity as applicable

Obtain urine sample for:
Urinalysis with spot protein/ microalbumin/creatinine
Urine Pregnancy Test (female subjects of child bearing potential only)

Obtain blood samples for:
Hematology, ESR as applicable, chemistry and hsCRP
Complement (C3, C4, CH50), and CK
Biomarker samples


Filgotinib, GS-9876 and GS-4059
Protocol GS-US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 68
12 July 2018

VAS

Subject reported QOLs


Drug dispensing

Drug accountability

Adverse Events

Concomitant medications
6.14.
Week 48/Early Termination (ET)
If a subject discontinues study, every attempt should be made to perform the required study-
related ET visit and Follow-up visit procedures.
Subject should be instructed to hold their dose of study drugs in the morning of the visit. The 
dose should be taken at the clinic.
Subjects should be instructed to fast (no food or drink, except water [including for study drug 
intake]), starting from midnight (00:00) or earlier, as appropriate, on the evening prior to 
Week 48/ET visit to ensure an approximate 8-hour fast prior to the blood sample collection 
under fasting condition the next morning.
The following assessments will be completed at each visit or as specified in the Schedule of 
Assessments in Appendix 2.
Note: VAS and Subject reported QOL assessments 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.

Vital Signs, including weight

Complete Physical Examination

ESSDAI

PE for domains of ESSDAI

28 Swollen and Tender Joint count

Physician’s Global Assessment of SjS disease activity

Physician’s Global Assessment of concomitant RA or SLE disease activity as applicable
CCI


Filgotinib, GS-9876 and GS-4059
Protocol GS-US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 69
12 July 2018

Obtain urine sample for:
Urinalysis with spot protein/ microalbumin/creatinine
Urine Pregnancy Test (female subjects of child bearing potential only)
Fasting urine for biomarker

Obtain blood samples for:
Hematology, ESR as applicable, chemistry and hsCRP
Viral Monitoring
Autoantibodies: deamidated gliadin peptide antibodies (anti DGP IgA or IgG); Anti 
endomysial antibodies (EMA), RF, CCP, dsDNA, ANA, SSA, SSB, IgA anti tTA (tissue 
transglutaminase antibodies)
Complement (C3, C4, CH50), and CK
Cryoglobulins, total Ig, quant IgG, IgA, and IgM, serum and urine immunofixation
Fasting lipid profile



VAS

Subject reported QOLs

TSQM


12‑Lead ECG

PFTs (if available, at selected sites)



CCI
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

Drug accountability

Adverse Events

Concomitant medications
6.15.
Follow-up Visit
The following procedures will be completed 4 weeks after the subject’s last dose of study 
treatment.

Vital Signs, including weight

Symptom‑directed PE

Urine Pregnancy Test (female subjects of child bearing potential only)

Physician’s Global Assessment of SjS disease activity

Physician’s Global Assessment of concomitant RA or SLE disease activity as applicable

Obtain blood sample for:
hematology, ESR as applicable, chemistry and hsCRP
Biomarker samples

VAS

12‑Lead ECG

Adverse Events

Concomitant medications
6.16.
Study Assessments
This study consists of 14 scheduled visits plus a follow up visit 4 weeks after study drug is 
stopped, with total study duration of 48 weeks (+4 weeks).
The study procedures to be conducted for each subject enrolled in the study are described in the
following sections. In addition, Appendix 2 presents the study procedures in tabular form.
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6.16.1.
Patient Reported Outcomes: Visual Analogue Scales and Questionnaires
PROs, including Visual Analogue Scales (VAS) and questionnaires, are to be completed by the 
subject (where local language questionnaires are available) and should be recommended to be 
completed before any other study procedures. Please refer to schedule of assessments in 
Appendix 2 for the time points for which all PRO assessments are to be completed.
6.16.1.1.
Global Assessment of Disease Activity
The subject will complete a Global Assessment of Disease Activity, recorded on a 0-100 mm
VAS, with 0 indicating “no Sjogren’s Syndrome activity” and 100 indicating “most severe 
Sjogren’s Syndrome activity”.
For subjects who have concomitant RA or SLE, a second global disease activity VAS will be 
completed by the subject.
For subjects with concomitant RA: The Global Assessment of Disease Activity will be recorded 
on a 0-100 mm VAS, with 0 indicating “no Rheumatoid arthritis activity” and 100 indicating 
“most severe Rheumatoid arthritis activity”.
For subjects with concomitant SLE: The Global Assessment of Disease Activity will be recorded 
on a 0-100 mm VAS, with 0 indicating “no SLE activity” and 100 indicating “most severe SLE
activity”.
6.16.1.2.
Assessment of Vaginal Dryness, Ocular Dryness and Oral Dryness
Subjects will complete an assessment of vaginal dryness, ocular dryness and of oral dryness. 
These assessments will be recorded on 0-100 mm VAS’s, with 0 indicating “no dryness” and 
100 indicating “most severe dryness”.
6.16.1.3.
Assessment of Pain and Fatigue
Subjects will complete an assessment of overall pain and fatigue related to the underlying 
disease. These assessments will be recorded on 0-100 mm VAS’s, with 0 indicating “no 
pain”/”no fatigue” and 100 indicating “most intense pain”/”most severe fatigue”.
6.16.1.4.
FACIT-Fatigue Scale
Fatigue will be assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue 
(FACIT-fatigue) scale. The FACIT-fatigue scale measures an individual’s level of fatigue during 
their usual daily activities over the past week. It consists of 13 questions with a 7-day recall 
period on a 5-point Likert scale, with 0 indicating “not at all” and 4 indicating “very much”.
The total score ranges from 0 to 52. Higher scores indicate a better the quality of life.


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6.16.1.5. 
36-Item Short-fonn Health Survey 
Final 
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The SF-36 is a health related quality of life instrnment 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 pali of the above domains, but is kept separately. 
These scales will be rescaled from O to 100 ( conve1iing the lowest possible score to O 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. 
6.16.1.6. 
Explorato1y Patient Repo1ied Outcomes 
6.16.1.7. 
EULAR Sjogren's Syndrome Patient Repo1ied Index 
EULAR Sjogren's Syndrome Patient Repo1ied Index (ESSPRI) is completed by the patient and it 
contains just three items to be given an activity level score between 0-10: pain, fatigue and 
diyness, the final ESSPRI score is the mean of all three scores and therefore also between 0-10. 
6.16.1.8. 
Treatment Satisfaction Questionnaire for Medication 
The TSQM is a composite measure based on the subject's rating of medication effectiveness, 
side effects, and convenience. At Day 1, this questionnaire will be used to assess prior 
medications used to treat the subject's SjS. At all other time points, specified in the schedule of 
assessments in Appendix 2, the TSQM will be used to assess the subject's opinion of the study 
diugs. Site staff should remind the subject of which Sj S diugs they should be evaluating at each 
visit. 
6.16.1.9. 
Oral Health Impact Profile 
The Oral Health Impact Profile (OHIP- 14) has been endorsed as a disease specific QOL and 
measures aspects directly related to oral health and function independent of other problems 
associated with SjS in 14 questions. 
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6.16.1.10.
Impact of Dry Eye on Everyday Life
Impact of Dry Eye on Everyday Life (IDEEL) is a dry eye questionnaires, that evaluates QOL 
in subjects with dry eye disease. It covers 57 items organized into 3 modules, Dry Eye 
Symptom-Bother, Dry Eye Impact on Daily Life, and Dry Eye Treatment Satisfaction, that allow 
a comprehensive evaluation of the burden of the dry eye condition on patients with SjS.
6.16.1.11.
Profile of Fatigue and Discomfort-Sicca Symptoms Inventory
Profile of Fatigue and Discomfort-Sicca Symptoms Inventory (PROFAD-SSI- SF) is 
questionnaire developed specifically to assess fatigue in SjS patients with 19 questions.
6.16.2.
Physician Reported Outcomes: Visual Analogue Scales, Joint Exam and 
Disease Activity Index
Physician reported outcomes, including VAS, joint exam and disease activity index, are to be 
completed by the physician, independently of the subject’s responses to any PRO assessments. 
Please refer to schedule of assessments in Appendix 2 for the time points for which all 
assessments are to be completed.
6.16.2.1.
Physician Assessment of Disease Activity
The evaluating physician should complete the global assessment independently of the subject’s 
assessments. The Global Assessment of Disease Activity will be recorded on a 0-100 mm VAS, 
with 0 indicating “no Sjogren’s Syndrome activity” and 100 indicating “most severe Sjogren’s 
Syndrome activity.”
For subjects who have concomitant RA or SLE, a second global disease activity VAS will be 
completed by the provider.
For subjects with concomitant RA: The Global Assessment of Disease Activity will be 
completed by the provider on a 0-100 mm VAS, with 0 indicating “no Rheumatoid arthritis 
activity” and 100 indicating “most severe Rheumatoid arthritis activity”.
For subjects with concomitant SLE: The Global Assessment of Disease Activity will be 
completed by the provider on a 0-100 mm VAS, with 0 indicating “no SLE activity” and 
100 indicating “most severe SLE activity”.
6.16.2.2.
Evaluation of Disease Activity: Tender and Swollen Joint Counts
Sites will complete an assessment of tenderness and swelling for 28 of their joints. A list of the 
28 joints to be evaluated will be outlined in the site operations manual.


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A designated joint assessor with adequate training and experience in performing joint 
assessments at each study site should perform all joint assessments. The joint assessor should 
preferably be a rheumatologist; however, if a rheumatologist is not available, he/she should be a 
health care worker with experience in performing joint assessments. The subject’s joint assessor 
should remain the same throughout the study, as much as possible.
6.16.2.3.
EULAR Sjogren’s Syndrome Disease Activity Index
EULAR Sjogren’s Syndrome Disease Activity Index (ESSDAI) is a disease activity instrument 
to measure disease activity of primary Sjogren’s Syndrome. It consists of 12 domains and each 
domain is divided into 3–4 levels of activity (Appendix 8). Definition of each activity level is 
provided by a detailed description of what should be considered in that item. The ESSDAI 
should be filled out by the health care provider.
6.16.3.
Pulmonary Function Testing
6.16.3.1.
Spirometry
Spirometry testing will be performed as outlined in the site operations manual (at selected sites). 
Please refer to schedule of assessments in Appendix 2 for the time points at which spirometry is 
to be completed. The following measurements are performed at the visits where spirometry is 
indicated, where available

Vital capacity (VC)

Forced vital capacity (FVC)

Forced expiratory volume (FEV) at timed intervals of 0.5, 1.0 (FEV1), 2.0, and 3.0 seconds

Forced expiratory flow 25–75% (FEF25–75)
6.16.4.
Clinical Laboratory Evaluations
Hematology, chemistry, urinalysis (with spot protein/microalbumin/creatinine), endocrine, 
serology, drug screen, hsCRP, TB testing and pregnancy assessments will be carried out as per 
laboratory assessment table in Appendix 6.
All females of childbearing potential will have urine pregnancy testing every 4 weeks during 
their study participation. During the periods where study visits are every 6-8 weeks, women of 
childbearing potential should continue to have pregnancy tests every 4 weeks, using home 
pregnancy urine tests, which will be provided to them. The site will call the subject every 
4 weeks to obtain results of these pregnancy tests and will record the information in the source 
documents and CRF. If a positive urine pregnancy test is reported, the subject will be asked to 
stop all study medications and return to the clinic for a serum pregnancy test.


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Plasma concentrntions of filgotinib (and its metabolite, GS-829845), GS-9876, and GS-4059 will 
be measured and PK parameters detennined. 
PK samples will be collected prior to study drng administration (pre-dose) at Weeks 4, 12, and 
24; anytime in relation to last study drng administration at Weeks 8, 36, and 48/ET visit. At 
Week 18, PK samples will be collected approximately 2 hours after study chug achninistration 
(post dose). 
The samples will be used to evaluate PK of study chug and may also be used to measure protein 
binding of filgotinib, GS-987 6, or GS-4059. Plasma concentrations of other metabolites may be 
determined, as applicable. 
Refer to the centrnl laborato1y instrnction manual for information on collection and shipment of 
required study samples. 
6.16.5. 
Salivary Flow Measurements 
6.16.6. 
Tear Production 
6.16.7. 
Parotid Gland Ultrasound 
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6.16.8. 
Vital Signs 
Vital signs will be measured at the time points indicated in the study procedures table 
(Appendix 2). 
Final 
Amendment 1 
Vital signs should be taken after the subject has been resting for 5 min and are to include HR, 
respirato1y rate, systolic blood pressure, diastolic blood pressure, and body temperature. 
6.16.9. 
Cognitive Test 
Paper questionnaires will be considered source documents. 
6.16.10. 
Physical Examination 
A physical examination should be perfonned 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 
(subjects should remove shoes). At Screening, Week 24, and Week 48 (or at ET), a complete 
physical examination should be perfo1med. Symptom~ irected physical examinations should be 
perfo1med at all other visits. Physical exam evaluating the domains of the ESSDAI should be 
perfo1med at the time points indicated in the schedule of assessments (Appendix 2). 
Weight is measured at all visits. 
6.16.11. 
Other Assessments 
12-lead Electrocardiogram 
A resting 12-lead ECG should be perfo1med 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 HR, inter-beat (RR), QRS, unco1Tected QT, morphology, and rhythm analysis. 
QT interval co1Tected 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. 
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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 (e.g., 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.)

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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately life-threatening
or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes constituting SAEs. Medical and scientific 
judgment must be exercised to determine whether such an event is a reportable under 
expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, 
an alternative causality must be provided (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 rather than by another etiology.
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)


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7.2.2.
Assessment of Severity
The severity of AEs will be graded using the modified Common Terminology Criteria for 
Adverse Events (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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Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30-days after last administrntion of study IMP must be repo1ted 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 ce1tain AEs be followed beyond the protocol defined follow up 
period. 
Serious Adverse Events 
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
paiticipate in the study (ie, signing the infonned consent) and throughout the duration of the 
study, including the protocol-required post tr·eatinent follow-up period, must be reported to the 
CRF/eCRF database and Gilead PVE as instr11cted. This also includes any SAEs resulting from 
protocol-associated procedures perfonned after infonned consent is signed. 
Any SAEs and deaths that occur after the post tr·eatinent follow-up visit but within 30-days of the 
last dose of study IMP, regai·dless of causality, should also be reported. 
Investigators ai·e not obligated to actively seek SAEs after the protocol defined follow up period; 
however, if the investigator learns of any SAEs that occur after study pa1ticipation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and repo1t 
the event to Gilead PVE. 
• 
All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline. 
Electi-onic Serious Adverse Event (eSAE) Repo1ting Process 
• 
Site personnel record all SAE data in the eCRF database and from there tr·ansmit the SAE 
infonnation to Gilead PVE 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 infonnation electr·onically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
fo1m and submit within 24 hours as described above. 
Gilead PVE 
Fax: 
IPIPD 
E-mail: IPPU 
• 
As soon as it is possible to do so, any SAE repo1ted via paper must be ti-anscribed 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 IBs.
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments
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 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, respectively. If the 


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laboratory abnormality is part of a syndrome, record the syndrome or diagnosis (i.e., anemia) 
not the laboratory result (i.e., decreased hemoglobin).
Severity of laboratory abnormality should be recorded and graded according to the modified 
CTCAE Grading Scale Version 4.03, which can be found in Appendix 4.
For adverse events associated with laboratory abnormalities, the event should be graded on the 
basis of the clinical severity in the context of the underlying conditions; this may or may not be 
in agreement with the grading of the laboratory abnormality.
7.6.
Toxicity Management
Treatment-emergent toxicities will be noted by the investigator and brought to the attention of 
the Gilead Sciences Medical Monitor or designee. Whether or not considered treatment -related, 
all subjects experiencing AEs should be monitored as clinically indicated, until symptoms 
subside, and until any abnormal laboratory values have resolved or returned to baseline levels or 
are considered irreversible, or until there is a satisfactory explanation for the changes observed.
All clinical and clinically significant laboratory toxicities will be managed according to uniform
guidelines detailed in Appendix 3 and as outlined below.
Grade 3 or 4 clinically significant laboratory abnormalities should be confirmed by repeat testing
within 3 calendar days after receipt of the original test results. Grade 3 or 4 clinically significant 
laboratory abnormalities should be managed as outlined in Appendix 3 and Section 3.4.
Any questions regarding toxicity management should be directed to the Gilead Sciences Medical 
Monitor or designee.
7.7.
Special Situations Reports
7.7.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, 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.


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An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
Occupational exposure is defined as exposure to a medicinal product as a result of one's 
professional or non-professional occupation.
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, Gilead PVE 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 PVE.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead PVE 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 PVE. Gilead PVE contact information is as follows: 
Email:
 and Fax: 
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Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead PVE using the 
pregnancy and pregnancy outcome forms within 24 hours. If the end of the pregnancy occurs 
after the study has been completed, the outcome should be reported directly to Gilead PVE, fax 
number 
 or email 
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.7.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead PVE within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications.
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form.
Any inappropriate use of concomitant medications prohibited by this protocol should not be
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.
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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of this study is:

To assess the efficacy of filgotinib, GS-9876 and GS-4059 in adult subjects with active SjS.
The secondary objectives of this study are:

To assess the safety and tolerability of filgotinib, GS-9876 and GS-4059 in adult subjects 
with active SjS

To assess the effect of filgotinib, GS-9876 and GS-4059 on patient reported outcomes in 
active SjS, including fatigue, disability and quality of life
The exploratory objectives of this study are:
8.1.2.
Primary Endpoint
The primary endpoint is the proportion of subjects at who fulfill response criteria as outlined in 
Section 2.
8.1.3.
Secondary Endpoint
Secondary endpoints are:

Change from baseline in ESSDAI at Week 12 

Change from baseline in ESSPRI at Week 12 

Change from baseline in ESSDAI at Week 24

Change from baseline in ESSPRI at Week 24
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8.1.4.
Exploratory Endpoints
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8.2. 
8.2.1. 
8.2.1.1. 
Analysis Conventions 
Analysis Sets 
All Randomized 
Final 
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The All Randomized Analysis Set includes all subjects who are randomized in the study. This is 
the primaiy analysis set for by-subject listings. 
8.2.1.2. 
Efficacy 
The primaiy analysis set for efficacy analyses will be the Full Analysis Set, which includes all 
randomized subjects who received at least one dose of study chug. 
8.2.1.3. 
Safety 
The prima1y analysis set for safety analyses will be the Safety Analysis Set, which includes all 
subjects who received at least one dose of study chug. 
8.2.1.4. 
8.2.1.4.1. 
8.2.1.4.2. 
Phaimacokinetics 
PK Substudy Analysis Set 
PK Analysis Set 
The prima1y analysis set for PK analyses will be the PK Analysis Set, which includes all subjects 
in the Safety Analysis Set who have at least 1 non-missing PK concentration data for GS-9876, 
filgotinib, GS-4059, and/or their metabolite(s). 
8.2.1.5. 
Biomai·ker 
The prima1y analysis set for biomai·ker analyses will be the Biomarker Analysis Set, which 
includes all subjects in the Safety Analysis Set who have at least one evaluable measurement 
available at any time point for a given biomai·ker of interest. 
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Data Handling Conventions 
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Phaimacokinetic concentrntion 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). 
Laborato1y data that ai·e 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 laborato1y test is 
< 20, a value of 19 will be assigned; if the result of a continuous laborato1y test is < 20.0, a value 
of 19.9 will be assigned). 
8.4. 
Demographic Data and Baseline Characteristics 
Demographic and baseline measurements will be summarized using standard descriptive 
statistics including sample size, mean, SD, median, Ql , Q3, minimum, and maximum for 
continuous vai·iables and number and percentages of subjects for categorical vai·iables. 
Demographic summai·ies will include sex, race/ethnicity, and age. 
Baseline chai·acteristics will include a summaiy of at least PROs, ESSDAI, disease duration 
(time from diagnosis), 
, 28-joint count, cunent or prior use of DMARD(s), and oral 
co1iicosteroids. 
8.5. 
8.5.1. 
Efficacy Analysis 
Primary Analysis 
The prima1y endpoint is the propo1iion of subjects fulfilling response criteria (as outlined in 
Section 2). The prima1y analysis will consist of a superiority test of each of filgotinib, GS-9876 
or GS-4059 compared to placebo, respectively. CMH approach adjusting for the randomization 
stratification factors will be used for the hypothesis testing at the 2-sided 0.05-level. 
8.5.2. 
Secondary and Exploratory Analyses 
8.6. 
Safety Analysis 
All safety analyses will be perfo1med using the Safety Analysis Set 
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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 date that study drug was first dispensed up to the date of 
last dose of study drug + 30 days will be summarized by treatment group (according to the 
IMP 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 defined as one or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug.

Any AEs leading to premature discontinuation of study drug.
Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC, 
and PT) will be provided by treatment group.
8.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) by treatment group. Absolute values and change from baseline at all scheduled time
points will be summarized.
Graded laboratory abnormalities will be defined using CTCAE 4.03 grading scale.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
one toxicity grade from baseline at any time post baseline up to the date of last dose of study 
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8.7. 
Pharmacokinetic Analysis 
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Plasma concentrntions of filgotinib, the active metabolite of filgotinib (GS-829845), GS-9876, 
and GS-4059 will be listed and summarized using descriptive statistics ( eg, sample size, 
arithmetic mean, geometric mean, % coefficient of variation, standard deviation, median, 
minimum, and maximum). 
Plasma concentrntions of GS-9876 metabolite(s), other filgotinib metabolite(s), and/or GS-4059 
metabolite(s) may also be detennined and analyzed. 
8.8. 
Biomarker Analysis 
For analysis of biomarkers (eg, cytokines, chemokines, leukocyte flow cytometiy , etc.) 
collected at baseline and post-baseline visits, the baseline levels and the modulation pattern upon 
ti·eatinent, including change over time from baseline levels, will be evaluated by ti·eatinent group. 
Descriptive statistics will be provided at each sampling time, by ti·eatinent group. Additionally 
graphical summaries, e.g. mean+/-SD, median+/-interquartile range (QI, Q3), box plots, and 
scatter plots to explore con-elations between different biomarkers may also be generated, 
as needed. These graphs may be generated for raw values as well as change from baseline, 
as appropriate. 
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8.9.
Sample Size
Based on results of prior SjS studies, assuming a response rate of 70% for an active arm and 30% 
for the placebo arm at Week 12, approximately 35 evaluable subjects will be needed in each arm 
to achieve 85% power to detect a significant difference at a 2-sided, 0.05-level. Enrollment of 
approximately 35 subjects per am is planned to ensure that a sufficient number of subjects is 
available analysis of the primary endpoint.
8.10.
Analysis Schedule
The primary and secondary analysis will be conducted after all subjects either complete the
Week 24 visit or prematurely discontinue from the study. Gilead personnel involved in the study
conduct, as well as study investigators and subjects will remain blinded to the individual 
treatment assignments. The final analysis will be performed when all subjects complete the study
(as defined in Section 3.5) or prematurely discontinue from the study.
Additionally, to assess the safety and efficacy of GS-9876, filgotinib and GS-4059 for further 
planning and development of these products, a Gilead internal unblinded team independent of the 
blinded study team will be assembled. This group will consist of at least one representative from 
Clinical Research, Biostatistics, and Pharmacovigilance/Epidemiology, and may include other 
personnel as necessary. The Gilead internal unblinded team will be granted access to unblinded 
clinical data including treatment assignments to closely monitor study progress and drug safety.
To mitigate the risks of inadvertently releasing the treatment information to the sites and 
subjects, the internal team will keep the unblinded information confidential and will not 
communicate the information to the blinded study team, site staff or subjects. Data unblinding 
due to medical emergency will follow standard Gilead procedures.


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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, International Council for 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 the Code of Federal Regulations (CFR) Title 21 part 312 (21 CFR 312), subpart D, 
“Responsibilities of Sponsors and Investigators,” 21 CFR, part 50 and 21 CFR, part 56.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 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.


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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 study 
investigator must ensure that the potential risk of loss of fertility is discussed with all male 
subjects during the informed consent process. The 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.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB/IEC, or laboratory. Laboratory 
specimens must be labeled in such a way as to protect subject identity while allowing the 
results to be recorded to the proper subject. Refer to specific laboratory instructions. 
NOTE: The investigator must keep a screening log showing codes, names, and addresses for all 
subjects screened and for all subjects enrolled in the trial. Subject data will be processed in 
accordance with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol eCRF, the IMP, and any other study information, remain the 
sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, 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.


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


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9.1.6.
Case Report Forms
For each subject consented, an eCRF casebook will be completed by an authorized study staff 
member whose training for this function is completed in EDC. The eCRF casebook will only 
capture the data required per the protocol schedule of events and procedures. 
The Inclusion/Exclusion Criteria and Enrollment eCRFs should be completed only after all data 
related to eligibility have been received. Subsequent to data entry, a study monitor will perform 
source data verification within the EDC system. System-generated or manual queries will be 
issued to the investigative site staff as data discrepancies are identified by the monitor or internal 
Gilead staff, who routinely review the data for completeness, correctness, and consistency. 
The site coordinator is responsible for responding to the queries in a timely manner, within the 
system, either by confirming the data as correct or updating the original entry, and providing the 
reason for the update (e.g. data entry error). Original entries as well as any changes to data fields 
will be stored in the audit trail of the system. Prior to any interim time points or database lock 
(as instructed by Gilead), 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. At the conclusion of the trial, Gilead will provide the site with a read-only archive 
copy of the data entered by that site. This archive must be stored in accordance with the records 
retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Where possible, IMP should be destroyed at the site. At the start of the study, the study monitor 
will evaluate each study center’s IMP disposal procedures and provide appropriate instruction for 
disposal or return of unused IMP supplies. If the site has an appropriate standard operating 
procedure (SOP) for drug destruction as determined by Gilead Sciences, the site may destroy 
used (empty or partially empty) and unused IMP supplies as long as performed in accordance 
with the site’s SOP. This can occur only after the study monitor has performed drug 
accountability during an on-site monitoring visit.
A copy of the site’s IMP Disposal SOP or written procedure (signed and dated by the PI 
or designee) will be obtained for Gilead site files. If the site does not have acceptable 
procedures in place, arrangements will be made between the site and Gilead Sciences 
(or Gilead Sciences’ representative) for return of unused study drug supplies.
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.


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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.
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 IRBs / IECs
in accordance with local requirements and receive documented IRBs / IECs approval before 
modifications can be implemented. Substantial modifications (as classified by EU Directive 
2001/20/EC) will be submitted and approved by relevant EU competent authorities, and by non-
EU competent authorities as required by local regulations, prior to implementation.
9.2.2.
Study Report and Publications
A clinical study report will be prepared and provided to the regulatory agency(ies). Gilead will 
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content 
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases.
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.


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9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
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
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spleen tyrosine kinase inhibitor delays disease progression and prolongs survival 
in murine lupus. Arthritis Rheum 2008;58 (5):1433-44.
Barr PM, Wei C, Roger J, Schaefer-Cutillo J, Kelly JL, Rosenberg AF, et al. Syk inhibition with 
fostamatinib leads to transitional B lymphocyte depletion. Clin Immunol 
2012;142 (3):237-42.
Braselmann S, Taylor V, Zhao H, Wang S, Sylvain C, Baluom M, et al. R406, an orally available 
spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune 
complex-mediated inflammation. J Pharmacol Exp Ther 2006;319 (3):998-1008.
Coffey G, DeGuzman F, Inagaki M, Pak Y, Delaney SM, Ives D, et al. Specific inhibition of 
spleen tyrosine kinase suppresses leukocyte immune function and inflammation in 
animal models of rheumatoid arthritis. J Pharmacol Exp Ther 2012;340 (2):350-9.
de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, et al. The clinically active 
BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled 
adhesion and migration in chronic lymphocytic leukemia. Blood 2012;119 
(11):2590-4.
de Weers M, Verschuren MC, Kraakman ME, Mensink RG, Schuurman RK, van Dongen JJ, et 
al. The Bruton's tyrosine kinase gene is expressed throughout B cell 
differentiation, from early precursor B cell stages preceding immunoglobulin gene 
rearrangement up to mature B cell stages. European journal of immunology 
1993;23 (12):3109-14.
Deng GM, Liu L, Bahjat FR, Pine PR, Tsokos GC. Suppression of skin and kidney disease by 
inhibition of spleen tyrosine kinase in lupus-prone mice. Arthritis Rheum 2010;62 
(7):2086-92.
Devauchelle-Pensec V, Pennec Y, Morvan J, Pers JO, Daridon C, Jousse-Joulin S, et al. 
Improvement of Sjogren's syndrome after two infusions of rituximab (anti-CD20). 
Arthritis Rheum 2007;57 (2):310-7.
Fife RS, Chase WF, Dore RK, Wiesenhutter CW, Lockhart PB, Tindall E, et al. Cevimeline for 
the treatment of xerostomia in patients with Sjogren syndrome: a randomized 
trial. Arch Intern Med 2002;162 (11):1293-300.
Fox RI. Sjogren's syndrome. Lancet 2005;366 (9482):321-31.


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Genevier HC, Hinshelwood S, Gaspar HB, Rigley KP, Brown D, Saeland S, et al. Expression of 
Bruton's tyrosine kinase protein within the B cell lineage. European journal of 
immunology 1994;24 (12):3100-5.
Hutcheson J, Vanarsa K, Bashmakov A, Grewal S, Sajitharan D, Chang BY, et al. Modulating 
proximal cell signaling by targeting Btk ameliorates humoral autoimmunity and 
end-organ disease in murine lupus. Arthritis research & therapy 2012;14 
(6):R243.
Kruszka P, O'Brian RJ. Diagnosis and management of Sjogren syndrome. Am Fam Physician 
2009;79 (6):465-70.
Lee SH, Kim T, Jeong D, Kim N, Choi Y. The tec family tyrosine kinase Btk Regulates 
RANKL-induced osteoclast maturation. J Biol Chem 2008;283 (17):11526-34.
Mariette X, Seror R, Quartuccio L, Baron G, Salvin S, Fabris M, et al. Efficacy and safety of 
belimumab in primary Sjogren's syndrome: results of the BELISS open-label 
phase II study. Annals of the rheumatic diseases 2015;74 (3):526-31.
Martin F, Chan AC. B cell immunobiology in disease: evolving concepts from the clinic. Annu 
Rev Immunol 2006;24:467-96.
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.
Patel R, Shahane A. The epidemiology of Sjogren's syndrome. Clinical epidemiology 
2014;6:247-55.
Pfizer. SALAGEN - 5mg tablets. Product Monograph.  2014:
Pijpe J, Meijer JM, Bootsma H, van der Wal JE, Spijkervet FK, Kallenberg CG, et al. Clinical 
and histologic evidence of salivary gland restoration supports the efficacy of 
rituximab treatment in Sjogren's syndrome. Arthritis Rheum 2009;60 (11):3251-6.
Ramos-Casals M, Tzioufas AG, Font J. Primary Sjogren's syndrome: new clinical and 
therapeutic concepts. Annals of the rheumatic diseases 2005;64 (3):347-54.
Rankin AL, Seth N, Keegan S, Andreyeva T, Cook TA, Edmonds J, et al. Selective inhibition of 
BTK prevents murine lupus and antibody-mediated glomerulonephritis. J 
Immunol 2013;191 (9):4540-50.
Rising Pharmaceuticals Inc. Cevimeline - 20 Capsules, 250mg  - Prescribing Information.  


Filgotinib, GS-9876 and GS-4059
Protocol GS-US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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Shinohara M, Koga T, Okamoto K, Sakaguchi S, Arai K, Yasuda H, et al. Tyrosine kinases Btk 
and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. 
Cell 2008;132 (5):794-806.
Smith CI, Baskin B, Humire-Greiff P, Zhou JN, Olsson PG, Maniar HS, et al. Expression of 
Bruton's agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-
regulated in T lymphocytes and plasma cells. J Immunol 1994;152 (2):557-65.
Song YW, Kang EH. Autoantibodies in rheumatoid arthritis: rheumatoid factors and 
anticitrullinated protein antibodies. QJM 2010;103 (3):139-46.
Stone JH, Khosroshahi A, Deshpande V, Chan JK, Heathcote JG, Aalberse R, et al. 
Recommendations for the nomenclature of IgG4-related disease and its individual 
organ system manifestations. Arthritis Rheum 2012;64 (10):3061-7.
Tai YT, Chang BY, Kong SY, Fulciniti M, Yang G, Calle Y, et al. Bruton tyrosine kinase 
inhibition is a novel therapeutic strategy targeting tumor in the bone marrow 
microenvironment in multiple myeloma. Blood 2012;120 (9):1877-87.
The Sjogren's Syndrome Foundation. Ask the SSF Staff: Treating Primary vs. Secondary 
Sjögren’s. Available at: 
http://info.sjogrens.org/conqueringsjogrens/bid/359061/AsktheSSFStaffTreatingP
rimaryvsSecondarySjgrens. Posted December 2014. Accessed: 17 October.  2016.
Tobon GJ, Pers JO, Youinou P, Saraux A. B cell-targeted therapies in Sjogren's syndrome. 
Autoimmunity reviews 2010;9 (4):224-8.
Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. A novel clinical 
entity, IgG4-related disease (IgG4RD): general concept and details. Modern 
rheumatology / the Japan Rheumatism Association 2012;22 (1):1-14.
Wang S, Yang N, Zhang L, Huang B, Tan H, Liang Y, et al. Jak/STAT signaling is involved in 
the inflammatory infiltration of the kidneys in MRL/lpr mice. Lupus 2010;19 
(10):1171-80.
Wu CH, Hsieh SC, Lee KL, Li KJ, Lu MC, Yu CL. Pilocarpine hydrochloride for the treatment 
of xerostomia in patients with Sjogren's syndrome in Taiwan--a double-blind, 
placebo-controlled trial. J Formos Med Assoc 2006;105 (10):796-803.


Filgotinib, GS-9876 and GS-4059
Protocol GS-US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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12 July 2018
11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Schedule of Activities
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 of Female of Childbearing 
Potential, and Contraceptive Measures
Appendix 6.
Laboratory Assessment Table
Appendix 7.
American European Consensus Group (AECG) classification criteria 
for Sjogren’s Syndrome
Appendix 8.
EULAR Sjogren’s Syndrome Disease Activity Score (ESSDAI)


Filgotinib, GS-9876 and GS-4059 
Protocol GS-US-445-4189 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER ClTY, CA 94404 
USA 
STUDY ACKNOWLEDGEMENT 
Final 
Amendment l 
A Randomized, Phase 2, Double-blind, Placebo-controlled Study to Assess the Safety and 
Efficacy of Filgotinib, GS-9876 and GS-4059 in Adult Subjects with Active Sjogren' s Syndrome 
GS-US-445-4189, Amendment 1, 12 July 2018 
This protocol has been approved by Gi lead Sciences, Inc. The following signature documents 
this a 
roval. 
Name (Printed) 
Author 
Date 
INVESTIGATOR ST A TEMENT 
l have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. 1 will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 103 
12July20I8 


Filgotinib, GS-9876 and GS-4059
Protocol GS–US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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12 July 2018
Appendix 2.
Schedule of Assessments Table
Visit window
Screening a
Day 1b
Week 2
Week 4
Week 8
Week 12
Week 18
Week 24
Week 26
Week 28
Week 32
Week 36
Week 42
Week 48/ETc
Follow Up visit
4 weeks after
subject’s last 
study visit d
None
None
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
7 days
+/-
7 days
+/-
7 days
+/-
7 days
Fasting visit
x
X
x
x
IP to be taken at the clinic
x
x
x
x
X
x
x
x
x
x
x
x
x
Written Informed Consent
x
Randomization
xe
xf
Physical exam and provider assessments
SjS medical/surgical history, 
including diagnosis and prior 
treatments,
x
Medical /Surgical History
(non-SjS)
x
Vital Signs, including weight
and heightg
x
x
x
x
x
X
x
x
x
x
x
x
x
x
x
Complete Physical 
Examination
x
x
x
Symptom-directed PE
x
x
x
x
X
x
x
x
x
x
x
x
ESSDAI
x
xy
x
x
X
x
x
x
x
x
x
x
PE for domains of ESSDAIh
x
x
x
x
X
x
x
x
x
x
x
x
28 Swollen and Tender Joint 
count
x
x
x
x
x
X
x
x
x
x
x
x
x
x
Physician’s Global Assessment 
of SjS activity
x
x
x
x
x
X
x
x
x
x
x
x
x
x
x


Filgotinib, GS-9876 and GS-4059
Protocol GS–US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 105
12 July 2018
Visit window
Screening a
Day 1b
Week 2
Week 4
Week 8
Week 12
Week 18
Week 24
Week 26
Week 28
Week 32
Week 36
Week 42
Week 48/ETc
Follow Up visit
4 weeks after
subject’s last 
study visit d
None
None
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
7 days
+/-
7 days
+/-
7 days
+/-
7 days
Physician’s Global Assessment 
of concomitant RA or SLE 
disease activity as applicable
x
x
x
x
x
X
x
x
x
x
x
x
x
x
x
Laboratory assessments
Urine drug screeni
x
Urinalysis with spot protein/
microalbumin/creatinine
x
x
x
x
x
X
x
x
x
x
x
x
x
x
Urine Pregnancy Test (female 
subjects of child bearing 
potential only)
x
x
x
x
X
x
x
x
x
x
x
x
x
x
Urine for biomarker (fasting)
x
X
x
x
Serum Pregnancy Test (female 
subjects of child bearing 
potential) or FSH
x
TB testingj
x
CD19+ B cell countk
x
HbA1c, TSH
x
Hematology, ESR as 
applicable, chemistry and 
hsCRP
x
x
x
x
x
X
x
x
x
x
x
x
x
x
x
Viral Screening and Reflex 
PCR l
x
Viral Monitoringm
X
x
x
x
Autoantibodiesn
x
x
X
x
x


Filgotinib, GS-9876 and GS-4059
Protocol GS–US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 106
12 July 2018
Visit window
Screening a
Day 1b
Week 2
Week 4
Week 8
Week 12
Week 18
Week 24
Week 26
Week 28
Week 32
Week 36
Week 42
Week 48/ETc
Follow Up visit
4 weeks after
subject’s last 
study visit d
None
None
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
7 days
+/-
7 days
+/-
7 days
+/-
7 days
Complement (C3, C4, CH50), 
and CK
x
x
x
x
x
X
x
x
x
x
x
x
x
x
Cryoglobulins, total Ig, quant 
IgG, IgA, and IgM, serum and 
urine immunofixation
x
x
X
x
x
x
x
Lipid profile (fasting)o
x
X
x
x
PK samplesp
x
x
X
x
x
x
x
Blood for Biomarker samplesr
x
x
x
x
x
X
x
x
x
x
x
x
x
x
x
PROs and questionnaires
VASt
x
x
x
x
x
X
x
x
x
x
x
x
x
x
x
ESSPRI
x
x
x
x
x
X
x
x
x
x
x
x
x
x
x
FACIT- Fatigue, OHIP-14, 
PROFAD-SSI-SF u
x
x
x
X
x
x
x
x
x
x
x
SF-36, IDEEL u
x
X
x
x
x
TSQM
x
X
x
x
x
CCI
CCI
CCI


Filgotinib, GS-9876 and GS-4059
Protocol GS–US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 107
12 July 2018
Visit window
Screening a
Day 1b
Week 2
Week 4
Week 8
Week 12
Week 18
Week 24
Week 26
Week 28
Week 32
Week 36
Week 42
Week 48/ETc
Follow Up visit
4 weeks after
subject’s last 
study visit d
None
None
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
7 days
+/-
7 days
+/-
7 days
+/-
7 days
Procedures and Exams
12-Lead ECG
x
x
x
x
x
x
x
x
x
x
x
Pulmonary function testsv
x
x
x
x
Chest X-ray (as applicable)z
x
Drug dispensing
x
x
x
x
x
x
x
x
x
x
Drug accountability
x
x
x
x
x
x
x
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant medicationsx
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
a
Screening window is 28 days prior to Day 1
b
Subject will begin study drug on Day 1, following baseline assessments and randomization.
c
Early Termination Visit to be performed if subject discontinues before Week 48
d
Follow up visit not needed if subject’s last dose of study drug was >4 weeks prior to their last study visit
e
Subjects will be randomized on Day 1 based on their use of concomitant medications (y/n: csDMARD and/or oral corticosteroid) and ESSDAI hematological plus biological 
domains score at Day 1, (Y/N: ESSDAI ≥2).
f
Subjects on placebo will be re-randomized 1:1:1 to either filgotinib, or GS-9876 or GS-4059
CCICCI
CCI


Filgotinib, GS-9876 and GS-4059 
Protocol GS-US-445-4189 
Gilead Sciences, Inc. 
Final 
Amendment 1 
g 
Height is only required at Visit 1 and subjects are to remove shoes during measurement 
h 
Exam should include glandular exam, lymph nodes, general skin, nem·ologic exam for peripheral nem·opathy, puhnona1y exam 
Amphetamines Cocaine, Methadone Opiates 
J 
Quantiferon gold 
k 
As applicable 
1 
Hepatitis B stuface Ag and core Ab, Hepatitis C Ab, reflex HCV RNA, HIV 1 and 2 at Screening 
m 
Viral monitoring for HCV as applicable (see Exclusion criteria, Section 4.3) 
n 
At screening only: anti SSA and anti SSB 
At Day 1: deamidated gliadin peptide antibodies (anti-DGP IgA or IgG); Anti-endomysial antibodies (EMA), RF, CCP, dsDNA, ANA, IgA anti-tTA (tissue transglutarninase 
antibodies), 
At all subsequent time points: dearn.idated gliadin peptide antibodies (anti-DGP IgA or IgG); Anti-endomysial antibodies (EMA), RF, CCP, dsDNA, ANA, SSA, SSB, IgA 
anti-tTA (tissue transglutantinase antibodies), 
o 
As outline in Appendix 6 
p 
PK samples will be collected prior to study dmg administration (pre-dose) at Weeks 4, 8, 12, 24, 36, and 48/ET visit. At Week 18, PK samples will be collected 
. 
t l21 
t d 
I 
• 
• • 
: 
•,I~ • 
" 
: 
• 
:.: 
.. 
• 
pj 
y 
p ' 
p 
q 
p 
p 
g 
to be done if and when the material is available at site. 
s 
p 
, 
. 
. 
. 
. 
t 
,,, 
p 
,,, 
ty 
pp 
ment of ocular, oral 
dtyness, vaginal dtyness (if applicable) assessment of pain, fatigue, 
u 
If available in tlte prima1y language of the subject. Questionna!fes a 
·essmg 1sease, activity an fatigue may be prnvided when and where available. 
v 
PFT includes Spirometiy. Subjects with the following conti·aindications to spirometry should not pe1fon11 the exam: nausea, vomiting, recent stroke, eye stu·ge1y, 
thoracic/abdominal sm· e1 and recent neumothorax 
z 
mg, 
CONFIDENTIAL 
Page 108 
12 July2018 


Filgotinib, GS-9876 and GS-4059 
Protocol GS-US-445-4189 
Gilead Sciences, Inc. 
Final 
Amendment 1 
Appendix 3. 
Management of Clinical and Laboratory Adverse Events 
G1·adel 
.__ __ 
G_r_ad_e_2 __ __.I 
... I ___ 
Gt_·_ad_e_3 __ __.l l ... ____ 
Gt_·a_d_e 4 ____ 
__, 
! 
! 
!\fay continue dosing 
Repeat lab to 
Repeat lab to 
at the discretion of 
confinn toxicity 
confirm. toxicity 
H confirmed and 
the innstigator 
gnde 
grade 
--+ possibly or probably 
1·elated to IMP, 
discontinue IMP 
dosing permanently 
and follow at pe1iodic 
inten-als at least 
H confirmed and possibly and/or probably related to IMP: 
H confirmed and unrelated to IMP, 
weekly until a return 
1. 
Withhold IMP until:, G1·ade 2 
dosing may continue at the 
to baseline or is 
2. 
Restart IMP 
discretion of the investigator 
otherwise explained 
..--l 
,---------------------, 
H Grade 3 or 4 recu1Tence that is confumed and possibly or probably 
related to IMP, discontinue 11\IP dosing permanently 
See also Sections 3 .4 and 7. 
H Grade 3 or 4 rec,UJTence that is considered unrelated to IMP, 
continue 11\IP at the discretion of the innstigator 
CONFIDENTIAL 
Page 109 
12 July 2018 


Filgotinib, GS-9876 and GS-4059
Protocol GS–US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 110
12 July 2018
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).


Filgotinib, GS-9876 and GS-4059
Protocol GS–US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 111
12 July 2018
Appendix 5.
Pregnancy Precautions, Definition of Female of Childbearing 
Potential, and Contraceptive Measures
For participation in this study, the use of highly effective contraception is required as outlined 
below for all subjects who are of childbearing potential.
1) Definitions
a. Definition of Female of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, 
unless permanently sterile or with medically documented ovarian failure.
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause. 
In addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their FSH level is in the postmenopausal range and they are not using 
hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
Also see I/E Criteria in Section 4.2.
b. Definition of Male Fertility
For the purposes of this study, a male-born subject is considered fertile unless permanently 
sterile by bilateral orchiectomy or vasectomy with documentation of sperm-free ejaculate at least 
3 months after the procedure. Other types of documented permanent infertility may be allowed, 
after discussion with the Sponsor and approval in writing.
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. Data from a drug-drug 
interaction study of filgotinib and hormonal contraceptives demonstrated that filgotinib does not 
alter the pharmacokinetics of representative hormonal contraceptives levonorgestrel/ethinyl 
estradiol. 
GS-9876 has not been studied in pregnant women. There is no evidence of genotoxic potential. 
Relevant non-clinical reproductive toxicity studies of GS-9876 did not have findings that raise a 
strong suspicion for human teratogenicity/fetotoxicity. In vitro drug interaction assessment of 
GS-9876 and hormonal contraceptives suggests that there is no clinically relevant effects that 
would decrease contraception efficacy. 


Filgotinib, GS-9876 and GS-4059
Protocol GS–US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 112
12 July 2018
GS-4059 is contraindicated in pregnancy as its teratogenicity/fetotoxicity profile is unknown. 
GS-4059 has insufficient data to exclude the possibility of a clinically relevant interaction with 
hormonal contraception that results in reduced contraception efficacy.
In this study, contraceptive steroids are not recommended as a contraceptive method, either 
solely or as a part of a contraceptive regimen. Subjects may remain on their hormonal 
contraception if they prefer to do so, but will still be required to choose from additional 
contraceptive methods delineated below as the efficacy of their hormonal contraception during 
study dosing is unknown.
Please refer to the latest versions of the filgotinib, GS-9876, and GS-4059 IBs for additional 
information.
b. Contraceptive Methods Permitted for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective
contraceptive measures. Women must not rely on hormone-containing contraceptives as a sole 
form of birth control during the study, though they may continue hormonal contraception if they 
prefer to do so. Women must have a negative serum pregnancy test at Screening and a negative 
pregnancy test on the Day 1 visit prior to first dose of study drug. Pregnancy tests will be 
performed as defined in Section 6.16.6.
Female subjects of childbearing potential must agree to one of the following from Screening 
until 36 days following the last dose of study drug.

Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below.
Intrauterine device (IUD) with a failure rate of < 1% per year
Tubal sterilization
Ensure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 36 days after the last dose of study drug.


Filgotinib, GS-9876 and GS-4059
Protocol GS–US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 113
12 July 2018
3) Contraception for Male Subjects
It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure of the male subject’s seminal fluid. Therefore, male subjects with female 
partners of childbearing potential must use condoms during treatment and until 90 days after the 
last dose of study drug. Additional contraception recommendations should also be considered if 
the female partner is not pregnant.
Male subjects must also refrain from sperm donation during treatment and until at least 90 days
after last dose of study drug.
4) Unacceptable Methods of Birth Control
Birth control methods that are unacceptable include periodic abstinence (including calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), use of 
spermicides alone, and lactational amenorrhea method (LAM). The female condom and male 
condom should not be used together.
5) Procedures to be Followed in the Event of Pregnancy
Female subjects will be instructed to notify the investigator if they become pregnant at any time 
during the study, or within 36 days after the last dose of study drug. Subjects who become 
pregnant or who suspect that they are pregnant during the study are to discontinue study drug 
immediately and report the information to the investigator.
Male subjects whose partner has become pregnant or suspects she is pregnant, either during the 
study or for 90 days after his last dose of study drug, 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.


Filgotinib, GS-9876 and GS-4059
Protocol GS–US-445-4189
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 114
12 July 2018
Appendix 6.
Laboratory Assessment Table
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Hemoglobin
Platelet count
Red blood cell (RBC) 
count
WBC count
Differentials (absolute 
and percentage), 
including:
Leucocytes
Monocytes
Neutrophils
Eosinophils
Basophils
Mean corpuscular 
volume (MCV)
INR
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
Serum creatinine
Glucose
Phosphorus
Magnesium
Potassium
Sodium
Amylase
Lipase
Lipid profile:
Triglycerides
Cholesterol and its 
subfractions (high-density 
lipoprotein [HDL] and 
low-density lipoprotein 
[LDL])
Leptin
LDL particle
Homocysteine
Apo A1/B
Appearance
Blood
Color
Glucose
Leukocyte esterase
pH
Protein
Urobilinogen
Reflex to microscopic 
urinalysis if dipstick result 
is abnormal.
Urine drug screen for:
Amphetamines
Cocaine
Methadone
Opiates
C-reactive protein (hsCRP)
QuantiFERON- TB GOLD
and other test as outlined in 
Schedule of assessment
Endocrine at screening 
only
Serology
Pregnancy
Hemoglobin A1c
TSH
FSH (see Appendix 5)
Hepatitis BsAg, Hepatitis 
B surface antibody and 
core Ab
Hepatitis C Ab (if positive 
reflex HCV RNA)
HIV antibodies
In females of childbearing
potential:
Serum β-hCG (at screening 
and if positive urine β-hCG)
Urine β-hCG (all other visits) †
†
During the periods where visits are every 6-8 weeks, women should continue to have monthly home pregnancy tests every 
4 weeks; the site will contact the subject to obtain the results of the home testing.


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Appendix 7.
American European Consensus Group (AECG)
Vitali C, et al. Classification criteria for Sjogren’s syndrome: a revised version of the 
European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 
2002; 61:554-558.
I.
Ocular symptoms: a positive response to at least one of the following questions:
1) Have you had daily, persistent, troublesome dry eyes for more than 3 months?
2) Do you have a recurrent sensation of sand or gravel in the eyes?
3) Do you use tear substitutes more than 3 times a day?
II.
Oral symptoms: a positive response to at least one of the following questions:
4) Have you had a daily feeling of dry mouth for more than 3 months?
5) Have you had recurrently or persistently swollen salivary glands as an adult?
6) Do you frequently drink liquids to aid in swallowing dry food?
III.
Ocular signs—that is, objective evidence of ocular involvement defined as a positive result 
for at least one of the following two tests:
1) Schirmer's I test, performed without anaesthesia (≤5 mm in 5 minutes)
2) Rose bengal score or other ocular dye score (≥4 according to van Bijsterveld's scoring 
system)
IV.
Histopathology: In minor salivary glands (obtained through normal-appearing mucosa) 
focal lymphocytic sialoadenitis, evaluated by an expert histopathologist, with a focus score 
≥1, defined as a number of lymphocytic foci (which are adjacent to normal-appearing 
mucous acini and contain more than 50 lymphocytes) per 4 mm2 of glandular tissue18
V.
Salivary gland involvement: objective evidence of salivary gland involvement defined by a 
positive result for at least one of the following diagnostic tests:
1) Unstimulated whole salivary flow (≤1.5 ml in 15 minutes)
2) Parotid sialography showing the presence of diffuse sialectasias (punctate, cavitary or 
destructive pattern), without evidence of obstruction in the major ducts19
3) Salivary scintigraphy showing delayed uptake, reduced concentration and/or delayed 
excretion of tracer20


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VI.
Autoantibodies: presence in the serum of the following autoantibodies:
1) 1. Antibodies to Ro(SSA) or La(SSB) antigens, or both
For primary SjS:
In patients without any potentially associated disease, primary SjS may be defined as follows:
a) The presence of any 4 of the 6 items is indicative of primary SS, as long as either item IV 
(Histopathology) or VI (Serology) is positive
b) The presence of any 3 of the 4 objective criteria items (that is, items III, IV, V, VI)
c) The classification tree procedure represents a valid alternative method for classification, 
although it should be more properly used in clinical-epidemiological survey
For secondary SjS:
In patients with a potentially associated disease (for instance, another well-defined connective 
tissue disease), the presence of item I or item II plus any 2 from among items III, IV, and V may 
be considered as indicative of secondary SjS.
Exclusion criteria: 

Past head and neck radiation treatment 

Hepatitis C infection 

Acquired immunodeficiency disease (AIDS) 

Pre-existing lymphoma 

Sarcoidosis 

Graft versus host disease 

Use of anticholinergic drugs (since a time shorter than 4-fold the half-life of the drug).


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Appendix 8.
EULAR Sjogren’s Syndrome Disease Activity Index (ESSDAI)
Seror R, Bowman SJ, Brito-Zeron P,et al. EULAR Sjögren’s syndrome disease activity 
index (ESSDAI): a user guide. RMD Open 2015;1:e000022. doi: 10.1136/rmdopen-2014-
000022
Domain
Activity Level
Description
Constitutional
Exclusion of fever of infectious origin
and voluntary weight loss
No = 0
Absence of the following symptoms
Low = 3
Mild or intermittent fever (37.5°–38.5°C)/night sweats and/or involuntary 
weight loss of 5 to 10% of body weight
Moderate = 6
Severe fever (>38.5°C)/night sweats and/or involuntary weight loss of 
>10% of body weight
Lymphadenopathy and lymphoma
Exclusion of infection
No = 0
Absence of the following features
Low = 4
Lymphadenopathy ≥ 1 cm in any nodal region or ≥ 2 cm in inguinal 
region
Moderate = 8
Lymphadenopathy ≥ 2 cm in any nodal region or ≥ 3 cm in inguinal 
region, and/or splenomegaly (clinically palpable or assessed by imaging)
High = 12
Current malignant B-cell proliferative disorder
Glandular
Exclusion of stone or infection
No = 0
Absence of glandular swelling
Low = 2
Small glandular swelling with enlarged parotid (≤ 3 cm), or limited 
submandibular (<2 cm) or lachrymal swelling (<1 cm)
Moderate = 4
Major glandular swelling with enlarged parotid (> 3 cm), or important 
submandibular or lachrymal swelling
Articular
Exclusion of osteoarthritis
No = 0
Absence of currently active articular involvement
Low = 2
Arthralgias in hands, wrists, ankles and feet accompanied by morning 
stiffness (>30 min)
Moderate = 4
1 to 5 (of 28 total count) synovitis
High = 6
≥ 6 (of 28 total count) synovitis
Cutaneous
Rate as “No activity” stable long- lasting
features related to damage
No = 0
Absence of currently active cutaneous involvement
Low = 3
Erythema multiforma
Moderate = 6
Limited cutaneous vasculitis, including urticarial vasculitis, or purpura 
limited to feet and ankle, or subacute cutaneous lupus
High = 9
Diffuse cutaneous vasculitis, including urticarial vasculitis, or diffuse 
purpura, or ulcers related to vasculitis
Pulmonary
Rate as “No activity” stable long- lasting
features related to damage, or 
respiratory involvement not related to 
the disease (tobacco use, etc.)
No = 0
Absence of currently active pulmonary involvement
Low = 5
Persistent cough due to bronchial involvement with no radiographic 
abnormalities on radiography
Or radiological or HRCT evidence of interstitial lung disease with: No 
breathlessness and normal lung function test.
Moderate = 10
Moderately active pulmonary involvement, such as interstitial lung 
disease shown by HRCT with shortness of breath on exercise (NHYA II) 
or abnormal lung function tests restricted to: 70% >DLco ≥ 40% or 80% 
>FVC≥60%
High = 15
Highly active pulmonary involvement, such as interstitial lung disease 
shown by HRCT with shortness of breath at rest (NHYA III, IV) or with 


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abnormal lung function tests: DLco < 40% or FVC< 60%
FVC, forced vital capacity: HRCT high- resolution CT; NYHA New York Heart Association.
Renal
Rate as “No activity” stable long- lasting 
features related to damage, and renal 
involvement not related to the disease.
If biopsy has been performed, please
rate activity based on histological 
features first
No = 0
Absence of currently active renal involvement with 
proteinuria< 0.5 g/day, no haematuria, no leucocyturia, no acidosis, or 
long-lasting stable proteinuria due to damage
Low = 5
Evidence of mild active renal involvement, limited to tubular acidosis 
without renal failure or glomerular involvement with proteinuria (between 
0.5 and 1 g/day) and without haematuria or renal failure (GFR ≥60 
ml/min)
Moderate = 10
Moderately active renal involvement, such as tubular acidosis with renal 
failure (GFR <60 ml/min) or glomerular involvement with proteinuria 
between 1 and 1.5 g/day and without haematuria or renal failure (GFR 
≥60 ml/min) or histological evidence of extra-membranous 
glomerulonephritis or important interstitial lymphoid infiltrate
High = 15
Highly active renal involvement, such as glomerular involvement with 
proteinuria >1.5 g/day or haematuria or renal failure (GFR <60 ml/min), 
or histological evidence of proliferative glomerulonephritis or 
cryoglobulinemia related renal involvement
GFR, glomerular filtration rate.
Muscular
Exclusion of weakness due to
corticosteroids
No = 0
Absence of currently active muscular involvement
Low = 6
Mild active myositis shown by abnormal EMG, MRI* or biopsy with no 
weakness and creatine kinase (N < CK ≤ 2N)
Moderate = 12
Moderately active myositis proven by abnormal EMG, MRI* or biopsy 
with weakness (maximal deficit of 4/5), or elevated creatine kinase (2N <
CK ≤4N),
High = 18
Highly active myositis shown by abnormal EMG, MRI* or biopsy with 
weakness (deficit ≤ 3/5) or elevated creatine kinase (>4N)
*We decided to add this item not included in the initial version since the value of this examination for the diagnosis of myositis was not 
clear until recently.                                                                                                                                                                                                         
EMG electromyogram.
PNS
Rate as “No activity” stable long -lasting
features related to damage or PNS 
involvement not related to the disease
No = 0
Absence of currently active PNS involvement
Low = 5
Mild active PNS involvement, such as pure sensory axonal 
polyneuropathy shown by NCS or trigeminal (V) neuralgia             
*Proven small fibre neuropathy
Moderate = 10
Moderately active PNS involvement shown by NCS, such as axonal 
sensory-motor neuropathy with maximal motor deficit of 4/5, pure 
sensory neuropathy with presence of cryoglobulinemic vasculitis, 
ganglionopathy with symptoms restricted to mild/moderate ataxia, 
inflammatory demyelinating polyneuropathy (CIDP) with mild functional 
impairment (maximal motor deficit of 4/5or mild ataxia),
Or cranial nerve involvement of peripheral origin (except trigeminal (V) 
neuralgia)
High = 15
Highly active PNS involvement shown by NCS, such as axonal sensory-
motor neuropathy with motor deficit ≤3/5, peripheral nerve involvement 
due to vasculitis (mononeuritis multiplex, etc.), severe ataxia due to 
ganglionopathy, inflammatory demyelinating polyneuropathy (CIDP) with 
severe functional impairment: motor deficit ≤3/5 or severe ataxia


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*We decided to add this item not included in the initial version since the link between this entity and SS was not clear until recently. 
CIDP, chronic inflammatory demyelinating polyneuropathy; NCS nerve conduction study.
CNS
Rate as “No activity” stable long- lasting
features related to damage or CNS 
involvement not related to the disease
No = 0
Absence of currently active CNS involvement
Moderate = 10
Moderately active CNS features, such as cranial nerve involvement of 
central origin, optic neuritis or multiple sclerosis-like syndrome with 
symptoms restricted to pure sensory impairment or proven cognitive 
impairment
High = 15
Highly active CNS features, such as cerebral vasculitis with 
cerebrovascular accident or transient ischaemic attack, seizures, transverse 
myelitis, lymphocytic meningitis, multiple sclerosis-like syndrome with 
motor deficit.
Haematological
For anaemia, neutropenia, and 
thrombopenia, only auto-immune 
cytopenia must be considered Exclusion 
of vitamin or iron deficiency, 
drug-induced cytopenia
No = 0
Absence of auto-immune cytopenia
Low = 2
Cytopenia of auto-immune origin with neutropenia (1000 < neutrophils <
1500/mm3), and/or anaemia (10 < haemoglobin < 12 g/dL), and/or 
thrombocytopenia (100,000 < platelets < 150,000/mm3)
Or lymphopenia (500 < lymphocytes < 1000/mm3)
Moderate = 4
Cytopenia of auto-immune origin with neutropenia (500 ≤ neutrophils ≤ 
1000/mm3), and/or anaemia (8 ≤ haemoglobin ≤ 10 g/dL), and/or 
thrombocytopenia (50,000 ≤ platelets ≤ 100,000/mm3)
Or lymphopenia (≤500/mm3)
High = 6
Cytopenia of auto-immune origin with neutropenia (neutrophils 
< 500/mm3), and/or or anaemia (haemoglobin < 8 g/dL) and/or 
thrombocytopenia (platelets <50,000/mm3)
Biological 
No = 0
Absence of any of the following biological feature
Low = 1
Clonal component and/or hypocomplementemia (low C4 or C3 or CH50) 
and/or hypergammaglobulinemia or high IgG level between 16 and 20 g/L
Moderate = 2
Presence of cryoglobulinemia and/or hypergammaglobulinemia or high 
IgG level > 20 g/L, and/or recent onset hypogammaglobulinemia or recent 
decrease of IgG level (<5 g/L)
CIDP= chronic inflammatory demyelinating polyneuropathy; CK= creatine kinase; CNS= central nervous system; DLCO= 
diffusing CO capacity; EMG= electromyogram; FVC= forced vital capacity; GFR= glomerular filtration rate; Hb= hemoglobin; 
HRCT= high-resolution computed tomography; IgG= immunoglobulin G; NCS= nerve conduction studies; NHYA= New York 
heart association classification; Plt= platelet; PNS=peripheral nervous system

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Randomized, Phase 2, Double-blind, Placebo-controlled 
Study to Assess the Safety and Efficacy of Filgotinib, 
GS-9876 and GS-4059 in Adult Subjects with Active 
Sjogren’s Syndrome
Name of Test Drug:
Filgotinib, Lanraplenib (GS-9876) and Tirabrutinib
(GS-4059)
Study Number:
GS-US-445-4189
Protocol Version (Date):
Amendment 1 (12 July 2018)
Analysis Type:
Final
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
30 May 2019
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(r} GILEAU 


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TABLE OF CONTENTS
LIST OF ABBREVIATIONS........................................................................................................................................4
PHARMACOKINETIC ABBREVIATIONS................................................................................................................6
1.
INTRODUCTION ................................................................................................................................................7
1.1.
Study Objectives ......................................................................................................................................7
1.2.
Study Design............................................................................................................................................7
1.3.
Sample Size and Power............................................................................................................................8
2.
TYPE OF PLANNED ANALYSIS ......................................................................................................................9
2.1.
Interim Analyses ......................................................................................................................................9
2.2.
Internal Data Monitoring..........................................................................................................................9
2.3.
Primary (Week 24) Analysis....................................................................................................................9
2.4.
Final Analysis ........................................................................................................................................10
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................11
3.1.
Analysis Sets..........................................................................................................................................11
3.1.1.
All Randomized Analysis Set...............................................................................................11
3.1.2.
Full Analysis Set ..................................................................................................................11
3.1.3.
Safety Analysis Set...............................................................................................................11
3.1.4.
Per-Protocol Analysis Set.....................................................................................................11
3.1.5.
Pharmacokinetic Analysis Set..............................................................................................12
3.1.6.
PK Substudy Analysis Set....................................................................................................12
3.1.7.
Biomarker Analysis Set........................................................................................................12
3.2.
Subject Grouping ...................................................................................................................................12
3.3.
Strata and Covariates..............................................................................................................................13
3.4.
Examination of Subject Subgroups........................................................................................................13
3.5.
Multiple Comparisons............................................................................................................................14
3.6.
Missing Data and Outliers......................................................................................................................14
3.6.1.
Missing Data ........................................................................................................................14
3.6.2.
Outliers.................................................................................................................................14
3.7.
Data Handling Conventions and Transformations .................................................................................14
3.8.
Analysis Visit Windows.........................................................................................................................15
3.8.1.
Definition of Study Day .......................................................................................................15
3.8.2.
Analysis Visit Windows.......................................................................................................15
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window................................................................................................................................17
3.9.
Efficacy Estimands.................................................................................................................................17
4.
SUBJECT DISPOSITION ..................................................................................................................................19
4.1.
Subject Enrollment and Disposition.......................................................................................................19
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................20
4.2.1.
Duration of Exposure to Study Drug....................................................................................20
4.2.2.
Adherence to Study Drug.....................................................................................................21
4.2.2.1.
Prescribed Adherence .....................................................................................21
4.3.
Protocol Deviations................................................................................................................................22
5.
BASELINE CHARACTERISTICS....................................................................................................................23
5.1.
Demographics ........................................................................................................................................23
5.2.
Baseline Characteristics .........................................................................................................................23
5.3.
Medical History......................................................................................................................................24
6.
EFFICACY ANALYSES ...................................................................................................................................25


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6.1.
Multiple Imputations of Missing Data ...................................................................................................26
6.2.
Definition of the Primary Efficacy Endpoint .........................................................................................26
6.3.
Analysis for the Primary Efficacy Endpoint ..........................................................................................27
6.3.1.
Primary Analysis of Primary Endpoint ................................................................................27
6.3.2.
Sensitivity Analysis of Primary Endpoint ............................................................................27
6.4.
Secondary Efficacy Endpoints ...............................................................................................................27
6.4.1.
Definition of Secondary Efficacy Endpoints........................................................................27
6.4.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................28
6.5.
Exploratory Efficacy Endpoints.............................................................................................................28
6.5.1.
Definition of Exploratory Efficacy Endpoints......................................................................28
6.5.2.
Analysis Methods for Exploratory Efficacy Endpoints........................................................31
6.6.
Changes From Protocol-Specified Efficacy Analyses............................................................................32
7.
SAFETY ANALYSES........................................................................................................................................33
7.1.
Adverse Events and Deaths....................................................................................................................33
7.1.1.
Adverse Event Dictionary ....................................................................................................33
7.1.2.
Adverse Event Severity........................................................................................................33
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................33
7.1.4.
Serious Adverse Events........................................................................................................33
7.1.5.
Treatment-Emergent Adverse Events...................................................................................34
7.1.5.1.
Definition of Treatment-Emergent Adverse Events .......................................34
7.1.5.2.
Incomplete Dates ............................................................................................34
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................35
7.1.7.
Adverse Events of Special Interest.......................................................................................36
7.2.
Laboratory Evaluations ..........................................................................................................................38
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................38
7.2.2.
Graded Laboratory Values ...................................................................................................39
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities.............................................40
7.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities ...............................40
7.2.2.3.
Summaries of Laboratory Abnormalities........................................................40
7.2.3.
Liver-related Laboratory Evaluations...................................................................................41
7.2.4.
Shifts Relative to the Baseline Value ...................................................................................41
7.3.
Body Weight and Vital Signs.................................................................................................................42
7.4.
Prior and Concomitant Medications.......................................................................................................42
7.4.1.
Prior Medications .................................................................................................................42
7.4.2.
Concomitant Medications.....................................................................................................43
7.5.
Electrocardiogram Results .....................................................................................................................44
7.6.
Other Safety Measures ...........................................................................................................................44
7.7.
Changes From Protocol-Specified Safety Analyses...............................................................................44
8.
PHARMACOKINETIC (PK) ANALYSES........................................................................................................45
8.1.
Pharmacokinetic Sample Collection ......................................................................................................45
8.2.
PK Analyses Related to Intensive PK Sampling....................................................................................45
8.3.
Estimation of Pharmacokinetic Parameters............................................................................................45
8.4.
Pharmacokinetic Parameters ..................................................................................................................46
8.5.
Statistical Analysis Methods ..................................................................................................................46
9.
REFERENCES ...................................................................................................................................................48
10.
SOFTWARE.......................................................................................................................................................49
11.
SAP REVISION..................................................................................................................................................50
12.
APPENDIXES ....................................................................................................................................................51


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
Analysis of covariance
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
area under the curve
BLQ
below the limit of quantitation
BMI
body mass index
CFR
Code of Federal Regulations
CI
confidence interval
CMH
Cochran Mantel Haenszel
CK
creatine kinase
csDMARD
Conventional synthetic disease-modifying antirheumatic drug
CRF
case report form
CSR
clinical study report
CTCAE
Common Toxicity Criteria for Adverse Events
DILI
drug-induced liver injury
DMC
data monitoring committee
DMARD
Disease-modifying antirheumatic drug
ECG
Electrocardiogram
EDC
Electronic Data Capture
ESSDAI
EULAR Sjogren’s Syndrome Disease Activity Index
ESSPRI
EULAR Sjögren’s Syndrome Patient Reported Index
ET
early termination
FAS
Full Analysis Set
Hb
hemoglobin
HLT
high-level term
hsCRP
high sensitivity C-Reactive Protein
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
LLOQ
lower limits of quantitation
IDEEL
Impact of Dry Eye on Everyday Life
IXRS
interactive voice or web response system
LOCF
last observation carry forward
LTT
lower-level term
LOQ
limit of quantitation
MACE
major adverse cardiovascular event
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed effects repeated measures


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MST
MedDRA Search Term
OHIP
Oral Health Impact Profile
PP
Per Protocol
PT
Preferred Term
Q1, Q3
first quartile, third quartile
QRS
electrocardiographic deflection between the beginning of the Q wave and termination of the 
S wave representing time for ventricular depolarization
QT
electrocardiographic interval between the beginning of the Q wave and termination of the T wave 
representing the time for both ventricular depolarization and repolarization to occur
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RA
rheumatoid arthritis
RR
electrocardiographic interval representing the time measurement between the R wave of one 
heartbeat and the R wave of the preceding heartbeat
SAP
statistical analysis plan
SAE
serious adverse event
SD
standard deviation
SI (units)
international system of units
SjS
Sjogren’s Syndrome
SLE
systemic lupus erythematosus
SMQs
Standardized Medical Queries
SOC
system organ class
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
TMT
Trail Making Test
TSQM
Treatment Satisfaction Questionnaire for Medication
ULN
upper limit of normal
VAS
visual analog scale
VR
ventricular rate
WHO
World Health Organization


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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
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination phase 
of the concentration of drug versus time curve


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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-445-4189. This SAP is based on the study protocol amendment 1 dated 
12 July 2018 and the electronic case report forms (eCRF). The SAP will be finalized before the 
primary analysis (Week 24) is performed. 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:

To assess the efficacy of filgotinib, lanraplenib (GS-9876), and tirabrutinib (GS-4059) in 
adult subjects with active Sjogren’s Syndrome (SjS)
The secondary objectives of this study are:

To assess the safety and tolerability of filgotinib, lanraplenib, and tirabrutinib in active SjS

To assess the effect of filgotinib, lanraplenib, and tirabrutinib on patient reported outcomes in 
active SjS
The exploratory objectives of this study are:
1.2.
Study Design
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study to evaluate 
the safety and efficacy of filgotinib, lanraplenib (GS-9876), and tirabrutinib (GS-4059) in adult 
male and female subjects with active SjS. 
At Day 1, eligible subjects will be randomized 1:1:1:1 to daily oral filgotinib (200 mg), 
lanraplenib (30 mg), tirabrutinib (40 mg) or placebo to match (PTM). Randomization will be 
stratified by: use of concurrent immunomodulatory drugs at baseline (Y/N: conventional 
synthetic disease modifying antirheumatic drugs (csDMARD[s]) or corticosteroids), and the 
hematologic + biological component scores of the EULAR Sjogren’s syndrome disease activity 
index (ESSDAI) obtained at screening (combined score of <2 or ≥ 2).
Stable medications at Day 1 should be continued during the study dosing period through 
Week 48. Dose adjustments for toxicities and dose adjustment of corticosteroids are allowed 
after Week 12. Subjects will return to the study site for scheduled study visits at Weeks 2, 4, 8, 
12, 18, 24, 26, 28, 32, 36, 42, and 48 (Appendix 1). 
CCI


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At completion of the Week 24 visits, subjects on placebo will be re-randomized 1: 1: 1, in a 
blinded fashion, to daily oral filgotinib (200 mg), lanraplenib (30 mg), or tirabmtinib ( 40 mg) 
without further stratification. Dosing and assessments for all subjects will continue through 
Week 48. 
Subjects who discontinue study dmg for any reason ( other than noncompliance) may continue to 
participate in scheduled study visits and procedures, as long as deemed medically appropriate by 
the investigator. Subjects who discontinue all study paiiicipation will have an early tennination 
(ET) visit; these subjects, and those who complete the study, should return to the study site for a 
follow-up visit, 4 weeks after the last dose of study drng (subjects who have discontinued study 
dmg 
4 weeks prior to the ET/Week 48 visit, do not need a follow up visit). 
Figure 1. 
Dayl 
Scr·eening 
28 days 
Study Design Schematic 
Placebo 
Week24 
Filgotinib 
200mgQD 
Lan.-aplenib 
30mgQD 
Tirabrutinib 
40mgQD 
1.3. 
Sample Size and Power 
Filgotinib 200 mg QD 
Lanraplenib 30 mg QD 
Tirabrutinib 40 mg QD 
Week48 
FU visit 
4weeks 
after dose. of 
study drug 
The sample size was estimated based on historical data. Assuming a response rate of 70% for an 
active ann and 30% for the placebo arm at Week 12, approximately 35 evaluable subjects will be 
needed in each rum to achieve 85% power to detect a significant difference at a 2-sided, 
0.05-level. Enrollment of approximately 35 subjects per aim is planned to ensure that a sufficient 
number of subjects is available for the analysis of the prima1y endpoint. 
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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analyses
An external data monitoring committee (DMC) has not been established for this study. 
Therefore, no analyses will be conducted for the external DMC.
2.2.
Internal Data Monitoring
To assess the safety and efficacy of filgotinib, lanraplenib and tirabrutinib, and for further 
planning and development of these products, a Gilead internal unblinded team independent of the 
blinded study team will be assembled. This group will consist of at least one representative from 
Clinical Research, Biostatistics, and Pharmacovigilance/Epidemiology, and may include other 
personnel as necessary. The Gilead internal unblinded team will be granted access to unblinded 
clinical data including treatment assignments to closely monitor study progress and drug safety. 
The activities of the internal unblinded data monitoring team will be governed by the team 
Charter. 
To mitigate the risks of inadvertently releasing the treatment information to the sites and 
subjects, the internal team will keep the unblinded information confidential and will not 
communicate the information to the blinded study team, site staff or subjects. Data unblinding 
due to medical emergency will follow standard Gilead procedures.  
2.3.
Primary (Week 24) Analysis
A planned Week 24 analysis will be conducted after all subjects have either completed their 
Week 24 visit or prematurely discontinued from the study. 
A pre-specified sponsor team (members are not actively involved in the conduct of the study) 
will review the Week 24 unblinded safety and efficacy analysis results. A memo and a list will 
be maintained which documents the individuals granted access to the Week 24 unblinded results 
along with the justification for unblinding in accordance with Gilead SOPs. The Interim Analysis 
Data Integrity and Communication Plan will be developed prior to unblinding. The Study 
Management Team members with direct involvement in the conduct of the study will remain 
blinded to treatment assignments throughout the trial, until all subjects have completed all 
planned study visits and the database has been locked.
All planned analyses of the placebo-controlled period described in this SAP will be provided to 
the Designated Unblinded Study Team (see the Interim Analysis Data Integrity and 
Communication Plan) and will contain individual subject treatment assignments.
The following primary and secondary analysis reports and summaries may be provided to the 
project planning team (specified Gilead executives and the designated study team members):  

Demographic characteristics (only Total column - all treatment groups combined)

Baseline characteristics (only Total column)


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
Disposition (only Total column)

Primary Responder Analysis at Week 12

Inferential analysis of ESSDAI Change from Baseline to Week 12 and Week 24

Inferential analysis of EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI)
Change from Baseline to Week 12 and Week 24

Other analyses as deemed necessary for program planning purposes
These reports will contain unblinded treatment group level information (not the individual 
subject treatment assignments). 
2.4.
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), median, first quartile (Q1), third 
quartile (Q3), minimum, and maximum will be presented.
All statistical tests will be 2-sided and performed at the 0.05 significance level unless otherwise 
specified.
By-subject listings will be presented for all subjects in the All Randomized Analysis Set and 
sorted by subject 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 initially assigned will be used in the listings. Age, sex at birth, race, and 
ethnicity will be included in the listings, as space permits.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. Subjects included in each analysis set will be determined before the 
study blind is broken for analysis. The analysis set will be identified and included as a subtitle of 
each table, figure, and listing.
For each analysis set, the number and percentage of subjects eligible for inclusion, 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 were randomized in the study. This is the 
primary analysis set for by subject listings.
3.1.2.
Full Analysis Set
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. 
3.1.3.
Safety Analysis Set
The primary analysis set for safety analyses will be the Safety Analysis Set, which includes all 
subjects who received at least one dose of study drug.
3.1.4.
Per-Protocol Analysis Set
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3.1.5. 
Pharmacokinetic Analysis Set 
The Phan nacokinetic (PK) Analysis Set will include all subjects in the Safety Analysis Set who 
have at least 1 non-missing post-dose PK concentration data for filgotinib, lanraplenib, 
tirabrntinib, and/or their metabolite(s). This is the prima1y analysis set for all PK analyses. 
3.1.6. 
PK Substudy Analysis Set 
3.1.7. 
Biomarker Analysis Set 
The prima1y analysis set for biomarker analyses will be the Biomarker Analysis Set, which 
includes all randomized subjects who received at least one dose of study diug and have at least 
one evaluable measurement available at any time point for a given biomarker of interest. 
3.2. 
Subject Grouping 
For the analysis of placebo-controlled period (up to week 24), subjects will be presented by four 
treatment groups: 
• 
Filgotinib 200 mg 
• 
Lanraplenib 30 mg 
• 
Tirabrntinib 40 mg 
• 
Placebo 
For the analyses of the entire study period, subjects will be grouped into seven treatment groups 
as specified in Table 1. For the analyses based on the FAS Analysis Set, subjects will be grouped 
according to the treatment to which they were randomized at Study Day 1 and Week 24. For the 
analyses based on the Safety Analysis Set, subjects will be grouped according to the actual 
treatment that they 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. 
Table 1. 
Treatment Groups for the Entire Study Summaries 
Filgotinib 200 mg 
Filgotinib 200 mg from Study Day 1 
Lanraplenib 30 mg 
Lanraplenib 30 mg from Study Day 1 
Tirabrntinib 40 mg 
Tirabrntinib 40 mg from Study Day 1 
Placebo/Filgotinib 200 mg 
Placebo up to Week 24 and Filgotinib 200 mg after Week 24 first dose 
Placebo/Lanraplenib 30 mg 
Placebo up to Week 24 and Lanraplenib 30 mg after Week 24 first dose 
Placebo/Tirabrntinib 40 mg 
Placebo up to Week 24 and Tirabrntinib 40 mg after Week 24 first dose 
Placebo 
Placebo group with study drng withdrawn prior to or at Week 24 (not received drng 
assigned at Week 24) 
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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 1:1:1:1 ratio using a stratified randomization schedule. Stratification will be based 
on the following variables:

Use of concurrent immunomodulatory drugs at baseline (Y/N: conventional synthetic disease 
modifying antirheumatic drugs (csDMARD[s]) or corticosteroids)

Hematologic + biological component scores of the ESSDAI obtained at screening (combined 
score of <2 or ≥2)
Only systemic use of csDMARDs (route of administration oral, subcutaneous, intramuscular, or 
intravenous) is considered for the stratification. 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. If it is impossible to derive the stratification factor from the clinical 
database due to missing values, data from IWRS will be used. 
Efficacy endpoints will be evaluated using stratification factors as covariates or stratification 
variables for analyses, as specified in Section 6. 
For efficacy endpoints, the baseline value of the efficacy variable(s) will be included as a 
covariate in the efficacy analysis model.
3.4.
Examination of Subject Subgroups
The primary and secondary efficacy endpoints will be examined using the following baseline 
characteristics and randomization stratification variables:

Age (< 50 years and 50 years)

Diagnosis of autoimmune disease (Yes and No)

Diagnosis of SLE (Yes, No)

Diagnosis of RA (Yes, No)

Duration of the disease (<5 years, >= 5 years)

Use of concurrent immunomodulatory drugs (csDMARD or corticosteroids) at baseline
(systemic use of these medications at Day1 – Yes and No)

Hematological + biological component scores of the ESSDAI obtained at screening 
(combined score of <2 and ≥2).

ESSDAI at Baseline (<14 and >=14)


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3.5.
Multiple Comparisons
All endpoint tests will be done at the significance level of 0.05 with no multiplicity adjustment in 
this proof-of-concept study.
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. The 
handling of missing or incomplete dates for determining treatment emergent AE status is 
described in Section 7.1.5.2. The handling of missing date for prior and concomitant medications
is described in Section 7.4. Imputation rules adopted in the efficacy analyses are specified in 
Section 6.
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 analysis.
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 informed consent was signed will be used for age calculation. If only the birth year is 
collected on the CRF, “01 July” will be used for the unknown birth day and month for the 
purpose of age calculation. If only birth year and month are collected, “01” will be used for the 
unknown birth day.
Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ)
or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “x” (where x is considered the LOQ). For example, if the 
values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to 
calculate summary statistics. An exception to this rule is any value reported as < 1 or < 0.1, 
etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to 
calculate summary statistics.

A value that is 1 unit above the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “> x” (where x is considered the LOQ). Values with decimal 
points will follow the same logic as above.

The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of 
“≤ x” or “≥ x” (where x is considered the LOQ).


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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.”

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
Study day will be calculated from the first dosing date of study drug and derived as follows:

For postdose study days: Assessment Date – First Dosing Date + 1

For days prior to the first dose: Assessment Date – First Dosing Date
Therefore, study Day 1 is the day of first dose of study drug administration.
For placebo subjects who were re-randomized to active treatment, the On-Active-Treatment 
study day will be calculated as: Assessment Date – Date of the first dose of active treatment + 1. 
The date of the first dose of active treatment is recorded on CRF.
3.8.2.
Analysis Visit Windows
The target study days for analysis visits are provided in the Table 2 below: 


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Table 2.
Target Days for Analysis Visits 
Nominal Visit
Nominal Study Day/
Study Day on Active Treatment
Screening
< 1 
Baseline
<=1
Week 2
15
Week 4
29
Week 8
57
Week 12
85
Week 18
127
Week 24
169/1
Week 26
183/15
Week 28
197/29
Week 32
225/57
Week 36
253/85
Week 42
295/127
Week 48
337/169
Follow-up Visit
NA
The nominal visit as recorded on the CRF will be used when data are summarized by visit. 
Any data recorded under unscheduled visits will not be assigned to a particular visit or time 
point. However, the following exceptions will be made:

An unscheduled visit prior to the first dosing of study drug may be included in the calculation 
of the baseline or screening value, if applicable

Unscheduled visits after the first dose of study drug will be included in determining the 
maximum postbaseline toxicity grade in safety analyses
For subjects who prematurely discontinue from the study, early termination (ET) data will be 
assigned to what would have been the next scheduled visit where the respective data were 
scheduled to be collected. If this next scheduled visit for parameter falls on the visit after the 
latest performed scheduled visit as reported in the clinical database then the analysis visit is not 
assigned and the value is not included in the analyses.
Data collected at a follow-up visit will be summarized under a separate visit, and labeled 
“Follow-up Visit.”


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3.8.3.
Selection of 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. 
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 dosing 
date of study drug, unless specified differently. If multiple measurements occur on the same 
day, the last nonmissing value prior to the time of first dosing 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 will be considered the baseline 
value.

For postbaseline values:
The record closest to the nominal day for that visit will be selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken, unless 
otherwise specified.
If multiple valid, non-missing, 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 (e.g., normal will be selected 
over abnormal for safety electrocardiogram [ECG] findings).

For postbaseline visits, if there are multiple records with the same time or no time recorded 
on the same day, the value with the worst severity within the window will be selected (e.g., 
abnormal will be selected over normal for safety ECG findings).
All records will be listed by collection date. 
3.9.
Efficacy Estimands
Three efficacy estimands: a treatment-policy estimand, a hypothetical estimand and a composite 
estimand, are defined for the primary and secondary efficacy endpoints.
The treatment-policy estimand is the primary estimand for the primary and secondary efficacy 
endpoints.
1) Population: Subjects in the FAS


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2) Variable: Primary and secondary endpoints 
3) Intercurrent events: The occurrence of an intercurrent event is irrelevant. All observed values 
will be used regardless of occurrence of an intercurrent event
The hypothetical estimand is defined as following. This is the supportive estimand for the 
primary and secondary efficacy endpoints.
1) Population: Subjects in the Full Analysis Set (FAS).
2) Variable: Primary and secondary endpoints 
3) Intercurrent events: The following intercurrent events are taken into account:

Subject takes prohibited medication 

Subject changes the dose of the medication required to be stable per protocol

Subject discontinues from study treatment
The composite estimand is defined as following. This is the supportive estimand for the primary 
and secondary efficacy endpoints.
1) Population: Subjects in the Full Analysis Set (FAS).
2) Variable: Primary and secondary endpoints 
3) Intercurrent events: The following intercurrent events are taken into account:

Subject takes prohibited medication 

Subject changes the dose of the medication required to be stable per protocol

Subject discontinues from study treatment
The estimators associated with each of these estimands are described in Table 3 of Section 6.


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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,
investigator within a country and overall. 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 randomization 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 or other source document 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 or other source document at the time of 
data finalization will be provided.
The randomization schedule used for the study will be provided as an appendix to the CSR.
A summary of subject disposition will be provided for the entire study duration and by treatment 
phase. This summary will present the number of subjects screened, the number of subjects 
randomized, and the number of subjects in each of the categories listed below:

Safety Analysis Set 

Completed Study

Prematurely discontinued study with reasons for discontinuation 

Completed study drug

Prematurely discontinued study drug with reasons for discontinuation 
The study and drug disposition will also be presented by study period with the following 
categories:

Completed study up to Week 12, Week 24, and through the end of the study

Completed study drug up to Week 12, Week 24, and through the end of study

Did not complete the study/study drug up to Week 12, Week 24, and through the end of 
study with reasons for premature discontinuation of the study

Re-randomized at Week 24

Continuing study drug (Week 24 Analysis only)

Continuing study (Week 24 Analysis only)


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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. In addition, a flowchart will be provided to depict the disposition.
Completion of the study up to Week 12 will be based on the presence of the corresponding visit 
in EDC or presence of Early Termination visit which is after Week 8 visit. Completion of 
treatment up to Week 12 is considered when the [date of last dose – date of first dose + 1] 
>= 82 days (target date for Week 12 visit minus protocol allowed visit window). Similar 
algorithm is applied to Week 24 completion. Subjects are considered to complete 24 weeks of 
treatment if the start date of Week 24 treatment is provided or the [last dose date – first dose date 
+1] >= 166. Subjects who complete Week 24 visit/treatment but did not continue beyond 
Week 24 are reported as “Discontinued at Week 24”.
The by-subject listing of disposition will be provided by subject identification (ID) number in 
ascending order to support the above summary tables.
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 study drug will be defined as the last dosing date of any study drug 
minus the first dosing date of any study drug plus 1, regardless of any temporary interruptions in 
study drug administration, and will be expressed in weeks using up to 1 decimal place 
(e.g. 4.5 weeks). For Week 24 primary analysis, the data cut-off date can be used as the last 
dosing date for subjects continuing on study. 
For subjects with a partial last dosing date (i.e., month and year of last dose are known), the 
latest of the dispensing dates of study drug bottles,  and the imputed last dose date [day imputed 
as last day of the month] will be used as the final imputed last dose date. 
If only year is recorded (i.e., month and day of last dose are missing) or the entire date is missing 
then the latest of the dispensing month of study drug bottles, study drug start month, and study 
drug bottle return month will be used to impute the unknown last dose month (and a year if the 
entire date is missing). With the month imputed, the aforementioned method will be used to 
impute the last dose date. If the imputed date is after the date of death, choose the death date.
In addition, the duration of active treatment will be provided. The calculation for the subjects 
originally randomized to placebo will include the period starting from the first day of active 
study drug (Week 24 treatment start date is recorded on CRF).
The total duration of exposure to study drug will be summarized using descriptive statistics 
(number of subjects [n], mean, SD, median, Q1, Q3, minimum, and maximum) and the 
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24, 30, 36, 42, and 48. The subject is considered to be exposed up to Week X if the last dose of 
any study drug is at least visit target day (per Table 2) minus protocol-allowed window 
(Appendix 1).
Summaries will be provided by treatment group for the Safety Analysis Set.  No formal 
statistical testing is planned.
4.2.2.
Adherence to Study Drug
The total number of doses administered will be summarized using descriptive statistics for each 
study drug. 
The presumed total number of doses administered to a subject will be determined by the data 
collected on the drug accountability CRF using the following formula:
Total Number of Doses Administered =
No. of Doses Dispensed
No. of Doses Returned















If a bottle was dispensed and returned empty, then the number of tablets returned will be counted 
as zero. If a bottle was dispensed but not returned (missing), zero tablets from that bottle will be 
considered to be returned.
If calculated adherence is greater than 100%, the result will be set to 100%.
For each subject, the adherence will be calculated separately for each treatment administered: 
lanraplenib 30 mg/PTM, filgotinib 200 mg/PTM, or tirabrutinib 40 mg/PTM. The overall 
adherence to study drug will be defined as the lowest of the three.  
4.2.2.1.
Prescribed Adherence
The level of prescribed adherence to the study drug regimen will be determined by the total 
amount of study drug administered relative to the total amount of study drug specified by the 
protocol for a subject who completes treatment in the study.
The total amount of study drug administered up to week 12/24 will be calculated based on the 
drug accountability reported on CRF: (total pills dispensed – total pills returned) up to 
Week 12/24 visit.
The level of prescribed adherence will be expressed as a percentage using the following formula:
Total Amount of Study Drug Administered
Prescribed Adherence (%) =
 x 100
Total Amount of Study Drug Specified by Protocol








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Descriptive statistics for the level of prescribed adherence up to Week 12, up to Week 24, and 
the entire study duration as well as the number and percentage of subjects in each of the two 
adherence categories, < 80% and ≥ 80%, will be presented by treatment group for the Safety 
Analysis Set. 
The expected amount of study drug to be administered per protocol is defined as follows:

Up to Week 12: 84 (7 * 12) doses 

Up to Week 24: 168 (7 * 24) doses

Entire study duration: 336 (7 * 48) doses 
No formal statistical testing is planned.
By-subject listings of study drug administration and accountability will be provided separately 
by subject ID number in ascending order and in chronological order for each treatment 
separately.
4.3.
Protocol Deviations 
Subjects who did not meet the eligibility criteria for study entry but enrolled in the study will be 
summarized. 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 the 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 (e.g., non-adherence to study drug, violation of select inclusion/exclusion 
criteria) will be summarized by treatment group for the Safety Analysis Set. A by-subject listing 
will be provided for those subjects with important protocol deviations.


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5.
BASELINE CHARACTERISTICS  
5.1.
Demographics
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) as a continuous variable

age group (< 50 years, ≥ 50 years)

sex at birth (male, female)

race 

ethnicity (Hispanic or Latino, not Hispanic or Latino)

geographic region and country
Subject demographic variables (i.e., age, sex, race, and ethnicity) will be summarized by 
treatment group and overall using descriptive statistics for age, and using number and percentage 
of subjects for sex, race, and ethnicity. 
A by-subject demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order.
5.2.
Baseline Characteristics
Baseline characteristics include:

Weight (kg)

Body mass index (BMI; in kg/m2) 

Concurrent immunomodulatory drugs at baseline (Y/N: conventional synthetic disease 
modifying antirheumatic drugs (csDMARD[s]) or corticosteroids on Day 1)

Concurrent background disease-modifying antirheumatic drug [DMARD] use (Yes, No)

Concurrent use of systemic (oral) corticosteroids at baseline (Yes, No)

Concurrent background use of anti-malarial DMARDs at baseline (Yes, No)

hsCRP (descriptive statistics and categories above/below 1.5 ULN)


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
ESSDAI (descriptive statistics and categories  (<14 and >=14)

ESSPRI (descriptive statistics)

Diagnosis of autoimmune disease (Yes and No)

Diagnosis of SLE (Yes, No)

Diagnosis of RA (Yes, No)

Diagnosis of SLE or RA (Yes, No)

Duration of SjS disease (<5 years, >= 5 years)

Hematological + biological component scores of the ESSDAI obtained at screening 
(combined score of <2 or ≥2) 

Baseline VAS: patient’s global assessment of SjS, pain, fatigue, oral dryness, ocular dryness, 
vaginal dryness, sexual function, physician’s global assessment of SjS

Baseline Trail Making Test part A (TMT-A) and Trail Making Test part B (TMT-B)

Baseline Schirmer’s test result (average of eyes)

Baseline unstimulated and stimulated salivary flow rate

Baseline swollen and tender joint count (descriptive statistic and categorical: n> 0)

SS-A and SS-B antibodies at baseline (positive and negative)
The time from SjS diagnosis will be calculated in years between the date of enrollment and the 
date of diagnosis. The missing month will be imputed with January; the missing day will be 
imputed with 1st day of the month.
These baseline characteristics will be summarized by treatment group and overall using 
descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) for continuous 
variables, and using number and percentage of subjects for categorical variables. The summary 
of baseline characteristics will be provided for the FAS. No formal statistical testing is planned.
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.
5.3.
Medical History
Medical history will be collected at screening for SjS and other conditions.  
The medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).
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. The 
summary will be provided for the Safety Analysis Set. No formal statistical testing is planned.
The autoimmune comorbidities will be identified by Clinical Research based on MedDRA 
preferred terms. 


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6.
EFFICACY ANALYSES
Efficacy endpoints will be evaluated for the following treatment periods: placebo-controlled 
period up to Week 24 and the entire study up to Week 48.
The primary and secondary endpoints analyses will be based on the estimands presented in the 
Table 3.
Table 3.
Efficacy Estimands
Binary Endpoint
Treatment Policy (main)
Hypothetical 
Composite 
Population
FAS
FAS
FAS
Intercurrent 
Event
Ignore all intercurrent 
events
Treatment discontinuation
Start of prohibited 
medication
The dose change of 
medication that is required to 
be stable
Data after the event are treated 
as missing
Treatment discontinuation
Start of prohibited 
medication
The dose change of 
medication that is required 
to be stable 
Data after the event are treated 
as no response
Main Estimator
Stratified CMH test with 
imputation of missing 
data using logistic 
regression
Stratified CMH test with 
imputation of missing data
using logistic regression
Stratified CMH test with non-
responder imputation of 
missing data 
Continuous 
Endpoints
Treatment Policy (main)
Hypothetical 
Composite 
Intercurrent 
Event
Ignore all intercurrent 
events
Treatment discontinuation
Start of prohibited 
medication
The dose change of 
medication that is required 
to be stable
Treatment discontinuation
Start of prohibited 
medication
The dose change of 
medication that is required to 
be stable 
Main Estimator
The treatment difference 
will be estimated using a 
mixed effects model for 
repeated measures. 
Missing data will be 
imputed using multiple 
imputation 
The treatment difference will 
be estimated using a mixed 
effects model for repeated 
measures. Missing data will be 
imputed using multiple 
imputation 
The treatment difference will be 
estimated using a mixed effects 
model for repeated measures. 
Missing data will be imputed 
using multiple imputation based 
on observed data from the 
placebo group


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6.1.
Multiple Imputations of Missing Data
Multiple imputation of binary variables: The MI procedure replaces each missing binary 
response value with a set of plausible values that represent the uncertainty about the right value 
to impute. Twenty 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 6.3. The results from each set of imputed data sets will 
then be combined using Rubin’s rule {Rubin 1987}. Stratification factors will be included in the 
imputation model.
Multiple imputation of continuous variables: 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. Twenty imputed datasets will be 
generated based on linear regression models on observed values. These multiple imputed data 
sets are then analyzed by using the analysis method specified in Section 6.4 for complete data. 
The result of each imputed data set will be combined using Rubin’s rule {Rubin 1987}. 
Stratification factors and baseline values will be included in the imputation model as covariates.
6.2.
Definition of the Primary Efficacy Endpoint
The primary endpoint is the proportion of subjects fulfilling protocol-specified response criteria 
at Week 12, as compared to baseline.
Response is defined as follows (also see Appendix 2):

For subjects with elevated hsCRP (defined as hsCRP ≥1.5 upper limit of normal [ULN]) on
Day 1, response is defined as achieving all of the following:
≥ 20% improvement in hsCRP
≥20% improvement in at least 3 out of 5 subject reported, SjS related visual analog 
scales (VAS; subject’s assessment of global disease, pain, oral dryness, ocular dryness,
and fatigue)
no worsening (i.e., no increase >30 mm from baseline) in any of the above VAS

For subjects without elevated hsCRP (hsCRP <1.5 ULN) on Day 1, response is defined as 
achieving all of the following:
no increase in hsCRP to ≥ 1.5 ULN 
≥20% improvement in at least 3 out of 5 subject reported, SjS related VAS (subject’s 
assessment of global disease, pain, oral dryness, ocular dryness, and fatigue)
no worsening (i.e., no increase >30 mm from baseline) in any of the above VAS


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6.3.
Analysis for the Primary Efficacy Endpoint
6.3.1.
Primary Analysis of Primary Endpoint
In the primary analysis, the primary outcome in each active treatment group will be compared to 
the outcome in the placebo group using a superiority test at the 2-sided 0.05-level.  The 
following null hypotheses will be tested (vs. the respective alternative hypotheses):

H01:  There is no difference in the responder rate between filgotinib 200 mg group and 
placebo group at Week 12

H02:  There is no difference in the responder rate between lanraplenib 30 mg group and 
placebo group at Week 12

H03:  There is no difference in the responder rate between tirabrutinib 40 mg group and 
placebo group at Week 12
The analyses will be performed using Cochran Mantel Haenszel (CMH) test adjusted for the 
randomization stratification factors. If CMH test stratified by both stratification factors is not 
appropriate due to small cell counts then the levels of the stratification by ESSDAI scores will be 
pooled, and the analysis will be stratified only by use of concurrent immunomodulatory drugs at 
baseline. Each of the three hypotheses will be tested separately at the 2-sided, 0.05-level.
The primary analysis will be based on the Treatment Policy Estimand, with missing values
imputed by multiple imputation method described in Section 6.1.
The number and percentage of responders in each treatment group as well as 95% confidence 
intervals (CIs) will be presented for each visit.
6.3.2.
Sensitivity Analysis of Primary Endpoint
The following sensitivity analyses of the primary endpoint will be performed:

Using composite estimand

Using hypothetical estimand
6.4.
Secondary Efficacy Endpoints
6.4.1.
Definition of Secondary Efficacy Endpoints
Secondary efficacy endpoints include:

Change from baseline in ESSDAI total score at Week 12

Change from baseline in ESSPRI total score at Week 12

Change from baseline in ESSDAI total score at Week 24 

Change from baseline in ESSPRI total score at Week 24


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6.4.2.
Analysis Methods for Secondary Efficacy Endpoints
Each secondary endpoint will be analyzed using a mixed-effect repeated measures (MMRM) 
model with treatment, randomization stratification factors, visit, treatment-by-visit interaction as 
fixed effects, subjects as a random effect, and the respective baseline value (ESSDAI or ESSPRI) 
as a covariate. The Kenward-Roger method will be used to estimate the degrees of freedom. 
Each of the four endpoints will be tested separately at the 2-sided 0.05 level. The unstructured 
(UN) variance-covariance matrix of repeated measures will be considered first. If a model does 
not converge, then ARH(1) structure will be applied. 
For each secondary endpoint, adjusted means (LS means) and 95% confidence intervals (CIs) 
obtained from the model will be presented for Weeks12 and Week 24 time points.
Missing data will be handled using the method described in Table 3.
The inferential analyses of the secondary endpoints will be based on the treatment policy 
estimand (main analysis of each secondary endpoint). Sensitivity non-parametric analyses of the 
secondary endpoints will be performed on rank-transformed data utilizing ANCOVA models
with treatment group and stratification factors as effects and the rank-transformed baseline value 
as a covariate.
In addition, secondary efficacy analyses will be repeated for the hypothetical estimand and 
composite estimand.
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be presented 
by visit and treatment group, overall and for the subgroups listed in section 3.4.
Line plots for median (Q1, Q3) change from baseline, mean (+/- 95% CI) change from baseline,
and adjusted mean (LS mean) change from baseline (+/- 95% CI) will be provided for ESSDAI 
total score, ESSPRI total score and its components.
In addition, the box plots for ESSDAI total score and ESSPRI total score and change from 
baseline will be presented by visit and treatment group.
A cumulative plot of change from baseline in ESSDAI total score and in ESSPRI total score at 
Week 12 and Week 24 will be presented by treatment group. 
6.5.
Exploratory Efficacy Endpoints
  
CCI


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Analysis Methods for Exploratory Efficacy Endpoints 
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Changes From Protocol-Specified Efficacy Analyses 
Statistical Analysis Plan 
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The ti·eatment policy, hypothetical and composite estimands have been added to the analyses of 
the primaiy and secondaiy endpoints. 
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7.
SAFETY ANALYSES
The safety analyses will be performed for the placebo-controlled treatment period up to 
Week 24, and for the entire study duration. Analyses for these periods will be presented by the 
treatment groups specified in Section 3.  
For the analyses of adverse events (AEs) that include data after Week 24 the exposure-adjusted 
analyses will be presented.
For the AEs, laboratory results and concomitant medication data, the collection/start date will be 
used to determine which reporting period the record belongs to. For other parameters collected 
on CRFs, the nominal visits will be used.
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory AEs will be coded using the current version of MedDRA. 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 (CTCAE 4.03). 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 lanraplenib/placebo”, “Related to filgotinib/placebo” or “Related to 
tirabrutinib/placebo”. If AE is reported as “Related” to any of 3 study drugs then the AE is 
considered “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 the AEs met the 
definitions of SAEs 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.


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7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) of the entire study duration are defined as 1 or both 
of the following:

Any AEs with an onset date on or after any study drug start date and no later than 30 days 
after permanent discontinuation of any study drug 

Any AEs leading to premature discontinuation of study drug.
TEAEs up to Week 24 are defined as 1 or both of the following:

Any AEs with an onset date on or after Day 1 and no later than the day before the Week 24 
treatment start date. 

For subjects who discontinued treatment prior to Week 24 visit, any AEs with an onset date 
no later than 30 days after permanent discontinuation of study drug 
TEAEs of active treatment are defined similarly as the definition of the entire study duration, 
except that active study drug instead of any study drug will be used: 

Any AEs with an onset date on or after the first dose of active study drug and no later than 
30 days after permanent discontinuation of active study drug.
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.


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7.1.6.
Summaries of Adverse Events and Deaths
TEAEs will be summarized based on the Safety Analysis Set.
The tables will be presented by treatment period: placebo-controlled period (up to Week 24) and 
active treatment period.  The overall summary of TEAEs will also be provided for the entire 
study duration.
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:

All TEAEs

TEAEs of Grade 3 or higher (by maximum severity)

All TE treatment-related AEs

TE treatment-related AEs of Grade 3 or higher (by maximum severity)

All TE SAEs

All TE treatment-related SAEs 

All TEAEs leading to premature discontinuation of study drug

All TEAEs leading to premature discontinuation of study

All TEAEs leading to death (i.e. outcome of death)
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 also be included in this summary.
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetic order of SOC and 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.
The data listings will be provided for the following:

All AEs, indicating whether the event is treatment emergent


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
All AEs of Grade 3 or higher

SAEs

Deaths

AEs leading to premature discontinuation of study drug

AEs leading to premature discontinuation of study
7.1.7.
Adverse Events of Special Interest
Adverse 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.
Adverse events of interest include:

All infections (defined as all PTs within the Infections and Infestations SOC)
Infections of interest as defined below 
■
Herpes zoster
■
Active tuberculosis 
■
Opportunistic infections 
■
Hepatitis B (HBV) or C (HCV) infections

Serious infections (defined as all PTs within the Infections and Infestations SOC that are 
SAEs)

Venous thrombotic events

Malignancies 

Gastrointestinal (GI) perforations 

Liver transaminase elevation

Bleeding or Haemorrhage (SMQ)

Renal toxicity (MST)

Cytopenia
HLT Anaemia deficiencies


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HLT Anaemias haemolytic immune
HLT Anaemias haemolytic mechanical factor
HLT Anaemias haemolytic NEC (not elsewhere classified) 
HLT Anaemias NEC
HLT Leukopenias NEC
HLT Marrow depression and hypoplastic anaemias
HLT Neutropenias
HLT Thrombocytopenias 
but excluding PTs in: 
■
HLT Anaemias congenital (excluding haemoglobinopathies) 
■
HLT Anaemias due to chronic disorders
■
HLT Anaemias haemolytic immune newborn

Serious potential major adverse cardiovascular events (MACE) including the following:
Cardiovascular events
Myocardial infarction
Hospitalization for unstable angina
Transient ischemic attack
Stroke
Hospitalization for cardiac failure
Percutaneous coronary intervention

Noninfectious Diarrhoea (SMQ)
Potential serious MACE events will not be adjudicated. 
The number and percentage of patients with aforementioned events of special interest will be 
provided by the PT term for each category of AE of special interests.


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A by-subject listing for all patients having AE of special interests at any time will be provided 
for each AE of special interests. 
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study drug plus 30 days
for subjects who have permanently discontinued study drug, 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. Hemolyzed test results will not be 
included in the analysis, but they will be listed in by-subject laboratory listings.
A baseline laboratory value for the placebo-controlled and entire study period will be defined as 
the last nonmissing measurement obtained on or prior to the date/time of first dose of any study 
drug. For the active treatment period, the baseline for the subjects originally randomized to 
placebo will be the latest measurement before or on the day when the first dose of active study 
treatment is administered. 
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 will be provided by treatment group for each laboratory test specified in the 
study protocol as follows:

Baseline values 

Values at each postbaseline visit

Change and percentage change from baseline at each postbaseline visit.
Descriptive statistics will be provided by treatment group for the following laboratory tests:

Hematology
Hematocrit
Hemoglobin
Platelet count
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White blood cell (WBC) count
Mean corpuscular volume
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
Triglycerides
Total cholesterol
High Density Lipoprotein (HDL)
LDL (Low Density Lipoprotein)
LDL/HDL ratio
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 within the visit, data will be selected for analysis as described in 
Section 3.8.3
7.2.2.
Graded Laboratory Values
The Common Terminology Criteria for Adverse Events (CTCAE) 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 


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and decreased levels, analyses for each direction (i.e., increased, decreased) will be presented 
separately. 
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities for the entire study period and in subjects 
discontinued treatment prematurely 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 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.
For the analyses of active treatment period, the baseline is the day of the first dose of active 
study drug administration. 
For the analyses of placebo-controlled period, the laboratory abnormality occurring after 
Week 24 visit and no later than 30 days after the last dose of study drug is included only if 
subject does not continue treatment after Week 24.  
The listing of all laboratory abnormalities will be provided.
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 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 primary Week 24 analysis. If the relevant baseline laboratory value is missing, any 
Grade 3 or 4 values observed within the timeframe specified above will be considered treatment-
emergent marked abnormalities.
Same rules as in the Section 7.2.2.1 apply for determination of TE abnormality in the placebo-
controlled period and entire study period.
7.2.2.3.
Summaries of Laboratory Abnormalities
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by lab test and treatment group; subjects will be categorized 
according to the most severe postbaseline abnormality grade for a given lab test:

Treatment-emergent laboratory abnormalities

Treatment-emergent grade 3 or 4 laboratory abnormalities

Treatment-emergent marked laboratory abnormalities


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The summaries of treatment-emergent laboratory abnormalities will be presented by treatment 
group and highest grade for the placebo-controlled and entire study period. The listing of all 
laboratory abnormalities will be provided.
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values, with the baseline determined per Section 7.2.
By-subject listings of treatment-emergent Grade 3 or 4 laboratory abnormalities and marked 
laboratory abnormalities will be provided by subject ID number and visit in chronological order. 
This listing will include all test results that were collected throughout the study for the lab test of 
interest, with all applicable severity grades displayed.
7.2.3.
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:

Aspartate aminotransferase (AST): (a) > 3 times of the upper limit of reference range  
(ULN); (b) > 5 x ULN; (c) > 10 x ULN; (d) > 20 x ULN

Alanine aminotransferase (ALT): (a) > 3 x ULN; (b) > 5 x ULN; (c) > 10 x ULN; (d) > 20 x 
ULN

AST or ALT: (a) > 3 x ULN; (b) > 5 x ULN; (c) > 10 x ULN; (d) > 20 x ULN

Total bilirubin: > 2 x ULN

Alkaline phosphatase (ALP) > 1.5 x ULN

AST or ALT > 3 x ULN and total bilirubin: (a) > 1.5 x ULN; (b) > 2 x ULN
The summary will include data from all postbaseline visits on active treatment up to 30 days 
after the last dose of study drug. For individual laboratory tests, subjects will be counted once 
based on the most severe postbaseline values. For both the composite endpoint 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. 
The analyses will be presented for the placebo-controlled period and entire study period. 
A listing of subjects who met at least 1 of the above criteria will be provided.
7.2.4.
Shifts Relative to the Baseline Value
Shift tables will be presented for change in severity grade from baseline to Week 12 and 
Week 24.


Filgotinib, Lanraplenib, and Tirabrutinib
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7.3.
Body Weight and Vital Signs
Descriptive statistics will be provided by treatment group for body weight, BMI and vital signs 
(pulse rate, systolic and diastolic blood pressure, body temperature, and respiratory rate) as 
follows:

Baseline value

Values at each postbaseline visit

Change from baseline at each postbaseline visit
A baseline value will be defined as the last available value collected on or prior to the date of 
first dose of 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 at the visit, 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 will be provided by subject ID number and visit in 
chronological order. Body weight and BMI will be included in the vital signs listing, if space 
permits. If not, they will be provided separately.
7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the Gilead-modified World Health Organization (WHO) Drug dictionary.
The presentations of prior and concomitant medications are described below. In addition, prior 
and concomitant medication for SjS, SLE and RA will be presented in a separate summary table 
by medication category (systemic corticosteroids, other corticosteroids, csDMARDs, anti-
malarial DMARDs, biologic DMARDs, NSAIDs, other) and preferred term.  
All prior and concomitant medications will be provided in a by-subject listing sorted by subject 
ID number and administration date in chronological order based on Safety Analysis Set.
7.4.1.
Prior Medications
Prior medications are defined as any medications taken before a subject took the first study drug
(stop date is prior to Day 1).
Prior medications will be summarized by each Anatomical Therapeutic Chemical (ATC) drug 
class level 2 and 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 ordered alphabetically by preferred term in order of descending overall 


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frequency. For drugs with the same frequency, sorting will be done alphabetically. For the 
purposes of analysis, any medication with a stop date prior to the first dosing date of study drug 
will be included in the prior medication. If a partial stop 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 stop date are after the first dosing date. 
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 is on study drug, 
regardless of when the medication was started. Use of general and disease-specific concomitant 
medications will be summarized by 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 percentage of subjects who received that 
medication. The summary will be ordered alphabetically by preferred term in descending overall 
frequency. For drugs with the same frequency, sorting will be done alphabetically.
For the purposes of analysis, any medications with a start date prior to or on the first dosing date 
of study drug and continued to be taken 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 study drug will also be considered concomitant. Medications with a stop date prior 
to the date of first dosing date of study drug or a start date after the last dosing date of 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 listed but not included in the 
concomitant medication summary, unless the medication is reported as ongoing. 
In addition, prior and concomitant medications for SjS, SLE and RA will be presented in a 
separate summary table by medication category (csDMARD, systemic corticosteroids, other 
corticosteroids, NSAIDs, anti-malarial drugs and other), and preferred term.  
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 
based on Safety Analysis Set.
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned.


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7.5.
Electrocardiogram Results
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.


Filgotinib, Lanraplenib, and Tirabrntinib 
GS-US-445-4189 
8. 
PHARMACOKINETIC (PK) ANALYSES 
Statistical Analysis Plan 
Version 1.0 
Plasma concentrntions of filgotinib, the active metabolite of filgotinib (GS-829845), lamaplenib 
and tirabrntinib will be listed and summarized using descriptive statistics ( eg, sample size, 
arithmetic mean, geometi·ic mean, % coefficient of variation, standard deviation, median, 
minimum, and maximum). 
8.1. 
Pharmacokinetic Sample Collection 
8.2. 
PK Analyses Related to Intensive PK Sampling 
8.3. 
Estimation of Pharmacokinetic Parameters 
PK parameters will be estimated using Phoenix WinNonlin® software using standard 
noncompartmental methods. The linear/log h'apezoidal rnle will be used in conjunction with the 
appropriate noncompartmental model, with input values for dose level, dosing time, plasma 
concenti·ation, and con esponding real-time values, based on dmg dosing times whenever 
possible. 
For area under the cmve (AUC), samples BLQ of the bioanalytical assays occmTing prior to the 
achievement of the first quantifiable concenti·ation will be assigned a concenti·ation value of O to 
prevent overestimation of the initial AUC. Samples that are BLQ at all other time points will be 
ti·eated as missing data in WinNonlin. The nominal time point for a key event or dosing inte1val 
(t) may be used to permit direct calculation of AUC over specific time inte1vals. The 
appropriateness of this approach will be assessed by the PK scientist on a profile-by-profile 
basis. 
CONFIDENTIAL 
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May 30 2019 


Filgotinib, Lanraplenib, and Tirabrntinib 
GS-US-445-4189 
Statistical Analysis Plan 
Version 1.0 
Phaimacokinetic pai·ameters such as AUC1au, 1vz. and ti12 are dependent on an accurate estimation 
of the te1minal elimination phase of diug. The appropriateness of calculating these pai·ameters 
will be evaluated upon inspection of PK data on a profile-by-profile basis by the PK scientist. 
8.4. 
Pharmacokinetic Parameters 
Table 4. 
Study Treatments and Associated Analytes 
Treatment 
Analyte 
Filgotinib 200 mg 
Filgotinib, GS-829845 
Lanraplenib 30 mg 
Lanraplenib 
Tirabrntinib 40 mg 
Tirabrntinib 
The analytes and pai·ameters presented in Table 5 will be used to evaluate the PK objectives of 
the study. The primaiy PK parameters ai·e AUC1au, Ciau, and Cmax of filgotinib, and active 
metabolite of filgotinib (GS-829845), lanraplenib and tirabrntinib. The PK parameters to be 
estimated in this study ai·e listed and defined in the Phaimacokinetic Abbreviations section. 
Table 5. 
Phaimacokinetic Parameters for Each Analyte 
Analyte 
Parameters 
Filgotinib 
AUCtau, Ctau, Cmax, T max, AZ, CUF, Vz/F and t112, if appropriate 
GS-829845 
AUCtau, Ctau, Cmax, Tmax, AZ, and t112, if appropriate 
Lanraplenib 
AUCtau, Ctau, Cmax, Tmax,, AZ, CUF, Vz/F and t112, if appropriate 
Tirabrntinib 
AUCtau, Ctau, Cmax, T max, AZ, CUF, Vz/F and t112, if appropriate 
8.5. 
Statistical Analysis Methods 
Individual subject concentration data and individual subject PK pai·ameters for filgotinib, 
GS-829845, lanraplenib and tirabrntinib will be listed and summarized using descriptive 
statistics by treatment. Summaiy statistics (number [n], mean, SD, coefficient of variation 
[%CV], median, min, max, Ql, and Q3) will be presented for both individual subject 
concentration data by time point and individual subject PK pai·ameters by treatment. Moreover, 
the geometric mean, 95% CI, and the mean and SD of the natural log-transfo1med values will be 
presented for individual subject PK parameter data. 
Individual concentration data listings and sUllllnai·ies 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 
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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. 
For Weeks 4, 8, 12, 24, 36, and 48/ET visit data, only samples collected 20 to 28 hours after the 
prior dose will be included in the summary statistics. For Week 18 data, only samples collected 
1 to 4 hours after the administration of study drug on the visit day will be included in the 
summary statistics.
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 will be provided for each analyte by treatment:

Individual subject concentration data and summary statistics

Individual subject plasma PK parameters and summary statistics
The following figures may be provided for each analyte by treatment:

Individual subject concentration data versus time (on linear and semilogarithmic scales)

Mean (± SD) concentration data versus time (on linear and semilogarithmic scales)

Median (Q1, Q3) concentration data versus time (on linear and semilogarithmic scales)
Individual, mean, and median postdose concentration values that are ≤ LLOQ will not be 
displayed in the figures and remaining points connected.
The following listings will be provided:

PK sampling details (and PK concentrations) by subject, including procedures, differences in 
scheduled and actual draw times, and sample age


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9.
REFERENCES
Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York, NY: John Wiley & 
Sons, Inc; 1987. 


Filgotinib, Lanraplenib, and Tirabrutinib
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Version 1.0
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10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.
nQuery Advisor(R) Version X.0. Statistical Solutions, Cork, Ireland.


Filgotinib, Lanraplenib, and Tirabrutinib
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11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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12.
APPENDIXES
Appendix 1.
Schedule of Assessments
Visit window
Screening a
Day 1b
Week 2
Week 4
Week 8
Week 12
Week 18
Week 24
Week 26
Week 28
Week 32
Week 36
Week 42
Week 48/ETc
Follow Up visit 
4 weeks after 
subject’s last 
study visit d
None
None
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
7 days
+/-
7 days
+/-
7 days
+/-
7 days
Fasting visit
x
X
x
x
IP to be taken at the clinic
x
x
x
x
X
x
x
x
x
x
x
x
x
Written Informed Consent
x
Randomization
xe
xf
Physical exam and provider assessments
SjS medical/surgical history, 
including diagnosis and prior 
treatments,
x
Medical /Surgical History 
(non-SjS)
x
Vital Signs, including weight 
and heightg
x
x
x
x
x
X
x
x
x
x
x
x
x
x
x
Complete Physical 
Examination
x
x
x
Symptom-directed PE
x
x
x
x
X
x
x
x
x
x
x
x
ESSDAI
x
xy
x
x
X
x
x
x
x
x
x
x
PE for domains of ESSDAIh
x
x
x
x
X
x
x
x
x
x
x
x
28 Swollen and Tender Joint 
count
x
x
x
x
x
X
x
x
x
x
x
x
x
x


Filgotinib, Lanraplenib, and Tirabrutinib
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Version 0.1
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Visit window
Screening a
Day 1b
Week 2
Week 4
Week 8
Week 12
Week 18
Week 24
Week 26
Week 28
Week 32
Week 36
Week 42
Week 48/ETc
Follow Up visit 
4 weeks after 
subject’s last 
study visit d
None
None
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
7 days
+/-
7 days
+/-
7 days
+/-
7 days
Physician’s Global Assessment 
of SjS activity
x
x
x
x
x
X
x
x
x
x
x
x
x
x
x
Physician’s Global Assessment 
of concomitant RA or SLE 
disease activity as applicable
x
x
x
x
x
X
x
x
x
x
x
x
x
x
x
Laboratory assessments
Urine drug screeni
x
Urinalysis with spot protein/ 
microalbumin/creatinine
x
x
x
x
x
X
x
x
x
x
x
x
x
x
Urine Pregnancy Test (female 
subjects of child bearing 
potential only)
x
x
x
x
X
x
x
x
x
x
x
x
x
x
Urine for biomarker (fasting)
x
X
x
x
Serum Pregnancy Test (female 
subjects of child bearing 
potential) or FSH
x
TB testingj
x
CD19+ B cell countk
x
HbA1c, TSH
x
Hematology, ESR as 
applicable, chemistry and 
hsCRP
x
x
x
x
x
X
x
x
x
x
x
x
x
x
x
Viral Screening and Reflex 
PCR l
x
Viral Monitoringm
X
x
x
x


Filgotinib, Lanraplenib, and Tirabrutinib
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Visit window
Screening a
Day 1b
Week 2
Week 4
Week 8
Week 12
Week 18
Week 24
Week 26
Week 28
Week 32
Week 36
Week 42
Week 48/ETc
Follow Up visit 
4 weeks after 
subject’s last 
study visit d
None
None
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
3 days
+/-
7 days
+/-
7 days
+/-
7 days
+/-
7 days
Autoantibodiesn
x
x
X
x
x
Complement (C3, C4, CH50), 
and CK
x
x
x
x
x
X
x
x
x
x
x
x
x
x
Cryoglobulins, total Ig, quant 
IgG, IgA, and IgM, serum and 
urine immunofixation
x
x
X
x
x
x
x
Lipid profile (fasting)o
x
X
x
x
PK samplesp
x
x
X
x
x
x
x
Blood for Biomarker samplesr
x
x
x
x
x
X
x
x
x
x
x
x
x
x
x
PROs and questionnaires
VASt
x
x
x
x
x
X
x
x
x
x
x
x
x
x
x
ESSPRI
x
x
x
x
x
X
x
x
x
x
x
x
x
x
x
FACIT- Fatigue, OHIP-14, 
PROFAD-SSI-SF u
x
x
x
X
x
x
x
x
x
x
x
SF-36, IDEEL u
x
X
x
x
x
TSQM
x
X
x
x
x
Cognitive testing
x
x
x
X
x
x
x
x
x
x
x
CCI
CCI


Filgotinib, Lanraplenib, and Tirabrutinib 
GS-US-445-4189 
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Procedures and Exams 
12-Lead ECG 
X 
X 
X 
X 
X 
Pulmona1y function testsv 
X 
X 
Drug dispensing 
X 
X 
X 
X 
X 
Drug accountability 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Concomitant medicationsx 
X 
X 
X 
X 
X 
X 
X 
a 
Screening window is 28 days prior to Day 1 
b 
Subject will begin study dmg on Day 1, following baseline assessments and randomization. 
c 
Early Temt.ination Visit to be performed if subject discontinues before Week 48 
...,. 
M 
.:,: .. .. 
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3 days 
X 
X 
X 
X 
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d 
Follow up visit not needed if subject's last dose of study drug was >4 weeks prior to their last study visit 
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3 days 
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7 days 
X 
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e 
Subjects will be randomized on Day 1 based on their use of concomitant medications (y/n: csDMARD and/or oral corticosteroid) and ESSDAI hematological plus biological 
domains score at Day 1, (YIN: ESSDAI c:: 2). 
f 
Subjects on placebo will be re-randomized 1: 1: 1 to either filgotinib, or GS-9876 or GS-4059 
g 
Height is only required at Visit 1 and subjects are to remove shoes during measurement 
h 
Exam should include glandular exam, lymph nodes, general skin, netu·ologic exam for peripheral netu·opathy, pulmona1y exam 
CONFIDENTIAL 
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May 30 2019 


Filgotinib, Lanraplenib, and Tirabrutinib 
GS-US-445-4189 
Amphetamines Cocaine, Methadone Opiates 
J 
Quantiferon gold 
k 
As applicable 
1 
Hepatitis B smface Ag and core Ab, Hepatitis C Ab, reflex HCV RNA, HIV 1 and 2 at Screening 
m 
Viral monitoring for HCV as applicable (see study protocol.) 
n 
At screening only: anti SSA and anti SSB 
Statistical Analysis Plan 
Version 0.1 
At Day 1: deamidated gliadin peptide antibodies (anti-DGP IgA or IgG); Anti-endomysial antibodies (EMA), RF, CCP, dsDNA, ANA, IgA anti-tTA (tissue transglutaminase 
antibodies), 
At all subsequent time points: deamidated gliadin peptide antibodies (anti-DGP IgA or IgG); Anti-endomysial antibodies (EMA), RF, CCP, dsDNA, ANA, SSA, SSB, IgA 
anti-tTA (tissue transglutaminase antibodies), 
o 
As outline in protocol Appendix 6 
p 
PK samples will be collected prior to study drug administration (pre-dose) at Weeks 4, 8, 12, 24, 36, and 48/ET visit. At Week 18, PK samples will be collected 
q 
r 
s 
u 
V 
w 
X 
y 
z 
a 
roximatel 2 hours est-dose 
ammation and Pathway Biomarkers, RNA Sample, Whole Blood Sample for MoA Studies. For biomarkers which require specific material for sampling and/or processing, 
to be done if and when the material is available at site. 
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Appendix 2. 
Primary Endpoint Derivation 
Responder=No 
Responder=N o 
Responde1=No 
Scena1ios for VAS V aloes 
Baseline 
Post-baseline 
Percent Change Calculated/ 
20% Improvement de1ived? 
>0 
>0 
Calculated/ derived 
0 
>0 
Assign % Change = blank/ 
20% Improvement = NO 
0 
0 
Assign % Change = 0; 
20% Improvement = NO 
> 0 
0 
Assign % Change = -100% 
Missing 
Not Missing 
Blank 
Not Missing 
Missing 
Blank 
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Statistical Analysis Plan 
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Responder=No 
Responder= Yes 
Effect on 
30 mm Worsening 
Primary 
Derived? 
Endpoint 
Derived 
Not affected 
Derived 
Not affected 
Worsening = NO 
Not affected 
Worsening = NO 
Not affected 
Blank 
Missing 
Blank 
Missing 
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Appendix 3.
EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI)
Promoted by European League Against Rheumatism (EULAR), the EULAR Sjögren's syndrome (SjS) disease activity index 
(ESSDAI) is a systemic disease physician-reported activity index that was designed to measure disease activity in patients with 
primary SjS. The ESSDAI is now used in multiple clinical trials as primary outcome measure.
In total, twelve organ-specific domains contributing to disease activity were identified. Each domain is divided into 3–4 levels of 
activity. 
Domain
Activity Level
Description
Constitutional
Exclusion of fever of infectious origin
and voluntary weight loss
No = 0
Absence of the following symptoms
Low = 3
Mild or intermittent fever (37.5°–38.5°C)/night sweats and/or involuntary weight loss 
of 5 to 10% of body weight
Moderate = 6
Severe fever (>38.5°C)/night sweats and/or involuntary weight loss of >10% of body 
weight
Lymphadenopathy
and lymphoma
Exclusion of infection
No = 0
Absence of the following features
Low = 4
Lymphadenopathy ≥ 1 cm in any nodal region or ≥ 2 cm in inguinal region
Moderate = 8
Lymphadenopathy ≥ 2 cm in any nodal region or ≥ 3 cm in inguinal region, and/or 
splenomegaly (clinically palpable or assessed by imaging)
High = 12
Current malignant B-cell proliferative disorder
Glandular
Exclusion of stone or infection
No = 0
Absence of glandular swelling
Low = 2
Small glandular swelling with enlarged parotid (≤ 3 cm), or limited submandibular 
(>2 cm) or lachrymal swelling (>1 cm)
Moderate = 4
Major glandular swelling with enlarged parotid (> 3 cm), or important submandibular 
or lachrymal swelling
Articular
Exclusion of osteoarthritis
No = 0
Absence of currently active articular involvement
Low = 2
Arthralgias in hands, wrists, ankles and feet accompanied by morning stiffness (>30 
min)
Moderate = 4
1 to 5 (of 28 total count) synovitis
High = 6
≥ 6 (of 28 total count) synovitis


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Cutaneous
Rate as “No activity” stable long lasting
features related to damage
No = 0
Absence of currently active cutaneous involvement
Low = 3
Erythema multiforma
Moderate = 6
Limited cutaneous vasculitis, including urticarial vasculitis, or purpura limited to feet 
and ankle, or subacute cutaneous lupus
High = 9
Diffuse cutaneous vasculitis, including urticarial vasculitis, or diffuse purpura, or 
ulcers related to vasculitis
Pulmonary
Rate as “No activity” stable long lasting
features related to damage, or respiratory 
involvement not related to the disease (tobacco 
use etc.)
No = 0
Absence of currently active pulmonary involvement
Low = 5
Persistent cough or bronchial involvement with no radiographic abnormalities on 
radiography
Or radiological or HRCT evidence of interstitial lung disease with: No breathlessness 
and normal lung function test.
Moderate = 10
Moderately active pulmonary involvement, such as interstitial lung disease shown by 
HRCT with shortness of breath on exercise (NHYA II) or abnormal lung function 
tests restricted to: 70% >DL ≥ 40% or 80% >FVC≥60%
High = 15
Highly active pulmonary involvement, such as interstitial lung disease shown by 
HRCT with shortness of breath at rest (NHYA III, IV) or with abnormal lung function 
tests: DL < 40% or FVC< 60%
Renal
Rate as “No activity” stable long lasting 
features related to damage, and renal 
involvement not related to the disease.
If biopsy has been performed, please
rate activity based on histological features first
No = 0
Absence of currently active renal involvement with proteinuria< 0.5 g/d, no 
hematuria, no leucocyturia, no acidosis, or long-lasting stable proteinuria due to 
damage
Low = 5
Evidence of mild active renal involvement, limited to tubular acidosis without renal 
failure or glomerular involvement with proteinuria (between 0.5 and 1 g/d) and 
without hematuria or renal failure (GFR ≥60 ml/min)
Moderate = 10
Moderately active renal involvement, such as tubular acidosis with renal failure (GFR 
<60 ml/min) or glomerular involvement with proteinuria between 1 and 1.5 g/d and 
without hematuria or renal failure (GFR ≥60 ml/min) or histological evidence of 
extra-membranous glomerulonephritis or important interstitial lymphoid infiltrate
High = 15
Highly active renal involvement, such as glomerular involvement with proteinuria 
>1.5 g/d or hematuria or renal failure (GFR <60 ml/min), or histological evidence of 
proliferative glomerulonephritis or cryoglobulinemia related renal involvement


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Muscular
Exclusion of weakness due to
corticosteroids
No = 0
Absence of currently active muscular involvement
Low = 6
Mild active myositis shown by abnormal EMG, MRI* or biopsy with no weakness 
and creatine kinase (N <CK ≤ 2N)
Moderate = 12
Moderately active myositis proven by abnormal EMG , MRI* or biopsy with 
weakness (maximal deficit of 4/5), or elevated creatine kinase (2N<CK ≤4N),
High = 18
Highly active myositis shown by abnormal EMG,  MRI* or biopsy with weakness 
(deficit ≤ 3/5) or elevated creatine kinase (>4N)
PNS
Rate as “No activity” stable long lasting
features related to damage or PNS involvement 
not related to the disease
No = 0
Absence of currently active PNS involvement
Low = 5
Mild active peripheral nervous system involvement, such as pure sensory axonal 
polyneuropathy shown by NCS or trigeminal (V) neuralgia
Moderate = 10
Moderately active peripheral nervous system involvement shown by NCS, such as 
axonal sensory-motor neuropathy with maximal motor deficit of 4/5, pure sensory 
neuropathy with presence of cryoglobulinemic vasculitis, ganglionopathy with 
symptoms restricted to mild/moderate ataxia, inflammatory demyelinating 
polyneuropathy (CIDP) with mild functional impairment (maximal motor deficit of 
4/5or mild ataxia),
Or cranial nerve involvement of peripheral origin (except trigeminal (V) neralgia)
High = 15
Highly active PNS involvement shown by NCS, such as axonal sensorymotor 
neuropathy with motor deficit ≤3/5, peripheral nerve involvement due to vasculitis 
(mononeuritis multiplex etc.), severe ataxia due to ganglionopathy, inflammatory 
demyelinating polyneuropathy (CIDP) with severe functional impairment: motor 
deficit ≤3/5 or severe ataxia
CNS
Rate as “No activity” stable long lasting
features related to damage or CNS involvement 
not related to the disease
No = 0
Absence of currently active CNS involvement
Moderate = 10
Moderately active CNS features, such as cranial nerve involvement of central origin, 
optic neuritis or multiple sclerosis-like syndrome with symptoms restricted to pure 
sensory impairment or proven cognitive impairment
High = 15
Highly active CNS features, such as cerebral vasculitis with cerebrovascular accident 
or transient ischemic attack, seizures, transverse myelitis, lymphocytic meningitis, 
multiple sclerosis-like syndrome with motor deficit.


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Hematological
For anemia, neutropenia, and thrombopenia, 
only auto-immune cytopenia must be 
considered Exclusion of vitamin or iron 
deficiency, drug-induced cytopenia
No = 0
Absence of auto-immune cytopenia
Low = 2
Cytopenia of auto-immune origin with neutropenia (1000 < neutrophils <
1500/mm3), and/or anemia (10 < hemoglobin < 12 g/dl), and/or thrombocytopenia 
(100,000 < platelets < 150,000/mm3)
Or lymphopenia (500 < lymphocytes < 1000/mm3)
Moderate = 4
Cytopenia of auto-immune origin with neutropenia (500 ≤ neutrophils ≤ 1000/mm3), 
and/or anemia (8 ≤ hemoglobin ≤ 10 g/dl), and/or thrombocytopenia (50,000 ≤ 
platelets ≤ 100,000/mm3)
Or lymphopenia (≤500/mm3)
High = 6
3 Cytopenia of auto-immune origin with neutropenia (neutrophils < 500/mm3), and/or 
or anemia (hemoglobin < 8 g/dl) and/or thrombocytopenia (platelets <50,000/mm3)
Biological 
No = 0
Absence of any of the following biological feature
Low = 1
Clonal component and/or hypocomplementemia (low C4 or C3 or CH50) and/or 
hypergammaglobulinemia or high IgG level between 16 and 20 g/L
Moderate = 2
Presence of cryoglobulinemia and/or hypergammaglobulinemia or high IgG level > 
20 g/L, and/or recent onset hypogammaglobulinemia or recent decrease of IgG level 
(<5 g/L)
CIDP= chronic inflammatory demyelinating polyneuropathy; CK= creatine kinase; CNS= central nervous system; DLCO= diffusing CO capacity; EMG= electromyogram; FVC= 
forced vital capacity; GFR= glomerular filtration rate; Hb= hemoglobin; HRCT= high-resolution computed tomography; IgG= immunoglobulin G; NCS= nerve conduction 
studies; NHYA= New York heart association classification; Plt= platelet; PNS=peripheral nervous system
The ESSDAI overall score is obtained by addition of the twelve domain scores. The maximum theoretical ESSDAI score is 123. 
Usually, the score does not exceed 50.


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Appendix 4.
EULAR Sjögren’s Syndrome Patients Reported Index (ESSPRI)
The ESSPRI is a patient-reported outcome assessment designed to evaluate the severity of 
patients’ symptoms such as dryness, pain and fatigue in primary Sjögren’s Syndrome. ESSPRI 
is being extensively used in SjS research. This index has shown a correlation with quality of life 
and functional status measures, and can be considered a useful predictor of health status of 
patients with SjS. 
The ESSPRI questionnaire (see below) is completed by the patient and consists of three items to 
be given an activity level score between 0–10: pain (joint and/or muscle pain), fatigue and 
dryness (0 = no symptom at all and 10 = worst symptom imaginable). The patient must check 
one that best describes the severity of his/her symptoms in the worst stages. 
Each domain represents the severity of the symptom independently. The total ESSPRI score is 
the mean of all three scores and therefore can range between 0–10.
Your doctor asked you to answer some questions related to your disease. To answer the 
questions, please consider the severity of your symptoms in the worst stages only during the last 
two weeks. 
Please check the alternative that best describes your answer Please 
answer all questions carefully 
Example: 
No pain 
0 
2 
3 
4 
5 
6 
7 
8 
9 
10 
1) How severe has your dryness been during the last 2 weeks? 
No dryness 
Maximal 
imaginable 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
2) How severe has your fatigue been during the last 2 weeks? 
Maximum 
No fatigue 
imaginable fatigue 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
3) How severe has your pain Ooint or muscular pain, in your arms or legs) been during 
the last 2 weeks? 
Maximal 
No pain 
imaginable pain 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Maximal 
imaginable pain