A 24-week, Phase 3, Multicentre, Randomised, Double-blind, Efficacy and Safety Study, Comparing GSK3196165 With Placebo and With Sarilumab, in Combination With Conventional Synthetic DMARDs, in Participants With Moderately to Severely Active Rheumatoid Arthritis Who Have an Inadequate Response to Biological DMARDs and/or Janus Kinase Inhibitors
Phase: PHASE3
Conditions: Arthritis, Rheumatoid
Sponsor: GlaxoSmithKline

2018N385816_02
CONFIDENTIAL
GlaxoSmithKline group of companies
202018
1
TITLE PAGE
Protocol Title: A 24-week, phase 3, multicentre, randomised, double-blind, efficacy and 
safety study, comparing GSK3196165 with placebo and with sarilumab, in combination 
with conventional synthetic DMARDs, in participants with moderately to severely active 
rheumatoid arthritis who have an inadequate response to biological DMARDs and/or 
Janus Kinase inhibitors.
Protocol Number: 202018 / Amendment 02
Compound Number:
GSK3196165 
Compound Name:
Otilimab
Study Phase: Phase 3 
Short Title: Efficacy and safety of GSK3196165 versus placebo and sarilumab in 
participants with moderately to severely active rheumatoid arthritis who have an 
inadequate response to biological DMARDs and/or Janus Kinase inhibitors.
Study Name: contRAst-3
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual
Regulatory Agency Identifying Number(s):
IND: 121958
EudraCT:  2019-000868-18
Approval Date: 21-JAN-2020
Copyright 2020 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.

P P D
P P D
P P D

2018N385816_02
CONFIDENTIAL
202018
3
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
DNG Number
Amendment 2
21-JAN-2020
2018N385816_02
Amendment 1
22-MAY-2019
2018N385816_01
Original Protocol
06-MAR-2019
2018N385816_00
Amendment 2: 21-JAN-2020
Overall Rationale for the Amendment:  To introduce new medical device safety 
reporting wording, required in advance of roll out of pre-filled syringes to this study.  
Other minor corrections and clarifications added throughout the protocol.
Section # and Name
Description of Change
Brief Rationale
Section 1.1 Synopsis
Addition of time points to safety and 
tolerability endpoint; update to Number 
of Participants section, to clarify key 
Asian country subgroup.
To reflect the updates in body of 
protocol (detailed below).
Section 1.2 Schema
Addition of “JAKi-IR” to schema
Correction.
Section 1.3 Schedule of 
Activities (SoA)
Updated SoAs: remove fasting 
requirement for lipid test; clarify ECG 
requirement; refer to SAE section for 
reporting times at screening; add urine 
pregnancy test at safety f/u; and remove 
cholesterol sample from early 
withdrawal.
Clarifications and reflect updates 
in body of protocol.
Section 2.3.1 Risk 
Assessment
Injection site reaction mitigation strategy 
- recommendation to rotate sites.
Clarification.
Handling and usage risks associated 
with the prefilled syringe devices
Addition to align with introduction 
of prefilled syringes.
Section 3 Objectives and 
Endpoints
Addition of time points to safety and 
tolerability endpoint.
Clarification.
Section 5 Study 
Population
Addition of reference to EULAR 
recommendations for vaccination.
Provide guidance for countries 
where no local guidelines exist. 
Section 5.2 Exclusion 
Criteria
Exclusion 12: Reduce myocardial 
infarction exclusion to 3 months.
3 months is considered to be 
appropriate to stabilise ischemic 
heart disease.
Section 5.4 Screen 
Failures
Update to clarify implications of a 
positive repeat TB test.
Clarification.
Section 6.1. Study 
Intervention(s) 
Administered
Added timepoints for permitted home 
administration of pre-filled syringe.
Clarification.
Section 6.1.1 Medical 
Devices
Description of pre-filled syringes 
(medical devices) used in the study.
To comply with new regulatory 
requirements.

2018N385816_02
CONFIDENTIAL
202018
4
Section # and Name
Description of Change
Brief Rationale
Section 6.5.1 Permitted 
Therapies, Table 2
Permit PRN use of NSAIDs and weak 
opioids except 24hr before assessment 
visits, and permit PRN use of strong 
opioids after week 12 except 24hr before 
assessment visits.
Clarification to make clear how 
PRN use is managed.
Addition of Hyaluronic acid and 
associated restrictions.
To clarify and align with clinical 
practice.
Section 6.5.2 Prohibited 
Therapies, Table 3
Removal of marijuana from prohibited list 
and update to vaccination 
recommendations wording.
To clarify and align with clinical 
practice.
Update exclusion period for tsDMARDs.
Clarification.
Section 7.1.2 Other 
Stopping Criteria
Permit permanent discontinuation due to 
a significant medical event, at discretion 
of investigator.
Clarification.
Section 7.1.3.3
Haematologic 
Abnormalities
Clarification of local confirmatory test 
requirement.
Clarification.
Section 8.2.7.2 
Tuberculosis Testing
Addition of unscheduled TB testing if 
participant has been in contact with 
someone who has untreated active TB.
To mitigate risk further
Section 8.3.1 Time Period 
and Frequency for 
Collecting AE and SAE 
Information
Clarification that SAE collection is from 
beginning of study intervention (except in 
China, or if related to study 
participation).
Clarification of safety reporting 
requirements.
Section 8.3.8 Medical 
Device Deficiencies
Added sections covering the reporting 
and follow-up of medical device 
deficiencies.
To comply with new regulatory 
requirements.
Section 8.4 Treatment of 
Overdose
Clarify definition, require documentation 
to be handled by unblinded CRA.
Clarification.
Section 9.2 Sample Size 
Determination
Update to more clearly explain that key 
Asian country subgroup may continue to 
be recruited after study target reached.
Clarification.
Section 9.5 Interim 
Analyses
Interim analysis wording updated to 
describe how the key Asian country 
subgroup will be analysed.
Clarification.
Section 10.1.8 Data 
Quality Assurance
Addition of eCOA quality wording.
Clarification
Section 10.2: Clinical 
Laboratory Tests
Removal of fasting requirement for lipid 
tests.
Not considered necessary, so 
remove fasting requirement to 
minimise unnecessary 
inconvenience to participants.
Permit final assessment visit values of 
hsCRP & ESR to be provided to site.
These are baseline for LTE and 
are not individually unblinding.

2018N385816_02
CONFIDENTIAL
202018
5
Section # and Name
Description of Change
Brief Rationale
Section 10.3 Appendix 3: 
Adverse Events: 
definitions and 
procedures for Recording, 
Evaluation, Follow-up and 
Reporting
Explain that this section is for AEs and 
SAEs which are not related to medical 
devices, and reference to Appendix 9 for 
medical device incidents. 
To enable addition of medical 
device incidents appendix.
Section 10.9: Appendix 9: 
Medical Device Adverse 
Events (AEs), Adverse 
Device Effects (ADEs), 
Serious Adverse Events 
(SAEs) and Device 
Deficiencies: Definition 
and procedures for 
Recording, evaluating, 
Follow-up and reporting
Addition of medical Device Adverse 
Effects reporting appendix.
To comply with new regulatory 
requirements.
All sections
Other minor, grammatical and typographical corrections to improve 
readability.

2018N385816_02
CONFIDENTIAL
202018
6
TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
PROTOCOL SUMMARY........................................................................................10
1.1.
Synopsis.....................................................................................................10
1.2.
Schema ......................................................................................................13
1.3.
Schedule of Activities (SoA)........................................................................13
2.
INTRODUCTION....................................................................................................17
2.1.
Study Rationale ..........................................................................................17
2.2.
Background ................................................................................................17
2.3.
Benefit/Risk Assessment ............................................................................18
2.3.1.
Risk Assessment .........................................................................19
2.3.2.
Benefit Assessment.....................................................................30
2.3.3.
Overall Benefit: Risk Conclusion..................................................30
3.
OBJECTIVES AND ENDPOINTS...........................................................................31
4.
STUDY DESIGN ....................................................................................................33
4.1.
Overall Design ............................................................................................33
4.2.
Scientific Rationale for Study Design ..........................................................34
4.3.
Justification for Dose ..................................................................................34
4.4.
End of Study Definition ...............................................................................36
5.
STUDY POPULATION...........................................................................................36
5.1.
Inclusion Criteria.........................................................................................37
5.2.
Exclusion Criteria........................................................................................38
5.3.
Lifestyle Considerations..............................................................................41
5.4.
Screen Failures...........................................................................................41
6.
STUDY INTERVENTION........................................................................................42
6.1.
Study Intervention(s) Administered .............................................................42
6.1.1.
Medical Devices...........................................................................46
6.2.
Preparation/Handling/Storage/Accountability..............................................46
6.3.
Measures to Minimise Bias: Randomisation and Blinding ...........................47
6.4.
Study Intervention Compliance ...................................................................48
6.5.
Prior and Concomitant Therapies ...............................................................49
6.5.1.
Permitted Therapies ....................................................................49
6.5.2.
Prohibited Therapies....................................................................52
6.5.3.
Rescue Medicine .........................................................................53
6.6.
Dose Modification .......................................................................................54
6.6.1.
Dose Modification of Study Intervention.......................................54
6.6.2.
Dose Modification of Background Therapy...................................54
6.7.
Intervention after the End of the Study........................................................54
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................54
7.1.
Discontinuation of Study Intervention..........................................................54
7.1.1.
Liver Chemistry Stopping Criteria ................................................55
7.1.1.1.
Study Intervention Restart or Rechallenge after 
liver stopping criteria met............................................55

2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
7
7. 1. 2.  
Ot h er St o p pi n g Crit eri a ................................................................5 6
7. 1. 3.
T e m p or ar y Di s c o nti n u ati o n ..........................................................5 6
7. 1. 3. 1.
R e s pir at or y S y m pt o m s ...............................................5 6
7. 1. 3. 2.
S eri o u s a n d O p p ort u ni sti c I nf e cti o n s ..........................5 7
7. 1. 3. 3.
H e m at ol o gi c A b n or m aliti e s .........................................5 7
7. 1. 3. 4.
T B R e a cti v ati o n ..........................................................5 7
7. 2.
P arti ci p a nt Di s c o nti n u ati o n/ W it h dr a w al fr o m t h e St u d y...............................5 7
7. 3.
L o st t o F oll o w U p ........................................................................................5 8
8.
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S .....................................................5 9
8. 1.
Effi c a c y A s s e s s m e nt s .................................................................................5 9
8. 1. 1.
J oi nt A s s e s s m e nt s .......................................................................5 9
8. 1. 2.
P h y si ci a n’ s Gl o b al A s s e s s m e nt of Art hriti s ..................................6 0
8. 1. 3. 1.
P ati e nt’ s A s s e s s m e nt of Art hr iti s P ai n........................6 0
8. 1. 3. 2.
P ati e nt’ s Gl o b al A s s e s s m e nt of Art hriti s .....................6 0
8. 1. 3. 3.
H e alt h A s s e s s m e nt Q u e sti o n n air e – Di s a bilit y 
I n d e x ( H A Q- DI)...........................................................6 0
8 . 1. 3. 7.
F u n cti o n al A s s e s s m e nt of C hr o ni c Ill n e s s 
T h er a p y ( F A CI T) -F ati g u e ............................................6 1
8. 1. 3. 8.
S F -3 6 S h ort F or m H e alt h S ur v e y ................................6 1
8. 2.
S af et y A s s e s s m e nt s ...................................................................................6 2
8. 2. 1.
D y s p n o e a A s s e s s m e nt s ..............................................................6 2
8. 2. 2.
P h y si c al E x a mi n ati o n s .................................................................6 2
8. 2. 3.
El e ctr o c ar di o gr a m s ......................................................................6 2
8. 2. 4.
Vit al Si g n s ....................................................................................6 3
8. 2. 5.
Cli ni c al S af et y L a b or at or y A s s e s s m e nt s ......................................6 3
8. 2. 6.
P ul m o n ar y A s s e s s m e nt s .............................................................6 4
8. 2. 7.
T u b er c ul o si s M o n it ori n g...............................................................6 5
8. 2. 7. 1.
T u b er c ul o si s St at u s D efi niti o n s ..................................6 5
8. 2. 7. 2.
T u b er c ul o si s T e sti n g ..................................................6 6
8. 2. 7. 3.
Tr e at m e nt of L at e nt T B D uri n g t h e St u d y ...................6 6
8. 2. 7. 4.
M o nit ori n g f or T B I nf e cti o n a n d R e -a cti v ati o n 
D uri n g t h e St u d y .........................................................6 6
8. 2. 8.
H e p atiti s B M o nit ori n g ..................................................................6 7
8. 2. 8. 1.
Ri s k of R e a cti v ati o n i n P arti ci p a nt s P o siti v e f or 
H e p atiti s B C or e A nti b o d y ( H B c A b) ............................6 8
8. 2. 8. 2.
Tr e at m e nt of P arti ci p a nt s W h o Ar e H B c A b 
P o siti v e a n d W h o D e v el o p D et e ct a bl e H B V 
D N A R e q uiri n g I niti ati o n of A nti vir al T h er a p y ..............6 8
8. 2. 8. 3.
F oll o w U p of P arti ci p a nt s Tr e at e d Wi t h A nti-
v ir al T h er a p y...............................................................6 8
8. 2. 9.
M ar k er s of dr u g -dr u g i nt er a cti o n s ................................................6 8
8. 3.
A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s .............................................6 8
C CI
C CI
C CI

2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
8
8. 3. 1.
Ti m e P eri o d a n d Fr e q u e n c y f or C oll e cti n g A E a n d S A E 
I nf or m ati o n...................................................................................6 9
8. 3. 2.
M et h o d of D et e cti n g A E s a n d S A E s .............................................6 9
8. 3. 3.
F oll o w -u p of A E s a n d S A E s .........................................................7 0
8. 3. 4.
R e g ul at or y R e p orti n g R e q uir e m e nt s f or S A E s .............................7 0
8. 3. 5.
Pr e g n a n c y ...................................................................................7 0
8. 3. 6.
C ar di o v a s c ul ar a n d D e at h E v e nt s ................................................7 1
8. 3. 7.
A E s of S p e ci al I nt er e st .................................................................7 1
8. 3. 8.
M e di c al D e vi c e D efi ci e n ci e s ........................................................7 2
8. 3. 8. 1
Ti m e P eri o d f or D et e cti n g M e di c al D e vi c e 
D efi ci e n ci e s ................................................................7 2
8. 3. 8. 2
F oll o w -u p of M e di c al D e vi c e D efi ci e n ci e s ...................7 2
8. 3. 8. 3
Pr o m pt R e p orti n g of M e di c al D e vi c e 
D efi ci e n ci e s t o S p o n s or ..............................................7 2
8. 3. 8. 4
R e g ul at or y R e p orti n g R e q uir e m e nt s f or 
M e di c al D e vi c e I n ci d e nt s ............................................7 3
8. 4.
Tr e at m e nt of O v er d o s e ...............................................................................7 3
8. 5.
P h ar m a c o ki n eti c s .......................................................................................7 3
8. 6.
P h ar m a c o d y n a mi c s ....................................................................................7 4
8. 6. 1.
T ar g et e n g a g e m e nt .....................................................................7 4
8. 7.
G e n eti c s .....................................................................................................7 4
8. 8. 1.
P h ar m a c o d y n a mi c ( P D) Bi o m ar k er s ............................................7 5
8. 9.
I m m u n o g e ni cit y A s s e s s m e nt s.....................................................................7 6
8. 1 0.
M e di c al R e s o ur c e Utili s ati o n a n d H e alt h E c o n o mi c s ..................................7 6
9.
S T A TI S TI C A L C O N SI D E R A TI O N S ........................................................................7 7
9. 1.
St ati sti c al H y p ot h e s e s .................................................................................7 7
9. 2.
S a m pl e Si z e D et er mi n ati o n ........................................................................7 7
9. 2. 1.
S a m pl e Si z e S e n siti vit y ................................................................7 7
9. 3.
P o p ul ati o n s f or A n al y s e s ............................................................................7 8
9. 4.
St ati sti c al A n al y s e s .....................................................................................7 9
9. 4. 1.
Effi c a c y A n al y s e s .........................................................................8 0
9. 4. 1. 1.
E sti m a n d str at e g y .......................................................8 0
9. 4. 2.
S af et y A n al y s e s ...........................................................................8 1
9. 4. 3.
Ot h er A n al y s e s ............................................................................8 1
9. 5.
I nt eri m A n al y s e s .........................................................................................8 1
9. 5. 1.
D at a M o nit ori n g C o m mitt e e ( D M C) ..............................................8 2
1 0.
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L
C O N SI D E R A TI O N S ...............................................................................................8 3
1 0. 1.
A p p e n di x 1: R e g ul at or y, Et hi c al, a n d St u d y O v er si g ht 
C o n si d er ati o n s ............................................................................................8 3
1 0. 1. 1.
R e g ul at or y a n d Et hi c al C o n si d er ati o n s ........................................8 3
1 0. 1. 2.
Fi n a n ci al Di s cl o s ur e .....................................................................8 3
1 0. 1. 3.
I nf or m e d C o n s e nt Pr o c e s s ..........................................................8 4
1 0. 1. 4.
D at a Pr ot e cti o n ............................................................................8 4
1 0. 1. 5.  
C o m mitt e e s Str u ct ur e ..................................................................8 4
1 0. 1. 6.
P u bli c ati o n P oli c y .........................................................................8 5
1 0. 1. 7.
Di s s e mi n ati o n of Cli ni c al St u d y D at a ...........................................8 5
C CI
C CI

2018N385816_02
CONFIDENTIAL
202018
9
10.1.8.
Data Quality Assurance ...............................................................86
10.1.9.
Source Documents ......................................................................87
10.1.10. Study and Site Closure ................................................................87
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................88
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................90
10.3.1.
Definition of AE............................................................................90
10.3.2.
Definition of SAE..........................................................................91
10.3.3.
Definition of Cardiovascular Events .............................................92
10.3.4.
Recording and Follow-Up of AE and SAE....................................93
10.3.5.
Reporting of SAE to GSK.............................................................94
10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................96
10.4.1.
Definitions:...................................................................................96
10.4.1.1.
Woman of Childbearing Potential (WOCBP)...............96
10.4.1.2.
Women in the following categories are not 
considered WOCBP ...................................................96
10.4.2.
Contraception Guidance: .............................................................97
10.4.3.
Collection of Pregnancy Information: ...........................................98
10.4.4.
Contraception Eligibility Criteria for Female and Male 
Participants..................................................................................99
10.5.
Appendix 5: Genetics................................................................................101
10.6.
Appendix 6: Liver chemistry stopping and monitoring criteria and 
required actions and follow up assessments (study specific for 
202018) ....................................................................................................102
10.6.1.
Liver chemistry stopping criteria and required follow up 
assessments..............................................................................102
10.6.2.
Liver chemistry increased monitoring criteria with 
temporary discontinuation of study intervention .........................104
10.7.
Appendix 7: Summary of composite endpoints .........................................105
10.7.1.
ACR...........................................................................................105
10.7.2.
Disease Activity Score ...............................................................105
10.7.3.
Clinical Disease Activity Index (CDAI)........................................105
10.8.
Appendix 8: Hierarchy Options to Demonstrate Superiority of Each 
Dose of GSK3196165 Versus Placebo or Sarilumab ................................107
10.9.
Appendix 9: Medical Device Adverse Events (AEs), Adverse Device 
Effects (ADEs), Serious Adverse Events (SAEs) and Device 
Deficiencies: Definition and Procedures for Recording, Evaluating, 
Follow-up, and Reporting..........................................................................108
10.9.1.
Definition of Medical Device AE and ADE..................................108
10.9.2.
Definition of Medical Device SAE, SADE and USADE ...............108
10.9.3.
Definition of Device Deficiency...................................................109
10.9.4.
Recording and Follow-Up of Medical Device AE and/or 
SAE and Device Deficiencies.....................................................109
10.9.5.
Reporting of Medical Device SAEs ............................................111
10.9.6.
Reporting of SADEs...................................................................112
10.10. Appendix 10: Country-specific requirements.............................................113
10.11. Appendix 11: Abbreviations and Trademarks............................................114
10.12. Appendix 12: Protocol Amendment History...............................................118
11. REFERENCES.....................................................................................................119

2018N385816_02
CONFIDENTIAL
202018
10
1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A 24-week, phase 3, multicentre, randomised, double-blind, efficacy and 
safety study, comparing GSK3196165 with placebo and with sarilumab, in combination 
with conventional synthetic DMARDs, in participants with moderately to severely active 
rheumatoid arthritis who have an inadequate response to biological DMARDs and/or 
Janus Kinase inhibitors.
Short Title: Efficacy and safety of GSK3196165 versus placebo and sarilumab in 
participants with moderately to severely active rheumatoid arthritis who have an 
inadequate response to biological DMARDs and/or Janus Kinase inhibitors.
Rationale: The aim of this study is to determine the efficacy and safety of GSK3196165, 
in combination with conventional synthetic disease-modifying antirheumatic drug(s)
(csDMARD)(s), for the treatment of adults with moderately to severely active rheumatoid 
arthritis (RA) who have had an inadequate response to biologic DMARD(s) 
(bDMARD)(s) and/or JAK inhibitors.  Two doses of GSK3196165 (90 mg subcutaneous 
[SC] weekly and 150 mg SC weekly) will be compared with placebo (to Week 12) and 
with sarilumab (200 mg SC every other week), an inhibitor of IL-6 that is approved in 
many countries for the treatment of adults with moderately to severely active RA who 
have an inadequate response to bDMARD(s) and/or JAK inhibitors.
Objectives and Endpoints:
Objectives
Endpoints
Primary

To compare the efficacy of GSK3196165 
at doses of 90 mg and 150 mg weekly 
versus placebo, for the treatment of 
participants with moderately to severely 
active RA who are on a stable background 
of csDMARD(s) and who have had an 
inadequate response to biological 
DMARDs and/or JAK inhibitors.

Proportion of participants achieving ACR20 
at Week 12.
Secondary
To compare:

Efficacy of GSK3196165 at doses of 90 mg 
and 150 mg weekly versus sarilumab, for 
the treatment of participants with 
moderately to severely active RA who are 
on a stable background of csDMARD(s) 
and who have had an inadequate 
response to biological DMARDs and/or 
JAK inhibitors.
Major Secondary Efficacy Endpoints
Change from baseline at Week 12 (versus 
placebo) in:

HAQ-DI.
Change from baseline at Week 12 (versus 
sarilumab) in: 

CDAI total score.

Arthritis pain VAS.

2018N385816_02
CONFIDENTIAL
202018
11
Objectives
Endpoints
Other Secondary Efficacy Endpoints
Proportion of participants at Week 12 (vs. 
placebo and vs. sarilumab) and Week 24 (vs. 
sarilumab) achieving:

CDAI total score ≤10 (CDAI LDA).

CDAI total score ≤2.8 (CDAI Remission).

ACR20/50/70.

DAS28-CRP ≤3.2 and DAS28(ESR) ≤3.2
(DAS28 LDA).

DAS28(CRP) <2.6 and DAS28(ESR) <2.6 
(DAS28 Remission).

A good/moderate EULAR response

ACR/EULAR Remission.
Change from baseline at Week 12 (vs. placebo 
and vs. sarilumab) and Week 24 (vs. 
sarilumab) in:

CDAI total score.

DAS28(CRP)/DAS28(ESR).

The effect of GSK3196165 on Patient 
Reported Outcomes (PROs) versus 
placebo and the active comparator 
sarilumab.
Change from baseline at Week 12 (vs. placebo 
and vs. sarilumab) and Week 24 (vs. 
sarilumab) in:

HAQ-DI.

Arthritis pain VAS.

SF-36 physical and mental component 
scores, and domain scores.

FACIT-Fatigue.

Safety and tolerability of GSK3196165 
versus placebo and the active comparator 
sarilumab

Incidence of AEs, SAEs and AESIs.

Change from baseline in key lab 
parameters at Weeks 12 and 24.

Proportion of participants with NCI-CTCAE 
≥Grade 3 haematology/clinical chemistry 
abnormalities.

To determine the immunogenic potential of 
GSK3196165
Safety Biomarker Endpoints

GM-CSF autoantibody concentrations.

Immunogenicity.
csDMARD = conventional synthetic disease modifying antirheumatic drug; ACR20/50/70 = 20%/50%/70% 
improvement in American College of Rheumatology criteria; CDAI = clinical disease activity index; HAQ-DI = health 
assessment questionnaire disability index; VAS = visual analogue scale; LDA = low disease activity; DAS28 = 
disease activity score including 28 different joints; CRP = C-reactive protein; EULAR = European league against 
rheumatism; ESR = erythrocyte sedimentation rate; AEs = adverse events; SAEs = serious adverse events; AESIs = 
adverse events of special interest; NCI-CTCAE = National Cancer Institute-common terminology criteria for adverse 
events; GM-CSF = granulocyte-macrophage colony stimulating factor; SF-36 = short form-36; FACIT = functional 
assessment of chronic illness therapy; RA = rheumatoid arthritis

2018N385816_02
CONFIDENTIAL
202018
12
Overall Design: This is a double-blind, parallel group, multicentre, placebo and active 
comparator-controlled study of the efficacy and safety of GSK3196165 in participants 
with moderately to severely active RA, who have had an inadequate response to 
treatment with bDMARDs and/or JAK inhibitors.  The study consists of a screening 
phase of up to 6 weeks, a 24-week treatment phase and a safety follow-up visit at 
Week 34.  Upon successful screening, participants will be randomised to one of six 
intervention arms.  Participants who complete the treatment period of this study may be 
eligible to participate in a long-term extension study to further evaluate the efficacy and 
safety of GSK3196165.
Disclosure Statement: This is a parallel group treatment study with 6 arms that is 
participant, investigator and outcomes assessor blinded.
Number of Participants: Approximately 1050-1200 participants will be screened to 
achieve between 525 and 600 randomly assigned to study intervention.  Approximately 
525 evaluable participants are expected to be included in the primary analysis, of whom 
approximately 473 are expected to complete the Week 12 visit.  When the approximate 
target of 525 participants is reached, recruitment may continue up to a maximum of 600 
participants to ensure sufficient numbers in the key Asian country subgroup. 
The sample size calculation is provided in Section 9.2.
Intervention Groups and Duration:
Participants will be randomised to one of six intervention arms, in a ratio of 6:6:6:1:1:1 to 
GSK3196165 150 mg SC weekly, GSK3196165 90 mg SC weekly, sarilumab 200 mg SC 
every other week or placebo (3 arms) respectively, all in combination with background 
csDMARD(s).  At Week 12, the 3 placebo arms will switch from placebo to active 
intervention (either GSK3196165 150 mg SC weekly, GSK3196165 90 mg SC weekly, 
or sarilumab 200 mg SC every other week).  Randomisation will be stratified by 
previously failed medication (1 bDMARD, >1 bDMARD or ≥1 JAK inhibitor [regardless 
of whether bDMARD received in past]).
A separate randomisation cohort in addition to the main randomisation may be utilised 
for the key Asian country subgroup, in order to allow separate analyses for these 
countries if required.
The total treatment period is 24 weeks, with a safety follow-up visit at Week 34, for those 
participants who do not continue into the long term-extension study.
Independent Data Monitoring Committee: Yes.
Major Adverse Cardiac Event/Gastrointestinal Perforation Adjudication 
Committee: Yes.
Pulmonary Adjudication Committee: Yes.

2018N385816_02
CONFIDENTIAL
202018
13
1.2.
Schema
1.3.
Schedule of Activities (SoA)
See Section 8 for further details of study procedures listed in the SoA.
Order of Assessments:

PROs should be completed first, before any other assessments, procedures or 
consultations, to avoid influencing participants’ perception.

Where possible, joint counts should follow PRO completion. PhGA should then 
take place, followed by other assessments (including safety), ECGs, vital signs 
and blood draws, before dosing.

PK sampling and blood draws must always take place before dosing.
Study Dosing and Visit Schedule:

Study SC injection should be administered weekly, on the same day each week. 

A window of 2 days is acceptable for the SC injection (minimum gap of 5 days 
between each dose, for no more than 2 consecutive doses). Participants should 
return to their 7 day dosing schedule as soon as possible thereafter. See 
Section 6.1 for further information.

Where possible, assessment visits should be scheduled to coincide with the 
weekly administration of study intervention, the injection will then be 
performed at the site, after completion of PK sampling.

Dosing must always be performed by an unblinded administrator on weeks 0, 2, 4, 
6, 8, 10, 12, 14, 16, 18, 20, 22, even if PFS are available.  On Weeks 0, 1, 12 and 
13, participants must be dosed at site (after completion of study assessments) and 
monitored for 1 hour post dose.

2018N385816_02
CONFIDENTIAL
202018
14
SoA – Screening Period
Participant Screening
Task List
Screening assessment notes
(after informed consent, all screening assessments 
must be completed within the 42 days prior to 
Randomisation)
Day -42 to Day -1

Informed Consent and optional Genetics consent
1) ECGs should be performed before vital signs 
and blood draws.
2) Joint assessments should be performed by 
an independent assessor. Where possible the 
same assessor should perform all joint 
assessments for an individual participant.
3) Unless performed within previous 12 weeks.
4) For women of child-bearing potential.
5) Fasting is not required, but 6hr fasting status 
at time of blood draw must be noted on 
requisition form.
6) See Section 8.3.1 for the time period of SAE 
collection, which varies between countries. 
See Section 5.4 for screen failures and 
rescreening.
Inclusion/exclusion criteria
Participant Demographics
Medical, disease and therapy history
Review of asthma/COPD/pulmonary disease history
Concomitant Medication Review
Assessments
Triplicate 12-lead ECG1
Vital signs
Full Physical Exam
Dyspnoea & Cough assessment, Lung Auscultation, 
Pulse Oximetry
TB evaluation
SAE assessment6
Swollen (66) & Tender (68) joint count2
Chest X-ray (posteroanterior)3
Labs
Haematology, Chemistry, Urinalysis (dip stick)
HIV, TB, Hepatitis B & Hepatitis C screen
hsCRP
Serum pregnancy test4
Lipid profile5

2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
1 5
S o A  – Tr e at m e nt P eri o d
St u d y i nt er v e nti o n G S K 3 1 9 6 1 6 5 v s 
s aril u m a b v s Pl a c e b o ( W 0 -W 1 1)
St u d y i nt er v e nti o n G S K 3 1 9 6 1 6 5 v s s aril u m a b
( W 1 2-W 2 4)
N ot e s
W e e k
0
1
2
3
4
5
6
7
8
9
1 0 1 1
1 2
1 3 1 4 1 5 1 6 1 7 1 8 1 9 2 0 2 1 2 2 2 3
2 4
1. P R Os s h o ul d b e c o m p l et e d b ef or e a ny 
ot h er ass ess m e nts, pr oc e d ur es or 
c o ns ult ati o ns, t o av oi d i nfl u e nci n g 
p artici p a nts’ p erc e pti o n.
2. E C Gs s h o ul d b e p erf or m e d b ef or e vit al 
si g ns a n d bl o o d dr a ws.
3. J oi nt ass ess m e nts s h o ul d b e p erf or m e d 
by a n i n d e p e n d e nt ass ess or. W h er e 
p ossi bl e t h e s a m e ass ess or s h o ul d 
p erf or m all j oi nt ass ess m e nts f or a n 
i n divi d u al p artici p a nt.
4. W h er e p ossi bl e, t h e s a m e i n divi d u al 
s h o ul d p erf or m all p hysici a n gl o b al 
ass ess m e nts f or a n i n divi d u al p artici p a nt.
5. Sc h e d ul e X -r ay b et w e e n W e eks 2 2-2 3.
6. F asti n g is n ot r e q uir e d, b ut 6 hr f asti n g 
st at us at ti m e of bl o o d dr a w m ust b e n ot e d 
o n r e q uisiti o n f or m.
7. F or w o m e n of c hil d -b e ari n g p ot e nti al.
8. E S R m e as ur e d l oc ally ( usi n g kit pr ovi d e d) 
by u n bli n d sit e st aff.
9. D ay 1 s a m pl e i ncl u d es a nti -G M -C S F a ut o -
a nti b o dy a n d fr e e G M -C S F a n aly sis.
1 0. G e n etics c o ns e nti n g p artici p a nts o nly.
1 1. First a n d s ec o n d S C i nj ecti o n giv e n at sit e
f or all p artici p a nts; m o nit or p artici p a nts f or 
1 h o ur p ost d osi n g at W e eks 0, 1, 1 2, a n d 
1 3.
1 2. D osi n g m ust al w ays b e p erf or m e d b y a n 
u n bli n d e d a d mi ni str at or o n w e e k s 0, 2 , 
4, 6, 8, 1 0, 1 2, 1 4, 1 6, 1 8, 2 0, 2 2, e v e n if 
P F S ar e a v ail a bl e . R ef er t o S ecti o n 6. 1 .
1 3. Dis p e ns e w e ekly f or sit e a d mi nistr ati o n; 
O R if av ail a bl e, dis p e ns e P F S i n b ox es of 
4, ev ery 4 w e eks, f or h o m e S C d osi n g.
1 4. Mi ni m u m w e ekly r evi e w t o W e ek 1 2, t h e n 
ev ery t w o w e eks t o W e ek 2 4. A p h o n e c all 
is acc e pt a bl e if a sit e visit is n ot 
sc h e d ul e d.
1 5. M ay b e p erf or m e d b ef or e D ay 1 if r e q uir e d.
A s s e s s m e nt vi sit D a y   
      St u d y a cti viti e s 1
B a s eli n e
D ay 1
D ay 8 ( 2 d)
D ay 1 5 ( 2 d)
D ay 2 2 ( 2 d)
D ay 2 9 ( 2 d)
D ay 3 6 ( 2 d)
D ay 4 3 ( 2 d)
D ay 5 0 ( 2 d)
D ay 5 7 ( 2 d)
D ay 6 4 ( 2 d)
D ay 7 1 ( 2 d)
D ay 7 8 ( 2 d)
Pri m ar y e n d p oi nt 
D ay 8 5 ( 3 d)
D ay 9 2 ( 3 d)
D ay 9 9 ( 3 d)
D ay 1 0 6 ( 3 d)
D ay 1 1 3 ( 3 d)
D ay 1 2 0 ( 3 d)
D ay 1 2 7 ( 3 d)
D ay 1 3 4 ( 3 d)
D ay 1 4 1 ( 3 d)
D ay 1 4 8 ( 3 d)
D ay 1 5 5 ( 3 d)
D ay 1 6 2 ( 3 d)
E n d of tr e at m e nt
D ay 1 6 9 ( 7 d)
R a n d o mis ati o n
X
P R Os 1
Art hritis p ai n V A S, Pt G A, H A Q -DI
X
X
X
X
X
X
X
X
X
F A CI T -F ati g u e, S F -3 6, P R O MI S Sl e e p
X
X
X
X
X
Ass ess m e nts
1 2 -l e a d E C G2 ( S =si n gl e, T =tri plic at e)
S
T
Vit al si g ns
X
X
X
X
X
X
X
X
Bri ef P hysic al Ex a m
X
X
X
X
X
X
X
X
Dys p n o e a & C o u g h ass ess m e nt, L u n g 
A usc ult ati o n, P uls e Oxi m etry
X 
X
X
X
X
X 
X
X
X
P ul m o n ary f u ncti o n t ests ( F E V 1, F V C)
X 1 5
S w oll e n ( 6 6) & T e n d er ( 6 8) j oi nt c o u nt 3
X
X
X
X
X
X
X
X
X
P hysici a n Gl o b al Ass ess m e nt 4
X
X
X
X
X
X
X
X
X
C h est x -r ay ( p ost er o a nt eri or)
X 5
L a bs a n d bl o o d dr a ws
H a e m at ol o gy, C h e mistry, Uri n alysis
X
X
X
X
X
X
X
X
X
Li pi d pr ofil e 6
X
X
X 6
Uri n e pr e g n a ncy t est 7
X
X
X
X
X
X
hs C R P, E S R 8
X
X
X
X
X
X
X
X
X
R F, A C P A ( a nti -C C P)
X
4 ß -O H c h ol est er ol a n d c h ol est er ol
X
X
X
T B t esti n g
X
Pr e -d os e P K s a m pl e ( & G M C S F c o m pl ex)
X
X
X
X
X
X
I m m u n o g e nicity bl o o d s a m pli n g
X 9
X
X
X
X
X
G e n etic s a m pl e 1 0
X
S a m pli n g f or R N A a n alysis
X
X
X
X
Bl o o d P D & Bi o m ark ers
X
X
X
X
X
X
W e ekly st u dy S C i nj e cti o n 1 1, 1 2, 1 3
X 1 1, 1 2 X 1 1 X 1 2 X X 1 2 X X 1 2 X X 1 2 X X 1 2 X
X 1 1, 1 2 X 1 1 X 1 2 X X 1 2 X X 1 2 X X 1 2 X X 1 2 X
S A E/ A E r evi e w 1 4
< ------------------------------------------------------------ X ------------------------------------------------------------>
C o nc o mit a nt m e dic ati o n r evi e w 1 4
< ------------------------------------------------------------ X ------------------------------------------------------------>
C CI
C CI

2018N385816_02
CONFIDENTIAL
202018
16
SoA – Safety follow-up visit
Safety follow-up visit procedures
(Follow-up visit only for participants who do not 
transition into LTE study 209564)
Week 34 (Day 239 7 days)

Assessments
Vital signs
Full Physical Exam
Dyspnoea & Cough assessment, Lung Auscultation, 
Pulse Oximetry
Concomitant Medication Review
SAE/AE review
Labs
Haematology, Chemistry, Urinalysis (dip stick)
Urine pregnancy test (for women of child bearing 
potential only)
Immunogenicity blood sampling
Assessments for Early withdrawal from study
Follow Week 24 procedures (with the exception of the 4ß-OH cholesterol sample) at the 
time of withdrawal, or within 1 week, then schedule a safety follow-up visit 12 weeks 
post last dose of study intervention.

2018N385816_02
CONFIDENTIAL
202018
17
2.
INTRODUCTION
GSK3196165 is a novel human monoclonal anti-granulocyte-macrophage colony 
stimulating factor (GM-CSF) antibody that is being developed for once-weekly treatment 
of rheumatoid arthritis (RA).
2.1.
Study Rationale
The aim of this study is to determine the efficacy and safety of GSK3196165, in 
combination with conventional synthetic disease-modifying antirheumatic drug(s)
(csDMARD)(s), for the treatment of adults with moderately to severely active RA who 
have had an inadequate response to biologic DMARD(s) (bDMARD)(s) and/or JAK 
inhibitors.  Two doses of GSK3196165 (90 mg subcutaneous [SC] weekly and 150 mg 
SC weekly) will be compared with placebo (to Week 12) and with sarilumab 200 mg SC 
every other week, an inhibitor of IL-6 that is approved for the treatment of adults with 
moderately to severely active RA who have had an inadequate response to bDMARD(s) 
and/or JAK inhibitors.
2.2.
Background
RA is a chronic, systemic inflammatory autoimmune disease, characterised by a 
symmetrical polyarthritis that is associated with substantial disability and morbidity.  RA 
affects approximately 0.5-1.0% of the worldwide population, primarily women, with a 
peak incidence of onset between 40 and 60 years of age.
A substantial proportion of patients either fail to respond, or have inadequate response, to 
currently available RA therapies [Gaujoux-Viala, 2014; Nam, 2014].  Therefore, there is 
still a medical need for more effective treatments for RA with alternative mechanisms of 
action.
GM-CSF is a pro-inflammatory cytokine that regulates the functions of myeloid lineage 
cells that are considered to play key roles in the pathology of RA including macrophages 
and neutrophils [Avci, 2016; Hamilton, 2016; Wicks, 2016].  Increased levels of GM-
CSF are found in the synovial fluid from RA patients and its receptor is expressed in 
synovial tissue [Avci, 2016; Wicks, 2016].  Preclinical studies using various 
inflammatory arthritis models have shown that GM-CSF removal or neutralisation 
improved pain, function and joint histologic structure [Cook, 2001; Plater-Zyberk, 2007; 
Cook, 2013; Cook 2018a] and inhibited matrix metalloproteinase (MMP)-mediated 
cartilage degradation in experimental arthritis induced by joint instability [Cook, 2012].
GSK3196165 is a high-affinity recombinant human monoclonal antibody (mAb) that 
binds specifically to human GM-CSF and prevents its interaction with its cell surface 
receptor [Steidl, 2008].  Clinical studies in patients with RA have shown that 
GSK3196165 [Behrens, 2015] and mavrilimumab (an anti-GM-CSF receptor -subunit 
antibody) [Burmester, 2017; Burmester, 2018; Cook, 2018b] are able to reduce RA 
disease activity and pain.  A Phase IIb dose-ranging study of GSK3196165 with 
methotrexate (MTX) treatment, in patients with RA and an inadequate response to MTX, 
has also been completed.

2018N385816_02
CONFIDENTIAL
202018
18
In the BAROQUE Phase IIb study (201755), treatment with GSK3196165 in 
combination with MTX demonstrated efficacy in the treatment of active RA.  At Week 
12 of the study, all doses above 22.5 mg resulted in a significant reduction in 
DAS28(CRP) (Disease Activity Score including 28 different joints) and significantly 
higher ACR20 (20% improvement in American College of Rheumatology criteria)
response rates in comparison to placebo.  Substantial improvements in tender and swollen 
joint counts, a large effect in CDAI (Clinical Disease Activity Index) and rapid 
improvements in pain were also identified. The overall adverse event (AE) and serious 
adverse event (SAE) profile was unremarkable.  The majority of AEs were of mild or 
moderate intensity and there were no deaths, malignancies or venous thromboembolisms 
during the trial.  Additional information is provided in the GSK3196165 Investigator’s 
Brochure (IB) [GSK Document Number 2014N190256_02].  It is therefore hypothesised 
that GSK3196165, in combination with csDMARD(s), may provide clinical benefit to 
patients with RA.
2.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK3196165 may be found in the IB.  The risks 
associated with the active comparator sarilumab can be found in the approved product 
label or local prescribing information.
The potential risk assessment and mitigation strategy for the administration of 
GSK3196165 in this protocol is outlined below.

2018N385816_02
CONFIDENTIAL
202018
19
2.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK3196165]
Infections
Immune-modulating biologic drugs used in RA (such 
as anti-TNF agents) are associated with an increased 
risk of serious and opportunistic infections.  Similarly, 
because of the role of GM-CSF in anti-infective 
immunity, GSK3196165 also has the potential to 
increase the risk of infection.
Non-clinical Data:
No changes in peripheral blood populations 
(lymphocytes, neutrophils, monocytes, eosinophils or 
basophils), phagocytic activity of peripheral blood 
polymorphonuclear cells (investigational endpoint in 
the 26 week study), T-cell dependent B-cell primary or 
secondary response, or circulating cytokine levels (26 
week study) were observed.
Studies in knock-out mice showed that GM-CSF 
deficiency (GM-CSF-/-) affects the ability of mice to 
control infection when infected with M. tuberculosis or 
pulmonary group B streptococcus [LeVine, 1999].
Clinical Data:
Based on the mechanism of action of GSK3196165 
an increased risk of infection including TB, fungal and 
opportunistic infections could be expected for anti-
GM-CSF treatment, because of the role of GM-CSF in 
anti-infective immunity.
One healthy volunteer (HV) in study MSC-1000 
experienced septic shock secondary to pneumonia 29 
days after receiving a single dose of 1.5 mg/kg but 
Eligibility Criteria (Section 5.2):
Exclusion of participants with:

Active infections (including localised 
infections), or a history of recurrent infections 
or has required interventions to manage 
acute/chronic infections.

Symptomatic herpes zoster.

Hereditary or acquired immunodeficiency 
disorder, including immunoglobulin 
deficiency.

History of infected joint prosthesis, chronic leg 
ulcers, permanent in-dwelling catheters, 
chronic sinusitis, recurrent chest infections or 
recurrent urinary tract infections.

White blood cell (WBC) count ≤3.0 x 109/L

Evidence of untreated latent TB (unless 
willing to undergo TB therapy or have 
successfully undergone TB therapy).

Current or previous active TB regardless of 
treatment.

Previous close contact with a person with 
active TB and did not receive satisfactory 
anti-tuberculosis treatment.

Current acute or chronic Hepatitis B and/or 
Hepatitis C.

Known infection with human 
immunodeficiency virus (HIV) or positive test 

2018N385816_02
CONFIDENTIAL
202018
20
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
recovered after treatment with antibiotics.
In Phase II completed studies, no significant infections 
or opportunistic infections were reported.
at screening.
Assessment of vaccination status (including against 
influenza and pneumococcus, according to local 
guidelines) prior to enrolment.
Monitoring:

Serious and opportunistic infections, TB and 
TB reactivation are categorised as AESIs.

Monitoring for signs of infection with 
appropriate diagnostic tests as necessary.

Instructions to participants as to the signs and 
symptoms of infection, and to contact site 
personnel should they develop (also 
contained within the ICF).

TB evaluation at screening and monitoring for 
TB and TB re-activation throughout the study 
(Section 8.2.7.4).

Participants diagnosed with latent TB during 
screening will need to complete a course of at 
least 6 months of isoniazid (INH) therapy 
during the study including at least 4 weeks of 
therapy prior to randomisation (Section 
8.2.7.3).
Withdrawal Criteria:
Temporarily discontinue the study intervention for: 

Serious infections until the infection has 
resolved.

Suspected TB reactivation.

WBC count (<2 x 109/L)
Permanently discontinue the study intervention for:

New latent or active TB infection

HBV DNA level ≥200 IU/mL or HBV DNA 

2018N385816_02
CONFIDENTIAL
202018
21
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
detected at any level with recent increase in 
hepatic transaminases (see Figure 2 in 
Section 8.2.8).

HBV DNA positive (any level ≤200 IU/mL) 
and on repeat testing within 1 week either: 
HBV DNA positive (any level) OR HBV 
surface antigen positive OR increase in 
hepatic transaminases (see Figure 2 in 
Section 8.2.8).
Pulmonary alveolar proteinosis (PAP)
GM-CSF signalling is required to maintain the normal 
function of alveolar macrophages.  Long-term 
absence of GM-CSF signalling (e.g., via hereditary 
GM-CSF deficiency or development of anti-GM-CSF 
auto-antibodies) is known to cause the extremely rare 
condition of PAP.  PAP is characterised by the 
accumulation of surfactant lipids and protein in the 
alveolar spaces, which might lead to persistent dry 
cough and is also associated with impairment in gas 
exchange which may lead to an increased risk of 
pulmonary infection.
The exposure duration to GSK3196165 in this study is 
24 weeks.  Although the time course of PAP 
development in humans is unknown, the published 
literature suggests that the clinical onset of PAP 
requires prolonged and complete inhibition of GM-
CSF [Martinez-Moczygemba, 2008; Suzuki, 2008]. 
Risk of PAP is anticipated to be low.
Non-clinical Data:
Non-adverse minimal to mild foamy alveolar 
macrophage accumulation were noted in lungs of 
monkeys in the 13-week SC and 26-week IV 
Eligibility Criteria (Section 5.2):
Exclusion of participants with:

Any baseline symptomatology that in the 
investigator’s opinion would confound the 
early detection of PAP based upon clinical 
features, such as persistent cough (CTC 
Grade ≥2) or dyspnoea (dyspnoea scale 
Grade ≥2).
Monitoring:

Diagnosis of PAP, persistent cough (CTCAE 
Grade 2) or persistent dyspnoea (dyspnoea 
scale Grade 2) are categorised as AESIs.

Regular chest auscultation and pulse 
oximetry measurements.

Specific pulmonary assessments throughout 
the study with referral to a pulmonologist for 
clinically-significant pulmonary events.

Pulmonary Safety Guidance Document 
containing pulmonary assessment and 
management algorithms will be provided to 
the investigator.

2018N385816_02
CONFIDENTIAL
202018
22
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
toxicology studies but were reversible following an off 
drug period.  Dose levels at which foamy alveolar 
macrophages were not observed were identified in 
these studies.
Clinical Data:
No cases of PAP have been reported to date in the 
clinical development program.  Pulmonary function 
tests have not identified any safety signals.

A Pulmonary Adjudication Panel consisting of 
external experts is available for adjudication 
of cases. 
Withdrawal Criteria:
Temporarily discontinue study intervention for:

persistent cough (CTCAE Grade 2) or 
persistent dyspnoea (dyspnoea scale Grade 
2) for 3 consecutive weeks (21 days).
Permanently discontinue study intervention for:

Confirmed PAP
Hypersensitivity reactions
There is a potential risk of hypersensitivity reactions, 
including anaphylaxis, during and following the 
administration of protein-based products, such as 
GSK3196165.
Clinical Data:
No serious allergic or acute systemic reactions have 
been observed to date in the clinical development 
program.
Eligibility Criteria (Section 5.2):
Exclusion of participants with:

Significant allergies to humanised monoclonal 
antibodies.

Clinically significant multiple or severe drug 
allergies, or severe post-treatment 
hypersensitivity reactions

A history of sensitivity to any of the study 
interventions, or components thereof.
Monitoring:

Serious hypersensitivity reactions are 
categorised as AESIs.

Instructions to participants as to the signs and 
symptoms of an acute hypersensitivity 
reaction and to seek immediate medical care 
should they develop (also contained within 
the ICF)

Hypersensitivity to be managed appropriately 
per local guidelines/medical judgement

All participants will be monitored for 1 hour 

2018N385816_02
CONFIDENTIAL
202018
23
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
after the first two exposures of GSK3196165 
(i.e. Weeks 0, 1, 12, and 13).
Withdrawal Criteria:

Permanently discontinue study intervention 
for serious hypersensitivity reactions
Injection site reactions
SC injections may be associated with local reactions 
(e.g., swelling, induration, pain).
Non-clinical Data:
No macroscopic or microscopic changes indicative of 
local injection site reactions were observed following 
SC administration in cynomolgus monkeys.
Clinical Data:
Injection site reactions have been reported in 
completed Phase II studies and were non-serious and 
of mild to moderate intensity.
Monitoring:

Injection site reactions are categorised as 
AESIs and reported as an AE.

Monitor for injection site reactions throughout 
study.

Recommended that injection sites are 
rotated.
Neutropenia
Although there is a perceived theoretical risk that GM-
CSF blockade may affect maturation of leukocytes 
and their precursors, mice lacking GM-CSF do not 
develop neutropenia or show any major perturbation 
of hematopoiesis [Stanley, 1994].
Clinical Data:
Neutropenia has been observed in completed studies 
of GSK3196165; however, no clinically significant 
cases have been observed.
Eligibility Criteria (Section 5.2):
Exclusion of participants with 

Significant neutropenia (absolute neutrophil 
count <2 x 109/L) at screening.
Monitoring:

Neutropenia Grade 3 (<1.0 x 109/L) is 
categorised as an AESI.

Full blood count (with differential) performed 
at regular intervals throughout the study
Withdrawal Criteria:
Temporarily discontinue study intervention for the 
following haematological abnormality until resolved 
(Section 7.1.3.3):

Absolute neutrophil count (ANC) ≤1.0 x 109/L
Permanently discontinue study intervention for the 
following haematological abnormality (Section 7.1.2):

2018N385816_02
CONFIDENTIAL
202018
24
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy

ANC <0.5 x 109/L
Reproductive toxicity
Published studies performed with GM-CSF -/- mice 
have indicated that GM-CSF depletion potentially 
affects fertility, establishment of pregnancy and 
postpartum development of offspring in the mouse.
Non-clinical Data:
No GSK3196165-related effects on female or male 
fertility were noted in the SC 13-week repeat dose 
monkey study at doses up to 100 mg/kg/week (highest 
dose tested).  In addition, no maternal, embryofoetal 
or effects on fertility were noted in the reproductive 
toxicology studies using the surrogate rat anti-mouse 
GM-CSF monoclonal antibody, 22E9.
Clinical Data:
Two pregnancies have been reported during clinical 
studies with GSK3196165, 1 in a female partner of a 
HV participant and 1 in an MS participant. Both 
pregnancies were electively terminated. The effect of 
GSK3196165 on human pregnancy is unknown.
Eligibility Criteria (Section 5.1 and Section 5.2):

WOCBP and males to meet contraceptive 
requirements.

Negative serum pregnancy test at screening.
Exclusion of female participants who are:

Pregnant, lactating, planning to become 
pregnant or initiating breastfeeding.
Monitoring:

Females of reproductive potential using 
hormonal contraceptives, including oral, 
injections, implants, and patches, are 
required to use a secondary method of 
contraception.

Routine urine pregnancy testing of WOCBP 
throughout the study.

Collection of pregnancy information in 
females and in female partners of male 
participants.

Pregnancy to be followed to determine 
outcome.

Report as AE/SAE any pregnancy 
complication or elective termination.
Withdrawal criteria:

Permanently discontinue study intervention in 
event of pregnancy (Section 7.1.2).
Malignancy
Risk of malignancy is increased in RA and the 
immunomodulatory therapies may also increase the 
risk.
Non-clinical & Clinical Data:
There are no reports of malignancy in the non-clinical 
Eligibility Criteria (Section 5.2):
Exclusion of participants with:

Breast cancer within the past 10 years or 
lymphoma, leukaemia, or any other 

2018N385816_02
CONFIDENTIAL
202018
25
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
or clinical GSK3196165 program.
malignancy within the past 5 years except for 
cervical carcinoma in situ that has been 
resected with no evidence of recurrence or 
metastatic disease, or basal cell or squamous 
epithelial cancers of the skin that have been 
resected with no evidence of recurrence or 
metastatic disease for at least 3 years.

History of any lymphoproliferative disorder, 
such as Epstein Barr Virus (EBV) related 
lymphoproliferative disorder, or signs and 
symptoms suggestive of current lymphatic 
disease.
Immunogenicity
GSK3196165 is a humanised monoclonal antibody 
that will be delivered by the subcutaneous route and is 
targeted to bind and neutralise a soluble target, and 
for these reasons, is considered to be a relatively low 
risk of inducing adverse immune responses [FDA, 
2014].
Non-clinical Data:
Anti-drug antibodies (ADAs) to GSK3196165 were 
detected in some monkeys and this was associated 
with reduced serum levels of GSK3196165; ADA 
associated toxicity was not observed.
Clinical Data:
In clinical trials to date, there is no evidence that anti-
GSK3196165 antibodies affect GSK3196165 serum 
concentrations.
Blood samples will be tested for anti-drug antibodies 
(ADAs) to GSK3196165 on Day 1 and at select time 
points throughout the study (including Follow-up). If 
present, ADA titres and presence of neutralising 
antibodies will be assessed.
In addition to scheduled immunogenicity assessments, 
“event-driven” testing will be performed in the context 
of serious hypersensitivity reactions or AEs deemed to 
be clinically significant in the opinion of the investigator 
resulting in discontinuation from study intervention.
Potential drug interaction with CYP450 substrates
Cytokines can produce concentration-dependent 
inhibition on various CYP isoforms at the transcription 
level or by alteration of CYP enzyme stability in 
patients with infection or inflammation and increase 

Information will be collected on concomitant 
warfarin use (e.g. INR results and any 
information related to warfarin dose).

4β-hydroxycholesterol to cholesterol ratio 

2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
2 6
P ot e nti al Ri s k of Cli ni c al Si g nifi c a n c e
S u m m ar y of D at a/ R ati o n al e f or Ri s k
Miti g ati o n Str at e g y
t h e pl as m a co nc e ntr ati o ns of s p ecific C Y P s u bstr at e 
dr u gs.
Cyt oki n e m o d ul at ors m ay r ev ers e t h e a p p ar e nt 
“i n hi biti o n” eff ect of t h e cyt oki n es o n C Y P s u bstr at es, 
r es ulti n g i n a “ n or m alis ati o n” of C Y P activiti es. 
G S K 3 1 9 6 1 6 5 is a cyt oki n e m o d ul at or, s o it h as t h e 
p ot e nti al t o ‘ n or m alis e’ C Y P ex pr essi o n fr o m a 
s u p pr ess e d st at e i n p ati e nts wit h a pr o-i nfl a m m at ory 
dis e as e ( R A).
Cli ni c al D at a:
m e as ur e m e nts will b e c oll ect e d.

P artici p a nts of r e pr o d uctiv e p ot e nti al usi n g 
h or m o n al c o ntr ac e ptiv es, i ncl u di n g or al, 
i nj ecti o ns, i mpl a nts, a n d p atc h es ar e r e q uir e d 
t o us e a s ec o n d ary m et h o d of c o ntr ac e pti o n.

P artici p a nts r ec eivi n g a c o nc o mit a nt C Y P 4 5 0 
s u bstr at e wit h n arr o w t h er a p e utic i n d ex ( e. g. 
t h e o p hylli n e) s h o ul d b e m o nit or e d f or si g ns i n 
c h a n g es i n dr u g ex p os ur e.
St u d y Pr o c e d ur e s
Pl ac e b o
D u e t o et hic al c o nsi d er ati o ns, pl ac e b o c o ntr ol will o nly 
b e all o w e d u ntil W e ek 1 2, wit h all pl ac e b o p artici p a nts 
b ei n g s witc h e d t o o n e of t h e 3 activ e i nt erv e nti o n ar ms 
( G S K 3 1 9 6 1 6 5 9 0 m g, 1 5 0 m g or s aril u m a b 2 0 0 m g 
S C ev ery ot h er w e ek) at t h eir W e ek 1 2 visit. T his will 
e n a bl e t h e st u dy t o g e n er at e c o ntr oll e d d at a i n 
p artici p a nts i niti ally r a n d o mis e d t o pl ac e b o.

P artici p a nts r a n d o mis e d t o t h e pl ac e b o ar m 
will s witc h at W e ek 1 2 t o 1 of 3 activ e 
i nt erv e nti o n ar ms ( S ecti o n 4. 1 , S ecti o n 6. 3 ).

R a n d o mis ati o n r ati o of 6: 6: 6: 1: 1: 1 will 
mi ni miz e t h e n u m b er of p artici p a nts i n t h e 
pl ac e b o ar m ( S ecti o n 1. 1 , S ecti o n 4. 1 , 
S ecti o n 6. 1 , S ecti o n 6. 3 ).

B ack gr o u n d t h er a py wit h cs D M A R D(s) is 
r e q uir e d, h o w ev er t h e p artici p a nts ar e lik ely 
t o h av e f ail e d cs D M A R D t h er a py pri or t o t h eir 
pr evi o us b D M A R D or J A K tr e at m e nt.

C h a n g es i n b ack gr o u n d m e dic ati o n ar e n ot 
p er mitt e d u nl ess r e q uir e d f or s af ety a n d a ny 
C CI

2018N385816_02
CONFIDENTIAL
202018
27
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
dose adjustments must be documented. 

Participants are permitted to receive a stable 
dose of ≤10 mg/day oral prednisolone or 
equivalent and/or a stable dose of NSAID(s).
Blood draws
Venous access in some participants may be 
problematic and the needles used may cause 
bruising (ecchymosis) around the access site.

A maximum of 400 mL of whole blood will 
be collected over the course of the study.

At visits to collect whole blood samples, 
one or more samples of sufficient volume 
will be collected and divided into suitable 
portions for the various analyses such as 
PD biomarkers.

Whole blood samples for genetic research 
will only be collected from those 
consenting to participate in this research.

Whole blood samples will be collected by 
site personnel experienced in 
phlebotomy.
Chest X-ray
Generally, the amount of radiation during an X-ray is 
equivalent to between a few days and a few years of 
exposure to natural radiation from the environment. 
The risk of cancer from exposure to X-rays is very 
small.

Minimal procedures performed at Screening 
and end of treatment phase (Week 24).

No requirement for screening X-ray if one 
was performed within the previous 12 weeks.

Exposure to radiation from X-rays is far less 
than the exposure to natural radiation.
Study Medical Devices
Handling and usage risks associated with the prefilled 
syringe devices.
A life-threatening serious risk has been identified that 
is caused by the participant removing the rigid needle 
shield with their teeth and choking on the small part. 
This risk is considered improbable and non-intuitive, it 

Instructions For Use (IFU) on how to correctly 
handle and use the device is provided.

2018N385816_02
CONFIDENTIAL
202018
28
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
has not been observed in human factors studies for 
this patient group and is not precedented with other 
GSK products using the same devices.
All other anticipated device effects are non-serious 
and primarily unlikely, improbable, occasional or 
remote and are due to user error.
Other
Sarilumab (risks per label)
Label includes a warning for risk of serious infections, 
including opportunistic infections such as TB resulting 
in hospitalisation or death.  GI perforations have been 
reported in clinical studies, primarily as a complication 
of diverticulitis.
Decreases in absolute neutrophil count and platelets 
and increases in liver enzymes and lipid parameters 
(low-density lipoprotein [LDL] cholesterol, and high-
density lipoprotein [HDL] cholesterol and/or 
triglycerides) have been reported.
Malignancies were reported in clinical studies; 
however, the impact of sarilumab on development of 
malignancies is not known.
Hypersensitivity reactions have been reported with 
sarilumab.
See GSK3196165 above for serious infections, 
malignancies, laboratory changes and hypersensitivity.
Eligibility criteria (Section 5.2):
Exclusion of participants with:

Any condition or contraindication as 
addressed in the local product information or 
local clinical practice for sarilumab.

Evidence of untreated latent TB (unless 
willing to undergo TB therapy or have 
successfully undergone TB therapy).

Current or previous active TB regardless of 
treatment.

Previous close contact with a person with 
active TB and did not receive satisfactory 
anti-tuberculosis treatment.

Hepatic exclusion criteria included in protocol 
per sarilumab label.

History of gastrointestinal disease, including 
diverticulitis.
Monitoring:
As above for GSK3196165

Laboratory tests to assess potential changes 

2018N385816_02
CONFIDENTIAL
202018
29
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
in lymphocytes, neutrophils, haemoglobin, 
liver enzymes and lipids. Participants should 
be managed according to clinical 
guidelines/standard of care for the 
management of hyperlipidaemia.

TB evaluation at screening and monitoring for 
TB and TB re-activation throughout the study 
(Section 8.2.7.4). 

Participants diagnosed with latent TB during 
screening will need to complete a course of at 
least 6 months of INH therapy during the 
study including at least 4 weeks of therapy 
prior to randomisation (Section 8.2.7.3).

Study specific Liver monitoring and 
interruption criteria included in protocol 
(Section 7.1.1).
Withdrawal:
As above for GSK3196165. 

Study specific liver stopping criteria (Section 
7.1.1)

Permanently discontinue for gastrointestinal 
perforation.

2018N385816_02
CONFIDENTIAL
202018
30
2.3.2.
Benefit Assessment
GM-CSF plays a key role in initiation and progression of inflammation in RA and 
indirectly increases the destruction of the bone and cartilage.  GSK3196165 binds human 
GM-CSF and inhibits GM-CSF mediated responses in vitro.  Clinical studies in RA have 
shown that GSK3196165 [Behrens, 2015] and mavrilimumab (an anti-GM-CSF alpha-
subunit receptor antibody) [Burmester, 2017, Burmester, 2018; Cook, 2018b] were able 
to reduce RA disease activity and pain. In addition, results from BAROQUE showed that 
all doses of GSK3196165 above 22.5 mg in combination with MTX resulted in a 
significant reduction in DAS28(CRP), significantly higher ACR20 response rates, 
substantial improvements in tender and swollen joint counts, a large effect in CDAI and 
rapid improvements in pain with an acceptable safety profile when compared with 
placebo. These data support further evaluation of GSK3196165 as a treatment option in 
RA.
Participants randomised to the active comparator arm, will receive the marketed drug 
sarilumab, which is approved in many countries for the treatment of adults with 
moderately to severely active RA.  Participants randomised to one of the placebo arms, 
will receive placebo intervention only for 12 weeks, and will switch at Week 12 to 
receiving either GSK3196165 or active comparator for the remainder of the study.
Furthermore, each participant will benefit from extensive monitoring of their disease 
activity with numerous assessments throughout the study such as physical examinations, 
X-rays, ECGs, vital signs, pulse oximetry, respiratory function tests, laboratory tests, and 
swollen/tender joint assessments among others.
2.3.3.
Overall Benefit: Risk Conclusion
Current preclinical and clinical data with GSK3196165 indicates that it binds and inhibits 
the function of GM-CSF and that this inhibition may have clinical utility in the treatment 
of inflammatory and autoimmune diseases, such as RA.
The main potential risks are those that may be associated with inhibition of GM-CSF, 
including infection, pulmonary alveolar proteinosis, neutropenia, malignancy and 
reproductive toxicity, plus those associated with the administration of a therapeutic 
monoclonal antibody, including hypersensitivity reactions, injection site reactions and 
immunogenicity.
In addition to routine pharmacovigilance, the safety review team (SRT) will review 
blinded safety data approximately every 4 weeks during the period of study conduct and 
unblinded safety data will be reviewed by the Independent Data Monitoring Committee 
(IDMC) at scheduled intervals (see Section 10.1.5).  Key safety data that meets 
predefined thresholds will be reviewed by the IDMC allowing ongoing assessment of the 
overall benefit:risk throughout the study.  Full details of safety thresholds will be 
provided in the IDMC charter.
Taking into account the measures taken to minimise risk to participants randomised in 
this study, the potential risks identified in association with GSK3196165 are justified by 
the anticipated benefits that may be afforded to participants with RA.

2018N385816_02
CONFIDENTIAL
202018
31
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To compare the efficacy of GSK3196165 at 
doses of 90 mg and 150 mg weekly versus 
placebo for the treatment of participants 
with moderately to severely active RA who 
are on a stable background of 
csDMARD(s) and who have had an 
inadequate response to biological 
DMARDs and/or JAK inhibitors.

Proportion of participants achieving ACR20 
at Week 12.
Secondary
To compare:

Efficacy of GSK3196165 at doses of 90 mg 
and 150 mg weekly versus sarilumab, for 
the treatment of participants with 
moderately to severely active RA who are 
on a stable background of csDMARD(s) 
and who have had an inadequate response 
to biological DMARDs and/or JAK 
inhibitors.
Major Secondary Efficacy Endpoints
Change from baseline at Week 12 (versus 
placebo) in:

HAQ-DI.
Change from baseline at Week 12 (versus 
sarilumab) in: 

CDAI total score.

Arthritis pain VAS.
Other Secondary Efficacy Endpoints
Proportion of participants at Week 12 (vs. 
placebo and vs. sarilumab) and Week 24 (vs. 
sarilumab) achieving:

CDAI total score ≤10 (CDAI LDA).

CDAI total score ≤2.8 (CDAI Remission).

ACR20/50/70.

DAS28-CRP ≤3.2 and DAS28(ESR) ≤3.2
(DAS28 LDA).

DAS28(CRP) <2.6 and DAS28(ESR) <2.6 
(DAS28 Remission).

A good/moderate EULAR response.

ACR/EULAR Remission.
Change from baseline at Week 12 (vs. placebo 
and vs. sarilumab) and Week 24 (vs. 
sarilumab) in:

CDAI total score.

DAS28(CRP)/DAS28(ESR).

The effect of GSK3196165 on Patient 
Reported Outcomes (PROs) versus 
placebo and the active comparator 
sarilumab.
Change from baseline at Week 12 (vs. placebo 
and vs. sarilumab) and Week 24 (vs. 
sarilumab) in:

HAQ-DI.

2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
3 2
O bj e cti v e s
E n d p oi nt s

Art hritis p ai n V A S.

S F -3 6 p hysic al a n d m e nt al c o m p o n e nt 
sc or es a n d d o m ai n sc or es.

F A CI T -F ati g u e.

S af ety a n d t ol er a bility of G S K 3 1 9 6 1 6 5 
v ers us pl ac e b o a n d t h e activ e c o m p ar at or 
s aril u m a b

I nci d e nc e of A Es, S A Es a n d A E SIs.

C h a n g e fr o m b as eli n e i n k ey l a b 
p ar a m et ers at W e eks 1 2 a n d 2 4.

Pr o p orti o n of p artici p a nts wit h N CI -C T C A E 
≥Gr a d e 3 [ N CI , 2 0 1 7] h a e m at ol o gy/cli nic al 
c h e mistry a b n or m aliti es.
T o d et er mi n e t h e i m m u n o g e nic p ot e nti al of 
G S K 3 1 9 6 1 6 5.
S af et y Bi o m ar k er E n d p oi nt s

G M -C S F a ut o a nti b o dy c o nc e ntr ati o ns.

I m m u n o g e nicity.
E x pl or at or y
T o d et er mi n e:

P h ar m ac oki n etics ( P K)

Ex p os ur e -r es p o ns e

P h ar m ac o dy n a mic ( P D) bi o m ark ers
P K/ P D E n d p oi nt s

G S K 3 1 9 6 1 6 5 a p p ar e nt cl e ar a nc e ( C L/ F) 
a n d ot h er P K p ar a m et ers as a p pr o pri at e.

Ex p os ur e -r es p o ns e r el ati o ns hi p f or k ey 
effic acy a n d s af ety e n d p oi nts.

Bi o m ark ers of t ar g et e n g a g e m e nt, 
d o w nstr e a m si g n alli n g of G M- C S F a n d 
E C M d e gr a d ati o n.

.
cs D M A R D = c o nv e nti o n al sy nt h etic dis e as e m o difyi n g a ntir h e u m atic dr u g; A C R 2 0/ 5 0/ 7 0 = 2 0%/50 %/ 7 0 % 
i m pr ov e m e nt i n A m eric a n C oll e g e of R h e u m at ol o gy crit eri a; C D AI = cli nic al dis e as e activity i n d ex; H A Q-DI = h e alt h 
ass ess m e nt q u esti o n n air e dis a bility i n d ex; V A S = vis u al a n al o g u e s c al e; L D A = l o w dis e as e activity; D A S 2 8 = 
dis e as e activity sc or e i ncl u di n g 2 8 diff er e nt j oi nts; C R P = C -r e activ e pr ot ei n; E U L A R = E ur o p e a n l e a g u e a g ai nst 
r h e u m atis m
 E S R = eryt hr ocyt e 
C CI
C CI
C CI
C CI

2018N385816_02
CONFIDENTIAL
202018
33
sedimentation rate; AEs = adverse events; SAEs = serious adverse events; AESIs = adverse events of special 
interest; NCI-CTCAE = National Cancer Institute-common terminology criteria for adverse events; GM-CSF = 
granulocyte-macrophage colony stimulating factor; ECM = extracellular matrix; RNA = ribonucleic acid; SF-36 = short 
form-36; FACIT = functional assessment of chronic illness therapy; RA = rheumatoid arthritis
4.
STUDY DESIGN
4.1.
Overall Design

This is a Phase 3, randomised, multicentre, double-blind, parallel group, placebo 
and active comparator (sarilumab) controlled study, with primary objective to 
assess the efficacy and safety of GSK3196165 in combination with csDMARD(s) 
in participants with moderately to severely active RA who have an inadequate 
response to bDMARDs and/or JAK inhibitors.

This is a 24-week study with primary endpoint at Week 12 to coincide with the 
duration of placebo intervention.

Upon successful screening, participants will be randomised to one of six 
intervention arms, in a ratio of 6:6:6:1:1:1 to GSK3196165 150 mg SC weekly, 
GSK3196165 90 mg SC weekly, sarilumab 200 mg SC every other week or 
placebo (three arms) respectively, all in combination with background 
csDMARD(s).  At Week 12, participants in the three placebo arms will switch 
from placebo to active intervention (either GSK3196165 150 mg SC weekly, 
GSK3196165 90 mg SC weekly, or sarilumab 200 mg SC every other week).  
Randomisation will be stratified by previously failed medication (1 bDMARD, >1 
bDMARD or ≥1 JAK inhibitor [regardless of whether bDMARD received in 
past]).

GSK3196165 and placebo will be administered by weekly subcutaneous (SC) 
injection; participants randomised to sarilumab will receive SC injections of 
sarilumab every other week, plus a placebo injection in the intervening weeks to 
maintain the blind.  See Section 6.1.

Due to ethical considerations, placebo control will only be allowed until Week 12.  
At their Week 12 visit, participants in the three placebo arms will switch to 
receiving the active intervention specified for that arm.  This will enable placebo 
participants to receive active intervention from Week 12 onwards and for the 
study to accrue additional randomised safety data. The intervention switch at 
Week 12 will be managed automatically by the Interactive Response Technology 
(IRT) in order to maintain the blind.

Participants who successfully complete the 24-week treatment period may be 
eligible to transition into long term extension study 209564.  Any participant who 
does not transition into study 209564 will undergo a safety follow-up visit at 
Week 34 (corresponding to 12 weeks after the last potential dose of sarilumab, at 
Week 22).

2018N385816_02
CONFIDENTIAL
202018
34
4.2.
Scientific Rationale for Study Design
This study is a placebo-controlled, sarilumab-controlled, parallel-dose study of SC doses 
of GSK3196165 added on to stable dose(s) of csDMARD(s).  Participants will be 
allowed to receive a stable dose of ≤10 mg/day oral prednisolone or equivalent and/or a 
stable dose of NSAID(s).
The double-blind, placebo-controlled, randomised clinical study is considered the gold 
standard for the safety and efficacy assessment of a new therapy both by clinicians and 
regulatory authorities.  Control with a comparator, sarilumab, will also comply with 
recent guidelines from regulatory authorities and help further establish the safety and 
efficacy in comparison with an established bDMARD.  In the proposed study, 
participants will continue to receive stable dose(s) of csDMARD(s).  All placebo 
participants will switch to active intervention (either GSK3196165 150 mg or 90 mg or 
sarilumab 200 mg) at their Week 12 visit.  Participants are not allowed to receive any 
additional bDMARDs other than GSK3196165 or sarilumab, or any targeted synthetic 
DMARD (tsDMARD) (including JAK inhibitors) during the study, to mitigate the 
potential increased safety risks of administering a combination of bDMARDs or a 
combination of a bDMARD and a tsDMARD.
Efficacy and safety of GSK3196165 will be compared with placebo (until Week 12) and 
an established active comparator (until Week 24), sarilumab which is approved in many 
countries for the treatment of RA in patients inadequately controlled with DMARDs.
ACR20 is considered an established endpoint which continues to be an acceptable 
measure to demonstrate reduction in disease activity as recommended in the US 
regulatory guidelines.
Health assessment Questionnaire Disability Index (HAQ-DI) is considered an established 
endpoint which continues to be an acceptable measure to demonstrate improvement in 
physical function as recommended in the US and EU regulatory guidelines.
4.3.
Justification for Dose
GSK3196165
The GSK3196165 doses for this study have been selected based on pharmacokinetics 
(PK), efficacy, safety data and exposure-response relationship for efficacy endpoints 
from the phase 2b dose finding study, BAROQUE (201755).
The BAROQUE study showed an acceptable safety profile and clinically meaningful 
efficacy at the highest dose of 180 mg SC weekly for 5 injections, then every other week 
until Week 50.  The efficacy however started to plateau after Week 6 with no further 
improvement post Week 12.  This effect is likely due to lower trough concentrations 
achieved in BAROQUE than predicted from PK data from historic studies (MSC-1000, 
MSC1001 and MOR103C104).  The reason for the lower than expected exposure to 
GSK3196165 in RA participants in BAROQUE is not fully understood.  The PK of 
GSK3196165 was linear over the tested dose range (IV; 0.025 – 3 mg/kg and SC; 22.5 –
180 mg), which is consistent with the PK profile of a mAb against soluble cytokine [GSK 

2018N385816_02
CONFIDENTIAL
202018
35
Document Number 2017N353526_00].  However, GSK3196165 clearance in healthy 
volunteers (HV) was 3 times higher (0.93, confidence interval [CI]: 0.83 – 1.04 L/day) 
than generally reported for a mAb (0.3 L/day) and the half-life (t1/2) of 12 days was 
shorter than a typical mAb.  In addition, the SC bioavailability (0.34, CI: 0.26 – 0.44) was 
lower than expected for a mAb.  In RA participants, the apparent clearance (CL/F) after 
SC administration of GSK3196165 was 2.4 times higher than HV and the estimated t1/2 
was 10 days.
In this study, the dosing frequency will be increased to every week to overcome the 
higher CL/F and lower t1/2 of 10 days.  The GM-CSF-GSK3196165 complex data from 
BAROQUE also supports weekly administration as an optimal dosing regimen for 
GSK3196165.  This dosing frequency with a 90 and 150 mg dose is predicted to result in 
steady-state pre-dose concentrations of 1500 and 2500 ng/mL, respectively.  Based on a 
longitudinal exposure-response model of DAS28(CRP), a dose of 90 mg SC every week 
is predicted to provide clinically meaningful efficacy similar to the 180 mg regimen in 
the BAROQUE study and in line with other RA targeted DMARDs, whilst 150 mg SC 
every week dose is predicted to provide greater efficacy to that achieved in BAROQUE.
Figure 1
Comparison of PK/PD Model Predicted Median Change from 
Baseline in DAS28(CRP) given 3 Dose Regimens of GSK3196165: 
180 mg Weekly for 5 Weeks Followed by Every Other Week 
(BAROQUE Regimen), 90 mg Weekly and 150 mg Weekly
Based on dose-response relationship at Week 4 (matching the weekly dose regimen to be 
used in this study) the 90 mg and 150 mg doses translate into a ED70 and ED80 
respectively.  Logistic regression analysis of ACR20 and ACR50 response at Week 12, 
also indicated higher trough concentrations are associated with response rate.  The 
predicted ACR20 response rate for the 90 mg and 150 mg weekly doses are 63% and 
69%, respectively.

2018N385816_02
CONFIDENTIAL
202018
36
Furthermore, the safety profile of GSK3196165 in BAROQUE was acceptable at all 
doses with no apparent dose response in the incidence of AEs or SAEs.  More details are 
provided in the GSK3196165 IB.
Given the GSK3196165 half-life of 10 days, steady-state is expected to be reached after 5 
weekly doses (as in BAROQUE), therefore GSK3196165 concentrations with the 150 mg 
every week dosing regimen should not exceed concentrations studied in BAROQUE.  
The highest dose of 150 mg weekly provides a 3 to 5-fold safety margin to the 5 mg/kg 
dose in the 26-week monkey toxicology study where no foamy alveolar macrophages 
were observed (NOEL).
In summary, PK, exposure-response, dose-response and safety data from the BAROQUE
study, supported by modelling strongly support the selection of the 90 mg and 150 mg 
weekly doses, where 90 mg is expected to provide clinically-meaningful efficacy at 
levels similar to BAROQUE and existing targeted DMARDs, and 150 mg is predicted to 
provide greater clinical benefit.  Both doses are also covered by an appropriate safety 
margin.
Sarilumab
The sarilumab dose has been selected based on the recommended approved dose (200 mg 
every other week) in the countries where it is commercially available.
4.4.
End of Study Definition
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last visit.  This will be the Week 24 visit for those 
participants who transition into the long-term follow-up study or the safety follow-up 
visit for all other participants.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Investigators should review and update the vaccination status of potential participants as 
per local guidelines for adult vaccination prior to entering them into the study (refer to 
EULAR recommendations where no local guidelines are available [Furer, 2019]).  All 
participants who have not received the herpes zoster vaccine at study entry will be
recommended to complete vaccination >30 days prior to randomisation.  All participants 
may receive inactivated flu vaccines during the study at the discretion of the investigator.
Note that “Inadequate response” to prior treatment in this population, is defined as: In the 
opinion of the investigator, after at least 3 months of treatment the participant 
experienced insufficient efficacy or loss of response (e.g. no EULAR response; failure to 
achieve ACR20; any other clinical criteria recommended per local guidelines that would 

2018N385816_02
CONFIDENTIAL
202018
37
trigger a change of treatment), or the participant discontinued treatment due to 
intolerability or toxicity irrespective of treatment duration.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
AGE
1. Age ≥18 years at the time of signing informed consent.
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS
2. Meets ACR/EULAR 2010 RA Classification Criteria (see study reference manual 
[SRM]) with a duration of RA disease of ≥6 months at time of screening and 
participant not diagnosed before 16 years of age.
3. Must have active disease at both screening and baseline, as defined by having both:
a.
≥6/68 tender/painful joints (TJC), and
b. ≥6/66 swollen joints (SJC).
If surgical treatment of a joint has been performed, that joint cannot be 
counted in the TJC or SJC for enrolment purposes
4. Must have a high sensitivity C-reactive protein (hsCRP) measurement ≥3 mg/L at 
screening.
5. Must meet Class I, II or III of the ACR 1991 Revised Criteria for Global Functional 
Status in RA (see SRM).
6. Must have inadequate response despite currently taking at least one and at most two 
concomitant csDMARDs for at least 12 weeks prior to Day 1, from the following:
a.
Methotrexate (MTX): weekly 15-25 mg oral or injected, for at least 12 weeks 
at the maximum tolerated dose prior to Day 1, with no change in route of 
administration in this time.  A lower dose of ≥7.5 mg/week is acceptable if 
reduced for reasons of intolerance to MTX, e.g. nausea/vomiting, hepatic or 
hematologic toxicity, or per local requirement (there must be clear 
documentation in the medical record).  Exception: A lower dose of 6 mg/week 
is allowed if the minimum locally approved or recommended dose is lower 
than 7.5 mg/week.
b. Hydroxychloroquine up to 400 mg/day or chloroquine up to 250 mg/day.
c.
Sulfasalazine up to 3000 mg/day.
d. Leflunomide up to 20 mg/day.  Note: concomitant use of leflunomide and 
methotrexate is not allowed, for safety reasons.
e.
Bucillamine up to 100 mg/day (or up to 300 mg/day if permitted per local 
requirements).

2018N385816_02
CONFIDENTIAL
202018
38
f.
Iguratimod up to 50 mg/day.
g. Tacrolimus up to 3 mg/day.
NOTE: The dose of csDMARD(s) must be stable and tolerated for at least 8 
weeks prior to Day 1 and should remain stable throughout the study from 
screening to end of treatment period, except adjustment for safety reasons.  See 
Section 6.5.
7. Must have inadequate response to at least one biologic DMARD at an approved dose 
and/or at least one JAK inhibitor (JAKi) at an approved dose.  In both cases this may 
be with or without combination with a csDMARD.  Prior bDMARD or JAKi therapy 
must be discontinued before randomisation per the guidance in Section 6.5.2
Prohibited Therapies.
WEIGHT
8. Body weight 40 kg
SEX
9. Male or female participants are eligible to participate so long as they meet the 
contraceptive eligibility criteria in Section 10.4.4 and agree to abide by the 
contraceptive requirements detailed in Appendix 4.
INFORMED CONSENT
10. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol.
OTHER SAFETY-RELATED
11. For participants on MTX: must be willing to continue or initiate treatment at 
screening, with oral folic acid (at least 5 mg/week) or equivalent and be treated during 
the entire study (mandatory co-medication for MTX treatment).
5.2.
Exclusion Criteria
A participant will not be eligible for inclusion in this study if any of the following criteria 
apply:
MEDICAL CONDITIONS
1. Active infections (including localised infections), or history of recurrent infections 
(excluding recurrent fungal infections of the nail bed), or has required management of 
acute or chronic infections, as follows:

Currently taking any suppressive anti-infective therapy for a chronic infection 
(such as pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster 

2018N385816_02
CONFIDENTIAL
202018
39
and atypical mycobacteria) OR

Hospitalisation for treatment of infection within 26 weeks of Day 1 OR

Use of parenteral (IV) or intramuscular (IM) antimicrobials (antibacterials, 
antivirals, antifungals, or antiparasitic agents) within 26 weeks of Day 1 or 
oral antimicrobials (apart from INH use for latent TB treatment) within 
14 days of Day 1.
2. Symptomatic herpes zoster within 3 months prior to screening
3. Hereditary or acquired immunodeficiency disorder, including immunoglobulin 
deficiency.
4. Known infection with human immunodeficiency virus (HIV) or positive test at 
screening.
5. History of infected joint prosthesis at any time, with the prosthesis still in situ.  
History of chronic leg ulcers, permanent in-dwelling catheters, chronic sinusitis, 
recurrent chest infections or recurrent urinary tract infections.
6. Any baseline symptomatology that in the investigator’s opinion would confound the 
early detection of pulmonary alveolar proteinosis based upon clinical features, such as 
persistent cough (CTC grade ≥2) or persistent dyspnoea (dyspnoea scale Grade ≥2).
7. Current unstable liver or biliary disease per investigator assessment defined by the 
presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal 
or gastric varices, persistent jaundice, or cirrhosis.
8. Current acute or chronic Hepatitis B and/or Hepatitis C.
9. Current or history of renal disease or estimated glomerular filtration rate (eGFR) by 
Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) 
calculation <30 mL/min/1.73m2 at screening.
10. Breast cancer within the past 10 years or lymphoma, leukaemia, or any other 
malignancy within the past 5 years except for cervical carcinoma in situ that has been 
resected with no evidence of recurrence or metastatic disease, or basal cell or 
squamous epithelial cancers of the skin that have been resected with no evidence of 
recurrence or metastatic disease for at least 3 years.
11. History of any lymphoproliferative disorder, such as Epstein Barr Virus (EBV) 
related lymphoproliferative disorder, or signs and symptoms suggestive of current 
lymphatic disease.
12. Have a history or presence of significant other concomitant illness according to the 
Investigator judgment such as, but not limited to cardiovascular (including Stage III 
or IV cardiac failure according to New York Heart Association classification, 
myocardial infarction within 3 months, unstable angina pectoris, uncontrolled 
hypertension, uncontrolled hypercholesterolemia), neurological, endocrinological, 
gastrointestinal (including diverticulitis), hepatic disease, metabolic, lymphatic 
disease, or previous renal transplant that would adversely affect the participant’s 
participation in this study.
13. Any condition or contraindication as addressed in the local product information or 

2018N385816_02
CONFIDENTIAL
202018
40
local clinical practice for sarilumab that would preclude the participant from 
participating in this protocol.
14. History of other inflammatory rheumatologic or systemic autoimmune disorder, other 
than Sjögren’s syndrome secondary to RA, that may confound the evaluation of the 
effect of the investigational product such as mixed connective tissue disease, psoriatic 
arthritis, juvenile chronic arthritis, spondyloarthritis, Felty’s Syndrome, systemic 
lupus erythematosus, scleroderma, Crohn’s disease, ulcerative colitis, or vasculitis. 
15. Presence of fibromyalgia that, in the investigator’s opinion, would make it difficult to 
appropriately assess RA activity for the purposes of this study.
16. Undergone any major surgery within 8 weeks prior to study entry or will require 
major surgery during the study that, in the opinion of the investigator in consultation 
with the medical monitor, would pose an unacceptable risk to the participant.
17. Current or previous active Mycobacterium tuberculosis (TB) regardless of treatment.
18. Evidence of latent TB (as documented by a positive QuantiFERON-TB Gold plus test 
or T-SPOT.TB test at screening, no findings on medical history or clinical 
examination consistent with active TB, and a normal chest radiograph) except for 
participants that either:

Are willing to complete at least 4 weeks of anti-TB therapy as per WHO or 
national guidelines prior to randomisation and agree to complete the 
remainder of treatment while in the study OR

Are documented as having evidence of satisfactory anti-TB treatment as per 
WHO or national guidelines within the last 5 years following review by a 
physician specialising in TB.
19. Previous close contact with a person with active TB and did not receive satisfactory 
anti-tuberculosis treatment as per WHO or national guidelines.
20. Significant allergies to humanised monoclonal antibodies or known hypersensitivity 
to sarilumab or any of its inactive ingredients.
21. Clinically significant multiple or severe drug allergies or severe post-treatment 
hypersensitivity reactions (including, but not limited to, erythema multiforme major, 
linear immunoglobulin A [IgA] dermatosis, toxic epidermal necrolysis, and 
exfoliative dermatitis).
PRIOR/CONCOMITANT THERAPY 
22. Any prior treatment antagonising GM-CSF or its receptor.
23. Any prior treatment with Anti-interleukin 6 (IL-6) or IL-6 receptor (IL-6R) 
antagonists (including but not limited to sarilumab and tocilizumab).
24. Participants who are expected to be non-compliant with restrictions on medications 
and vaccinations prior to the study, during the study or during the 12-week safety 
follow-up of the study.  See Table 3 in Section 6.5.2 for details of prohibited 
medications/treatments and Table 2 in Section 6.5.1 for details of permitted 
medications/treatments.

2018N385816_02
CONFIDENTIAL
202018
41
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
25. Current enrolment or past participation within the last 42 days before randomisation 
in any other clinical study involving an investigational study treatment or any other 
type of medical research.
DIAGNOSTIC ASSESSMENTS
26. Alanine transferase (ALT) or aspartate aminotransferase (AST) >1.5 x upper limit of 
normal (ULN).
27. Bilirubin >1.5 x ULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
28. Has a positive test for hepatitis B virus (HBV) defined as either:

positive for hepatitis B surface antigen (HBsAg) or

positive for hepatitis B core antibody (HBcAb) and positive for HBV 
deoxyribonucleic acid (DNA).
29. Positive test for hepatitis C antibody at screening. Participants with positive Hepatitis 
C antibody due to prior resolved disease can be enrolled, only if a confirmatory 
negative hepatitis C RNA test is obtained.
30. Haemoglobin ≤9 g/dL; white blood cell (WBC) count ≤3.0 x 109/L; platelet count 
<150 x 109/L; absolute neutrophil count (ANC) <2 x 109/L; lymphocyte count ≤0.75 x 
109/L at screening.
31. Abnormal chest radiograph within 12 weeks of screening judged by the investigator 
as clinically-significant.
OTHER EXCLUSIONS
32. Pregnant or lactating, or women planning to become pregnant or initiating 
breastfeeding.
33. Current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or 
dependence within a year prior to Day 1.
34. History of sensitivity to any of the study treatments, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation.
5.3.
Lifestyle Considerations
There are no lifestyle restrictions in this study.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomised. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 

2018N385816_02
CONFIDENTIAL
202018
42
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened once with the agreement of the Medical Monitor.  The entire 
screening process must be repeated (except for chest X-ray if performed within 12 weeks 
of the re-screening period).
A QuantiFERON-TB Gold plus test may be repeated once during screening if the initial 
result is indeterminate, alternatively a T-SPOT.TB test may be used following an 
indeterminate result.  This is not considered a rescreening.  If the repeat test is positive or 
indeterminate, then the participant will be considered to have active or latent TB.
For those participants requiring Isoniazid (INH) therapy for latent TB, LFTs must be 
assessed following 3 weeks of INH treatment in screening. Participants will fail screening 
if ALT >1.5 x ULN is identified; these participants may be re-screened if ALT elevation 
resolves to ALT <x 1.5 ULN during ongoing INH therapy following discussion with the 
medical monitor.
If a participant fails any of the laboratory exclusion criteria, the test may be repeated once 
within the screening period.  If the participant fails the laboratory criteria for a second 
time, they will be considered a screen failure.
Retesting within screening window of any blood sample withdrawn due to sample 
handling problems, breakage or sample integrity is not considered a rescreening.
Further details regarding the procedure for re-screening can be found in the SRM.
6.
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
6.1.
Study Intervention(s) Administered
An overview of the study interventions is provided in Table 1.  Investigators should note 
the following:

GSK3196165 and placebo will be administered by weekly subcutaneous (SC) 
injection; participants randomised to sarilumab will receive SC injections of 
sarilumab every other week, plus a placebo injection in the intervening weeks to 
maintain the blind.

Study SC injection should be administered weekly, on the same day each week.  
The weekly SC injections of study intervention should rotate between the thighs 
and abdomen.

2018N385816_02
CONFIDENTIAL
202018
43

A window of 2 days is acceptable for the SC injection (minimum gap of 5 days 
between each dose, for no more than 2 consecutive doses).  Participants should 
return to their 7 day dosing schedule as soon as possible thereafter.

Participants must receive their SC injection at the site and be monitored for 
general safety for 1 hour after the injection at Weeks 0, 1, 12, and 13; the safety 
monitoring at Weeks 12 and 13 is due to the switch of the placebo participants to 
active intervention at the Week 12 visit.  Safety monitoring will include 
monitoring for systemic hypersensitivity and local injection site reactions.

Until such time as GSK3196165 becomes available in a pre-filled syringe, every 
SC injection must be delivered by an unblinded administrator and the syringe 
must be shielded from the participant at all times, to avoid unblinding.

If/when GSK3196165 becomes available in a pre-filled syringe, the SC injection 
must still be delivered by an unblinded administrator at weeks corresponding to 
sarilumab dosing (i.e. Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22), to avoid 
unblinding.  Self-administration of pre-filled syringe may be permitted on 
intervening weeks (i.e. Weeks 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23).  Prior to 
permitting home dosing, the investigator must first ensure the participant (or 
caregiver) is able to correctly administer the injection from PFS.  Any participant 
who doses at home must be instructed to contact the site immediately if they 
experience any symptoms following dosing.

Where possible, assessment visits should be scheduled to coincide with the 
weekly administration of study SC injection, the injection will then be 
performed at the site, after completion of PK sampling (see Section 1.3).

Participants who are initially dosed with SC injections of study intervention 
supplied from vials, should continue to be dosed from the vials until at least Week 
12 to coincide with the timing of the primary endpoint unless this is impractical 
due to supply issues; these participants may be switched to SC injections from the 
pre-filled syringes after Week 12, if sufficient supply is available.

Participants who are initially dosed with SC injections of study intervention from 
the pre-filled syringes should continue to be dosed in this manner for the duration 
of the study providing sufficient supplies are available.
In parallel to receiving study intervention, all participants will receive a stable dose of 
background csDMARD(s) (refer to Section 6.5).  Any participant whose background 
DMARD is MTX must also receive ≥5 mg/week folic (or folinic) acid orally (dosing 
regimen at the discretion of the investigator). Dose modifications to background
DMARDs are discussed in Section 6.6.2.
All local standard-of-care practices for the administration of csDMARD(s), including 
laboratory testing, follow-up care, contraindications, and (for MTX) folic acid 
administration, should be performed throughout the study.

2018N385816_02
CONFIDENTIAL
202018
44
Table 1
Overview of Study Intervention
ARM Name
GSK3196165
90 mg
GSK3196165
150 mg
Placebo*
Sarilumab
Intervention 
Name
GSK3196165 
(Approved Name 
not yet assigned)
GSK3196165 
(Approved Name 
not yet assigned)
Placebo to 
GSK3196165 and 
Sarilumab
Kevzara
Type 
Biologic
Biologic
Placebo to 
Biologic
Biologic
Dose 
Formulation
Solution in vial 
(1.2 mL) or PFS 
(1.0 mL)
Solution in vial 
(1.2 mL) or PFS 
(1.0 mL)
Sterile 0.9% (w/v) 
sodium chloride 
solution or PFS 
(1.0 mL)
Solution in PFS 
(1.14 mL)
Unit Dose 
Strength(s)
180 mg/vial
(180 mg/1.2 mL)
PFS 90 mg/mL
180 mg/vial
(180 mg/1.2 mL)
PFS 150 mg/mL
Not applicable
200 mg/1.14 mL 
solution in a 
single-dose PFS
Dosage 
Level(s)
90 mg once-
weekly
150 mg once 
weekly
Weekly
(every other week 
on Sarilumab 
arm)
200 mg every 
other week
Route of 
Administration
SC injection
SC injection
SC injection
SC injection
IMP and NIMP
IMP
IMP
IMP
IMP
Sourcing
Provided centrally 
by the Sponsor
Provided centrally 
by the Sponsor
Locally approved 
sodium chloride 
solution may be 
sourced at site or 
provided centrally. 
PFS provided 
centrally by the 
Sponsor
Provided 
centrally by the 
Sponsor
Dosing 
instructions
Vials: withdraw 
0.6 mL into a 
small syringe and 
dose immediately; 
discard remaining 
material.
Vials: withdraw 
1.0 mL into a 
small syringe and 
dose immediately; 
discard remaining 
material.
Withdraw 1.0 mL 
into a small 
syringe and dose 
immediately; 
discard remaining 
material.
PFS - inject all

2018N385816_02
CONFIDENTIAL
202018
45
ARM Name
GSK3196165
90 mg
GSK3196165
150 mg
Placebo*
Sarilumab
PFS: Inject all
PFS: Inject all
PFS: Inject all
Special 
instructions
Avoid excessive 
shaking of 
GSK3196165 
vials as this could 
lead to product 
precipitation. Do 
not administer 
with other drugs 
concomitantly in 
the same syringe
Avoid excessive 
shaking of 
GSK3196165 
vials as this could 
lead to product 
precipitation. Do 
not administer 
with other drugs 
concomitantly in 
the same syringe
None
None
Packaging and 
Labelling
Study Intervention 
will be provided in 
a single use vial 
or PFS in an 
individual carton 
and labelled as 
required per 
country 
requirement
Study Intervention 
will be provided in 
a single use vial 
or PFS in an 
individual carton 
and labelled as 
required per 
country 
requirement
Commercial 
saline may be 
sourced at site or 
provided centrally 
/ PFS will be 
provided for 
single-use in an 
individual carton 
and labelled as 
required per 
country 
requirement
Study 
Intervention will 
be provided in a 
single use PFS 
in an individual 
carton and 
labelled as 
required per 
country 
requirement
Current/Former 
Name(s) or 
Alias(es)
GSK3196165, 
otilimab, anti-
human GM-CSF 
monoclonal Ab, 
MOR103, 
MOR04357
GSK3196165, 
otilimab, anti-
human GM-CSF 
monoclonal Ab, 
MOR103, 
MOR04357
Not applicable
Kevzara, 
sarilumab, 
SAR153191 and 
REGN88
* Placebo consists of 3 arms to Week 12, after which participants will be switched to 1 of the 3 active intervention arms.
PFS = prefilled syringe; GM-CSF = granulocyte macrophage colony stimulating factor; Ab = antibody.
GSK3196165 in vials and placebo will be administered SC, using syringes and needles commonly used for SC 
administration (e.g. 1 mL syringe, with 25 or 27 gauge needle); compatibility with commonly used syringes and needles 
has been demonstrated.

2018N385816_02
CONFIDENTIAL
202018
46
6.1.1.
Medical Devices

The medical devices provided for use in this study are injection devices: 
o
a prefilled syringe (PFS) containing 150 mg or 90 mg otilimab solution, or 
placebo, assembled into a safety syringe device (SSD)
o
a prefilled syringe containing 200 mg sarilumab solution.  
The otilimab PFS/SSD devices used in the study are representative of the 
devices and regionally appropriate device instructions planned to be marketed 
for the product.

The components that comprise the otilimab and placebo PFS/SSD, including glass 
barrel with prestaked needle, flange, plunger and needle guard are sourced for GSK 
by a third-party provider.  The otilimab and placebo PFS is filled and assembled 
with the safety syringe components by GSK (or its affiliates). 

The sarilumab PFS is marketed, manufactured and assembled by Sanofi and 
Regeneron Pharmaceuticals, Inc. (or its affiliates).

The instructions for use (IFU) for these injection devices are provided in the study 
reference manual (SRM).  

The otilimab and placebo PFS instructions were developed and optimised as a result 
of formative human factors (HF) studies and are representative of those that are 
planned for the product.  The summary HF information will be provided in the 
regulatory submission.
All device deficiencies (including malfunction, use error and inadequate labelling) shall 
be documented and reported by the investigator throughout the clinical investigation (see 
Section 8.3.8) and appropriately managed by the sponsor.
6.2.
Preparation/Handling/Storage/Accountability

The site pharmacist or unblind administrator must confirm appropriate 
temperature conditions have been maintained during transit for all study 
intervention received and any discrepancies are reported and resolved before use 
of the study intervention.

Only participants enrolled in the study may receive study intervention and only 
authorised site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorised site staff.

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study intervention accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study 
intervention are provided in the SRM.

2018N385816_02
CONFIDENTIAL
202018
47

Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.  Take adequate precautions 
to avoid direct eye or skin contact and the generation of aerosols or mists. In the 
case of unintentional occupational exposure notify the monitor, Medical Monitor 
and/or GSK study contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.
6.3.
Measures to Minimise Bias: Randomisation and Blinding
All participants will be centrally randomised using Interactive Response Technology 
(IRT). Before the study is initiated, the log in information and directions for the IRT will 
be provided to each site.  Study intervention will be dispensed at the study visits 
summarised in the SoA for the treatment period (Section 1.3). Returned study 
intervention should not be re-dispensed to the participants.
The IRT will be programmed with blind-breaking instructions. In case of an emergency, 
the investigator has the sole responsibility for determining if unblinding of a participant’s 
intervention assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding 
is warranted, the investigator should make every effort to contact GSK or designee prior 
to unblinding a participant’s intervention assignment unless this could delay emergency 
intervention of the participant. If a participant’s intervention assignment is unblinded 
GSK must be notified within 24 hours after breaking the blind. The date and reason that 
the blind was broken must be recorded in the source documentation and case report form, 
as applicable.
Participants will be randomised in a ratio of 6:6:6:1:1:1 to receive study intervention 
(Section 1.2 and Section 6.1).  Investigators will remain blinded to each participant’s 
assigned study intervention throughout the course of the study.  To maintain this blind, all 
participants will receive once-weekly SC injections for the duration of the treatment 
period. Until such time as a matched placebo becomes available for GSK3196165, every 
SC injection must be delivered by an unblinded administrator and the syringe must be 
shielded from the participant to avoid unblinding.
The sarilumab dosing regimen is every other week, therefore participants randomised to 
sarilumab will receive SC injections of sarilumab every other week, plus a placebo 
injection in the intervening weeks to maintain the blind.  This will be managed by the 
IRT.  In addition, regardless of whether PFS are available, on weeks corresponding to 
sarilumab dosing (weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22), all participants must 
receive their study SC injection from an unblinded administrator, with the injection 
syringe shielded from the participant, to avoid unblinding.
An unblinded pharmacist (or unblinded designee) will be responsible for the dispensation 
of the study intervention and will endeavour to ensure that there are no differences in 
time taken to dispense between the different intervention arms.  While the study drug is 

2018N385816_02
CONFIDENTIAL
202018
48
supplied in vials, care will be taken to ensure that participants are not able to see the 
injection volume, syringe size or colour of liquid. The syringe should be prepared away 
from view of the participant, and appropriate shielding or masking of the syringe applied 
prior to administration.
In addition, in order to maintain the integrity of the blind, investigators and site staff will 
not have access to ongoing post-randomisation hsCRP/ESR analyses and should refrain 
from performing either routine ESR or CRP assessments unless clinically indicated for 
AE assessment.  Furthermore, the results of the PK analyses of GSK3196165 will not be 
provided to the sites.
In order to reduce bias, an independent joint assessor will perform all joint assessments 
(Section 8.1.1).
Unblinded monitors and in the event of a Quality Assurance audit, the auditor(s) will be 
allowed access to unblinded study intervention records at the site(s) to verify that 
randomisation/dispensing has been done accurately.
A participant may continue in the study if that participant’s intervention assignment is 
unblinded.
GSK’s Pharma Safety staff may unblind the intervention assignment for any participant 
with an SAE. If the SAE requires that an expedited regulatory report be sent to one or 
more regulatory agencies, a copy of the report, identifying the participant’s intervention 
assignment, may be sent to investigators in accordance with local regulations and/or GSK 
policy.
6.4.
Study Intervention Compliance
GSK3196165 or matching placebo will be administered by SC injection at the times 
indicated in the SoA (Section 1.3).  Participants should receive all doses per schedule, 
however exceptional circumstances may lead to a dose being missed.  If a dose is missed, 
the dose may be rescheduled to a new date/time providing the new date is within the SoA 
window for the missed dose.  If the dose cannot be rescheduled within the visit window, 
the dose must not be given outside the window and must be marked as missed in the IRT.  
After a missed dosed, further dosing may continue per SoA with the following 
requirements:

Except for doses temporarily interrupted for safety reasons, the investigator must 
meet to discuss compliance with the study intervention with any participant who 
appears to be non-compliant.

If the participant continues to be non-compliant and missed further doses, the 
investigator may decide to permanently discontinue the participant from study 
intervention and initiate standard of care.  The participant will be encouraged to 
continue to attend study visits until week 24.
A record of the number of study intervention injections dispensed to and taken by each 
participant must be maintained by the site staff and reconciled with study intervention 

2018N385816_02
CONFIDENTIAL
202018
49
and compliance records.  Intervention start and stop dates, including dates for 
intervention delays will also be recorded in the CRF. 
6.5.
Prior and Concomitant Therapies
Due to effect of cytokines on the CYP450 enzymes (Section 2.3.1) initiation or 
discontinuation of study intervention may have clinically relevant effect for CYP
substrates with a narrow therapeutic index e.g. warfarin and theophylline.  Where a 
CYP3A4 substrate drug is co-administered during the study, in addition to recording the 
initial dose and any dosage changes over time in the CRF, the results of any therapeutic 
monitoring (e.g. INR results), if available, should also be recorded.
Investigators should exercise caution when study intervention is co-administered with 
CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral 
contraceptives, lovastatin, atorvastatin, etc.
6.5.1.
Permitted Therapies
Medications or treatments deemed necessary by the investigator to provide supportive 
care will be permitted during the study except when administration would occur during a 
time of restricted use, as in Table 2, or if the medication is specifically excluded, as in 
Section 6.5.2.  The permitted dose is the usual marketed dose approved in the country in 
which the study is being conducted. Any use of these medications must be recorded in 
the eCRF, along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. The requirements for use of specific permitted 
medications/treatments are listed in Table 2.

2018N385816_02
CONFIDENTIAL
202018
50
Table 2
Requirements for Use of Specific Permitted Medications/Treatments
Medications/Treatments
Restriction
Prior to study treatment 
period
During study treatment 
period
Day 1 to Week 24
During 12-
week follow-
up
Conventional synthetic DMARDs
Participants must currently be taking at least one and at most two of the following concomitant csDMARDs
Methotrexate 15-25mg/week oral or 
injected. 
A lower dose of ≥7.5 mg/week is 
acceptable if reduced for reasons of 
intolerance to MTX. e.g. hepatic or 
hematologic toxicity, or per local 
requirement (this must be clearly 
documented in medical records). 
Exception: A lower dose of 6 mg/week 
is only allowed if the minimum locally 
approved or recommended dose is 
lower than 7.5 mg/week.
At least one and at most two 
required
(must have received at least 
12 weeks treatment prior to 
Day 1, with stable and 
tolerated dose for at least 8 
weeks prior to Day 1)
At least one and at most two 
required
(dose must remain stable 
except adjustment for safety 
reasons)
Permitted
Hydroxychloroquine up to 400 mg/day
Chloroquine up to 250 mg/day
Sulfasalazine up to 3000 mg/day
Leflunomide up to 20 mg/day
Tacrolimus up to 3 mg/day
Bucillamine up to 100 mg/day (or up to 
300 mg/day if permitted per local 
requirements)
Iguratimod up to 50 mg/day
Corticosteroids
Stable dosing regimen of oral 
corticosteroids ≤10 mg/day 
prednisolone or equivalent.
Permitted
(dose must be stable 4 
weeks prior to Day 1 and 
during screening if longer, 
with no changes except for 
safety reasons)
Permitted
(dose must remain stable 
except for safety reasons)
Permitted
Intra-articular corticosteroids
Prohibited within 4 weeks 
prior to Day 1 and during 
screening, if longer.
A single IA injection will be 
permitted between Week 12 
and Week 20 only. The site 
of injection must be 
recorded.
Permitted
Inhaled steroids, topical steroids or 
topical immunosuppressive agents 
(e.g., eye drops, creams)
Permitted
Permitted
Permitted
Analgesics
Acetaminophen (paracetamol) taken as 
rescue for RA pain: up to a maximum 
of 4g/day or locally approved maximum 
(if lower).
Permitted as needed
(but not within 24 hours of 
Day 1 baseline visit)
Permitted as needed
(but not within 24 hours of 
assessment visits)
Permitted

2018N385816_02
CONFIDENTIAL
202018
51
Medications/Treatments
Restriction
Prior to study treatment 
period
During study treatment 
period
Day 1 to Week 24
During 12-
week follow-
up
NSAIDs including aspirin and selective 
cyclooxygenase inhibitors.

In this study, aspirin is considered 
a NSAID, except for low-doses 
(e.g. 75-150 mg/day) prescribed 
for cardiovascular or 
cerebrovascular disease.
Permitted
Participants on regular 
doses: Dosing regimen 
must be stable 7 days prior 
to Day 1, no changes 
except for safety reasons. 
Do not discontinue in 
advance of visits.
Participants on PRN 
prescription: Record each 
dose during screening, or 
frequency with start/end 
dates, in CRF. Should not 
be taken within 24h of Day 1 
baseline visit.
Permitted
Participants on stable, 
regular doses: From Day 1 
to Week 12, dose regimen 
must not change except for 
safety reasons. Do not 
discontinue in advance of 
visits.
After Week 12, any new 
analgesic or change in 
regimen should not occur 
within 24h of assessment 
visits.
Participants on PRN 
prescription: Record each 
dose, or frequency with 
start/end dates, in CRF.
Should not be taken within 
24h of assessment visits.
Permitted
Weak opioid analgesics (e.g. tramadol 
up to 400 mg/day, codeine)
Strong opioid analgesics (e.g. 
morphine, hydromorphone, oxycodone, 
hydrocodone, fentanyl, meperidine, 
methadone)
Prohibited within 4 weeks 
prior to Day 1 and during 
screening, if longer.
Permitted after Week 12
After week 12, PRN or 
regular doses may be 
considered, but any new 
analgesic or change in 
regimen should not occur 
within 24h of assessment 
visits. 
Participants on PRN 
prescription: Record each 
dose, or frequency with 
start/end dates, in CRF.
Should not be taken within 
24h of assessment visits.
Permitted
Other Medications
Intra-articular Hyaluronic acid and any 
other intra-articular compounds used as 
lubricant in the joints.
Prohibited within 2 weeks 
prior to Day 1 and during 
screening, if longer.
Prohibited within 2 weeks 
prior to Week 12 and Week 
24 assessments.
Permitted
Prior to any dose changes in csDMARD(s) or oral corticosteroids, it is recommended that 
the Investigator contacts the medical monitor to discuss and agree with the dose change. 
Use of analgesics is restricted during the first 12 weeks of study intervention and 
thereafter, investigators should follow routine clinical practice to manage RA pain (see 
Table 2).  Any new analgesic or change in analgesic use must be recorded in the 
concomitant medication eCRF.

2018N385816_02
CONFIDENTIAL
202018
52
Other medications (including vitamins, herbal and dietary supplements) will be 
considered on a case-by-case basis and will be permitted if in the opinion of the 
Investigator, after consultation with the medical monitor as necessary, the medication 
will not interfere with the study procedures or compromise participant safety.
6.5.2.
Prohibited Therapies
Medications prohibited or restricted prior to the study, during the study and/or during the 
safety follow-up of the study are listed in Table 3, along with any period of exclusion 
which must be applied.
Table 3
Prohibited medications/treatments
Medications/Treatments
Restriction
Prior to study treatment 
period
During study treatment 
period
Day 1 to Week 24
During 12-week 
follow-up
Treatments affecting GM-CSF pathway
Any treatment antagonising GM-CSF or 
its receptor
Prohibited
(Exclusion)
Prohibited
(except study intervention)
Prohibited
Conventional synthetic DMARDs
Combination treatment with MTX and 
Leflunomide
Discontinue at least 12 
weeks prior to Day 1
Prohibited
No restriction
Combination treatment of 3 or more 
csDMARDs
Discontinue at least 4 
weeks prior to Day 1
Prohibited
No restriction
Combination treatment with Azathioprine 
and Methotrexate
Discontinue at least 4 
weeks prior to Day 1
Prohibited
No restriction
Hydroxychloroquine, chloroquine, 
sulfasalazine, minocycline, tacrolimus, 
cyclosporin, bucillamine, iguratimod.
If not being continued as background 
medication during the study.
Discontinue at least 4 
weeks prior to Day 1
Prohibited
No restriction
Leflunomide If 
not being 
continued as 
background 
medication 
during the 
study.
Without washout 
treatment
Discontinue at least 12 
weeks prior to Day 1
Prohibited
No restriction
With washout treatment 
for 11 days with oral 
cholestyramine (8 g 
three times daily) or 
charcoal (50 g four 
times daily)
Washout treatment must 
complete at least 2 weeks 
prior to Day 1
Prohibited
No restriction
Other csDMARDs
If not being continued as background 
medication during the study.
Discontinue at least 4 
weeks prior to Day 1
Prohibited
No restriction
Biologic DMARDs
Anti-interleukin 6 (IL-6), IL-6 receptor (IL-
6R) antagonist (including but not limited 
to sarilumab and tocilizumab)
Prohibited
(Exclusion)
Prohibited
(except study intervention)
Prohibited
Etanercept (including its biosimilars).
Discontinue at least 4 
weeks prior to Day 1
Prohibited
Prohibited

2018N385816_02
CONFIDENTIAL
202018
53
Medications/Treatments
Restriction
Prior to study treatment 
period
During study treatment 
period
Day 1 to Week 24
During 12-week 
follow-up
Any cell-depleting therapies, e.g., anti-
CD20.
Discontinue at least 52 
weeks prior to Day 1.
Prohibited
Prohibited
Any other biologic DMARDs 
(experimental or approved)
Discontinue at least 8 
weeks prior to Day 1.
Prohibited
Prohibited
Targeted synthetic DMARDs
Janus kinase (JAK) inhibitors (e.g. 
tofacitinib, baricitinib, upadacitinib, 
filgotinib and peficitinib).
Discontinue at least 4 
weeks or 5 half-lives, 
(whichever is longer) prior 
to Day 1.
Prohibited
Prohibited
Any other Targeted Synthetic DMARDs 
(either experimental or approved)
Other RA therapies
Plasmapheresis or intravenous 
immunoglobulin (IVIG) or use of plasma 
filtering devices (eg. Staph protein A 
column (Prosorba))
Discontinue at least 26 
weeks prior to Day 1.
Prohibited
Prohibited
Corticosteroids
Irregular (not stable) doses of oral 
corticosteroids ≤10 mg/day prednisolone 
or equivalent
Prohibited (except for 
safety reasons)
Prohibited (except for 
safety reasons)
No restriction
Oral corticosteroids >10 mg/day 
prednisolone or equivalent
Discontinue or reduce to 
≤10 mg/day, at least 4 
weeks prior to Day 1.
Prohibited (except for 
safety reasons)
No restriction
Intra-muscular or intravenous 
corticosteroids
Discontinue at least 4 
weeks prior to Day 1.
Prohibited (except for 
safety reasons)
No restriction
Vaccine immunisations
Note: Investigators should review and update the vaccination status of potential participants as per local guidelines for 
adult vaccination prior to entering them into the study (refer to EULAR recommendations where no local guidelines are 
available [Furer, 2019]). All participants who have not received the herpes zoster vaccine at study entry will be 
recommended to complete vaccination >30 days prior to randomisation. All participants may receive inactivated flu 
vaccines during the study at the discretion of the investigator.
Live-attenuated vaccinations
Discontinue at least 30 
days prior to Day 1
Prohibited
Prohibited
BCG vaccination
Discontinue at least 365 
days prior to Day 1.
Prohibited
Prohibited
6.5.3.
Rescue Medicine
Acetaminophen (paracetamol) is permitted as needed, both prior to and during the study 
as rescue medicine for RA pain management, up to 4g/day or to the maximum permitted 
under local label (if lower than 4g/day).  However, acetaminophen (paracetamol) must 
not be taken within 24 hours prior to the baseline (Day 1) or any assessment visit.
Any use of rescue medication must be recorded in the appropriate concomitant 
medication form, in the CRF.

2018N385816_02
CONFIDENTIAL
202018
54
6.6.
Dose Modification
6.6.1.
Dose Modification of Study Intervention
Dose adjustment of the study SC injection is not permitted in this study.
The dose adjustment criteria described in the Sarilumab prescribing information has been 
incorporated in the study stopping criteria (refer to the temporary discontinuation and 
stopping criteria guidance in Section 7).
6.6.2.
Dose Modification of Background Therapy
Dose reduction or temporary interruption of the background csDMARD medication(s) 
may be performed at any time for safety reasons (e.g. intolerance or toxicity) but must be 
clearly documented.  If clinically indicated, csDMARD may be re-started following an
interruption and increased back to the dose taken prior to the change.
Dose modifications for reasons other than safety are not permitted during the study 
treatment period.
6.7.
Intervention after the End of the Study
Participants who complete the 24-week treatment period may have the option to 
transition into long term extension study 209564.  Exceptionally, participants who missed 
their final dose at Week 23 in this study may still be eligible, after consultation with the 
medical monitor.  Participants receiving GSK3196165 in this study will continue to
receive the same dose in the extension study.  Participants receiving sarilumab in this 
study will be re-randomised in a 1:1 ratio to either GSK3196165 90 mg or GSK3196165 
150 mg once-weekly in the extension study, following a blinded washout period (three 
weeks of placebo SC injection).
Participants who do not transition into long term extension study 209564, will not receive 
any further treatment with GSK3196165 but will be treated according to local standard of 
care for RA disease.
7.
DISCONTINUATION OF STUDY INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. A participant will permanently discontinue study intervention if there is no 
longer a positive risk:benefit ratio at any time point in the study as determined by the 
investigator. If study intervention is permanently discontinued, the participant will, where 
possible, remain in the study and continue with study visits in order to be evaluated for 
efficacy and safety.  These participants will not be eligible for the long term extension 
study 209564.

2018N385816_02
CONFIDENTIAL
202018
55
7.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Discontinuation of study intervention for abnormal liver tests is required when a 
participant meets one of the conditions outlined in the algorithm below.  Additionally, 
study intervention must be discontinued if there are any clinical signs/symptoms 
suggestive of hepatic decompensation such as ascites and hepatic encephalopathy.
Liver Chemistry Stopping and Increased Monitoring Algorithm for Study 202018
Temporarily Discontinue Intervention and Monitor Weekly
Study intervention may be restarted if ALT < 1.5 x ULN.  Monitor ALT as directed in the Appendix.
OR
If ALT does not resolve to ≤ 1.5 x ULN within 4 weeks or other stopping criteria met, 
permanently discontinue study intervention
*INR value not applicable to participants on anticoagulants
If participant to be monitored weekly, must refer to Liver Safety Required Actions and Follow up 
Assessments section in the Appendix
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT ≥ 3 x ULN and Bilirubin ≥ 2 x ULN (>35% direct) or 
INR > 1.5*
Permanently Discontinue Study Intervention 
Yes
Yes
Yes
No
Plus
Bilirubin ≥ 2 x 
ULN (>35% 
direct) or plus
INR > 1.5*
Possible
Hy’s Law
ALT ≥ 5 x 
ULN
ALT ≥ 3 x ULN
Plus
Symptoms of liver 
injury
or hypersensitivity
ALT ≥ 3 x ULN
but able to 
monitor weekly 
for 
4 weeks
ALT ≥ 3 x ULN
Yes
No
No
No
Yes
No
Continue 
Study 
Intervention 
Abbreviations: ALT = alanine transaminase; bili = bilirubin; INR = international normalised ratio; SAE = 
serious adverse event; ULN = upper limit of normal.
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.
7.1.1.1.
Study Intervention Restart or Rechallenge after liver stopping criteria 
met
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.

2018N385816_02
CONFIDENTIAL
202018
56
7.1.2.
Other Stopping Criteria
A participant will be permanently discontinued from study intervention (but may 
continue to be followed in the study) if any of the following criteria are met:

Pregnancy (see Section 8.3.5 and Appendix 4).

Confirmed pulmonary alveolar proteinosis (see Section 8.2.6).

Serious hypersensitivity reactions (see Section 8.3.7).

Other serious or severe adverse events or other significant medical event, at the 
discretion of the investigator, after consultation with the Medical Monitor.

HBV DNA level ≥200 IU/mL or HBV DNA detected at any level with recent 
increase in hepatic transaminases (see Figure 2 in Section 8.2.8).

HBV DNA positive (any level ≤200 IU/mL) and on repeat testing within 1 week 
(see Figure 2 in Section 8.2.8) either:
o
HBV DNA positive (any level) OR
o
HBV surface antigen positive OR
o
increase in hepatic transaminases.

New latent or active TB infection (see Section 8.2.7.4).

Gastrointestinal perforation.

Platelet count <50 x 109/L.

Absolute neutrophil count (ANC) <0.5 x 109/L.

Introduction of prohibited therapies or dosages where continuation of the study 
intervention would place the participant at risk in the opinion of the investigator 
and medical monitor.
7.1.3.
Temporary Discontinuation
7.1.3.1.
Respiratory Symptoms
Study intervention will be temporarily discontinued if a participant develops a persistent 
cough (CTCAE Grade ≥2) [NCI, 2017] or persistent dyspnoea (dyspnoea scale Grade 
2) for 3 consecutive weeks (21 days).  The participant should be referred to a 
pulmonologist for further assessment.  Study intervention should remain suspended until 
the symptoms or signs that caused referral have resolved and/or the diagnosis has been 
determined and clinically significant events have been excluded by the pulmonologist. 
Participants with a confirmed diagnosis of pulmonary alveolar proteinosis must 
permanently discontinue study intervention (Section 7.1). Suggested pulmonary 
assessment and management algorithms are provided in a separate Pulmonary Safety 
Guidance Document in the SRM.

2018N385816_02
CONFIDENTIAL
202018
57
7.1.3.2.
Serious and Opportunistic Infections
If a serious or opportunistic infection or sepsis develops, temporarily discontinue study 
intervention until the infection is controlled and discuss further management with the 
medical monitor.
7.1.3.3.
Hematologic Abnormalities
Study intervention will be temporarily discontinued upon confirmatory (local) repeat test, 
for the following haematological abnormalities:

Platelet count ≤100 x 109/L. (Dosing should be interrupted until Platelets ≥150 x 
109/L.)

Absolute neutrophil count (ANC) ≤1 x 109/L. (Dosing should be interrupted until 
ANC >2 x 109/L.)

White blood cell (WBC) count <2.0 x 109/L

Lymphocyte count <0.5 x 109/L
The local repeat test must be performed and assessed within 7 days (ideally 3-5 days), 
with additional sample(s) sent for central testing.
If study intervention is temporarily discontinued, the abnormality must be reported as an 
AE and a further repeat test should be performed within 7 days of discontinuation.  The 
medical monitor should be consulted if the repeat test is still abnormal.  Study 
intervention can be restarted if the haematological parameters rise above these values.
7.1.3.4.
TB Reactivation
Study intervention may be temporarily discontinued for the following after consultation 
with the medical monitor:

Suspected TB reactivation (see Section 8.2.7.4).
7.2.
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons. This is expected to be 
uncommon.

At the time of discontinuing from the study, if possible, an early withdrawal visit 
should be conducted following the procedures at the Week 24 visit, as shown in 
the SoA (Section 1.3).  A safety follow-up visit should also be scheduled, per the 
SoA, to take place 12 weeks post last dose of study intervention.

The participant will be permanently discontinued both from the study intervention 
and from the study at that time.

2018N385816_02
CONFIDENTIAL
202018
58

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.
7.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1.

2018N385816_02
CONFIDENTIAL
202018
59
8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarised in the SoA (Section 1.3). 

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should be discussed with the medical monitor 
immediately upon occurrence or awareness to determine if the participant should 
continue or discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of ICF may be utilised for 
screening or baseline purposes provided the procedure met the protocol-specified 
criteria and was performed within the time frame defined in the SoA (Section 
1.3).

The maximum amount of blood collected from each participant over the duration 
of the study, including any extra assessments that may be required, will not 
exceed 400 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
8.1.
Efficacy Assessments
8.1.1.
Joint Assessments
An evaluation of all 68 joints for tenderness and 66 joints for swelling will be performed 
by an independent joint evaluator. Replaced or fused joints are considered non-evaluable 
and will not be included in joint evaluations.  The reason for absence of the evaluations 
of those joints must be recorded.  If a joint has undergone intra-articular injection of 
corticosteroid during the course of the study, the injected joint must be recorded.
One or more independent assessors, who have documented experience in performing 
joint assessments, will be designated at each trial site to perform joint assessments.  
Preferably the same independent assessor will perform all joint assessment for the same 
participant throughout the trial.  The principal investigator must ensure that the 
independent joint assessor has documented experience and he/she is adhering to locally 
accepted and implemented standards.  This also applies if the independent joint assessor 
is replaced during the trial.
The independent joint assessor should have no other contact with the participant during 
the trial, must not be the treating physician (investigator), should not discuss the clinical 
status of the participant with them during the joint assessment nor with other site 

2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
6 0
pers o n nel, a n d will n ot be per mitte d t o re vie w t he partici pa nt’s me dical rec or ds, t he 
e C R F, n or a n y of t he pre vi o us j oi nt assess me nts.
T he pr oce d ure f or j oi nt assess me nts is pr o vi de d i n t he S R M. 
8. 1. 2.
P h y si ci a n’ s Gl o b al A s s e s s m e nt of A rt hriti s
In vesti gat ors will c o m plete a gl o bal assess me nt of R A disease acti vit y usi n g t he 
p h y sicia n gl o bal assess me nt ite m ( P h G A), a vis ual a nal o g ue scale ( V A S) wit h a nc h ors 
“ 0” ( 
) t o “ 1 0 0” (
), res pecti vel y.
8. 1. 3. 1.
P ati e nt’ s A s s e s s m e nt of A rt hriti s P ai n
Partici pa nts will assess t he se verit y of t heir art hritis pai n o ve r t he past wee k, usi n g a 1 0 0 
u nit V A S, wit h a nc h ors “ 0” ( 
) a n d “ 1 0 0” (
).
T he res ults of t his q uesti o n will be use d f or t he H A Q -DI , w here t he l ocal versi o n of 
H A Q -DI  as ks t he sa me q uesti o n.
8. 1. 3. 2.
P ati e nt’ s Gl o b al A s s e s s m e nt of A rt hriti s
Par tici pa nts will c o m plete a gl o bal assess me nt of disease acti vit y usi n g t he patie nt gl o bal 
assess me nt ( Pt G A) ite m, a V A S wit h a nc h ors “ 0” (
) t o “ 1 0 0” (
).
8. 1. 3. 3.
H e alt h A s s e s s m e nt Q u e sti o n n air e – Di s a bilit y I n d e x ( H A Q- DI)
T he f u ncti o nal stat us of t he partici pa nt will be assesse d b y mea ns of t he Disa bilit y  In de x 
of t he Sta nf or d Healt h Assess me nt Q uesti o n naire ( H A Q- DI ).  T his 2 0-q uesti o n 
i nstr u me nt assesses t he de gree of diffic ulty a pers o n has i n acc o m plis hi n g tas ks i n ei g ht 
f u ncti o nal areas [Fries , 1 9 8 0]: dressi n g a n d gr o o mi n g, arisi n g, eati n g, wal ki n g, h y gie ne, 
reac h, gri p, a n d c o m m o n dail y acti vities.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
6 1
8. 1. 3. 7.
F u n cti o n al A s s e s s m e nt of C hr o ni c Ill n e s s T h er a p y  ( F ACI T) - F ati g u e
T he F u ncti o nal Assess me nt of C hr o nic Ill nes s T hera py ( F A CI T) -fati g ue q uesti o n naire is 
a vali date d patie nt -re p orte d meas ure de vel o pe d ori gi nally t o assess fati g ue i n i n di vi d uals 
wit h ca ncer.  T he F A CI T -fati g ue has s u bse q ue ntl y bee n use d a n d vali date d i n n u mer o us 
c hr o nic c o n diti o ns, i ncl u di n g R A.
8. 1. 3. 8.
S F -3 6 S h ort F or m H e alt h S ur v e y
Healt h -relate d q uality of life ( H R Q L) will be assesse d usi n g t he partici pa nt -c o m plete d 
Me dical O utc o mes St u d y ( M O S) S h ort -F or m 3 6 ( S F -3 6) w hic h is a ge neric healt h s ur ve y  
t hat c o ntai ns 3 6 q uesti o ns c o veri n g ei g ht d o mai ns of healt h.  T he S F-3 6 y iel ds a n ei g ht-
scale pr ofile of f u ncti o nal healt h a n d well-bei n g sc ores as well as p h y sical a n d me ntal 
c o m p o ne nt healt h s u m mar y sc ores.  T he versi o n 2, 1 -wee k recall q uesti o n naire will be 
use d.
C CI
C CI

2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
6 2
8. 2.
S af et y A s s e s s m e nt s
Pla n ne d ti me p oi nts f or all safet y  assess me nts are pr o vi de d i n t he S o A ( Secti o n 1. 3 ).
I n t he e ve nt t hat p ul m o nar y f oll o w-u p criter ia are tri g gere d, all sites m ust ha ve access t o 
a p ul m o n ol o gist (see Secti o n 7. 1. 3. 1 a n d Secti o n 8. 2. 6 ).
8. 2. 1.
D y s p n o e a A s s e s s m e nt s
T he d y s p n oea scale gra des t he effect of breat hless ness o n dail y  acti vities a n d meas ures 
percei ve d res pirat or y  disa bilit y.  T he scale will be c o m plete d b y t he i n vesti gat or i n 
c o ns ultati o n wit h t he partici pa nt.  D ys p n oea will be re p orte d o n a rati n g scale fr o m 0 ( 
 
) t hr o u g h 4 (
).
8. 2. 2.
P h y si c al E x a mi n ati o n s

A c o m plete p h ys ical e xa mi nati o n (e. g. at t he Scree ni n g visit) will i ncl u de, at a 
mi ni m u m, assess me nts of t he S ki n, Car di o vasc ular, Res pirat or y , Gastr oi ntesti nal 
a n d Ne ur ol o gical s yste ms. Hei g ht a n d wei g ht will als o be meas ure d a n d rec or de d.

A brief p h ys ical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he s ki n, 
l u n gs, car di o vasc ular sys te m, a n d a b d o me n (li ver a n d s plee n).

I n vesti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us 
seri o us ill nesses.

All p h y sical e xa mi nati o ns will i ncl u de m o nit ori n g f or si g ns a n d sy m pt o ms of T B 
(see Secti o n 8. 2. 7 ).
8. 2. 3.
El e ctr o c ar di o gr a m s

1 2-lea d E C G meas ure me nts s h o ul d be rec or de d pre- d ose a n d w here p ossi ble 
bef o re vital si g n meas ure me nts a n d bl o o d dra ws.

Partici pa nts s h o ul d be i n a q uiet setti n g wit h o ut distracti o ns a n d rest i n a s u pi ne 
p ositi o n f or at least 5 or 1 0 mi n utes bef ore E C G c ollecti o n.

Tri plicate 1 2 -lea d E C G meas ure me nts will be o btai ne d at scree ni n g wit h si n gle 
E C G meas ure me nts o btai ne d p ost -baseli ne as o utli ne d i n t he S o A (see Secti o n 
1. 3 ) usi n g a n E C G mac hi ne t hat a ut o matically calc ulates t he heart rate a n d 
meas ures P R, Q R S, Q T, a n d Q Tc i nter vals.

At t he s cree ni n g visit w here tri plicate E C G are re q uire d, t hree i n di vi d ual E C G 
traci n gs s h o ul d be o btai ne d as cl osely as p ossi ble i n s uccessi o n, b ut n o m ore t ha n 
2 mi n utes a part. T he f ull set of tri plicates s h o ul d be c o m plete d i n less t ha n 4 
mi n utes.

E C G traces wi ll be rea d l ocall y.
C CI
C CI
C CI

2018N385816_02
CONFIDENTIAL
202018
63
8.2.4.
Vital Signs

Vital signs should be measured pre-dose, and where possible before blood draws.

Temperature, pulse rate, respiratory rate and blood pressure will be assessed.

Blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is 
not available. The participant should use the same position throughout all visits.

All blood pressure readings will be recorded using an appropriate cuff size with 
the same arm being used throughout the study.

Blood pressure and pulse measurements should be preceded by at least 5 minutes 
of rest for the participant in a quiet setting without distractions (e.g., television, 
cell phones).

When the timing of these measurements coincides with blood collection, the 
blood pressure and heart rate should be obtained first.
8.2.5.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to 
the SoA in Section 1.3 for the timing and frequency. 

All study-required laboratory assessments will be performed by a central 
laboratory except erythrocyte sedimentation rate (ESR), dipstick urinalysis, and 
urine pregnancy tests which will be analysed locally.

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant’s condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 15 weeks after the last dose of study 
intervention should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

In this study, the key laboratory parameters are WBCs, lipids, haemoglobin, 
platelets, lymphocytes, neutrophils and liver function tests.

Participants who develop hyperlipidemia should be managed according to clinical 
guidelines [e.g., National Cholesterol Educational Program (NCEP)].

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3).

2018N385816_02
CONFIDENTIAL
202018
64
8.2.6.
Pulmonary Assessments
Pulmonary assessments are a key aspect of the safety monitoring in this study. The 
following pulmonary assessments will be performed as specified in the SoA (Section 
1.3).

Chest X-ray (posteroanterior).

Cough assessment.

Dyspnoea assessment (see Section 8.2.1).

Lung auscultation.

Pulse oximetry.

Pulmonary function tests (PFTs) – spirometry (FEV1 and FVC) at baseline only 
(or prior to Day 1) or as required by the pulmonologist in the event of participant 
referrals for further assessment.
In the event of any new or clinically significant pulmonary abnormalities that may 
develop during the study (e.g., increased shortness of breath/dyspnoea, or unexplained 
and persistent coughing), it is recommended that the participant be referred to a 
pulmonologist for further assessment.  
If, at any time during the study, a participant reports new onset or increase (if present at 
baseline) in cough (CTC Grade ≥2) or dyspnoea (Grade ≥2), they must be asked again 
(either by phone or during the site visit) on a weekly basis for 3 further consecutive 
weeks or until symptoms resolve, if earlier.  Any new onset or worsening cough and/or 
dyspnoea must be reported as an AE.
If a participant experiences persistent cough Grade ≥2 for three consecutive weeks (≥21 
days) or persistent dyspnoea Grade ≥2 for three consecutive weeks (≥21 days), study 
intervention must be temporarily discontinued immediately, and the participant undergo a 
local pulmonologist review within 1-2 days. Chest X-ray and repeat spirometry must be 
performed within 1 week in addition to any other assessments deemed appropriate by the 
consulting pulmonologist. The study intervention must be temporarily discontinued as 
per the pulmonary guidance document until the symptoms or signs that caused referral 
have resolved and/or the underlying diagnosis has been determined and clinically 
significant events have been excluded by the pulmonologist. Pulmonary 
assessment/management algorithms are provided in a separate Pulmonary Safety 
Guidance Document in the SRM.
The participant may undergo additional pulmonary imaging (high-resolution computed 
tomography [HRCT]) or other tests during the study to investigate pulmonary 
abnormalities; the Pulmonary Adjudication Committee (PAC), IDMC or SRT may 
request copies of any reports or images for central review.
Any participant with a diagnosis of pulmonary alveolar proteinosis must permanently 
discontinue study intervention (Section 7.1.2).

2018N385816_02
CONFIDENTIAL
202018
65
8.2.7.
Tuberculosis Monitoring
8.2.7.1.
Tuberculosis Status Definitions
In this study the following definitions for active TB, latent TB and adequate treatment of 
latent TB will be utilised. 
Active TB is defined as:

Microbiological evidence of TB (including, but not limited to, microscopy for 
acid-fast bacilli, mycobacterial culture, GeneXpert, or other validated PCR) in 
any clinical sample (including, but not limited to, sputum, pus, or biopsied tissue),
OR

Findings on medical history or clinical examination and/or chest radiograph 
consistent with active TB as assessed by a physician specialising in TB, sufficient 
to warrant empirical treatment for active TB even in the absence of 
microbiological evidence of TB.
Latent TB is defined as:

A positive QuantiFERON-TB Gold plus test or T-SPOT.TB test, no findings on 
medical history or clinical examination consistent with active TB and a normal 
chest radiograph.
Adequate latent TB treatment status
For participants that have received treatment for latent TB within the previous 5 years, a 
participant is considered to have received adequate treatment if a physician specialising 
in TB agrees that:

sufficient evidence exists demonstrating that completion of treatment has 
occurred AND

the participant has no findings on medical history or clinical examination 
consistent with active TB, and a normal chest radiograph.
Appropriate treatment for latent TB is considered to be:

Completion of at least 6 months of INH or an alternative regimen consistent with 
WHO or national guidelines.

Participants who received treatment more than 5 years ago for latent TB infection 
and who remain QuantiFERON-TB Gold plus or T-SPOT.TB test positive will 
need to complete treatment for latent TB prior to study entry as per Section 
8.2.7.3.

2018N385816_02
CONFIDENTIAL
202018
66
8.2.7.2.
Tuberculosis Testing
In this study the following testing for TB must be followed:

The QuantiFERON-TB Gold plus test will be used in countries where it is 
available.  Where QuantiFERON-TB Gold plus test is not available T-SPOT.TB 
will be used.

A QuantiFERON-TB Gold plus test may be repeated once during screening if the 
initial result is indeterminate, alternatively a T-SPOT.TB test may be used 
following an indeterminate result.  This is not considered a rescreening.

Unscheduled TB testing should be performed if a participant is known or 
suspected to have come in close contact with someone who has untreated active
TB.
8.2.7.3.
Treatment of Latent TB During the Study
Participants diagnosed with latent TB during screening will need to complete a course of 
at least 6 months of INH therapy during the study including at least 4 weeks of therapy 
prior to randomisation.
Following 3 weeks of INH treatment in screening, LFTs must be assessed. Participants 
will fail screening if ALT >1.5 x ULN is identified, these participants may be re-screened 
if ALT elevation resolves to ALT <x 1.5 ULN during ongoing INH therapy following 
discussion with the medical monitor. Participants who are randomised will require LFT 
assessment every 4 weeks during the study.
8.2.7.4.
Monitoring for TB Infection and Re-activation During the Study
Routine monitoring for the signs and symptoms of TB will be performed during this 
study as part of every full or brief physical exam (see SoA in Section 1.3).
If at any point during the study, the investigator suspects that a participant may have TB 
reactivation or new TB infection, an immediate and thorough investigation should be 
undertaken including consultation with a physician specialising in TB.  The investigator 
should discuss with the medical monitor and interruption of study intervention should be 
considered.
A QuantiFERON-TB Gold Plus test or a T.SPOT.TB test must be performed as part of 
the Week 22 assessment (see SoA in Section 1.3).  If a participant has a positive result at 
Week 22 who previously had a negative result at study start, then the participant must be 
referred to a physician specialising in TB to determine if the participant has active or 
latent TB.
If TB infection is diagnosed, study intervention must be discontinued.

2018N385816_02
CONFIDENTIAL
202018
67
8.2.8.
Hepatitis B Monitoring
All participants with positive HBcAb results will have HBV DNA levels monitored 
throughout the study as summarised in Figure 2.
Figure 2
Monitoring of HBV DNA Levels in HBcAb Positive Participants
HBV DNA level ≥ 200 IU/mL
or
HBV DNA detected at any level with 
recent increase in hepatic 
transaminases
HBV DNA level <200 IU/mL 
(with no increase in hepatic 
transaminases)
Discontinue study intervention and 
refer to expert for initiation of 
appropriate antiviral therapy
Repeat HBV DNA with HBV surface 
antigen and hepatic transaminases 
within 1 week
Result:  HBV DNA 
positive (any level) 
or HBV surface 
antigen positive or 
increase in hepatic 
transaminases
Discontinue study 
intervention and refer 
to expert for initiation of
appropriate antiviral 
therapy
Result: HBV DNA 
negative, HBV surface 
antigen negative and no 
increase in hepatic 
transaminases
Repeat HBV DNA at 
4 weeks then return 
to routine 
monitoring
HBV DNA detected
From the start of study intervention, HBV DNA levels will be assessed every 4 weeks to 
Week 24.

2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
6 8
8. 2. 8. 1.
Ri s k of R e a cti v ati o n i n P arti ci p a nt s P o siti v e f or H e p atiti s B C or e 
A n ti b o d y ( H B c Ab)
Partici pa nts w h o are H Bc A b p ositi ve, will be i nf or me d of t he ris k of reacti vati o n a n d t hat 
if t his occ urs treat me nt wit h a nti viral t hera py, s uc h as wit h n ucle o(s)ti de a nal o g ues li ke 
e nteca vir or te n of o vir, will be nee de d.
8. 2. 8. 2.
Tr e at m e nt of P arti ci p a nt s W h o A r e H B c Ab P o siti v e a n d W h o D e v el o p 
D et e ct a bl e H B V D N A  R e q uiri n g I niti ati o n of A nti vir al T h er a p y
H Bc A b p ositi ve partici pa nts w h o bec o me p ositi ve f or H B V D N A a n d re q uire a nti viral 
t hera py m ust ha ve st u d y i nter ve nti o n disc o nti n ue d. T he partici pa nt m ust als o be referre d 
t o a he pat ol o gist or i nfecti o us diseases e x pert s o t hat treat me nt a d vice re gar di n g w het her 
t o c o m me nce a nti-viral t hera p y is recei ve d wit hi n 7 da ys of H B V D N A ele vati o n bei n g 
i de ntifie d. T he partici pa nt s h o ul d t he n be re vie we d b y  t he e x pert wit hi n 1 4 da ys of H B V 
D N A ele vati o n bei n g i de ntifie d a n d ma na ge d as per l ocal g ui deli nes or u n der E A S L or 
A A S L D g ui deli nes if n o ne are a vaila ble.
8. 2. 8. 3.
F oll o w U p of P arti ci p a nt s Tr e at e d Wit h A nti -vir al T h er a p y
All partici pa nts will be f oll o we d u p w it hi n t he st u d y b y t he i n vesti gat or i n a d diti o n t o 
l ocal e x pert f oll o w u p. After c o m pleti o n of t he st u d y, partici pa nts s h o ul d be f oll o we d u p 
as per l ocal e x pert o pi ni o n base d o n g ui deli ne rec o m me n dati o ns.
8. 2. 9.
M ar k er s of dr u g -dr u g i nt er a cti o n s
Plas ma deri ve d fr o m w h ole bl o o d of a p pr o xi matel y  2 m L will be c ollecte d f or 4 β-
h y dr o x yc h olester ol a n d c h olester ol c o nce ntrati o n a nal ys is, at t he visits s pecifie d i n t he 
S o A ( Secti o n 1. 3 ).  T he act ual date a n d ti me ( 2 4-h o ur cl oc k ti me) of eac h s a m ple will be 
rec or de d. 
 
 
.
8. 3.
A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s

T he defi niti o ns of a n A E or S A E ca n be f o u n d i n A p pe n di x 3 .

T he i n vesti gat or a n d a n y q ualifie d desi g nees are res p o nsi ble f or detecti n g, 
d oc u me nti n g, a n d re p orti n g e ve nts t hat meet t he defi niti o n of a n A E or S A E a n d 
re mai n res p o nsi ble f or f oll o wi n g u p A Es t hat are seri o us, c o nsi dere d relate d t o t he 
st u d y i nter ve nti o n or t he st u d y, or t hat ca use d t he partici pa nt t o disc o nti n ue t he 
st u d y i nter ve nti o n (see Secti o n 7 ). 

Partici pa nts will be assesse d f or c o u g h or d ys p n oea at selecte d visits as s pecifie d 
i n t he S o A ( Secti o n 1. 3 .  T he i n vesti gat or will c o m plete t he C T C c o u g h scale if a 
c o u g h is prese nt a n d will rec or d d ys p n oea as per t he d y s p n oea scale.  L u n g 
a usc ultati o n a n d p ulse o xi metr y  will als o be perf or me d at t he visits s pecifie d i n 
t he S o A ( Secti o n 1. 3 ).
C CI

2018N385816_02
CONFIDENTIAL
202018
69

If a participant, at times other than scheduled visits, reports new onset or an 
increase (if present at baseline) in cough (CTCAE Grade ≥2) or dyspnoea 
(dyspnoea scale Grade ≥2), the participant will be questioned (in clinic or by 
phone) on a weekly basis for 3 further consecutive weeks or until symptoms 
resolve, if earlier.  Any new onset or worsening cough and/or dyspnoea must be 
reported as an AE.
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of study intervention until the follow-up 
visit (for participants who do not enter the long-term safety study) or the Week 24 
visit (for participants who enter the long-term safety study) at the time points 
specified in the SoA (Section 1.3). 

In addition, any SAEs assessed as related to study participation (e.g., study 
intervention, protocol-mandated procedures, invasive tests, or change in existing 
therapy) or related to a GSK product will be recorded from the time a participant 
consents to participate in the study. In China (and where this is a local 
requirement) all SAEs will be collected from the time of signing informed 
consent.

All AEs will be collected from the start of study intervention until the follow-up 
visit (for participants who do not enter the long-term safety study) or the Week 24 
visit (for participants who enter the long-term safety study) at the time points 
specified in the SoA (Section 1.3).

Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in Appendix 
3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs after the conclusion 
of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the 
sponsor.
8.3.2.
Method of Detecting AEs and SAEs

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3.

2018N385816_02
CONFIDENTIAL
202018
70

Care will be taken not to introduce bias when detecting AE and/or SAE. Open-
ended and non-leading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence. 
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special 
interest (as defined in Section 8.3.7), will be followed until the event is resolved, 
stabilised, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is given in Appendix 3.
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study intervention under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under 
clinical investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
8.3.5.
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners 
of male participants will be collected after the start of study intervention and until 
the safety follow-up visit at Week 34 (or until 12 weeks after the last dose, for 
participants who withdraw from the study early).

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 
4.

Female participants who become pregnant after the start of study intervention 
must be permanently discontinue study intervention but can continue to be 
followed in the study if they wish (Section 7.1.2).  If the participant does not wish 
to continue in the study, follow guidance in Section 7.2.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.

2018N385816_02
CONFIDENTIAL
202018
71
8.3.6.
Cardiovascular and Death Events
For any cardiovascular (CV) events detailed in Appendix 3 and all deaths, whether or not 
they are considered SAEs, specific CV and Death sections of the CRF will be required to 
be completed. These sections include questions regarding CV (including sudden cardiac 
death) and non-CV death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
(Medical dictionary for regulatory activities) terms. The CV information should be 
recorded in the specific CV section of the CRF within one week of receipt of a CV Event 
data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:

Myocardial infarction/unstable angina.

Congestive heart failure.

Arrhythmias.

Valvulopathy.

Pulmonary hypertension.

Cerebrovascular events/stroke and transient ischemic attack.

Peripheral arterial thromboembolism.

Deep venous thrombosis/pulmonary embolism.

Revascularisation.
This information should be recorded in the specific CV CRF/eCRF within one week of 
when the AE/SAE(s) are first reported.
8.3.7.
AEs of Special Interest
The potential risks with GSK3196165 are discussed in Section 2.3.1. 
Adverse events of special interest (AESIs) for GSK3196165 include:

Serious infections

Opportunistic infections.

TB and TB reactivation.

Neutropenia Grade 3 (<1.0 x 109/L).

Pulmonary alveolar proteinosis

2018N385816_02
CONFIDENTIAL
202018
72

Hypersensitivity reactions.

Injection site reactions.

Persistent cough (CTCAE Grade 2)

Persistent dyspnoea (dyspnoea scale Grade 2).
8.3.8.
Medical Device Deficiencies
Medical devices are being provided for use in this study, in the form of pre-filled 
syringes.  In order to fulfil regulatory reporting obligations worldwide, the investigator is 
responsible for the detection and documentation of events meeting the definitions of 
device deficiency that occur during the study with such devices.
The definition of a Medical Device Deficiency can be found in Appendix 9.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 8.3.3 and Appendix 3 of the protocol.
8.3.8.1
Time Period for Detecting Medical Device Deficiencies

Medical device deficiencies will be detected, documented, and reported during 
all periods of the study in which the medical device is used. 

If the investigator learns of any device deficiency at any time after a participant 
has been discharged from the study, and such device deficiency is considered 
reasonably related to a medical device provided for the study, the investigator 
will promptly notify the sponsor.

The method of documenting Medical Device Incidents is provided in Appendix 
9.
8.3.8.2
Follow-up of Medical Device Deficiencies

Follow-up applies to all participants, including those who discontinue study 
intervention or the study.

The investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality 
of the deficiency.

New or updated information will be recorded on the originally completed form 
with all changes signed and dated by the investigator.
8.3.8.3
Prompt Reporting of Medical Device Deficiencies to Sponsor

Device deficiencies will be reported to the sponsor using the Medical Device 
Deficiency Report Form (provided in the Pharmacy Manual), within 24 hours 
after the investigator determines that the event meets the protocol definition of a 
device deficiency.

2018N385816_02
CONFIDENTIAL
202018
73

The Medical Device Deficiency Report Form will be sent to the sponsor device 
complaints email address, as provided in the Pharmacy Manual.

The sponsor will be the contact for the receipt of device deficiency reports.

Refer to the Pharmacy Manual for further guidance.
8.3.8.4
Regulatory Reporting Requirements for Medical Device Incidents

The investigator will promptly report all deficiencies occurring with any medical 
device provided for use in the study in order for the sponsor to fulfil the legal 
responsibility to notify appropriate regulatory authorities and other entities about 
certain safety information relating to medical devices being used in clinical 
studies.

The investigator, or responsible person according to local requirements (e.g., the 
head of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of device deficiencies to the IRB/IEC.
8.4.
Treatment of Overdose
For this study, any dose of GSK3196165 or sarilumab greater than the dose used in this 
study, or used more frequently than permitted (GSK3196165 once-weekly, sarilumab 
every other week) will be considered an overdose.  It should be noted that the minimum 
time between dosing with GSK3196165 is 5 days but it is strongly recommended that 
dosing should revert back to 7 days as soon as possible.
No specific treatment is recommended for an overdose of GSK3196165, and the 
investigator should treat as clinically indicated. Investigators should refer to the approved 
product label or local prescribing information for treatment of an overdose of sarilumab.
In the event of a potential overdose, the investigator should:

Contact the Medical Monitor immediately.

Closely monitor the participant for AE/SAE and laboratory abnormalities.

Obtain a plasma sample for PK analysis within 3-5 days from the date of the last 
dose of study intervention if requested by the Medical Monitor (determined on a
case-by-case basis).

Contact the unblinded CRA/Monitor with the quantity and duration of the 
overdose to be documented.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
8.5.
Pharmacokinetics

Whole blood samples of approximately 3.5 mL will be collected prior to dosing, 
for measurement of serum concentrations of GSK3196165 at the visits specified 
in the SoA (Section 1.3); SC study intervention must be withheld until after PK 

2018N385816_02
CONFIDENTIAL
202018
74
sampling has been performed.  The actual date and time (24-hour clock time) of 
each sample will be recorded.

Samples will be used to evaluate the PK of GSK3196165. Each serum sample will 
be divided into 2 aliquots (1 each for PK and target engagement (TE) [Section 
8.8]). Samples collected for analyses of GSK3196165 serum concentration may 
also be used to evaluate safety or efficacy aspects related to concerns arising 
during or after the study.

Samples may be stored for a maximum of 15 years (or according to local 
regulations) following the last participant’s last visit for the study at a facility 
selected by the sponsor to enable further analysis.  Further details on the blood 
sample collection, processing, storage and shipping procedures are provided in the 
Central Laboratory Manual.

Note: Drug concentration information that would unblind the study will not be 
reported to investigative sites or blinded personnel until the study has been 
unblinded.
8.6.
Pharmacodynamics
The pharmacodynamic (PD) biomarkers evaluated in this study are described in Section 
8.8.
8.6.1.
Target engagement
The same blood samples obtained for PK analysis (see Section 8.5) will also be assessed 
for target engagement of GSK3196165, by measurement of serum concentrations of 
soluble GM-CSF-GSK3196165 complex, at the time points specified in the SoA (Section 
1.3).  Excess material from the immunogenicity baseline Day 1 blood sample (see 
Section 8.9) will be assessed for serum concentrations of free GM-CSF.
8.7.
Genetics
A 6 mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Appendix 5 for Information regarding genetic research.  Further details on the blood 
sample collection, processing, storage and shipping procedures are provided in the 
Central Laboratory Manual.

2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
7 5
8. 8. 1.
P h ar m a c o d y n a mi c ( P D) Bi o m ar k er s
A bl o o d sa m ple of a p pr o xi matel y  1 2 m L will be c ollecte d a n d di vi de d i nt o s uita ble 
p orti o ns f or meas ure me nt of t he f oll o wi n g bi o mar kers ass ociate d wit h G M -C S F 
si g nalli n g a n d/ or disease pat h ol o g y:

Meas ure me nt of ser u m P D bi o mar kers of d o w nstrea m si g nalli n g of G M -C S F t o 
assess t he res p o nse t o G S K 3 1 9 6 1 6 5. T he bi o mar kers ma y  i ncl u de b ut are n ot 
li mite d t o C C L1 7.

Meas ure me nt of ser u m P D bi o mar kers t o assess or pre dict t he res p o nse t o 
G S K 3 1 9 6 1 6 5. T he bi o mar kers ma y  i ncl u de b ut are n ot li mite d t o C C L2 2, s ol u ble 
i nterle u ki n (I L) 2 R, a n d I L 6.

Assess me nt of ser u m bi o mar kers of E C M de gra dati o n. T he bi o mar kers ma y  
i ncl u de b ut are n ot li mite d t o C 1 M, C 3 M, a n d P 4 N P 7 S.
C CI
C CI

2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
7 6
8. 9.
I m m u n o g e ni cit y As s e s s m e nt s
W h ole bl o o d sa m ples of a p pr o xi matel y  6 m L will be c ollecte d fr o m all partici pa nts a n d 
di vi de d i nt o s uita ble p orti o ns f or i m m u n o ge nicit y assess me nts of a nti-dr u g a nti b o d y  
( A D A) de vel o p me nt. A nti b o dies t o G S K 3 1 9 6 1 6 5 will be e val uate d i n ser u m sa m ples 
c ollecte d fr o m all partici pa nts acc or di n g t o t he S o A ( Secti o n 1. 3 ). Ser u m sa m ples s h o ul d 
als o be c ol lecte d at t he fi nal visit fr o m partici pa nts w h o disc o nti n ue d st u d y i nter ve nti o n 
or are wit h dra w n fr o m t he st u d y .  I n a d diti o n t o sc he d ule d i m m u n o ge nicit y assess me nts, 
“e ve nt-dri ve n” testi n g will be perf or me d i n t he c o nte xt of seri o us h y perse nsiti vit y  
reacti o ns or A Es dee me d t o be cli nicall y si g nifica nt i n t he o pi ni o n of t he i n vesti gat or 
res ulti n g i n wit h dra wal.
Ser u m sa m ples will be scree ne d f or a nti b o dies bi n di n g t o G S K 3 1 9 6 1 6 5 a n d t he titre of 
c o nfir me d p ositi ve sa m ples will be re p orte d. Ot her a nal ys es ma y be perf or me d t o verif y  
t he sta bilit y of a nti b o dies t o G S K 3 1 9 6 1 6 5 a n d/ or f urt her c haracterise t he i m m u n o ge nicity 
of G S K 3 1 9 6 1 6 5. T he ser u m sa m ple c ollecte d at Da y 1 will als o be a nal ys e d f or a nti-G M -
C S F a ut o -a nti b o dies a n d free G M-C S F le vels.
T he detecti o n a n d c haracterisati o n of a nti b o dies t o G S K 3 1 9 6 1 6 5 will be perf or me d usi n g 
vali date d assa y  met h o ds b y or u n der t he s u per visi o n of t he s p o ns or.  A nti b o dies ma y be 
f urt her c haracterise d a n d/ or e val uate d f or t heir a bilit y t o ne utralise t he acti vit y of t he 
st u d y i nter ve nti o n(s).  Sa m ples ma y be st ore d f or a ma xi m u m of 1 5 years ( or acc or di n g 
t o l ocal re g ulati o ns) f oll o wi n g t he last partici pa nt’s last visit f or t he st u d y at a facilit y 
selecte d by t he s p o ns or t o e na ble f urt her a nal ys is.
8. 1 0.
M e di c al R e s o ur c e Utili s ati o n a n d H e alt h E c o n o mi c s
Me dical Res o urce Utilisati o n a n d Healt h Ec o n o mics para meters are n ot e val uate d i n t his 
st u d y.
C CI

2018N385816_02
CONFIDENTIAL
202018
77
9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
The primary objective of the study is to determine whether GSK3196165 is superior to 
placebo in the treatment of participants with moderately to severely active RA despite 
treatment with biological DMARDs and/or Janus Kinase inhibitors (i.e. bDMARD-IR 
and/or JAK-IR), as assessed by the proportion of participants achieving ACR20 at Week 
12. 
The study will test the null hypothesis that there is no difference between 150 mg dose of
GSK3196165 and placebo in the proportion of participants achieving ACR20 response at 
Week 12 versus the alternative hypothesis that the 150 mg dose of GSK3196165 differs
from placebo in the proportion of participants with ACR20 response at Week 12.
9.2.
Sample Size Determination
Approximately 1050-1200 participants will be screened to achieve between 525 and 600 
randomly assigned to study intervention. Approximately 525 evaluable participants are 
expected to be included in the primary analysis, of whom approximately 473 are expected 
to complete the week 12 visit. When the approximate target of 525 participants is 
reached, recruitment may continue up to a maximum of 600 participants to ensure 
sufficient numbers in the key Asian country subgroup.
For the purpose of analyses up to week 12, the placebo-sequence groups will be pooled 
into a single pooled placebo arm.
The minimum sample size of 525 will provide:

96% power to detect a 25% difference between GSK3196165 and the pooled 
placebo group in ACR20 response rate (52% vs. 27%) at Week 12 based on a 2-
sided significance level of 0.05, using a pooled Z-test. The Least Significant 
Difference this sample size will detect is 13.3%.

In addition, the above sample size will detect a Least Significant Difference of 3.5 
against sarilumab in the CDAI score change from baseline at Week 12, based on a 
2-sided significance level of 0.05, using a Z-test assuming equal variance of 15.6 
in each group.
The above sample size and power estimates were obtained from PASS version 12.0.2.
9.2.1.
Sample Size Sensitivity
The power of the primary analysis of the study will be affected by changes in the 
assumed response rate. The effect on power under varying response rates on both placebo 
and GSK3196165 assuming a fixed sample size of 150 in the GSK3196165 arm and 75 in 
the placebo arm, based on a 2-sided significance level of 0.05, using a pooled Z-test are 
shown in Table 4:

2018N385816_02
CONFIDENTIAL
202018
78
Table 4
Power for ACR20 Response at Week 12 under varying response 
rates on GSK3196165 and Placebo
Placebo Response Rate
GSK3196165 Response Rate
49%
52%
55%
27%
90%
96%
99%
30%
79%
89%
95%
33%
63%
78%
89%
9.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign the ICF
Intent-to-treat (ITT)
All randomised participants who receive at least one dose of study 
intervention.
Per-protocol (PP)
All randomised participants who are compliant with intervention, who 
do not have significant protocol violations, and whose investigator site 
does not have any GCP issues that require report to the regulatory 
agencies.
Safety
All randomised participants who take at least 1 dose of study 
intervention. Participants will be analysed according to the 
intervention they actually received.
The primary analysis population will be the ITT population. In addition, the primary and 
major secondary analyses will be repeated using the PP population. Full details of all 
protocol violations that lead to exclusion from the PP population will be listed in the 
Reporting and Analysis plan (RAP).

2018N385816_02
CONFIDENTIAL
202018
79
9.4.
Statistical Analyses
Full details of all analyses will be described in the RAP.
The primary analysis will be performed when the minimum target sample size of 525 has 
been achieved.  All inferences will be drawn from the primary analysis.
The proposed sequence of primary and key secondary endpoints is:
1. ACR20 at week 12
2. HAQ-DI at week 12
3. CDAI total score at week 12
4. Pain VAS at week 12
In order to preserve the type I error, each endpoint will be assessed sequentially using a 
step-down approach where statistical significance can be claimed for the second endpoint 
only if the first endpoint in the sequence meets the requirements for significance.
Additionally, as there are two doses of GSK3196165 within each endpoint, each to be 
compared with placebo, a step-down procedure, where the high dose will be tested first, 
will be used within each endpoint, i.e. the high dose (150mg) at a given endpoint can 
achieve significance only if the high dose at the prior endpoint is significant; the low dose 
(90mg) at a given endpoint can achieve significance only if both the high dose at the 
same endpoint and the low dose at the prior endpoint are significant. For each endpoint, 
and for each GSK3196165 dose group, the comparison will be conducted using a 2-sided 
significance level of 0.05.
The comparisons for ACR20 and HAQ-DI will be against placebo, after which the 
comparisons for CDAI and Pain VAS will be against sarilumab. The schematic is shown 
in Appendix 8.
This step-down approach strongly protects the Type I error rate at the 0.05 (2-sided) level 
across endpoints within each dose and across doses within each endpoint. However, there 
is weak control of the Type I error rate when the low dose at the first endpoint and the 
high dose at the second endpoint are tested simultaneously. Note this is only a risk in 
situations where the high dose has some effect at the first endpoint but not the second, 
and the low dose is not effective at the first endpoint. This is a situation that is not 
expected since if the high dose is effective for a given endpoint, there is likely to be some 
effect (non-zero) at the low dose.

2018N385816_02
CONFIDENTIAL
202018
80
9.4.1.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
The proportion of participants with ACR20 response will be summarised 
using counts and proportions of responders, and analysed using a 
Generalised Estimating Equations (GEE) model, comparing intervention 
group with placebo at each time point, with fixed effects of intervention, visit, 
baseline swollen joint count (66), baseline tender joint count (68), previously 
failed medication, intervention-by-visit interaction and a random effect of 
participant.
Secondary
The CDAI total score will be expressed as a change from baseline and will be 
analysed using a mixed effect repeated measures model (MMRM) with fixed 
effects of intervention, visit, baseline value, intervention-by-visit interaction 
and a random effect of participant. An unstructured covariance structure will 
be used to model the between and within-participant errors, however if this 
analysis fails to converge, other structures will be tested. The Kenward-
Roger method will be used to estimate the degrees of freedom. Least 
Squares means will be used for the statistical comparisons; CIs will also be 
reported. Intervention group comparisons versus placebo at week 12 and 
other visits will be tested.
The HAQ-DI total score will be analysed using the same method as 
described above for CDAI total score. 
The Pain VAS will be analysed using the same method as described above 
for CDAI total score.
Additional 
Secondary 
and 
Exploratory
Will be described in the reporting and analysis plan
9.4.1.1.
Estimand strategy
The main intercurrent (post-randomisation) event anticipated to impact on the 
interpretation of the treatment effect for the primary objective is withdrawal from study 
intervention.
The estimand for the primary comparison will be defined using:
1. Population: defined through the inclusion/exclusion criteria
2. Variable: Proportion of participants at week 12 with ACR20 response
3. Intercurrent Event: the participant withdrew from intervention
4. Population Level Summary: Comparisons of proportions between the active 
groups and placebo

2018N385816_02
CONFIDENTIAL
202018
81
The primary estimand used will be the treatment policy estimand.  This follows the 
principle that participants should be followed up, assessed and analysed irrespective of 
compliance to planned intervention.  This strategy answers the question of what the effect 
is of assigning participants to an intervention.  Therefore, if a participant withdraws from 
study intervention but efficacy data continues to be collected, their data will be analysed 
as if they were still on the original randomised intervention.
Further details will be provided in the RAP on any sensitivity estimators 
and supplementary estimands used to assess the primary objective and any estimands 
used to assess the secondary objectives.
9.4.2.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Endpoint
Statistical Analysis Methods
Secondary
For safety data, no formal hypotheses will be tested. Incidence of AEs, SAEs, and 
AESIs, including laboratory tests, vital signs, pulmonary function tests and 12-Lead 
ECGs will be displayed in the form of listings, frequencies, summary statistics, 
graphs and statistical analyses where appropriate. Interpretation will be aided by 
clinical expertise. Full details, including example outputs, will be documented in the 
RAP.
9.4.3.
Other Analyses
PK, pharmacodynamic, and biomarker exploratory analyses will be described in the 
reporting and analysis plan, as well as PROs (Patient Reported Outcomes). The 
population PK analysis and pharmacodynamic analyses will be presented separately from 
the main clinical study report (CSR). 
9.5.
Interim Analyses
The primary analysis will be conducted when the planned target of 525 randomised 
participants has been reached. No interim analysis with respect to this population is 
planned. However, if at the time of reaching approximately 525 randomised participants a 
sufficient number of participants that are required for the key Asian country subgroups is 
not reached, then recruitment in these countries may continue. Participants who have 
already been enrolled from Asian country subgroups at the time of reaching the 525 
target will be included in the primary analysis. Double-blinding will be maintained for 
any subjects continuing in the study at the time of the primary analysis. The primary 
analysis will be the basis of all inferences. If enrolment continues beyond the planned 
target of 525 randomised participants, secondary analyses will be conducted upon 
completion of enrolment/follow-up for the entire study population, based on all 
randomised subjects.

2018N385816_02
CONFIDENTIAL
202018
82
9.5.1.
Data Monitoring Committee (DMC)
An IDMC will be utilised in this study to ensure ongoing objective medical and/or 
statistical review of safety data in order to protect the ethical and safety interests of 
participants and to protect the scientific validity of the study.  See Section 10.1.5 for 
further details.
Full details of the data to be reviewed and membership of the committee will be available 
in the charter which will be available prior to the first participant’s visit.

2018N385816_02
CONFIDENTIAL
202018
83
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organisations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
10.1.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.

2018N385816_02
CONFIDENTIAL
202018
84
10.1.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorised representative and answer all 
questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorised representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study centre. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorised person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorised representative. 

Participants who are rescreened are required to sign a new ICF.
10.1.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorised personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
10.1.5.
Committees Structure
An Independent Data Monitoring Committee (IDMC), a Major Adverse Cardiac 
Event/Gastrointestinal Perforation (MACE/GI Perforation) Adjudication Committee and 
a Pulmonary Adjudication Committee (PAC) will be utilised in this study, in addition to 
the routine sponsor review of blinded safety data that will occur approximately every 4 
weeks during the period of study conduct.

2018N385816_02
CONFIDENTIAL
202018
85
The overall responsibility of the IDMC is to protect the ethical and safety interests of 
participants recruited into this study while protecting as far as possible the scientific 
validity of the data.  The IDMC and Adjudication Committees will include physicians 
with relevant clinical expertise and a statistician, none of whom is affiliated with the 
sponsor.  The IDMC will adopt a staggered approach to reviewing unblinded data.  The 
initial early review, frequency of further reviews and the safety data included, will be 
detailed in the IDMC charter.
The MACE/GI Perforation Adjudication Committee and PAC will function as detailed in 
the IDMC charter.
10.1.6.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments. 

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicentre studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
10.1.7.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study participants, as appropriate.

GSK will provide the investigator with the randomisation codes for their site 
only after completion of the full statistical analysis.

The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy.

GSK intends to make anonymised participant-level data from this trial available 
to external researchers for scientific analyses or to conduct further research that 
can help advance medical science or improve patient care. This helps ensure the 
data provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding

2018N385816_02
CONFIDENTIAL
202018
86
10.1.8.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 

This study uses a number of assessments and questionnaires to evaluate the 
participant’s symptoms and impacts at a particular moment in time (see efficacy 
assessments listed in Section 8.1).  These patient-reported outcomes and impact 
instruments completed directly by participants, investigators and joint assessors 
as source records (e.g. site tablet or electronic clinical outcome assessment 
(eCOA) portal contribute to the secondary and exploratory endpoints and must 
not be changed or overwritten (with the exception of administrative/operational 
data items), in order to minimize bias.

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, 
or on-site monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organisations).

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorised site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 

2018N385816_02
CONFIDENTIAL
202018
87
10.1.9.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the Source Data 
Agreement.
10.1.10.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development

2018N385816_02
CONFIDENTIAL
202018
88
10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 5 will be performed by the central laboratory except 
for ESR, dipstick urinalysis and urine pregnancy tests, which will be analysed 
locally.

Except for ESR, dipstick urinalysis, and urine pregnancy tests, local laboratory 
results are only required in the event that the central laboratory results are not 
available in time for either study intervention administration and/or safety 
evaluation.  If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Pregnancy Testing 
o
Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria.
o
Pregnancy testing (urine or serum as required by local regulations) for 
WOCBP should be conducted once every 4 weeks to Week 16 and then 
again at Week 24.
o
Pregnancy testing (urine or serum as required by local regulations) will 
also be conducted at the safety follow up visit. 
o
Additional serum or urine pregnancy tests may be performed, as 
determined necessary by the investigator or required by local regulation, 
to establish the absence of pregnancy at any time during the participation 
of a WOCBP in the study.
Table 5
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
%Reticulocytes
erythrocyte count
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase (AST)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase (ALT)
Total Protein
Glucose (non-
fasting)
Calcium
Alkaline phosphatase 
(AP)
Albumin

2018N385816_02
CONFIDENTIAL
202018
89
Laboratory 
Assessments
Parameters
Albumin/globulin 
ratio
Phosphate
Creatine 
Phosphokinase (CPK)
High sensitivity 
C-reactive 
protein (hsCRP)
γ-Glutamyl 
transpeptidase 
(GGT)
Lactate 
dehydrogenase
(LDH)
Lipid profile
Total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density 
lipoprotein-cholesterol, triglycerides and other lipoprotein tests as needed.
Urinalysis
Performed locally by dipstick
Urine 
pregnancy test

Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy test 
(as needed for women of childbearing potential)2
Other Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Highly sensitive serum hCG pregnancy test (as needed for women of 
childbearing potential)2

Serology [HIV antibody, hepatitis B surface antigen (HBsAg), hepatitis B core 
antibody (HBcAb), HB DNA, HCV RNA and hepatitis C virus antibody], 
rheumatoid factor (RF), ACPA (anti-CCP), hsCRP, ESR, QuantiFERON-TB 
Gold plus test (or, if unavailable, T-Spot TB)

eGFR calculated by the CKD-EPI calculation.

All study-required laboratory assessments will be performed by a central 
laboratory, except ESR, dipstick urinalysis and urine pregnancy tests which 
will be performed locally. Only the results of tests performed locally will be 
recorded in the eCRF. Details for recording the post-randomisation ESR 
values will be provided in the SRM
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1 and Appendix 6. All events of ALT 3 × upper limit of normal (ULN) and 
bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalised ratio (INR) >1.5, if INR 
measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).
2.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.
Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded. This 
includes results of PK analyses, ESR (performed locally by an unblinded independent 
study team member) and hsCRP.  The only exception is the result of ESR and hsCRP at
the participant’s final assessment visit, if the participant is moving to the extension study.
Note: Monitoring of CRP/hsCRP during the course of this study by local measurements, 
is not permitted, in order to protect the blind.  However individual local measured 
CRP/hsCRP may be performed if required for safety reasons.

2018N385816_02
CONFIDENTIAL
202018
90
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting

This Appendix contains definitions and procedures required for AEs and SAEs 
which do not involve Medical Devices used in this study (see Section 6.1.1 for the 
list of medical devices).

Refer to Appendix 9 for definitions and reporting requirements of Medical Device 
AEs, SAEs, incidents and deficiencies.
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not considered 
related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE 
or SAE. 

2018N385816_02
CONFIDENTIAL
202018
91
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalisation for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
Results in death
Is life-threatening
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
Requires inpatient hospitalisation or prolongation of existing hospitalisation
In general, hospitalisation signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalisation are AE. If a 
complication prolongs hospitalisation or fulfils any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalisation” occurred or was necessary, the AE 
should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.

2018N385816_02
CONFIDENTIAL
202018
92
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalisation but may 
jeopardise the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation, or development of drug dependency 
or drug abuse.
10.3.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation

2018N385816_02
CONFIDENTIAL
202018
93
10.3.4.
Recording and Follow-Up of AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilised for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 

2018N385816_02
CONFIDENTIAL
202018
94
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognised follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
10.3.5.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 

2018N385816_02
CONFIDENTIAL
202018
95
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the SRM.
SAE Reporting to GSK via Paper CRF

Secure email transmission of the scanned SAE paper CRF is the preferred method to 
transmit this information to the medical monitor or the SAE coordinator.

In rare circumstances and in the absence of secure email facilities, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in SRM.

2018N385816_02
CONFIDENTIAL
202018
96
10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
10.4.1.
Definitions:
10.4.1.1.
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered.
10.4.1.2.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the 
participant’s medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 

A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement is required. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before 
study enrolment.

2018N385816_02
CONFIDENTIAL
202018
97
10.4.2.
Contraception Guidance:

CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:

Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year 
when used consistently and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of ovulationc

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Vasectomised partner

Note: Vasectomised partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the absence of 
sperm has been confirmed. If not, an additional highly effective method of contraception 
should be used. Spermatogenesis cycle is approximately 90 days.

Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly.

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc
oral
intravaginal
transdermal

injectable

Progestogen-only hormone contraception associated with inhibition of ovulationc
oral

injectable

Sexual abstinence

Note: Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for those participating in clinical studies.
b.
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when 
used consistently and correctly.
c.
Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with Clinical 
Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those which inhibit 
ovulation as the primary mode of action.
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Male condom 
and female condom should not be used together (due to risk of failure with friction)

2018N385816_02
CONFIDENTIAL
202018
98
10.4.3.
Collection of Pregnancy Information:
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to male participants who receive study intervention.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK.

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant’s pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such. 

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study intervention by the investigator, will be reported to 
GSK as described in Appendix 3. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE 
through spontaneous reporting. 
Any female participant who becomes pregnant while participating will discontinue study 
intervention but may continue in the study and attend all clinic visits if she wishes.

2018N385816_02
CONFIDENTIAL
202018
99
10.4.4.
Contraception Eligibility Criteria for Female and Male Participants
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
a.
Male Participants:
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 12 weeks post last dose of study intervention:

Refrain from donating sperm
PLUS, either:

Be abstinent from heterosexual or homosexual intercourse as their preferred 
and usual lifestyle (abstinent on a long term and persistent basis) and agree to 
remain abstinent 
OR

Must agree to use contraception/barrier as detailed below 
o
Agree to use a male condom AND female partner to use an additional 
highly effective contraceptive method with a failure rate of <1% per 
year (as described in Section 10.4.2) when having sexual intercourse 
with a woman of childbearing potential who is not currently pregnant.
b. Female Participants: 

A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and at least one of the following conditions applies:
o
Is NOT a woman of childbearing potential (WOCBP) as defined in Section 
10.4.1.
OR
o
Is a WOCBP and using a contraceptive method that is highly effective with a 
failure rate of <1% per year (see Section 10.4.2), for 30 days before the first 
dose of study intervention, during the intervention period and at least 12 
weeks after the last dose of study intervention and agrees not to donate eggs 
(ova, oocytes) for the purpose of reproduction during this period.  
Additionally, WOCBP using hormonal contraceptives, including oral, 
injections, implants, and patches, are required to use a secondary method of 
contraception. The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention.

In addition to contraception requirements for study medication as outlined 
above, participants should follow csDMARD local labelling.

A WOCBP must have both: 

A confirmed menstrual period prior to the first dose of study intervention
AND

2018N385816_02
CONFIDENTIAL
202018
100

A negative highly sensitive pregnancy test (urine or serum as required by 
local regulations) within 24 hours before the first dose of study intervention. 
If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a 
serum pregnancy test is required. In such cases, the participant must be excluded 
from participation if the serum pregnancy result is positive.

The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy
Pregnancy tests for WOCBP are specified in the SoA (Section 1.3).

2018N385816_02
CONFIDENTIAL
202018
101
10.5.
Appendix 5: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility, severity and progression of disease. Variable response to study 
intervention may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; disease 
etiology; and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis

DNA samples will be used for research related to GSK3196165 or RA and related 
diseases. They may also be used to develop tests/assays (including diagnostic tests) 
related to GSK3196165, and RA. Genetic research may consist of the analysis of one 
or more candidate genes or the analysis of genetic markers throughout the genome or 
analysis of the entire genome (as appropriate)

DNA samples will be analysed if it is hypothesised that this may help further 
understand the clinical data. 

The samples may be analysed as part of a multi-study assessment of genetic factors 
involved in the response to GSK3196165 or study interventions of this class. The 
results of genetic analyses may be reported in the clinical study report or in a 
separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on GSK3196165 (or study interventions 
of this class) or RA continues but no longer than 15 years after the last participant 
last visit or other period as per local requirements.

2018N385816_02
CONFIDENTIAL
202018
102
10.6.
Appendix 6: Liver chemistry stopping and monitoring 
criteria and required actions and follow up assessments 
(study specific for 202018)
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology 
10.6.1.
Liver chemistry stopping criteria and required follow up 
assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT absolute
ALT 5xULN
ALT Increase
ALT 3xULN and does not resolve to ALT ≤1.5 x ULN after 4 weeks of increased 
monitoring (see below)
Bilirubin1,2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5
Cannot 
Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT 3xULN associated with symptoms (new or worsening) believed to be related to 
liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments
Immediately discontinue study intervention
Report the event to GSK within 24 hours
Complete the liver event CRF and complete SAE 
data collection tool if the event also meets the 
criteria for an SAE2
Perform liver event follow up assessments 
Monitor the participant until liver chemistries
resolve, stabilise, or return to within baseline (see 
MONITORING below)
Since restart/rechallenge is not allowed per 
protocol permanently discontinue study 
intervention but may continue participant in the 
study for any protocol specified follow up 
assessments.
Viral hepatitis serology4
Obtain INR and recheck with each liver 
chemistry assessment until the transaminases 
values show downward trend
Blood sample for pharmacokinetic (PK) 
analysis, obtained 8 weeks after last dose5
Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).
Fractionate bilirubin, if total bilirubin2xULN
Obtain complete blood count with differential to 
assess eosinophilia
Record the appearance or worsening of clinical 
symptoms of liver injury, or hypersensitivity, on 
the AE report form
Record use of concomitant medications on the 
concomitant medications report form including 
acetaminophen, herbal remedies, other over the 

2018N385816_02
CONFIDENTIAL
202018
103
MONITORING:
For bilirubin or INR criteria:
Repeat liver chemistries(include ALT, AST, alkaline 
phosphatase, bilirubin and INR) and perform liver 
event follow up assessments within 24 hours
Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to within 
baseline
A specialist or hepatology consultation is 
recommended
For All other criteria:
Repeat liver chemistries(include ALT, AST, alkaline 
phosphatase, bilirubin, and INR) and perform liver 
event follow up assessments within 24-72 hours 
Monitor participants weekly until liver chemistries 
resolve, stabilise or return to within baseline
counter medications.
Record alcohol use on the liver event alcohol 
intake case report form
For bilirubin or INR criteria:
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total 
immunoglobulin G (IgG or gamma globulins).
Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen contribution 
to liver injury in participants with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]). NOTE: not required in China
Liver imaging (ultrasound, magnetic resonance, 
or computerised tomography) and /or liver 
biopsy to evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5 which may 
indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the INR threshold value stated will not apply to participants receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A immunoglobulin M (IgM) antibody; Hepatitis B surface antigen (HBsAg) and Hepatitis B Core 
Antibody (HBcAb); Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM 
antibody (or if unavailable, obtain heterophile antibody or monospot testing); Hepatitis E IgM antibody.
5.
PK sample may not be required for participants known to be receiving placebo or non-comparator interventions. 
Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention prior to 
the PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the Central Laboratory Manual.

2018N385816_02
CONFIDENTIAL
202018
104
10.6.2.
Liver chemistry increased monitoring criteria with temporary 
discontinuation of study intervention
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event with temporary 
discontinuation of study intervention
If ALT 3xULN, temporarily discontinue study intervention and monitor weekly for up to 4 weeks.  If 
participant cannot be monitored, then permanently discontinue study intervention.  After temporary 
discontinuation, study intervention may be restarted if ALT <1.5 x ULN with additional monitoring.  If ALT 
does not resolve to ≤1.5 x ULN within 4 weeks or other stopping criteria met, permanently discontinue 
study intervention.
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks
Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss participant 
safety. 
Temporarily discontinue study intervention.
Participant must return weekly for repeat liver
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 
Study intervention may be restarted if ALT <1.5 x 
ULN.  After restarting study intervention, participant 
must return for repeat liver chemistries at 1, 2 and 4 
weeks, then scheduled monitoring can resume. If 
ALT ≥1.5 x ULN during additional monitoring, 
permanently discontinue study intervention.
                                 OR
If ALT does not resolve to ≤1.5 x ULN within 4 
weeks or other stopping criteria met, permanently 
discontinue study intervention.  
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.

2018N385816_02
CONFIDENTIAL
202018
105
10.7.
Appendix 7: Summary of composite endpoints
These composite endpoints are derived using the data collected from assessments 
described in Section 8.1.
10.7.1.
ACR
The American College of Rheumatology’s definition for calculating improvement in RA 
(ACR20) is calculated as a 20% improvement from baseline in tender and swollen joint 
counts and 20% improvement in 3 of the 5 remaining ACR-core set measures: patient and 
physician global assessments, pain, disability, and an acute-phase reactant.  Similarly, 
ACR50 and ACR70 are calculated with the respective percent improvement.
The specific components of the ACR Assessments that will be used in this study are:

Tender/Painful Joint count (68).

Swollen Joint Count (66).

Pain VAS.

Patient’s Global Assessment of Arthritis.

Physician’s Global Assessment of Arthritis.

Acute-phase reactant (hsCRP or ESR).

Health Assessment Questionnaire – Disability Index (HAQ-DI).
10.7.2.
Disease Activity Score
The Disease Activity Score (DAS) assessment is a derived measurement with differential 
weighting given to each component.  The DAS 28(CRP) or DAS 28(ESR) will be 
calculated at each assessment timepoint.
The components of the DAS 28 arthritis assessment include:

Tender/Painful Joint Count (28).

Swollen Joint Count (28).

hsCRP or ESR.

Patient’s Global Assessment of Arthritis.
10.7.3.
Clinical Disease Activity Index (CDAI)
The CDAI for rheumatoid arthritis is a clinical composite score to determine disease 
severity using only clinical data.  The CDAI score will be calculated at each assessment 
timepoint.
The components of the CDAI include:

Tender/Painful Joint Count (28).

2018N385816_02
CONFIDENTIAL
202018
106

Swollen Joint Count (28).

Patient’s Global Assessment of Arthritis.

Physician’s Global Assessment of Arthritis.

2018N385816_02
CONFIDENTIAL
202018
107
10.8.
Appendix 8: Hierarchy Options to Demonstrate Superiority 
of Each Dose of GSK3196165 Versus Placebo or Sarilumab

2018N385816_02
CONFIDENTIAL
202018
108
10.9.
Appendix 9: Medical Device Adverse Events (AEs), Adverse 
Device Effects (ADEs), Serious Adverse Events (SAEs) and 
Device Deficiencies: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting

The detection and documentation procedures described in this Appendix apply to 
the medical devices provided for use in the study as detailed in Section 6.1.1.  
Refer to Appendix 3 for all other AE/SAE reporting not involving a medical 
device.

The definitions and procedures detailed in this appendix are in accordance with 
ISO 14155.

Both the investigator and the sponsor will comply with all local medical device 
reporting requirements.
10.9.1.
Definition of Medical Device AE and ADE
Medical Device AE and ADE Definition 

An AE is defined as any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory finding) in study participants, 
users, or other persons, whether or not related to the investigational medical device. 
This definition includes events related to the investigational medical device or 
comparator and events related to the procedures involved except for events in users or 
other persons, which only include events related to investigational devices.

An adverse device effect (ADE) is defined as an adverse event related to the use of an 
investigational medical device. This definition includes any adverse events resulting 
from insufficient or inadequate instructions for use, deployment, implantation, 
installation, or operation, or any malfunction of the investigational medical device as 
well as any event resulting from use error or from intentional misuse of the 
investigational medical device.
10.9.2.
Definition of Medical Device SAE, SADE and USADE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A Medical Device SAE is a Medical Device AE that:
a.
Led to death 
b.
Led to serious deterioration in the health of the participant, that either resulted in:
1. A life-threatening illness or injury. The term ‘life-threatening' in the definition of 
serious' refers to an event in which the participant was at risk of death at the time of 
the event. It does not refer to an event, which hypothetically might have caused 
death, if it were more severe

2018N385816_02
CONFIDENTIAL
202018
109
2. A permanent impairment of a body structure or a body function,
3. Inpatient or prolonged hospitalization, Planned hospitalization for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration in 
health, is not considered an SAE
4. Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function
c.
Led to fetal distress, fetal death or a congenital abnormality or birth defect
Serious Adverse Device Effect (SADE) definition

A SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event.
Unanticipated Serious Adverse Device Effect (USADE) definition

A USADE is a serious adverse device effect which by its nature, incidence, severity or 
outcome has not been identified in the current version of the risk analysis report (see 
Section 2.3.1).
10.9.3.
Definition of Device Deficiency
Device Deficiency definition

A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety, or performance. Device deficiencies include 
malfunctions, use errors, and inadequate labelling.
10.9.4.
Recording and Follow-Up of Medical Device AE and/or SAE and 
Device Deficiencies
Medical Device AE, SAE and Device Deficiency Recording

When an AE/SAE/device deficiency occurs, it is the responsibility of the investigator 
to review all documentation (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event.

The investigator will then record all relevant AE/SAE/device deficiency information in 
the participant’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate form of the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to GSK in lieu of completion of the AE/SAE/device deficiency CRF page.

There may be instances when copies of medical records for certain cases are requested 
by GSK. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to 
GSK.

2018N385816_02
CONFIDENTIAL
202018
110

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.

For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of a device 
deficiency. This includes any amendment to the device design to prevent recurrence.
Assessment of Intensity

The investigator will make an assessment of intensity for each AE/SAE/device 
deficiency reported during the study and assign it to one of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.

Other measures to evaluate AEs and SAEs may be utilized (e.g., National Cancer 
Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE]).
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE/device deficiency

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE/device deficiency, the investigator must document in the medical 
notes that he/she has reviewed the AE/SAE/device deficiency and has provided an 

2018N385816_02
CONFIDENTIAL
202018
111
assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of Medical Device AE/SAE/device deficiency

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE/SAE/device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of receipt 
of the information.
10.9.5.
Reporting of Medical Device SAEs
Medical Device SAE Reporting to GSK via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor or the SAE coordinator by telephone.

Contacts for SAE reporting can be found in SRM.

2018N385816_02
CONFIDENTIAL
202018
112
Medical Device SAE Reporting to GSK via Paper CRF

Secure email transmission of the scanned SAE paper CRF is the preferred method to 
transmit this information to the medical monitor or the SAE coordinator.

In rare circumstances and in the absence of secure email facilities, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the SRM.
10.9.6.
Reporting of SADEs
SADE Reporting to GSK 
NOTE: There are additional reporting obligations for medical device incidents that are 
potentially related to SAEs that must fulfil the legal responsibility to notify appropriate 
regulatory authorities and other entities about certain safety information relating to medical 
devices being used in clinical studies. For medical device deficiencies with no associated 
AE or SAE please refer to Section 8.3.8.4.

Any device deficiency that is associated with an SAE must be reported to GSK 
within 24 hours after the investigator determines that the event meets the definition 
of a device deficiency.

GSK shall review all device deficiencies and determine and document in writing 
whether they could have led to an SAE. These shall be reported to the regulatory 
authorities and IRBs/IECs as required by national regulations.

Contacts for SAE reporting can be found in the SRM.

2018N385816_02
CONFIDENTIAL
202018
113
10.10.
Appendix 10: Country-specific requirements
Not Applicable.

2018N385816_02
CONFIDENTIAL
202018
114
10.11.
Appendix 11: Abbreviations and Trademarks
Abbreviations
ACPA
Anti-citrullinated protein antibody
ACR
American College of Rheumatology
ACR20/50/70
20%/50%/70% improvement in American College of Rheumatology 
Criteria
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine transaminase
AP
Alkaline phosphatase
AST
Aspartate transaminase
BCG
Bacillus Calmette-Guérin
bDMARD
Biologic disease-modifying antirheumatic drug
BID
Twice daily
CDAI
Clinical disease activity index
CD20
Cluster of differentiation antigen 20
CDC
Complement-dependent cytotoxicity
CI
Confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
COX
Cyclo-oxygenase
CPK
Creatine phosphokinase
CRP
C-reactive protein
csDMARD
Conventional synthetic disease modifying antirheumatic drug
CTC
Common terminology criteria
CTFG
Clinical Trial Facilitation Group
DAS28
Disease activity score including 28 different joints
DAS28(CRP)
Disease activity score including 28 different joints with CRP value
DAS28(ESR)
Disease activity score including 28 different joints with ESR value
DNA
Deoxyribonucleic acid
DMARD
Disease-modifying antirheumatic drug
DRE
Disease-related event
EBV
Epstein Barr Virus
ECG
Electrocardiogram
ECM
Extracellular matrix
eCRF
Electronic case report form
ED
Effective dose
ESR
Erythrocyte sedimentation rate
EULAR
European League against Rheumatism
FACIT
Functional assessment of chronic illness therapy
FEV1
Forced expiratory volume in one second
FSH
Follicle-stimulating hormone
FVC
Forced vital capacity
GCP
Good Clinical Practice

2018N385816_02
CONFIDENTIAL
202018
115
GEE
Generalised Estimating Equation
GFR
Glomerular filtration rate
GM-CSF
Granulocyte-macrophage colony stimulating factor
GSK
GlaxoSmithKline
HAQ-DI
Health Assessment Questionnaire Disability Index
hCG
Human chorionic gonadotropin
HF
Human Factors
HOA
Hand osteoarthritis
HRCT
High-resolution computed tomography
HRT
Hormone replacement therapy
HV
Healthy volunteer
IA
Intra-articular
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Institutional ethics committee
IFU
Instructions For Use
IgM
Immunoglobulin M
IL
Interleukin
IM
Intramuscular
IMP
Investigational medicinal product
INR
International normalised ratio
IP
Investigational product
IR
Inadequate response
IRB
Institutional review board
ITT
Intent to Treat
IU
International units
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IVIG
Intravenous immunoglobulin
IRT
Interactive Response Technology
JAK
Janus Kinase
kg
Kilogram
L
Litre
LAM
Lactational amenorrhoea method
LDA
Low disease activity
LDH
Lactate dehydrogenase
LFT
Liver function test
LTE
Long-term extension
mAb
Monoclonal antibody
MCV
Mean cell volume
MCH
Mean corpuscular haemoglobin
MCHC
Mean corpuscular haemoglobin concentration
MedDRA
Medical dictionary for regulatory activities

2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
1 1 6
m g
Milli gra m
m L
Millilitre
M M P
Matri x metall o pr otei nase
M M R M
Mi xe d M o del f or Re peate d Meas ures
M O S
Me dical O utc o mes St u d y
M S
M ulti ple scler osis
M S D S
Material safet y data s heet
m T S S
M o difie d T otal S har p Sc ore
M T X
Met h otre xate
N C E P
Nati o nal C h olester ol E d ucati o nal Pr o gra m
N CI -C T C A E
Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y  Criteria f or A d verse 
E ve nts
N O E L
N o o bser ve d effect le vel
N R S
N u merical Rati n g Scale
N S AI D
N o n -ster oi dal a nti-i nfla m mat or y dr u g
P A C
P ul m o nar y  A dj u dicati o n C o m mittee
P A P
P ul m o nar y  al ve olar pr otei n osis
P C R
P ol y merase c hai n reacti o n
P D
P har mac o d y na mic
P F S
Prefille d s y ri n ge
P F T
P ul m o nar y  f u ncti o n test
P P
Per Pr ot oc ol
P R N
Pr o Re Nata (as nee de d)
Pt G A
Patie nt’s Gl o bal Assess me nt of Art hritis
P h G A
P h y sicia n’s Gl o bal Assess me nt of Art hritis
P K
P har mac o ki netics
R A
R he u mat oi d art hritis
R A P
Re p orti n g a n d a nal ys is pla n
R F
R he u mat oi d fact or
R N A
Ri b o n ucleic aci d
S C
S u bc uta ne o us
S A E
Seri o us a d verse e ve nt
SJ C
S w olle n j oi nt c o u nt
S F - 3 6
S h ort f or m ( 3 6)
S O P
Sta n dar d o pe rati n g pr oce d ure
S R M
St u d y  Refere nce Ma n ual
S R T
Safet y  Re vie w Tea m
S S D
Safet y  Syri n ge De vice
T B
Myc o b acteri u m t u berc ul osis
T E
Tar get e n ga ge me nt
TJ C
Te n der j oi nt c o u nt
T N F α
T u m or necr osis fact or al p ha
ts D M A R D
Tar gete d s y nt hetic disease -m o dif y i n g a ntir he u matic dr u g
T S T
T u berc uli n s ki n test
U L N
U p per li mit of n or mal
C CI

2018N385816_02
CONFIDENTIAL
202018
117
VAS
Visual Analogue Scale
WOCBP
Woman of Childbearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Kevzara
MedDRA
PROMIS
Prosorba
QuantiFERON
T.SPOT TB

2018N385816_02
CONFIDENTIAL
202018
118
10.12.
Appendix 12: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Protocol Amendment 01 22-MAY-2019
Overall Rationale for the Amendment:  Correction of contraceptive requirements for 
Women of Child Bearing Potential (WOCBP) and additional clarifications.
Section # and Name
Description of Change
Brief Rationale
Section 10.4.4 
Contraception Eligibility 
Criteria for Female and 
Male Participants
Correction of bullet ‘b’ for WOCBP, to 
remove “with low user dependency” 
wording and remove requirement for 
“two” methods, except if hormonal 
contraceptives are used.
Corrected to align with the 
Investigator Brochure (IB) 
Development Core Safety 
Information and the Study Risk 
Assessment (see Section 2.3).
Section 8.1.3 Patient 
reported outcomes
Clarification that some (exploratory) 
PROs will only be implemented if, and 
when translations are available.
Some PROs may be delayed or 
may not be available in all 
languages for the global study.
Section 5.1 Inclusion 
criteria and Section 6.5.1 
Permitted therapies
Maximum allowed dose of Bucillamine 
increased to 300 mg/day if permitted per 
local requirements.
Enable dosing of permitted 
regimen in countries including 
Republic of Korea/China.
Section 1.3 SoA and
Section 2.3.1 Study risk 
table and Section 5.4 
Screen Failures
Correction, a baseline chest X-ray is 
required during rescreening (if not 
carried out recently).
Correction of requirement.
Section 8.6.1 Target 
engagement and Section 
8.9 Immunogenicity
Clarification that free GM-CSF levels will 
be measured at baseline using excess 
material from immunogenicity sample.
Clarification of procedure.
Section 1.3 SoA
Footnotes updated for above changes.
Guidance.
Section 9 Statistical 
Considerations
Correction of hypothesis to state 150 mg 
dose, and addition of stratification factor 
to the model specification.
Align hypothesis with multiple 
testing hierarchy and adjust for 
stratification factor in the model.
All sections
Minor grammatical and typographical corrections to improve readability.

2018N385816_02
CONFIDENTIAL
202018
119
11.
REFERENCES
Avci AB, Feist E, Burmester GR. Targeting GM-CSF in rheumatoid arthritis. Clin Exp 
Rheumatol. 2016, 34(4 Suppl 98):39-44.
Behrens F, Tak PP, Østergaard M, Stoilov R, Wiland P, Huizinga TW, et al. MOR103, a 
human monoclonal antibody to granulocyte-macrophage colony-stimulating factor, in the 
treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa 
randomised, double-blind, placebo-controlled, dose-escalation trial. Ann Rheum Dis 
2015;74:1058-64.
Bjorner JB, Rose M, Gandek B; Stone AA, Junghaenel DU, Ware Jr JE. Method of 
administration of PROMIS scales did not significantly impact score level, reliability, or 
validity. Journal of Clinical Epidemiology 2014;67:108-113.
Burmester G, McInnes IB, Kremer JM, Miranda P, Korkosz M, Vencovsky J, et al. A 
randomised phase IIb study of mavrilimumab, a novel GM-CSF receptor alpha 
monoclonal antibody, in the treatment of rheumatoid arthritis. Ann Rheum Dis 
2017;76:1020-30.
Burmester GR, McInnes IB, Kremer JM, Miranda P, Vencovský J, Godwood A, et al. M. 
Mavrilimumab, a Fully Human Granulocyte-Macrophage Colony-Stimulating Factor 
Receptor α Monoclonal Antibody: Long-Term Safety and Efficacy in Patients With 
Rheumatoid Arthritis. Arthritis Rheumatol. 2018;70(5):679-689.
Cella D, Riley W, Stone A, Rothrock N, Reeve B, Yount S, et al. The Patient-Reported 
Outcomes Measurement Information System (PROMIS) developed and tested its first 
wave of adult self-reported health outcome item banks: 2005–2008. Journal of clinical 
epidemiology 2010;63:1179-1194.
Cook AD, Braine EL, Campbell IK, Rich MJ, Hamilton JA. Blockade of collagen-
induced arthritis post-onset by antibody to granulocyte-macrophage colony-stimulating 
factor (GM-CSF): requirement for GM-CSF in the effector phase of disease. Arthritis Res 
2001;3:293-8.
Cook AD, Hamilton JA. Investigational therapies targeting the granulocyte macrophage 
colony-stimulating factor receptor-α in rheumatoid arthritis: focus on mavrilimumab. 
Ther Adv Musculoskelet Dis. 2018b;10(2):29-38.
Cook AD, Lee MC, Saleh R, Khiew HW, Christensen AD, Achuthan A, et al. TNF and 
granulocyte macrophage-colony stimulating factor interdependence mediates 
inflammation via CCL17. JCI Insight. 2018a, 3(6).
Cook AD, Pobjoy J, Sarros S, Steidl S, Dürr M, Lacey DC, et al. Granulocyte-
macrophage colony-stimulating factor is a key mediator in inflammatory and arthritic 
pain. Ann Rheum Dis. 2013, 72(2):265-70.

2018N385816_02
CONFIDENTIAL
202018
120
Cook AD, Pobjoy J, Steidl S, Dürr M, Braine EL, Turner AL, et al. Granulocyte-
macrophage colony-stimulating factor is a key mediator in experimental osteoarthritis 
pain and disease development. Arthritis Res Ther 2012;14:R199.
FDA (Food and Drug Administration, 2014). Guidance for Industry: Immunogenicity 
Assessment for Therapeutic Protein Products. 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm338856.pdf
Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcomes in arthritis. 
Arthritis Rheum 1980;23:137-45.
Furer V, Rondaan C, Heijstek MW, Agmon-Levin N, van Assen S, Bijl M,et al. 2019 
update of EULAR recommendations for vaccination in adult patients with autoimmune 
inflammatory rheumatic diseases. Ann Rheum Dis. 2020 Jan;79(1):39-52.
Gaujoux-Viala C, Nam J, Ramiro S, Landewé R, Buch MH, Smolen JS, et al. Efficacy of 
conventional synthetic disease-modifying antirheumatic drugs, glucocorticoids and 
tofacitinib: a systematic literature review informing the 2013 update of the EULAR 
recommendations for management of rheumatoid arthritis. Ann Rheum Dis 2014;73:510-
5.
GSK Document Number 2014N190256_02. GSK3196165 Investigator's Brochure 
Version 9 (2019).
GSK Document Number 2017N353526_00. Pharmacokinetic Study Analysis Report. 
Population Pharmacokinetic Analysis of GSK3196165 Following Intravenous and 
Subcutaneous Administration to Healthy Volunteers, and Subjects with Rheumatoid 
Arthritis and Multiple Sclerosis, Date: 07-Dec-2017
Hamilton JA, Cook AD, Tak PP. Anti-colony-stimulating factor therapies for 
inflammatory and autoimmune diseases. Nat Rev Drug Discov. 2016 29;16(1):53-70.
LeVine AM, Reed JA, Kurak KE, Cianciolo E, Whitsett JA. GM-CSF-deficient mice are 
susceptible to pulmonary group B streptococcal infection. J Clin Invest 1999;103:563-9.
Martinez-Moczygemba M, Doan ML, Elidemir O, Fan LL, Cheung SW, Lei JT, et al. 
Pulmonary alveolar proteinosis caused by deletion of GM-CSFRalpha gene in the X 
chromosome pseudoautosomal region 1. J Exp Med 2008;205:2711-6.
Nam JL, Ramiro S, Gaujoux-Viala C, Takase K, Leon-Garcia M, Emery P, et al. Efficacy 
of biological disease-modifying antirheumatic drugs: a systematic literature review 
informing the 2013 update of the EULAR recommendations for the management of 
rheumatoid arthritis. Ann Rheum Dis 2014;73:516-28.
NCI. National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 
NCI, NIH, DHHS. November 27th. 2017. 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Q
uick_Reference_5x7.pdf

2018N385816_02
CONFIDENTIAL
202018
121
Plater-Zyberk C, Joosten LAB, Helsen MM, Hepp J, Baeuerle PA, van den Berg WB. 
GM-CSF neutralisation suppresses inflammation and protects cartilage in acute 
streptococcal cell wall arthritis of mice. Ann Rheum Dis 2007;66:452-7.
Stanley E, Lieschke GJ, Grail D, Metcalf D, Hodgson G, Gall JA, et al. 
Granulocyte/macrophage colony-stimulating factor-deficient mice show no major 
perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc 
Natl Acad Sci USA 1994;91:5592-6.
Steidl S, Ratsch O, Brocks B, Dürr M, Thomassen-Wolf E. In vitro affinity maturation of 
human GM-CSF antibodies by targeted CDR-diversification. Mol Immunol 2008;46:135-
44.
Suzuki T, Sakagami T, Rubin BK, Nogee LM, Wood RE, Zimmerman SL, et al. Familial 
pulmonary alveolar proteinosis caused by mutations in CSF2RA. J Exp Med 
2008;205:2703-10.
Wicks IP, Roberts AW. Targeting GM-CSF in inflammatory diseases. Nat Rev 
Rheumatol. 2016; 12(1):37-48.