A 52-week, Phase 3, Multicentre, Randomised, Double Blind, Efficacy and Safety Study, Comparing GSK3196165 With Placebo and With Tofacitinib in Combination With Conventional Synthetic DMARDs, in Participants With Moderately to Severely Active Rheumatoid Arthritis Who Have an Inadequate Response to Conventional Synthetic DMARDs or Biologic DMARDs
Phase: PHASE3
Conditions: Arthritis, Rheumatoid
Sponsor: GlaxoSmithKline

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GlaxoSmithKline group of companies
201791
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TITLE PAGE
Protocol Title: A 52-week, phase 3, multicentre, randomised, double blind, efficacy and 
safety study, comparing GSK3196165 with placebo and with tofacitinib in combination 
with conventional synthetic DMARDs, in participants with moderately to severely active 
rheumatoid arthritis who have an inadequate response to conventional synthetic 
DMARDs or biologic DMARDs.
Protocol Number: 201791 / Amendment 02
Compound Number: GSK3196165
Compound Name:
Otilimab
Study Phase: Phase 3 
Short Title: Efficacy and safety of GSK3196165 versus placebo and tofacitinib in 
participants with moderately to severely active rheumatoid arthritis who have an 
inadequate response to conventional synthetic/biologic DMARDs.
Study Name: contRAst-2
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: 2019-000867-26
Approval Date: 21-JAN-2020
Copyright 2020 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.

PPD
PPD
PPD

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
DNG Number
Amendment 2
21-JAN-2020
2018N385740_02
Amendment 1
22-MAY-2019
2018N385740_01
Original Protocol
06-MAR-2019
2018N385740_00
Amendment 2: 21-JAN-2020
Overall Rationale for the Amendment: (1) To detail revised risks, entry and stopping 
criteria following the update to comparator drug (tofacitinib) label; (2) To introduce new 
medical device safety reporting wording, required in advance of roll out of pre-filled 
syringes to this study. (3) Other minor corrections and clarifications.
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 1.3 Schedule of 
Activities (SoA)
Updated SoAs: remove fasting 
requirement for lipid test; clarify ECG 
requirement; refer to SAE section for 
reporting times at screening; and add 
urine pregnancy test at safety f/u.
Clarifications and reflect updates 
in body of protocol.
Section 2.3.1 Risk 
Assessment
Injection site reaction mitigation strategy 
- recommend to rotate sites.
Clarification.
Tofacitinib risks and mitigation strategy 
updated.
Recent safety update for 
tofacitinib label.
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 5.1 Inclusion 
Criteria
Clarification of inclusion criteria 7, 
permitting prior bDMARD exposure.
Clarification.
Section 5.2 Exclusion 
Criteria
Updates to exclusion criteria 12 and 13.
Due to recent safety update for 
Tofacitinib label.
Exclusion 12: Reduce myocardial 
infarction exclusion to 3 months.
3 months is considered to be 
appropriate to stabilise ischemic 
heart disease.
Change to exclusion criteria 24 to 
remove exclusion of participants with 
prior non-JAKi tsDMARD treatment.
Not necessary to exclude prior 
non-JAKi tsDMARD treatment.
Section 5.4 Screen 
Failures
Update to clarify implications of a 
positive repeat TB test.
Clarification

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Section # and Name
Description of Change
Brief Rationale
Section 6.1.1 Medical 
Devices
Description of pre-filled syringes 
(medical devices) used in the study.
To comply with new regulatory
requirements.
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 of tsDMARD restrictions and 
clarify duration of exclusion.
Clarification and reflect changes 
to exclusion 24.
Section 7.1.2
Other Stopping Criteria
Updates to permanent stopping criteria
including discontinuation due to VTE, PE 
and DVT.
Recent safety update for 
Tofacitinib per local label.
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 7.1.3.5 Renal 
Abnormalities
Addition of reassessment renal test
Risk mitigation
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 9.6 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.

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Section # and Name
Description of Change
Brief Rationale
Permit final assessment visit values of 
hsCRP & ESR to be provided to site.
These are baseline for LTE and 
are not individually unblinding.
Section 10.3: 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: 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.

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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.....................................................................31
2.3.3.
Overall Benefit: Risk Conclusion..................................................31
3.
OBJECTIVES AND ENDPOINTS...........................................................................32
4.
STUDY DESIGN ....................................................................................................34
4.1.
Overall Design ............................................................................................34
4.2.
Scientific Rationale for Study Design ..........................................................35
4.3.
Justification for Dose ..................................................................................36
4.4.
End of Study Definition ...............................................................................38
5.
STUDY POPULATION...........................................................................................38
5.1.
Inclusion Criteria.........................................................................................38
5.2.
Exclusion Criteria........................................................................................40
5.3.
Lifestyle Considerations..............................................................................43
5.3.1.
Dietary Restrictions......................................................................43
5.4.
Screen Failures...........................................................................................43
6.
STUDY INTERVENTION........................................................................................44
6.1.
Study Intervention(s) Administered .............................................................44
6.2.
Preparation/Handling/Storage/Accountability..............................................49
6.3.
Measures to Minimise Bias: Randomisation and Blinding ...........................50
6.4.
Study Intervention Compliance ...................................................................51
6.5.
Prior and Concomitant Therapies ...............................................................52
6.5.1.
Permitted Therapies ....................................................................52
6.5.2.
Prohibited Therapies....................................................................55
6.5.3.
Rescue Medicine .........................................................................57
6.6.
Dose Modification .......................................................................................57
6.6.1.
Dose Modification of Study Intervention.......................................57
6.6.2.
Dose Modification of Background Therapy...................................57
6.7.
Intervention after the End of the Study........................................................57
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................58
7.1.
Discontinuation of Study Intervention..........................................................58
7.1.1.
Liver Chemistry Stopping Criteria ................................................58

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7.1.1.1.
Study Intervention Restart or Rechallenge after
liver stopping criteria met............................................60
7.1.2.
Other Stopping Criteria ................................................................60
7.1.3.
Temporary Discontinuation ..........................................................61
7.1.3.1.
Respiratory Symptoms ...............................................61
7.1.3.2.
Serious and Opportunistic Infections ..........................61
7.1.3.3.
Haematologic Abnormalities.......................................61
7.1.3.4.
TB Reactivation..........................................................62
7.1.3.5.
Renal Abnormalities ...................................................62
7.2.
Participant Discontinuation/Withdrawal from the Study ...............................62
7.3.
Lost to Follow Up........................................................................................63
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................64
8.1.
Efficacy Assessments.................................................................................64
8.1.1.
Joint Assessments.......................................................................64
8.1.2.
Physician’s Global Assessment of Arthritis ..................................65
8.1.3.
Joint X-Rays ................................................................................65
8.1.4.
Patient Reported Outcomes.........................................................65
8.1.4.1.
Patient’s Assessment of Arthritis Pain ........................65
8.1.4.2.
Patient’s Global Assessment of Arthritis .....................65
8.1.4.3.
Health Assessment Questionnaire – Disability 
8.1.4.7.
Functional Assessment of Chronic Illness 
Therapy (FACIT)-Fatigue............................................66
8.1.4.8.
SF-36 Short Form Health Survey................................66
8.2.
Safety Assessments ...................................................................................67
8.2.1.
Dyspnoea Assessments ..............................................................67
8.2.2.
Physical Examinations.................................................................67
8.2.3.
Electrocardiograms......................................................................67
8.2.4.
Vital Signs....................................................................................68
8.2.5.
Clinical Safety Laboratory Assessments ......................................68
8.2.6.
Pulmonary Assessments .............................................................69
8.2.7.
Tuberculosis Monitoring...............................................................70
8.2.7.1.
Tuberculosis Status Definitions ..................................70
8.2.7.2.
Tuberculosis Testing ..................................................71
8.2.7.3.
Treatment of Latent TB During the Study ...................71
8.2.7.4.
Monitoring for TB Infection and Re-activation 
During the Study.........................................................71
8.2.8.
Hepatitis B Monitoring..................................................................72
8.2.8.1.
Risk of Reactivation in Participants Positive for 
Hepatitis B Core Antibody (HBcAb) ............................74
8.2.8.2.
Treatment of Participants Who Are HBcAb 
Positive and Who Develop Detectable HBV 
DNA Requiring Initiation of Antiviral Therapy..............74
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8.2.8.3.
Follow Up of Participants Treated With Anti-
viral Therapy...............................................................74
8.3.
Adverse Events and Serious Adverse Events.............................................74
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................75
8.3.2.
Method of Detecting AEs and SAEs.............................................75
8.3.3.
Follow-up of AEs and SAEs.........................................................75
8.3.4.
Regulatory Reporting Requirements for SAEs .............................76
8.3.5.
Pregnancy ...................................................................................76
8.3.6.
Cardiovascular and Death Events................................................76
8.3.7.
AEs of Special Interest.................................................................77
8.3.8.
Medical Device Deficiencies ........................................................78
8.3.8.1
Time Period for Detecting Medical Device 
Deficiencies................................................................78
8.3.8.2
Follow-up of Medical Device Deficiencies...................78
8.3.8.3
Prompt Reporting of Medical Device 
Deficiencies to Sponsor..............................................78
8.3.8.4
Regulatory Reporting Requirements for 
Medical Device Incidents............................................78
8.4.
Treatment of Overdose...............................................................................79
8.9.
Immunogenicity Assessments.....................................................................82
8.10.
Medical Resource Utilisation and Health Economics ..................................82
9.
STATISTICAL CONSIDERATIONS........................................................................83
9.1.
Statistical Hypotheses.................................................................................83
9.2.
Sample Size Determination ........................................................................83
9.3.
Sample Size Sensitivity...............................................................................84
9.4.
Populations for Analyses ............................................................................84
9.5.
Statistical Analyses.....................................................................................85
9.5.1.
Efficacy Analyses.........................................................................86
9.5.2.
Estimand Strategy .......................................................................86
9.5.3.
Safety Analyses...........................................................................87
9.6.
Interim Analyses .........................................................................................87
9.6.1.
Data Monitoring Committee (DMC)..............................................88
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................89
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................89
10.1.1.
Regulatory and Ethical Considerations ........................................89
10.1.2.
Financial Disclosure.....................................................................89
10.1.3.
Informed Consent Process ..........................................................90
10.1.4.
Data Protection............................................................................90
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10.1.5.
Committees Structure ..................................................................90
10.1.6.
Publication Policy.........................................................................91
10.1.7.
Dissemination of Clinical Study Data ...........................................91
10.1.8.
Data Quality Assurance ...............................................................92
10.1.9.
Source Documents ......................................................................93
10.1.10. Study and Site Closure ................................................................93
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................94
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................96
10.3.1.
Definition of AE............................................................................96
10.3.2.
Definition of SAE..........................................................................97
10.3.3.
Definition of Cardiovascular Events .............................................98
10.3.4.
Recording and Follow-Up of AE and SAE....................................99
10.3.5.
Reporting of SAE to GSK...........................................................100
10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................102
10.4.1.
Definitions:.................................................................................102
10.4.1.1.
Woman of Childbearing Potential (WOCBP).............102
10.4.1.2.
Women in the following categories are not 
considered WOCBP .................................................102
10.4.2.
Contraception Guidance: ...........................................................103
10.4.3.
Collection of Pregnancy Information: .........................................104
10.4.4.
Contraception Eligibility Criteria for Female and Male 
Participants................................................................................105
10.5.
Appendix 5: Genetics................................................................................107
10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ............................................................................................108
10.7.
Appendix 7: Summary of composite endpoints .........................................111
10.7.1.
ACR...........................................................................................111
10.7.2.
Disease Activity Score ...............................................................111
10.7.3.
Clinical Disease Activity Index (CDAI)........................................111
10.8.
Appendix 8: Hierarchy Options to Demonstrate Superiority or Non-
inferiority of Each Dose of GSK3196165 Versus Placebo or 
Tofacitinib, Respectively ...........................................................................113
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..........................................................................114
10.9.1.
Definition of Medical Device AE and ADE..................................114
10.9.2.
Definition of Medical Device SAE, SADE and USADE ...............114
10.9.3.
Definition of Device Deficiency...................................................115
10.9.4.
Recording and Follow-Up of Medical Device AE and/or 
SAE and Device Deficiencies.....................................................115
10.9.5.
Reporting of Medical Device SAEs ............................................117
10.9.6.
Reporting of SADEs...................................................................118
10.10. Appendix 10: Country-specific requirements.............................................119
10.11. Appendix 11: Abbreviations and Trademarks............................................120
10.12. Appendix 12: Protocol Amendment History...............................................124
11. REFERENCES.....................................................................................................125

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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A 52-week, phase 3, multicentre, randomised, double blind, efficacy and 
safety study, comparing GSK3196165 with placebo and with tofacitinib in combination 
with conventional synthetic DMARDs, in participants with moderately to severely active 
rheumatoid arthritis who have an inadequate response to conventional synthetic 
DMARDs or biologic DMARDs.
Short Title: Efficacy and safety of GSK3196165 versus placebo and tofacitinib in 
participants with moderately to severely active rheumatoid arthritis who have an 
inadequate response to conventional synthetic/biologic DMARDs.
Rationale: The aim of this study is to determine the efficacy and safety of GSK3196165, 
in combination with conventional synthetic disease-modifying antirheumatic drugs
(csDMARDs), for the treatment of adults with moderately to severely active rheumatoid 
arthritis (RA) who have had an inadequate response to csDMARDs or biologic DMARDs 
(bDMARDs).  Two doses of GSK3196165 (90 mg subcutaneous [SC] weekly and 150 
mg SC weekly) will be compared with placebo (to Week 12) and with tofacitinib (5 mg 
twice daily [BID]), an inhibitor of Janus Kinase (JAK) that is approved for the treatment 
of adults with moderately to severely active RA who have had an inadequate response to 
cs/bDMARDs.
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 csDMARDs and who have 
had an inadequate response to 
csDMARDs or bDMARDs.

Proportion of participants achieving 
ACR20 at Week 12
Secondary
To compare:

Efficacy of GSK3196165 at doses of 90 
mg and 150 mg weekly versus tofacitinib 
for the treatment of participants with 
moderately to severely active RA who 
are on a stable background of 
csDMARDs and who have had an 
inadequate response to csDMARDs or 
bDMARDs
Major Secondary Efficacy Endpoints
Week 12 versus placebo:

Proportion of participants achieving CDAI 
total score ≤10 (CDAI LDA).

Change from baseline in HAQ-DI.
Non-inferiority versus tofacitinib at Week 12: 

Proportion of participants achieving 
ACR20.

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Objectives
Endpoints
Other Secondary Efficacy Endpoints
Week 12 (vs. placebo and vs. tofacitinib), 
Week 24 and Week 52 (vs. tofacitinib): 
Proportion of participants 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.

No radiographic progression defined as a 
change from baseline in van der Heijde 
mTSS score of ≤0.5.
Change from baseline in: 

CDAI total score.

DAS28-CRP/DAS28-ESR.

van der Heijde mTSS.

Effect of GSK3196165 on Patient 
Reported Outcomes (PROs) versus 
placebo and the active comparator 
tofacitinib
Change from baseline at Week 12 (vs. 
placebo and vs. tofacitinib), Week 24 and 
Week 52 (vs. tofacitinib) 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 tofacitinib

Incidence of AEs, SAEs and AESIs.

Change from baseline in key laboratory 
parameters at Weeks 12, 24 and 52.

Proportion of participants with NCI-
CTCAE ≥Grade 3 haematological/clinical 
chemistry abnormalities.

To determine the immunogenic potential 
of GSK3196165
Safety Biomarker Endpoints

GM-CSF autoantibody concentrations.

Anti-GSK3196165 antibodies.
csDMARDs = conventional synthetic disease-modifying antirheumatic drugs; bDMARDs = biologic disease-
modifying antirheumatic drugs; ACR2050/70 = 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; mTSS = modified total sharp score; AEs = adverse events; SAEs = serious 
adverse events; AESIs = adverse events of special interest; NCI-CTCAE = National Cancer Institute-common 
terminology criteria for adverse events; SF-36 = short form-36; FACIT = functional assessment of chronic illness 
therapy; RA = rheumatoid arthritis; GM-CSF = granulocyte-macrophage colony stimulating factor.

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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 
cs/bDMARDs.  The study consists of a screening phase of up to 6 weeks, a 52-week 
treatment phase and an 8-week safety follow-up visit.  Upon successful screening, 
participants will be randomised to one of six intervention arms.  Participants who 
complete 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 3000-3600 participants will be screened to 
achieve between 1500 and 1800 randomly assigned to study intervention.  Approximately 
1500 evaluable participants are expected to be included in the primary analysis, of whom 
approximately 1350 are expected to complete the Week 12 visit.  When the approximate 
target of 1500 participants is reached, recruitment may continue up to a maximum of 
1800 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 in a ratio of 6:6:3:1:1:1 to GSK3196165 150 mg SC 
weekly, GSK3196165 90 mg SC weekly, tofacitinib capsules 5 mg BID or placebo (3 
arms) respectively, all in combination with 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 tofacitinib capsules 5 mg BID).  
Randomisation will be stratified by previously failed medication (csDMARD only, 1 
bDMARD or >1 bDMARD).
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 52 weeks, with an 8-week safety follow‑up period after the 
last SC dose of study intervention 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.

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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 SC 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 SC injection, the injection will then be 
performed at the site, after completion of PK sampling.

The study SC injection must be performed at site on Weeks 0, 1, 12 and 13, after 
completion of study assessments, and participants must be monitored for 1 hour 
post dose.
W 0
Tofacitinib BID + csDMARD
W24
Screening
GSK3196165 90mg weekly + csDMARD
End of study 
treatment
W52
Option to transition 
to LTE study 209564 
or exit after safety 
follow-up at 8w post 
last SC dose.
W-6
W24
Endpoint visit
& switch all 
Placebo to active
GSK3196165 150mg weekly + csDMARD
Placebo + csDMARD
Tofacitinib BID + csDMARD
Placebo + csDMARD
GSK3196165 90mg weekly+csDMARD
Placebo + csDMARD
GSK3196165 150mg weekly+csDMARD
csDMARD-IR 
(allowing 
bDMARD-IR)
W12

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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) Will be read centrally & imaging CRO will 
assess presence or absence of erosion(s).
4) Unless performed within previous 12 weeks. 
5) For women of child-bearing potential.
6) Fasting is not required, but 6hr fasting status 
at time of blood draw must be noted on 
requisition form.
7) 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 assessment7
Swollen (66) & Tender (68) joint count2
Hands and feet X-ray3
Chest X-ray (posteroanterior)4
Labs
Haematology, Chemistry, Urinalysis (dip stick)
HIV, TB, Hepatitis B & Hepatitis C screen
hsCRP
Serum pregnancy test5
Lipid profile6

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SoA – Treatment Period
Study intervention GSK3196165 
vs tofacitinib vs placebo (W0-11)
Study intervention GSK3196165 vs
Tofacitinib (W12-52)
Notes
Week
0
1
2
3
4
5-7
8
9-11
12
13 14-15 16 17-23 24 25-35 36 37-47 48 49-51
52
1. PROs should be completed first, before 
any other assessments, procedures or 
consultations, to avoid influencing 
participants’ perception.
2. ECGs should be performed before vital 
signs and blood draws, where possible.
3. Joint assessments should be performed by 
an independent assessor. Where possible 
the same assessor should perform all joint 
assessments for an individual participant.
4. Where possible, the same individual should 
perform all physician global assessments 
for an individual participant.
5. Will be centrally read & assessed for 
presence or absence of erosion(s).
6. Schedule X-ray between Weeks 48-51.
7. Fasting is not required, but 6hr fasting 
status at time of blood draw must be noted 
on requisition form.
8. For women of child-bearing potential.
9. ESR measured locally (using kit provided) 
by unblind site staff.
10. Day 1 sample includes anti-GM-CSF auto-
antibody and free GM-CSF analysis.
13. Monitor participants for 1 hour after SC 
dosing at site at Weeks 0, 1, 12 and 13. 
SC injection must be administered at site
when dosing on assessment visit days.
14. Dispense weekly for site administration; 
OR if available, dispense PFS in boxes of 
4, every 4 weeks, for home SC dosing.
15. Dispense 2 bottles of oral intervention 
every 4 weeks.
16. Minimum weekly review to Week 12, then 
every two weeks to Week 36, then every 
four weeks to Week 52. A phone call is 
acceptable if a site visit is not scheduled.
17. May be performed before Day 1 if required.
Assessment visit Day   
      Study activities1
Baseline Day 1
Day 8 (2d)
Day 15 (2d)
Day 22 (2d)
Day 29 (2d)
Day 57 (2d)
Primary endpoint 
Day 85 (3d)
Day 92 (3d)
Day 113 (5d)
Day 169 (7d)
Day 253 (7d)
Day 337 (7d)
End of treatment
Day 365 (7d) 
Randomisation
X
PROs1
Arthritis pain VAS, PtGA, HAQ-DI
X X
X
X
X
X
X
X
X
X
X
FACIT-Fatigue, SF-36, 
X
X
X
X
X
X
X
Assessments
12-lead ECG2 (S=single, T=triplicate)
S
T
Vital signs
X
X
X
X
X
X
X
X
X
X
Brief Physical Exam
X
X
X
X
X
X
X
X
Dyspnoea & Cough assessment, Lung 
Auscultation, Pulse Oximetry
X X
X
X
X
X
X
X
X
X
X
Pulmonary function tests (FEV1, FVC)
X17
Swollen (66) & Tender (68) joint count3
X X
X
X
X
X
X
X
X
X
X
Physician Global Assessment4
X X
X
X
X
X
X
X
X
X
X
Hands and Feet X-ray5
X
X
X
Chest x-ray (posteroanterior)
X6
Labs and blood draws
Haematology, Chemistry, Urinalysis
X
X
X
X
X
X
X
X
X
X
X
Lipid profile7
X
X
X7
Urine pregnancy test8
X
X
X
X
X
<------ Every 8 weeks ------>
X
hsCRP, ESR9
X X
X
X
X
X
X
X
X
X
X
RF, ACPA (anti-CCP)
X
TB testing
X
Pre-dose PK sample (& GMCSF complex)
X
X
X
X
X
X
X
X
Immunogenicity blood sampling
X10
X
X
X
X
X
X
X
Dose
Dispense: Weekly SC injection13,14
X13 X13 X
<---------- X14 ---------->
X13 X13
<------------------------ X14 ------------------------>
Dispense: BID oral intervention15
X
X
X
X
<------------- Every 4 weeks ----------->
SAE/AE review16
<------------------------------------------------------------- X ------------------------------------------------------------->
Concomitant medication review16
<------------------------------------------------------------- X ------------------------------------------------------------->
AE/conmed phone call if no site visit16
Weekly to Week 12
Every two weeks to W36, every four weeks to W52
CCI
CCI
CCI
CCI
CCI

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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 59 (Day 414 14 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 the Week 52 procedures* at the time of withdrawal from the study, or within 1 
week of withdrawal, and schedule a safety follow-up visit 8 weeks post last dose of SC 
administered study intervention.
*Note: A hands/feet x-ray should not be performed at early withdrawal if the 
participant’s last dose of study drug was prior to week 8, OR if a hands/feet x-ray has 
been carried out within 8 weeks of the early withdrawal date, as part of study 
assessments.

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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) 
(csDMARDs), for the treatment of adults with moderately to severely active RA who 
have had an inadequate response to csDMARDs or biologic DMARDs (bDMARDs).  
Two doses of GSK3196165 (90 mg subcutaneous [SC] weekly and 150 mg SC weekly) 
will be compared with placebo (to Week 12) and with tofacitinib (5 mg twice daily 
[BID]), an inhibitor of Janus Kinase (JAK) that is approved for the treatment of adults 
with moderately to severely active RA who have had an inadequate response to 
cs/bDMARDs.
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 then 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 now been completed.

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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 with 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 tofacitinib 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.

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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 
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.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
29 days after receiving a single dose of 1.5 mg/kg but 
recovered after treatment with antibiotics.
In Phase II completed studies, no significant 
infections or opportunistic infections were reported.

Known infection with human 
immunodeficiency virus (HIV) or positive test 
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:

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy

New latent or active TB infection

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 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 12 months.  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:
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.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Non-adverse minimal to mild foamy alveolar 
macrophage accumulation were noted in lungs of 
monkeys in the 13-week SC and 26-week IV 
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.

Pulmonary Safety Guidance Document 
containing pulmonary assessment and 
management algorithms will be provided to 
the investigator.  

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 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 
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 <1.0 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

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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):

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.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 
or clinical GSK3196165 program.
Eligibility Criteria (Section 5.2):
Exclusion of participants with:

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.

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.
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.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Clinical Data:
In clinical trials to date, there is no evidence that anti-
GSK3196165 antibodies affect GSK3196165 serum 
concentrations.
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 the plasma concentrations of specific CYP 
substrate drugs.
Cytokine modulators may reverse the apparent 
“inhibition” effect of the cytokines on CYP substrates, 
resulting in a “normalisation” of CYP activities. 
GSK3196165 is a cytokine modulator, so it has the 
potential to ‘normalise’ CYP expression from a 
suppressed state in patients with a pro-inflammatory 
disease (RA).
Clinical Data:
In a phase II study for GSK3196165, the ratio of 4β-
hydroxycholesterol to cholesterol was monitored as a 
biomarker predictive of change in CYP3A4 
activity. Based on the data, GSK3196165 showed no 
risk of alteration of CYP450 3A4 enzyme.

Information will be collected on concomitant 
warfarin use (e.g. INR results and any 
information related to warfarin dose).

Participants of reproductive potential using 
hormonal contraceptives, including oral, 
injections, implants, and patches are 
required to use a secondary method of 
contraception.

Participants receiving a concomitant 
CYP450 substrate with narrow therapeutic 
index (e.g. theophylline) should be monitored 
for signs in changes in drug exposure.
Study Procedures
Placebo
Due to ethical considerations, placebo control will 
only be allowed until Week 12, with all placebo 
participants being switched to one of the 3 active 
intervention arms (GSK3196165 90 mg, 150 mg or 
tofacitinib 5 mg BID) at their Week 12 visit. This will 

Participants randomised to the placebo arm 
will switch at Week 12 to 1 of 3 active 
intervention arms (Section 4.1, Section 6.3).

Randomisation ratio of 6:6:3:1:1:1 will 
minimise the number of participants in the 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
enable the study to generate controlled data in 
participants initially randomised to placebo.
placebo arm (Section 1.1, Section 4.1, 
Section 6.1, Section 6.3).

Although background therapy with 
csDMARDS is permitted, the participants 
have already failed these therapies.

Changes in background medication are not 
permitted unless required for safety and any 
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 approximately 450 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 52).

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.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
X-rays of the hands/feet
Structural joint damage evaluation by X–rays (van 
der Heijde modified total Sharp scores mTSS) is an 
established endpoint that is accepted in the US and 
EMA regulatory guidelines to demonstrate prevention 
of joint damage.  Tofacitinib prevents structural joint 
damage and this study aims to establish if structural 
bone damage does or does not deteriorate after 
treatment with GSK3196165.

Minimal procedures performed at Screening 
and 3 times post-randomisation (Weeks 12, 
24 and 52) to assess structural joint damage

Exposure to radiation from X-rays is far less 
than the exposure to natural radiation.

A repeat X-ray is not required for participants 
who are re-screened, only if re-screening is 
within 4 weeks of original screening x-ray.

Positioning devices will be used to minimise 
the risk of repeat X-ray
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 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.
Instructions For Use (IFU) on how to correctly handle 
and use the device is provided.
Other
Tofacitinib
Serious infections, malignancies and serious cases 
of thrombosis including pulmonary embolism, deep 
vein thrombosis and arterial thrombosis have been 
reported with tofacitinib.
See GSK3196165 above for serious infections, 
malignancies and laboratory changes.
Eligibility criteria (Section 5.2):
Exclusion of participants with

Any condition or contraindication as 
addressed in the local product information or 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
An interim analysis from a post marketing safety 
study evaluating tofacitinib 5 and 10 mg twice daily 
compared to TNF inhibitors in RA patients who were 
50 years of age and older and had at least one 
cardiovascular risk factor showed that tofacitinib in a 
dose dependent fashion was associated with:  1) 
higher all-cause mortality and 2) increased risk of 
VTE and serious infections. 
Tofacitinib should be used with caution in patients 
who have known risk factors for VTE, regardless of 
indication and dosage. 
There is a higher incidence of serious and fatal 
infections in patients over 65 years of age.  Patients 
should be monitored for signs of serious infection 
including active TB even if the initial latent 
tuberculosis test is negative.
Increases in lipid parameters including total 
cholesterol, low-density lipoprotein (LDL) cholesterol, 
and high-density lipoprotein (HDL) cholesterol have 
been noted in clinical studies with tofacitinib with 
maximal effects within 6 weeks. The effect of these 
lipid parameter elevations on cardiovascular 
morbidity and mortality has not been determined.
GI perforations have been reported in clinical studies 
with tofacitinib in RA, although the role of JAK 
inhibition in these events is not known. Tofacitinib 
local clinical practice for tofacitinib that would 
preclude the participant from participating in 
this protocol.  For all participants, 
investigators should carefully review 
potential risk factors related to VTE, 
including deep vein thrombosis (DVT) and 
pulmonary embolism (PE) and review the 
risk of infection in participants older than 65 
years of age.

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.

Rare hereditary problems of galactose 
intolerance, the Lapp lactase deficiency or 
glucose-galactose malabsorption.
Monitoring:
As above for GSK3196165

Laboratory tests to assess potential changes 
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).

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
should be used with caution in patients at increased 
risk of GI perforations.

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).

Participants with signs and symptoms of 
VTE should be promptly evaluated.

All potential events of GI perforation will be 
adjudicated.
Withdrawal:
In addition to the above for GSK3196165:

Temporarily discontinue study intervention in 
the event of serious or opportunistic infection 
or sepsis develops. Do not restart until 
infection has resolved.

Permanently discontinue study intervention 
in event of venous thromboembolism, 
including PE and DVT, requiring 
anticoagulation (Section 7.1.2).

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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 
tofacitinib, which is approved globally 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.

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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 csDMARDs and who have 
had an inadequate response to 
csDMARDs or bDMARDs.

Proportion of participants achieving 
ACR20 at Week 12.
Secondary
To compare:

Efficacy of GSK3196165 at doses of 90 
mg and 150 mg weekly versus tofacitinib 
for the treatment of participants with 
moderately to severely active RA who 
are on a stable background of 
csDMARDs and who have had an 
inadequate response to csDMARDs or 
bDMARDs
Major Secondary Efficacy Endpoints
Week 12 versus placebo:

Proportion of participants achieving CDAI 
total score ≤10 (CDAI LDA).

Change from baseline in HAQ-DI.
Non-inferiority versus tofacitinib at Week 12: 

Proportion of participants achieving 
ACR20.
Other Secondary Efficacy Endpoints
Week 12 (vs. placebo and vs. tofacitinib), 
Week 24 and Week 52 (vs. tofacitinib): 
Proportion of participants 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.

No radiographic progression defined as a 
change from baseline in van der Heijde 
mTSS score of ≤0.5.
Change from baseline in: 

CDAI total score.

DAS28-CRP/DAS28-ESR.

van der Heijde mTSS.

Effect of GSK3196165 on Patient 
Reported Outcomes (PROs) versus 
Change from baseline at Week 12 (vs. 
placebo and vs. tofacitinib), Week 24 and 
Week 52 (vs. tofacitinib) in:

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Objectives
Endpoints
placebo and the active comparator 
tofacitinib

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 tofacitinib

Incidence of AEs, SAEs and AESIs.

Change from baseline in key laboratory 
parameters at Weeks 12, 24 and 52.

Proportion of participants with NCI-
CTCAE ≥Grade 3 [NCI, 2017] 
haematological/clinical chemistry 
abnormalities.

To determine the immunogenic potential 
of GSK3196165
Safety Biomarker Endpoints

GM-CSF autoantibody concentrations.

Anti-GSK3196165 antibodies.
csDMARDs = conventional synthetic disease-modifying antirheumatic drugs; bDMARDs = biologic disease-modifying 
antirheumatic drugs; ACR2050/70 = 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 
CCI

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protein; EULAR = European league against rheumatism; ESR = erythrocyte sedimentation rate; mTSS = modified total 
sharp score; AEs = adverse events; SAEs = serious adverse events; AESIs = adverse events of special interest; NCI-
CTCAE = National Cancer Institute-common terminology criteria for adverse events; RNA = ribonucleic acid; SF-36 = 
short form-36; FACIT = functional assessment of chronic illness therapy; RA = rheumatoid arthritis; GM-CSF = 
granulocyte-macrophage colony stimulating factor
 
4.
STUDY DESIGN
4.1.
Overall Design

This is a Phase 3, randomised, multicentre, double-blind, parallel group, placebo 
and active comparator (tofacitinib) controlled study, with primary objective to 
assess the efficacy and safety of GSK3196165 in combination with csDMARDs 
in participants with moderately to severely active RA who have an inadequate 
response to csDMARDs or bDMARDs.

This is a 52-week study with the primary endpoint at Week 12 to coincide with 
the duration of placebo intervention.

This study includes X-rays of the hands and feet to assess radiographic 
progression of structural joint damage.

Upon successful screening, participants will be randomised to one of six 
intervention arms in a ratio of 6:6:3:1:1:1 to GSK3196165 150 mg SC weekly, 
GSK3196165 90 mg SC weekly, tofacitinib capsules 5 mg BID or placebo (three 
arms) respectively, all in combination with 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 tofacitinib capsules 5 mg BID).  Randomisation will be stratified by 
previously failed medication (csDMARD only, 1 bDMARD or >1 bDMARD).

To maintain the blind, all participants will receive capsules BID and weekly SC 
injections.  A double dummy approach will be followed with matching placebo 
capsules to tofacitinib, and either weekly SC dosing of GSK3196165 and placebo 
to GSK3196165 by an unblinded administrator or by the use of matching pre-
filled syringes of GSK3196165 and GSK3196165 placebo.

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.

Participants who successfully complete the 52 week treatment period may be 
eligible to transition into the long-term extension study 209564. Any participant 
who does not transition into Study 209564 will undergo a safety follow-up visit at 
8 weeks post last dose of SC study intervention.
CCI
CCI
CCI

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
Participants who transition into the long-term extension study 209564, will be 
instructed to take their last capsule of oral study intervention no later than 6pm
on the evening before their Week 52 visit.
4.2.
Scientific Rationale for Study Design
This study is a placebo-controlled, tofacitinib-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, tofacitinib, will also comply with 
recent guidelines from regulatory authorities and help further establish the safety and 
efficacy in comparison with an established targeted synthetic disease-modifying 
antirheumatic drug (tsDMARD).  In this study, participants will continue to receive a 
stable dose of csDMARD(s).  Participants are not allowed to receive any additional 
bDMARDs other than GSK3196165 or any other additional JAK inhibitor other than 
tofacitinib during the study, to mitigate the potential increased safety risks of 
administering a combination of bDMARDs, or a combination of a bDMARD and a JAK 
inhibitor, or a combination of JAK inhibitors.
Efficacy and safety of GSK3196165 will be compared with placebo (until Week 12) and 
an established active comparator (until Week 52), tofacitinib which is approved globally 
for the treatment of RA in participants inadequately controlled with csDMARDs, 
including MTX.
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 to demonstrate improvement in physical function as recommended 
in the US and EU regulatory guidelines.
The prevention of structural joint damage will be assessed via X-rays using change from 
baseline in van der Heijde modified total Sharp scores (mTSS), which is the only 
currently accepted approach by regulatory agencies.  Data from the placebo control and 
comparative data from tofacitinib, which has established efficacy in the prevention of 
structural damage, will also be analysed to ascertain how the effects with GSK3196165 
compare with tofacitinib.

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4.3.
Justification for Dose
GSK3196165
The GSK3196165 doses for this study have been selected based on pharmacokinetics 
(PK), efficacy, safety data, exposure-response and dose-response relationships for 
efficacy endpoints from the phase 2b dose finding BAROQUE (201755) study.
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 being investigated.  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 
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.

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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 a higher response rate.  
The predicted ACR20 response rate for the 90 mg and 150 mg weekly doses are 63% and 
69%, respectively.
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.

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Tofacitinib
The tofacitinib dose has been selected based on the recommended approved dose (5 mg 
BID) in the countries where the study is intended to be executed.
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 52 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]), with 
particular attention to the vaccination status of participants over 65 years of age.  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 
trigger a change of treatment), or the participant discontinued treatment due to 
intolerability or toxicity irrespective of treatment duration.
5.1.
Inclusion Criteria
A participant will be eligible for inclusion in this 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.

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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 at least 1 bone erosion present on hand/wrist or foot radiographs confirmed 
by central reading at screening.
7. 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).
f.
Iguratimod up to 50 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.
In addition, participants with prior bDMARD exposure: Prior exposure to one or 
more bDMARDs is permitted.  The prior bDMARD exposure may have been 
with or without combination with a csDMARD.  Prior bDMARD therapy must be 
discontinued before randomisation per the guidance in Section 6.5.2 Prohibited 
Therapies.

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WEIGHT
8. Body weight 40 kg 
SEX
9. Male or female participants are eligible to participate so long as they meet and agree 
to abide by the contraceptive criteria 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 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 
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.

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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 <60 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. 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, uncontrolled diabetes mellitus, 
VTE requiring anticoagulation), 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 
local clinical practice for tofacitinib that would preclude the participant from 
participating in this protocol. For all participants, investigators should carefully 
review potential risk factors related to VTE, including deep vein thrombosis (DVT) 
and pulmonary embolism (PE) and review the risk of infection in participants older 
than 65 years of age.  Refer to the risk table for tofacitinib in Section 2.3.1.
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 study intervention 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.

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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. 
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).
22. Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or 
glucose-galactose malabsorption.
PRIOR/CONCOMITANT THERAPY 
23. Any prior treatment antagonising GM-CSF or its receptor.
24. Any prior treatment with Janus kinase (JAK) inhibitor(s) (either experimental or 
approved) including, but not limited to tofacitinib, baricitinib, upadacitinib, filgotinib 
and peficitinib.
25. Participants who are expected to be non-compliant with restrictions on medications 
and vaccinations prior to the study, during the study or during the 8-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.
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
26. 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
27. Alanine transferase (ALT) or aspartate transaminase (AST) >1.5 x upper limit of 
normal (ULN).

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28. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
29. 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).
30. 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.
31. Haemoglobin ≤9 g/dL; white blood cell (WBC) count ≤3.0 x 109/L; platelet count 
≤100 x 109/L; absolute neutrophil count (ANC) <1.0 x 109/L; lymphocyte count 
≤0.75 x 109/L at screening.
32. Abnormal chest radiograph within 12 weeks of screening judged by the investigator 
as clinically-significant.
OTHER EXCLUSIONS
33. Pregnant or lactating, or women planning to become pregnant or initiating 
breastfeeding.
34. Current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or 
dependence within a year prior to Day 1. 
35. 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
5.3.1.
Dietary Restrictions
Participants must refrain from consumption of grapefruit and grapefruit juice from 5 days
before the start of study intervention until after the final assessment visit.
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 
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 the chest X-ray if performed within 12 

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weeks of the re-screening period, and hands and feet x-ray, if the original screening 
hands/feet x-ray was performed within 4 weeks of the re-screening period and passed 
central reading).
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, 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 <1.5 x 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:

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.

Study oral capsules should be taken twice daily (one in morning, one in evening).

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 

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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, participants may 
be permitted to receive some of their SC injections at home; in this case, the 
investigator should first ensure the participant (or caregiver) is able to correctly 
administer the injection from PFS.  PFS for home dosing will be dispensed every 
4 weeks as a 4-week supply.  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.

Participants who transition into the long-term extension study 209564, will 
receive their last weekly SC injection at Week 51 and will be instructed to take 
their last capsule of oral study intervention no later than 6pm on the evening 
before their Week 52 visit.
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.

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Table 1
Overview of Study Intervention
ARM Name
GSK3196165 
90 mg
GSK3196165
150 mg
Placebo*
Tofacitinib
Intervention Name
GSK3196165 (Approved 
Name not yet assigned)
GSK3196165 
(Approved Name not 
yet assigned)
Placebo to 
GSK3196165
Placebo to tofacitinib
Xeljanz
Type 
Biologic
Biologic
Placebo to Biologic
Placebo Drug
Drug
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)
Capsule (containing 
lactose)
Capsule (over-
encapsulated tablet)
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
Not applicable
5 mg
Dosage Level(s)
90 mg once-weekly
150 mg once weekly
Weekly injection
One capsule BID
5 mg BID (10 mg/day)
Route of 
Administration
SC injection
SC injection
SC injection
Oral
Oral
IMP and NIMP
IMP
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 by 
the Sponsor
Provided centrally by 
the Sponsor

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ARM Name
GSK3196165 
90 mg
GSK3196165
150 mg
Placebo*
Tofacitinib
provided centrally. 
PFS provided centrally 
by the Sponsor
Dosing instructions
Vials: withdraw 0.6 mL 
into a small syringe and 
dose immediately; 
discard remaining 
material.
PFS: Inject all
Vials: withdraw 1.0 mL 
into a small syringe 
and dose immediately; 
discard remaining
material.
PFS: Inject all
Withdraw 1.0 mL into 
a small syringe and 
dose immediately; 
discard remaining 
material.
PFS: Inject all
Instruct participant to 
take 1 capsule in the 
morning and 1 
capsule in the 
evening
Instruct participant to 
take 1 capsule in the 
morning and 1 
capsule in the 
evening
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
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 
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 
Study Intervention will 
be provided in a 
bottle containing 31 
capsules and labelled 
as required per 
country requirement
Study Intervention will 
be provided in a bottle 
containing 31 
capsules and labelled 
as required per 
country requirement

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ARM Name
GSK3196165 
90 mg
GSK3196165
150 mg
Placebo*
Tofacitinib
per country 
requirement
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
Not applicable
Xeljanz, tofacitinib, 
Jakvinus, Jaquinus,
CP-690,550
* 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; compatibility with commonly used syringes and needles 
has been demonstrated.

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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)
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 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 unblinded 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.

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 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.

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
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 6:6:3:1:1:1 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 oral capsules twice daily and once-weekly SC injections.  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.
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 
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, 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.
Dose modifications to the oral study intervention will not be permitted in this study as it 
will have the potential to unblind the treatment assignments.  For this reason, the 
eligibility criteria have been designed to exclude potential participants that may require a 

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dose reduction for safety reasons and any concomitant medications that may require a 
dose reduction will also be prohibited.
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 52.
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 
and compliance records.  Intervention start and stop dates, including dates for 
intervention delays will also be recorded in the CRF. 
Compliance with tofacitinib and matching placebo capsules will be assessed through 
querying the participant during the site visits and documented in the source documents.  
A record of the number of capsules dispensed to and taken by each participant must be 
maintained and reconciled with study intervention and compliance records.  Intervention 

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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.

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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 52
During 8-
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
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.
Permitted after Week 12
(Post week 12, the number 
of IA steroid injections 
should be limited to 2 
injections through Week 52, 
administration should not 
occur during the 4 weeks 
prior to Week 24 or Week 
52. The site(s) of injection 
must be recorded)
Permitted
Inhaled steroids, topical steroids or 
topical immunosuppressive agents 
(e.g., eye drops, creams)
Permitted
Permitted
Permitted

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Medications/Treatments
Restriction
Prior to study treatment 
period
During study treatment 
period
Day 1 to Week 52
During 8-
week follow-
up
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
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, Week 24 
and Week 52 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.

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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.
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 52
During 8-week 
follow-up
Treatments affecting GM-CSF pathway
Any treatment antagonising GM-CSF or 
its receptor
Prohibited
(Exclusion criterion)
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
Azathioprine alone or in combination 
with Methotrexate
Discontinue at least 4 
weeks prior to Day 1
Prohibited
No restriction
Tacrolimus
Not permitted as background medication
Discontinue at least 4 
weeks prior to Day 1
Prohibited
No restriction
Hydroxychloroquine, chloroquine, 
sulfasalazine, minocycline, 
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

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Medications/Treatments
Restriction
Prior to study treatment 
period
During study treatment 
period
Day 1 to Week 52
During 8-week 
follow-up
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
Etanercept (including its biosimilars).
Discontinue at least 4 
weeks prior to Day 1
Prohibited
Prohibited
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 , 
experimental or approved (e.g. 
tofacitinib, baricitinib, upadacitinib, 
filgotinib and peficitinib).
Prohibited
(Exclusion criterion)
Prohibited
(except study 
intervention)
Prohibited
Other (non-JAKi) tsDMARDs either 
experimental or approved.
Discontinue at least 4 
weeks or 5 half-lives, 
(whichever is longer) prior 
to Day 1.
Prohibited
Prohibited
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
Dose changes in oral corticosteroids 
≤10 mg/day prednisolone or equivalent
Prohibited 4 weeks prior 
to Day 1, and during 
screening if longer, 
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, and 
during screening if longer.
Prohibited (except for 
safety reasons)
No restriction
Other Medications
Potent inhibitors of Cytochrome P450 
3A4 (CYP3A4) (e.g., ketoconazole). 
One or more concomitant medications 
that result in both moderate inhibition of 
CYP3A4 and potent inhibition of 
CYP2C19 (e.g., fluconazole).
Potent CYP3A4 inducers (e.g., 
rifampin).
Refer to SRM for 
additional guidance
Prohibited
No restriction

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Medications/Treatments
Restriction
Prior to study treatment 
period
During study treatment 
period
Day 1 to Week 52
During 8-week 
follow-up
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]), with particular attention to the vaccination status of participants over 65 years of age. 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.
6.6.
Dose Modification
6.6.1.
Dose Modification of Study Intervention
Dose reduction of the SC and/or oral study interventions is not permitted in this study. 
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 52-week treatment period visit may have the option to 
transition into long term extension study 209564.  Exceptionally, participants who missed 
their final SC dose at Week 51 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 tofacitinib in this 

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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.
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 (oral capsules and SC injection).  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 to participate in long term extension study 209564.
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 algorithms.  Additionally, study 
intervention must be discontinued if there are any clinical signs/symptoms suggestive of 
hepatic decompensation such as ascites and hepatic encephalopathy.

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Algorithm A: Phase III-IV Liver Chemistry Stopping and Increased Monitoring 
Algorithm
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.
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
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≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5*

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Algorithm B: Phase III-IV Liver Chemistry Increased Monitoring Algorithm with 
Continued Therapy for ALT 3xULN but <8xULN
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.
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:

VTE, including PE and DVT, requiring anti-coagulation

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.
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
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≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5*

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
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.

Absolute neutrophil count (ANC) <0.5 x 109/L.

Lymphocyte count <0.5 x 109/L.

Severe renal impairment (eGFR <30 mL/min/1.73m2) and confirmed upon repeat 
testing.

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.
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.
Haematologic Abnormalities
Study intervention will be temporarily discontinued upon confirmatory (local) repeat test, 
for the following haematological abnormalities:

White blood cell (WBC) count <2.0 x 109/L.

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
ANC ≤1.0 x 109/L.

Lymphocyte count ≤0.75 x 109/L

Decrease in haemoglobin >2g/dL or haemoglobin <8.0g/dL. Dosing should be 
interrupted until haemoglobin values have normalised.
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).
7.1.3.5.
Renal Abnormalities
Study intervention will be temporarily discontinued for the following renal abnormality:

Moderate to severe renal impairment (eGFR ≥30 to <45 mL/min/1.73m2).
A repeat test must be performed locally and assessed within 7 days with additional 
sample(s) sent for central testing.  The medical monitor should be consulted if the repeat 
test is still abnormal and a further repeat test performed again within 7 days.  Study 
intervention can be restarted if renal function improves to ≥45 mL/min/1.73m2.
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 52 visit, as shown in 
the SoA (Section 1.3).  A safety follow-up visit should be scheduled at 8 weeks 
post last dose of study SC intervention.

The participant will be permanently discontinued both from the study intervention 
and withdrawn from the study at that time.

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.

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
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.

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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 450 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 

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personnel, and will not be permitted to review the participant’s medical records, the 
eCRF, nor any of the previous joint assessments.
The procedure for joint assessments is provided in the SRM.
8.1.2.
Physician’s Global Assessment of Arthritis
Investigators will complete a global assessment of RA disease activity using the 
physician global assessment item (PhGA), a visual analogue scale (VAS) with anchors 
“0” (
) to “100” (
), respectively.
8.1.3.
Joint X-Rays
Radiographic progression of structural joint damage will be assessed using X-rays of the 
hands and feet.  All X-rays will be read centrally by the imaging CRO and will be 
assessed for the presence or absence of erosion(s).  X-rays will be taken at screening to 
confirm eligibility.
8.1.4.
Patient Reported Outcomes
All patient reported outcomes (PROs) should be administered before any laboratory 
assessments and other procedures or consultations to avoid influencing the participants’ 
perception of their RA disease.
8.1.4.1.
Patient’s Assessment of Arthritis Pain
Participants will assess the severity of their arthritis pain over the past week, using a 100 
unit VAS, with anchors “0” (
) and “100” (
).
The results of this question will be used for the HAQ-DI, where the local version of 
HAQ-DI asks the same question.
8.1.4.2.
Patient’s Global Assessment of Arthritis
Participants will complete a global assessment of disease activity using the patient global 
assessment (PtGA) item, a VAS with anchors “0” (
) to “100” (
).
8.1.4.3.
Health Assessment Questionnaire – Disability Index (HAQ-DI)
The functional status of the participant will be assessed by means of the Disability Index 
of the Stanford Health Assessment Questionnaire (HAQ-DI).  This 20-question 
instrument assesses the degree of difficulty a person has in accomplishing tasks in eight 
functional areas [Fries, 1980]: dressing and grooming, arising, eating, walking, hygiene, 
reach, grip, and common daily activities.
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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8.1.4.7.
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue
The Functional Assessment of Chronic Illness Therapy (FACIT)-fatigue questionnaire is 
a validated patient-reported measure developed originally to assess fatigue in individuals 
with cancer.  The FACIT-fatigue has subsequently been used and validated in numerous 
chronic conditions, including RA.
8.1.4.8.
SF-36 Short Form Health Survey
Health-related quality of life (HRQL) will be assessed using the participant-completed 
Medical Outcomes Study (MOS) Short-Form 36 (SF-36) which is a generic health survey 
that contains 36 questions covering eight domains of health.  The SF-36 yields an eight-
scale profile of functional health and well-being scores as well as physical and mental 
component health summary scores.  The version 2, 1-week recall questionnaire will be 
used.
CCI
CCI
CCI

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8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
In the event that pulmonary follow-up criteria are triggered, all sites must have access to 
a pulmonologist (see Section 7.1.3.1 and Section 8.2.6).
8.2.1.
Dyspnoea Assessments
The dyspnoea scale grades the effect of breathlessness on daily activities and measures 
perceived respiratory disability.  The scale will be completed by the investigator in 
consultation with the participant.  Dyspnoea will be reported on a rating scale from 0 (
 
) through 4 (
).
8.2.2.
Physical Examinations

A complete physical examination (e.g. at the Screening visit) will include, at a 
minimum, assessments of the Skin, Cardiovascular, Respiratory, Gastrointestinal 
and Neurological systems.  Height and weight will also be measured and 
recorded.

A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.

All physical examinations will include monitoring for signs and symptoms of TB 
(see Section 8.2.7).
8.2.3.
Electrocardiograms

12-lead ECG measurements should be recorded pre-dose, and where possible 
before vital sign measurements and blood draws.

Participants should be in a quiet setting without distractions and rest in a supine 
position for at least 5 or 10 minutes before ECG collection.

Triplicate 12-lead ECG measurements will be obtained at screening with single 
ECG measurements obtained post-baseline as outlined in the SoA (see 
CCI
CCI
CCI

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Section 1.3) using an ECG machine that automatically calculates the heart rate 
and measures PR, QRS, QT, and QTc intervals.

At the screening visit where triplicate ECG are required, three individual ECG 
tracings should be obtained as closely as possible in succession, but no more than 
2 minutes apart.  The full set of triplicates should be completed in less than 
4 minutes.

ECG traces will be read locally.
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 8 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. 

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
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).
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 (or 
prior to Day 1) only 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 an increase (if present 
at baseline) in cough (CTC Grade ≥2) or dyspnoea (Grade ≥2), they must be questioned 
again (either by phone or during the site visit) on a weekly basis for 3 further consecutive 
weeks or until the 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 

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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).
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.

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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.
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.

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A QuantiFERON-TB Gold Plus test or a T.SPOT.TB test must be performed as part of 
the Week 48 assessment (see SoA in Section 1.3).  If a participant has a positive result at 
Week 48 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.
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.

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Figure 2
Monitoring of HBV DNA Levels in HBcAb Positive Participants
From the start of study intervention, HBV DNA levels will be assessed every 4 weeks to 
Week 24, then every 8 weeks to Week 40 and then every 12 weeks to Week 52.
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

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8.2.8.1.
Risk of Reactivation in Participants Positive for Hepatitis B Core 
Antibody (HBcAb)
Participants who are HBcAb positive, will be informed of the risk of reactivation and that 
if this occurs treatment with antiviral therapy, such as with nucleo(s)tide analogues such 
as entecavir or tenofovir, will be needed.
8.2.8.2.
Treatment of Participants Who Are HBcAb Positive and Who Develop 
Detectable HBV DNA Requiring Initiation of Antiviral Therapy
HBcAb positive participants who become positive for HBV DNA and require antiviral 
therapy must have study intervention discontinued.  The participant must also be referred 
to a hepatologist or infectious diseases expert so that treatment advice regarding whether 
to commence anti-viral therapy is received within 7 days of HBV DNA elevation being 
identified.  The participant should then be reviewed by the expert within 14 days of HBV 
DNA elevation being identified and managed as per local guidelines or under EASL or 
AASLD guidelines if none are available.
8.2.8.3.
Follow Up of Participants Treated With Anti-viral Therapy
All participants will be followed up within the study by the investigator in addition to 
local expert follow up.  After completion of the study, participants should be followed up 
as per local expert opinion based on guideline recommendations.
8.3.
Adverse Events and Serious Adverse Events

The definitions of an AE or SAE can be found in Appendix 3.

The investigator and any qualified designees are responsible for detecting, 
documenting, and reporting events that meet the definition of an AE or SAE and 
remain responsible for following up AEs that are serious, considered related to the 
study intervention or the study, or that caused the participant to discontinue the 
study intervention (see Section 7).

Participants will be assessed for cough or dyspnoea at selected visits as specified 
in the SoA (Section 1.3.  The investigator will complete the CTC cough scale if a 
cough is present and will record dyspnoea as per the dyspnoea scale.  Lung 
auscultation and pulse oximetry will also be performed at the visits specified in 
the SoA (Section 1.3).

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.

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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 52 
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 
form.

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.

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.

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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 SAEs) 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 
8 weeks after the last SC dose.

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 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.
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.

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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 GSK3196165 include:

Serious infections

Opportunistic infections

TB and TB reactivation

Neutropenia Grade 3 (<1.0 x 109/L)

Pulmonary alveolar proteinosis

Hypersensitivity reactions

Injection site reactions

Persistent cough (CTCAE Grade 2)

Persistent dyspnoea (dyspnoea scale Grade 2).

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8.3.8.
Medical Device Deficiencies
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.

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 

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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 tofacitinib greater than the dose used in this 
study, or used more frequently than permitted (GSK3196165 once-weekly, tofacitinib 
twice daily) will be considered an overdose.  It should be noted that the minimum 
permitted 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 tofacitinib.
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 SC 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.
CCI

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CCI
CCI
CCI
CCI

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CCI
CCI

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8.9.
Immunogenicity Assessments
Whole blood samples of approximately 6 mL will be collected from all participants and 
divided into suitable portions for immunogenicity assessments of anti-drug antibody 
(ADA) development.  Antibodies to GSK3196165 will be evaluated in serum samples 
collected from all participants according to the SoA (Section 1.3).  Serum samples should 
also be collected at the final visit from participants who discontinued study intervention 
or are withdrawn from the study.  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.
Serum samples will be screened for antibodies binding to GSK3196165 and the titre of 
confirmed positive samples will be reported.  Other analyses may be performed to verify 
the stability of antibodies to GSK3196165 and/or further characterise the immunogenicity 
of GSK3196165.  The serum sample collected at Day 1 will also be analysed for anti-
GM-CSF auto-antibodies and free GM-CSF levels.
The detection and characterisation of antibodies to GSK3196165 will be performed using 
validated assay methods by or under the supervision of the sponsor.  Antibodies may be 
further characterised and/or evaluated for their ability to neutralise the activity of the 
study intervention(s).  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.
8.10.
Medical Resource Utilisation and Health Economics
Medical Resource Utilisation and Health Economics parameters are not evaluated in this 
study.

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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 
csDMARD treatment (i.e. csDMARD-IR), as assessed by the proportion of participants 
achieving ACR20 response 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 achieving ACR20 response at Week 12.
9.2.
Sample Size Determination
Approximately 3000-3600 participants will be screened to achieve between 1500 and 
1800 randomly assigned to study intervention.  Approximately 1500 evaluable 
participants are expected to be included in the primary analysis, of whom approximately 
1350 are expected to complete the Week 12 visit.  When the approximate target of 1500 
participants is reached, recruitment may continue up to a maximum of 1800 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 placebo arm. 
The minimum sample size of 1500 will provide:

>99% power to detect a 25% difference between GSK3196165 and placebo in the 
ACR20 response at Week 12 (55% vs 30%) 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 7.2%

>99% power to detect a 20% difference between GSK3196165 and placebo in the 
CDAI-LDA response at Week 12 (37% vs 17%) based on a 2-sided significance 
level of 0.025 using a pooled z-test.  The least significant difference this sample 
size will detect is 7.2%

Approximately 82% power for the non-inferiority analysis of ACR20 response 
rate at Week 12 between GSK3196165 and tofacitinib groups, where a response 
rate of 60% in each group, a non-inferiority margin of 12% and a 1 sided 
significance level of 0.0125 using a pooled z-test are assumed.  The non-
inferiority margin was calculated using the FDA fixed margin approach [FDA, 
2016].  With this sample size, the difference in proportions between tofacitinib 
and GSK3196165 can be up to 3% in favour of tofacitinib and still conclude non-
inferiority.  In order to conclude superiority, the difference in proportions must be 
at least 8% in favour of GSK3196165.
The above sample size and power estimates were obtained from PASS version 12.0.2.

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9.3.
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 500 in the GSK3196165 arm 
and 250 on the placebo arm based on a 2-sided significance level of 0.05 using a pooled 
z-test are shown in Table 4.
Table 4
Power for ACR20 Response at Week 12 Under Varying Response 
Rates on GSK3196165 and Placebo
Placebo Response Rate
GSK3196165 Response Rate
50%
55%
60%
30%
>99%
>99%
>99%
35%
98%
>99%
>99%
40%
74%
97%
>99%
The power of the non-inferiority analysis will be affected by changes in the assumed 
response rate.  The effect on power under varying response rates on both tofacitinib and 
GSK3196165 assuming a fixed sample size of 500 in the GSK3196165 arm and 250 on 
the tofacitinib arm, and a fixed non-inferiority margin of 12% based on a 1 sided 
significance level of 0.0125 using a pooled z-test are shown in Table 5.
Table 5
Power for Non-Inferiority Analysis on ACR20 Response at Week 12 
Under Varying Response Rates on GSK3196165 and Tofacitinib
Tofacitinib Response Rate
GSK3196165 Response Rate
58%
60%
62%
58%
82%
92%
98%
60%
65%
82%
93%
62%
44%
66%
83%
9.4.
Populations for Analyses
For purposes of analyses, 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 
reporting to the regulatory agencies.

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Population
Description
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).
9.5.
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 1500 
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.
CDAI LDA at Week 12
3.
HAQ-DI 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 (150 mg) at a given endpoint can 
achieve significance only if the high dose at the prior endpoint is significant; the low dose 
(90 mg) 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 with placebo will be conducted 
using a 2-sided significance level of either 0.05 or 0.025.
Following all comparisons with placebo, assuming that the full sequence of endpoints 
meets the requirements for significance, the step down approach will be used for the non-
inferiority comparison with tofacitinib on the ACR20 endpoint using a 1-sided 
significance level of 0.0125.
A graphical presentation of the step-down procedure is provided in Appendix 8.

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9.5.1.
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.
Key 
Secondary
The proportion of participants achieving CDAI LDA response will be analysed 
using the same method as described for the primary endpoint, however this 
model will include fixed effects of intervention, visit, baseline CDAI Total 
Score, intervention-by-visit interaction and a random effect of participant.
The HAQ-DI 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.
Additional 
Secondary 
and 
Exploratory
Full details on all additional analyses will be described in the RAP.
9.5.2.
Estimand Strategy
The main intercurrent (post-randomisation) event anticipated to impact on the 
interpretation of the treatment effect for the primary objective is discontinuation of 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 study intervention.
4.
Population Level Summary: Comparisons of proportions between the active 
groups and placebo.

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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 discontinues 
study intervention but efficacy data continues to be collected, their data will be analysed 
as if they were still on the original randomised intervention.  If a participant discontinues 
study intervention and data does not continue to be collected or if missing data occurs 
while on study intervention, their missing data will be imputed using multiple imputation.  
Full details on the missing data techniques will be provided in the RAP.
Further details on any sensitivity estimators and supplementary estimands used to assess 
the primary objective and any estimands used to assess the secondary objectives will be 
provided in the RAP.
9.5.3.
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.
9.6.
Interim Analyses
The primary analysis will be conducted when the planned target of 1500 randomised 
participants has been reached. No interim analysis with respect to this population is 
planned. However, if at the time of reaching approximately 1500 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 1500 
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 1500 randomised participants, secondary analyses will be conducted upon 
completion of enrolment/follow-up for the entire study population, based on all 
randomised subjects.
CCI

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9.6.1.
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.

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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.

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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.

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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.

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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 minimise 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.

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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 Document 
Acknowledgement.
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

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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 6 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 

Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria.

Pregnancy testing (urine or serum as required by local regulations) for 
WOCBP should be conducted once every 4 weeks to Week 16 and then every 
8 weeks to Week 52 during intervention.

Pregnancy testing (urine or serum as required by local regulations) will also 
be conducted at the safety follow up visit.

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 6
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Haemoglobin
Haematocrit
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

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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 (FSH) 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), HBV 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.

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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 (haematology, 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. 

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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.

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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

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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 in lieu of completion of the 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 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 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.

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
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, 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 a 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.

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
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 
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 the SRM.

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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.

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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)

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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 can continue in the study and attend all clinic visits if she wishes.

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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 8 weeks after last dose of study SC 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 8 
weeks after the last dose of study SC 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 blinded 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

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
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).

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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.

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10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments
Phase 3-4 liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology 
Phase 3-4 liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN persists for 2 weeks
ALT 3xULN but <5xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN 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
Symptomatic
Any clinical signs/symptoms suggestive of hepatic decompensation such as 
ascites and hepatic encephalopathy
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study intervention

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
a 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)

If restart/rechallenge not allowed or not 
granted, permanently discontinue study 
intervention and continue participant in the 

Viral hepatitis serology4

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained less than 8 weeks
after last dose5

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin 2xULN

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study for any protocol specified follow up 
assessments
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 hrs

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 hrs 

Monitor participants weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

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 counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form (CRF) 
page
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 high 
performance liquid chromatography 
(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 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)   

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4.
Includes: Hepatitis A immunoglobulin M (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; cytomegalovirus 
IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot 
testing); and 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 SRM.
Phase 3-4 liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
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. 

Participant can continue study intervention

Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and <8xULN 
to ≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice 
monthly until liver chemistries normalise or return 
to within baseline.
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.

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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).

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
Swollen Joint Count (28).

Patient’s Global Assessment of Arthritis.

Physician’s Global Assessment of Arthritis.

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10.8.
Appendix 8: Hierarchy Options to Demonstrate Superiority 
or Non-inferiority of Each Dose of GSK3196165 Versus 
Placebo or Tofacitinib, Respectively

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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 

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of the event. It does not refer to an event, which hypothetically might have caused 
death, if it were more severe
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.

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
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.

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.

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
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 
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.

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
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.
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.

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10.10.
Appendix 10: Country-specific requirements
Not Applicable.

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10.11.
Appendix 11: Abbreviations and Trademarks
Abbreviations
AASLD
American Association for the Study of Liver Diseases
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
CTFG
Clinical Trial Facilitation Group
CTC
Common terminology criteria
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
DVT
Deep vein thrombosis
EASL
European Association for the Study of the Liver
EBV
Epstein Barr Virus
ECG
Electrocardiogram
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
CCI

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FSH
Follicle-stimulating hormone
FVC
Forced vital capacity
GCP
Good Clinical Practice
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
hsCRP
High sensitivity C-reactive protein
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
INH
Isoniazid
INR
International normalised ratio
IP
Investigational product
IR
Inadequate response
IRB
Institutional review board
IRT
Interactive Response Technology
ITT
Intent to Treat
IU
International units
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IVIG
Intravenous immunoglobulin
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

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mAb
Monoclonal antibody
MCV
Mean cell volume
MCH
Mean corpuscular haemoglobin
MCHC
Mean corpuscular haemoglobin concentration
MedDRA
Medical dictionary for regulatory activities
mg
Milligram
mL
Millilitre
MMP
Matrix metalloproteinase
MMRM
Mixed Model for Repeated Measures
MOS
Medical Outcomes Study
MS
Multiple sclerosis
MSDS
Material safety data sheet
mTSS
Modified Total Sharp Score
MTX
Methotrexate
NCEP
National Cholesterol Educational Program
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse 
Events
NOEL
No observed effect level
NRS
Numerical Rating Scale
NSAID
Non-steroidal anti-inflammatory drug
PAC
Pulmonary Adjudication Committee
PAP
Pulmonary alveolar proteinosis
PCP
Pneumocystis Pneumonia
PCR
Polymerase chain reaction
PD
Pharmacodynamic
PE
Pulmonary embolism
PFS
Prefilled syringe
PFT
Pulmonary function test
PP
Per Protocol
PRN
Pro re nata (as needed)
PtGA
Patient’s Global Assessment of Arthritis
PhGA
Physician’s Global Assessment of Arthritis
PK
Pharmacokinetics
RA
Rheumatoid arthritis
RAP
Reporting and analysis plan
RF
Rheumatoid factor
RNA
Ribonucleic acid
SC
Subcutaneous
SAE
Serious adverse event
SJC
Swollen joint count
SF-36
Short form (36)
SRM
Study Reference Manual
SRT
Safety Review Team
SSD
Safety Syringe Device
TB
Mycobacterium tuberculosis
CCI

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TE
Target engagement
TJC
Tender joint count
TNFα
Tumor necrosis factor alpha
tsDMARD
Targeted synthetic disease-modifying antirheumatic drug
TST
Tuberculin skin test
ULN
Upper limit of normal
VAS
Visual Analogue Scale
VTE
Venous thromboembolism
WOCBP
Woman of Childbearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
None
Jakvinus
Jaquinus
MedDRA
Prosorba
QuantiFERON
T.SPOT TB
Xeljanz
CCI

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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 8.1.4 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, Section 
2.3.1 Study risk table and
Section 5.4 Screen 
Failures
Correction, a baseline chest X-ray and 
hands/feet X-ray are required during 
rescreening (if not carried out recently), 
but a hands/feet x-ray is not required at 
early withdrawal, if carried out recently.
Correction of requirements.
Section 6.5.2 Prohibited 
therapies
Washout period for Marijuana corrected 
to “at least 4 weeks prior to Day 1.”
Correction.
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.

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11.
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