A Phase IIb, Double-Blind, Placebo-Controlled, Dose-Adaptive, Study of the Efficacy and Safety of GSK3196165 in Combination With Methotrexate Therapy, in Subjects With Active Moderate-Severe Rheumatoid Arthritis Despite Treatment With Methotrexate
Phase: PHASE2
Conditions: Arthritis, Rheumatoid
Sponsor: GlaxoSmithKline

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GlaxoSmithKline group of companies
201755
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TITLE PAGE
Division: Worldwide Development
Information Type: Clinical Protocol Amendment
Title:
A Phase IIb, Double-Blind, Placebo-Controlled, Dose-Adaptive,
Study of the Efficacy and Safety of GSK3196165 in 
Combination with Methotrexate Therapy, in Subjects with Active 
Moderate-Severe Rheumatoid Arthritis Despite Treatment with 
Methotrexate.
Compound Number:
GSK3196165
Development Phase:
IIB
Effective Date:
11-MAR-2016
Subject: Rheumatoid Arthritis, GSK3196165, DMARD-IR.
Protocol Amendment Number:  07
Author (s):
 
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD

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Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2014N210890_00
2014-DEC-12
Original
2014N210890_01
2015-FEB-27
Amendment 1
This amendment includes removal of the Medical Monitor Contact Information on the 
Sponsor Information page, missing assessments in Section 7.1, and removal of example 
PRO Questionnaires as Appendix 12.7.
2014N210890_02
2015-MAR-13
Amendment 2
This amendment includes revision of the study title on the Title page, clarification that 
actigraphy will only be at participating sites in Section 3, Section 7.2, Section 7.3, 
Section 7.10.5, Section 7.10.6, Appendix 12.7, minor revisions to placebo and co-
medications information in Section 6.1, changes to the guidance on dosing instructions in 
Section 6.1, and revisions of anchors for Global Assessment of Arthritis in Section 7.3.2.
2014N210890_03
2015-MAY-01
Amendment 3
This amendment includes removal of flow cytometry assessments from Section 3, 7.1 and 
Section 7.7, clarification of biomarkers in Section 3, corrections to neutropenia levels in 
Section 4.7.1, clarification of TB testing in Section 5.1 and Section 7.2, changes to
administration of MTX in Section 6.1 and Section 6.9.2, clarification of unblinded 
administrator in Section 6.5, compliance of MTX in Section 6.8, and corrected Routine 
Laboratory Assessments in Section 7.4.11 (Table 2).
2014N210890_04
2015-MAY-01
Amendment 4
This amendment includes removal of blank line in Section 7.1.
2014N210890_05
2015-OCT-20
Amendment 5
This amendment includes additional criteria for continuation or withdrawal in the study at 
Week 38 in Section 4.2 and Section 5.4, clarification that SoC is standard of care in 
Section 4.5, clarification of rescreening procedure in Section 5.3.1, Section 5.3.2.2, 
clarification of DLCO retesting in Section 5.3.2, addition of lipid measurements in Section
7.1 and Section 7.4.11 (Table 2), clarification of header version numbers and footnotes in 
Section 7.1, clarification of eligibility in Section 7.3.5, clarification of pregnancy in 
Section 7.4.7, additions to Appendix 12.1, revisions of Appendix 12.2 and Appendix 
12.5, and added Appendix 12.9 to track all protocol text changes.
2014N210890_06
2015-NOV-25
Amendment 6
This amendment includes clarification that the DLCO tests may be repeated twice within 
the screening period in Section 5.1, clarification that only Fridericia’s formula (QTcF) 
will be used in Section 5.2 and Section 5.4.2, clarification that the screening ECG test 
may be repeated once in Section 5.3.2.3, clarification of footnotes in Section 7.1, removal 
of biomarker IL-22 measurement in Section 7.7, and reinsertion of contraception 
guidance inadvertently deleted in Appendix 12.2 of previous Amendment 5.
2014N210890_07
2016-MAR-11
Amendment 7
This amendment includes correction of the example formula to calculate the EULAR 
good/moderate response at Week 12 and Week 36 in Section 4.2 and Section 6.4; 
confirmation of mandatory chest HRCT if DLCO ≥60% to <70% predicted in Section 5.1, 
Section 5.3.2.2, Section 7.1 and Section 7.4.1; update to IB document number and added
reference in Section 11.

P P D
P P D
P P D

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SPONSOR INFORMATION PAGE
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Sponsor Contact Address
GlaxoSmithKline Research & Development Limited
Iron Bridge Road 
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone:  
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee).  If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.
Regulatory Agency Identifying Number(s):
EudraCT number – 2014-003453-34
PPD

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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 201755

I confirm agreement to conduct the study in compliance with the protocol, as 
amended by this protocol amendment.

I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.

I agree to ensure that all associates, colleagues and employees assisting in the 
conduct of the study are informed about their obligations. Mechanisms are in place 
to ensure that site staff receives the appropriate information throughout the study.
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date

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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201755......................................................10
2.
INTRODUCTION....................................................................................................14
2.1.
Rationale ....................................................................................................14
2.1.1.
Rheumatoid Arthritis ....................................................................14
2.1.2.
GM-CSF and RA..........................................................................14
2.1.3.
GSK3196165...............................................................................15
2.1.4.
Clinical Data ................................................................................15
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................16
4.
STUDY DESIGN ....................................................................................................18
4.1.
Overall Design ............................................................................................18
4.2.
Treatment Arms and Duration.....................................................................19
4.3.
Study oversight and dose selection.............................................................20
4.4.
Type and Number of Subjects.....................................................................21
4.5.
Design Justification.....................................................................................21
4.6.
Dose Rationale ...........................................................................................22
4.6.1.
Dose Recommendation ...............................................................22
4.6.2.
Placebo control............................................................................24
4.6.3.
Methotrexate background ............................................................24
4.7.
Benefit:Risk Assessment ............................................................................25
4.7.1.
Risk Assessment .........................................................................25
4.7.2.
Benefit Assessment.....................................................................29
4.7.3.
Overall Benefit:Risk Conclusion...................................................29
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............30
5.1.
Inclusion Criteria.........................................................................................30
5.2.
Exclusion Criteria........................................................................................32
5.3.
Screening/Baseline Failures .......................................................................35
5.3.1.
Re-Screening...............................................................................35
5.3.2.
Re-Testing...................................................................................36
5.3.2.1.
Laboratory tests..........................................................36
5.3.2.2.
DLCO test .....................................................................36
5.3.2.3.
ECG test.....................................................................36
5.4.
Withdrawal/Stopping Criteria.......................................................................36
5.4.1.
Liver Chemistry Stopping Criteria ................................................37
5.4.1.1.
Liver Chemistry Stopping and Increased 
Monitoring Algorithm...................................................38
5.4.1.2.
Study Treatment Restart or Rechallenge....................38
5.4.2.
QTc Stopping Criteria ..................................................................38
5.5.
Treatment interruption.................................................................................39
5.5.1.
Respiratory Symptoms.................................................................39
5.5.2.
Hematologic abnormalities...........................................................39
5.6.
Subject and Study Completion....................................................................39
6.
STUDY TREATMENT ............................................................................................40
6.1.
Investigational Product and Other Study Treatment....................................40
6.2.
Treatment Assignment................................................................................42

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6.3.
Planned Dose Adjustments.........................................................................43
6.4.
Subject Specific Dose Adjustment Criteria..................................................43
6.5.
Blinding.......................................................................................................43
6.6.
Packaging and Labeling..............................................................................44
6.7.
Preparation/Handling/Storage/Accountability..............................................44
6.8.
Compliance with Study Treatment Administration.......................................45
6.9.
Treatment of Study Treatment Overdose....................................................45
6.9.1.
Overdose of GSK3196165...........................................................45
6.9.2.
Overdose of Methotrexate ...........................................................46
6.10.
Treatment after the End of the Study ..........................................................46
6.11.
Concomitant Medications and Non-Drug Therapies....................................46
6.11.1.
Permitted Medications and Non-Drug Therapies..........................47
6.11.1.1.
Corticosteroids ...........................................................47
6.11.1.1.1.
Oral Corticosteroids................................47
6.11.1.1.2.
NSAIDS..................................................47
6.11.1.2.
Analgesics..................................................................47
6.11.2.
DMARD/Biologic Rescue Medications .........................................47
6.11.3.
Prohibited Medications and Non-Drug Therapies.........................48
6.11.3.1.
Related to the Study...................................................48
6.11.3.2.
Related to Methotrexate .............................................48
6.11.3.3.
Complementary Therapies .........................................49
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................49
7.1.
Time and Events Table (Combination Treatment with GSK3196165 
and MTX)....................................................................................................50
7.2.
Screening and Critical Baseline Assessments ............................................54
7.3.
Efficacy.......................................................................................................55
7.3.1.
Joint assessments .......................................................................55
7.3.1.1.
Replaced or Fused Joints...........................................56
7.3.1.2.
Independent Joint Evaluator.......................................56
7.3.2.
Patient’s Assessment of Arthritis Pain..........................................56
7.3.3.
Patient’s Global Assessment of Arthritis ......................................56
7.3.4.
Physician’s Global Assessment of Arthritis ..................................56
7.3.5.
DAS Assessments.......................................................................56
7.3.6.
ACR Assessments.......................................................................57
7.4.
Safety .........................................................................................................57
7.4.1.
Screening visit(s) .........................................................................57
7.4.2.
Study visits ..................................................................................58
7.4.3.
Safety endpoints and other assessments.....................................58
7.4.4.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........58
7.4.4.1.
Time period and Frequency for collecting AE 
and SAE information...................................................59
7.4.4.2.
Method of Detecting AEs and SAEs ...........................59
7.4.4.3.
Follow-up of AEs and SAEs........................................59
7.4.4.4.
Cardiovascular and Death Events ..............................59
7.4.5.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs.........................................................60
7.4.6.
AEs of Special Interest.................................................................60
7.4.6.1.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................61
7.4.6.2.
Regulatory Reporting Requirements for SAEs............61
7.4.7.
Pregnancy ...................................................................................62

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7.4.8.
Physical Exams ...........................................................................62
7.4.9.
Vital Signs....................................................................................62
7.4.10.
Electrocardiogram (ECG).............................................................62
7.4.11.
Clinical Safety Laboratory Assessments ......................................63
7.4.12.
Pulmonary Assessments .............................................................64
7.5.
Pharmacokinetics .......................................................................................65
7.5.1.
Sample analysis...........................................................................65
7.6.
Immunogenicity...........................................................................................65
7.7.
Biomarker(s)/Pharmacodynamic Markers ...................................................66
7.8.
Novel Biomarkers .......................................................................................67
7.9.
Genetics .....................................................................................................68
7.10.
Value Evidence and Outcomes...................................................................68
7.10.1.
Health Assessment Questionnaire – Disability Index 
(HAQ-DI)......................................................................................68
7.10.2.
Brief Fatigue Inventory (BFI)........................................................68
7.10.3.
FACIT-Fatigue .............................................................................69
7.10.4.
SF-36 Short Form Health Survey.................................................69
7.10.5.
RA Symptom and Impact Diary PRO ...........................................69
7.10.6.
Exploratory Health Outcomes Assessment - Actigraphy ..............69
8.
DATA MANAGEMENT ...........................................................................................70
9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................71
9.1.
Hypotheses.................................................................................................71
9.2.
Study Design Considerations......................................................................71
9.2.1.
Sample Size Assumptions ...........................................................71
9.2.1.1.
Primary Analysis.........................................................71
9.2.1.2.
Dose Response Analysis............................................72
9.2.2.
Sample Size Sensitivity................................................................74
9.2.2.1.
Primary Analysis.........................................................74
9.2.2.2.
Dose Response Analysis............................................74
9.2.3.
Sample Size Re-estimation..........................................................75
9.3.
Data Analysis Considerations .....................................................................75
9.3.1.
Analysis Populations....................................................................75
9.3.2.
Analysis Data Sets.......................................................................75
9.3.3.
Interim Analyses ..........................................................................75
9.4.
Key Elements of Analysis Plan ...................................................................76
9.4.1.
Primary Analyses.........................................................................76
9.4.2.
Secondary Analyses ....................................................................76
9.4.3.
Other Analyses ............................................................................77
9.4.4.
Pharmacokinetic Analyses...........................................................77
9.4.4.1.
Pharmacodynamic Analyses ......................................78
9.4.4.2.
Pharmacokinetic/Pharmacodynamic Analyses ...........78
9.4.5.
Immunogenicity Analysis .............................................................78
9.4.6.
Novel Biomarker(s) Analyses.......................................................78
9.4.7.
RNA Transcriptome Analysis .......................................................79
9.4.8.
RNA Expression Analysis of a Subset of RNA Species................79
10. STUDY GOVERNANCE CONSIDERATIONS........................................................79
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............79
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................79

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10.3.
Quality Control (Study Monitoring) ..............................................................80
10.4.
Quality Assurance.......................................................................................80
10.5.
Study and Site Closure ...............................................................................81
10.6.
Records Retention......................................................................................81
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................82
10.8.
Review Committees....................................................................................82
10.8.1.
Data Review Committee (DRC) ...................................................82
11. REFERENCES.......................................................................................................84
12. APPENDICES........................................................................................................89
12.1.
Appendix 12.1 - Abbreviations and Trademarks..........................................89
12.2.
Appendix 12.2 - Contraception eligibility criteria for female and male 
subjects ......................................................................................................93
12.2.1.
Females.......................................................................................93
12.2.2.
Males...........................................................................................94
12.3.
Appendix 12.3 - Liver Safety Required Actions and Follow-up 
Assessments ..............................................................................................95
12.4.
Appendix 12.4 - Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events ............................98
12.4.1.
Definition of Adverse Events........................................................98
12.4.2.
Definition of Serious Adverse Events...........................................99
12.4.3.
Sentinel Events..........................................................................100
12.4.4.
Definition of Cardiovascular Events ...........................................101
12.4.5.
Recording of AEs and SAEs ......................................................101
12.4.6.
Evaluating AEs and SAEs..........................................................102
12.4.7.
Reporting of SAEs to GSK.........................................................103
12.5.
Appendix 12.5 - Collection of Pregnancy Information................................104
12.5.1.
Female subjects.........................................................................104
12.5.2.
Female partners of male subjects ..............................................104
12.6.
Appendix 12.6 - Genetic Research ...........................................................105
12.7.
Appendix 12.7 - Important Study Assessment Details & Study 
Specific Equipment...................................................................................108
12.8.
Appendix 12.8 - Country Specific Requirements.......................................110
12.9.
Appendix 12.9 - Protocol Changes............................................................111

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1.
PROTOCOL SYNOPSIS FOR STUDY 201755
Rationale
This study is designed to provide the data necessary to select the optimal effective and 
safe dose(s) of GSK3196165 to be carried forward into Phase 3 studies in subjects with 
rheumatoid arthritis (RA).
Objectives and Endpoints
Objectives
Endpoints
Primary

To assess the efficacy of GSK3196165

Proportion of subjects who achieve disease 
activity score for 28 different joints with CRP 
value (DAS28(CRP)) remission (DAS28 
<2.6) at Week 24.
Secondary
To assess

Dose-efficacy response of GSK3196165

Safety

Population pharmacokinetics

Pharmacodynamics

Novel biomarkers
O To examine the molecular profiles of
blood samples to identify factors that 
may influence biological and clinical 
responses to GSK3196165 and/or 
associated with the development or 
progression of RA or medically related 
conditions.
Major Secondary Efficacy Endpoints

Change from baseline in DAS28(CRP) at 
Week 12 (to support dose response 
evaluation).

Proportion of subjects achieving 
DAS28(CRP) remission at all assessment 
timepoints.

Change from baseline in DAS28(CRP) at all 
assessment timepoints.

Time to first DAS28(CRP) remission.

Proportion of subjects achieving categorical 
DAS28(CRP) response (moderate/good 
EULAR response) at all assessment 
timepoints.

ACR 20/50/70 response rates at all 
assessment timepoints.

Index- and Boolean-based ACR/EULAR 
remission rates, and CDAI remission rate at 
all assessment timepoints.

Change from baseline in SDAI and CDAI at 
all assessment timepoints.

Change from baseline in HAQ-DI score at 
all assessment timepoints.

Change from baseline in pain score at all 
assessment timepoints.

Change from baseline in physical and 
mental component scores and in domain 
scores of SF-36 at all assessment 
timepoints.

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Objectives
Endpoints

Change from baseline in FACIT-Fatigue at 
all assessment timepoints.

Change from baseline in BFI Question 3 at 
all assessment timepoints.
Note: For composite endpoints, e.g., 
DAS28(CRP), ACR Response, etc., each 
component of the assessment will also be 
reported.  Results over time, reflecting all 
assessment time points, will also be reported 
(e.g., graphically, as well as in Tables and 
Listings).
Major Secondary Safety Endpoints

Incidence of adverse events and serious 
adverse events.

Incidence of infections.

Incidence of pulmonary events.
Overall Design
This is a randomised, Phase IIb, dose-adaptive, multicentre, double-blind, parallel group, 
placebo-controlled study with the primary objective to assess the efficacy of 
GSK3196165, in combination with methotrexate (MTX), in subjects with active 
moderate-severe RA despite treatment with MTX.

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Study design:
Treatment Arms and Duration

Screening period up to four weeks, then 52 week combination dosing with rescue for 
subjects with insufficient response at Week 12 and Week 24, with a 12 week follow-
up visit after the last dose.

Five doses (22.5 mg, 45 mg, 90 mg, 135 mg and 180 mg) of GSK3196165 vs 
placebo given weekly for first five weeks, then every other week thereafter until 
Week 50.
Type and Number of Subjects

Approximately 210 subjects with active moderate-severe rheumatoid arthritis despite 
treatment with methotrexate will be randomized.
Analysis

The primary endpoint of the study is to evaluate the proportion of subjects that 
achieve DAS28(CRP) remission (DAS28 <2.6) following 24 weeks of treatment 
with GSK3196165 or matching placebo in adult subjects on concomitant MTX 
therapy.

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
The study will test the null hypothesis that there is no difference between any dose of 
GSK3196165 and placebo in the proportion of subjects with remission at week 24 
versus the alternative hypothesis that at least one of the GSK3196165 dose groups 
differs from placebo in the proportion of subjects with DAS28(CRP) remission at 
Week 24.

A key secondary objective is to evaluate the clinical dose response following 12 
weeks of GSK3196165 treatment at 5 separate doses or placebo in adult subjects on 
concomitant MTX therapy.

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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 the treatment of 
rheumatoid arthritis (RA).
2.1.
Rationale
This study is designed to provide the data necessary to select the optimal effective and 
safe dose(s) of GSK3196165 to be carried forward into Phase 3 studies in subjects with 
rheumatoid arthritis.
2.1.1.
Rheumatoid Arthritis
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.
Disease-modifying antirheumatic drugs (DMARDs) are the cornerstone of RA treatment 
throughout all stages of disease, and have been demonstrated to maintain or improve 
physical function and retard radiographic damage.  This wide class of drugs includes 
conventional DMARDs, of which methotrexate (MTX) is the gold standard, and 
biological DMARDs which target cytokines (e.g. tumor necrosis factor α [TNFα], 
interleukin 6 [IL-6]), B-cells or T-cells.  However, 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.
Intensive treatment (i.e. with a biologic drug) early in the disease course of RA, provides 
an opportunity to induce a sustained remission that can be maintained on conventional 
DMARDs alone thereby limiting the overall exposure to biological treatments during a 
patient’s lifetime, which should translate into a better overall safety profile.
2.1.2.
GM-CSF and RA
GM-CSF, in combination with other inflammatory stimuli, can activate macrophages 
[Fleetwood, 2007; Mantovani, 2002], which produce a range of inflammatory cytokines, 
such as TNFα, IL-6, IL-1, IL-12p70 and IL-23 and various chemokines, and can also 
express class II MHC and present antigen to T cells, further contributing to the 
inflammatory process.
Accumulating evidence suggests that the GM-CSF pathway may play a central role in the 
pathogenesis of RA, via the activation and differentiation of neutrophils and macrophages 
[Cornish, 2009].  GM-CSF induces the proliferation and activation of macrophage 
lineage cells leading to strongly increased production of key proinflammatory cytokines 
(including TNF, IL-6, and IL-1), chemokines and matrix degrading proteases 
[Fleetwood, 2007; Gasson, 1991; Hamilton, 2004; Hamilton, 2013; Hart, 1991; 
Mantovani, 2007].  GM-CSF also serves as a differentiation factor for dendritic cells and 
induces upregulation of human lymphocyte antigen (HLA) class II on antigen presenting 
cells, which in turn will activate CD4+ T cells.  In addition, GM-CSF is a strong chemo-
attractant factor for neutrophils and induces the release of activated oxygen species from 

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neutrophils, which can directly damage cartilage structure [Dang, 1999; Gomez-
Cambronero, 2003].
GM-CSF and its receptors are found abundantly in the synovial fluid, synovial tissue and 
plasma of patients with RA [Bell, 1995; Davis, 2010; Fiehn, 1992].  GM-CSF also 
contributes to osteoclastic bone resorption and subsequent joint damage [Nakano, 2007].  
Synovial CD68+ macrophages from RA patients correlate with disease activity scores and 
are potential biomarkers for treatment response [Bresnihan, 2009; Haringman, 2005].  
The number of macrophages in synovial tissue is correlated with radiographic 
progression [Michelson, 1994; Mulherin, 1996].  In mouse models of collagen-induced 
arthritis (CIA), GM-CSF knockout or anti-GM-CSF treatment reduced disease activity 
and prevented progression of established arthritis and, furthermore administration of 
recombinant GM-CSF led to exacerbation of arthritis [Campbell, 1998; Cook, 2001; 
Plater-Zyberk, 2007; Yang, 2001].
Taken together, pre-clinical and clinical data suggest that GM-CSF is a key mediator of 
inflammatory and immune disorders and central to RA pathogenesis, providing a strong 
rationale for considering it as a candidate for therapeutic intervention.  Blocking GM-
CSF should interfere with several pathophysiological pathways and significantly reduce 
inflammation by inhibiting activation of inflammatory cells and by blocking the 
chemotaxis of such cells into the joint thus inhibiting bone and cartilage destruction.
2.1.3.
GSK3196165
GSK3196165 is a high-affinity recombinant human monoclonal antibody (mAb that 
binds specifically to human GM-CSF and neutralises its biological function by blocking 
the interaction of GM-CSF with its cell surface receptor [Steidl, 2008].
Detailed information relating to non-clinical pharmacology, safety pharmacology, 
pharmacokinetics and metabolism, toxicology and other pre-clinical and clinical data 
with GSK3196165 can be found in the GSK3196165 Investigator’s Brochure (IB) [GSK 
Document Number 2014N190256_01].
2.1.4.
Clinical Data
GSK3196165 has been studied in 4 clinical trials to date as summarised in the IB GSK 
Document Number [2014N190256_01].
MSC-1001 was a Phase1b/2a multi-center, randomized, sequential group, double-blind, 
placebo-controlled study which evaluated the safety, preliminary efficacy, and PK of 
multiple doses of GSK3195165 in subjects (N=96) with active, mild-moderate RA 
[Behrens, 2014].  Previous treatment with biological/immunosuppressive therapies other 
than cell-depleting agents was allowed with an adequate washout period.  Eligible 
patients had active moderate RA (1987 American College of Rheumatology [ACR] RA 
classification criteria, 3 swollen and ≥3 tender joints), an elevated CRP >5 mg/L (in 
sero-negative subjects) or CRP >2 mg/L (in RF and/or ACPA sero-positive subjects) and 
DAS28 score ≤5.1.  Subjects received 4 IV weekly doses of GSK3195165 at 0.3 mg/kg, 
1.0 mg/kg or 1.5 mg/kg or placebo in addition to stable concomitant treatment with 
DMARDs or low doses of oral corticosteroids.  Rapid and significant reductions in 
disease activity (as measured by DAS28) were observed with the 1.0 mg/kg and 1.5 
mg/kg doses.  Greater reduction in disease activity to Week 4 was observed with 1.0 
mg/kg than 1.5 mg/kg in this dose-escalation cohort study.  A significant reduction in 

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mean DAS28 was not observed in the 0.3 mg/kg group.  Other disease activity measures 
(e.g., ACR response) and patient-reported outcomes were consistent with the results for 
DAS28.  GSK3196165 was generally safe and well-tolerated in this study.  Treatment 
emergent adverse events (AEs) in the GSK3195165 groups were mild or moderate in 
intensity and generally reported at frequencies similar to those in the placebo group.  
Infections were the most commonly reported AEs and occurred in 26.1% and 29.6% of 
GSK3196165 and placebo subjects, respectively.  There was a numerical imbalance in 
cough (0/27 placebo, 3/69 active).  There were no apparent trends in PFTs or DLCO
changes.  In two cases, AEs were classified as serious because of hospitalization: 
paronychia in a placebo subject and pleurisy (which responded to antibiotics and 
therefore may have had an infectious etiology) in a GSK3195165 0.3 mg/kg subject.  
Both patients recovered.
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To assess the efficacy of GSK3196165

Proportion of subjects who achieve 
DAS28(CRP) remission (DAS28(CRP) 
<2.6) at Week 24.
Secondary
To assess

Dose-efficacy response of GSK3196165

Safety

Population pharmacokinetics

Pharmacodynamics

Novel biomarkers
o
To examine the molecular profiles of
blood samples to identify factors that 
may influence biological and clinical 
responses to GSK3196165 and/or 
associated with the development or 
progression of RA or medically related 
conditions.
Major Secondary Efficacy Endpoints

Change from baseline in DAS28(CRP) at 
Week 12 (to support dose response 
evaluation).

Proportion of subjects achieving 
DAS28(CRP) remission at all assessment 
timepoints.

Change from baseline in DAS28(CRP) at all 
assessment timepoints.

Time to first DAS28(CRP) remission.

Proportion of subjects achieving categorical 
DAS28(CRP) response (moderate/good 
EULAR response) at all assessment 
timepoints.

ACR 20/50/70 response rates at all 
assessment timepoints.

Index- and Boolean-based ACR/EULAR 
remission rates, and CDAI remission rate at 
all assessment timepoints.

Change from baseline in SDAI and CDAI at 
all assessment timepoints.

Change from baseline in HAQ-DI score at 
all assessment timepoints.

Change from baseline in pain score at all 
assessment timepoints.

Change from baseline in physical and 

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Objectives
Endpoints
mental component scores and in domain 
scores of SF-36 at all assessment 
timepoints.

Change from baseline in FACIT-Fatigue at 
all assessment timepoints.

Change from baseline in BFI Question 3 at 
all assessment timepoints.
Note: For composite endpoints, e.g., 
DAS28(CRP), ACR Response, etc., each 
component of the assessment will also be 
reported.  Results over time, reflecting all 
assessment time points, will also be reported 
(e.g., graphically, as well as in Tables and 
Listings).
Major Secondary Safety Endpoints

Incidence of adverse events and serious 
adverse events.

Incidence of infections.

Incidence of pulmonary events.
Exploratory
Efficacy Endpoints

Time to first sustained (≥24 continuous weeks) DAS28(CRP) remission.

Proportion of subjects achieving sustained (≥24 continuous weeks) DAS28(CRP) remission.

Proportion of subjects achieving Major Clinical Response (proportion of subjects achieving 
ACR70 for 24 continuous weeks).

Time to sustained (24 weeks) discontinuation of all systemic corticosteroids administered for 
RA.

DAS28(ESR) scores/responses at all assessment timepoints.
Pharmacokinetic/Pharmacodynamic Endpoints

GSK3196165 pharmacokinetic parameters derived from serum concentration using sparse 
sampling.

Pharmacodynamic biomarkers to assess target engagement (e.g., serum concentration of free 
GM-CSF, GM-CSF-GSK3196165 complex).

Pharmacodynamic biomarkers which may be predictive of response to GSK3196165 (e.g. may 
include, but not limited to, 14-3-3η, MRP8/14, MMP-3, SAA).

Pharmacodynamic biomarkers to assess response to GSK3196165  (e.g. may include, but not 
limited to, IL-6, IL-1β, TNFα, IL-17F, CCL17/Thymus and activation regulated cytokine).
Safety Biomarkers

Serum biomarkers which may be indicative of lung damage (e.g. KL-6, LDH, SP-D, 
cholestenoic acid).

Plasma biomarkers predictive of change in CYP3A4 activity.

Baseline concentrations of GM-CSF autoantibodies.

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
Immunogenicity.
Patient-Reported Outcomes

Change over time and change from baseline in RA Symptom and Impact Diary measures.

Change from baseline in BFI (Question 3) at Weeks 12, 24 and 52.
Actigraphy substudy at participating sites
To explore how actigraphy measurements of physical activity correlate to disease activity, the 
following measures will be explored as change over time and change from baseline:

Inter- and intra-daily measures of physical activity including but not limited to:
o
Time spent sedentary (sitting and lying), time spent active (walking and standing), total 
activity score (function of duration and intensity of activity), number and duration of 
continuous walking periods.
o
Duration of morning stiffness.

Measures of sleep quality including but not be limited to:
o
Time lying, number of movement episodes, sleep efficiency (function of % of movement 
time and total % of lying time) and fragmentation index (function of movement time % and 
number of movement episodes).

RA Symptom and Impact Diary.
4.
STUDY DESIGN
4.1.
Overall Design
This is a randomised, Phase IIb, dose-adaptive, multicentre, double-blind, parallel group, 
placebo-controlled study with the primary objective to define the optimal therapeutic 
dose(s) of GSK3196165, in combination with MTX, in subjects with active moderate-
severe RA despite treatment with MTX.
Approximately 210 subjects will be randomised into the study, following a screening 
period of up to four weeks.  The total treatment period is up to 52 weeks, with a 12-week 
follow-up period after the last dose (Week 50).
In order to facilitate a sub-analysis of subjects with early RA (who may have greater 
benefit of treatment [Jones, 2010; Yazici, 2011]), the study aims to recruit up to 
approximately 40% of subjects with RA disease duration of <2 years, however the actual 
proportion of subjects required will be assessed throughout the study.

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The study schematic is as shown below.
Study design - 52 week combination dosing with dose escalation for subjects with 
insufficient response at Week 12 and Week 24, with a 12-week follow-up visit after the 
last dose (Week 50):
4.2.
Treatment Arms and Duration
In the “dose selection” component of the study, subjects will be randomised (1:1:1:1:1:1) 
to placebo or one of five subcutaneous GSK3196165 doses, in combination with MTX (at 
a dose between 15-25 mg previously received for at least 12 weeks, with a stable and 
tolerated dose and route of administration for ≥4 weeks).
Treatment with GSK3196165 will be given as a single subcutaneous (SC) injection by an 
unblinded administrator (shielded to subjects) weekly for 5 injections (Days 1, 8, 15, 22, 
29), then EOW thereafter beginning at Day 43 (Week 6).
GSK3196165/placebo must be administered on the same day each week ±1 day for the 
first 5 weekly doses.  Following this GSK3196165/placebo must be administered on the 
same day EOW ±3 days.

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After the Day 85 (Week 12) administration:

“Escape therapy” is provided for all subjects not on the 180 mg dose:

Subjects in the placebo, 22.5 mg, 45 mg, 90 mg and 135 mg arms will be 
escalated in a double-blind fashion to the 180 mg (or the highest remaining) 
dose at Week 14 if they have failed to achieve EULAR good/moderate 
response* at Week 12.
*EULAR good or moderate response
Week 12
DAS28(CRP)
DAS28(CRP) improvement from baseline
>1.2
>0.6 and ≤1.2
≤0.6
≤3.2
Good response
Moderate response
No response
>3.2 and ≤5.1
Moderate response
Moderate response
No response
>5.1
Moderate response
No response
No response
Source: [Fransen, 2005]

Subjects in these groups who do not meet this criterion and therefore do not 
escalate therapy at Week 14 have another opportunity for “escape” at Week 
24 with escalation in a double-blind fashion to the 180 mg (or the highest 
remaining) dose at Week 26 if their DAS28(CRP) score at this timepoint is 
>3.2.
This escape requirement is based on EULAR guidance [Smolen, 2014] and a review of 
response to MTX in randomised clinical studies [Boers, 2010].
Any subject that does not achieve EULAR good/moderate response** at Week 36 will 
not be dosed at Week 38, and will be withdrawn from the study.
**EULAR good or moderate response
Week 36
DAS28(CRP)
DAS28(CRP) improvement from baseline
>1.2
>0.6 and ≤1.2
≤0.6
≤3.2
Good response
Moderate response
No response
>3.2 and ≤5.1
Moderate response
Moderate response
No response
>5.1
Moderate response
No response
No response
Source: [Fransen, 2005]
4.3.
Study oversight and dose selection
A Data Review Committee (DRC) consisting of external rheumatology, infectious 
disease and respiratory experts, and GSK study team members that have no involvement 
in the acquisition of the data or direct contact with sites, will review ongoing unblinded 
safety data from the study and unblinded efficacy data at the interim analyses.  The first 
DRC review of safety data will be conducted after approximately 10 subjects per arm 
have completed 5 weeks of treatment, and subsequent reviews will take place 
approximately every 12 weeks thereafter until the end of the study.  The decision to stop 
the study or randomisation to specific arms will be made by the DRC.

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Interim analyses will be performed to assess futility and the dose-efficacy relationship 
once appropriate data are available.  Based on these interim analyses, the overall efficacy 
and the dose-response model will be defined and the effective therapeutic dose(s) of 
GSK3196165 selected.  New subjects will be randomised to the dose(s) identified, which 
will be from the dose range already studied, with the maximum dose not exceeding 180 
mg.  If there is no evidence of efficacy, the study could also be stopped for futility.
There will be no pause in recruitment whilst the review of safety data or interim analyses 
are conducted.
Once the effective therapeutic dose(s) have been selected at the interim analyses, 
treatment allocation could be adapted so that randomisation is stopped to the ineffective 
doses and future subjects are randomised to only the effective dose(s) and placebo.  
Subjects already in the study will remain on the arm to which they were randomised.  
There is a rescue option for all subjects, whereby the subjects can be escalated to the 
highest remaining dose for the remainder of the study.  The randomisation ratio will be 
1:1:1:1:1:1 across the original 6 arms of the study (i.e., n=35 in each dosing group).  
However, due to the re-allocation of subjects once the effective dose(s) are known, it is 
likely that at the end of the study there will be more subjects in the effective dose groups 
and placebo.
4.4.
Type and Number of Subjects
Approximately 350 subjects with active moderate-severe RA despite treatment with 
MTX will be screened (subjects can be rescreened once) to achieve 210 randomised.  
Rescreening criteria are listed in the Study Reference Manual (SRM).
4.5.
Design Justification
The overall study design is well established to assess the efficacy of a novel mAb, in 
combination with MTX, in subjects with active moderate-severe RA despite treatment 
with MTX.  A key feature of the study is that interim analyses will be performed to assess 
futility and the dose-efficacy relationship once appropriate data are available.  In 
addition, once the effective therapeutic dose(s) have been selected, treatment allocation 
may be adapted so that randomisation is stopped to the ineffective doses and future 
subjects are randomised to only the effective dose(s) and placebo.
Escape therapy is provided for subjects who have an inadequate response to treatment 
assessed at 12- and 24 weeks is aligned with routine standard of care.  In addition, there 
is a mandatory withdrawal point at Week 38 to ensure that subjects do not experience 
prolonged exposure to an inadequate therapy.
The beneficial effect of sustained (i.e. ≥24 consecutive weeks) remission in comparison 
has been documented in numerous studies, in terms of reduction in radiographic 
progression as well as halting loss of physical function (Emery, 2014; Keystone, 2014; 
van Ingen, 2014), and  EULAR/ACR have also recommended that sustained remission be 
reported in clinical trials (Aletaha, 2008).  As such, the 52 week dosing period in this 
study provides an opportunity to assess the ability of GSK3196165 to induce sustained 
remission.

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The proposed combination dosing duration of 52 weeks also facilitates a better 
assessment of tolerability and safety profile than a shorter duration.
4.6.
Dose Rationale
Complete inhibition of GM-CSF function by GSK3196165 has been observed in different 
assays in vitro at concentrations averaging 0.2 μg/mL.  Although the level of penetration 
of GSK3196165 into the inflamed synovial tissues is not known, it is reasonable to 
assume that its penetration rate is in the range as seen with other mAbs.  Concentration 
levels of mAbs in the synovium vary among patients and have been reported to be below 
30% of the plasma values [Choy, 2000].  Based on a 30% penetration rate, the continuous 
GM-CSF production and considering patient heterogeneity, the minimal or sub-optimal 
clinical effect level is anticipated to be at approximately 10-fold higher (2 μg/mL) than 
the inhibitory concentration derived from in vitro studies.
4.6.1.
Dose Recommendation
An eight-fold range of doses, that are expected to result in largely non-overlapping 
exposures, as well as placebo, are proposed for evaluation: placebo, 22.5 mg, 45 mg, 90 
mg, 135 mg and 180 mg, with corresponding volumes of 0.15, 0.3, 0.6, 0.9, and 1.2 mL, 
respectively, which allow for ease of administration with standard syringes.  Study agent 
will be administered SC weekly for 5 injections (Days 1, 8, 15, 22, 29), then EOW 
thereafter beginning at Day 43 (Week 6) and ending at Day 351 (Week 50).  The doses of 
GSK3196165 have been selected based upon the results from previously conducted 
studies of the molecule.
A wide range of doses is being studied in order to fully characterise the dose response 
(Figure 1).  The dose range includes doses that are anticipated to be effective or 
minimally effective based on the Phase 1b/2a RA study where IV doses of 1.0 mg/kg and 
1.5 mg/kg showed activity and 0.3 mg/kg showed little to no activity after 4 weeks of 
treatment (see IB GSK Document Number [2014N190256_01]).  Furthermore, doses of 
90, 135, and 180 mg SC given every other week (EOW) are anticipated to result in steady 
state Cmin concentration levels of approximately 2 μg/mL or greater (a hypothetical target 
to bind synovial GM-CSF based on in vitro data, and early clinical data, see IB GSK 
Document Number [2014N190256_01]).  The weekly loading dose regimen is intended 
to achieve rapid reduction in disease activity, as supported by the completed 4 week RA 
study (MSC1001) where doses of 1.0 and 1.5 mg/kg IV weekly were associated with 
reduction of DAS28 score after the first dose that continued to decrease through Week 3 
and 6, respectively (see IB GSK Document Number [2014N190256_01]).

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Figure 1
Simulated GSK3196165 serum concentration-time profiles with 5 
weekly doses followed by EOW dosing
Finally, the maximum dose proposed, 180 mg SC is comparable to approximately 1.2 
mg/kg IV for a 70 kg individual, when bioavailability is taken into account.  The 
maximum dose proposed, 180 mg, has been selected to allow ample margin to the No 
Adverse Effect level (NOAEL), and also a margin to the No Effect Level (NOEL) (the 
dose at which foamy alveolar macrophages were not observed in the 26-week rhesus 
monkey study).  A dose of 180 mg SC is predicted to result in steady-state exposures 
which will allow a 26-fold margin to the NOAEL (50 mg/kg), where reversible minimal 
to mild foamy alveolar macrophages (considered non-adverse) were seen in the 26-week 
monkey toxicity study, with a 3-fold margin to the NOEL (5 mg/kg) (Table 1).  The 
weekly dosing period is also supported by the completed RA study (MSC1001) where 4 
weekly IV doses were generally well tolerated up to 1.5 mg/kg (approximately 225 mg 
SC in 70 kg patient).

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Table 1
Safety margins with 180 mg SC GSK3196165 relative to exposures in 
nonclinical toxicology studies
Study
Species
Assessment
Dose
(mg/kg/wk)
AUC(0-336)
µg.hr/mLb
Fold difference
vs. QW
(end of weekly 
dosing phase)
Fold difference 
vs. every other 
week dosing
(steady state)
Repeat Dose 
Toxicology,
4 weeks IV
Rhesus 
Monkey
Week 4
5
8814
3.5
NA
25
44500
18
100c,d
110201
44
Repeat Dose 
Toxicology,
13 weeks SC
Cynomolgus 
Monkey
Week 13
10
7124
2.8
3.8
30d
25870
10
14
100c
75594
30
40
Repeat Dose 
Toxicology,
26 weeks IV
Rhesus 
Monkey
Week 26
5d
5704
2.3
3.0
15
22528
9.0
12
50c
48734
19
26
MSC-1000 
and 
MOR103C10
4 single dose
(IV & SC)a
Human
End of weekly 
dosing phase
Days 28-42
180 mg 
weekly x5
SC
2515
Every other 
week at steady 
state
Days 140-154
180 mg 
every other 
week
SC
1873
IV intravenous; SC subcutaneous
a Simulated mean AUC based on analysis of SC and IV data for doses ≥0.5 mg/kg from study MSC1000 
(N=18) and study MOR103C104 (N=32) with a 2 compartment model and calculation of F by ratio of 
Cliv/CLSC with bioavailability of 44% (95% CI 37%-53%)
b As there were no significant differences on sampling occasions or gender differences within each primate 
study, the end of study mean AUC (0-168) values have been used and multiplied by 2 to obtain mean 
concentrations over a two week period
c No observed adverse effect dose level (NOAEL)
d No observed effect dose level (NOEL)
4.6.2.
Placebo control
A placebo arm is included to measure the absolute effect of each dose tested thereby 
allowing a robust determination of DAS28(CRP) reduction and remission rates, and the 
dose-response.  Inclusion of a placebo arm will also allow a more robust exploration of 
the safety profile and therapeutic index of GSK3196165 when given in combination with 
MTX.
4.6.3.
Methotrexate background
All subjects will continue to receive MTX, and there are rescue options at specific 
timepoints built into the study design.  In addition, the investigator can withdraw the 
subject from study at any time as clinically indicated, so subjects having insufficient 
benefit will not be inadequately treated.

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4.7.
Benefit:Risk Assessment
Since GSK3196165 is still in early development with limited efficacy and safety data 
available, an integrated Benefit/Risk evaluation has not been performed at this point in 
time.  However, summaries of findings from both non-clinical and clinical studies 
conducted with GSK3196165 can be found in the IB GSK Document Number 
[2014N190256_01].  The following section outlines the potential risk assessment and 
mitigation strategy for this protocol:
4.7.1.
Risk Assessment
Potential Risk 
of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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:
One healthy volunteer in study MSC-1000 
experienced septic shock secondary to 
pneumonia 29 days after receiving a 
single dose of IP at 1.5 mg/kg.  Subject 
recovered after treatment with antibiotics, 
and the subject completed the study 
follow-up period as per protocol.
One RA subject in study MSC-1001 
experienced serious pleurisy which 
responded to antibiotics.
Subject selection (see Section 5.1):

Subjects with active infections, or a 
history of recent or recurrent 
infections are not permitted to enter 
the study.

Subjects with significant leukopenia 
are not permitted to enter the study.

Subjects will be screened for TB, HIV 
and Hepatitis B and C, and excluded 
from study participation if positive.

Investigators are expected to assess 
vaccination status, including against 
influenza and pneumococcus, 
according to local guidelines.
Subject monitoring:

Serious infections and opportunistic 
infections are categorised as adverse 
events of special interest (AESIs).

Subjects will be monitored for 
infection similar to subjects receiving 
any immune-modulating biologic 
therapy for RA.  Appropriate 
diagnostic tests will be considered 
during the study if clinically indicated 
to ensure appropriate safety 
monitoring.

Subjects will be instructed as to the 
signs and symptoms of infection, and 
to contact site personnel should they 
develop.  This information will also be 
contained within the patient Informed 
Consent Form.
Withdrawal criteria:

In the event of a serious or 
opportunistic infection, study 
medication should be discontinued 
and the subject withdrawn from the 

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Potential Risk 
of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
study.
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, which is characterized by the 
accumulation of surfactant lipids and 
protein in the alveolar spaces, with 
resultant impairment in gas exchange.
Non-clinical Data:
Non-adverse minimal to mild foamy 
alveolar macrophage accumulation were 
noted in lungs of monkeys in the 13-week 
SC and 26-week IV toxicology studies, but 
reversible following 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.  
Furthermore evaluation of pulmonary 
function has not demonstrated any 
abnormalities in pulmonary functions.
Subject selection (see Section 5.1):

Subjects with history of clinically-
significant respiratory diseases that 
required treatment and/or follow up, 
or chronic cough or dyspnea will not 
be permitted to enter the study.

Pulmonary function testing 
(spirometry, DLCO) measurements) will 
be performed at baseline in order to 
exclude those subjects with 
moderate-severe impairment.
Dose Duration:

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 it requires full inhibition 
of GM-CSF for years before clinical 
manifestation of the disease can be 
detected (refer to IB GSK Document 
Number [2014N190256_01] for 
further details).  Therefore, the risk of 
development of PAP in this study is 
anticipated to be low.
Subject Monitoring:

Specific pulmonary assessments are 
a requirement of the study protocol:
o
Subjects will be assessed every 
visit for the development of 
cough and dyspnea, and will also 
have regular chest auscultation 
and pulse oximetry 
measurements.  Persistent cough 
or dyspnea will be reported as an 
AESI.
o
Pulmonary function testing 
(spirometry and DLCO
measurements) will be performed 
at baseline, and then every 3 
months during treatment and at 
the follow-up visit.  Relative 
change in DLCO >15% from 
baseline will be reported as an 
AESI if confirmed with three 
consecutive weekly tests.

In the event of clinically-significant 
pulmonary events, it is recommended 

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Potential Risk 
of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
that the subject is referred to a 
pulmonologist for further assessment.  
The study drug should be 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.  
Suggested pulmonary assessment 
and management algorithms will be 
provided in a separate Pulmonary 
Safety Guidance Document in the 
SRM.
Hypersensitivity 
reactions, 
including
anaphylaxis
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 allergic or acute systemic reactions 
have been observed to date in the clinical 
development program.
Subject selection (see Section 5.1):

Subjects with a 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, will not be permitted to 
enter the study.
Study treatment administration/Subject 
monitoring:

All SC administrations will be 
performed at the clinical site.

Subjects will be required to remain 
monitored at the site for 1 hour after 
the injection for the first 3 injections, 
and then for 30 minutes for 
subsequent injections.

Subjects should be informed of the 
signs and symptoms of an acute 
hypersensitivity reaction, and be 
instructed to seek immediate medical 
care should they develop.  This 
information will also be contained 
within the patient Informed Consent 
Form.

Should hypersensitivity or 
anaphylaxis occur, subjects should be 
managed appropriately per local 
guidelines/medical judgement.

Severe hypersensitivity or 
anaphylaxis are categorised as 
AESIs.
Withdrawal criteria:

In the event of severe hypersensitivity 

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Potential Risk 
of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
or anaphylaxis, study medication 
should be discontinued and the 
subject withdrawn from the study.
Injection site 
reactions
SC injections may be associated with local 
reactions (e.g., swelling, induration, pain).
Non-clinical & Clinical Data:
No macroscopic or microscopic changes 
indicative of local injection site reactions 
were observed following IV or SC
administration.
Subject monitoring:

Subjects should be monitored for 
injection site reactions throughout the 
study, and the information recorded in 
the eCRF.

Injection sites will be rotated.

Any clinically-significant event should 
be reported as an AE.
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].
Non-clinical & Clinical Data:
There have been no reports of 
neutropenia or decreases in leukocytes in 
the non-clinical and clinical GSK3196165 
program.
Subject selection (see Section 5.1):

Subjects with significant leukopenia 
(≤3.0 x 109/L); thrombocytopenia 
(platelet count ≤100 x 109/L); 
neutropenia (absolute neutrophil 
count ≤1.5 x 109/L); lymphocytopenia
(≤0.5 x 109/L) within 28 days prior to 
Day 1 are not permitted to enter the 
study.
Subject monitoring:

A full blood count (with differential) 
will be performed at regular intervals 
throughout the study (ref. Time and 
Events Table, Section 7.1).

Neutropenia is categorised as an 
AESI.
Reproductive 
toxicity
Published studies performed with GM-
CSF -/- mice have indicated that GM-CSF 
depletion potentially affects fertility, 
establishment of pregnancy and post 
partum 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.
The effect on human pregnancy is 
unknown.
Clinical Data:
No HVs or RA subjects became pregnant 
during the studies, but one MS subject 
Subject selection (see Section 5.1):

Male and female subjects will only be 
permitted to enter the study if they 
meet the contraception requirements 
detailed in inclusion criterion #10.

In addition, females of child bearing 
potential will undergo pregnancy 
testing at screening and at regular 
intervals during the study (ref. Time 
and Events Table, Section 7.1).
Withdrawal criteria:

In the event of a pregnancy in a 
female subject in the study, study 
medication should be discontinued 
and the subject withdrawn from the 
study.
Other considerations

Subject will be followed to determine 
the outcome of the pregnancy

Any pregnancy complication or 

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Potential Risk 
of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
was found to be pregnant during study 
MOR103C10301028 and received four 2.0 
mg/kg doses, the pregnancy was 
terminated 2 weeks later by elective 
abortion.
elective termination of a pregnancy 
will be reported as an AE or SAE.
Malignancy
The risk of malignancy is increased in 
patients with RA.  In addition, 
immunomodulatory therapies may
increase the risk of malignancy.
Non-clinical & Clinical Data:
There have been no reports of malignancy 
in the non-clinical and clinical 
GSK3196165 program.
Subject selection (see Section 5.1):

Subjects with a history of malignant 
neoplasm within the last 10 years or 
breast cancer within the last 20 years, 
except for non-melanoma skin 
cancers that have been excised and 
cured or carcinoma in situ of the 
uterine cervix, will not be permitted to 
enter the study.
4.7.2.
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, inhibits GM-CSF mediated responses in vitro and reduces inflammatory 
responses in rat arthritis models.  GSK3196165 has shown evidence of efficacy in a 
Phase 1b/2a trial in patients with active RA [Behrens, 2014].  In addition, mavrilimumab 
(an anti-GMCSF -subunit receptor mAb), has also shown substantial activity in RA 
subjects who had an inadequate response to MTX in studies of up to 24 weeks of dosing 
[Burmester, 2013; Burmester, 2014].  These data support the clinical evaluation of 
GSK3196165 in subjects with RA.
4.7.3.
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.  Data with mavrilimumab, an 
anti-GMCSF -subunit receptor mAb, also supports this contention.
Key potential risks are those described above that may be associated with inhibition of 
GM-CSF (e.g., pulmonary toxicity, infection) and those associated with administration of 
a therapeutic monoclonal antibody (e.g. allergic reactions).  Robust and systematic safety 
monitoring will be undertaken in studies of GSK3196165 to proactively address and 
mitigate the potential risks.  Recent data with mavrilimumab administered for 24 weeks 
in combination with MTX in subjects with active RA [Burmester, 2014] provides further 
support that targeting this pathway is associated with an acceptable benefit:risk profile.
Given the safety monitoring that has been put in place to minimize risk to subjects 
participating in clinical studies of GSK3196165, the potential risks identified are justified 
by the potential benefits that may be afforded to patients with RA.

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In addition, in accordance with routine pharmacovigilance, the safety review team (SRT) 
will review blinded safety data, including clinical laboratory parameters and adverse 
events, approximately every 4 weeks during the period of study conduct and unblinded 
safety data will be reviewed by the DRC at scheduled intervals (see Section 10.8.1).  Key 
safety data that meets predefined thresholds will be reviewed by the DRC and will be a 
trigger for further investigation into the data and an assessment of the overall benefit:risk.  
Full details of safety thresholds will be provided in the DRC charter.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB GSK Document 
Number [2014N190256_01].
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety.  Therefore, adherence to the criteria as specified in the protocol is 
essential.  In addition, investigators are expected to assess vaccination status, including 
against influenza and pneumococcus according to local guidelines.
The study aims to recruit up to approximately 40% of subjects with RA disease duration 
of <2 years.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
Subjects eligible for enrolment in the study must meet all of the following criteria:
[1] AGE
1. Age ≥18 years at the time of signing informed consent.
[2] TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Meets ACR/EULAR 2010 RA Classification Criteria.
3. Functional class I, II or III defined by the 1992 ACR Classification of Functional 
Status in RA.
4. Disease duration of ≥12 weeks (time from onset of patient-reported symptoms of 
either pain or stiffness or swelling in hands, feet or wrists).
5. Swollen joint count of ≥4 (66-joint count) and tender joint count of ≥4 (68-joint 
count) at screening and at Day 1.
6. DAS28(CRP) ≥3.2 at screening and DAS28(ESR) ≥3.2 at Day 1.

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7. C-Reactive Protein (CRP) ≥5.0 mg/L at screening.
8. Must have previously received MTX (15-25 mg weekly) for at least 12 weeks before 
screening, with no change in route of administration, with a stable and tolerated dose 
for ≥4 weeks prior to Day 1.  A stable dose of MTX ≥7.5 mg/week is acceptable, if 
the MTX dose has been reduced for reasons of documented intolerance to MTX, e.g. 
hepatic or hematologic toxicity, or per local requirement.
[3] WEIGHT
9. Weight ≥45 kg.
[4] SEX
10. Male or female subjects are eligible to participate so long as they meet and agree to 
abide by the contraceptive criteria detailed in Appendix 12.2.
[5] INFORMED CONSENT
11. Written informed consent prior to any of the screening procedures including 
discontinuation of prohibited medications.
[6] OTHER SAFETY-RELATED
12. 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).
13. Diffusing capacity of the lung for carbon monoxide (DLCO) ≥60%a,b predicted; forced 
expiratory volume in 1 second (FEV1) ≥70% predicted.
a. Screening and Day 1 values within 10% of each other (the test may be repeated 
twice within the screening period, i.e. subjects may undergo a total of three DLCO
tests during the screening period).
b. For subjects with DLCO values ≥60% to <70%, a baseline chest HRCT must be 
performed during the screening period, and it is recommended that the subject be 
reviewed by a local pulmonologist to exclude significant pre-existing respiratory 
disease.
14. No evidence of active or latent infection with Mycobacterium tuberculosis (TB), as 
defined by all of the following:
a. No history of active or latent TB infection irrespective of treatment status.
b. A negative diagnostic TB test within 28 days of baseline (Day 1) defined as:
i. A negative QuantiFERON Gold test or T-spot test (may be performed locally) 
(NB: 2 successive indeterminate QuantiFERON tests will be considered as a 
positive result).
OR

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ii. If QuantiFERON gold or T-spot test not approved or registered in country of 
participation, then a negative tuberculin skin test (TST) reaction as per local 
guidelines is required (it is strongly recommended that subjects with a history 
of BCG vaccination be tested with QuantiFERON gold test).
c. Chest X-ray within 12 weeks of Day 1, locally read by a radiologist, with no 
evidence of current or previous pulmonary tuberculosis.
NB: If there has been recent close contact with persons who have active TB prior to study 
enrolment the subject will be referred to a TB physician to undergo additional evaluation.
Refer to Section 6.11.1 for detailed information on permitted therapies.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
[1] CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL)
1. Pregnant or lactating women.
2. History of other inflammatory rheumatological or autoimmune disorders, other than 
Sjögren’s syndrome secondary to RA.
3. History of any respiratory disease which (in the opinion of the investigator) would
compromise subject safety or the ability of the subject to complete the study (e.g.
significant interstitial lung disease, such as pulmonary fibrosis, chronic obstructive
pulmonary disease (COPD), moderate-severe asthma, bronchiectasis, previous PAP).
4. Clinically-significant or unstable (in the opinion of the investigator) persistent cough
or dyspnea that is unexplained.
5. QTc >450msec or QTc >480msec for subjects with bundle branch block.
The QTc is the QT interval corrected for heart rate according to Fridericia’s 
formula (QTcF).
6. Liver function tests: alanine aminotransferase (ALT) >1.5x upper limit of normal 
(ULN); aspartate transaminase (AST) >1.5 upper limit of normal; alkaline 
phosphatase and bilirubin ≥1.5xULN (isolated bilirubin >1.5xULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%).
7. Current active liver or biliary disease (with the exception of Gilbert’s syndrome or 
asymptomatic gallstones or otherwise stable chronic liver disease per investigator 
assessment).
8. Significant unstable or uncontrolled acute or chronic disease (e.g., cardiovascular 
including uncompensated congestive cardiac failure NYHA III or IV, myocardial 
infarction within 12 months, unstable angina pectoris, uncontrolled hypertension, 
uncontrolled hypercholesterolemia) pulmonary, hematologic, gastrointestinal 
(including Crohn’s Disease or ulcerative colitis), hepatic, renal, neurological, 
psychiatric, malignancy, endocrinological or infectious diseases, which, in the 

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opinion of the investigator, could confound the results of the study or put the subject 
at undue risk.
9. A history of malignant neoplasm within the last 10 years or breast cancer within the 
last 20 years, except for non-melanoma skin cancers that have been excised and cured 
or carcinoma in situ of the uterine cervix.
10. Kidney disease: Current or history of renal disease, or estimated creatinine clearance 
<60 mL/min/1.73m2 or serum creatinine >1.5xULN within 28 days of Day 1.
11. Hereditary or acquired immunodeficiency disorder, including immunoglobulin 
deficiency.
12. History of infected joint prosthesis at any time, with the prosthesis still in situ.  
History of leg ulcers, catheters, chronic sinusitis or recurrent chest or urinary tract 
infections.
13. Active infections, or history of recurrent infections (excluding recurrent fungal 
infections of the nail bed), or have required management of acute or chronic 
infections, as follows:
a. Currently on any suppressive therapy for a chronic infection (such as tuberculosis, 
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical 
mycobacteria).
OR
b. Hospitalization for treatment of infection within 26 weeks of Day 1.
OR
c. Use of parenteral (IV or IM) antimicrobials (antibacterials, antivirals, antifungals, 
or antiparasitic agents) within 26 weeks of Day 1 or oral antimicrobials within 14 
days of Day 1.
14. A vaccination (live or attenuated) within 30 days of Day 1 or BCG vaccination within 
365 days of Day 1, or a live vaccination planned during the course of the study.
15. Any surgical procedure, including bone or joint surgery/synovectomy within 12 
weeks prior to Day 1 or any planned surgery within the duration of the study or 
follow-up period.
16. For those subjects in the actigraphy substudy:

wheelchair, walking aids, artificial limbs

history of severe skin allergy

active implantable device

pacemaker.
[2] CONCOMITANT MEDICATIONS
17. Use of prohibited medications:
Prior to AND throughout the study:

Any conventional DMARDs other than MTX (including hydroxychloroquine, 

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sulphasalazine, minocycline, ciclosporin) should be withdrawn at least 2 weeks prior 
to Day 1.
oSubjects may require longer to discontinue azathioprine or leflunomide prior to 
randomization:

Azathioprine must be discontinued ≥28 days prior to randomization.

Leflunomide must be discontinued ≥12 weeks prior to randomization (or ≥14 
days after 11 days of standard cholestyramine or activated charcoal washout).
oFor these subjects, written informed consent for the study (or sub-studies) 
must be obtained prior to beginning the screening period.  However, other 
screening assessments, other than consent, must occur within 28 days prior to 
randomization.

Any biologic agents (such as TNF inhibitors such as adalimumab, etanercept, 
infliximab, certolizumab pegol, golimumab or non-TNF inhibitors (including 
abatacept, rituximab, tocilizumab, belimumab).

Any anti-rheumatic investigational compounds.

Any alkylating agents (such as cyclophosphamide or chlorambucil).

Plasmapheresis or intravenous immunoglobulin (IVIG) within 26 weeks of Day 1.
18. Corticosteroids:

Any IM, IV or IA corticosteroids within 8 weeks of Day 1.

Oral corticosteroids:

Any treatment with >10 mg/day dose oral prednisolone (or equivalent) within 28 
days of Day 1.

New oral corticosteroid or changes in corticosteroid dose within the 28 days prior 
to Day 1.  (New topical steroids and immunosuppressive agents (e.g., eye drops, 
creams) are permitted).
19. Non-steroidal anti-inflammatory drugs (NSAIDs):

New or change in dose of NSAID within 14 days of Day 1.
20. Any non-anti-rheumatic investigational treatment must be discontinued for at least 4 
weeks or 5 half-lives, whichever is longer, prior to Day 1.
[3] RELEVANT HABITS
21. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol 
abuse or dependence within a year prior to Day 1.
[4] CONTRAINDICATIONS
22. 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 

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Monitor, contraindicates their participation.
[5] DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
23. Abnormal chest X-ray within 12 weeks of Day 1 (locally read and reported by a
radiologist) judged by the investigator as clinically-significant.
24. Any Grade 3 or 4 hematology or clinical chemistry laboratory abnormality [CTCAE, 
2009 v4.0] within 28 days of Day 1.
25. Hemoglobin ≤9 g/dL; white blood cell count ≤3.0 x 109/L; platelet count ≤100 x 
109/L; absolute neutrophil count ≤1.5 x 109/L; lymphocyte count ≤0.5 x 109/L within 
28 days of Day 1.
26. Serologic evidence of current/previous Hepatitis B virus (HBV) infection based on 
the results of testing for Hepatitis B surface antigen (HBsAg) and anti-Hepatitis B 
core (anti-HBc) antibody as follows within 28 days of Day 1:

Subjects positive for HBsAg and/or positive for anti-HBc antibody (regardless of 
anti-HBs antibody status) are excluded.
27. Hepatitis C: Positive test for Hepatitis C virus (HCV) antibody confirmed on a 
subsequent blood sample by RNA-PCR assay within 28 days of Day 1.

Subjects who are positive for Hepatitis C antibody and negative when the 
Hepatitis C RNA-PCR assay is performed on a subsequent sample will be eligible 
to participate.  Subjects who are positive for Hepatitis C antibody and have a 
positive result for the HCV when the Hepatitis C RNA-PCR assay is performed 
on the subsequent sample will not be eligible to participate.
28. Positive serology for human immunodeficiency virus (HIV) 1 or 2 (within 28 days of 
Day 1).
5.3.
Screening/Baseline Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and any Serious Adverse Events.
5.3.1.
Re-Screening
If a subject has not met all of the Eligibility Criteria within the 28 day screening period, 
re-screening is required.  Subjects are only allowed to be re-screened once; the entire 
screening process must be repeated (with the exception of chest X-ray if within 12 weeks 
of the first screening period or HRCT if this was already performed within the first 
screening period).
If a blood sample has to be withdrawn due to sample handling problems, breakage or 
sample integrity, this is not considered a re-screening.

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Further details regarding the procedure for re-screening may be found in the SRM.
5.3.2.
Re-Testing
5.3.2.1.
Laboratory tests
If a subject fails any of the laboratory exclusion criteria, the test may be repeated twice 
within the screening period.  If the subject fails the laboratory criteria for a third time 
they will be considered a screen failure; these subjects may be re-screened as described in 
Section 5.3.1.
If a blood sample has to be withdrawn due to sample handling problems, breakage or 
sample integrity, this is not considered a re-testing.
Further details regarding the procedure for laboratory re-testing may be found in the 
SRM.
5.3.2.2.
DLCO test
If the screening DLCO value is ≥70% predicted, but the subsequent “Day 1” value is <70%
but ≥60% predicted, the DLCO test may be repeated if still within the screening window.  
If the repeat value is ≥70%, the “Day 1” activities may be completed, but if the value is 
again <70%, dosing must be postponed and a chest HRCT performed.  If this cannot be 
done within the screening window, then the subject must be re-screened.
5.3.2.3.
ECG test
The ECG may be repeated once within the screening period if the recorded QTcF value 
was slightly out of range, and the Investigator does not consider that there are any other 
clinically-significant ECG abnormalities that would preclude the subject from 
participating in the study.
5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible.

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study.

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods).  These contact attempts should be documented 
in the subject’s medical record.

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
Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”.
Any subject that fails to achieve EULAR good/moderate response at Week 36 will not be 
dosed at Week 38, and will be withdrawn from the study; no further study treatment will 
be administered.  A notification that the subject must be withdrawn will be sent to the 
investigator prior to the scheduled Week 38 visit.
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons.
In addition, study medications will be discontinued and the subject withdrawn from 
the study in the event of any of the following:

All serious infections.

Pregnancy.

Confirmed PAP.

Severe or serious hypersensitivity reactions, including anaphylaxis.

If the liver chemistry stopping criteria (Section 5.4.1) or QTc stopping criteria 
(Section 5.4.2) are met.

Persistent or recurrent hematological laboratory abnormalities (see Section 5.5.2).

Other serious or severe adverse events, at the discretion of the investigator, after 
consultation with the Medical Monitor.
If a subject withdraws from the study, he/she may request destruction of any samples 
taken, and the investigator must document this in the site study records.
Any subject who withdraws must complete an early withdrawal visit and the 12 week 
follow-up visit.
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
subject safety and evaluate liver event etiology (in alignment with the FDA premarketing 
clinical liver safety guidance) [FDA, 2009].

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5.4.1.1.
Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 12.3.
5.4.1.2.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.4.2.
QTc Stopping Criteria
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:
a. QTc >500 msec OR uncorrected QT >600 msec
b. Change from baseline of QTc >60 msec
The QTc is the QT interval corrected for heart rate according to Fridericia’s formula 
(QTcF).
For subjects with underlying bundle branch block, follow the discontinuation criteria 
listed below:

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Baseline QTc with
bundle branch block
Discontinuation QTc with
bundle branch block
< 450 msec
> 500 msec
450 – 480 msec
≥ 530 msec
5.5.
Treatment interruption
5.5.1.
Respiratory Symptoms
Study medications will be temporarily suspended to allow investigation in the event of 
any of the following:

Persistent reduction in DLCO >15% relative decrease from baseline for three 
consecutive weeks.

Persistent cough (CTC grade 2 or 3) or dyspnea (Borg scale grade 3 or above) for 
three consecutive weeks.
It is recommended that the subject be referred to a pulmonologist for further assessment.  
The study drug should be 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.  As described in Section 5.4, a confirmed diagnosis 
of PAP necessitates permanent cessation of study medication and withdrawal of the 
subject from the study.  Suggested pulmonary assessment and management algorithms 
are provided in a separate Pulmonary Safety Guidance Document in the SRM.
5.5.2.
Hematologic abnormalities
The following haematological laboratory abnormalities require temporary suspension of 
study medications and prompt retesting, ideally within 3-5 days:

White blood cell count <2.0 x 109/L

Absolute neutrophil count <1.0 x 109/L

Lymphocyte count <0.5 x 109/L
Study medication should not be restarted until the parameters are above these values, and 
subjects should be followed as appropriate until resolution of the event.
If these abnormalities are persistent (present on ≥2 sequential tests), or occur recurrently 
(on 2 separate occasions), study medications will be permanently discontinued and the 
subject withdrawn from the study.
5.6.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit.

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6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design.  Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Study Treatment
Co-medication
Product name:
GSK3196165
Placebo
Methotrexate and folic (or 
folinic) acid.
Function
Test 
(investigational 
product)
Control
Background treatment 
(started prior to and 
maintained during the 
study).
Formulation description:
See IB GSK 
Document Number 
[2014N190256_01] 
for details.
The placebo in this
study will be sterile 
0.9% (w/v) sodium 
chloride solution.
Variable. See labels for 
details.
Dosage form:
Liquid
Liquid
MTX: tablet or liquid
Folic (or folinic) acid: 
capsule, tablet or liquid.
Dosage levels (volumes):
22.5 mg (0.15mL)
45 mg (0.3mL)
90 mg (0.6mL)
135 mg (0.9mL)
180 mg (1.2mL)
0.6 mL
MTX:7.5-25mg/week
Folic (or folinic) acid: ≥5 
mg/week.
Note: Folic (or folinic) acid 
dose may be increased to 
counteract side-effects of 
MTX (including nausea, 
mucositis, and headache).
Route of Administration:
Investigational product should be 
administered SC into thigh or abdomen, 
sites should be rotated.  Safety should be 
monitored for 1 hour after the injection, 
for the first 3 injections, then for 30 
minutes thereafter.  Such monitoring will 
include general safety monitoring 
including monitoring for systemic 
hypersensitivity infusion reactions and 
local injection site reactions.  Trained 
rescue personnel and rescue 
medications/equipment must be available 
for use at all times.
MTX: oral or 
subcutaneous injection
Folic (or folinic) acid: oral

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Study Treatment
Co-medication
Dosing instructions:
GSK3196165/placebo should be 
administered on the same day each week 
± 1 day for the first 5 weekly doses (with 
a minimum of 5 days between doses, for 
no more than 2 consecutive doses).  
Following this GSK3196165/placebo 
should be administered on the same day 
EOW ± 3 days (with a minimum of 8 days 
between doses).
GSK3196165/placebo will be 
discontinued or interrupted as described 
in Section 5.4 or Section 5.5.
Subjects will be randomized as shown in 
Time and Events Table, Section 7.1, and 
the dosing schedule should be followed 
as closely as possible.
The unblinded administrator (study co-
ordinator or nurse) assigned to the study 
will be required to prepare and administer 
the appropriate medication according to 
the study subject’s treatment assignment.  
Subjects eligible to enter the study will be 
assigned to treatment randomly through 
an interactive response technology 
system (IRTS).  Procedures must be in 
place to ensure the blind is maintained by 
any site staff involved in clinical care or 
assessment of the subject, and by the 
subject themselves.
During the first 12 weeks of study every 
attempt should be made to ensure all 
doses are administered.
After 12 weeks, up to 1 dose in an 8 
week period may be missed, not to 
exceed 2 missed doses total over the 52 
weeks of treatment.
If at any time the subject misses 2 doses 
over 52 weeks, the Medical Monitor must 
be contacted for permission to continue 
study medication.
MTX: can be taken as a 
single weekly dose, or 
divided weekly dose, per 
investigator’s discretion.  
Folic (or folinic) acid 
should be taken the day 
after and at least 12 hours 
following MTX 
administration.
Physical description:
Sterile, aqueous 
solution of purified 
monoclonal 
antibody 150 
mg/mL
Sterile 0.9% (w/v) 
sodium chloride 
solution.
See label for details

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Study Treatment
Co-medication
Method for individualizing 
dosage:
22.5 and 45 mg 
doses - required 
volume will be 
drawn into a small, 
(e.g. 0.3 or 0.5 mL) 
syringe.
90 and 135 mg 
doses - required 
volume will be 
drawn into a small 
(e.g. 1 mL) syringe.
180 mg dose -
required volume 
will be drawn into a 
small (e.g. 2 mL or 
3 mL) syringe.
The required 
volume should be 
dosed immediately.
A volume of 0.6 mL 
will be drawn into a 
small (e.g. 1 mL) 
syringe.
See label for details.
Investigators are responsible for ensuring that subjects continue to receive MTX and folic 
acid.
Timing of MTX is unrelated to food intake, and may be changed at the investigator’s 
discretion in case of intolerability.
Subjects will receive ≥5 mg/week folic (or folinic) acid orally.  The dosing regimen is at 
the discretion of the investigator.  Folic (or folinic) acid should be taken the day after 
MTX administration and at least 12 hours following the MTX.  Folic (or folinic) acid 
dose may be increased to counteract side-effects of MTX (including nausea, mucositis, 
and headache).
MTX dosing should be kept stable throughout the study as far as possible.  Dose
reduction is permitted to a minimum of 7.5 mg/week due to intolerance or toxicity, and
dose increase, following reduction, is permitted back to the subject’s dose prior to 
reduction (maximum dose 25 mg/week).  Likewise, temporary interruption of MTX 
dosing for the management of intolerance will be permitted, and any reduction or 
interruption should be recorded, with the reason, in the eCRF.
All local standard-of-care practices for the administration of MTX, including laboratory 
testing, follow-up care, contraindications, and folic acid administration should be 
performed throughout the study.
6.2.
Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomization 
schedule.

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The study will use central randomization and the randomization schedule will be 
generated by Clinical Statistics using validated randomization software.  Once a 
randomization number has been assigned to a subject, it cannot be assigned to another 
subject in the study, even if the original subject withdraws before taking study 
medication.
Randomization numbers will be assigned to subjects using an Interactive Response 
Technology system (IRTS).
Subjects should be randomized and receive their first dose of study medications on the 
same day (Day 1).
6.3.
Planned Dose Adjustments
This protocol allows some alteration from the currently outlined dosing schedule, but the 
maximum dose will not exceed 180 mg.
6.4.
Subject Specific Dose Adjustment Criteria

“Escape therapy” is provided for all subjects not on the 180 mg dose:
Subjects in the placebo, 22.5 mg, 45 mg, 90 mg and 135 mg arms will be 
escalated in a double-blind fashion to the 180 mg (or highest remaining) dose 
at Week 14 if they have failed to achieve EULAR good/moderate response* 
at Week 12.

Subjects in these groups who do not meet this criterion and therefore do not escalate 
therapy at Week 14 have another opportunity for “escape” at Week 24 with 
escalation in a double-blind fashion to the 180 mg (or highest remaining) dose of the 
study after the Interim Analysis) at Week 26 if their DAS28(CRP) score at this 
timepoint is >3.2.
*EULAR good or moderate response
Week 12
DAS28(CRP)
DAS28(CRP) improvement from baseline
>1.2
>0.6 and ≤1.2
≤0.6
≤3.2
Good response
Moderate response
No response
>3.2 and ≤5.1
Moderate response
Moderate response
No response
>5.1
Moderate response
No response
No response
Source: [Fransen, 2005]
6.5.
Blinding
The study will be double-blind, which means that the investigator and trial staff at site 
(apart from the unblinded administrator [study co-ordinator or nurse]), subject, and 
sponsor personnel who are not members of the DRC will be blinded to the trial treatment 
allocated to each individual subject.
There will be an unblinded administrator (study co-ordinator or nurse) that will prepare 
and administer the study treatment.  A shield (e.g., eye mask or blindfold) will be used 
during investigational product administration so that subjects are not able to see the 

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injection volume, syringe size, or any difference in color between GSK3196165 and 
placebo.
In this Phase 2b study, the DRC (see Section 10.8.1) will have access to unblinded data at 
a group level, but will not have individual subject level data.

The investigator or treating physician may unblind a subject’s treatment assignment 
only in the case of an emergency OR in the event of a serious medical condition 
when knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject as judged by the investigator.

Investigators have direct access to the subject’s individual study treatment.

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the subject’s treatment assignment.

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the treatment 
assignment of the unblinded subject, unless that information is important for the 
safety of subjects currently in the study.

The date and reason for the unblinding must be fully documented in the eCRF
A subject will be withdrawn if the subject’s treatment code is unblinded by the 
investigator or treating physician.  The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the eCRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject 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 subject’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy.
6.6.
Packaging and Labeling
The contents of the label for GSK3196165 will be in accordance with all applicable 
regulatory requirements for clinical supplies.
6.7.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

Only subjects enrolled in the study may receive study treatment and only the 
unblinded administrator (study co-ordinator or nurse) may administer study 
treatment.  All study treatments must be stored in a secure environmentally 
controlled and monitored (manual or automated) area in accordance with the labelled 
storage conditions with access limited to the investigator and authorized site staff.

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records).

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
Further guidance and information for final disposition of unused study treatment are 
provided in the SRM.

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists.  In the case 
of unintentional occupational exposure notify the Medical Monitor and/or GSK 
study contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
6.8.
Compliance with Study Treatment Administration
GSK3196165 or placebo will be administered by subcutaneous injection to subjects at the 
site by the unblinded administrator (study co-ordinator or nurse).  The date and time of 
each dose and volume administered in the clinic will be recorded in the eCRF.
Subjects will be given instructions on compliance and treatment with MTX.  The date 
taken and total weekly dose will be recorded in the eCRF.
Folic (or folinic) acid must also be taken as instructed in Section 6.1.
6.9.
Treatment of Study Treatment Overdose
6.9.1.
Overdose of GSK3196165
There is very limited clinical safety data at this stage of development.  However there 
have been no reports of overdose with GSK3196165 to date.  The risk of overdose 
occurring is considered low because in GSK3196165 will be administered by an 
independent administrator, and the maximum volume that can be withdrawn from the vial 
is equivalent to the highest dose to be evaluated.  No specific treatment is recommended 
for an overdose of GSK3196165, and the investigator should treat as clinically indicated.  
Details (amount of investigational product given and any resulting AEs/SAEs) should be 
recorded in the eCRF.
In the event of an overdose the investigator should:

contact the Medical Monitor immediately

closely monitor the subject for AEs/SAEs and laboratory abnormalities

obtain a plasma sample for PK analysis at the time of the event, and three days 
after the event (unless otherwise requested by the Medical Monitor)

consult with the Medical Monitor for any decisions regarding dose interruptions 
or modifications based on the clinical evaluation of the subject.

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6.9.2.
Overdose of Methotrexate
Refer to the local prescribing information for advice on treatment of MTX overdose.  
Some guidance is provided below.
Cases of overdose, sometimes fatal, due to erroneous daily intake instead of weekly 
intake of oral MTX have been reported.  In these cases, symptoms that have been 
commonly reported are hematological and gastrointestinal reactions.  Folinic acid is a 
specific antidote for MTX and, following accidental overdosage, should be administered 
within one hour at a dosage equal to, or greater than, the MTX dose.  It may be 
administered by IV bolus or infusion.  Further doses may be required.  The subject should 
be observed carefully and blood transfusions, renal dialysis and reverse barrier nursing 
may be necessary.  In cases of massive overdose, hydration and urinary alkalisation may 
be necessary to prevent precipitation of MTX and/or its metabolites in the renal tubules.  
Neither hemodialysis nor peritoneal dialysis has been shown to improve MTX 
elimination.  Effective clearance of MTX has been reported with acute, intermittent 
hemodialysis using a high flux dialyser.
6.10.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
6.11.
Concomitant Medications and Non-Drug Therapies
During the past decade, the ability of pro-inflammatory cytokines to alter the expression 
and activity of drug metabolising enzymes has become increasingly evident [Lee, 2010; 
Zhou, 2011; Evers, 2013].  During inflammation, enzymes such as CYP450 can be down-
regulated leading to instances of reduced clearance and increased plasma concentrations 
of administered drugs.  The administration of GSK3196165 can potentially alter 
circulating cytokine levels to a patient whose cytokine levels have been elevated.  This 
may partially or completely reverse the impact of cytokines on CYP450 enzymes leading 
to changes in the exposure of co-administered drugs whose metabolism is dependent on 
CYP450 enzymes.  The reports so far suggest the magnitude of drug interaction by 
therapeutic proteins (clinically) is generally small (less than two-fold) and therefore only 
likely to be clinically relevant for CYP450 substrates with a narrow therapeutic index, 
where the dose is individually adjusted.  Upon initiation or discontinuation of 
GSK3196165, in subjects being treated with these types of medicinal products, 
therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g. theophylline) 
should be performed and the individual dose of the medicinal product adjusted as needed.  
Prescribers should exercise caution when GSK3196165 is co administered with CYP3A4 
substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, 
lovastatin, atorvastatin, etc.  The effect of GSK3196165 on CYP450 enzyme activity may 
persist for several weeks after stopping therapy.

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6.11.1.
Permitted Medications and Non-Drug Therapies
All permitted medications and non-drug therapies will be recorded as concomitant 
medications.
6.11.1.1.
Corticosteroids
6.11.1.1.1. Oral Corticosteroids
Stable use of oral corticosteroids 10 mg/day prednisone or equivalent agent is permitted 
if the dose is stable for at least 28 days prior to Day 1 (baseline).  This dose should 
remain constant throughout the first 12 weeks of the study.  Dose reductions before Week 
12 are not permitted, unless required for safety or tolerability.
If the corticosteroid dose is increased above 10 mg/day prednisone, the subject will be 
deemed a treatment failure and investigational product will be discontinued, although the 
subject will remain on study and undergo study visits as outlined in the Time and Event 
Table Section 7.1.
6.11.1.1.2. NSAIDS
Continued use of single NSAID (including Cox-2 inhibitors) is permitted (i.e. diclofenac, 
ibuprofen, naproxen, celecoxib) in daily doses up to the maximum recommended dose, 
according to locally accepted clinical practices, if the dosage was stable for at least 14 
days prior Day 1.  The dose/type of NSAID may be changed for safety or tolerability 
problems.  If the subject is not regularly using NSAIDs, he/she may take the NSAIDs 
mentioned above as breakthrough pain management, which must be recorded in the 
eCRF.  However, subjects should be advised not to take any NSAIDs for breakthrough 
pain within 12 hours prior to an efficacy assessment visit.
6.11.1.2.
Analgesics
Regular use of codeine, opium alkaloid, paracetamol/acetaminophen, propoxyphene, and 
tramadol are permitted in daily doses up to the maximum recommended according to 
locally accepted clinical practices.  If the subject is not regularly using any analgesics, 
he/she may take the analgesics mentioned above as breakthrough pain management.  
However, the subjects should be advised not to take any analgesics for breakthrough pain 
within 12 hours prior to an efficacy assessment visit.
6.11.2.
DMARD/Biologic Rescue Medications
The subject’s disease will be assessed regularly throughout the study (as shown in 
Section 7.1).  Subjects (other than those on the 180 mg dose) will be escalated to the 180 
mg (or highest remaining) dose of GSK3196165 at Week 12 if they fail to achieve a 
EULAR good/moderate response, or at Week 24 if their DAS28(CRP) score is above 3.2.  
Every effort should be made to keep the subject on study treatment unless the subject 
experiences an excessive disease flare that, in the investigator’s opinion, warrants a 
change in therapy.

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6.11.3.
Prohibited Medications and Non-Drug Therapies
6.11.3.1.
Related to the Study

Any conventional DMARDs other than MTX (including hydroxychloroquine, 
leflunomide, sulphasalazine, minocycline, ciclosporin, azathioprine).

Any biologic agent (such as TNF inhibitors such as adalimumab, etanercept, 
infliximab, certolizumab pegol, golimumab or non-TNF inhibitors (including 
abatacept, rituximab, tocilizumab and belimumab) and any anti-rheumatic 
investigational compounds.

IA corticosteroids are strongly discouraged within 8 weeks prior to Day 1, and then 
through Week 52.
However, IA corticosteroids may be used in a limited fashion as treatment for 
severe RA flares.
No more than 1 joint per 24-week period or 2 joints per 52-week period 
should be injected.
No single injection should exceed 40 mg of triamcinolone (or equivalent) and 
the total dose of IA corticosteroid should not exceed 80 mg of triamcinolone 
(or equivalent) during the 52-week period.

IV and/or IM steroids are not permitted for at least 28 days prior to Day 1, or 
throughout the study.

Live vaccines should not be administered for 12 weeks after the last dose of 
GSK3196165.  Furthermore, GSK3196165 and MTX are immunosuppressive and 
may therefore reduce immunological response to concurrent vaccination.  In 
addition, investigators are expected to assess vaccination status, including against 
influenza and pneumococcus according to local guidelines.
6.11.3.2.
Related to Methotrexate
Refer to local prescribing information for warnings, precautions and contraindications 
with MTX treatment.

Prohibited:
Concomitant administration of folate antagonists such as trimethoprim, 
cotrimoxazole and nitrous oxide are prohibited.
Vitamin preparations containing folic acid or its derivatives may alter 
response to MTX (although folic acid is recommended to reduce the side-
effects of MTX, it must not be administered on the same day as MTX)

Caution advised with the following:
MTX is extensively protein bound and may displace, or be displaced by, 
other acidic drugs.  The concurrent administration of agents such as p-
aminobenzoic acid, chloramphenicol, penicillins, ciprofloxacin, 
diphenylhydantoins, phenytoin, acidic anti-inflammatory agents, salicylates, 

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sulphonamides, tetracyclines, thiazide diuretics, probenicid or sulfinpyrazone 
or oral hypoglycemics will decrease the MTX transport function of renal 
tubules, thereby reducing excretion and may increase MTX toxicity.
MTX may also interact with mercaptopurine and theophylline.  Acitretin (a 
treatment for psoriasis) is metabolised to eretinate.  MTX levels may be 
increased by eretinate and severe hepatitis has been reported following 
concomitant use.
Concomitant use of aspirin or NSAIDs
Hepatotoxic and nephrotoxic drugs.
6.11.3.3.
Complementary Therapies
The use of complementary therapies that may affect RA disease activity or assessments, 
including, but not limited to, traditional medicine (e.g. Chinese, acupuncture, Ayurvedic) 
is prohibited.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns.  Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table (Section 7.1).

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7.1.
Time and Events Table (Combination Treatment with GSK3196165 and MTX)
Procedures
Screening
- up to 4 
weeks
Baseline
Treatment Period
FU EW
1
Week
1
2
3
4
6
8
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
62
Visit
Visit
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
32
Day Day
Day21
-7
1
3* 8 15 22 29 43 57 71 85 99 113 127 141 155 169 183 197 211 225 239 253 267 281 295 309 323 337 351 365 435
Written Informed 
Consent(s)
X
Subject Demography
X
Medical, Disease, Therapy 
History
X
Inclusion/Exclusion 
Criteria
X
Efficacy2 and PRO Assessments3
Swollen (66) & Tender 
(68) Joint Count2
X
X4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient’s Assessment of 
Arthritis Pain, Patient’s 
Global Assessment of 
Arthritis, Physician’s 
Global Assessment of 
Arthritis3
X
X4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HAQ-DI3
X
X4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BFI Question 3, FACIT-
Fatigue, SF-36 (acute v2)3
X4
X
X
X
X
X
X
X
RA Symptom and Impact 
Diary3,5
X4
X
X
X
X
X
X
RA Symptom and Impact 
Diary, Actigraphy 
process3,6
X7
X8
X7
X8
X7
X8
X7
X8
X7
X8
X8

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Procedures
Screening
- up to 4 
weeks
Baseline
Treatment Period
FU EW
1
Week
1
2
3
4
6
8
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
62
Visit
Visit
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
32
Day Day
Day21
-7
1
3* 8 15 22 29 43 57 71 85 99 113 127 141 155 169 183 197 211 225 239 253 267 281 295 309 323 337 351 365 435
Safety Evaluations9
Concomitant Medication
X
X4
Record all concomitant medications
Physical Examination10, 
Vital Signs
X4
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG11
X
X
X
X
X
AEs/SAEs/AESI
X
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cough, Lung Auscultation, 
Pulse Oximetry, Borg 
Dyspnea Scale
X
X4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chest X-ray12
X
Spirometry (FEV1, FVC)
X
X4
X
X
X
X
X
X
DLCO
X13
X4,14
X
X
X
X
X
X
Laboratory Assessments
Hematology, Chemistry
X
X4
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis (dip stick)
X
X
X
X
X
X
X
X
X
X
X
X
Cholesterol, triglycerides, 
HDL, LDL15
X4
X
X
X
X
X
Pregnancy test16
S
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
TB, HBsAg, Hep B cAb, 
HepC Ab, HIV
X
RF, ACPA (anti-CCP)
X
CRP, ESR17
X
X4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Other Laboratory Assessments
PK Sampling 
(GSK3196165)18
X4
X* X
X
X
X
X
X
X
X
X
X
X
X

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Procedures
Screening
- up to 4 
weeks
Baseline
Treatment Period
FU EW
1
Week
1
2
3
4
6
8
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
62
Visit
Visit
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
32
Day Day
Day21
-7
1
3* 8 15 22 29 43 57 71 85 99 113 127 141 155 169 183 197 211 225 239 253 267 281 295 309 323 337 351 365 435
GM-CSF & PD blood 
biomarkers
X4
X* X
X
X
X
X
X
X
X
X
X
PGx sampling RNA19
X4
X
X
X
X
X
X
PGx sampling DNA19
X4
Lung biomarkers20
X4
X
X
X
X
X
X
Cholesterol/4-
hydroxycholesterol
X4
X
Immunogenicity21
X4
X
X
X
X
X
X
X
X
Anti-GM-CSF auto-
antibodies20
X4
Study Treatment 
GSK3196165/placebo22
(Methotrexate and folic 
acid weekly throughout 
treatment with 
GSK3196165)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Rescue point for possible 
dose escalation
X
X
Decision point for 
mandated withdrawal23
X

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1.
All subjects who discontinue study medication prematurely should have an early withdrawal (EW) visit as soon as possible after study agent discontinuation and then return for a 
follow-up safety visit at least 12 weeks after last dose of study medication.
2.
The same individual (where possible) should perform all disease assessments for an individual subject (with separate joint assessor).
3.
All PRO assessments should be conducted before any tests, procedures, assessments or consultations, to avoid influencing the subjects’ perception.
4.
Assessments may be performed up to 24 hours before dosing GSK3196165.
5.
Non-actigraphy sub-study subjects only.
6.
Performed in a subset of consenting subjects only.
7.
Actigraphy device placed and tagging process started (as detailed in the SRM), RA Symptom and Impact Diary questionnaire started on the same day at home using an electronic 
PRO (ePRO) device and completed on a daily basis until next visit.
8.
Actigraphy device collected and RA Symptom and Impact Diary questionnaire completed at site visit and ePRO device collected.
9.
All safety evaluations should be conducted before dosing GSK3196165.
10. Complete physical at baseline, and then limited physical examination (abdominal examination and heart sounds) thereafter.
11. ECG should be performed before vital signs, blood draws, and dosing.
12. Unless performed within previous 12 weeks (No need to repeat if subject re-screened).
13. Chest HRCT if DLCO ≥60% - <70% predicted (No need to repeat if subject re-screened).
14. If the screening DLCO value is ≥70% predicted, but the subsequent “Day 1” value is <70 but ≥60% predicted, the DLCO test must be repeated if still within the screening window.  If 
the repeat value is ≥70%, the “Day 1” activities may be completed, but if the value is again <70%, dosing must be postponed and a chest HRCT performed.  If this cannot be done 
within the screening window then the subject must be re-screened.
15. >8h fasting required before blood draw.
16. For women of child-bearing potential. S=serum; U=urine.
17. ESR measured locally.
18. Blood samples taken before dosing GSK3196165.
19. In consenting subjects.
20. To be analysed at end of study or in event of pulmonary safety signal.
21. In addition to these scheduled immunogenicity assessments, “event-driven” testing (see Section 7.6) will also be employed for those subjects that experience anaphylaxis, serious 
hypersensitivity, or adverse events related to study drug administration that led to withdrawal from the study.
22. GSK3196165 or placebo must be administered on the same day each week ±1 day for the first 5 weekly doses, thereafter on the same day EOW ±3 days.
23. Any subject not achieving EULAR good/moderate response at Week 36 will be withdrawn from the study at Week 38.
*
The Day 3 blood sample may be drawn ±1 day.

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7.2.
Screening and Critical Baseline Assessments
After written, informed consent (including separate consent for genetics research and 
actigraphy sub-study at participating sites), screening assessments will be performed.  
Screening procedures are outlined in the Time and Events Table (Section 7.1).  All 
screening assessments must be performed within 28 days of Day 1 (except for subjects 
being treated with azathioprine or leflunomide, where written informed consent for the 
study, or sub-study, must be obtained prior to beginning the screening period).  Women 
and men of reproductive potential must consent to use of a highly effective method of 
contraception for the duration of the study and for 12 weeks after study end (see 
Appendix 12.2), and the method (s) used by each subject must be documented.

The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.

Medical/medication/family history will be assessed as related to the 
inclusion/exclusion criteria listed in Section 5.

Cardiovascular medical history/risk factors (as detailed in the eCRF) will be assessed 
at screening.

Rheumatoid arthritis history – disease duration, medication history, RA functional 
class (I, II or III).

Physical examination (complete examination at screening, and brief examination at 
Day 1 visit; see Section 7.4.8).

Vital signs including temperature, sitting blood pressure, and heart rate.

Triplicate 12-lead ECG (before blood samples are taken).

Spirometry FEV1, FVC and DLCO (see SRM for additional details).

Blood samples for:

Hematology (full/complete blood count and differential), including ESR 
(screening and baseline).

Biochemistry (screening and baseline).

Serum βhCG pregnancy test (screening).

HIV antibody, Hepatitis B surface antigen, anti-HBc, and Hepatitis C antibody 
testing (screening).

CRP (screening and baseline).

Autoimmune serology: RF and ACPA (i.e., anti-CCP antibodies) (screening).

QuantiFERON Gold or T-spot test for TB (If unavailable/unapproved, then 
tuberculin skin test is permitted).  TB tests may be performed locally.

Exploratory GM-CSF, PD and lung biomarkers (baseline).

Plasma PK samples and immunogenicity (baseline).

Pharmacogenomic and RNA transcriptomic tests (in consenting subjects).

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
Urine sample for:

Routine urinalysis (screening).

Urine βhCG pregnancy test (baseline).

Disease activity assessments (screening and baseline) (see Section 7.3)

Tender joint count (68 joints).

Swollen joint count (66 joints).

Patient’s Assessment of Arthritis Pain.

Patient’s Global Assessment of Arthritis.

Physician’s Global Assessment of Arthritis.

HAQ-DI.

Patient-reported outcome questionnaires (baseline) (see Section 7.10)

Component of BFI.

FACIT-Fatigue.

Acute SF-36.

RA Symptom and Impact Diary.

Actigraphy (in consenting subjects at participating sites).
Patient-reported outcomes questionnaires should be completed by subjects before any 
other assessment at a clinic visit, in the order specified in the SRM.
7.3.
Efficacy
Efficacy assessments will be performed at the time points presented in the Time and 
Events Table (Section 7.1).
Efficacy assessments will include evaluation of all 68 joints for tenderness and 66 joints 
for swelling to be performed by an independent joint evaluator, VAS (global disease) for 
the subject and treating physician, health assessment questionnaire – disability index 
(HAQ-DI – physical function, which includes an item on pain severity in the past week), 
as well as other Health outcome measures described in more detail in Section 7.10 and 
laboratory assessments (CRP).  Based on these assessments ACR (20, 50 and 70), 
DAS28(CRP) and the EULAR response will be calculated.
For those subjects in the actigraphy sub-study at participating sites, physical activity 
levels will be assessed using actigraphy/an accelerometer.  RA symptoms will be 
assessed through the subject completion of a daily RA Symptom and Impact Diary (see 
Section 7.10).
7.3.1.
Joint assessments
The procedure for joint assessments can be found in the SRM.

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7.3.1.1.
Replaced or Fused Joints
Replaced or fused joint will not be included in joint evaluations.  The reason for absence 
of the evaluations of those joints must be recorded.
7.3.1.2.
Independent Joint Evaluator
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 
subject 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 subject during the 
trial, must not be the treating physician (investigator), should not discuss the subject's 
clinical status with the subject during the joint assessment nor with other site personnel, 
and will not be permitted to review the subject's medical records, the eCRF, nor any of 
the previous joint assessments.
7.3.2.
Patient’s Assessment of Arthritis Pain
Subjects will assess the severity of their current arthritis pain using a 100 unit visual 
analog scale (VAS) by placing a mark on the scale between “0” (no pain) and “100” 
(most severe pain), which corresponds to the magnitude of their pain.
Further details of this assessment are provided in the SRM.
7.3.3.
Patient’s Global Assessment of Arthritis
Subjects will complete a global assessment of disease activity using the patient global 
assessment (PtGA) item, a VAS with anchors “0” (very well) to “100” (very poor).
Further details of this assessment are provided in the SRM.
7.3.4.
Physician’s Global Assessment of Arthritis
Physicians will complete a global assessment of disease activity using the physician 
global assessment item (PhGA), a VAS with anchors “0” (none) to “100” (extremely 
active), respectively.
Further details of this assessment are provided in the SRM.
7.3.5.
DAS Assessments
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.

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The components of the DAS 28 arthritis assessment include:

Tender/Painful Joint Count (28).

Swollen Joint Count (28).

CRP or ESR.

Patient’s Global Assessment of Arthritis.
Sites/investigators will not have access to ongoing DAS scores, apart from the screening 
and Day 1 results (needed to confirm eligibility).  DAS28(ESR) value on Day 1 will be 
used to confirm disease activity eligibility by the IRTS before dosing.
7.3.6.
ACR Assessments
The American College of Rheumatology’s definition for calculating improvement in RA 
(ACR20) is calculated as a 20% improvement 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 
70 are calculated with the respective percent improvement.  This efficacy measurement 
will be made at every study assessment timepoint.
The specific components of the ACR Assessments that will be used in this study are:

Tender/Painful Joint count (68).

Swollen Joint Count (66).

Patient’s Assessment of Arthritis Pain.

Patient’s Global Assessment of Arthritis.

Physician’s Global Assessment of Arthritis.

CRP or ESR.

Health Assessment Questionnaire – Disability Index (HAQ-DI).
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).
7.4.1.
Screening visit(s)

Chest X-ray (PA and lateral, or in accordance with local requirements).
if a chest X-ray has been taken within the past 12 weeks that shows no 
clinically-significant abnormality, and there are no signs or symptoms 
suggestive of pulmonary disease that would exclude the subject, then a 
further chest X-ray is not required.

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
Baseline chest HRCT for subjects with DLCO values ≥60% to <70%, and it is 
recommended that the subject will be reviewed by a local pulmonologist to exclude 
significant pre-existing respiratory disease.

Immunogenicity testing.
7.4.2.
Study visits
Subjects will have systematic safety monitoring throughout the study.  Additional time 
points for safety tests (such as vital signs, physical exams and laboratory safety tests) 
may be added during the course of the study based on newly available data to ensure 
appropriate safety monitoring.
In addition to routine laboratory assessments, ECG monitoring, and evaluation of adverse 
events, particular attention will be paid to respiratory events and function given the 
potential risk associated with targeting GM-CSF and the effects on alveolar macrophages.  
This may result in the occurrence of the extremely rare condition of PAP, which is 
characterized by the accumulation of surfactant lipids and protein in the alveolar spaces 
(with no fibrosis), with resultant impairment in gas exchange, which may lead to increase 
a risk of secondary pulmonary infections.
All subjects will return for a follow-up visit at 12 weeks after last dose of study 
medication.
7.4.3.
Safety endpoints and other assessments

Incidence of AEs/SAEs.

Incidence of serious infections and opportunistic infections.

Pulmonary events (cough, dyspnea, pulse oximetry, spirometry, DLCO).

Lung biomarkers (such as SP-D, KL-6, LDH, cholestenoic acid).

ECG measurements.

Vital signs.

Hematological and clinical chemistry parameters.

Physical examinations.

Pregnancy test (for women of child-bearing potential).
7.4.4.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 12.4.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.

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7.4.4.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the follow-
up contact (12 weeks after the last dose of investigational product), at the timepoints 
specified in the Time and Events Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF.

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 12.4.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects.  However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the investigator 
must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 12.4.
7.4.4.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”
7.4.4.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.7.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4).  Further information on follow-up procedures is given in 
Appendix 12.4.
7.4.4.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 12.4 and all deaths, whether or not 
they are considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF 

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will be required to be completed.  These sections include questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death.
The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion.
The Death eCRF 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 cardiovascular eCRF within one week 
of when the AE/SAE(s) are first reported.
7.4.5.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgement of the investigator are to be recorded as AEs or SAEs.
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs.
7.4.6.
AEs of Special Interest
Please see Section 4.7.1 for a discussion of potential risks with GSK3196165.  Adverse 
events of special interest include:

Serious infections, including serious respiratory infections.

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
Opportunistic infections including TB reactivation.

Neutropenia.

Non life-threatening pulmonary changes related to surfactant accumulation.

PAP.

Hypersensitivity reactions, including anaphylaxis.

Injection site reactions.

Persistent cough or dyspnea.
7.4.6.1.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The following have been specified as disease-related events (DREs) for the study:

Events related to exacerbation of articular/peri-articular manifestations of RA, will 
not be reported as AEs, and will be recorded in the DRE eCRF.

Events related to the articular/peri-articular flare up of the disease, and that require 
hospitalization, will not be reported as SAEs.  However, such events must still be 
recorded in the DRE eCRF.
These DREs will be monitored by an SRT on a routine basis.
NOTE: However, if either of the following conditions apply, then the event must be 
recorded and reported as an SAE (instead of a DRE):

The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual subject.
OR

The investigator considers that there is a reasonable possibility that the event was 
related to treatment with the investigational product.
New onset or worsening of extra-articular manifestations of RA should be reported as 
AEs/SAEs.
7.4.6.2.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to 
study treatment (even for non- interventional post-marketing studies) is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the safety 
of a product under clinical investigation are met.
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.

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Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB GSK Document Number [2014N190256_01] and will notify the IRB/IEC, if 
appropriate according to local requirements.
7.4.7.
Pregnancy
Any pregnancy (participating females and female partners of participating males) that 
occurs during study participation must be reported using a clinical trial pregnancy form.  
To ensure subject safety, each pregnancy must be reported to GSK within 2 weeks of 
learning of its occurrence and should follow the procedures outlined in Appendix 12.5.
7.4.8.
Physical Exams

A complete physical examination at the Screening visit will include, at a minimum, 
assessment of the Cardiovascular, Respiratory, Gastrointestinal and Neurological 
systems.  Height and weight will also be measured and recorded.

A brief physical examination at subsequent assessments 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
7.4.9.
Vital Signs

Vital signs will be performed prior to dosing with GSK3196165.

Vital signs will be collected as indicated in the Time and Event Table (Section 7.1).

Vital signs will be measured in semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, pulse rate and respiratory 
rate.

A single set of values will be collected and recorded in the source documentation and 
eCRF.
7.4.10.
Electrocardiogram (ECG)
See Section 5.2 regarding QTc exclusion criteria.

Triplicate 12-lead ECGs will be obtained (before dosing and blood samples taken) at 
the time points presented in the Time and Events Table (Section 7.1) during the 
study using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTc intervals.  Refer to Section 5.4.2 for QTc 
withdrawal criteria and additional QTc readings that may be necessary.  ECGs will 
also be transferred and read centrally.

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7.4.11.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Section 7.1, must be 
conducted in accordance with the Laboratory Manual, and Protocol Time and Events 
Schedule (Section 7.1).  Laboratory requisition forms must be completed and samples 
must be clearly labelled with the subject number, protocol number, site/centre number, 
and visit date.  Details for the preparation and shipment of samples will be provided by 
the laboratory and are detailed in the Central Laboratory Manual.  Reference ranges for 
all safety parameters will be provided to the site by the laboratory responsible for the 
assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF.
Refer to the central laboratory manual for appropriate processing and handling of samples 
to avoid duplicate and/or additional blood draws.
All study-required laboratory assessments will be performed by a central laboratory, apart 
from:

ESR

The results of each test must be entered into the eCRF.
NOTE:  Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either a treatment and/or response evaluation to be 
performed.  If a local sample is required it is important that the sample for central 
analysis is obtained at the same time.  Additionally if the local laboratory results are used 
to make either a treatment or response evaluation, the results must be entered into the 
eCRF.
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 2.
Table 2
Routine Laboratory Assessments
Hematology
Biochemistry
Urinalysis 
Hemoglobin
Hematocrit
Mean cell volume (MCV)
Mean corpuscular hemoglobin (MCH)
Mean corpuscular hemoglobin concentration 
(MCHC)
Erythrocyte count
Reticulocyte count
Leukocyte count
Leukocyte differential count
neutrophils
eosinophils
Sodium
Potassium
Calcium
Phosphate
Urea
Creatinine
Creatinine clearance 
(calculated)
Aspartate transaminase 
(AST)
Alanine transaminase (ALT)
γ-glutamyl transpeptidase 
Urine dipstick
Glucose
Protein
Creatinine
Microscopy of 
urine sediment for 
erythrocytes, 
leukocytes and 
casts if urine 
dipstick abnormal

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Hematology
Biochemistry
Urinalysis 
basophils
monocytes
lymphocytes
Platelets
Activated partial thromboplastin time (aPTT)
Prothrombin Time (PT)
International Normalised Ratio (INR)
Fibrinogen
Erythrocyte Sedimentation Rate (ESR)*
(GGT)
Lactate dehydrogenase 
(LDH)
Alkaline phosphatase (AP)
Bilirubin (total)
Creatine Phosphokinase 
(CPK)
Total protein
Albumin
Albumin/globulin ratio
Serum Glucose
C-reactive protein (CRP)
Cholesterol**
Triglycerides**
High-density lipoprotein 
(HDL)**
Low-density lipoprotein 
(LDL)**
Urine pregnancy 
test
*Measured locally
**Fasting tests
All laboratory tests with values that are considered clinically-significantly abnormal 
during participation in the study or within 12 weeks after the last dose of study treatment 
should be repeated until the values return to normal or baseline.  If such values do not 
return to normal within a period judged reasonable by the investigator, the etiology 
should be identified and the sponsor notified.
Serum will be collected at baseline and throughout the study to measure potential 
biomarkers of lung damage such as SP-D, KL-6, LDH, and cholestenoic acid (see Section 
7.7).  Baseline measurement of GM-CSF autoantibodies will be measured.
7.4.12.
Pulmonary Assessments
Pulmonary assessments are a key aspect of the safety monitoring in this study.
The following pulmonary assessments will be performed at the time points presented in 
the Time and Events Table (Section 7.1).

Chest X-ray.

Cough.

Borg dyspnea questionnaire.

Lung auscultation.

Pulse oximetry.

Pulmonary function tests (PFTs - spirometry, gas transfer [DLCO]).

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PFT assessments will be standardized across study sites by the vendor.
In the event of any new or clinically significant pulmonary abnormalities that may 
develop during the study (e.g., increased shortness of breath/dyspnea, or unexplained and 
persistent coughing; or >15% relative decrease in DLCO from baseline), it is 
recommended that the subject be referred to a pulmonologist for further assessment.  The 
study drug should be suspended until the symptoms or signs that caused referral have 
resolved and/or the underlying diagnosis has been determined and clinically significant 
events have been excluded by the pulmonologist.  Suggested pulmonary 
assessment/management algorithms are provided in a separate Pulmonary Safety 
Guidance Document in the SRM.
Additional pulmonary imaging (HRCT) or other tests may be performed on a subject 
during the study to investigate pulmonary abnormalities, and the DRC or SRT may 
request copies of any reports or images for central review.
7.5.
Pharmacokinetics
Blood samples for pharmacokinetic analysis of GSK3196165 will be collected at the time 
points indicated in the Time and Events Table (Section 7.1).  The actual date and time of 
each blood sample will be recorded.  The timing of PK samples may be altered and/or PK 
samples may be obtained at additional time points to ensure thorough PK monitoring.  
Details of PK blood sample collection, processing, storage and shipping procedures are 
provided in the central laboratory manual.
7.5.1.
Sample analysis
Sample analysis will be performed under the control of GSK.  Concentrations of 
GSK3196165 will be determined in serum samples using the currently approved 
bioanalytical methodology.  Raw data will be archived at the bioanalytical site (detailed 
in the SRM).
PK analyses are described in Section 9.4.4.
7.6.
Immunogenicity
GSK3196165 is a humanized monoclonal antibody that will be delivered by the 
subcutaneous route and is targeted to bind and neutralize a soluble target, and for these 
reasons, is considered to be a relatively low risk of inducing adverse immune responses 
[FDA, 2014].
Serum samples will be collected and tested for presence of antibodies that bind to 
GSK3196165.  Serum samples for testing anti-GSK3196165 antibodies will be collected 
as described in the Time and Events schedule (Section 7.1).  The actual date and time of 
each blood sample collection will be recorded.  Details of blood sample collection 
(including volume to be collected), processing, storage and shipping procedures are 
provided in the Central Laboratory Manual.

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The timing and number of planned immunogenicity samples may be altered during the 
course of the study, based on newly-available data to ensure appropriate safety 
monitoring.  In the event of a hypersensitivity reaction that is either 1) clinically-
significant in the opinion of the investigator, or 2) leads to the subject withdrawing from 
the study, blood samples should be taken from the subject for immunogenicity testing, at 
the time of the event and again 12 weeks after.  For subjects who prematurely withdraw 
from the study, immunogenicity testing will occur at withdrawal and at follow-up 12 
weeks after last dose.
Serum will be tested for the presence of anti-GSK3196165 antibodies using the currently 
approved analytical methodology using a tiered testing schema: screening, confirmation 
and titration steps.  The presence of treatment emergent anti-drug antibodies (ADA) will 
be determined using a GSK3196165 bridging style ADA assay with a bio-analytically 
determined cut point determined during assay validation.  Samples taken after dosing 
with GSK3196165 that have a value at or above the cut-point will be considered 
treatment-emergent ADA-positive.  These ADA positive samples will be further 
evaluated in a confirmatory assay, and confirmed positive samples will be further 
characterized by assessment of titer.  Results of anti-GSK3196165 antibody testing will 
be reported at the end of the study and will include incidence and titer.  The presence or 
absence of antibodies to GSK3196165 in dosed subjects will be analyzed, then 
summarized descriptively and/or graphically presented.
7.7.
Biomarker(s)/Pharmacodynamic Markers
With the subject’s consent, blood samples will be collected at the time points indicated in 
the Time and Events Table (Section 7.1) to investigate pharmacodynamic response to 
GSK3196165 and will be analysed pre- and post-GSK3196165.  In addition blood 
samples will be collected and may be analysed for markers which may be predictive of 
lung damage and changes in CYP3A4 activity.  The timing of the collections may be 
adjusted on the basis of emerging PK, pharmacodynamic or safety data from this study or 
other new information in order to ensure optimal evaluation of the pharmacodynamic 
endpoints.  Details on the blood sample collection, processing, storage and shipping 
procedures are provided in the Central Laboratory Manual.  All samples may be retained 
for a maximum of 15 years after the last subject completes the study.  Results of 
biomarker studies may be reported separately from the main clinical study report, and 
additional exploratory analyses may be performed to further characterize novel 
biomarkers.
Target engagement with soluble GM-CSF will be assessed.  Serum will be collected to 
measure concentrations of free soluble GM-CSF and soluble GM-CSF complexed to 
GSK3196165 and correlated to PK.
A broad range of markers in serum collected at various timepoints as outlined in the Time 
and Events Table (Section 7.1) may be measured in serum including, but not limited, to:

Safety biomarkers which may be predictive of lung damage including, but not 
limited to, the following:

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-
Analysis of SP-D, KL-6, cholestenoic acid, LDH and measurement of GM-CSF 
autoantibodies at baseline.
-
These will be analysed at the end of the study or in the event of a pulmonary safety 
signal which would require further investigation.
Therapeutic proteins, such as GSK3196165, have the potential to reverse the suppression 
of cytochrome P450 expression levels.  To investigate this endogenous 4β-
hydroxycholesterol, a metabolite of cholesterol previously reported to be a clinical 
biomarker of CYP3A enzyme activity will be monitored [Nylén, 2011].  Since the 
cholesterol levels are expected to fluctuate throughout the study, the ratio of 4β-
hydroxycholesterol to cholesterol, instead of 4β-hydroxycholesterol alone, will be 
explored as a potential biomarker of CYP3A activity in this study.  Biomarkers predictive 
of a change in CYP3A4 activity may include, but not limited to, the following:

Plasma analysis of cholesterol/4β-hydroxycholesterol ratio
Pharmacodynamic biomarkers may include, but not limited to, the following:

Target engagement: analysis of free soluble GM-CSF and soluble GM-CSF 
complexed to GSK3196165.

Soluble biomarkers which may be predictive of response to GSK3196165 such as 
MRP8/14, CCL17 (TARC), ARGS, MMP-3, YKL-40, SAA and 14-3-3η.

Serum cytokines to monitor mechanism of action of GSK3196165 such as IL-6, IL-
1β, TNFα, IL-17A, IL-17F, CCL17/Thymus and activation regulated cytokine 
(TARC).

Additional cytokines on a Mesoscale discovery (MSD) multiplex panel will include 
measurement of IL-8, IL-4, IL-10, IL-13, and IFNγ.
Additional exploratory biomarkers in the blood/serum (RNA, DNA, protein) may include 
but will not be limited to the following:

Serum analysis (e.g., MMP-3, YKL-40, SAA, IL-23, etc.).

RNA analysis of blood.
7.8.
Novel Biomarkers
With the subject’s consent, blood sample(s) will be collected during this study and may 
be used for the purposes of measuring novel biomarkers to identify factors that may 
influence RA, and/or medically related conditions, as well as the biological and clinical 
responses to GSK3196165.  If relevant, this approach will be extended to include the 
identification of biomarkers associated with adverse events.
Evaluation of a range of exploratory novel biomarkers will allow confirmation of target 
engagement and expected pharmacologic effects.  These data may also allow hypotheses 
to be generated with respect to subgroups that are most likely to benefit from 
GSK3196165 treatment or early on-treatment biomarkers that may predict subsequent 
response/remission (or lack of response/remission), that may guide Phase III 
development and ultimately treatment guidelines for prescribers.

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Performance of these investigations may be conditional on the results of the clinical trial 
principally, but not exclusively, on the primary measures of the clinical trial outcome and 
samples may be selected for analysis on the basis of the clinical outcome.  Unless stated 
otherwise, these investigations may be performed irrespective of whether a response to 
GSK3196165 is observed.
Comparative examination of pre-dosing profiles of participants may uncover known or 
novel candidate biomarkers/profiles which could be used to predict response to treatment 
with GSK3196165 or provide new insights into RA and medically related conditions.  
Comparative examination of post-dosing profiles in conjunction with pre-dosing profiles 
may yield known and novel candidate biomarkers/profiles and new insights which relate 
to the action of GSK3196165.  All samples will be retained for a maximum of 15 years 
after the last subject completes the trial.
Details on the blood sample collection, processing, storage and shipping procedures are 
provided in the Central Laboratory Manual.
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with RA or medically related conditions and/or the action of 
GSK3196165 may be identified by application of:

RNA transcriptome analysis of blood samples.

Measurement of the levels of a subset of RNA species on blood samples.
7.9.
Genetics
Information regarding genetic research is included in Appendix 12.6.
7.10.
Value Evidence and Outcomes
Planned timepoints for all health outcomes assessments are presented in the Time and 
Events Table (Section 7.1), and further details of all assessments are provided in the 
SRM.
7.10.1.
Health Assessment Questionnaire – Disability Index (HAQ-DI)
The functional status of the subject 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.
7.10.2.
Brief Fatigue Inventory (BFI)
The purpose of the BFI is to assess the severity of fatigue and the impact of fatigue on 
daily functioning.  This self-reported instrument consists of nine questions which 
correlate well with quality-of-life measures.  For this study, Question 3 only will be used 
which asks about fatigue severity at its worst in the last 24 hours.

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7.10.3.
FACIT-Fatigue
The Functional Assessment of Chronic Illness Therapy (FACIT) -fatigue questionnaire is 
a patient-reported measure developed originally to assess fatigue in individuals with 
cancer validated.  The FACIT-fatigue has subsequently been used and validated in 
numerous chronic conditions, including RA.
7.10.4.
SF-36 Short Form Health Survey
Health-related quality of life (HRQL) will be assessed using the subject-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.
7.10.5.
RA Symptom and Impact Diary PRO
Symptoms associated with RA will be assessed using a novel RA Symptom and Impact 
Diary. Subjects participating in the actigraphy sub-study at participating sites will 
complete the RA Symptom and Impact Diary on a daily basis, at home, during the 
periods when the actigraphy device is placed on their person.  All other subjects will 
complete the RA Symptom and Impact Diary PRO during a study visit at 12-weekly 
intervals, as per the Time and Events Schedule (Section 7.1).
7.10.6.
Exploratory Health Outcomes Assessment - Actigraphy
Actigraphy is a non-invasive method of measuring rest and activity cycles.  Daily activity 
and walking can be measured over time using motion-sensing devices, such as 
accelerometers, which measure positional change and motion.  Actigraphy has been used 
as a tool to assess daily activity of subjects with impaired mobility [Reiterer, 2008], and 
may be particularly appropriate as the majority of RA patients present with arthritis of the 
feet and 20% of them have radiographic damage at the time of diagnosis [Michelson, 
1994].  Sleep deficit associated with RA and fatigue associated with osteoarthritis (OA) 
have also previously been investigated using actigraphy [Clarke, 2013; Murphy, 2013].  
The development of a tool which “objectively” measures RA subjects’ degree of gross 
mobility and activity could provide useful novel endpoints for demonstrating treatment-
associated improvement of RA symptoms including fatigue, morning stiffness and joint 
inflammation.
In this study, actigraphy data will be captured for a subset of consenting subjects at 
participating sites by a commercially available, continuous logging, three-axis electronic 
accelerometer.  Actigraphy data will be collected throughout the study as described in the 
Time and Events Table (Section 7.1).  Exploratory actigraphy endpoints may be 
evaluated as change from baseline and change over time.  The accelerometer will be 
placed on the subject upon visiting the clinic (asked to perform a short set of specific 
physical exercises) and will be worn by the subject continuously for up to 14 days of data 
collection.  At the end of the data collection period, coinciding with a study visit, the 
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recharged for reuse.  The raw accelerometer data will be analysed using an RA-specific 
algorithm being developed by GSK.  At present, the algorithms are exploratory and un-
validated.  The processed data will be sent to GSK for final statistical analysis.  The 
subject’s activity/lifestyle, residence and working status during the data collection period 
will be recorded in the eCRF.  The date and time of sensor placement and removal will 
also be recorded in the eCRF.
This study will aim to explore the application of actigraphy by:
1. Measuring quantitative measures of physical activity and sleep in RA patients.
2. Evaluating treatment effects of GSK3196165 on physical activity and sleep in RA 
patients.
3. Evaluating how measures of physical activity relate to subject reported measures 
of symptoms and other efficacy assessments including DAS28(CRP), ACR and 
biomarkers of disease activity.
Measures to include but may not be limited to:
1. Daily and intra-daily physical activity to include time spent walking, time spent 
standing, time spent lying down, time spent sitting.  Other measures may be 
derived from these data including overall time spend active, overall time spent 
sedentary, total Activity Score (amount and intensity of activity), duration of 
morning stiffness and number of continuous walking periods above a predefined 
threshold.
2. Sleep quality – to include time spent lying, number of movement episodes, sleep 
efficiency (function of % of movement time and % of lying time) and 
fragmentation index (function of movement time % and number of movement 
episodes).
The results from these assessments will be reported separately.
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK-defined eCRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.

eCRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials will 
not be collected or transmitted to GSK according to GSK policy.

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9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
9.1.
Hypotheses
The primary endpoint of the study is to evaluate the proportion of subjects that achieve 
DAS28(CRP) remission (DAS28 <2.6) following 24 weeks of treatment with 
GSK3196165 or matching placebo in adult subjects on concomitant MTX therapy.
The study will test the null hypothesis that there is no difference between any dose of 
GSK3196165 and placebo in the proportion of subjects with remission at Week 24 versus 
the alternative hypothesis that at least one of the GSK3196165 dose groups differs from 
placebo in the proportion of subjects with remission at Week 24.
The null hypothesis (H0) for the dose response relationships assumes that there is no 
effect of the test drug and hence no evidence of dose-response.  This is equivalent to 
saying that none of the doses are superior to placebo:
H0: Placebo = 22.5 mg = 45 mg = 90 mg = 135 mg = 180 mg
Whereas the alternate hypothesis (H1) assumes that there is a significant relationship 
between GSK3196165 dose and response with respect to the change from baseline in the 
DAS28(CRP) continuous score.  It is expected that this relationship will follow an Emax 
model.  The details of how the dose-response model will be described are outlined in 
Section 9.4.2.
The alternative hypotheses to be tested are as follows:
DAS28(CRP) Change from Baseline:  H1: Placebo ≥22.5 mg ≥45 mg ≥90 mg ≥135 mg 
≥180 mg
9.2.
Study Design Considerations
9.2.1.
Sample Size Assumptions
The sample size assumptions outlined below for the primary and key secondary 
objectives assume that all doses are carried through to the end of the study, although there 
is the option to stop randomisation to doses following the interim analyses if clinical 
response criteria are not met, therefore the sample size gives the minimum number of 
subjects per arm.
The following sample size assumptions have been applied for the primary analysis and 
the dose response analysis:
9.2.1.1.
Primary Analysis
The sample size for the primary analysis and hence the overall sample size for the study 
is based on detecting a 30% difference from placebo in the proportion of subjects in 
remission (DAS28 score <2.6) at Week 24 of the 52 week double-blind treatment period 
for each GSK3196165 dose.

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Using a Fisher’s exact test, a sample size of 35 subjects per arm will provide 
approximately 90% power to detect a difference of 30% in the proportion of subjects in 
remission between each GSK3196165 dose (33%) and placebo (3%) at the two-sided 
α=0.05 level at 24 weeks.  The placebo rate of 3% is based on a literature review of 
current therapies presenting DAS28(CRP) remission results.  No adjustments will be 
made to the sample size to account for the multiple doses in this Phase 2 study.
The least significant difference this sample size will detect is a 17% difference from 
placebo.
The sample size will not be increased to account for dropouts and all dropouts within the 
treatment period will be classed as non-remitters for the primary analysis.
9.2.1.2.
Dose Response Analysis
It is estimated the dose response analysis can be conducted once a minimum of 15 
subjects in each of the six treatment groups complete 12 weeks of treatment.  Other 
analyses at earlier time points may also be conducted.  The sample size has been 
estimated using simulation.
The anticipated dose response curve assuming the numbers summarised below, and the 
precision around it was obtained through 100000 simulations where the following 
changes from baseline in DAS28(CRP) have been assumed at each dose level, with a 
between subject standard deviation of 1 (based on Phase 2 data in a DMARD-IR 
population):
Table 3
Assumed Change from Baseline in DAS28(CRP) Responses at 12 
Weeks
Treatment
Placebo
22.5 mg
45 mg
90 mg
135 mg
180 mg
DAS28(CRP) change from baseline
-1.0
-1.54
-1.83
-2.1
-2.24
-2.32
N
N=15
N=15
N=15
N=15
N=15
N=15
The assumed change from baseline in DAS28(CRP) of 1.0 points on the placebo arm is 
based on a review of studies in a DMARD-IR population.
It is expected that the shape of the dose response curve will be sigmoidal and the data for 
the DAS28(CRP) change from baseline was simulated assuming the following three 
parameter Emax model:
Y = E0 + Emax * [Di /{ ED50 + Di }]
Where E0 is the minimum dose effect, Emax is the maximum achievable effect above E0, 
ED50 is the dose at half Emax and Di are the doses = 0, 22.5, 45, 90, 135 and 180 mg.  Y is 
a measure of DAS28(CRP) change from baseline.  In this case the E0 is the assumed 
effect with Dose=0 (placebo) which is -1.0 and the Emax is taken as -1.65, the maximum 
achievable effect above placebo.

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Figure 2 shows the first 100 prediction curves (from 100000 simulations) and the overall 
median curve with the assumptions outlined above, illustrating the anticipated dose 
response curve with 15 subjects per arm.  The black vertical intervals around each dose 
represent the change from baseline in DAS28(CRP) that are the 2.5 and 97.5 percentile 
values from all simulations.
Table 4 displays the proportion of simulations that are within a precision of 0.45 units in 
the change from baseline in DAS28(CRP) at each dose, with 15 subjects per arm.  For the 
135mg dose this is 98.9%.
Table 4
Proportion of Simulations that are Within a Precision of 0.45 Units in 
the Change from Baseline in DAS28(CRP) at each Dose
22.5 mg
45 mg
90 mg
135 mg
180 mg
90.4%
97.9%
98.8%
98.9
95%
Figure 2
Plot of the First 100 Prediction Curves with the Overall Median Curve 
at the Dose Response Analysis

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9.2.2.
Sample Size Sensitivity
9.2.2.1.
Primary Analysis
The power of the study will be affected by changes from the assumed remission rate and 
Table 5 shows the effect on power under varying remission rates on both MTX and 
GSK3196165 assuming a fixed sample size of 35 per arm.
Table 5
Power for Remission Endpoint at 24 Weeks under Varying 
Remission Rates on MTX and GSK3196165
MTX Remission Rate
GSK3196165 Remission Rate
25%
33%
45%
3%
69%
90%
99%
10%
27%
57%
89%
15%
12%
32%
73%
9.2.2.2.
Dose Response Analysis
A key aspect of determining the sample size to assess dose response is the precision 
around the model estimates of the response (change from baseline on the DAS28(CRP)).  
Table 6 outlines the proportion of simulations that are within a precision of 0.45 units in 
the change from baseline in DAS28(CRP) at the 22.5 mg and 135 mg dose groups for 
different estimates of the sample size and different values of the SD estimate, following 
10000 simulations.
Table 6
Proportion of Simulations that are Within a Precision of 0.45 Units in 
the Change from Baseline in DAS28(CRP) at the 22.5 and 135 mg 
Dose Groups Following 10000 Simulations
SD Estimate
N per
Treatment group
Proportion
22.5 mg
135 mg
0.7
10
98.4%
99.7%
13
99.8%
99.9%
15
99.9%
99.9%
1.0
10
61.5%
96.5%
13
81.8%
98.2%
15
90.3%
98.9%
1.3
15
52.2%
94.7%
20
73.4%
97.5%
25
89.5%
98.4%
Table 7 gives the 2.5 and 97.5 percentiles around the median estimates of response 
(Change from baseline in DAS28(CRP)) at each dose level assuming 20 subjects per
treatment group for differing values of the SD estimates following 10000 simulations.

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Table 7
2.5 and 97.5 Percentiles around the Median Estimates of Response 
at each Dose Level Following 10000 Simulations
SD 
Estimate
Placebo
22.5 mg
45 mg
90 mg
135 mg
180 mg
0.7
-1.33, -0.64
-1.83, -1.33
-2.03, -1.61
-2.27, -1.92
-2.44, -2.03
-2.59, -2.08
1.0
-1.44, -0.49
-1.93, -1.24
-2.11, -1.54
-2.33, -1.85
-2.52, -1.95
-2.69, -1.99
1.3
-1.54, -0.34
-2.02, -1.17
-2.18, -1.47
-2.41, 1.78
-2.60, -1.88
-2.80, -1.93
9.2.3.
Sample Size Re-estimation
No sample size re-estimation is planned, though the maximum sample size per group may 
be higher than 35 subjects depending on any decisions to change the randomisation.  The 
maximum sample size of the study will not be increased.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Intent to Treat (ITT) population: The ITT population is defined as all subjects who 
were randomised to treatment and who received at least one dose of study treatment.
Pharmacokinetic (PK) population: The PK population is defined as all subjects who 
were randomised to treatment, who received at least one dose of study treatment and who 
have at least one valid pharmacokinetic assessment.
9.3.2.
Analysis Data Sets
For the binary endpoints (e.g. proportion of subjects achieving remission at 24 weeks), 
subjects with missing efficacy data (caused by prematurely discontinued subjects or 
otherwise) or subjects who received rescue treatment will be imputed as non-responders.  
A dataset will be created with this imputation and will be referred to as Non-Responder 
Imputation (NRI) and will be the primary dataset used for all binary endpoints.
In addition to the Non-Responder Imputation dataset for binary endpoints, for all efficacy 
endpoints a Observed Case (OC) dataset will be created, whereby the data are as 
collected or observed in the study and no imputation is made for missing data.  All 
continuous endpoints will be analysed using the OC dataset and all data will be listed 
using the (OC) dataset.
9.3.3.
Interim Analyses
Interim analyses will be conducted to assess the efficacy or futility of GSK3196165 in 
this study.  Recruitment will continue while the interim analyses are being conducted.
The interim analyses to assess futility and possible adaptation of doses will be performed 
when appropriate data are available and full details will be provided in a separate 
guidance document for the data review committee and the analysis plan which will be 
available prior to the data being unblinded.  To prevent potential unblinding of the 

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investigator and potential bias to the study, details of the timing of the interim analysis, 
data to be reviewed and the interim analysis decision rules are not being provided in the 
protocol.
The specific guidance around the decision to stop further randomisation will be specified 
in the review group guidance document and will be agreed with the review group 
members prior to the first data review.
Safety data will also be reviewed on an on-going basis as defined in Section 4.3 and 
Section 10.8.1.
In addition, the interim analysis may also allow an assessment of subjects with early RA 
(<2 years disease duration), and, based on results, the proportion of subjects in this 
subgroup required to be randomised may be revised.
9.4.
Key Elements of Analysis Plan
Full details of all analyses will be provided in the analysis plan.
9.4.1.
Primary Analyses
The primary efficacy endpoint is the proportion of subjects achieving DAS28(CRP) 
remission at Week 24 of the 52-week double-blind treatment period in the ITT population 
using NRI.  DAS28(CRP) remission is defined as a DAS28 score of <2.6 points.  The 
DAS28(CRP) score is calculated using the following formula, where TJC = tender joint 
count, SJC = swollen joint count and PtGA = Patient’s Global Assessment of Arthritis:
Subjects with missing DAS28(CRP) scores at Week 24 will be considered as non-
remitters.  The proportion of subjects in DAS28(CRP) remission will be summarised
using counts and proportions in remission and analyzed using a logistic regression 
analysis adjusted for treatment group and baseline DAS28(CRP) score and will be used 
to test the treatment comparison of each GSK3196165 dose group versus placebo.  For 
each treatment comparison, an estimate of the odds ratio of achieving remission and the 
corresponding p-value and 95% confidence interval will be summarised.
9.4.2.
Secondary Analyses
The key secondary analysis of assessing dose response at 12 weeks will be based on the 
change from baseline in the DAS28(CRP) continuous score after 12 weeks of treatment.  
Primary inference will be based on the ITT population, as defined in Section 9.3.1 and 
the analysis will be performed using the OC dataset.  Further sensitivity analyses using 
multiple imputation may be conducted if the rate of dropout is larger than expected 
(<10% to Week 12).

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It is expected that the shape of the dose response curve will be sigmoidal and the data 
will be initially analyzed using a three parameter Emax model of the form:
Y = E0 + Emax * [Di /{ ED50 + Di }]
where E0 is the minimum dose effect or placebo effect, Emax is the maximum achievable 
effect above placebo, ED50 is the dose at half Emax and Di are doses =0, 22.5, 45, 90, 135 
and 180 mg.  Y is a measure of DAS28(CRP) continuous score.
If this Emax model is not applicable then additional models will be investigated, including 
a four parameter Emax model and the model with the expected response as a linear 
function of dose.  These models will be detailed in the reporting and analysis plan (RAP), 
along with further details of the analyses to be conducted.  Each of the models will be 
fitted to the data and their fit compared using the Aikake information criteria (AIC), 
where the model with the lowest AIC will be the primary model for inference.  The 
additional models will be considered secondary models, and will not be utilised unless 
issues arise with the residual checks on the primary model.
Distributional assumptions underlying this analysis will be assessed (further details will 
be included in the RAP).
All binary secondary endpoints will be analyzed using the same methods as for the 
primary endpoint.  Continuous secondary endpoints, apart from the assessment of dose 
response, will be analyzed using a repeated measures model (MMRM).  Further 
sensitivity analyses may be conducted using multiple imputation if the rates of dropout 
are high.  Full details will be given in the RAP.
9.4.3.
Other Analyses
All safety evaluations will be based on the ITT population.  Clinical interpretation will be 
based upon review and displays of extent of exposure, adverse events (AE), serious 
adverse events (SAEs) and AEs of Special Interest, premature discontinuations, 
laboratory values, vital signs, and changes in pulmonary function (e.g., spirometry, 
DLCO).  Analyses of AEs by the investigator-reported relationship to investigational 
product will also be performed.
Full details of all summaries and analyses will be included in the RAP.
Safety data will be monitored throughout the study and key events will be analysed using 
Bayesian methods.  Full details will be provided in the DRC Charter and guidance 
document.
9.4.4.
Pharmacokinetic Analyses
PK analysis will be the responsibility of the Clinical Pharmacology Modelling and 
Simulation Department, GlaxoSmithKline.  Concentrations of GSK3196165 and MTX in 
serum will be listed and summarised by treatment group and nominal time.  Standard 
summary statistics will be calculated (i.e. mean, standard deviation, median, minimum 

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and maximum).  Individual serum concentration-time profiles and median/mean profiles 
by treatment group will be plotted.
Serum concentration levels of GSK3196165 from this study will be evaluated using a 
population pharmacokinetics model developed based on previous GSK3196165 data 
from healthy subjects (Phase I) and RA subjects from the Phase 1b study.  Primarily, the 
model buildings will be conducted with aid of NONMEM VII.  Other computing 
programs, e.g. MONOLIX, may also be used for model investigations.  The aim(s) of this 
modelling approach will include:

Define the population and individual systemic exposure (AUC0-t,ss, Cmax,ss, Cmin,ss), 
volume distribution and clearance of GSK3196165 and the associated between- and 
within-subject variability.

Explore the effects of subjects' characteristics (such as gender, weight, height, 
disease status, baseline GM-CSF levels, etc.) as potential sources of inter-individual 
variability in drug exposure.

The model predicted exposure of GSK3196165 for each individual randomised in the 
GSK3196165 groups will be used to assist further PK-PD relationships for 
biomarkers and/or clinical response if possible.  Further details on the analysis will 
be described in the RAP.
PK parameters will be presented in graphical and/or tabular form and will be summarised 
descriptively.  All PK data will be stored in the Archives, GlaxoSmithKline 
Pharmaceuticals, R&D.
9.4.4.1.
Pharmacodynamic Analyses
All pharmacodynamic data will be summarised, graphically represented and listed 
appropriately.  More details are included in the RAP.
9.4.4.2.
Pharmacokinetic/Pharmacodynamic Analyses
Exploratory plots will be presented for individual and/or pooled plasma GSK3196165 
concentrations versus the DAS28 change from baseline.  If data permit, potential 
association between systemic exposure of GSK3196165 and identified pharmacodynamic 
markers (e.g. CRP, MRP8/14) and efficacy endpoints (e.g. probability of achieving 
DAS28(CRP) remission or response) will be studied.  If deemed necessary, statistical 
modelling, including linear and non-linear models will be investigated.  All the modelling 
investigation will be exploratory and details will be provided in the RAP.
9.4.5.
Immunogenicity Analysis
Details of the statistical analysis will be provided in the RAP.
9.4.6.
Novel Biomarker(s) Analyses
The results of these biomarker investigations may be reported separately from the main 
clinical study report.  All endpoints of interest from all comparisons will be descriptively 

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and/or graphically summarised as appropriate to the data.  Additional exploratory 
analyses may be performed to further characterize the novel biomarker(s).
9.4.7.
RNA Transcriptome Analysis
RNA transcriptome profile data will first be normalised to enable direct comparison of all 
data sets.  Uninformative data (RNA species in all samples below detectable limits or 
levels unchanged across all samples under comparison) will be removed and multivariate 
statistical analyses will be performed on the remaining data to uncover intrinsic 
differences and similarities in the levels of RNAs between the different samples, and 
groups of samples.  Statistical tools such as Principal Component Analysis, PLS-
Discriminant Analysis, and ANOVA using either standard or customised software will be 
used for the profile analysis to assist identification of patterns/profiles which may 
associate with treatment outcome or RA and medically related conditions.
9.4.8.
RNA Expression Analysis of a Subset of RNA Species
RNA expression profile data are first normalised to enable direct comparison of all data 
sets.  After data reduction to remove uninformative data (RNAs whose levels are below 
levels of detection for all samples, and those whose levels are unchanged across all 
samples) the remaining data will be subject to a series of multivariate statistical analyses 
to uncover intrinsic differences and similarities in the levels of RNAs between the 
different samples.  This will include application of statistical tools such as Principal 
Component Analysis, and ANOVA using standard analysis software as well as software 
packages customised for such profile analysis to assist identification of patterns/profiles 
which may associate with treatment outcome and/or RA.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

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
IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable.

Signed informed consent  to be obtained for each subject before participation in the 
study (and for amendments as applicable).

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC).
GSK will provide full details of the above procedures, either verbally, in writing, or both.

Signed informed consent(s) must be obtained for each subject prior to participation 
in the study or sub-studies.

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, written 
approval of the clinical protocol should state that approval of optional assessments is 
being deferred and the study, with the exception of the optional assessments, can be 
initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK or designee monitors will contact the site prior to the start of the study to 
review with the site staff the protocol, study requirements, and their responsibilities 
to satisfy regulatory, ethical, and GSK requirements.

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF will 
serve as the source document.
GSK or designee will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK or 
designee may conduct a quality assurance assessment and/or audit of the site records, 

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and the regulatory agencies may conduct a regulatory inspection at any time during 
or after completion of the study.

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK or designee 
monitor will conduct site closure activities with the investigator or site staff, as 
appropriate, in accordance with applicable regulations including GCP, and GSK 
Standard Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance.  For multicenter studies, this can occur at one or more or at all sites.

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study.  GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.

Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.

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
The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required.  Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 
institutional requirements or local laws or regulations, GSK standards/procedures, 
and/or institutional requirements.

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership 
of the records in the event the investigator is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication

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 subjects, 
as appropriate.

GSK will provide the investigator with the randomization codes for their site only 
after completion of the full statistical analysis.

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
10.8.
Review Committees
10.8.1.
Data Review Committee (DRC)

A DRC will be utilised in this study to ensure objective medical and/or statistical 
review of efficacy and/or safety issues in order to protect the ethical and safety 
interests of subjects and to protect the scientific validity of the study via review of 
unblinded study data.

The DRC (consisting of external rheumatology, infectious disease and respiratory 
experts, and GSK study team members that have no involvement in the acquisition 
of the data or direct contact with sites) will review ongoing unblinded safety data 
from the study and unblinded efficacy data at the interim analyses.  The first DRC 
review of safety data will be conducted after approximately 10 subjects per arm have 
completed 5 weeks of treatment, and subsequent reviews will take place 

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approximately every 12 weeks thereafter until the end of the study.  The decision to 
stop the study or randomisation to specific arms will be made by the DRC.

The DRC members will review unblinded summary safety data, and if required will 
review anonymised individual data on request.  Only the DRC statistician will be 
unblinded to individual subject treatment allocations.

At the defined interim analysis time points the DRC will also review unblinded 
efficacy data.  Unblinded efficacy data will also be reviewed if needed outside of the 
planned interim analyses to assess benefit:risk based on the safety findings.  When 
possible, these reviews will be scheduled to align with planned safety reviews.  The 
schedule of planned interim analyses and the analysis plan for DRC reviews will be 
described in the relevant guidance documents that will be approved prior to the first 
analysis, which will be available upon request.

The DRC will remain in place for review of emerging unblinded safety data until all 
subjects have completed the safety follow-up visit (i.e., 12 weeks after the last dose 
of study medication, Week 62 visit).  The Week 24 efficacy and safety analyses 
(primary analysis) will be made available to the study team more broadly and to 
regulatory authorities as these data will support future clinical development plans.

A vote of the DRC committee will be taken at the conclusion of each meeting of the 
DRC.  Each meeting of the committee will be associated with an active 
recommendation of proceeding unchanged, modifying or terminating the study.  
Further details will be outlined in the DRC Charter.

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11.
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12.
APPENDICES
12.1.
Appendix 12.1 - Abbreviations and Trademarks
C
Degree Celsius
g
Microgram
ACPA
Anti-cyclic citrullinated protein antibody
ACR
American College of Rheumatology
ACR20/50/70
20%/50%/70% improvement in tender and swollen joint counts and 
20%/50%/70% improvement in 3 of the 5 ACR-core set measures
ADA
Anti-drug antibody
ADCC
Antibody-dependent cell mediated cytotoxicity
AE
Adverse event
ALT
Alanine transaminase
AMD
Age-related macular degeneration
AP
Alkaline phosphatase
aPTT
Activated partial thromboplastin time
AST
Aspartate transaminase
AUC
Area under the curve
AUC0-
Area under plasma (serum) concentration-versus-time curve (time zero 
to infinity)
AUC0-t
Area under the plasma (serum) concentration-versus-time curve (time 
zero to time of last quantifiable concentration)
BAL
Bronchoalveolar lavage
βhCG
Beta-subunit human chorionic gonadotropin
BCG
Bacillus Calmette-Guérin
BFI
Brief Fatigue Inventory
BMI
Body mass index
BNP
B-type natriuretic peptide
CDAI
Clinical disease activity index
CD20
Cluster of differentiation antigen 20
CDC
Complement-dependent cytotoxicity
CIA
Collagen-induced arthritis
COX
Cyclo-oxygenase
CPK
Creatine phosphokinase
CRO
Contract Research Organization
CRP
C-reactive protein
CTC
Common terminology criteria
CYP
Cytochrome P
CXR
Chest X-ray (radiograph)
DAS28
Disease activity score for 28 different joints
DAS28(CRP)
Disease activity score for 28 different joints with CRP value
DAS28(ESR)
Disease activity score for 28 different joints with ESR value
DLCO
Diffusing capacity of the lung for carbon monoxide
DNA
Deoxyribonucleic acid
DMARD
Disease modifying antirheumatic drugs

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DRC
Data Review Committee
DRE
Disease-related event
ECG
Electrocardiogram
eCRF
Electronic case report form
EOW
Every other week
ESR
Erythrocyte sedimentation rate
EULAR
European League against Rheumatism
EW
Early withdrawal
FACIT
Functional assessment of chronic illness therapy
FEV1
Forced expiratory volume in one second
FRP
Females of reproductive potential
FSH
Follicle-stimulating hormone
FVC
Forced vital capacity
GGH
Gamma-glutamyl transpeptidase
GM-CSF
Granulocyte-macrophage colony stimulating factor
GM-CSFRα
Granulocyte-macrophage colony stimulating factor receptor α chain
GSK
GlaxoSmithKline
h
Hour
HAQ-DI
Health Assessment Questionnaire Disability Index
HDL
High-density lipoprotein
HLA
Human leukocyte antigen
HRCT
High-resolution computed tomography
HRT
Hormone replacement therapy
HV
Healthy volunteer
IA
Intra-articular
IB
Investigator’s brochure
IC50
The half maximal inhibitory concentration
ICH
International Conference on Harmonization
IFNγ
Interferon gamma
IL-1β
Interleukin 1 beta
IL-4
Interleukin 4
IL-6
Interleukin 6
IL-10
Interleukin 10
IL-13
Interleukin 13
IL-17
Interleukin 17
IL-22
Interleukin 22
IL-23
Interleukin 23
IM
Intramuscular
IMP
Investigational medicinal product
INN
International non-proprietary name
INR
International normalized ratio
IP
Investigational product
IR
Inadequate response
IRTS
Interactive response technology system
ITT
Intent to Treat
IU
International units

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IV
Intravenous
kDa
Kilodalton
kg
Kilogram
KL-6
Krebs von den Lungen-6
L
Litre
LDH
Lactate dehydrogenase
LDL
Low-density lipoprotein
LFT
Lung function test
mAb
Monoclonal antibody
MCV
Mean cell volume
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MedDRA
Medical dictionary for regulatory activities
mg
Milligram
mL
Milliliter
MMP-3
Matrix metalloproteinase 3
MSD
Mesoscale discovery
MSDS
Material safety data sheet
MSS
Modified Sharp score
MTX
Methotrexate
n.a.
Not applicable
n.d.
Not determined
ng
Nanogram
NOEL
No observed effect level
NOAEL
No observed adverse effect level
NSAID
Non-steroidal anti-inflammatory drug
OMERACT
Outcome Measures in Rheumatology
PAP
Pulmonary alveolar proteinosis
PBMC
Peripheral blood mononuclear cells
PD
Pharmacodynamic
PFT
Pulmonary function test
PtGA
Patient’s Global Assessment of Arthritis
PhGA
Physician’s Global Assessment of Arthritis
PK
Pharmacokinetics
pM
Picomolar
PT
Prothrombin Time
PTS-DMPK
Platform Technologies and Science - Drug Metabolism and 
Pharmacokinetics
RA
Rheumatoid arthritis
RAP
Reporting and analysis plan
RF
Rheumatoid factor
SC
Subcutaneous
SAA
Serum amyloid A
SAE
Serious adverse event
SDAI
Simple disease activity index
SJC
Swollen joint count

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SF-36
Short form (36)
SOP
Standard operating procedure
SP-D
Surfactant D
SRM
Study Reference Manual
SRT
Safety Review Team
t½
Elimination half-life
TARC
Thymus and activation regulated cytokine
TB
Mycobacterium tuberculosis
TEAE
Treatment emergent adverse event
TJC
Tender joint count
TNFα
Tumor necrosis factor alpha
TST
Tuberculin skin test
ULN
Upper limit of normal
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
MEDdra
MONOLIX
NONMEM VII
SF-36v2

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12.2.
Appendix 12.2 - Contraception eligibility criteria for female 
and male subjects
12.2.1.
Females
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative serum human chorionic gonadotropin [βhCG] test), not lactating, and at least 
one of the following conditions applies:
a. Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation.
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion.
Hysterectomy.
Documented bilateral oophorectomy.
Postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable 
cases a blood sample with simultaneous follicle-stimulating hormone (FSH) and 
estradiol levels consistent with menopause (refer to laboratory reference ranges for 
confirmatory levels)].  Females on hormone replacement therapy (HRT) and whose 
menopausal status is in doubt will be required to use one of the highly effective 
contraception methods if they wish to continue their HRT during the study.  
Otherwise, they must discontinue HRT to allow confirmation of post-menopausal 
status prior to study enrolment.
b. Reproductive potential and agrees to follow one of the options listed below in the 
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) requirements from 30 days prior to the first dose of 
study medication and until 12 weeks after the last dose of study medication and 
completion of the follow-up visit.  If using hormonal contraceptives, including oral, 
injections, implants, and patches, a secondary method of contraception must be 
used.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
Modified List of Highly Effective Methods for Avoiding Pregnancy in 
Females of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle.  Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
Contraceptive subdermal implant.

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Intrauterine device or intrauterine system.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011].
Injectable progestogen [Hatcher, 2011].
Contraceptive vaginal ring [Hatcher, 2011].
Percutaneous contraceptive patches [Hatcher, 2011].
Male partner sterilization with documentation of azoospermia prior to the female
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011].  The documentation on male sterility can come from the site 
personnel’s review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  If using hormonal contraceptives, 
including oral, injections, implants, and patches, a secondary method of contraception 
must be used.  The investigator is responsible for ensuring that subjects understand 
how to properly use these methods of contraception.
12.2.2.
Males
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until 12 weeks after the last dose of study medication.
a. Vasectomy with documentation of azoospermia.  The documentation on male 
sterility can come from the site personnel’s review of subject’s medical records, 
medical examination and/or semen analysis, or medical history interview.
b. Male condom plus partner use of one of the contraceptive options below:
Contraceptive subdermal implant.
Intrauterine device or intrauterine system.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011].
Injectable progestogen [Hatcher, 2011].
Contraceptive vaginal ring [Hatcher, 2011].
Percutaneous contraceptive patches [Hatcher, 2011].
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
Male subjects should not donate sperm during the course of the study and should follow 
local guidelines thereafter.
Reference:
Hatcher RA, Trussell J, Nelson AL, et al, editors. Contraceptive Technology. 20th 
edition. Atlanta, Georgia: Ardent Media; 2011: 50. Table 3-2.

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12.3.
Appendix 12.3 - Liver Safety Required Actions and Follow-
up Assessments
Liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1,2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR >1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted.

If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 
treatment and may continue subject in the study 
for any protocol specified follow up assessments
MONITORING:
For bilirubin or INR criteria:

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained less than 12 weeks 
after last dose5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form

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
Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize 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 perform 
liver event follow up assessments within  24-72 
hrs

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]).

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 treatment for that subject 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, 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); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF.  If the date or time of the last dose is unclear, provide the subject’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.

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Liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the Medical Monitor within 24 hours of 
learning of the abnormality to discuss subject safety.

Subject can continue study treatment

Subject 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 subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
Reference:
James LP, Letzig L, Simpson PM, et al. Pharmacokinetics of acetaminophen-protein 
adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab 
Dispos 2009;37:1779-84.

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12.4.
Appendix 12.4 - Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

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 medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

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 treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This 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.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

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 subject’s condition.

Signs and symptoms of RA disease activity, e.g. joint pain, swelling, erythema, 
warmth, and stiffness, or expected progression, should not be reported as AEs, unless 
in the investigator’s opinion they are of greater intensity, frequency or duration than 

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expected for the individual subject.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where 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.
12.4.2.
Definition of Serious Adverse Events
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, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence 
that, at any dose:
Results in death
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject 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 out-patient setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfils any 
other serious criteria, the event is serious.  When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious.

Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE.
Results in disability/incapacity
NOTE:

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, 

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influenza, and accidental trauma (e.g. sprained ankle) which may interfere 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 reporting 
is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition.  These should also be 
considered serious.

Examples of such events are 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 hospitalization, or development of drug 
dependency or drug abuse.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** >1.5.
* Serum bilirubin fractionation should be performed if testing is available; if 
unavailable, measure urinary bilirubin via dipstick.  If fractionation is unavailable and 
ALT 3xULN and total bilirubin 2xULN, then the event is still to be reported as an 
SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.4.3.
Sentinel Events
A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been 
associated historically with adverse reactions for other drugs and is therefore worthy of 
heightened pharmacovigilance.  Medical Monitor review of all SAEs for possible 
Sentinel Events is mandated at GSK.  The Medical Monitor may request additional 
clinical information on an urgent basis if a possible Sentinel Event is identified on SAE 
review.  The current GSK-defined Sentinel Events are listed below:

Acquired Long QT Syndrome.

Agranulocytosis/Severe Neutropenia.

Anaphylaxis & Anaphylactoid Reactions.

Hepatotoxicity.

Acute Renal Failure.

Seizure.

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
Stevens Johnson syndrome/Toxic epidermal necrosis.
12.4.4.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the eCRF 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.

Revascularization.
12.4.5.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the eCRF.

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE eCRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
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the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
12.4.6.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities.

Severe:  An event that prevents normal everyday activities.  An AE that is assessed 
as severe will not be confused with an SAE.  Severity 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 one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence 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 natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the IB GSK Document Number 
[2014N190256_01] and/or Product Information, for marketed products, in the 
determination of 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 when 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 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 

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information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject 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 eCRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.4.7.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool.

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the SAE coordinator at the CRO.

Site will enter the serious adverse event 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 (e.g., 
InForm system) 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 subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the SAE 
coordinator at the CRO by telephone.

Contacts for SAE receipt can be found in the SRM.

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12.5.
Appendix 12.5 - Collection of Pregnancy Information
12.5.1.
Female subjects

Investigator will collect pregnancy information on any female who becomes 
pregnant during the course of the study.

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy.  The 
investigator will collect follow up information on mother and infant, 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 treatment by the investigator, will be reported to GSK 
as described in Appendix 12.4.  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 subject who becomes pregnant while participating will discontinue 
study medication and be withdrawn from the study.
12.5.2.
Female partners of male subjects

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.

After obtaining the necessary signed consent from the female partner directly, the 
investigator will record pregnancy information on the appropriate form and submit it 
to GSK within 2 weeks of learning of the partner’s pregnancy.

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.

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12.6.
Appendix 12.6 - Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases.  
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes.  For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012].  Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines.  Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and:

Response to medicine, including GSK3196165 or any concomitant medicines;

Rheumatoid arthritis susceptibility, severity, and progression and related conditions.
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses).  Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used.  A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis.  Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies.  Collection of samples, even when no a priori hypothesis has been 

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identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.

A 6 mL blood sample will be taken for Deoxyribonucleic acid (DNA) extraction.  A 
blood sample is collected at the baseline visit, after the subject has been randomized 
and provided informed consent for genetic research.  Instructions for collection and 
shipping of the genetic sample are described in the laboratory manual.  The DNA 
from the blood sample may undergo quality control analyses to confirm the integrity 
of the sample.  If there are concerns regarding the quality of the sample, then the 
sample may be destroyed.  The blood sample is taken on a single occasion unless a 
duplicate sample is required due to an inability to utilize the original sample.
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.  This number can be traced or linked back to 
the subject by the investigator or site staff.  Coded samples do not carry personal 
identifiers (such as name or social security number).
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA sample 
is retained.

Discontinue participation in the genetic research and destroy the genetic DNA 
sample.
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in
the site study records.

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Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis.

If a subject withdraws consent for genetic research and genotype data has not been
analyzed, it will not be analyzed or used for future research.

Genetic data that has been analyzed at the time of withdrawn consent will continue 
to be stored and used, as appropriate.
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed.  No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals.
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent.  GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law.  This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
References:
Chen H, Yu KD, Xu GZ. Association between variant Y402H in age-related macular 
degeneration (AMD) susceptibility gene CFH and treatment response of AMD: a meta-
analysis. PLoS One 2012;7:e42464.
Gorin MB. Genetic insights into age-related macular degeneration: controversies 
addressing risk, causality, and therapeutics. Mol Aspects Med 2012;33:467-86.

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12.7.
Appendix 12.7 - Important Study Assessment Details & 
Study Specific Equipment
Joint Assessments
To prevent potential unblinding because of observed efficacy changes, a “dual assessor” 
approach will be used to evaluate efficacy and safety.
The Joint Assessor (or designee) should be a rheumatologist or other skilled arthritis 
assessor and will be responsible only for completing the joint counts.  To ensure 
consistent joint evaluation throughout the trial, individual subjects should preferably be 
evaluated by the same joint assessor for all study visits.
The Treating Physician (or designee) should be a rheumatologist (or other medically 
qualified physician) and will have access to both safety and efficacy data.  The Treating 
Physician will have access to source documents with the exception of the calculated 
DAS28(CRP) score, laboratory results with the exception of the CRP results from the 
central laboratory and eCRFs and will be responsible for completing Physician’s Global 
Assessment of Disease Activity VAS, Morning stiffness assessment, and safety 
assessments (adverse events, vital signs, concomitant medications, review of laboratory 
data).
It is essential that assessments completed by the subject and Joint Assessor are made 
before those by the Treating Physician.
Quality of Life and Patient-Reported Outcomes
The questionnaires will be completed at relevant study visits as described in the Time and 
Events Table (Section 7.1), and the data will be directly entered into the ePRO.
The following services and hardware will be required:
Actigraphy
In this study, actigraphy data will be captured for a subset of subjects at participating sites
by a commercially available, continuous logging, three-axis electronic accelerometer 
which will be provided to all sites.  Actigraphy data will be collected throughout the 
study as described in the Time and Events Table (Section 7.1).  The accelerometer will be 
placed on the subject upon visiting the clinic and will be worn by the subject 
continuously for up to 14 days of data collection.  At the end of the data collection 
period, coinciding with a study visit, the accelerometer will be removed, the raw data 
downloaded, and the unit cleaned and recharged for reuse.
In addition, subjects that participate in the actigraphy assessments will be required to 
complete in parallel an RA Symptom and Impact Diary PRO.  The provision and 
collection of these diaries will coincide with the placement of the accelerometer.
Spirometry/DLCO
Equipment and site training for the standardised measurement of spirometry and DLCO
will be provided.  Results will be sent from the site to the vendor for evaluation, who will 
then send the data to designee electronically.

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Centralised ECG
Equipment and site training for the standardised measurement of ECGs will be provided.  
It is planned to collect and read the ECGs centrally.

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12.8.
Appendix 12.8 - Country Specific Requirements
No country-specific requirements exist.

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12.9.
Appendix 12.9 - Protocol Changes
Protocol Amendment: 01
Medical Monitor/Sponsor Information Page
Information concerning GSK Medical Monitor/SAE Contact Information removed.
Rationale
Details of Parexel Medical Monitor/SAE Contact Information were added to the Study 
Reference Manual.
Section 7.1. Time and Events Table
Scheduled assessments were revised.
Rationale
Patient’s Assessment of Arthritis Pain, Patient’s Global Assessment of Arthritis, 
Physician’s Global Assessment of Arthritis, HAQ-DI, and CRP, ESR were added at 
Weeks 28, 32, 40, 44, and 48, 12-lead ECG at EW; Spirometry (FEV1, FVC) at EW; 
DLCO at Weeks 52, 62, and EW.
Appendix 12.7. PRO Questionnaires
Entire Appendix with examples of PRO Questionnaires removed.
Rationale
The Appendix only gave examples of the PRO Questionnaires, the actual versions used 
were programmed into electronic PRO (ePRO) devices.
Protocol Amendment: 02
Title page
Revision of the study title.
Rationale
Added “Double-Blind, Placebo-Controlled” to the study title, and removed “versus 
Placebo”.
Section 3. Objective(s) and endpoint(s), Section 7.2. Screening and Critical Baseline 
Assessments, Section 7.3. Efficacy, Section 7.10.5. RA Symptom and Impact Diary 
PRO, 7.10.6. Exploratory Health Outcomes Assessment - Actigraphy, Appendix 
12.7. Important Study Assessment Details & Study Specific Equipment.

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Added “at participating sites”.
Rationale
Clarified that actigraphy will only be at participating sites.
Section 4.4. Type and Number of Subjects
Added “Study Reference Manual (SRM)”.
Rationale
Replaced “Study Procedures Manual SPM”, and throughout protocol.
Section 6.1. Investigational Product and Other Study Treatment.
Minor revisions to placebo and co-medications information.
Rationale
Replaced “Placebo (for blinding)” with “Control”; deleted “and will be provided by the 
study site” in reference to supply of saline; and deleted “MTX and folic acid will be 
sourced locally from commercial stock” as provision will vary by site.
Section 6.1.
Clarified guidance on dosing instructions.
Rationale
Revised text to “GSK3196165/placebo should be administered on the same day each 
week ± 1 day for the first 5 weekly doses (with a minimum of 5 days between doses, for 
no more than 2 consecutive doses).  Following this GSK3196165/placebo should be 
administered on the same day EOW ± 3 days (with a minimum of 8 days between doses)”; 
and “Subjects will be randomized as shown in Time and Events Table, Section 7.1, and 
the dosing schedule should be followed as closely as possible”.
Section 7.3.3. Patient’s Global Assessment of Arthritis
Revised anchor text.
Rationale
Replaced “no symptoms” with “very well” and “most severe disease activity” with “very 
poor” for consistency with other clinical studies.
Section 7.3.4. Physician’s Global Assessment of Arthritis
Revised anchor text.

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Rationale
Replaced “no symptoms” with “none” and “most severe disease activity” with 
“extremely active” for consistency with other clinical studies.
Protocol Amendment: 03
Section 3. Objective(s) and endpoint(s), Section 7.1. Time and Events Table and 
Section 7.7. Biomarker(s)/Pharmacodynamic Markers
Removal of flow cytometry analysis.
Rationale
The logistics of incorporating flow cytometry into a large multi-centre, global study with 
all sites collecting and processing samples, the difficulties of ensuring standardisation of 
methodology, and hence concerns that the quality of data might be compromised led to 
the decision not to keep this assessment of biological activity of GSK3196165.
Moreover, given the primary objective of this study is dose-finding, many subjects may 
be taking sub-therapeutic doses of GSK3196165.
Section 3. Objective(s) and endpoint(s)
The statements of “Pharmacodynamic biomarkers to assess biological response to 
GSK3196165 in serum” were revised to “Pharmacodynamic biomarkers which may be 
predictive of response to GSK3196165” and “Pharmacodynamic biomarkers to assess 
response to GSK3196165” with examples.
Rationale
The original statements were duplicate text, and revisions clarified the purpose and 
appropriate examples of biomarkers.
Section 4.7.1. Risk Assessment
Corrections to neutropenia levels.
Rationale
There were typographical errors in neutropenia (absolute neutrophil count) and 
lymphocytopenia thresholds, revised to align with values in Exclusion Criteria #25.
Section 5.1. Inclusion Criteria and Section 7.2. Screening and Critical Baseline 
Assessments
Clarification of TB testing.
Rationale
Clarification that TB tests may be performed locally.

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Section 6.1. Investigational Product and Other Study Treatment and Section 6.8. 
Compliance with Study Treatment Administration
Removal of irrelevant information on administration of MTX at sites.
Rationale
Protocol already had statement that Investigators are responsible for ensuring that 
subjects continue to receive MTX and folic acid and Subjects will be given instructions
on compliance and treatment with MTX.  Added that the date taken and total weekly dose 
will be recorded in the eCRF.
Section 6.1. Investigational Product and Other Study Treatment, Section 6.5. 
Blinding, Section 6.7. Preparation/Handling/Storage/Accountability, Section 6.8. 
Compliance with Study Treatment Administration
Clarification of unblinded administrator.
Rationale
Examples given as study co-ordinator or nurse; pharmacist removed.
Section 6.5. Blinding
Clarification of shield.
Rationale
Examples given as eye mask or blindfold.
Section 6.8. Compliance with Study Treatment Administration
Addition of volume dosed to be recorded.
Rationale
Clarification that the date and time of each dose and volume administered in the clinic 
will be recorded in the eCRF.
Section 7.4.11. Clinical Safety Laboratory Assessments (Table 2 Routine Laboratory 
Assessments).
Corrected Routine Laboratory Assessments.
Rationale
Added Erythrocyte count, removed Albumin and Protein/creatinine ratio.

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Protocol Amendment: 04
Section 7.1. Time and Events Table
Removal of blank line.
Rationale
Details of flow cytometry analysis had been deleted in Amendment 04, but the line in the 
Table had inadvertently been left.
Protocol Amendment: 05
Section 4.2. Treatment Arms and Duration and Section 5.4. Withdrawal/Stopping 
Criteria
Addition of mandated withdrawal at Week 38.
Rationale
Any subject not achieving EULAR good/moderate response at Week 36 will be 
withdrawn from the study at Week 38 to ensure that all continuing subjects are receiving 
effective treatment.
Section 4.5. Design Justification
Removal of abbreviation “SoC”.
Rationale
Clarification that the abbreviation “SoC” is “standard of care”.
Section 5.3.1. Re-Screening
Clarification of rescreening procedure.
Rationale
Clarification that entire rescreening is not required if chest X-ray within 12 weeks of the 
first screening period or HRCT within the first screening period.
Section 5.3.2.1. and Section 5.3.2.1. Laboratory tests and DLCO test
Split Section 5.3.2. into two parts.
Rationale
Clarification that if the DLCO repeat test cannot be done within the screening window, 
then the subject must be re-screened.

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Section 7.1. Time and Events Table and Section 7.4.11. Clinical Safety Laboratory 
Assessments (Table 2 Routine Laboratory Assessments)
Added lipid measurements.
Rationale
Recent European guideline (CPMP/EWP/556/95 Rev. 2, June 2015) on clinical 
investigation of medicinal products other than NSAIDs for treatment of rheumatoid 
arthritis proposes “The influence of the new drug on lipids and atherogenic potential need 
to be monitored.”  Cholesterol, Triglycerides, High-density lipoprotein (HDL) and Low-
density lipoprotein (LDL) added at Baseline, W12, W24, W52, W62, and EW.
Section 7.1. Time and Events Table
Clarification of header version numbers and footnotes.
Rationale
Previous version of protocol had an incorrect header version.  W62 visit corrected to 
D435 rather than D470. Footnotes revised to clarify that Chest X-ray or Chest HRCT not 
required to be repeated if subject re-screened; and >8h fasting required before blood draw 
for lipid assessments.
Section 7.3.5. DAS Assessments
Clarification of eligibility.
Rationale
Confirmation that the screening and Day 1 DAS28(ESR) scores will be confirmed by the 
IRTS for eligibility of subjects for randomization.
Section 7.4.7. Pregnancy
Clarification of any pregnancy.
Rationale
Clarification that any pregnancy includes participating females and female partners of 
participating males.
Appendix 12.1. Abbreviations and Trademarks
Added abbreviations.
Rationale
Abbreviations for disease-related event, high-density lipoprotein, and low-density 
lipoprotein missing from list.

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Appendix 12.2. Contraception eligibility criteria for female and male subjects
Clarification of methods of contraception and required documentation.
Rationale
Alignment with new GSK template.
Appendix 12.5. Collection of Pregnancy Information
Clarification that any female subject who becomes pregnant while participating will 
discontinue study medication and be withdrawn from the study.
Rationale
Previous statement did not include discontinuation of study medication.
Appendix 12.9. Protocol Changes
Appendix added to track all protocol text changes.
Rationale
Expanded explanation of all changes rather than just a summary at the beginning of the 
protocol.
Protocol Amendment: 06
Section 5.1. Inclusion Criteria
Clarification that the DLCO tests may be repeated twice within the screening period.
Rationale
To avoid any misunderstanding that there are three permitted tests in total.
Section 5.2. Exclusion Criteria and Section 5.4.2. QTc Stopping Criteria
Clarification that that only Fridericia’s formula (QTcF) will be used.
Rationale
Recent FDA/ICH Guidance for Industry (October 2012) “E14 Clinical Evaluation of 
QT/QTc” states “In adults, Bazett’s correction has been clearly shown to be an inferior 
method of correcting for differences in heart rate among and within subjects. Therefore, 
QT interval data corrected using Bazett’s corrections is no longer warranted in all 
applications unless there is a compelling reason for a comparison to historical Bazett’s 
corrected QT data. Presentation of data with a Fridericia correction is likely to be 
appropriate in most situations, but other methods could be more appropriate.”

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Section 5.3.2.3. ECG Test
Clarification that the ECG test may be repeated once within the screening period.
Rationale
To permit a repeat screening ECG if the QTcF value is slightly out of range, provided no 
other clinically-significant abnormalities are noted.
Section 7.1. Time and Events Table
Clarification of footnotes.
Rationale
Clarification that ECG should be performed before vital signs, blood draws, and dosing; 
that some Day 1 assessments may be performed up to 24 hours before dosing 
GSK3196165; and that blood sampling on Day 3 can be drawn ±1 day.
Section 7.7. Biomarker(s)/Pharmacodynamic Markers
Deletion of IL-22.
Rationale
Considered not essential as we are also measuring IL-23.
Appendix 12.2. Contraception eligibility criteria for female and male subjects
Clarification of required secondary method of contraception if using oral contraceptives.
Rationale
A sentence had been inadvertently deleted in the previous amendment’s revisions.
Protocol Amendment: 07
Section 4.2 Treatment Arms and Duration and Section 6.4. Subject Specific Dose 
Adjustment Criteria
Removed the example formula to calculate the EULAR good/moderate response at Week 
12 and Week 36, and inserted a table (and reference) to show requirements for EULAR 
good/moderate responses.
Rationale
The example formula was incorrect.

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Section 5.1. Inclusion Criteria, Section 5.3.2.2. DLCO test, Section 7.1. Time and 
Events Table, and Section 7.4.1. Screening visit(s)
Clarification that chest HRCT must be performed if DLCO ≥60% to <70% predicted.
Rationale
To avoid any misunderstanding of requirement for chest HRCT.
Section 11. References
Updated IB document number, and added reference for EULAR good/moderate response.
Rationale
New version of IB, and revised formula for EULAR good/moderate response.