Clinical trial NCT02504671
Conditions: Arthritis, Rheumatoid
Keywords: DMARD-IR GSK3196165 Rheumatoid Arthritis
Sponsor: GlaxoSmithKline
Start date: 2015-07-23; Completion date: 2017-12-29
Enrollment: 222 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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 rheumatoid arthritis (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). Subjects will be randomised (1:1:1:1:1:1) to placebo or one of five subcutaneous (SC) GSK3196165 doses, in combination with MTX (at a weekly dose between 15-25 milligram \[mg\]), previously received for at least 12 weeks, with a stable and tolerated dose and route of administration for \>=4 weeks. Escape therapy is provided at specified timepoints in the protocol for subjects that do not achieve adequate disease improvement.

Detailed description:

Arms: arm 1: Subject will receive GSK3196165 Dose 1 (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week. arm 2: Subject will receive GSK3196165 Dose 2 (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week. arm 3: Subject will receive GSK3196165 Dose 3 (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week. arm 4: Subject will receive GSK3196165 Dose 4 (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week. arm 5: Subject will receive GSK3196165 Dose 5 (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week. arm 6: Subjects will receive placebo (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week.
Interventions: intervention 1: GSK3196165 intervention 2: MTX intervention 3: Folic acid intervention 4: Placebo
Intervention descriptions: intervention 1: GSK3196165 is supplied as liquid and will be administered as SC injection. intervention 2: MTX will be supplied as capsule, tablet or liquid and will be administered orally or as SC injection. intervention 3: Folic acid will be supplied as capsule, tablet or liquid and will be administered orally. intervention 4: Placebo is supplied as liquid as sterile 0.9% weight by volume (w/v) sodium chloride solution and will be administered as SC injection

Protocol documents:
Prot_000.pdf: 
2014N210890_07
CONFIDENTIAL
GlaxoSmithKline group of companies
201755
1
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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201755
2
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
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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 
be treated in accordance with standard scoring and statistical procedures detailed by 


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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.


2014N210890_07
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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.

SAP_001.pdf: 
GlaxoSmithKline 
GSK Study 201755 
Reporting and Analysis Plan 
 
TP-GDO-WW-016-03 
CONFIDENTIAL 
Project Document Version No. 2.0 
Effective Date:  26 Aug 15 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 1 of 80 
 
PAREXEL International 
GlaxoSmithKline 
GSK Study 201755 (BAROQUE) 
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. 
Reporting and Analysis Plan 
 
PAREXEL Project Number: 220973 
 
 


PPD
PPD


GlaxoSmithKline 
GSK Study 201755 
Reporting and Analysis Plan 
 
TP-GDO-WW-016-03 
CONFIDENTIAL 
Project Document Version No. 2.0 
Effective Date:  26 Aug 15 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 3 of 80 
 
PAREXEL SIGNATURE PAGE 
 
 
 
This document has been signed electronically on the final page by the following: 
 
 
 
Signatory 
Author 
 
Project Role: Biostatistics Lead 
Biostatistics Reviewer 
 
Project Role: Biostatistician 
Statistical Programming 
Reviewer 
Dr. 
 
Project Role: Primary Statistical Programmer 
Medical Writing Reviewer 
 
Project Role: Medical Writer 
 
 
 
PPD
PPD
PPD
PPD


GlaxoSmithKline 
GSK Study 201755 
Reporting and Analysis Plan 
 
TP-GDO-WW-016-03 
CONFIDENTIAL 
Project Document Version No. 2.0 
Effective Date:  26 Aug 15 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 4 of 80 
TABLE OF CONTENTS 
 
1 
INTRODUCTION ..................................................................................................... 10 
2 
STUDY OBJECTIVES AND ENDPOINTS ............................................................ 11 
3 
INVESTIGATIONAL PLAN ................................................................................... 13 
3.1 Overall Study Design and Plan ........................................................................... 13 
3.1.1 Overall Design .......................................................................................... 13 
3.1.2 Time and Events Table (Combination Treatment with GSK3196165 and 
MTX) ........................................................................................................ 16 
3.1.3 Treatment Arms and Duration .................................................................. 20 
3.1.4 Study Oversight and Dose Selection......................................................... 20 
3.1.5 Type and Number of Subjects................................................................... 21 
3.2 Efficacy and Safety Variables ............................................................................ 22 
3.2.1 Disease Activity Score (DAS): ................................................................. 22 
3.2.2 ACR Response Rates ................................................................................ 23 
3.2.3 Swollen and Tender/Painful Joint Count .................................................. 24 
3.2.4 Patient’s Assessment of Arthritis Pain ...................................................... 25 
3.2.5 Patient’s Global Assessment of Disease Activity ..................................... 25 
3.2.6 Physician’s Global Assessment of Arthritis ............................................. 25 
3.2.7 SDAI ......................................................................................................... 25 
3.2.8 CDAI ......................................................................................................... 25 
3.2.9 Index- and Boolean-based ACR/EULAR Remission Rates ..................... 26 
3.2.10 
HAQ-DI ............................................................................................ 26 
3.2.11 
Short-Form 36 ................................................................................... 27 
3.2.11.1 Domain Scores of SF-36 ............................................................. 27 
3.2.11.2 Physical and Mental Component Scores ..................................... 31 
3.2.12 
FACIT-Fatigue .................................................................................. 32 
3.2.13 
BFI .................................................................................................... 32 
3.2.14 
Borg Dyspnea Scale .......................................................................... 32 
4 
STATISTICAL METHODS ..................................................................................... 33 
4.1 Data Quality Assurance ...................................................................................... 33 
4.2 General Presentation Considerations .................................................................. 33 
4.3 Analysis Populations .......................................................................................... 34 
4.3.1 Analysis Datasets ...................................................................................... 35 
4.4 Study Subjects .................................................................................................... 35 
4.4.1 Disposition of Subjects ............................................................................. 35 
4.4.2 Protocol Deviations ................................................................................... 36 
4.5 General Data Handling Conventions .................................................................. 37 
4.5.1 Missing Dates............................................................................................ 37 
4.5.2 Missing Data for Efficacy and Safety Endpoints ...................................... 38 
4.5.2.1 Missing Data for Efficacy Endpoints .......................................... 38 
4.5.2.2 Missing Data at Baseline for Efficacy and Safety Endpoints ..... 39 
4.5.2.3 Multiple Imputation: Predictive Mean Matching ........................ 39 
4.5.3 Multiple Assessments and Early Withdrawal Visits ................................. 40 
4.5.4 Oral Corticosteroid Conversion ................................................................ 40 
4.6 Demographic and Other Baseline Characteristics .............................................. 41 


GlaxoSmithKline 
GSK Study 201755 
Reporting and Analysis Plan 
 
TP-GDO-WW-016-03 
CONFIDENTIAL 
Project Document Version No. 2.0 
Effective Date:  26 Aug 15 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 5 of 80 
4.7 Medication Use ................................................................................................... 42 
4.8 Treatment Compliance ........................................................................................ 43 
4.9 Efficacy Evaluation ............................................................................................ 43 
4.9.1 Statistical Considerations .......................................................................... 43 
4.9.1.1 Hypotheses for Primary Endpoint and Dose-Response 
Relationship ........................................................................................... 43 
4.9.1.2 Multi-center Studies .................................................................... 44 
4.9.1.3 Adjustments for Covariates ......................................................... 44 
4.9.1.4 Multiple Comparisons/Multiplicity ............................................. 44 
4.9.1.5 Interim and Final Analyses .......................................................... 44 
4.9.1.6 Examination of Subgroups .......................................................... 46 
4.9.2 Key Efficacy Analyses .............................................................................. 47 
4.9.2.1 Interim Analyses .......................................................................... 47 
4.9.2.2 Week 24 Analysis and Final Analysis ......................................... 52 
4.9.3 Exploratory Efficacy Endpoints ................................................................ 55 
4.9.3.1 Proportion of subjects achieving sustained (≥24 continuous weeks 
including the Week 52 visit) DAS28(CRP) remission .......................... 55 
4.9.3.2 Proportion of subjects achieving Major Clinical Response 
(ACR70 for 24 continuous weeks including the Week 52 visit) ......... 55 
4.9.3.3 DAS28(ESR) scores/responses at all assessment timepoints. ..... 56 
4.10 
Safety Evaluation ...................................................................................... 56 
4.10.1 
Extent of Exposure ............................................................................ 56 
4.10.2 
Adverse Events ................................................................................. 56 
4.10.3 
Deaths and Serious Adverse Events ................................................. 58 
4.10.4 
Disease-related Events ...................................................................... 59 
4.10.5 
Respiratory Events ............................................................................ 59 
4.10.6 
Cardiovascular Events ...................................................................... 59 
4.10.7 
Liver Events ...................................................................................... 60 
4.10.8 
Clinical Laboratory Evaluation ......................................................... 60 
4.10.9 
Pulmonary assessments ..................................................................... 61 
4.10.10 
Vital Signs, Physical Findings and Other Observations Related to 
Safety ........................................................................................................ 62 
4.10.11 
Safety Monitoring ............................................................................. 63 
4.10.11.1 Data Review Committee ........................................................ 63 
4.10.11.2 Medical Monitoring................................................................ 64 
4.10.12 
Immunogenicity ................................................................................ 64 
4.11 
Patient Reported Outcome (PRO) Measures ............................................ 65 
4.11.1 
Actigraphy Substudy ......................................................................... 65 
4.11.1.1 Accelerometer data collection ..................................................... 65 
4.11.1.2 Endpoint derivation and summaries ............................................ 66 
4.12 
Other Analyses .......................................................................................... 68 
4.12.1 
Pharmacokinetic Analysis ................................................................. 68 
4.12.2 
Pharmacokinetic / Pharmacodynamic (PK/PD) Exploratory Analysis
 
68 
4.12.3 
Biomarkers ........................................................................................ 69 
4.12.4 
Genetic Research .............................................................................. 69 


GlaxoSmithKline 
GSK Study 201755 
Reporting and Analysis Plan 
 
TP-GDO-WW-016-03 
CONFIDENTIAL 
Project Document Version No. 2.0 
Effective Date:  26 Aug 15 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 6 of 80 
4.13 
Determination of Sample Size .................................................................. 69 
4.13.1 
Primary Analysis ............................................................................... 69 
4.13.2 
Dose Response Analysis ................................................................... 69 
4.13.3 
Sample Size Sensitivity for Primary Analysis .................................. 71 
4.13.4 
Sample Size Sensitivity for Dose Response Analysis ...................... 71 
4.14 
Changes in the Conduct of the Study or Planned Analysis ...................... 72 
5 
REFERENCES .......................................................................................................... 73 
6 
Appendix ................................................................................................................... 74 
6.1 Appendix A: Opportunistic Infections: MedDRA Preferred Terms ................... 74 
6.2 Appendix B: Laboratory Parameters of Interest ................................................. 79 
 


GlaxoSmithKline 
GSK Study 201755 
Reporting and Analysis Plan 
 
TP-GDO-WW-016-03 
CONFIDENTIAL 
Project Document Version No. 2.0 
Effective Date:  26 Aug 15 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 7 of 80 
LIST OF ABBREVIATIONS 
 
ACR 
American College of Rheumatology 
ADA 
Anti-Drug-Antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AIC 
Akaike information criterion 
AP 
Actigraphy Population 
ATC 
Anatomical Therapeutic Chemical 
BFI 
Brief Fatigue Inventory 
BLQ 
Below the limit of quantification 
BMI 
Body Mass Index 
BP 
Bodily Pain 
CfB 
Change from Baseline 
CDAI 
Clinical Disease Activity Index 
CI 
Confidence interval 
CR 
Compliance Ratio 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events v 4.0 
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 or transfer factor of the lung for carbon monoxide 
DLCOHCPP 
DLCO Hemoglobin-corrected Percent of Predicted 
DMARD 
Disease modifying antirheumatic drugs 
DRC 
Data Review Committee 
DRE 
Disease-related Events 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOW 
Every other week 
ESR 
Erythrocyte sedimentation rate 
EULAR 
European League against Rheumatism 
EW 
Early Withdrawal 
F 
Figure 
FEV1 
Forced Expiratory Volume in 1 Second 
FVC 
Forced Vital Capacity 
FACIT 
Functional Assessment of Chronic Illness Therapy 
GEE 
Generalized estimating equation 
GH 
General Health 
GM-CSF 
Granulocyte-macrophage colony stimulating factor 
GRP 
Genetic Research Population 
GSK 
GlaxoSmithKline 
H0 
Null Hypothesis 
H1 
Alternate Hypothesis 
HAQ-DI 
Health Assessment Questionnaire - Disability Index 


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IA1 
Interim Analysis 1 
IA2 
Interim Analysis 2 
ITT 
Intent-to-Treat 
IV 
Intravenous 
L 
Listing 
LOCF 
Last Observation Carried Forward 
MCMC 
Markov-Chain-Monte-Carlo 
MCS 
Mental Component Summary 
MDRP 
Medical Data Review Plan 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MH 
Mental Health 
MMP 
Medical Monitoring Plan 
MMRM 
Mixed model for repeated measures 
MTX 
Methotrexate 
NRI 
Non-Responder imputation 
NRS 
Numeric rating scale 
O 
Supportive Analysis SAS Output 
OC 
Observed Case 
PAP 
Pulmonary alveolar proteinosis 
PCS 
Physical Component Summary 
PD 
Protocol deviation 
PDS 
Protocol deviation specification 
PF 
Physical Functioning 
PFT 
Pulmonary function tests 
PhGA 
Physician's Global Assessment of Arthritis 
PK 
Pharmacokinetics 
PK/PD 
Pharmacokinetics/Pharmacodynamics 
PRO 
Patient reported outcome 
PT 
Preferred term 
PtGA 
Patient's Global Assessment of Arthritis Disease Activity 
QC 
Quality Check 
QTcF 
Fridericia's Correction Formula 
RA 
Rheumatoid arthritis 
RAP 
Reporting and Analysis Plan 
RE 
Role Emotional 
RP 
Randomised Population 
RPh 
Role Physical 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SDAI 
Simplified Disease Activity Index 
SC 
Subcutaneous 
SD 
Standard deviation 
SF 
Social Functioning 


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SF-36 
Short-Form 36 
SJC 
Swollen joint count 
SJC28 
Swollen joint count for 28 different joints 
SJC66 
Swollen joint count for 66 different joints 
SOC 
System organ class 
SOP 
Standard Operating Procedure 
SRT 
Safety Review Team 
STM 
Set to Missing 
T 
Table 
TEAE 
Treatment emergent adverse event 
TJC 
Tender joint count 
TJC28 
Tender joint count for 28 different joints 
TJC68 
Tender joint count for 68 different joints 
VAS 
Visual analogue scale 
VT 
Vitality 
 


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1 
INTRODUCTION 
Rationale: 
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). 
 
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 
RA. 
 
Rheumatoid Arthritis: 
RA is a chronic, systemic inflammatory autoimmune disease, characterised by a 
symmetrical polyarthritis that is associated with substantial disability and morbidity.  
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, B-cells or T-cells.  However, a substantial 
proportion of patients either fail to respond, or have inadequate response, to currently 
available RA therapies. 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. 
 
GM-CSF and RA: 
 
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. 
 
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. 
 
GSK3196165: 
 
GSK3196165 is a high-affinity recombinant human monoclonal antibody that binds 
specifically to human GM-CSF and neutralises its biological function by blocking the 
interaction of GM-CSF with its cell surface receptor. 


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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. 
 
Contents of this document: 
 
This document is based on the PAREXEL template for a Statistical Analysis Plan (SAP) 
and the following study documents: 
• 
Clinical Study Protocol, Version 06 (effective date: 25-Nov-2015) 
• 
electronic Case Report Form (eCRF) Blank Casebook, Version 3.0 (15-Sep-
2015) 
• 
Data Model Specification (TrialSlate) (16-Sep-2015) 
• 
Population Pharmacokinetic Analysis of GSK3196165 Following Intravenous 
and Subcutaneous Administration to Healthy Volunteers, Subjects with 
Rheumatoid Arthritis and Multiple Sclerosis, (Date: 08-Jan-2016) 
 
2 
STUDY 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 


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Objectives 
Endpoints 
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. 
 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 
 Proportion of subjects achieving sustained (≥24 continuous weeks including Week 52) 
DAS28(CRP) remission. 
 Proportion of subjects achieving Major Clinical Response (proportion of subjects achieving 
ACR70 for 24 continuous weeks including Week 52). 


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 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. 
 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. 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
3.1.1 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 


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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), 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.  A subgroup analysis of subjects with early RA will be 
performed if this subgroup accounts for at least 10% of subjects.  
 
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 withdrawal point at Week 36 and 
with a 12-week follow-up visit after the last dose (Week 50): 
 
 


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Study visits: 
 
Screening assessments (Visit 1) will be performed up to 28 days prior to the baseline visit 
(Visit 2) on Day 1 (start of study treatment).  Subsequent visits are planned on Days 3, 8, 
15, 22, 29 (=Week 4) and then every other week (EOW) in weeks 6 through 52, with a 
follow-up visit in Week 62.  Subjects who discontinue the study treatment should have an 
early withdrawal visit with a subsequent follow-up visit ≥12 weeks after the last dose of 
study treatment.  The exact timing of each assessment is listed in the Time and Events 
Table in section 3.1.2. 
 
 
 


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3.1.2 Time and Events Table (Combination Treatment with GSK3196165 and MTX) 
Table 1 Time and Events Table 
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 
 


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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 
 
RA Symptom and Impact 
Diary, Actigraphy 
process3,6 
 
X7 
 
 X8 
 
 
 
 
 
X7 X8 
 
 
 
 
X7 X8 
 
 
 
 
X7 X8 
 
 
 
 
 
 
X7 X8 
 
X8 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 
 
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 
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 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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3.1.3 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. 
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 European League against Rheumatism (EULAR) 
good/moderate response (see section 3.2.1) 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 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 and a review of response to MTX in 
randomised clinical studies. 
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. 
 
3.1.4 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. 
Pharmacokinetic (PK) concentration time data will be presented to DRC only if required to aid 
the interpretation of the efficacy or safety data. 
 
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 recommendation to stop the study or 
randomisation to specific arms will be made by the DRC and ratified by the GSK steering 
committee consisting of senior GlaxoSmithKline Pharmaceuticals, R&D leaders. 
 
Interim analyses will be performed to assess futility and the dose-efficacy relationship when 90 
subjects have completed 4 and 12 weeks of treatment.  If the recruitment rates allow, these 


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interim analyses will be aligned with safety reviews to allow an assessment of benefit versus 
risk.  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 is 
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. 
 
Medical monitoring will happen in the form of monthly blinded data review meetings which 
include but are not limited to: 
 Medical review of  protocol deviations 
 Medical review of high panic lab alerts 
 Cumulative data review (includes summaries of reason for screening failures, disposition, 
adverse events, serious adverse events, disease related events and chest x-rays) 
 Medical review of coding 
 
Further information on the medical monitoring can be found in the Medical Data Review Plan 
(MDRP) and the Medical Monitoring Plan (MMP). 
 
The primary analysis will occur 24 weeks after the last subject was randomised.  The final 
analysis will occur after the end of the study which is defined as the last subject’s last visit. 
 
3.1.5 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. 
 
 


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3.2 
Efficacy and Safety Variables 
 
3.2.1 Disease Activity Score (DAS): 
The DAS assessment is a derived measurement with differential weighting given to each 
component. 
The DAS28(CRP) and DAS28(ESR) will be calculated at each assessment time point.  The 
components of the DAS28 arthritis assessment include: 
 
 Tender Joint Count 28 (TJC28) 
 Swollen Joint Count 28 (SJC28)  
 C-reactive protein (CRP) (in mg/L) or Erythrocyte sedimentation rate (ESR) (in 
mm/hr) 
 Patient’s Global Assessment of Arthritis Disease Activity (PtGA) (visual analogue 
scale with values from 0=best to 100=worst) 
 
DAS28(CRP) 
 
The DAS28(CRP) score will be calculated using the following formula: 
 
DAS28(CRP) = 0.56 ∗√𝑇𝐽𝐶28 + 0.28 ∗√𝑆𝐽𝐶28 + 0.36 ∗ln(CRP + 1) + 0.014 ∗PtGA
+ 0.96. 
 
If one of the components is missing at an individual assessment point, the DAS28(CRP) value 
for that assessment will be set to missing.  An alternative imputation method for missing 
components will be applied as described in Section 4.5.2. 
 
DAS28(ESR) 
 
The DAS28(ESR) score will be calculated using the following formula: 
 
DAS28(ESR) = 0.56 ∗√𝑇𝐽𝐶28 + 0.28 ∗√𝑆𝐽𝐶28 + 0.7 ∗ln(ESR) + 0.014 ∗PtGA  
 
If one of the components is missing at an individual assessment point, the DAS28(ESR) value 
for that assessment will be set to missing.  An ESR value of 0 will be substituted with ESR=1 for 
the calculation of DAS28(ESR). 
 
DAS28 Remission 
 
DAS28(CRP) remission is achieved by a DAS28(CRP) value lower than 2.6.  Similarly, 
DAS28(ESR) remission is achieved by a DAS28(ESR) value lower than 2.6.  Missing DAS28 
values will be considered as not achieving remission. 
 
Sustained DAS28(CRP) Remission 
 
Sustained DAS28(CRP) remission is achieved if DAS28(CRP) remission is achieved (i.e. 
“response” in the Non-Responder imputation [NRI] dataset) at every visit within a period of time 


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that spans at least 24 weeks (168 days) and includes the Week 52 visit.  This is a change from the 
protocol defined endpoint.  If a subject has at most two nonconsecutive visits with missing 
remission data (“no response” in the NRI dataset due to a missed visit or missing DAS28(CRP) 
component scores) within the 24 week window and the subject was in remission (“response” in 
the NRI dataset) for all other visits, then the subject will be considered to have sustained 
remission.  Otherwise, two consecutive visits of missing data or more than two visits of missing 
data in a 24 week window will disqualify the subject for sustained remission. 
 
Two variables will be determined for each subject (not by visit): 
 Subject reached sustained DAS28(CRP) remission (yes/no) 
 The duration of sustained DAS28(CRP) remission in weeks. 
 
Categorical DAS28 Response 
 
DAS28(CRP) and DAS28(ESR) scores will each be categorised using EULAR response criteria.  
Response at a given time point is defined based on the combination of current DAS28 score and 
the improvement in the current DAS28 score relative to baseline.  The definition of no response, 
moderate response and good response is captured in the following table: 
 
Table 2 EULAR Response Criteria 
Current  
DAS28 
DAS28 decrease from baseline value 
>1.2 
>0.6 to ≤1.2 
≤ 0.6 
≤ 3.2 
Good response 
Moderate response 
No response 
> 3.2 to ≤ 5.1 
Moderate response 
Moderate response 
No response 
> 5.1 
Moderate response 
No response 
No response 
 
If the post-baseline DAS28(CRP) or DAS28(ESR) score is missing, then the corresponding 
EULAR category will be missing. 
 
 
3.2.2 ACR Response Rates 
 
The American College of Rheumatology’s (ACR) definition for calculating improvement in RA 
is calculated as a 20% improvement (ACR20) in both tender and swollen joint counts and 20% 
improvement in 3 of the 5 remaining ACR-core set measures: patient and physician global 
assessments, patient’s assessment of arthritis pain, disability, and an acute-phase reactant (i.e. 
CRP value).  Similarly, ACR50 and ACR70 are calculated with the respective percent 
improvement.  This efficacy measurement will be made at every post-baseline study assessment 
time point. 
 
The specific components of the ACR Assessments that will be used in this study are: 
 
 Tender/Painful Joint count 68 (TJC68) 
 Swollen Joint Count 66 (SJC66) 
 Patient’s Assessment of Arthritis Pain 
 Patient’s Global Assessment of Arthritis Disease Activity 


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 Physician’s Global Assessment of Arthritis 
 CRP (mg/L) 
 Health Assessment Questionnaire – Disability Index (HAQ-DI) 
 
For all visits, if any of the component scores are missing, then those scores will be considered as 
not having met the criteria for improvement.  Therefore, if TJC68 or SJC66 or 3 or more of the 5 
remaining ACR-core set measures are missing, ACR20/ ACR50/ ACR70 will each be considered 
as “no response” in the NRI dataset.   
 
For component scores with missing Baseline values or a Baseline value of 0, the percentage 
improvement can’t be calculated and the component will be considered as not having met the 
criteria for improvement for all visits.  If the baseline value is missing, do not use screening visit 
data for imputation.    
 
Major clinical response is achieved if ACR70 is achieved (i.e. “response” in the NRI dataset) at 
every visit within a period of time that spans at least 24 weeks (168 days) and includes the Week 
52 visit.  This is a change from the protocol defined endpoint.  If a subject has at most two 
nonconsecutive visits with missing ACR70 response data (“no response” in the NRI dataset due 
to a missed visit or missing ACR component scores) within the 24 week window and the subject 
had ACR70 response (“response” in the NRI dataset) for all other visits, then the subject will be 
considered to have achieved major clinical response.  Otherwise, two consecutive visits of 
missing data or more than two visits of missing data in a 24 week window will disqualify the 
subject for major clinical response. 
 
3.2.3 Swollen and Tender/Painful Joint Count 
 
Four different scores will be calculated to evaluate swelling and tenderness of joints. TJC28 and 
SJC28 will take 28 joints into account, SJC66 and TJC68 will use 66 and 68 joints, respectively.  
 
The assessment for swelling is the total number of joints with a present swelling and ranges from 
0 to 28 for SJC28 and 0 to 66 for SJC66. 
 
The assessment for tenderness is the total number of joints with a present tenderness and ranges 
from 0 to 28 for TJC28 and 0 to 68 for TJC68. 
 
The following 28 joints will be taken into account for TJC28 and SJC28: Shoulder (2 joints), 
Knee (2), Elbow (2), Wrist (2), Fingers (PIP, MCP: 20). 
 
Additionally the following joints will be taken into account for SJC66/TJC68: 
Temporomandibular (2), Sternoclavicular (2), Acromioclavicular (2), Fingers (DIP: 8), Ankle 
(2), Tarsus (2), Toes (PIP, MTP: 20), Hip (2, only for TJC). 
Artificial, ankylosed and missing joints are excluded from swelling and tenderness assessment. 
 
If there are missing observations for tender or swollen joints then the remaining observations will 
be assessed and weighted by dividing the number presented by number of non-missing and by 


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multiplying by 28/66/68 for the joint count. No imputations for individual joints will be done. If 
a joint is not evaluable at Baseline, then that joint is set to missing throughout the study. 
 
If data for more than 50% of the joints are missing at the time of a given assessment, then the 
total count will be set to missing for that visit. 
 
Observed joint states will be listed without any modification for every subject and visit. 
 
3.2.4 Patient’s Assessment of Arthritis Pain 
 
Subjects will assess the severity of their current arthritis pain using a continuous visual analog 
scale (VAS) with anchors “0” (no pain) and “100” (most severe pain). 
 
No Imputations for missing data will be done. 
 
3.2.5 Patient’s Global Assessment of Disease Activity 
 
Subjects will complete a global assessment of disease activity using the patient global 
assessment of disease activity (PtGA) item, a continuous VAS with anchors “0” (very well) to 
“100” (very poor). 
 
No imputations for missing data will be done. 
 
3.2.6 Physician’s Global Assessment of Arthritis 
 
Physicians will complete a global assessment of disease activity using the physician global 
assessment of disease activity item (PhGA), a continuous VAS with anchors “0” (none) to “100” 
(extremely active). 
 
No imputations for missing data will be done. 
 
3.2.7 SDAI 
 
The Simple Disease Activity Index (SDAI) is a composite score consisting of the sum of SJC28, 
TJC28, PtGA/10, PhGA/10, and CRP (mg/dl).  Higher values represent higher disease activity. 
 
If one of the components is missing at an individual assessment point, the SDAI value for that 
assessment will be set to missing. 
 
3.2.8 CDAI 
The Clinical Disease Activity Index (CDAI) is a composite score consisting of the sum of 
SJC28, TJC28, PtGA/10, PhGA/10.  CDAI ranges from 0 to 76 with higher values representing 
higher disease activity.  Remission is achieved for a non-missing CDAI value ≤2.8. 
 
If one of the components is missing at an individual assessment point, no imputations will be 
done and the CDAI value for that assessment will be set to missing. 


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3.2.9 Index- and Boolean-based ACR/EULAR Remission Rates 
 
Boolean-based remission (Felson, 2011) is achieved if all of the following requirements are met 
at the same time: 
 
 TJC68 ≤ 1 
 SJC66 ≤ 1 
 CRP ≤ 1mg/dl 
 PtGA ≤ 10 
 
If one of the components is missing at an individual assessment point, Boolean-based remission 
for that assessment will be set to missing. 
 
Index-based remission is achieved if the following requirement is met: 
 
 SDAI ≤ 3.3 
 
If the SDAI value is missing at an individual assessment point, Index-based remission for that 
assessment will be set to missing. 
 
3.2.10 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: 
 
 
dressing & grooming, rising, eating, walking, hygiene, reach, grip, and common daily 
activities. 
 
Each functional area contains at least two questions.  For each question, there is a four level 
response set that is scored from 0 (without any difficulty) to 3 (unable to do).  If aids or devices 
or physical assistance are used for a specific functional area and the maximum response of this 
functional area is 0 or 1 the according value is increased to a score of 2. 
 
Aid or equipment 
Will be associated with category score 
Walking stick/frame, crutches, wheelchair 
Walking 
Aids used for dressing 
Dressing and grooming 
Specially adapted utensils 
Eating 
Specially adapted chair 
Rising 
Raised toilet seat, bath rail, bath seat 
Hygiene 
Long-handled appliance in bathroom 
Hygiene 
Long-handled appliance for reaching 
Reach 
Jar opener 
Grip 
Other (1) 
Dressing & grooming, rising, eating, 
walking 


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Other (2) 
hygiene, reach, grip, common daily 
activities 
 
If “other” is marked as an aid or equipment then this can be assigned to a group of four 
functional areas and will be handled as an aid or equipment for each of the four functional areas. 
Therefore, if the maximum score of a functional area is 0 or 1 that value is increased to a score of 
2 for each of the four functional areas. 
 
Regarding these corrections, the highest response within each functional area determines the 
score of that specific functional area.  If no questions within a given functional area were 
answered, no score will be provided for that category (even if answers on aids or equipment are 
available). 
HAQ-DI is only calculated if there are at least 6 functional area scores available. 
The average of these non-missing functional area scores defines the continuous HAQ-DI score 
ranging from 0 to 3.  If there are less than 6 functional area scores available, no imputation will 
be done and the HAQ-DI will be set to missing for the according assessment. 
 
Severity of pain within the past week is also assessed by the HAQ-DI questionnaire but will not 
be considered for calculating the HAQ-DI score.  Severity of pain will not be included in 
summaries but will be listed. 
 
3.2.11 Short-Form 36  
 
Health-related quality of life will be assessed using the subject-completed Medical Outcomes 
Study 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. Recoding, calculations and standardisation 
will be done as recommended in the User’s manual for the SF-36 (Maruish, 2011). 
 
3.2.11.1 Domain Scores of SF-36 
 
Each of the 8 domain scores is the sum of some of the overall 36 item scores.  
 
Item 
Abbreviated Item Content 
Item 1 
Health 
Item 2 
Health now compared to 1 week ago 
Item 3a 
Health limits vigorous activities 
Item 3b 
Health limits moderate activities 
Item 3c 
Health limits lifting or carrying groceries 
Item 3d 
Health limits climbing several flights of stairs 
Item 3e 
Health limits climbing one flight of stairs 
Item 3f 
Health limits bending, kneeling or stopping 
Item 3g 
Health limits walking more than mile 
Item 3h 
Health limits walking several hundred yards 
Item 3i 
Health limits walking one hundred yards 


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Item 3j 
Health limits bathing or dressing  
Item 4a 
Cutting work time due to physical health 
Item 4b 
Accomplishing less due to physical health 
Item 4c 
Limited in kind of work due to physical health 
Item 4d 
Difficulty performing work due to physical health 
Item 5a 
Cutting work time due to emotional problems 
Item 5b 
Accomplishing less due to emotional problems 
Item 5c 
Less carefully due to emotional problems 
Item 6 
Physical health/emotional problems interfere with social activities (extent) 
Item 7 
Bodily Pain 
Item 8 
Pain interferes with work 
Item 9a 
Full of Life 
Item 9b 
Nervous 
Item 9c 
Down in the dumps 
Item 9d 
Calm and peacefully 
Item 9e 
Lot of energy 
Item 9f 
Downhearted and low 
Item 9g 
Worn out 
Item 9h 
Happy 
Item 9i 
Tired 
Item 10 
Physical health/emotional problems interfere with social activities (frequency) 
Item 11a 
Getting ill more easily than other people 
Item 11b 
As healthy as anybody 
Item 11c 
Expecting health to get worse 
Item 11d 
Excellent health 
 
 
For every one of the items, the answers will be rated in a way such that higher values will be 
associated with higher health-related quality of life (see ratings below). 
 
Rating of the item answers: 
 
Item 1: 
Answer 
Excellent 
Very Good 
Good 
Fair 
Poor 
Value 
5.0 
4.4 
3.4 
2.0 
1.0 
 
Item 2: 
Answer 
Much 
better now 
Somewhat 
better now 
About 
the same 
Somewhat 
worse 
Much worse 
Value 
1 
2 
3 
4 
5 
Item 2 is not used for the calculation of any of the 8 domain scores. 
 
Items 3a-3j: 
Answer 
Yes, limited a lot 
Yes, limited a little 
No, not limited at all 
Value 
1 
2 
3 


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Items 4a-4d and 5a-5c: 
Answer 
All of the 
time 
Most 
of 
the time 
Some of 
the time 
A little of 
the time 
None of the 
time 
Value 
1 
2 
3 
4 
5 
 
Item 6: 
Answer 
Not at all 
Slightly 
Moderately 
Quite a bit 
Extremely 
Value 
5 
4 
3 
2 
1 
 
Item 7: 
Answer None 
Very mild 
Mild 
Moderate 
Severe 
Very severe 
Value 
6.0 
5.4 
4.2 
3.1 
2.2 
1.0 
 
Item 8 is recoded depending on whether item 7 is answered or not: 
Original 
Answer 
item 8 
Not at 
all 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 
Answer 
item 7 
Very 
severe 
None, 
Very mild, 
Mild, 
Moderate, 
Severe 
None,  
Very mild, 
Mild, 
Moderate, 
Severe, 
Very severe 
None,  
Very mild, 
Mild, 
Moderate, 
Severe, 
Very severe 
None,  
Very mild, 
Mild, 
Moderate, 
Severe, 
Very severe 
None,  
Very mild, 
Mild, 
Moderate, 
Severe, 
Very severe 
Value 
item 8 
6 
5 
4 
3 
2 
1 
 
Original 
Answer item 8 
Not at all A little bit 
Moderately 
Quite a bit 
Extremely 
Answer item 7 
NA 
NA 
NA 
NA 
NA 
Value item 8 
6.0 
4.75 
3.5 
2.25 
1.0 
 
Items 9a, 9d, 9e, 9h: 
Answer 
All of the 
time 
Most of the 
time 
Some of the 
time  
A little of 
the time 
None of the time 
Value 
5 
4 
3 
2 
1 
 
Items 9b, 9c, 9f, 9g, 9i and 10: 
Answer 
All of the 
time 
Most of the 
time 
Some of the 
time  
A little of 
the time 
None of the time 
Value 
1 
2 
3 
4 
5 
 
Items 11a and 11c: 
Answer Definitely true 
Mostly true 
Don´t know 
Mostly false Definitely false 
Value 
1 
2 
3 
4 
5 
 


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Items 11b and 11d: 
Answer Definitely true 
Mostly true 
Don´t know 
Mostly false Definitely false 
Value 
5 
4 
3 
2 
1 
 
The initial domain scores are the sum of individual item scores: 
 
General Health (GH) 
GH = 1 + 11a + 11b + 11c + 11d 
 
Physical Functioning (PF) 
PF = 3a + 3b + 3c + 3d + 3e + 3f +3g + 3h + 3i + 3j 
 
Role Physical (RPh) 
RPh = 4a + 4b + 4c + 4d 
 
Role Emotional (RE) 
RE= 5a + 5b + 5c 
 
Social Functioning (SF) 
SF = 6 + 10 
 
Bodily Pain (BP) 
BP = 7 + 8 
 
Vitality (VT) 
VT = 9a + 9e + 9g + 9i 
 
Mental Health(MH) 
MH = 9b + 9c + 9d + 9f + 9h 
 
Imputation 
Domain scores will only be calculated if less than half of the item scores are missing.  Missing 
item scores will be imputed as the mean of the other item scores within the same domain.  If at 
least half of the item scores of a domain are missing, imputation will not be performed and the 
domain will be set to missing. 
 
Standardisation 
All raw domain scores will be transformed on a 0–100 scale (transformed domain scores) and 
then standardised into norm-based scores: 
Transformed domain score = 100 x (Actualraw score – lowest possible raw score) / (highest 
possible raw score – lowest possible raw score) 
One example would be: 
𝑃𝐹_𝑆= 100 ∗(𝑃𝐹−10)/(30 −10) 
Each transformed domain score is standardised using a z-score transformation. Z-scores are 
computed by subtracting the health domain scale’s 2009 U.S. general population mean from the 


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0–100 score for that scale, and then dividing the difference by the given scale’s standard 
deviation: 
  
PF_Z = (PF_S – 83.29094) / 23.75883 
RPh_Z = (RPh_S – 82.50964) / 25.52028 
BP_Z = (BP_S – 71.32527) / 23.66224 
GH_Z = (GH_S – 70.84570) / 20.97821 
VT_Z = (VT_S – 58.31411 / 20.01923 
SF_Z = (SF_S – 84.30250) / 22.91921 
RE_Z = (RE_S – 87.39733) / 21.43778 
MH_Z = (MH_S – 74.98685) / 17.75604 
 
The next step is the transformation of each z-score to a norm-based score using a t-score 
transformation (Mean=50, Standard Deviation (SD) =10) and the following formulas: 
 
PF_N = 50 + (PF_Z * 10) 
RPh_N = 50 + (RPh_Z * 10) 
BP_N = 50 + (BP_Z * 10) 
GH_N = 50 + (GH_Z * 10) 
VT_N = 50 + (VT_Z * 10) 
SF_N = 50 + (SF_Z * 10) 
RE_N = 50 + (RE_Z * 10) 
MH_N = 50 + (MH_Z * 10) 
 
These norm-based values (e.g. PF_N) are the final domain scores and will be used in summary 
tables.  The raw values (e.g. PF), the standardised values (e.g. PF_S) and the final scores (e.g. 
PF_N) will be shown in a listing for every subject and visit. 
 
3.2.11.2 Physical and Mental Component Scores 
 
Following the transformation of the eight domain scores into z-scores, the Mental Component 
Summary (MCS) and the Physical Component Summary (PCS) are aggregated using weights 
from the 1990 US general population: 
 
AGG_PHYS = (PF_Z * 0.42402) + (RPh_Z * 0.35119) + (BP_Z * 0.31754) + (GH_Z * 
0.24954) + (VT_Z * 0.02877) + (SF_Z * -0.00753) + (RE_Z * -0.19206) + (MH_Z * - 0.22069) 
 


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AGG_MENT = (PF_Z * -0.22999) + (RPh_Z * -0.12329) + (BP_Z * -0.09731) + (GH_Z * - 
0.01571) + (VT_Z * 0.23534) + (SF_Z * 0.26876) + (RE_Z * 0.43407) + (MH_Z * 0.48581) 
 
Finally, each component score is transformed to norm-based scoring using the following 
formulas: 
 
Transformed Physical Score: PCS = 50 + (AGG_PHYS * 10) 
Transformed Mental Score: MCS = 50 + (AGG_MENT * 10) 
 
Component scale scores (PCS and MCS) will be set to missing if the subject is missing any one 
of the eight SF-36 scales. 
 
While the norm-based scores are calculated such that the mean ± SD of these scores in the US 
general population is 50 ± 10, the lowest and highest possible scores for the PCS are 1 and 81, 
respectively. For the MCS, the lowest and highest possible scores are -9 and 82, respectively. 
 
3.2.12 FACIT-Fatigue 
 
The Functional Assessment of Chronic Illness Therapy (FACIT) -fatigue questionnaire is a 
patient-reported measure developed to assess fatigue consisting of 13 statements regarding 
feeling fatigue using a numeric rating scale (NRS) ranging from 0 to 4.  For only two of the 
items (i.e. An5 and An7) a higher value represents a lower fatigue; 11 of the item scores (i.e. 
HI7, HI12, An1, An2, An3, An4, An8, An12, An14, An15, An16) have to be reversed by 
subtracting the captured value from 4 (0 is turned to a 4; 1 into 3; 3 into 1; 4 into 0). 
After performing the reversals the sum of the non-missing individual items will be multiplied by 
13 and divided by the number of the non-missing individual items. 
The final score ranges from 0 to 52 with higher values representing a lower fatigue (i.e. a better 
quality of life). 
 
If more than 6 individual items are missing at an assessment the FACIT-Fatigue score will be set 
to missing at that assessment.  
 
3.2.13 BFI 
 
Brief Fatigue Inventory (BFI) is a self-reported instrument consisting 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. 
A discrete 11 unit NRS will be used where 0 is “No fatigue”, and 10 is “As bad as you can 
imagine”. 
 
No imputations will be done for missing data. 
 
3.2.14 Borg Dyspnea Scale 
 
The Borg dyspnea scale will be used to assess dyspnea. A discrete 18 unit scale will be used 
ranging from “Nothing at all” to “Absolute maximum”. 


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No imputations will be done for missing data. 
 
4 
STATISTICAL METHODS 
4.1 
Data Quality Assurance 
All tables, figures and data listings to be included in the report will be independently checked for 
consistency, integrity and in accordance with standard PAREXEL procedures. 
 
4.2 
General Presentation Considerations 
For each subject ‘Baseline’ is defined as the last available assessment prior to the start of study 
treatment. For Efficacy variables no Screening information will be used for Baseline.  For 
DLCO, separate Baseline rules are defined in section 4.10.9.  For each subject ‘End of Study’ is 
defined as the last available assessment which is on or after the day of last study treatment. 
 
The relative study day will be included in adverse event data, medical history and concomitant 
medication listings, and will be calculated as follows: 
 Relative Day 1 is the date of first study medication administration. 
 Relative Day of date X = date X - Date of first study medication administration + 1 if date X 
is on or after date of first study medication administration. 
 Relative Day of date X = date X - Date of first study medication administration if date X is 
before date of first study medication administration. 
Relative days before first study medication administration will have the prefix “-“.  Additionally 
for relative days after last study medication administration, the number of days since last study 
medication administration will be presented with the prefix “+”.  Calculations of “Relative Day” 
will not include partial dates, but will be left blank in listings. 
 
According to the design the study can be split into 5 time periods: 
 Baseline to <Week 14: Day of first study medication administration up to and including the 
day before Week 14 study medication administration  
 Week 14 to <Week 26 visit 
 Week 26 to <Week 38 visit 
 Week 38 to <Week 52 visit  
 Safety Period: Week 52 visit to end of study 
Safety period includes Week 52 and all later visits.  All other periods start with (and include) 
Baseline visit or Week 14/26/38 visit and end with the day before the next period starts.  Start of 
a new period is always the day of study medication administration.  Safety Period starts with the 
Week 52 Visit.  If the Week 52 visit is missing, Safety Period starts 14 days after the last study 
drug administration of the previous period. 
 
If the Week 14/26/38 visit is missing, the day of the next non-missing visit will be the first day of 
the new period.  For example, if the Week 14 visit was missed but the Week 16 visit was 


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conducted, the first time period will end the day prior to the Week 16 visit, This ensures that all 
Adverse Events (AEs) reported during the initial treatment period are attributed to the initial 
dose.  If no end date for a period can be identified with the above rules, then the period ends 13 
days after the last day of study drug administration of that period. 
 
Continuous data will be summarised in terms of the mean, SD, median, minimum, maximum and 
number of observations, unless otherwise stated.  The minimum and maximum will be reported 
to the same number of decimal places as the raw data recorded in the database.  The mean, 
median, lower quartile and upper quartile will be reported to one more decimal place than the 
raw data recorded in the database.  The SD will be reported to two more decimal places than the 
raw data recorded in the database.  In general, the maximum number of decimal places reported 
shall be four for any summary statistic. 
 
Categorical data will be summarised in terms of the number of subjects providing data at the 
relevant time point (n), frequency counts and percentages. 
 
If not stated otherwise percentages will be presented with one decimal place.  Percentages will 
not be presented for zero counts.  Percentages will be calculated using n as the denominator. 
100% will be presented without decimal places.  
 
P-values greater than or equal to 0.001, in general, will be presented to three decimal places.  P-
values less than 0.001 will be presented as “<0.001”. 
 
Confidence intervals (CI) will be presented to one more decimal place than the raw data. 
 
All report outputs will be produced using SAS® version 9.2 or a later version in a secure and 
validated environment.  Tables, listings and figures will each be provided in a separate rtf 
document as well as in a separate pdf documents.   
 
4.3 
Analysis Populations 
Screened Population: The SP will consist of all subjects who got screened. 
Randomised Population (RP): The RP will consist of all subjects who were randomised to 
treatment. 
Intent-to-Treat (ITT) Population: The ITT population will consist of all subjects who were 
randomised to treatment and who received at least one dose of study treatment (GSK3196165 or 
placebo). 
Pharmacokinetic (PK) Population: The PK population will consist of all subjects in the ITT 
population, who had at least one valid pharmacokinetic assessment. 
Immunogenicity Population: The immunogenicity population will consist of all subjects in the 
ITT population, who had at least one valid immunogenicity assessment. 


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Actigraphy Population (AP): The AP will consist of all subjects in the ITT population who 
consent to participate in the actigraphy substudy. 
Genetic Research Population (GRP): The GRP will consist of all subjects in the ITT 
population who consent to participate in the genetic research.  Any subject who has received an 
allogeneic bone marrow transplant must be excluded from the genetic research. 
All endpoints will be analysed for the ITT population by randomised treatment group.  Numbers 
and percentages of subjects in each analysis population will be summarised by randomised 
treatment group.  Subjects who received at least one wrong dose will be presented in a listing.  
Additional summaries may be provided if considered necessary. 
A by-subject listing of analysis population details will be provided.  This listing will be presented 
by randomised treatment group and will include: center, subject identifier, inclusion/exclusion 
flag for each population and reason for exclusion from each population.  All subjects screened 
will appear on this listing. 
4.3.1 Analysis Datasets 
 
For each of the efficacy evaluations of binary endpoints, subjects with missing efficacy data, 
early withdrawals, subjects who received more than 10 mg/day of prednisone equivalent oral 
corticosteroids, subjects with any new use of parenteral corticosteroids, more than one intra-
articular corticosteroid injection within a 24 week period, or subjects who received rescue 
treatment will be imputed as non-responders and therefore treated as a failure (e.g. no 
DAS28(CRP) remission or no moderate/good EULAR response).  Imputation rules for each case 
are described in section 4.5.2: 
 
A dataset will be created with these imputation rules and will be referred to as the NRI dataset. 
The NRI dataset will be the primary dataset used for all binary efficacy endpoints.  Imputed 
response for each binary endpoint will be presented by visit and subject in listings. 
 
For the efficacy evaluations of continuous endpoints, results recorded for subjects who received 
rescue treatment or exceeded 10 mg/day prednisone equivalent oral corticosteroids, subjects with 
any new use of parenteral corticosteroids, more than one intra-articular corticosteroid injection 
within a 24 week period, or subjects who received rescue treatment will be set to missing at the 
same visits that were set to non-responder for the binary endpoints.  This is a change from 
protocol section 9.3.2.  A dataset will be created and will be referred to as the Set-to-Missing 
(STM) dataset.  
 
For safety endpoints, no imputation for missing data will be done. 
 
4.4 
Study Subjects 
4.4.1 Disposition of Subjects 
A clear accounting of the disposition of all subjects who enter the study will be provided, from 
screening to study completion. 
 


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The following subject disposition summaries will be provided: See Section 4.3 for a description 
of the analysis populations. 
 
A summary of the number of subjects who were screened for entry into the study and 
 were excluded prior to randomisation by major reason and overall (Analysis population: 
All Subjects Screened) 
 were randomised per center, per country, and by disease duration (<2 years, ≥2 years) 
and randomised treatment group (Analysis population: Randomised Population) 
 received at least one dose of study medication by randomised treatment group (Analysis 
population: Randomised Population) 
 withdrew from the study by major reason by randomised treatment group (Analysis 
population: ITT Population) 
 completed the study by randomised treatment group (Analysis population: ITT 
Population) 
 completed 12/24/36/50 weeks of treatment by randomised treatment group (Analysis 
population: ITT Population) 
 completed 12/24/36/50 weeks of treatment without dose escalation by randomised 
treatment group (Analysis population: ITT Population) 
 were escalated to highest dose at Week 14/26 by randomised treatment group (Analysis 
population: ITT Population) 
 were escalated to highest dose at Week 14/26 and completed 24/36/52 weeks of 
treatment by randomised treatment group (Analysis population: ITT Population) 
 were withdrawn from study at Week 38 due to lack of EULAR good/moderate response 
by randomised treatment group (Analysis population: ITT Population) 
 
By-subject listings of eligibility details, randomisation details by site (including subject id, 
randomisation number and randomised treatment group and information whether the blind was 
broken at discontinuation), visit dates (including actual treatment received at each visit) and 
withdrawal/study completion details (including reason for discontinuation and duration of 
treatment prior to discontinuation) will be provided.  
4.4.2 Protocol Deviations 
 
Protocol deviations (PDs) will be managed and reported according to PAREXEL Standard 
Operating Procedures (SOPs). 
Details will be given in the Protocol Deviation Specification (PDS) document, which will 
include detailed information regarding definitions, classifications, tracking and management of 
PDs. 
PDs will be categorised as major or minor as further described in the PDS. 
PDs will also be classified into the following categories: Informed Consent, Inclusion/Exclusion 
Criteria, Withdrawal Criteria, IP Admin/Study Treat, Disallowed Medications, AE/SAE, Visit 
Schedule, Procedures/Tests, Other. 


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Observable PDs that can only be identified by project team members during the monitoring, but 
cannot be programmed, will be tracked and reconciled with programmable (data driven) PDs, 
that can be programmed from the recorded data. 
A combined PD dataset will include all PDs. 
Special considerations are needed for (potentially) unblinding PDs, which will be handled in 
separate unblinded areas with restricted access. 
Summaries of the number and percentage of subjects with a major/minor protocol deviation will 
be provided by randomised treatment group and by type of deviation (Analysis population: 
Randomised Population). 
 
A by-subject listing of all protocol deviations will be provided. 
 
4.5 
General Data Handling Conventions 
 
4.5.1 Missing Dates 
 
In analysis of AEs and medication a complete date will be established in order to identify AEs 
or medication as occurring during treatment or not. For handling partially reported onset/start 
and outcome/end dates for AEs or medication the following algorithms are applied: 
 AEs: 
 Missing onset day, but month and year present: 
If study medication had been taken in the same month and year as the occurrence of the 
AE, then the onset day of the event is assigned to the day of first dose of study 
medication. 
Otherwise the onset day is set to the first day of the month (eg, XX-Sep-2010 is 
considered as 01-Sep-2010). 
 Missing onset day and month, but year present: 
If study medication had been taken in the same year as the occurrence of the AE, then 
the onset date of the event is assigned to the date of first dose of study medication. 
Otherwise the onset day and month is set to 01 January (eg, XX-XXX-2010 is 
considered as 01-Jan-2010). 
 Missing outcome day, but month and year present: 
The day is set to the last day of the month (eg, XX-Sep-2010 is considered as 30-Sep-
2010). 
 Missing outcome day and month, but year present: 
The outcome day and month is set to 31 December (eg, XX-XXX-2010 is considered as 
31-Dec-2010). 
 Medications: 
 Missing start day, but month and year present: 
If first study medication administration had been taken place in the same month and 
year as the occurrence of the medication, then the start day of the medication is assigned 


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to the day of first study medication administration. Otherwise the start day is set to the 
first day of the month (eg, XX-Sep-2010 is considered as 01-Sep-2010). 
 Missing start day and month, but year present: 
If first study medication administration had been taken in the same year as the 
occurrence of the medication, then the start date of the medication is assigned to the date 
of first study medication administration. 
 Otherwise the start day and month is set to 01 January (eg, XX-XXX-2010 is considered 
as 01-Jan-2010). 
 Missing stop day, but month and year present: 
The day is set to the last day of the month (eg, XX-Sep-2010 is considered as 30-Sep-
2010). 
 Missing stop day and month, but year present: 
The stop day and month is set to 31 December (eg, XX-XXX-2010 is considered as 31-
Dec-2010). 
 RA diagnosis and symptom onset: 
 Missing day, but month and year present: 
Date is set to the first day of the month (eg, XX-Sep-2010 is considered as 01-Sep-
2010). 
 Missing day and month, but year present:  
Date is set to 01 January (eg, XX-XXX-2010 is considered as 01-Jan-2010) 
 End date of Tobacco use: 
 Missing outcome day, but month and year present: 
The day is set to the last day of the month (eg, XX-Sep-2010 is considered as 30-Sep-
2010). 
 Missing outcome day and month, but year present: 
The outcome day and month is set to 31 December (eg, XX-XXX-2010 is considered as 
31-Dec-2010). 
 
In data listings, onset/start and outcome/stop date of AEs, medication, diagnosis, or symptoms is 
displayed as reported. 
 
4.5.2 Missing Data for Efficacy and Safety Endpoints 
 
4.5.2.1 Missing Data for Efficacy Endpoints 
 
Missing visit data for each efficacy endpoint will be handled as described in Sections 3.2 and 
4.3.1.  For each continuous endpoint, change from baseline will be missing at visits with missing 
post-baseline values or where data were imputed to missing.   
 
For the binary endpoints, subjects with missing efficacy data, early withdrawals, subjects who 
exceed the allowed dose of corticosteroid, who received new parenteral corticosteroids or more 
than one intra-articular corticosteroid injection within a 24 week period, or subjects who received 
rescue treatment will be imputed as non-responders and therefore treated as a failure (e.g. no 
DAS28(CRP) remission or no moderate/good EULAR response).   


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For subjects who exceed the allowed dose of corticosteroid, who received new parenteral 
corticosteroids or more than one intra-articular corticosteroid injection within 24 weeks or 
subjects who received rescue treatment, continuous efficacy endpoints will be set to missing. 
 
- 
Missing efficacy data: visits with missing data (due to a missed visit or missing 
component of a composite endpoint) should be set to treatment failure. 
- 
Early withdrawals (including subjects that are withdrawn at Week 36 due to lack of 
EULAR response): only visits following the early withdrawal visit should be set to treatment 
failure. 
- 
Prednisone equivalent >10 mg/day: the visit after a period (time from previous visit up to 
the day before the current visit) of average daily corticosteroid use exceeding 10 mg/day 
prednisone and all following visits should be set to treatment failure (continuous endpoints will 
be set to missing). 
- 
Parenteral corticosteroids: all visits after a subject received any new parenteral 
corticosteroids (e.g. intravenous and intra-muscular) should be set to treatment failure 
(continuous endpoints will be set to missing).  
- 
Intra-articular corticosteroids: all visits after the second intra-articular corticosteroid 
injection within a 24 week period should be set to treatment failure (continuous endpoints will be 
set to missing).  
- 
Rescue: subjects who rescue to 180 mg dose at Week 14 or 26 should be set to treatment 
failure at that visit and all subsequent visits (continuous endpoints will be set to missing). 
 
4.5.2.2 Missing Data at Baseline for Efficacy and Safety Endpoints 
 
For efficacy endpoints (including CRP and ESR), a missing value at baseline will not be imputed 
with the screening results for change from baseline or percent change from baseline calculations; 
the endpoint will be missing for all visits. 
 
For safety endpoints, a missing value at baseline will be imputed using the prior result that is 
closest in proximity to baseline in order to calculate change from baseline or percent change 
from baseline. 
4.5.2.3 Multiple Imputation: Predictive Mean Matching 
 
For further sensitivity analyses for DAS28(CRP), multiple imputation may be conducted (see 
section 4.9.2).  If needed, this will be conducted as an ad-hoc analysis by GSK. 
 
The multiple imputation procedure will assume that the observed visit data are from a 
multivariate normal distribution and that data are missing at random.  Depending on the missing 
data pattern, either the predicted mean matching method (monotone missing pattern) or the 
MCMC method (either monotone or non-monotone missing pattern) for imputation will be used. 
The sensitivity analysis will follow steps 1 to 3: 
1. 
Using PROC MI, missing data will be filled in m times to generate m complete datasets 
using the observed data. If the MCMC method is used, specify IMPUTE=FULL to 
impute all missing values. 


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2. 
Change from baseline will be calculated in each of the m complete datasets and then 
analyzed using the appropriate dose response model identified at the second interim 
analysis. 
3. 
Using PROC MIANALYZE, the m sets of estimated parameters from the dose response 
model will be combined to form the mean and standard deviation of each parameter for 
use in inference regarding the dose response relationship at Weeks 24 or 52 visits. 
 
4.5.3 Multiple Assessments and Early Withdrawal Visits 
 
If a variable has been assessed multiple times at the same visit, only the last assessment will be 
used except for Electrocardiograms (ECGs) or laboratory measurements.  Triplicate ECG 
measures will be averaged for each subject and visit prior to generating summary tables. 
 
For laboratory values the value with the worst CTCAE grade will be considered.  If there is more 
than one value of this grade, the later value will be considered. 
 
Only scheduled visits will be included in summaries.  Listings will include scheduled and 
unscheduled visits. 
 
Early Withdrawal (EW) visits will be assigned to the respective visit according to the Time and 
Events table in Section 7.1 of the protocol using the day of the EW visit relative to Day 1.  For 
the first 4 weeks an EW visit more than ±3 days in comparison to the target visit will be assigned 
to the closest target visit.  Starting with Week 4, an EW visit more than 7 days after a target visit 
day will be assigned to the next visit. 
If a scheduled visit and an EW visit occur within the same visit window and are both available, 
the later visit will be used for analyses.  The earlier visit will appear in listing only.  For efficacy 
analyses, if an EW visit is assigned to a non-standard efficacy visit, i.e., a visit at which efficacy 
assessments are not scheduled per the Time and Events Table, then these EW data will be 
ignored in the statistical analysis. 
 
4.5.4 Oral Corticosteroid Conversion 
To assess corticosteroid use and determine average daily corticosteroid dose, all corticosteroid 
dosages will be converted to a prednisone equivalent in milligrams by multiplying the dose of 
the steroid (using the coded term from GSKDrug) by the conversion factor to get prednisone 
equivalent units.  Summaries refer to average daily prednisone dose instead of average daily 
corticosteroid dose.  See Table 3 for conversion factors. 
 


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Table 3 Corticosteroid Conversion Factors 
Conversion 
Steroid 
8.333  BETAMETHASONE 
8.333  BETROSPAM 
0.2  CORTISONE 
8.333  CRONOLEVEL 
0.83333  DEFLAZACORT 
6.667  DEXAMETHASONE 
0.25  HYDROCORTISONE 
1.25  MEPREDNISONE 
1.25  METHYLPREDNISOLONE 
2.5  PARAMETHASONE 
1  PREDNISOLONE 
1  PREDNISONE 
1.25  TRIAMCINOLONE 
 
For each scheduled visit, the average daily prednisone dose will be calculated by summing all 
oral corticosteroid doses (converted to prednisone) since the previous visit up to and including 
the current visit and then dividing by the number of days in this period (Date of current visit – 
Date of previous scheduled visit). 
 
4.6 
Demographic and Other Baseline Characteristics 
The following Baseline characteristics will be summarised based on the ITT population by 
randomised treatment group. 
Demographic Characteristics 
Continuous variables: age (years), height (cm), weight (kg), BMI-Body Mass Index (kg/m²).  
 
Categorical variables: age (18- <65 years and ≥65 years), sex (male, female), child bearing 
potential (for females: yes, no), ethnicity (Hispanic or Latino, Not Hispanic or Latino), race 
(African American/African Heritage, American Indian or Alaskan Native, Asian – Central/South 
Asian Heritage, Asian – East Asian Heritage, Asian – Japanese Heritage, Asian – South East 
Asian Heritage, Native Hawaiian or Other Pacific Islander, White – Arabic/North African 
Heritage, White/Caucasian/European Heritage) and BMI (<18.5, 18.5 - <25, 25 - <30, ≥30). 
 
An additional summary will include age, sex and race for placebo group and combined 
GSK3196165 treatment groups. 
 
Baseline efficacy parameters 
Continuous baseline efficacy parameters and components will be summarised in a separate table. 
 
Medical history 


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Prior and concomitant medical history will be summarised by reported term.  Cardiac disorders 
will be shown separately. 
 
Disease history 
RA disease history will be summarised in form of disease duration (duration from formal RA 
diagnosis to first study medication administration) categorical (< 2 years/ ≥ 2 years) and as 
summary statistics (in months), RA functional class and time since start of RA symptoms (in 
months). 
 
Separate by-subject listings of demographic data and other baseline characteristics, prior and 
concomitant medication, medical history, RA medication use and disease history will be 
provided. 
 
4.7 
Medication Use 
Prior and concomitant medication use 
Prior and concomitant medications will be summarised by Anatomical Therapeutic Chemical 
(ATC) classification and randomised treatment group in separate tables.  Medications that are 
both prior and concomitant will appear in both tables. 
 
Medications that start and stop prior to the date of first dose of study medication will be 
classified as Prior only.  If a medication starts before the date of first dose of study medication 
and stops on or after the date of first dose of study medication then the medication will be 
classified as both Prior and Concomitant.  Medications will be classified as Concomitant only if 
they have a start date on or after the date of first dose of study medication. 
 
If medication start and/or stop dates are missing or partial, imputations are done as described in 
section 4.5.1 and the dates will be compared as far as possible with the date of first dose of study 
medication.  Medications will be assumed to be Concomitant only, unless there is clear evidence 
(through partial dates as described in section 4.5.1) to suggest that the medication started prior to 
the first dose of study medication.  If there is clear evidence to suggest that the medication 
started prior to the first dose of study medication, the medication will be assumed to be both 
Prior and Concomitant, unless there is clear evidence to suggest that the medication stopped 
prior to the first dose of study medication.  If there is clear evidence to suggest that the 
medication stopped prior to the first dose of study medication, the medication will be assumed to 
be Prior only. 
 
Prior and concomitant corticosteroid use will be shown in a separate listing. 
 
RA medication use 
Prior and concomitant RA medication will be summarised by ATC classification and randomised 
treatment group. 
 
Oral Corticosteroid use 


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Change from baseline in average daily prednisone dose will be summarised by visit.  The 
number and percentage of subjects with ≥25% decrease from baseline and to below ≤7.5 mg/day 
will be summarised at Weeks 12, 24, 36, 48 and 52. 
 
 
4.8 
Treatment Compliance 
Summaries will be based on the ITT population and will be provided by randomised treatment 
group and time period. 
 
Study Treatment 
Treatment compliance for GSK3196165 will utilize the administered volume and compare it to 
the scheduled expected volume.  The general formula for the compliance ratio (CR) is given as 
follows: 
 
CR = actual volume (mL) ∗100
expected volume (mL)
% 
 
The expected volume is based on the planned number of doses (based on each subjects time in 
the study) and study treatment volumes provided in the protocol Section 6.1.  If a subject 
completed the study without escalation, then the total number of doses would be 28 and the total 
expected volume for each treatment group would be as follows: placebo=16.8mL; 
22.5mg=4.2mL; 45mg=8.4mL; 90mg=16.8mL; 135mg=25.2mL; 180mg=33.6mL.  The actual 
volume is the sum of the volume of doses received in mL.  If a subject escalates to 180mg dose, 
the 180mg volume times the number of doses would be included in the expected volume.  The 
ratio will be summarised as a continuous variable as well as categorically (<80% and ≥80%) and 
will be shown separately for administrations of randomised treatment and administrations after 
escalation. 
 
Additionally, number and percentage of subjects who missed at least two doses of GSK3196165 
will be summarised by period. 
 
Methotrexate 
Numbers and percentages of subjects who increased or decreased their MTX dose or missed a 
MTX dose during the conduct of the study will be shown separately for administrations before 
escalation and after escalation. 
 
A by-subject by-period listing of treatment compliance ratio for GSK3196165 will be provided. 
 
4.9 
Efficacy Evaluation 
4.9.1 Statistical Considerations 
 
4.9.1.1 Hypotheses for Primary Endpoint and Dose-Response Relationship 
 
Primary endpoint (remission at Week 24): 


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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 (DAS28(CRP)<2.6) 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. 
 
 
H0: No difference between placebo and the 5 active doses 
 
 
H1: At least one of the 5 active doses differs from placebo 
 
Dose response relationship (change from baseline in DAS28(CRP) at Week 12): 
 
The null hypothesis (H0) for the dose response relationship assumes that there is no effect of the 
test drug and hence no evidence of a dose response relationship with respect to the change from 
baseline in the DAS28(CRP) continuous score.  This is equivalent to saying that none of the 
active doses differs from 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 or more 
generally is a monotone relationship: 
 
 
H1: Placebo ≥22.5 mg ≥45 mg ≥90 mg ≥135 mg ≥180 mg 
 
4.9.1.2 Multi-center Studies 
 
This study will randomise 210 subjects into 6 treatment arms, so that on average only 35 subjects 
per arm will be enrolled (although some arms may have larger patient numbers if inferior arms 
are dropped at the interim analyses).  The number of sites (centres) may be roughly around 70, so 
that an adjustment of the analyses by centre will not be feasible.   
 
For all analyses all sites, countries and regions will be pooled. 
 
4.9.1.3 Adjustments for Covariates 
 
Adjustment for the following covariates will be considered: baseline value, disease duration (<2 
years, >=2 years), weight, age, and sex. 
 
4.9.1.4 Multiple Comparisons/Multiplicity 
 
For this phase II study no adjustment for multiple testing is planned. 
 
4.9.1.5 Interim and Final Analyses  
 


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Two interim analyses, one primary endpoint analysis and a final analysis are planned during the 
course of this study.  Unblinded results will be presented to the DRC where the decision to drop 
treatment arms or stop the study based on benefit/risk relationship or based on safety findings 
alone will be made as detailed in the DRC Charter or DRC Statistical Guidance document.  See 
section 4.10.11 for additional DRC information.  
 
The timing and content of each deliverable is summarised in the following table. 
 
Table 4 Interim and Final Deliveries 
Analysis Timing 
Deliverable 
Unblinded Team 
Main Objective 
Interim 
1 
90 subjects 
complete 
Week 4 
PAREXEL: 
ADAM datasets 
and 
demography 
table (see Table 
5) 
 
GSK:  
efficacy 
displays (see 
Table 5) and PK 
if required 
Unblinded 
PAREXEL 
programmers, GSK 
lead and QC 
statistician, DRC 
Evaluate whether to stop the 
study based on: 
 Dose response relationship 
at Week 4 (i.e., if all doses 
have > -0.4 point difference 
over placebo using the 
Week 4 dose response 
model estimates for change 
from baseline in 
DAS28(CRP)). 
Interim 
2 
90 subjects 
complete 
Week 12 
PAREXEL: 
ADAM datasets 
and 
demography 
table (see Table 
5) 
 
GSK:  
efficacy 
displays (see 
Table 5) and PK 
if required 
Unblinded 
PAREXEL 
programmers, GSK 
lead and QC 
statistician, DRC 
Evaluate whether to stop the 
study based on: 
 Dose response relationship 
at Week 12 (i.e., if all doses 
have > -1.0 point difference 
over placebo using the 
Week 12 dose response 
model estimates for the 
change from baseline in 
DAS28(CRP)). 
 Dose response relationship 
and predictive probabilities 
(i.e., if at least one dose ≤ -
1.0 over placebo using the 
Week 12 dose response 
model estimates but the 
predictive probabilities of 
seeing a 25% difference at 
Week 24 in DAS28(CRP) 
remission is <30%). 
Evaluate whether to drop a 
treatment arm based on: 
 An individual dose with > -
1.0 point difference over 
placebo using the Week 12 
dose response model 
estimates for change from 


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baseline in DAS28(CRP). 
Week 
24 
All 
subjects 
complete 
Week 24 
visit 
PAREXEL: 
Unblinded 
Week 24 
displays. 
PAREXEL lead and 
QC biostatisticians 
and programmers, 
GSK. 
Unblinded primary/ 
secondary analyses, safety 
and PK. 
Final 
All 
subjects 
complete 
the study 
(follow-up 
visit at 
Week 62) 
PAREXEL: 
All unblinded 
displays, 
including 
exploratory 
endpoints, 
SDTM and 
ADAM 
datasets. 
PAREXEL lead and 
QC biostatisticians 
and programmers, 
GSK. 
Final reporting for Study 
201755. 
 
Unblinded interim analyses will be conducted when 90 subjects (i.e. on average 15 per arm) have 
completed 4 and 12 weeks of treatment.  Efficacy analysis for the interim analyses will not be 
analysed by PAREXEL but by GSK.  These interim analyses will be aligned with the unblinded 
safety review of the DRC where possible, see section 4.10.11. 
 
4.9.1.6 Examination of Subgroups 
 
A subgroup analysis for subjects with early RA (i.e. < 2 years disease duration before first study 
medication administration) will be conducted if there are at least 10% subjects with early RA in 
the ITT population. 
Additionally, subgroup analyses for selected endpoints may be conducted by gender if an 
adequate number of subjects are represented in each subgroup. 
 
The following endpoints will be summarised for all subgroups in the same way as done for the 
entire population: 
 
 DAS28(CRP) remission at all assessment points 
 Change from Baseline in DAS28(CRP) at all assessment points 
 ACR 20/50/70 response rates at all assessment time points 
 
The following outputs for key safety endpoints will be provided by randomised treatment group 
for all subgroups:  
 
 Overall summary of AEs 
 Number and percentage of subjects reporting an AE by SOC and PT 
 Number and percentage of subjects reporting a serious AE by SOC and PT 
 Summary of AESIs 
 Summary of subjects with pulmonary findings 
 


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4.9.2 Key Efficacy Analyses 
 
4.9.2.1 Interim Analyses 
The outputs listed in Table 5 will be produced at the efficacy interims.  All data will be 
summarised using the Intent-to-Treat population. 
 
The second interim analysis may allow an assessment of subjects with early RA (<2 years 
disease duration).  Results may impact the proportion of subjects randomised to this subgroup. 
 
 


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Table 5 List of Outputs for Interim Analyses (IA) 
Endpoint 
Output 
IA1 
IA2 
Produced 
by 
n/a 
Summary of Demography Characteristics – 
Disease History 
Y 
Y 
PAREXEL1 
DAS28(CRP) 
change from 
baseline 
Summary of the Change from Baseline in 
DAS28(CRP) at Each Visit 
Y 
Y 
GSK 
Plot of Mean and 95% CI of Change from Baseline 
in DAS28(CRP) by Visit and Randomised 
Treatment Group (1 plot) 
Y 
Y 
GSK 
Plot of Mean and 95% CI of Change from Baseline 
in DAS28(CRP) Across Doses at Weeks 4, 8 and 
12 (3 plots) 
Y  
Y 
GSK 
Mixed Model Repeated Measures Analysis 
(MMRM) of Change from Baseline in 
DAS28(CRP) Through Week 12 
Y 
Y 
GSK 
Plot of Least Squares Means and 95% CI of 
Change from Baseline in DAS28(CRP) (from 
MMRM) 
Y 
Y 
GSK 
Dose Response Modelling of Change from 
Baseline in DAS28(CRP) at Weeks 4, 8 and 12  
Y 
Y 
GSK 
Plot of Dose Response Model at Weeks 4, 8 and 12 
Y 
Y 
GSK 
Posterior Probability of the Difference in the 
Change from Baseline over Placebo < -1.0 at Week 
12 for Each Dose  
Y 
N 
GSK 
DAS28(CRP) 
remission 
Proportion of Subjects in DAS28(CRP) Remission 
at Week 24 
N 
Y 
GSK 
Predictive Probability of the Difference Over 
Placebo in the Proportion of Subjects in 
DAS28(CRP) Remission at Week 24 being > 25% 
N 
Y 
GSK 
ACR 
response 
Proportion of Subjects with an ACR20/50/70 
Response at Each Visit 
Y 
Y 
GSK 
1 Produced by the unblinded programming team. 
 
DAS28(CRP) change from baseline 
DAS28(CRP) scores and changes from baseline will be summarised for each visit.  The mean 
change from baseline in DAS28(CRP) score and 95% CI will be plotted by randomised treatment 
group. 
 
For change from baseline in DAS28(CRP) score, a mixed model repeated measures (MMRM) 
analysis will be conducted including all weeks up through Week 12.  For the first interim the 
analysis will subset on those subjects with Week 12 DAS28(CRP) scores.  The model will be 
fitted with fixed effects for randomised treatment group, visit, treatment by visit interaction and 
baseline DAS28(CRP), and visit within subject as a repeated effect.  The covariance will initially 
be specified as unstructured covariance matrix.  If SAS® gives a non-convergence warning, the 


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results will not be used – instead the warning will be stored and the spatial power law structure 
will be used in order to reduce the number of parameters to be estimated.   
 
The point estimates and corresponding 95% CI for the treatment differences will be constructed 
using the residual error from the model; these estimates will be summarised and plotted for each 
randomised treatment group comparison over time.  
 
Dose-Response at Weeks 4, 8 and 12 
 
A plot of the mean change from baseline in DAS28(CRP) score and 95% CI versus dose will be 
provided separately for each of Weeks 4, 8 and 12. 
 
The dose-response relationship for the change from baseline in DAS28(CRP) score will be 
evaluated at Week 4, 8 and 12 using a three parameter Emax model of the form: 
 
 
Y = E0 + Emax * [Di /{ ED50 + Di }] 
 
where E0 is the 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 change 
from baseline in DAS28(CRP) continuous score. 
 
If this Emax model is not applicable then additional models will be investigated, including a four 
parameter Emax model with a slope factor 𝐵> 0: 
 
 
Y = E0 + Emax * [DiB /{ ED50B + DiB }] 
 
and the model with the expected response as a linear function of dose:   
 
 
Y = E0 + E1 * Di 
 
Each of the models will be fitted to the data and their fit compared using the Akaike 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 will be 
assessed by examining plots of the residuals from the primary model. 
 
The final model parameters for the dose-response will be summarised; a plot of the dose-
response relationship will be provided.  The chosen models might differ between Week 4, 8 and 
12.  SAS outputs of all secondary models will be shown. 
 
 
 


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Posterior Probabilities at Week 12 
In addition to assessing the dose response model for the DAS28(CRP) change from baseline data 
at Weeks 4, 8 and 12, the posterior distribution for the Week 12 change from baseline in 
DAS28(CRP) will be calculated.   
This will be derived assuming the data follow a normal distribution with mean µi and precision τi 
(where i=0 is the placebo group and i=1-5 are the treatment groups) and non-informative prior 
distributions for µ and τ:    
 
 
 
 
µi ~ N(0, 10-2) 
 
 
 
 
τi ~ Ga(0.001, 0.001) 
Given the small number of subjects expected with Week 12 data at the first interim analyses, 
alternative prior distributions for τ may be investigated. 
Markov-Chain-Monte-Carlo (MCMC) methods in SAS® will be used to derive the posterior 
distributions for each randomised treatment group and to also derive the distribution of the 
difference between each treatment group and the placebo group.  From this difference 
distribution the posterior probability that the treatment difference between each active dose and 
placebo being > 1 will be calculated. 
 
Decision criteria for stopping the study after Interim Analysis 1 are specified in the DRC 
Statistical Guidance Document. 
 
DAS28 (CRP) remission rates at Week 24 
 
The number and percentage of subjects achieving DAS28(CRP) remission (DAS28(CRP) < 2.6) 
will be summarised for each randomised treatment group and visit.  Fisher’s exact test will be 
used to test for randomised treatment group differences at Week 24 in the proportion of subjects 
achieving remission for each GSK3196165 treatment group versus placebo. 
 
Predictive Probabilities at Week 24 
The proportion of subjects with available DAS28(CRP) remission data at week 24 at the interim 
analysis will only be summarised using counts and proportions.  This is because only a low 
number of subjects with week 24 data are expected at the week 12 interim analysis. 
In addition, the predictive probability that the difference in DAS28(CRP) remission between 
each dose and placebo at the end of the study is > 15% and > 25%, given the results at the 
interim analysis and the prior information will be calculated using the procedure described 
below. 
The following information will be available at the interim: 


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- 
li = number of subjects that have reached week 24 in each randomised treatment group i, 
i=0,...,5 (i=0 being the placebo arm and i=1-5 being the 5 treatment groups, with i=1 
being 22.5mg) 
- 
xi = observed number of subjects in DAS28 remission at week 24 in each randomised 
treatment group i, i=0,...,5 (i=0 being the placebo arm and i=1-5 being the 5 treatment 
groups, with i=1 being 22.5mg)  
Our prior Beta distribution on the remission rate in each randomised treatment group: 
πi ~ Beta(α0i, β0i) 
- 
Placebo: α00 = 9, β00 = 91, so the prior mean remission rate is 9%, and the 95th interval is 
(4%, 15%) 
- 
Active group: α0i = 1, β0i = 1, equivalent to a uniform distribution (non informative).  This 
will apply to all active groups (i=1 to 5) 
 
The algorithm is as follows: 
1. Compute the interim posterior distribution of the remission rate πi in each randomised 
treatment group: 
πi ~ Beta(αi = α0i + xi, βi = β0i + li - xi) 
 
2. For each of the 6 treatment groups, a sample of the number of subjects with DAS28 
remission post-interim is generated from the following predictive distribution (Beta-
Binomial):  
yi ~ beta-Binomial(sample= mi – li, αi, βi) 
Where mi – li is the number of subjects remaining post-interim, αi and βi are the parameters 
of the interim posterior distribution of the remission rate as calculated in (1). 
10,000 replicates will be used per treatment group. 
3. For each replicate, compute the distribution of the remission rate in each treatment group: 
πj ~ Beta(αi + yi, βi + mi - yi) 
and therefore generate a sample of 10,000 simulations. 
 
For each treatment group, we will obtain a matrix with 10000x10000, each column 
corresponding to the predictive distribution of πi for each replicate from (2). 
 
4. Calculate the posterior predictive distribution of the difference πi – π0, for i = 1,...,5 
For each of the 5 differences, we obtain again a matrix with 10000x10000, each column 
corresponding to the predictive distribution of the difference for each replicate from (2). 
 
5. The posterior predictive probability pj = P( 15% < πj – π0 <25%), j=1,...,5, is calculated 
empirically by counting how many times the rule is met in the sample of the difference for 
each replicate. The median is used over the 10,000 replicates. 


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For sensitivity analysis purposes, other prior distributions for the placebo arm may be assessed 
based on emerging data on this endpoint, including assuming a non-informative prior. 
 
The predictive probabilities to have an improvement of 25 percentage points over placebo will be 
used for the decision making, i.e. potentially dropping treatment arms or stop the study for 
futility.  Decision criteria are specified in the DRC Statistical Guidance Document. 
 
ACR20/50/70 response rates at all assessment points 
 
The number and proportion of ACR20, ACR50 and ACR70 responders will be summarised for 
each randomised treatment group and visit.  Fisher’s exact test will be used to test for 
randomised treatment group differences in the proportion of ACR20/50/70 responders at all 
assessment points for each GSK3196165 treatment group versus placebo. 
 
4.9.2.2 Week 24 Analysis and Final Analysis 
The goal of the Week 24 analysis is to provide unblinded results for all endpoints that are 
evaluable at this timepoint except actigraphy. The Final analysis will include all analyses and 
endpoints. 
 
For the Week 24 analysis, tabular summaries of efficacy data will be provided at all visits 
through Week 62 where available.  Graphical presentations for efficacy endpoints will include 
data through the Week 24 visit.  Statistical analyses will also include data through the Week 24 
visit.  All safety data collected at the time of the Week 24 data cut will be summarised.  See 
section 4.9 for a description of safety summaries. 
 
The following table indicates the types of summaries and analyses that will be conducted for 
each primary and secondary efficacy endpoint. 
 
 
 


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Table 6 Summaries and Analyses for Primary and Secondary Endpoints 
 
Summary Statistics 
Statistical Analyses 
 
Observe
d 
CfB/ 
Proportio
n 
Subgroups  Dose Response 
MMRM/ 
Logistic 
Survival 
(Time to 
1st) 
 
T 
T F 
L 
T 
T 
F O T 
F 
O 
T 
F 
O 
DAS28(CRP) 
score 
Y 
Y Y Y 
Y1 
Y at 
Week 
24 
Y Y Y 
Y 
Y 
 
 
 
DAS28(CRP) 
remission 
 
Y 
 
Y 
Y1 
Option
al at 
Week 
24 
Y Y Y 
 
Y Y 
Y Y 
DAS28(CRP) 
EULAR response 
 
Y 
 
Y 
Y1 
 
 
 
Y 
 
Y 
 
 
 
ACR20/50/70 
 
Y 
 
Y 
Y1 
 
 
 
Y 
 
Y 
 
 
 
Components: 
TJC28, TJC68, 
SJC28, SJC66, 
CRP, PtGA, PhGA 
Y 
Y 
 
Y 
 
 
 
 
Y 
 
Y 
 
 
 
Index- and 
Boolean-based 
ACR/EULAR 
remission 
 
Y 
 
 
Y1 
 
 
 
Y 
 
Y 
 
 
 
CDAI remission 
 
Y 
 
 
 
 
 
 
Y 
 
Y 
 
 
 
SDAI, CDAI 
scores 
Y 
Y 
 
 
 
 
 
 
Y 
Y 
Y 
 
 
 
HAQ-DI score 
Y 
Y 
 
 
 
 
 
 
Y 
Y 
Y 
 
 
 
HAQ-DI pain 
severity 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Pain score 
Y 
Y 
 
 
 
 
 
 
Y 
Y 
Y 
 
 
 
SF-36 physical, 
mental and domain 
scores 
Y 
Y 
 
 
 
 
 
 
Y 
Y 
Y 
 
 
 
FACIT-Fatigue 
Y 
Y 
 
Y 
 
 
 
 
Y 
Y 
Y 
 
 
 
BFI Question 3 
Y 
Y 
 
Y 
 
 
 
 
Y 
Y 
Y 
 
 
 
CfB=Change from baseline; T=table; F=figure; L=listing; O=supportive analysis SAS output. 
1 Disease duration ((<2 years, ≥2 years), gender. 
 
 
For plots of change from baseline endpoints, the mean change from baseline and 95% CI will be 
plotted by randomised treatment group. 
 
Plots of Mean and 95% CI of Change from Baseline in DAS28(CRP) at Each Visit will be 
created. 
Subject profile plots of DAS28 score at each visit will be produced. 
 


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Dose response analyses for change from baseline in DAS28(CRP) will be conducted after visual 
inspection of the mean and 95% CI plots and using the final model from the second interim 
analysis as a starting point for the dose response modelling.  The Week 24 primary analysis 
model will be fitted without covariate terms.  A plot of the residuals versus predicted values will 
be examined to assess distributional assumptions.  If additional models are fit, the smallest AIC 
will be used to help identify the best fitting model.  Covariates from the Week 24 primary 
analysis of DAS28(CRP) remission may be added to the model in a sensitivity analysis.  Model 
results from the sensitivity analysis will be provided in the corresponding listing. 
 
Dose response analyses for DAS28(CRP) remission might be done as an ad-hoc analysis. 
MMRM analyses will be conducted similarly to interim analysis methods.  Distributional 
assumptions underlying the model used for analysis will be examined by obtaining a normal 
probability plot of the residuals and a plot of the residuals versus the predicted values (i.e. 
checking the normality assumption and constant variance assumption of the model respectively) 
to gain confidence that the model assumptions are reasonable.  If there are any departures from 
the distributional assumptions, alternative models may be explored using appropriate 
transformed data 
 
For change from baseline in DAS28(CRP), if the dropout rate is ≥10% for the Week 24 or Week 
52 analysis, further sensitivity analyses using multiple imputation as explained in section 4.5.2.3 
may be conducted as ad-hoc analyses.  In order to assess subgroup effects, additional analyses 
will be conducted with subgroup and subgroup interaction with treatment as covariates. 
 
For DAS28(CRP) remission, subjects with missing data as defined in Section 3.2.1 will be 
imputed as non-responders as described in Section4.5.2.1.  Differences in remission rates 
between each active arm and placebo will be summarised at each visit through Week 52.  95% 
CI for the differences will be constructed using their asymptotic standard errors (asymptotic 
Wald confidence limits) without continuity correction.   
 
Logistic regression models will have fixed effects for randomised treatment group and baseline 
value.  The odds ratios, 95% CI and p-values for the comparison of each GSK3196165 treatment 
group versus placebo at key time points will be presented.  Covariates age, gender, weight and 
disease duration (<2 years, ≥2 years) will be considered in alignment with the results of the 
primary analysis model.   
 
For ACR response, baseline values of TJC68 and SJC66 will be considered as fixed effects, as a 
baseline value of ACR response does not exist.  
 
For binary endpoints with repeated measures over time, Generalized Estimating Equations 
(GEE) methodology will be used to take correlation among subject-level responses over time 
into account.  The model will include data from all assessment points from Week 1 to Week 62.  
Due to only few expected subjects with remission in some randomised treatment groups 
(especially placebo) only standard errors and resulting confidence intervals will be adjusted.  To 
this end an independent working correlation structure will be assumed and standard errors will be 
calculated based on the empirical sandwich covariance estimate (default setting for PROC 
GENMOD in SAS) (Stokes, Davis, & Koch, 2012). 


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For the primary analysis of DAS28(CRP) remission at Week 24, the GEE model will include 
terms for randomised treatment group, baseline DAS28(CRP), visit and interaction terms for 
treatment group-by-visit and baseline-by-visit.  A sensitivity analysis including covariates age, 
gender, weight and disease duration (<2 years, ≥2 years) will be considered by adding covariate 
terms to the repeated measures model one at a time along with the covariate-by-treatment group 
interaction term.  If the interaction term is not significant at α=0.10 it will be removed from the 
model.  Likewise, if the covariate term is not significant at α=0.10 it will be removed from the 
model.  Other covariates will be tested in a similar manner. 
 
Survival analyses (time to event analyses) will be conducted for the final analysis using Kaplan-
Meier methods, comparing each GSK3196165 dose to placebo.  Between-group differences will 
be analysed using the log-rank statistic.  Median time to remission will be presented for each 
randomised treatment group.  Kaplan-Meier plots of the time to remission will be presented.  
Subjects who withdraw from the study are censored at the time of withdrawal.  All other subjects 
are censored at the end of the study. 
 
In addition to summaries of the individual components of composite endpoints, numbers and 
percentages of subjects meeting the following criteria will be presented: 
 TJC68 ≤ 1 
 SJC66 ≤ 1 
 CRP ≤ 1mg/dl 
 PtGA ≤ 10 
 SDAI ≤ 3.3 
 
4.9.3 Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints will only be analysed at the final analysis. 
 
4.9.3.1 Proportion of subjects achieving sustained (≥24 continuous weeks including the 
Week 52 visit) DAS28(CRP) remission 
 
Proportion of subjects achieving sustained remission will be analysed and summarised as 
described in section 4.9.2 for DAS28(CRP) remission, but without using any GEE methods..  
 
The duration of sustained DAS28(CRP) remission will be summarised. 
 
4.9.3.2 Proportion of subjects achieving Major Clinical Response (ACR70 for 24 
continuous weeks including the Week 52 visit) 
 
Proportion of subjects achieving major clinical response as described in section 3.2.2 will be 
analysed and summarised in the same way as described in section 4.9.2.2 for DAS28(CRP) 
remission, but without using any GEE methods. 
 
 


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4.9.3.3 DAS28(ESR) scores/responses at all assessment timepoints. 
 
DAS28(ESR) scores will be summarised by EULAR response (moderate/good response and no 
response), observed values, change from Baseline and remission (DAS28(ESR)<2.6) at all 
assessment points. 
 
4.10 Safety Evaluation 
All safety summaries and analyses will be based upon the ITT population by actual treatment 
group at the time of safety event or assessment.  Actual treatment group is either the randomised 
treatment group or “Rescued Subjects” for subjects who got escalated.  Only assessments that 
happen after the administration of the first dose of rescue treatment will be assigned to the 
treatment group of “Rescued Subjects”. 
4.10.1 Extent of Exposure  
The extent of exposure to GSK3196165 will be evaluated by summarizing the number of 
injections, the amount of study medication received in mg and the duration of drug exposure in 
days.  Exposure to GSK3196165 will be summarised by time period (Overall, Day 1 to 
<Week 14, Week 14 to <Week 26, Week 26 to <Week 38, and Week 38 to <Week 52). 
Duration of drug exposure will be calculated as: 
 
 date of the last injection during study – date of first injection during study + 1 day 
 
Weekly MTX dose will be averaged across the entire study and within each time period for each 
subject. 
MTX dose should be documented in mg, but in case ml is captured the following conversion 
should be used: 1ml is equivalent to 25mg. 
 
A contingency table will be created for Week 12 and Week 24 showing the number of subjects 
that were escalated/not escalated correctly/falsely. For Week 36 a corresponding table will be 
created showing correct and false withdrawals due to lack of EULAR good/moderate response. 
 
Overall Extent of exposure and extent of exposure by time period will also be presented in by-
subject listings.  
4.10.2 Adverse Events 
AEs will be coded using the MedDRA in the latest available version.   
 
Treatment emergent AEs (TEAE) are defined as AEs starting on or after the first administration 
of study medication and up to 12 weeks after last dose of study medication.  AEs that are not 
treatment emergent are defined as pre-treatment AEs or post-treatment AEs, respectively. 
 
Adverse events of special interest (AESI) will be derived using Common Terminology Criteria 
for Adverse Events, 2009 v4.0 (CTCAE) and will include: 
Table 7 Adverse Events of Special Interest 
AESI 
Programmatical Derivation 


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Serious infections, including serious 
respiratory infections. 
 
SAEs, Filter on infections SOC 
Opportunistic infections including TB 
reactivation 
Opportunistic infections will be adjudicated by 
the SRT, using the  preferred terms list given in 
Appendix A.  Final adjudication conducted by 
SRT. 
Neutropenia 
Based on Grade 3 or 4 absolute neutrophil count 
  
PAP (Pulmonary alveolar proteinosis) 
If identified then list all AEs for those subjects.  
Hypersensitivity reactions, including 
anaphylaxis 
Hypersensitivity reactions will be adjudicated by 
the SRT, using AE data and data from 
hypersensitivity reactions eCRF page.  Final 
adjudication conducted by SRT. 
Injection site reactions 
Using data from Injection site reactions eCRF 
page 
 
AEs with missing intensity will be considered severe.  AEs with missing relationship to study 
medication will be considered as related both to GSK3196165/Placebo and to MTX. 
 
Where dates are missing or partially missing, adverse events will be assumed to be treatment-
emergent, unless there is clear evidence (through partial dates as described in section 4.5) to 
suggest that the adverse event started prior to the first dose of study treatment or more than 12 
weeks after the last dose of study treatment.  
 
Adverse Events will be summarised by system organ class (SOC) and preferred term (PT) 
Summaries will provide the number of subjects reporting at least one AE and the total number of 
events reported. 
 
The following summaries of AEs will be provided by actual treatment group at the time of the 
AE: 
 
 Overall summary of AEs, including number and percentages of subjects with 
o Any AE 
o Serious AE 
o Discontinuation due to AE 
o Drug-related AE 
o AE leading to death 
 Overall summary of Adverse Events 
 Number and percentage of subjects reporting an Adverse Events  
 Most common AEs (reported by >5% of the subjects in total) 
 Plot of Most Common Adverse Events and Relative Risk 
 Number and percentage of subjects reporting an Adverse Events by maximum intensity 
 Number and percentage of subjects reporting an adverse events by relationship to study 
treatment 
 Number and percentage of subjects reporting an adverse events of special interest 


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 Number and percentage of subjects that withdraw from study or discontinue study 
treatment as result of an adverse event 
 Number and percentage of subjects with adverse events during the initial treatment period 
(up to Week 14 visit) 
 Number and percentage of subject reporting an adverse event by study period at the time 
of the first onset of the adverse events 
 Exposure-adjusted (patient years) adverse events by treatment group, where the total 
number of subjects for each column includes all subjects who took the dose at least once 
during the study.  The exposure-adjusted rate divides the total number of AEs attributed 
to each dose by duration of exposure (in years) to that dose.  The duration for subjects 
who complete the study on their randomised dose is (date of last dose – date of first dose 
+ 1).  For subjects who escape, duration is based on treatment periods defined in Section 
4.2. 
 
Exposure adjusted incidence rates are calculated as X/T*100 with 
 X being the number of occurrences of the relevant AE for subjects while being in the  
corresponding treatment group 
 T being the cumulative duration of exposure (in years) for subjects in the corresponding 
treatment group 
 
Adverse event summaries will be ordered by decreasing frequency for SOC, and PT within SOC, 
summed up for all subjects and then alphabetically for SOC, and PT within SOC. 
 
A by-subject listing of all adverse events will be provided as well as a by-subject listing of all 
AEs leading to withdrawal from study.  These listings will be presented by actual treatment 
group and will include: center, subject identifier, age, sex, race, weight, adverse event (SOC, PT, 
and verbatim term), date of onset, date of resolution, duration, intensity, action taken, outcome, 
relationship to study medication, action taken with study medication, other action taken and 
whether the AE is treatment-emergent, serious and an AE of interest. 
4.10.3 Deaths and Serious Adverse Events 
The following summaries will be provided by actual treatment group at the time of the event: 
 
 Number and percentage of subjects reporting a serious AE by SOC and PT 
 Number and percentage of subjects reporting a serious AE by relationship to study 
treatment 
 Number and percentage of AEs leading to death by relationship to study medication 
 Exposure-adjusted (patient years) serious adverse events by treatment group, where the 
total number of subjects for each column includes all subjects who took the dose at least 
once during the study.  The exposure-adjusted rate divides the total number of serious 
AEs attributed to each dose by duration of exposure (in years) to that dose.  The duration 
for subjects who complete the study on their randomised dose is (date of last dose – date 
of first dose + 1).  For subjects who escape, duration is based on treatment periods 
defined in Section 4.2. 
 
The following listings will be provided: 


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 A by-subject listing of all Serious AEs 
 A by-subject listing of all AEs leading to discontinuation of study treatment 
 A by-subject listing of all Serious AEs leading to death 
4.10.4 Disease-related Events 
 
Disease-related Events (DREs) will be summarised in alphabetical order by actual treatment 
group at the time of the event.  A by-subject listing of all DREs that occurred during the study 
will also be provided. 
4.10.5 Respiratory Events 
 
Numbers and percentages of subjects experiencing persistent cough, or persistent dyspnea or 
persistent DLCO decrease will be reported in a table by actual treatment group at the start time of 
the event. 
 
Event 
Definition 
Persistent cough  
Cough grade 2 or greater recorded for 3 
consecutive weeks (15 or more days) on the 
eCRF page. 
Persistent dyspnea 
Borg Scale grade 3 or greater recorded for 3 
consecutive weeks (15 or more days) on the 
eCRF page. 
Persistent decrease of DLCO by >15% 
Relative decrease of DLCOHCPP of ≥15% 
compared to Baseline for 3 consecutive weeks 
(15 or more days) 
 
These definitions are provided for guidance to identify potential cases.  Final adjudication will be 
conducted by the SRT. 
4.10.6 Cardiovascular Events 
Occurrences of the below cardiovascular events will be listed in 9 separate listings: 
 Arrhythmias 
 Congestive heart failure  
 Cerebrovascular event stroke and transient ischemic attack 
 Deep vein thrombosis/ Pulmonary embolism 
 Myocardial Infarction / Unstable Angina 
 Peripheral arterial thromboembolism 
 Pulmonary Hypertension 
 Revascularisation 
 Valvulopathy 
 
All relevant data captured in the CRF will be listed. However, as only very few events might 
occur during the conduct of the study, the design of the listings might be adapted to the actual 
observed data. 
 


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4.10.7 Liver Events 
Liver chemistry stopping events as defined in the protocol trigger further assessments (e.g. liver 
PK sampling, assessment of alcohol intake, liver biopsy…). 
All relevant data captured in the CRF will be listed. However, as only very few events might 
occur during the conduct of the study, the design of the listings might be adapted to the actual 
observed data. 
 
4.10.8 Clinical Laboratory Evaluation 
 
Hematology and biochemistry samples will be taken at Screening, Baseline, Weeks 1, 2, 4, 8, 12, 
16, 20, 24, 32, 36, 42, 52, at follow-up visit and at a potential early withdrawal visit. 
 
Urinalysis will be taken at Screening, Weeks 4, 8, 12, 16, 20, 24, 32, 42, 52, at follow-up visit 
and at a potential early withdrawal visit. 
 
The central laboratory will analyse and assess blood and urine samples for the following: 
 
Table 8 Laboratory Assessments 
Hematology 
Biochemistry 
Urinalysis  
Hemoglobin 
Hematocrit 
Mean cell volume (MCV) 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin concentration 
(MCHC) 
Erythrocyte mean corpuscular Volume 
Erythrocyte count 
Reticulocyte count 
Leukocyte count 
Leukocyte differential count 
neutrophils 
eosinophils 
basophils 
monocytes 
lymphocytes 
Platelets 
Activated partial thromboplastin time (aPTT) 
Prothrombin Time (PT) 
International Normalised Ratio (INR) 
Fibrinogen 
Erythrocyte Sedimentation Rate (ESR)* 
Sodium 
Potassium 
Calcium 
Phosphate 
Urea 
Creatinine 
Creatinine clearance 
(calculated) 
Aspartate transaminase (AST) 
Alanine transaminase (ALT) 
γ-glutamyl transpeptidase 
(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 dipstick 
Glucose 
Protein 
Creatinine 
 
Microscopy of urine 
sediment for 
erythrocytes, 
leukocytes and casts 
if urine dipstick 
abnormal 
 
Urine pregnancy 
test 
*Measured locally 
 


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Descriptive statistics for observed values and change from baseline will be presented by 
treatment for each visit and for all parameters for hematology, biochemistry and urinalysis, 
separately.  Estradiol, follicle stimulating hormone and rheumatoid factor will be assessed only 
at Baseline and will be listed. 
 
Laboratory values reported below the limit of quantification (BLQ) will be replaced by one-half 
the limit of quantification when reporting summary statistics. 
Laboratory parameters of interest will be summarised (number and percentages) by time point 
and by grade as defined in Appendix B. 
 
A summary of shift from baseline to worst grade during the study value will be provided for 
specific laboratory parameters of interest from Appendix B to be identified in the final version of 
this analysis plan. 
 
Boxplots will be produced to display the distribution of results for laboratory parameters of 
interest by time point and by actual treatment group; these parameters are specified in Appendix 
B. 
 
Separate by-subject listings of laboratory data for hematology, biochemistry and urinalysis will 
be provided by randomised treatment group, with abnormal values highlighted, and including 
center, subject identifier, age, sex, race, weight and visit.  For each subject, all results for any lab 
parameter that has at least one abnormal value will be included in the listing.  Laboratory 
reference ranges (Lower Limit of Normal, upper Limit of Normal) will be presented for each 
laboratory parameter. 
4.10.9 Pulmonary assessments 
 
All pulmonary assessment results (chest X-ray, cough, Borg dyspnea questionnaire, chest 
auscultation, pulmonary function tests (PFTs - spirometry, gas transfer [DLCO]) and pulse 
oximetry) will be provided in listings.   
 
Summary statistics will be provided for the change from baseline for the Borg dyspnea score, for 
pulmonary function tests, spirometry and DLCO, and for pulse oximetry by visit.  The number and 
percentages of subjects having a cough for each grade will be summarised by visit, in addition to 
the number and percentages of subjects having a relative decrease in DLCO Hemoglobin-corrected 
Percent of Predicted (DLCOHCPP) of >15% from baseline.   
 
A subject’s baseline DLCOHCPP value will be taken as the lowest value obtained from the 
Screening or Day 1 assessment, or any unscheduled visit in between.  For rescreened subjects, 
only the last available Screening assessment will be considered.   
The same visit that has been determined to provide the baseline value of DLCOHCPP will be 
used to provide the baseline value for all other pulmonary function test parameters (including 
DLCO Absolute Value, HGB corrected DLCO, FEV1, FVC, FEV1/FVC, percent predicted 
FEV1, percent predicted FVC, predicted FEV1, predicted FVC). 


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For summary tables, reporting of subjects with >15% decrease from baseline will be shown 
separately for subjects with current DLCO <70%.  A separate summary will be provided by 
baseline DLCO value (<70% and ≥70%). 
 
Individual patient profiles of DLCO over time will be shown in a figure by randomised treatment 
group. 
4.10.10Vital Signs, Physical Findings and Other Observations Related to Safety 
 
The following vital signs will be assessed at screening, baseline, follow-up visit, early 
withdrawal-visit and several visits in between: 
 
Temperature (in °C), systolic and diastolic blood pressure (mmHg), Heart rate (beats/min), 
respiration rate (breaths/min), weight(kg) and calculated BMI (kg/m²). 
 
Pregnancy testing must be carried out for women of childbearing potential and will consist of 
serum testing at Screening and urine testing every four weeks starting at Week 4 as well as urine 
testing at follow-up visit and early withdrawal-visit.  Pregnancy test results will be listed only. 
 
Physical examination will be performed at screening, baseline, follow-up visit, early withdrawal-
visit and several visits in between.  Findings will be assigned by investigator to medical history, 
adverse event or serious adverse events. 
Subjects with findings or subjects who missed examinations will be shown in a listing. 
 
The following summaries will be provided: 
 
 
A summary of each vital sign parameter by randomised treatment group and time point 
 
A summary of the change from Baseline in each vital sign parameter by randomised 
treatment group and time point. 
 
Boxplots of the change from Baseline in each vital sign parameter by randomised treatment 
group and time point.   
 
A summary of the number and percentage for history of tobacco use and family history of 
cardiovascular risk factors by randomised treatment group. 
 
 
Triplicate 12-lead ECGs will be obtained at screening, Week 12, 24, 52 and potential early 
withdrawal-visit.  All ECG parameters will be calculated by taking the mean of the non-missing 
values obtained in the up to three 12-lead ECG evaluations at each visit. 
 
The following summaries will be provided: 
 
 
A summary of each ECG parameter (i.e. heart rate, PR, QRS, QT, QTc) by randomised 
treatment group and time point 
 
A summary of the change from baseline in each ECG parameter by randomised treatment 
group and time point. 


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 
A summary of the number and percentage of subjects with abnormal findings for each ECG 
parameter by randomised treatment group and time point. 
 
A summary of the number and percentage of subjects with QTc interval exceeding >450ms/ 
>480ms/ >500ms by randomised treatment group and time point. 
 
A summary of the number and percentage of subjects with change from baseline in QTcF 
interval exceeding >30ms/ >60ms by randomised treatment group and time point. 
 
Boxplots of the change from baseline for each ECG parameter by randomised treatment 
group and time point. 
 
By-subject listings of vital sign parameters, and ECG results (individual and average) and any 
other observations related to safety will be provided.  
4.10.11Safety Monitoring 
 
4.10.11.1 
Data Review Committee 
 
A 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.   
  
Output shells for DRC outputs are provided in a separate document and the following outputs 
will be produced for each DRC review: 
 
 
Summary of Withdrawals by Reason for Withdrawal 
 
Summary of Demography Characteristics – Age, Gender and Weight 
 
Concomitant Medication 
 
Concomitant Medication of subjects with serious infections 
 
Concomitant Medication of subjects with DLCO Hemoglobin-corrected Percent of Predicted 
decrease >15% change from baseline 
 
Summary of Treatment Emergent AEs - Overview 
 
Summary of Treatment Emergent AEs by SOC and PT 
 
Summary of AEs Leading to Withdrawal 
 
Plot of Most Common Adverse Events and Relative Risk 
 
Summary of SAEs 
 
Summary of AESIs of Serious Infections, Opportunistic Infections, Neutropenia, and PAP 
 
Summary of Hypersensitivity and Injection Site Reactions  
 
Summary of persistent cough, dyspnea or DLCO decrease 
 
Summary of Change from Baseline in DLCO Hemoglobin-corrected Percent of Predicted 
 
Summary of Proportion of Subjects with a >15% Decrease from Baseline in DLCO 
Hemoglobin-corrected Percent of Predicted 


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 
Summary Statistics of Haematology and Clinical Chemistry Values at Each Visit 
 
Distribution of  Haemoglobin, Total WBCs, Neutrophil Counts, Platelet Counts, ALT, AST 
and Total Bilirubin by Visit and Treatment with Maximum over Time 
 
For the interim efficacy analyses (when 90 subjects have completed 4 and 12 weeks of 
treatment) the time interval between subsequent reviews may deviate from the 12 weeks to 
combine these interim analyses with a safety review.  
 
The decision to stop the study or randomisation to specific arms will be made by the DRC.  
Further details are given in the earlier sections of this RAP and will be included in the DRC 
Statistical Guidance document. 
 
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.   
 
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. 
 
4.10.11.2 
Medical Monitoring 
 
Medical monitoring will happen in form of monthly blinded data review meetings. Further 
details and the list of generated output can be found in the MDRP and the MMP. 
4.10.12Immunogenicity 
Immunogenicity samples for determination of anti-drug-antibody (ADA) will be collected.  
Samples taken after dosing with GSK3196165 that have a value at or above the cut-point will be 
considered potentially treatment-emergent ADA-positive.  Shift table from baseline to every 
assessment will be produced for the Immunogenicity population to assess the number of subjects 
going from: 
 
1) negative → negative,  
2) negative → positive,  
3) positive → negative, and  
4) positive → positive.  
 
Serum analysis will be performed under the management of Immunogenicity and Clinical 
Immunology (ICI), GlaxoSmithKline.  Serum will be tested for the presence of anti- 
GSK3196165 antibodies using the currently approved analytical methodology incorporating 
screening, confirmation and titration steps.   
Anti-GSK3196165 Binding AB Detection (positive/negative) will be listed together with titre 
value (mL) and Rheumatoid Factor (positive/negative) for each subject with at least one positive 
result of Anti-GSK3196165 Binding AB Detection. 
 


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A Listing of DAS28 values will be produced for all subjects who developed ADA in the study, 
including rheumatoid factor and ADA status by visit.  
 
4.11 Patient Reported Outcome (PRO) Measures  
Change over time and change from baseline in RA Symptom and Impact Diary measures will be 
summarised for subjects that are in the ITT population but separately for subjects that are in the 
Actigraphy Population and subjects that are not in the Actigraphy Population.  Responses for 
each of the 16 questions from the RA Symptom and Impact Diary will be summarised by visit.  
A repeated measures analysis of change from baseline in RA Symptom and Impact Diary 
measures will be done as done for DAS28(CRP) and other continuous efficacy parameters. 
4.11.1 Actigraphy Substudy  
During enrolment, subjects have the option to consent to participate in a substudy that collects 
data using an accelerometer in addition to the RA Symptom and Impact diary.  The objective of 
the actigraphy substudy is to explore how actigraphy measurements of physical activity correlate 
to disease activity.  Table 9 lists the measures used to meet the protocol objectives. 
Table 9 Actigraphy Measures 
Characteristic 
Measures 
Physical activity: 
 Percent time sedentary based on activity count cut-off* 
 Percent time walking* 
 Activity counts (i.e., total activity score)  
 Average walking speed for durations of walking >1 min (m/s) 
 Number of continuous walking periods from 2-10 min (w/ 1-30 second pause), 
10-30 min (w/1-1 min pause), >30 min (w/1-1 min pause) 
 
Morning 
stiffness: 
 Average sit-to-stand time during 1st 30 min after waking* 
 Average lie-to-stand time during 1st 30 min after waking* 
 Average activity counts for 2 hours after waking 
 Average activity counts for 4 hours after waking 
Sleep quality: 
 Percent time lying down during night-time  
 Average number of nighttime movement episodes (per hour) 
 Night-time rest efficiency defined as time NOT moving relative to time lying at 
night*  
 Fragmentation indices (movement time (%) divided by the number of movement 
episodes during night-time rest, and average duration of movement episodes)* 
RA Symptom and 
Impact Diary 
 13 Symptom questions and 3 Impact questions 
* Measure is a change to or clarification of protocol wording. 
 
4.11.1.1 Accelerometer data collection 
 
The accelerometer will be placed on the subject and returned to the site according to the Time 
and Events table in Table 1.  Results will be assigned to a visit as shown in Table 10. 
Table 10 Accelerometer Placement and Removal 
Day of Placement* 
Day of Removal* 
Visit 


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Day -7 
Day 7 
Baseline = Day -7 to Day -1 
Week 1 = Day 1 to Day 7 
Day 71 
Day 85 
Week 12 
Day 155 
Day 169 
Week 24 
Day 239 
Day 253 
Week 36 
Day 351 
Day 365 
Week 52 
 
 
 
* Day of placement and removal are approximations. 
 
The raw accelerometer data will be analysed using an RA-specific algorithm developed by GSK 
and Imperial College London.  At present, the algorithms are exploratory and not validated.  A 
simple measure of overall activity level, “counts”, will be used as previously reported in the 
literature.  Counts are a result of summing post-filtered accelerometer values into 1 minute epoch 
"chunks", and represent a mapping from the raw acceleration for this specific fixed time period.  
Hence the value of the counts will vary based on the frequency and intensity of the raw 
acceleration.  Measures determined in one minute epochs are collapsed into hourly and daily or 
24-hour periods.  The processed data will be reported according to whether the measure is 
collected during the daytime or night time hours, or over a 24-hour period: 
 24-hour period: The following measures will be reported within 24-hour periods 
starting at midnight and ending at 11:59:59 pm: average walking speed for walking 
bouts >1 minute, average activity counts per minute, number of continuous walking 
periods with duration 2-10 minutes, 10-30 minutes and >30 minutes, average sit-to-
stand time and lie-to-stand time during 1st 30 minutes of getting up in the morning, 
average activity counts for the 2 hours and 4 hours after getting up. 
 Night time:  The following measures will be reported from the time of going to bed 
for the night until arising from bed in the morning: number of night time movement 
episodes per hour, night time rest efficiency, and fragmentation indices. 
 Day time:  The following measures will be reported from the time of getting out of 
bed in the morning until going to bed for the night: percent time sedentary, percent 
time walking, percent time lying down. 
 
Each measure will be reported once per 24-hour period or day/night time unit of time to obtain 
up to approximately 7 days of data for baseline and Week 1, and up to approximately 14 days of 
data for Weeks 12, 24, 36, and 52.   
 
4.11.1.2 Endpoint derivation and summaries 
 
The median of the distribution of the daily values for each measure will be calculated for each 
subject and visit.  Similarly, the median of the distribution of the daily responses for each of the 
questions in the RA Symptom and Impact diary will be calculated for each subject and visit.  The 
endpoint for each measure (except for continuous walking periods) will be defined as the change 
from baseline for the median values, calculated as post-baseline median minus baseline median, 
where baseline is defined in Table 10. 
 
The median value and change from baseline in the median value for each actigraphy measure 
(excluding the number of continuous walking periods) and visit will be summarised with 
univariate statistics by actual treatment group, where visit data for subjects rescuing to the 


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highest dose will be grouped separately from the subjects randomised to that dose.  Boxplots of 
the change from baseline in the median value will be plotted by actual treatment group.  If less 
than 30 subjects participate in the Actigraphy substudy, then individual subject line plots will be 
produced for percent time sedentary, percent time walking, night-time rest efficiency and 
average counts/minute instead, using symbols to identify responses obtained at the rescue dose.  
Additional plots may be generated post hoc for other endpoints. 
 
The number and percentage of continuous walking periods from 2-10 minutes, 10-30 minutes 
and >30 minutes will be summarised with categories 1, 2, 3, and ≥4 at each visit.  The median 
response and change from baseline for the median response for each question from the RA 
Symptom and Impact diary questions will be summarised in a table.  These data will not be 
graphed. 
 
To assess the relationship between physical activity and DAS28(CRP), a scatter plot of activity 
counts versus DAS28(CRP) score over time will be provided using symbols to differentiate 
actual treatment group at each visit and a vertical bar where DAS28(CRP)=2.6 to identify 
responders from nonresponders.  If there is sufficient data, a plot of change from baseline in 
activity counts versus change from baseline in DAS28(CRP) score over time and by 
DAS28(CRP) remission status will be provided instead of plots of the observed data using 
symbols to differentiate dose at each visit.  Similarly, average walking speed versus 
DAS28(CRP) and night time rest efficiency versus DAS28(CRP) will be provided.  The 
relationship between physical activity measures and ACR or biomarkers will not be investigated 
as stated in the protocol. 
 
Plots will also be provided for the following efficacy endpoints versus questions from the RA 
Symptom and Impact diary by visit and by DAS28(CRP) remission status for all actigraphy 
subjects combined, using symbols to identify responses obtained at the rescue dose: 
 Median percent time sedentary vs median Symptom Question 4 (worst pain while 
walking) 
 Median activity counts vs median Symptom Question 8 (amount of energy) 
 Median average sit-to-stand time vs median Symptom Question 1 (worst pain when 
sitting) 
 Median average lie-to-stand time vs median Symptom Question 11 (early morning 
stiffness severity) 
 Median night time rest efficiency vs median Symptom Question 2 (worst pain lying 
down) 
 Median night time rest efficiency vs median Impact Question 2 (quality of sleep) 
 Median functional index 1 (movement % / movement episodes) vs median Impact 
Question 3 (sleep affected by joint pain) 
 Median functional index 2 (average duration of movement episodes) vs median 
Impact Question 3 (sleep affected by joint pain) 
 
The results from these analyses will be reported after the Final analysis in a separate deliverable. 
 


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4.12 Other Analyses 
4.12.1 Pharmacokinetic Analysis 
 
A population PK model of GSK3196165 will be developed based on PK data from the current 
study as well as the 5 studies in healthy, RA and MS adult subjects (MSC1000, MOR103C104, 
MSC1001 and MOR103C103) 
The main objectives of this analysis are as follows:  
- 
To develop a population pharmacokinetic model that describes the single- and repeat-
dose pharmacokinetics of GSK3196165 following intravenous (IV) and SC 
administration in healthy subjects and subjects with rheumatoid arthritis and multiple 
sclerosis; 
- 
To identify covariates that may influence pharmacokinetics of GSK3196165; 
- 
To derive post-hoc estimates of individual pharmacokinetic parameters characterising the 
PK time profile of GSK3196165 for any given dose 
 
Further details on the population PK analysis are provided in a separate technical Analysis Plan 
(Population 
Pharmacokinetic 
Analysis 
of 
GSK3196165 
Following 
Intravenous 
and 
Subcutaneous Administration to Healthy Volunteers, Subjects with Rheumatoid Arthritis and 
Multiple Sclerosis (Date: 08-Jan-2016)). 
 
4.12.2 Pharmacokinetic / Pharmacodynamic (PK/PD) Exploratory Analysis  
 
A graphical PK/PD exploration will be conducted to complement the statistical dose-response 
analysis and to visualize the nature of the concentration-response correlation.  A variety of 
graphs will be generated per subject and in overall; where GSK3196165 concentration is 
characterised by the individual post-hoc estimates from the PK model, and the response is 
characterised by the individual values of the pharmacodynamic markers or efficacy (e.g. 
DAS28(CRP)) or safety endpoints (e.g. AE of special interest, lung damage biomarkers). 
 
Example of PK/PD graphs:  
 Linear scatterplot of change from baseline in CRP levels at week 12 versus steady-state 
average concentration values (Cave) estimated from the PK model 
 Linear scatterplot of change from baseline in CRP levels at each visit versus pre-dose 
concentration values (Ctrough) at corresponding visit estimated from the PK model 
 Linear scatterplot of change from baseline in DAS28(CRP) measures at week 12 versus 
Cave estimated from the PK model  
 Linear scatterplot of change from baseline in DAS28(CRP) measures at each visit versus 
Ctrough at corresponding visit estimated from the PK model 
 Boxplot of Cave stratified by ACR20 at Week 12 
 Boxplot of Cave stratified by ACR50 at Week 12 
 Boxplot of Cave stratified by ACR70 at Week 12 
 Boxplot of Cave stratified by AE status  
 
A separate PK/PD RAP will be created to define further detail of the PK/PD analysis. 


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4.12.3 Biomarkers 
 
Analyses of biomarkers will be defined in a separate analysis plan. 
 
4.12.4 Genetic Research 
 
Analyses of genetics will be defined in a separate analysis plan, if deemed necessary. 
 
 
4.13 Determination of Sample Size 
 
The sample size assumptions outlined below for the primary objective 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: 
4.13.1 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. 
 
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 an approximate 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. 
4.13.2 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. 
 


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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 9 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. 
 
Figure 1 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. 
 
The following table 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 10 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% 
 


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Figure 1 Plot of the First 100 Prediction Curves with the Overall Median Curve at the Dose Response 
Analysis 
 
4.13.3 Sample Size Sensitivity for Primary Analysis 
The power of the study will be affected by changes from the assumed remission rate and the 
table below shows the effect on power under varying remission rates on both MTX and 
GSK3196165 assuming a fixed sample size of 35 per arm. 
 
Table 11 Power for Remission 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% 
 
4.13.4 Sample Size Sensitivity for 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)).  The following 
Table 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. 
 


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Table 12 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 10 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. 
 
Table 13 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 
 
4.14 Changes in the Conduct of the Study or Planned Analysis 
Continuous efficacy results for subjects who rescue to 180 mg dose or exceed the amount of 
allowed corticosteroid use will be set to missing as opposed to an observed cases analysis. 
 
The exploratory endpoint ‘time to first sustained (≥24 continuous weeks) DAS28(CRP) 
remission’ was modified to the proportion of subjects with sustained DAS28(CRP) remission 
including the Week 52 visit.  Similarly, the definition of ‘Major Clinical Response’ was modified 
to achieving ACR70 for ≥24 continuous weeks including the Week 52 visit. 
 
The exploratory endpoint ‘Time to sustained (≥24 weeks) discontinuation of all systemic 
corticosteroids administered for RA’ will not be investigated.  Instead a summary of 
corticosteroid concomitant medications will be converted to prednisone equivalent units, and the 
change from baseline in average daily prednisone dose will be summarised by visit.  The number 
and percentage of subjects with ≥25% decrease from baseline to ≤7.5 mg/day will be 
summarised at Weeks 12, 24, 36, 48 and 52. 
 
 


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6 
Appendix 
6.1 
Appendix A: Opportunistic Infections: MedDRA Preferred Terms 
 
Opportunistic Infections: MedDRA Preferred Terms 
AIDS retinopathy 
Herpes pharyngitis 
Acid fast bacilli infection 
Herpes sepsis 
Acinetobacter bacteraemia 
Herpes simplex 
Acinetobacter infection 
Herpes simplex cervicitis 
Acquired immunodeficiency syndrome 
Herpes simplex hepatitis 
Actinomycosis 
Herpes simplex meningoencephalitis 
Actinomycotic abdominal infection 
Herpes simplex otitis externa 
Actinomycotic pulmonary infection 
Herpes simplex test positive 
Acute HIV infection 
Herpes 
simplex 
virus 
conjunctivitis 
neonatal 
Acute hepatitis B 
Herpes simplex visceral 
Acute hepatitis C 
Herpes virus infection 
Adrenal gland tuberculosis 
Herpes zoster 
Arthritis fungal 
Herpes zoster cutaneous disseminated 
Arthritis salmonella 
Herpes zoster disseminated 
Aspergilloma 
Herpes zoster infection neurological 
Aspergillosis oral 
Herpes zoster meningitis 
Aspergillus infection 
Herpes zoster meningoencephalitis 
Asymptomatic HIV infection 
Herpes zoster meningomyelitis 
Asymptomatic viral hepatitis 
Herpes zoster necrotising retinopathy 
Atypical mycobacterial infection 
Herpes zoster oticus 
Atypical mycobacterial lower respiratory 
tract infection 
Herpes zoster pharyngitis 
Atypical mycobacterial lymphadenitis 
Histoplasmosis 
Atypical mycobacterial pneumonia 
Histoplasmosis cutaneous 
Atypical mycobacterium pericarditis 
Histoplasmosis disseminated 
Bacterial parotitis 
Human T-cell lymphocytic virus type II 
infection 
BK virus infection 
Human 
T-cell 
lymphotropic 
virus 
infection 
Biliary tract infection cryptosporidial 
Human T-cell lymphotropic virus type I 
infection 
Biliary tract infection fungal 
Human polyomavirus infection 
Blastomycosis 
Immune 
reconstitution 
inflammatory 
syndrome associated tuberculosis 
Bone tuberculosis 
Intestinal tuberculosis 
Brachyspira infection 
JC virus granule cell neuronopathy 
Brain empyema 
JC virus infection 


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Opportunistic Infections: MedDRA Preferred Terms 
Bronchitis fungal 
Joint tuberculosis 
Bronchopulmonary aspergillosis 
Kaposi's sarcoma 
Bronchopulmonary aspergillosis allergic 
Kaposi's sarcoma AIDS related 
Brucella sepsis 
Kaposi's varicelliform eruption 
Brucellosis 
Leptotrichia infection 
Candida endophthalmitis 
Listeria encephalitis 
Candida infection 
Listeria sepsis 
Candida osteomyelitis 
Listeriosis 
Candida pneumonia 
Lower respiratory tract herpes infection 
Candida retinitis 
Lower respiratory tract infection fungal 
Candida sepsis 
Lymph node tuberculosis 
Cerebral aspergillosis 
Lymphadenitis fungal 
Cerebral fungal infection 
Lymphoma AIDS related 
Cerebral toxoplasmosis 
Male genital tract tuberculosis 
Choroid tubercles 
Meningitis aspergillus 
Chronic hepatitis 
Meningitis candida 
Chronic hepatitis C 
Meningitis coccidioides 
Coccidioides encephalitis 
Meningitis cryptococcal 
Coccidioidomycosis 
Meningitis fungal 
Colitis herpes 
Meningitis herpes 
Congenital HIV infection 
Meningitis histoplasma 
Congenital cytomegalovirus infection 
Meningitis listeria 
Congenital hepatitis B infection 
Meningitis salmonella 
Congenital herpes simplex infection 
Meningitis toxoplasmal 
Congenital toxoplasmosis 
Meningitis tuberculous 
Congenital tuberculosis 
Meningoencephalitis 
herpes 
simplex 
neonatal 
Congenital varicella infection 
Meningoencephalitis herpetic 
Conjunctivitis tuberculous 
Minor cognitive motor disorder 
Corynebacterium infection 
Mucocutaneous candidiasis 
Corynebacterium sepsis 
Mycobacterial infection 
Cryptococcal cutaneous infection 
Mycobacterium abscessus infection 
Cryptococcal fungaemia 
Mycobacterium avium complex immune 
restoration disease 
Cryptococcosis 
Mycobacterium avium complex infection 
Cryptosporidiosis infection 
Mycobacterium chelonae infection 
Cutaneous coccidioidomycosis 
Mycobacterium fortuitum infection 
Cutaneous tuberculosis 
Mycobacterium kansasii infection 
Cytomegalovirus chorioretinitis 
Mycobacterium marinum infection 
Cytomegalovirus colitis 
Mycobacterium ulcerans infection 
Cytomegalovirus duodenitis 
Mycotic endophthalmitis 


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5 
REFERENCES 
Felson, D. T. (2011). American College of Rheumatology/European League against. Arthritis & 
Rheumatology. 
Maruish, M. E. (2011). User’s manual for the SF-36v2 Health Survey (3rd ed.). Lincoln, RI: 
QualityMetric Incorporated. 
Yuan, Y. (2011). Multiple Imputation using SAS software. pp. 45; 1-25. 
 
 
 
 


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Opportunistic Infections: MedDRA Preferred Terms 
Cytomegalovirus enteritis 
Mycotoxicosis 
Cytomegalovirus enterocolitis 
Myocarditis mycotic 
Cytomegalovirus gastritis 
Myocarditis toxoplasmal 
Cytomegalovirus gastroenteritis 
Nasal herpes 
Cytomegalovirus gastrointestinal infection 
Necrotising fasciitis fungal 
Cytomegalovirus gastrointestinal ulcer 
Necrotising herpetic retinopathy 
Cytomegalovirus infection 
Neonatal candida infection 
Cytomegalovirus mononucleosis 
Neonatal mucocutaneous herpes simplex 
Cytomegalovirus mucocutaneous ulcer 
Neurocryptococcosis 
Cytomegalovirus myelomeningoradiculitis 
Neutropenic sepsis 
Cytomegalovirus myocarditis 
Nocardia sepsis 
Cytomegalovirus oesophagitis 
Nocardiosis 
Cytomegalovirus pancreatitis 
Oesophageal candidiasis 
Cytomegalovirus pericarditis 
Oesophageal tuberculosis 
Cytomegalovirus syndrome 
Ophthalmic herpes simplex 
Cytomegalovirus urinary tract infection 
Ophthalmic herpes zoster 
Cytomegalovirus viraemia 
Oro-pharyngeal aspergillosis 
Disseminated cryptococcosis 
Oropharyngeal candidiasis 
Disseminated cytomegaloviral infection 
Osteomyelitis blastomyces 
Disseminated tuberculosis 
Osteomyelitis fungal 
Ear tuberculosis 
Osteomyelitis salmonella 
Eczema herpeticum 
Overgrowth fungal 
Encephalitis cytomegalovirus 
Pancreatitis fungal 
Encephalitis fungal 
Paratyphoid fever 
Encephalitis post immunisation 
Pericarditis fungal 
Encephalitis post varicella 
Pericarditis histoplasma 
End stage AIDS 
Pericarditis tuberculous 
Endocarditis candida 
Perinatal HIV infection 
Endocarditis histoplasma 
Peritoneal candidiasis 
Enterocolitis AIDS 
Peritoneal tuberculosis 
Enterocolitis fungal 
Persistent generalised lymphadenopathy 
Epididymitis blastomyces 
Pneumocystis jirovecii infection 
Epididymitis tuberculous 
Pneumocystis jirovecii pneumonia 
Epstein-Barr virus associated lymphoma 
Pneumonia blastomyces 
Erythema induratum 
Pneumonia cytomegaloviral 
Erythrasma 
Pneumonia fungal 
Exanthema subitum 
Pneumonia herpes viral 
Extrapulmonary tuberculosis 
Pneumonia salmonella 
Eye infection toxoplasmal 
Pneumonia toxoplasmal 
Female genital tract tuberculosis 
Polyomavirus-associated nephropathy 


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Opportunistic Infections: MedDRA Preferred Terms 
Fungaemia 
Presumed ocular histoplasmosis syndrome 
Fungal abscess central nervous system 
Proctitis herpes 
Fungal endocarditis 
Proctitis monilial 
Fungal infection 
Progressive 
multifocal 
leukoencephalopathy 
Fungal oesophagitis 
Prostatitis tuberculous 
Fungal peritonitis 
Pulmonary mycosis 
Fungal sepsis 
Pulmonary trichosporonosis 
Fungal tracheitis 
Pulmonary tuberculoma 
Funguria 
Pulmonary tuberculosis 
Gastritis fungal 
Pyelonephritis fungal 
Gastritis herpes 
Renal tuberculosis 
Gastroenteritis cryptococcal 
Respiratory moniliasis 
Gastroenteritis cryptosporidial 
Respiratory tract infection fungal 
Gastrointestinal candidiasis 
Retinitis histoplasma 
Gastrointestinal fungal infection 
Retroviral infection 
Genital blister 
Retroviral rebound syndrome 
Genital herpes 
Salmonella bacteraemia 
Genital herpes zoster 
Salmonella sepsis 
Haemorrhagic pneumonia 
Salmonellosis 
Hepatosplenic abscess 
Salpingitis tuberculous 
HIV associated nephropathy 
Silicotuberculosis 
HIV cardiomyopathy 
Sinusitis aspergillus 
HIV enteropathy 
Skin candida 
HIV infection 
Spleen tuberculosis 
HIV infection CDC Group I 
Splenic candidiasis 
HIV infection CDC Group II 
Splenic infection fungal 
HIV infection CDC Group III 
Stoma site candida 
HIV infection CDC Group IV subgroup A 
Stoma site infection 
HIV infection CDC Group IV subgroup B 
Superinfection fungal 
HIV infection CDC Group IV subgroup C1 Superinfection mycobacterial 
HIV infection CDC Group IV subgroup C2 Systemic candida 
HIV infection CDC Group IV subgroup D 
Systemic mycosis 
HIV infection CDC Group IV subgroup E 
T-cell lymphoma 
HIV infection CDC category A 
T-cell type acute leukaemia 
HIV infection CDC category B 
Thyroid tuberculosis 
HIV infection CDC category C 
Tongue fungal infection 
HIV infection CDC group IV 
Toxoplasmosis 
HIV infection WHO clinical stage I 
Tropical spastic paresis 
HIV infection WHO clinical stage II 
Tuberculoma of central nervous system 


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Opportunistic Infections: MedDRA Preferred Terms 
HIV infection WHO clinical stage III 
Tuberculosis 
HIV infection WHO clinical stage IV 
Tuberculosis bladder 
HIV peripheral neuropathy 
Tuberculosis gastrointestinal 
HIV wasting syndrome 
Tuberculosis liver 
Hepatic candidiasis 
Tuberculosis of central nervous system 
Hepatic infection fungal 
Tuberculosis of eye 
Hepatitis B 
Tuberculosis of genitourinary system 
Hepatitis C 
Tuberculosis of intrathoracic lymph nodes 
Hepatitis chronic persistent 
Tuberculosis of peripheral lymph nodes 
Hepatitis fulminant 
Tuberculosis ureter 
Hepatitis toxoplasmal 
Tuberculous 
abscess 
central 
nervous 
system 
Hepatitis viral 
Tuberculous endometritis 
Hepatitis virus-associated nephropathy 
Tuberculous laryngitis 
Hepatosplenic candidiasis 
Tuberculous pleurisy 
Herpes dermatitis 
Tuberculous tenosynovitis 
Herpes oesophagitis 
Typhoid fever 
Herpes ophthalmic 
Varicella keratitis 
 


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6.2 
Appendix B: Laboratory Parameters of Interest 
 
Lab parameters 
of interest 
Grade 
1 
2 
3 
4 
HEMOGLOBIN 
decrease 
 Hemoglobin (Hgb) <LLN - 10.0   g/dL; 
<LLN - 6.2 mmol/L; <LLN -  100 g/L   
 Hgb <10.0 - 8.0 g/dL; <6.2 - 4.9   
mmol/L; <100 - 80g/L   
 Hgb <8.0 g/dL; <4.9 mmol/L;   <80 g/L; 
transfusion indicated 
 Life-threatening 
consequences;   urgent 
intervention indicated   
WHITE CELL 
COUNT decrease 
 <LLN - 3000/mm3; <LLN - 3.0 x   10e9 
/L   
 <3000 - 2000/mm3; <3.0 - 2.0 x   10e9 
/L   
 <2000 - 1000/mm3; <2.0 - 1.0 x   10e9 
/L   
 <1000/mm3; <1.0 x 10e9 
/L   
TOTAL 
NEUTROPHILS 
ABSOLUTE 
COUNT 
 <LLN - 1500/mm3; <LLN - 1.5 x   10e9 
/L   
 <1500 - 1000/mm3; <1.5 - 1.0 x   10e9 
/L   
 <1000 - 500/mm3; <1.0 - 0.5 x   10e9 
/L   
 <500/mm3; <0.5 x 10e9 
/L   
LYMPHOCYTES 
ABSOLUTE 
COUNT 
decreased 
  <LLN - 800/mm3; <LLN - 0.8 x   10e9 
/L   
 <800 - 500/mm3; <0.8 - 0.5 x   10e9 /L   
 <500 - 200/mm3; <0.5 - 0.2 x   10e9 /L   
 <200/mm3; <0.2 x 10e9 
/L   
LYMPHOCYTES 
ABSOLUTE 
increased 
  
 >4000/mm3 - 20,000/mm3 ; >4-2 x  
10e9 /L  
 >20,000/mm3;  >20 x  10e9 /L   
  
PLATELET 
COUNT 
 <LLN - 75,000/mm3; <LLN -  75.0 x 
10e9 /L   
 <75,000 - 50,000/mm3; <75.0 -  50.0 x 
10e9 /L   
 <50,000 - 25,000/mm3; <50.0 -  25.0 x 
10e9 /L   
<25,000/mm3; <25.0 x 
10e9 /L 
CREATININE 
 >1 - 1.5 x baseline; >ULN - 1.5   x ULN   
 >1.5 - 3.0 x baseline; >1.5 - 3.0   x ULN   
 >3.0 baseline; >3.0 - 6.0 x ULN   x ULN   
 >6.0 x ULN   
SODIUM 
decrease 
<LLN - 130 mmol/L  
  
<130 - 120 mmol/L 
<120 mmol/L; 
SODIUM 
increase 
>ULN - 150 mmol/L   
>150 - 155 mmol/L   
>155 - 160 mmol/L 
>160 mmol/L 
POTASSIUM 
decrease 
<LLN - 3.0 mmol/L   
<LLN - 3.0 mmol/L 
<3.0 - 2.5 mmol/L 
<2.5 mmol/L 
POTASSIUM 
increase 
>ULN - 5.5 mmol/L   
>5.5 - 6.0 mmol/L   
>6.0 - 7.0 mmol/L   
 >7.0 mmol/L 


GlaxoSmithKline 
 
GSK Study 201755 
Reporting and Analysis Plan 
 
TP-GDO-WW-016-03 
CONFIDENTIAL 
Project Document Version No. 2.0 
Effective Date:  26 Aug 15 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 80 of 80 
CALCIUM 
increase 
>ULN - 11.5 mg/dL; >ULN - 2.9 
mmol/L 
>11.5 - 12.5 mg/dL; >2.9 - 3.1 
mmol/L 
>12.5 - 13.5 mg/dL; >3.1 - 3.4 
mmol/L; 
>13.5 mg/dL; >3.4 
mmol/L 
CALCIUM 
decrease 
<LLN -  1.0 mmol/L   
<1.0 -  0.9 mmol/L 
<0.9 -  0.8 mmol/L 
<0.8 mmol/L   
PHOSPHORUS 
INORGANIC 
<LLN - 2.5 mg/dL; <LLN - 0.8   mmol/L 
<2.5 - 2.0 mg/dL; <0.8 - 0.6   mmol/L 
<2.0 - 1.0 mg/dL; <0.6 - 0.3   mmol/L 
<1.0 mg/dL; <0.3 mmol/L 
ASAT (SGOT) 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
ALAT (SGPT) 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
GGT 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
ALKALINE 
PHOSPHATASE 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
BILIRUBIN, 
TOTAL 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 10.0 x ULN 
>10.0 x ULN 
CPK, TOTAL 
>ULN - 2.5 x ULN 
>2.5 x ULN - 5 x ULN 
>5 x ULN - 10 x ULN 
>10 x ULN 
ALBUMIN 
<LLN - 3 g/dL; <LLN - 30 g/L 
<3 - 2 g/dL; <30 - 20 g/L 
<2 g/dL; <20 g/L 
  
GLUCOSE 
>ULN -160 mg/dL;  >ULN - 8.9 mmol/L  
>160 -250 mg/dL; >8.9 - 13.9 mmol/L  
>250 - 500 mg/dL; >13.9 - 27.8  
>500 mg/dL; >27.8 
mmol/L 
EST.CREATININE 
CLEARANCE 
 <LLN - 60   ml/min/1.73 m2 
59 - 30  ml/min/1.73 m2   
29 - 15   ml/min/1.73 m2   
<15 ml/min/1.73 m2