Conditions: Arthritis, Rheumatoid
Keywords: GSK3196165 magnetic resonance imaging (MRI) disease-modifying antirheumatic drugs (DMARDs) granulocyte-macrophage colony stimulating factor (GM-CSF) Rheumatoid Arthritis Methotrexate
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 39
Healthy volunteers: no

Brief summary:
This study is designed to explore the activity of granulocyte-macrophage colony stimulating factor (GM-CSF) signaling pathway in subjects with rheumatoid arthritis (RA), the potential impact of inhibition of this axis by GSK3196165, and to evaluate whether there are any differences in the GM-CSF axis between subjects with early RA compared with those with more established disease. This study also aims to establish the potential impact of GSK3196165 on inflammatory structural joint damage in the hand/wrist using magnetic resonance imaging (MRI). This is a randomized Phase IIa, multi-center, double-blind, placebo-controlled parallel group study. Approximately 40 subjects with active RA despite treatment with disease-modifying antirheumatic drugs (DMARDs) (including conventional or biologic) will be randomized into the study, following a screening period of up to 6 weeks. The total treatment period is up to 10 weeks, with a 12-week follow-up period after the last dose (Week 22).

Detailed description:

Arms:
arm 1: Subjects will receive GSK3196165 (initially weekly, then every other week) in combination with MTX (15-25 mg/week) and folic (or folinic) acid (\>=5 mg/week). arm 2: Subjects will receive placebo (initially weekly, then every other week) in combination with MTX (15-25 mg/week) and folic (or folinic) acid (\>=5 mg/week).

Interventions: intervention 1: GSK3196165 intervention 2: Placebo intervention 3: MTX intervention 4: Folic (or folinic) acid
Intervention descriptions: intervention 1: GSK3196165 is supplied as liquid and will be administered as SC injection. intervention 2: 0.9% weight by volume (w/v) sodium chloride solution administered as SC injection. intervention 3: Capsule, tablet or liquid administered orally or as SC injection. intervention 4: Capsule, tablet or liquid and will be administered orally.

Protocol document:
Prot_000.pdf: 
2015N261421_01
CONFIDENTIAL
The GlaxoSmithKline group of companies
205180
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Phase IIa, Double-Blind, Mechanistic Study of GSK3196165 
in Combination with Methotrexate Therapy in Subjects with 
Active Rheumatoid Arthritis Despite Treatment with DMARDs
Compound Number:
GSK3196165
Development Phase:
IIA
Effective Date:
01-MAR-2016
Protocol Amendment Number:  1
Author(s):
 
 
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N261421_00
2015-DEC-16
Original
2015N261421_01
2016-MAR-01
Amendment No. 1
This amendment includes classification of primary and secondary objectives and 
endpoints in Section 1 and Section 3; extension of the screening window to six weeks in 
Section 1, Section 4.1, Section 5.3.1, Section 7.1, and Section 7.2; correction of several 
typographical errors; clarification of likely numbers of patients screened in Section 4.3; 
correction of >15% relative decrease in DLCO as a trigger point in Section 4.6.1; 
clarification of DLCO testing in Section 5.1, Section 5.3.2.2, Section 7.1, Section 7.2, and 
Section 7.6.12; addition of Day 1 joint count and correction of mandatory chest HRCT if 
DLCO ≥60% - <70% predicted in Section 5.1; revision that subjects must have passed all 
screening assessments (including laboratory tests) prior to undertaking MRI scanning, 
and that whole blood flow cytometry is scheduled on Day 1 in Section 7.1; an additional
Exclusion Criterion for MRI in Section 5.2; correction that re-screening is permitted in 
Section 5.3.1; correction that RNA analysis is not part of the pharmacogenetics substudy 
in Section 7.1 and Section 7.2; clarification of the RA Symptom and Impact Diary in 
Section 7.5.2; clarification of PK sample in Section 7.2; clarification of MRI image 
processing in Section 7.9; clarification of abbreviations in Appendix 12.1; revision of 
contraception guidance in Appendix 12.2; and clarification of data recording in Appendix 
12.7.
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


PPD
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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: 2015-004386-91
IND number: 121958
PPD


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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 205180
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 205180........................................................9
2.
INTRODUCTION....................................................................................................12
2.1.
Study Rationale ..........................................................................................12
2.1.1.
Rheumatoid Arthritis ....................................................................12
2.1.2.
GM-CSF and RA..........................................................................12
2.1.3.
GSK3196165...............................................................................13
2.1.4.
Clinical Data ................................................................................14
3.
OBJECTIVE AND ENDPOINTS .............................................................................15
4.
STUDY DESIGN ....................................................................................................16
4.1.
Overall Design ............................................................................................16
4.2.
Treatment Arms and Duration.....................................................................17
4.3.
Type and Number of Subjects.....................................................................17
4.4.
Design Justification.....................................................................................17
4.5.
Dose Justification........................................................................................18
4.5.1.
GSK3196165...............................................................................18
4.5.2.
Placebo .......................................................................................20
4.5.3.
Methotrexate Background............................................................20
4.6.
Benefit:Risk Assessment ............................................................................20
4.6.1.
Risk Assessment .........................................................................21
4.6.2.
Benefit Assessment.....................................................................31
4.6.3.
Overall Benefit:Risk Conclusion...................................................31
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............31
5.1.
Inclusion Criteria.........................................................................................32
5.2.
Exclusion Criteria........................................................................................34
5.3.
Screening/Baseline/Run-in Failures............................................................37
5.3.1.
Re-Screening...............................................................................38
5.3.2.
Re-Testing...................................................................................38
5.3.2.1.
Laboratory Tests ........................................................38
5.3.2.2.
Pulmonary Function Tests..........................................38
5.3.2.3.
Electrocardiogram (ECG) Test ...................................38
5.4.
Withdrawal/Stopping Criteria.......................................................................39
5.4.1.
Liver Chemistry Stopping Criteria ................................................40
5.4.1.1.
Liver Chemistry Stopping and Increased 
Monitoring Algorithm...................................................40
5.4.1.2.
Study Treatment Restart or Rechallenge....................40
5.4.2.
QTc Stopping Criteria ..................................................................40
5.5.
Treatment Interruption ................................................................................41
5.5.1.
Respiratory Symptoms.................................................................41
5.5.2.
Hematologic Abnormalities ..........................................................42
5.6.
Subject and Study Completion....................................................................42
6.
STUDY TREATMENT ............................................................................................42
6.1.
Investigational Product and Other Study Treatment....................................42
6.2.
Treatment Assignment................................................................................44


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6.3.
Planned Dose Adjustments.........................................................................44
6.4.
Blinding.......................................................................................................44
6.5.
Packaging and Labeling..............................................................................45
6.6.
Preparation/Handling/Storage/Accountability..............................................45
6.7.
Compliance with Study Treatment Administration.......................................46
6.8.
Treatment of Study Treatment Overdose....................................................46
6.8.1.
Overdose of GSK3196165...........................................................46
6.8.2.
Overdose of Methotrexate ...........................................................47
6.9.
Treatment after the End of the Study ..........................................................47
6.10.
Concomitant Medications and Non-Drug Therapies....................................47
6.10.1.
Permitted Medications and Non-Drug Therapies..........................48
6.10.1.1.
Corticosteroids ...........................................................48
6.10.1.1.1.
Oral Corticosteroids................................48
6.10.1.1.2.
NSAIDs...................................................48
6.10.1.1.3.
Analgesics..............................................48
6.10.1.1.4.
DMARD/Biologic Rescue 
Medications ............................................49
6.10.2.
Prohibited Medications and Non-Drug Therapies.........................49
6.10.2.1.
Related to the Study...................................................49
6.10.2.2.
Related to Methotrexate .............................................49
6.10.2.3.
Complementary Therapies .........................................50
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................50
7.1.
Time and Events Table...............................................................................51
7.2.
Screening and Critical Baseline Assessments ............................................54
7.3.
Efficacy.......................................................................................................56
7.3.1.
Exploratory Biomarker(s)/Pharmacodynamic Markers .................56
7.3.2.
Biomarkers ..................................................................................56
7.3.3.
Target Engagement (TE) .............................................................57
7.4.
Novel Biomarkers .......................................................................................57
7.5.
Clinical Efficacy...........................................................................................58
7.5.1.
Magnetic Resonance Imaging......................................................58
7.5.2.
Clinical assessments ...................................................................58
7.5.3.
Joint Assessments.......................................................................59
7.5.3.1.
Replaced or Fused Joints...........................................59
7.5.3.2.
Independent Joint Evaluator.......................................59
7.5.4.
Patient’s Assessment of Arthritis Pain..........................................59
7.5.5.
Patient’s Global Assessment of Arthritis ......................................59
7.5.6.
Physician’s Global Assessment of Arthritis ..................................60
7.5.7.
DAS Assessments.......................................................................60
7.5.8.
ACR Assessments.......................................................................60
7.6.
Safety .........................................................................................................60
7.6.1.
Screening Visits...........................................................................61
7.6.2.
Study Visits..................................................................................61
7.6.3.
Safety Endpoints and Other Assessments...................................61
7.6.4.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........62
7.6.4.1.
Time Period and Frequency for Collecting AE 
and SAE Information ..................................................62
7.6.4.2.
Method of Detecting AEs and SAEs ...........................62
7.6.4.3.
Follow-up of AEs and SAEs........................................63
7.6.4.4.
Cardiovascular and Death Events ..............................63


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7.6.5.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs.........................................................63
7.6.6.
Adverse Events of Special Interest ..............................................63
7.6.6.1.
Disease-Related Events and/or 
Disease-Related Outcomes Not Qualifying as 
SAEs ..........................................................................64
7.6.6.2.
Regulatory Reporting Requirements for SAEs............64
7.6.7.
Pregnancy ...................................................................................65
7.6.8.
Physical Exams ...........................................................................65
7.6.9.
Vital Signs....................................................................................65
7.6.10.
Electrocardiogram........................................................................65
7.6.11.
Clinical Safety Laboratory Assessments ......................................66
7.6.12.
Pulmonary Assessments .............................................................67
7.7.
Pharmacokinetics .......................................................................................68
7.7.1.
Blood Sample Collection..............................................................68
7.7.2.
Sample Analysis ..........................................................................68
7.8.
Immunogenicity...........................................................................................68
7.9.
Magnetic Resonance Imaging.....................................................................69
7.10.
Genetics .....................................................................................................70
7.11.
Value Evidence and Outcomes...................................................................70
7.11.1.
Health Assessment Questionnaire – Disability Index 
(HAQ-DI)......................................................................................70
7.11.2.
Rheumatoid Arthritis Symptoms and Impact Diary PRO ..............70
8.
DATA MANAGEMENT ...........................................................................................70
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................71
9.1.
Hypotheses.................................................................................................71
9.2.
Sample Size Considerations.......................................................................71
9.2.1.
Sample Size Assumptions ...........................................................71
9.2.2.
Sample Size Sensitivity................................................................71
9.2.3.
Sample Size Re-estimation or Adjustment...................................71
9.3.
Data Analysis Considerations .....................................................................72
9.3.1.
Analysis Populations....................................................................72
9.3.2.
Final Analysis ..............................................................................72
9.3.3.
Interim Analysis ...........................................................................72
9.4.
Key Elements of Analysis Plan ...................................................................72
10. STUDY GOVERNANCE CONSIDERATIONS........................................................73
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............73
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................73
10.3.
Quality Control (Study Monitoring) ..............................................................73
10.4.
Quality Assurance.......................................................................................74
10.5.
Study and Site Closure ...............................................................................74
10.6.
Records Retention......................................................................................75
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................75
11. REFERENCES.......................................................................................................77
12. APPENDICES........................................................................................................81


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12.1.
Appendix 12.1 – Abbreviations and Trademarks.........................................81
12.2.
Appendix 12.2 - Contraception Eligibility Criteria for Female and 
Male Subjects.............................................................................................86
12.2.1.
Females.......................................................................................86
12.2.2.
Males...........................................................................................87
12.3.
Appendix 12.3: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................88
12.4.
Appendix 12.4 - Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events ............................91
12.4.1.
Definition of Adverse Events........................................................91
12.4.2.
Definition of Serious Adverse Events...........................................92
12.4.3.
Sentinel Events............................................................................93
12.4.4.
Definition of Cardiovascular Events .............................................94
12.4.5.
Recording of AEs and SAEs ........................................................94
12.4.6.
Evaluating AEs and SAEs............................................................95
12.4.7.
Reporting of SAEs to GSK...........................................................96
12.5.
Appendix 12.5 – Collection of Pregnancy Information.................................98
12.5.1.
Female Subjects..........................................................................98
12.5.2.
Female Partners of Male Subjects ...............................................98
12.6.
Appendix 12.6 - Genetic Research .............................................................99
12.7.
Appendix 12.7: Important Study Assessment Details and Study 
Specific Equipment...................................................................................102
12.8.
Appendix 12.8 Country Specific Requirements .........................................103
12.9.
Appendix 12.9 - Protocol Changes............................................................104


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1.
PROTOCOL SYNOPSIS FOR STUDY 205180
Rationale
This study is designed to explore the activity of granulocyte-macrophage colony 
stimulating factor (GM-CSF) signaling pathway in subjects with rheumatoid arthritis 
(RA), and the potential impact of inhibition of this axis by GSK3196165.  An additional 
exploratory aim is to evaluate whether there are any differences in the GM-CSF axis 
between subjects with early RA compared with those with more established disease.
Finally, this study aims to establish the potential impact of GSK3196165 on 
inflammatory structural joint damage in the hand/wrist using magnetic resonance (MR) 
imaging (MRI).
Objective/Endpoints
Primary objectives
Primary endpoints
The main objectives of this study are to 
explore the activity of GM-CSF signaling 
pathway characterized by exploratory 
biomarkers in subjects with RA, the impact of 
GSK3196165 therapy, and whether there are 
any differences in this GM-CSF signaling 
pathway between subjects with early RA or 
established RA.
Changes from baseline in exploratory 
biomarkers.
Secondary objectives
Secondary endpoints
To evaluate the safety and tolerability of 
GSK3196165 in subjects with RA.
Incidence of adverse events (AEs), 
serious adverse events (SAEs), adverse 
events of special interest (AESIs).
Immunogenicity (anti drug antibodies 
[ADAs]).
To evaluate the impact of GSK3196165 on 
inflammatory structural joint damage in the 
hand/wrist using MRI.
Change from baseline in synovitis, osteitis 
and erosion as assessed by Outcome 
Measures in Rheumatology (OMERACT) 
rheumatoid arthritis MRI scoring system 
(RAMRIS) and rheumatoid arthritis MRI 
quantitative score (RAMRIQ) in the most 
affected hand/wrist.
Exploratory Biomarker Endpoints*
Identify/validate markers of downstream signaling of GM-CSF and/or potential novel 
markers for GSK3196165 activity.
Pharmacodynamic biomarkers to assess response to GSK3196165 (e.g. may include, but 
not limited to, interleukin [IL]-1β, tumor necrosis factor alpha [TNFα], IL-6, IL-8, IL-15, IL-23, 
IL-17A/F; chemokines such as CCL17, CXCL4, CXCL7, CXCL13, CCL22; and complement 
proteins such as C5a, ratio C3/C3dg, TCC, C4, C4a, sCD163).
Effect of GSK3196165 on target cell populations (e.g. may include, but not limited to, 


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circulating levels of T, B, natural killer (NK), Th17, T regulatory cells and activated 
monocytes, dendritic cells, neutrophils).
Whole blood ribonucleic acid (RNA) markers of engagement (e.g., serum concentration of 
free GM-CSF/macrophage signaling and response to GSK3196165.
Whole blood deoxyribonucleic acid (DNA) analysis to explore the relationship between 
genetic variants in the host and response to GSK3196165.
Biomarkers of extracellular matrix (ECM) or aggrecan degradation (e.g. may include, but 
not limited to, serum chondrex [YKL-40] also called human cartilage glycoprotein 39 [HC gp 
39], ARGS neoepitope).
Biomarkers which may be indicative of RA disease activity (e.g., may include, but not 
limited to 14-3-3η, anti-cyclic citrullinated protein antibody [ACPA], C-reactive protein 
[CRP], rheumatoid factor [RF]).
Pharmacodynamic biomarkers which may be predictive of response to GSK3196165 (e.g.
may include, but not limited to, C1M, C2M, C3M, CRPM, VICM, MRP8/14, matrix 
metalloproteinase 3 [MMP-3], 14-3-3η).
Exploratory MRI/Imaging Endpoints*
Change from baseline in joint inflammation as measured by dynamic contrast enhanced 
(DCE)-MRI in the most affected hand/wrist:

Exchange rate (Ktrans)

Interstitial volume (Ve)

Plasma volume (Vp)

Initial rate of enhancement (IRE)

Maximal signal intensity enhancement (ME).
Exploratory Clinical Efficacy Endpoints*
Change from baseline at all assessment timepoints for:

ACR20/50/70** response rates

Disease activity score for 28 different joints with CRP value (DAS28[CRP]) score

DAS28(CRP) remission rates and categorical (European League Against Rheumatism 
[EULAR] good/moderate) response.
Note: For composite endpoints, e.g., DAS28(CRP), American College of Rheumatology (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).
Pharmacokinetic/Target Engagement Endpoints
GSK3196165 pharmacokinetic (PK) parameters derived from the sparse blood samples 
and using a population PK analysis.
Pharmacodynamic biomarkers to assess target engagement (TE) (e.g., serum 
concentration of free GM-CSF, GM-CSF: GSK3196165 complex).
Exploratory Safety Endpoints

To evaluate potential biomarkers of 
pulmonary alveolar proteinosis (PAP) 
pathogenesis.
Biomarkers which may be predictive of 
lung damage (e.g., Krebs von den 
Lungen-6 [KL-6], serum amyloid A (SAA), 
surfactant protein-D [SP-D], cholestenoic 
acid).
GM-CSF auto-antibodies.


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*Where relevant, comparisons will be made between the early and established RA 
subject populations.
**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.
Overall Design
This is a randomized Phase IIa, multi-center, double-blind, placebo-controlled parallel 
group study to explore the mechanistic evidence that the GM-CSF signaling pathway is 
active in subjects with RA, and the potential impact of inhibition of this axis by 
GSK3196165.  In addition, the study will assess the potential impact of GSK3196165 on 
inflammatory structural joint damage in the most affected hand/wrist using MRI.
The randomization will be stratified by early or established disease (see below) and 
randomization will occur at the baseline visit on Day 1.
Treatment Arms and Duration

Screening period up to 6 weeks, then 10-week combination dosing with methotrexate 
(MTX), with a 12-week follow-up visit after the last dose (Week 22).

GSK3196165 180 mg vs. placebo administered by subcutaneous (SC) injection, 
given weekly for 5 weeks, then every other week thereafter until Week 10.
Type and Number of Subjects

Approximately 40 subjects with active RA despite treatment with DMARDs 
(including conventional or biologic) will be randomized into the study.

Ideally, 50% of subjects enrolled into the study should have early RA (≤2 years since 
diagnosis).  The actual proportion will be monitored throughout the study and 
randomization may be altered if the projected final proportion with early RA is less 
than 30%.

Subjects will be randomized on a 3:1 basis to GSK3196165 or placebo.

Randomization will be stratified by early RA (≤2 years since diagnosis) and 
established RA.
Analysis
All endpoints are exploratory.  They will be summarized for the overall population as 
well as by RA status (early vs. established).  GSK3196165 treatment effect will be 
measured by change from baseline.  They will be presented by tables and figures.  The 
relationships between endpoints will be graphically explored (and further quantified if 
permitted by adequate data).  Bayesian methods will be used to explore the probabilistic 
aspect of certain endpoints.


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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.
Study Rationale
This study is designed to explore the activity of the GM-CSF signaling pathway in 
subjects with RA, and the potential impact of inhibition of this axis by GSK3196165.  An 
additional exploratory aim is to evaluate whether there are any differences in the 
GM-CSF axis between subjects with early RA (≤2 years since diagnosis) compared with 
those with more established disease.
Finally, this study aims to establish the potential impact of GSK3196165 on 
inflammatory structural joint damage in the hand/wrist using magnetic resonance imaging 
(MRI).
2.1.1.
Rheumatoid Arthritis
RA is a chronic, systemic inflammatory autoimmune disease, characterized by 
asymmetrical 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 MTX is the gold standard, and biological DMARDs 
which target cytokines (e.g. tumor necrosis factor alpha [TNFα], interleukin [IL]-6), 
B-cells or T-cells.  However, a substantial proportion of subjects 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 
subject’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 cell surface major histocompatibility complex (MHC) class II heterodimers and 
present antigen to T cells, further contributing to the inflammatory process.


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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 TNFα, 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 cell surface MHC class II heterodimers on antigen presenting 
cells, which in turn will activate CD4+ T cells.  In addition, GM-CSF is a strong 
chemoattractant factor for neutrophils and induces the release of reactivated oxygen 
species from 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].  Moreover, there is evidence that early 
RA is the result of an already-established synovitis in which macrophage-derived 
cytokines play an important role in the clinical signs of inflammation [Tak, 1997].
In mouse models of collagen-induced arthritis (CIA), anti-GM-CSF treatment reduced 
disease activity and prevented progression of established arthritis [Cook, 2001; 
Plater-Zyberk, 2007] and, furthermore, administration of recombinant GM-CSF led to 
exacerbation of arthritis [Campbell, 1997]. Importantly, anti-GM-CSF was shown to be 
beneficial for either early or established arthritis [Cook, 2001]. Moreover, GM-CSF 
depletion appeared to have a more dramatic effect than depletion of TNF since only 2/15 
(13%) of GM-CSF-deficient mice developed CIA compared with 8/26 (31%) of TNF-
deficient mice [Campbell, 1998; Campbell, 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 (particularly in the 
early stages of RA), 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 neutralizes 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 


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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 four completed clinical trials to date, summarized in the 
IB (GSK Document Number 2014N190256_01), and one ongoing clinical trial (201755).
MSC-1001 was a Phase1b/2a multi-center, randomized, sequential group, double-blind, 
placebo-controlled study which evaluated the safety, preliminary efficacy, and 
pharmacokinetic (PK) of multiple doses of GSK3195165 in subjects (N=96) with active, 
mild-moderate RA [Behrens, 2015].  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 C-reactive protein (CRP) >5 mg/L (in sero-negative 
subjects) or CRP >2 mg/L (in rheumatoid factor (RF) and/or anti-cyclic citrullinated 
protein antibody (ACPA) sero-positive subjects) and disease activity score for 28 
different joints (DAS28) score ≤5.1.  Subjects received four weekly intravenous (IV) 
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 at Week 4 
was observed with 1.0 mg/kg than 1.5 mg/kg in this dose-escalation cohort study.  
A significant reduction in 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 (TEAEs) 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 adverse events (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 pulmonary function tests (PFTs) or 
diffusing capacity of the lung for carbon monoxide (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 subjects recovered.
An ongoing phase IIb, double-blind, placebo-controlled, dose-adaptive, study of the 
efficacy and safety of GSK3196165 in combination with MTX therapy, in subjects with 
active moderate to severe RA despite treatment with MTX.  Study 201755 commenced in 
July 2015 with doses of GSK3196165 from 22.5 mg up to 180 mg.  A total of 210 
methotrexate-inadequate response (MTX-IR) patients with moderate-severe RA are 
planned to be enrolled.


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3.
OBJECTIVE AND ENDPOINTS
Primary objectives
Primary endpoints
The main objectives of this study are to 
explore the activity of GM-CSF signaling 
pathway characterized by exploratory 
biomarkers in subjects with RA, the impact of 
GSK3196165 therapy, and whether there are 
any differences in this GM-CSF signaling 
pathway between subjects with early RA or 
established RA.
Changes from baseline in exploratory 
biomarkers.
Secondary objectives
Secondary endpoints
To evaluate the safety and tolerability of 
GSK3196165 in subjects with RA.
Incidence of adverse events (AEs), 
serious adverse events (SAEs), adverse 
events of special interest (AESIs).
Immunogenicity (anti drug antibodies 
[ADAs]).
To evaluate the impact of GSK3196165 on 
inflammatory structural joint damage in the 
hand/wrist using MRI.
Change from baseline in synovitis, osteitis 
and erosion as assessed by Outcome 
Measures in Rheumatology (OMERACT) 
rheumatoid arthritis MRI scoring system 
(RAMRIS) and rheumatoid arthritis MRI 
quantitative score (RAMRIQ) in the most 
affected hand/wrist.
Exploratory Biomarker Endpoints*
Identify/validate markers of downstream signaling of GM-CSF and/or potential novel 
markers for GSK3196165 activity.
Pharmacodynamic biomarkers to assess response to GSK3196165 (e.g. may include, but 
not limited to, IL-1β, TNFα, IL-6, IL-8, IL-15, IL-23, IL-17A/F; chemokines such as CCL17, 
CXCL4, CXCL7, CXCL13, CCL22; and complement proteins such as C5a, ratio C3/C3dg, 
TCC, C4, C4a, sCD163).
Effect of GSK3196165 on target cell populations (e.g. may include, but not limited to, 
circulating levels of T, B, natural killer (NK), Th17, T regulatory cells and activated 
monocytes, dendritic cells, neutrophils).
Whole blood ribonucleic acid (RNA) markers of engagement (e.g., serum concentration of 
free GM-CSF/macrophage signaling and response to GSK3196165.
Whole blood deoxyribonucleic acid (DNA) analysis to explore the relationship between 
genetic variants in the host and response to GSK3196165.
Biomarkers of extracellular matrix (ECM) or aggrecan degradation (e.g. may include, but 
not limited to, serum chondrex [YKL-40] also called human cartilage glycoprotein 39 [HC gp 
39], ARGS neoepitope).
Biomarkers which may be indicative of RA disease activity (e.g., may include, but not 
limited to 14-3-3η, ACPA, CRP, RF).
Pharmacodynamic biomarkers which may be predictive of response to GSK3196165 (e.g.
may include, but not limited to, C1M, C2M, C3M, CRPM, VICM, MRP8/14, matrix 
metalloproteinase 3 [MMP-3], 14-3-3η).


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Exploratory MRI/Imaging Endpoints*
Change from baseline in joint inflammation as measured by dynamic contrast enhanced 
(DCE)-MRI in the most affected hand/wrist:

Exchange rate (Ktrans)

Interstitial volume (Ve)

Plasma volume (Vp)

Initial rate of enhancement (IRE)

Maximal signal intensity enhancement (ME).
Exploratory Clinical Efficacy Endpoints*
Change from baseline at all assessment timepoints for:

ACR20/50/70** response rates

Disease activity score for 28 different joints with CRP value (DAS28[CRP]) score

DAS28(CRP) remission rates and categorical (European League Against Rheumatism 
[EULAR] good/moderate) response.
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).
Pharmacokinetic/Target Engagement Endpoints
GSK3196165 PK parameters derived from the sparse blood samples and using a 
population PK analysis.
Pharmacodynamic biomarkers to assess target engagement (TE) (e.g., serum 
concentration of free GM-CSF, GM-CSF: GSK3196165 complex).
Exploratory Safety Endpoints

To evaluate potential biomarkers of 
pulmonary alveolar proteinosis (PAP) 
pathogenesis.
Biomarkers which may be predictive of 
lung damage (e.g., Krebs von den 
Lungen-6 [KL-6], serum amyloid A (SAA), 
surfactant protein-D [SP-D], cholestenoic 
acid).
GM-CSF auto-antibodies.
*Where relevant, comparisons will be made between the early and established RA 
subject populations.
** 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.
4.
STUDY DESIGN
4.1.
Overall Design
This is a randomized Phase IIa, multi-center, double-blind, placebo-controlled parallel 
group study to explore the mechanistic evidence that the GM-CSF signaling pathway is 
active in subjects with RA, and the potential impact of inhibition of this axis by 
GSK3196165.  In addition, the study will assess the potential impact of GSK3196165 on 
inflammatory structural joint damage in the most affected hand/wrist using MRI.
Approximately 40 subjects with active RA despite treatment with DMARDs (including 
conventional or biologic) will be randomized into the study, following a screening period 


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of up to 6 weeks.  The total treatment period is up to 10 weeks, with a 12-week follow-up 
period after the last dose (Week 22).  Ideally, 50% of subjects enrolled into the study 
should have early RA (e.g. ≤2 years since diagnosis).  The actual proportion will be 
monitored throughout the study and randomization may be altered if the projected final 
proportion with early RA is less than 30%.
A schematic representation of the study design is shown in Figure 1.
Figure 1
Study design
4.2.
Treatment Arms and Duration
Subjects will be randomized on a 3:1 basis to GSK3196165 or placebo.  Subjects will 
receive GSK3196165 180 mg or placebo once weekly for 5 weeks, and then every other 
week until Week 10.
In addition to GSK3196165 or placebo, subjects will receive MTX 7.5–25 mg/week and 
folic (or folinic) acid ≥5 mg/week during the combination treatment period.
Details of the study treatment are presented in Section 6.
4.3.
Type and Number of Subjects
Approximately 80 subjects with active early/established RA despite treatment with 
DMARDs will be screened (subjects can be rescreened once) to achieve 40 randomized 
subjects.  Rescreening criteria are listed in the Study Reference Manual (SRM).
4.4.
Design Justification
This mechanistic study is designed to better understand the efficacy of GSK3196165 as a 
treatment option for RA (and in particular for subjects with early disease).
The main objectives of this study are to explore the activity of GM-CSF signaling 
pathway characterized by exploratory biomarkers) in subjects with RA, the impact of 
GSK3196165 therapy, and whether there are any differences in this GM-CSF signaling 
pathway between subjects with early RA or established RA.


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Exploratory endpoints include:

Identification of biomarkers of downstream signaling of GM-CSF;

Pharmacodynamic biomarkers to assess response to GSK3196165;

Effect of GSK3196165 on target cell populations;

Analysis of whole blood ribonucleic acid (RNA) markers of engagement (e.g. 
serum concentration of free G-CSF /macrophage signaling and response to 
GSK3196165;

Analysis of whole blood DNA to explore the relationship between genetic 
variants in the host and response to GSK3196165;

Biomarkers which may be indicative of RA disease;

Pharmacodynamic biomarkers which may be predictive of response to 
GSK3196165.
Additionally, exploratory MRI imaging (including DCE-MRI, the OMERACT RAMRIS 
[Østergaard, 2003], and the RAMRIQ system [Bowes, 2014]) will be employed to 
explore a potential effect of GSK3196165 on disease modification (which includes a 
reduction in inflammation in terms of synovitis and bone marrow lesions, structural 
progression in terms of cartilage space loss (as an analog of joint space narrowing).
All study endpoints will be evaluated throughout the study and at Week 12, following the 
completion of dosing at Week 10, to assess the efficacy of GSK3196165.  A follow-up 
(observational) period will then take place, completing the study at Week 22.
Justification of placebo control is detailed in Section 4.5.2.
4.5.
Dose Justification
4.5.1.
GSK3196165

The dosing regimen for this study includes five subcutaneous (SC) loading doses 
of GSK3196165 180 mg administered every week, followed by three doses of 
180 mg SC administered every other week.  The predicted PK plasma profile of 
GSK3196165 using this dosing regimen is shown in Figure 2 below.  This 
regimen was selected to i) produce sufficient drug exposure in both plasma and 
synovial fluid to inhibit free GM-CSF from binding to its receptor, and ii) be 
associated with an appropriate margin to the no observed adverse effect level 
(NOAEL) and the no observed effect level (NOEL) (the dose at which foamy 
alveolar macrophages were not observed in the 13-week cynomolgus monkey 
study; see IB (GSK Document Number 2014N190256_01).

The predicted exposures associated with the proposed dosing regimen over 
10 weeks, allows a 30-fold margin to the NOAEL and a 10-fold margin to the 
NOEL in preclinical studies of similar duration.  In addition, a dose of 180 mg SC 
is predicted to result in steady-state exposures which will allow an approximate 
26-fold margin to the NOAEL, and a three-fold margin to the NOEL based on the 


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findings in the 26-week monkey study.  Of note, in the monkey 26-week study, 
full reversibility of the foamy alveolar macrophages was observed following 
clearance of GSK3196165.  The IV 4-week monkey study provides additional 
safety cover for the weekly loading dosing phase of the proposed clinical study 
(Table 1).
Figure 2
Predicted GSK3196165 Plasma Concentrations at the Recommended 
Dosing Regimen (Median and 95% Confidence Interval)
Table 1
Safety Margins with 180 mg SC GSK3196165 Relative to Exposures 
in Non-clinical 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
Not applicable
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


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AUC(0-336)=Area under drug concentration time curve from time zero to 336 hours postdose; IV intravenous; QW=once 
a week; SC subcutaneous
a.
Simulated mean area under the plasma concentration time curve (AUC) based on analysis of SC and IV data for 
doses ≥0.5 mg/kg from study MSC-1000 (N=18) and study MOR103C104 (N=32) with a two compartment model 
and calculation of F by ratio of intravenous plasma clearance/subcutaneous plasma clearance (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 area under drug concentration time curve from time zero to 168 hours postdose (AUC[0-168]) 
values have been used and multiplied by two to obtain mean concentrations over a two-week period
c.
No observed adverse effect dose level (NOAEL)
d.
No observed effect dose level (NOEL)
4.5.2.
Placebo
Placebo control (on methotrexate background) is required for this study in order to 
provide an adequate internal control and reference group for the analysis of changes in 
biomarkers.  This is of particular importance given the exploratory nature of the
biomarker tests being used in this study.
Both the 3:1 randomization ratio and the treatment duration of 10 weeks will minimize 
the exposure to placebo in the study.  If a subject experiences an unacceptable level of 
disease activity during the study, the investigator may withdraw the subject at any point.
4.5.3.
Methotrexate Background
All subjects will continue to receive MTX (and folic or folinic acid) throughout the study.
4.6.
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.


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4.6.1.
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-tumor necrosis factor 
[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 TB 
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 investigational product 
Subject selection:
Subjects with active 
infections or a history of 
recent or recurrent 
infections are not permitted 
to enter the study.
Subjects with significant 
leukopenia (white blood cell 
count ≤3.0 x109/L) and 
neutropenia (absolute 
neutrophil count ≤1.5 x 
109/L) are not permitted to 
enter the study.
Subjects will be screened 
for Mycobacterium 
tuberculosis (TB), human 
immunodeficiency virus 
(HIV) and Hepatitis B and 
C, and excluded from study 
participation if positive.  
Subjects with any past 
history of TB or Hepatitis B 
will also be excluded.
Investigators are expected 
to assess vaccination 
status, including against 
influenza and 
pneumococcus, according 
to local guidelines.
Subject monitoring:
Serious infections are 
categorized as AESIs.
Subjects will be closely 
monitored for infections and 
additional information to 
clarify the events will be 
recorded in the electronic 
case report form (eCRF).  
Appropriate diagnostic tests 
will be considered during 
the study if clinically 
indicated to ensure 


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
(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.
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 subject 
Informed Consent Form.
Withdrawal criteria:
In the event of a serious 
infection, study medication 
should be discontinued and 
the subject withdrawn from 
the study.
Pulmonary alveolar proteinosis
GM-CSF signaling is required 
to maintain the normal function 
of alveolar macrophages.  
Long-term absence of 
GM-CSF signaling (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.
However, GSK believes that 
anti-GM-CSF therapy has a 
low risk of PAP development, 
for the following reasons:
Auto-antibodies to GM-CSF 
(GMAbs) have been shown 
to occur in healthy people at 
low levels, and the critical 
threshold of GMAbs 
associated with the presence 
of PAP is ~10μg/mL [Uchida, 
2009], and a serum threshold 
of >5μg/mL has been 
reported as the optimal cut 
Subject selection
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 during screening 
in order to exclude those 
subjects with impairment.  
Subjects with abnormal 
DLCO or forced expiratory 
volume in one second 
(FEV1) will be excluded.
Dose Duration:
The exposure duration to 
GSK3196165 in this study 
is 10 weeks.  Although the 
time course of PAP 
development in humans is 
unknown, the published 
literature suggests that it 
requires full inhibition of 


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
off value for distinguishing 
autoimmune PAP serum 
from normal serum [Uchida, 
2014].
A recent study has reported 
that individual auto-
antibodies from patients only 
partially-neutralized GM-CSF 
and when injected into mice 
together with human GM-
CSF led to the accumulation 
of a large pool of circulating 
GM-CSF that remained 
partially bioavailable [Piccoli, 
2015].  In contrast, a 
combination of three non-
cross-competing antibodies 
completely neutralized GM-
CSF activity in vitro by 
sequestering the cytokine in 
high-molecular-weight 
complexes, and in vivo 
promoted the rapid 
degradation of GM-CSF-
containing immune 
complexes in an Fc-
dependent manner.  These 
findings provide a plausible 
explanation for the severe 
phenotype of PAP patients 
and for the low likelihood of 
treatments based on single 
anti-GM-CSF monoclonal 
antibodies causing PAP.
Non-clinical Data:
Non-adverse minimal to mild 
foamy alveolar macrophage 
accumulation was noted in 
lungs of monkeys in the 
13-week SC and 26-week 
intravenous (IV) toxicology 
studies, but reversed following 
off drug period.  Dose levels at 
which foamy alveolar 
macrophages were not 
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:

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.

Pulmonary function 
testing (spirometry and 
DLCO measurements) 
will be performed 
during screening, at 
12 weeks, and at the 
follow-up visit. Relative 
decrease in DLCO >15% 
from screening will be 
reported as an AESI if 
confirmed with three 
consecutive weekly 
tests.

In the event of any new 
or clinically significant 
pulmonary 
abnormalities that may 
develop during the 


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
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.
study and persist for 
three consecutive 
weeks (e.g., increased 
shortness of 
breath/dyspnea, or 
unexplained and 
persistent coughing), 
the subject will be 
withdrawn from study 
drug for the remainder 
of the study and it is 
recommended that the 
subject be referred to a 
pulmonologist for 
further assessment. 
The subject should be 
followed until the 
symptoms or signs that 
caused referral have 
resolved and/or the 
diagnosis has been 
determined.  
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:
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 


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
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 three 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 subject 
Informed Consent Form.
Should hypersensitivity or 
anaphylaxis occur, subjects 
should be managed 
appropriately per local 
guidelines/medical 
judgment.
Severe or serious 
hypersensitivity or 
anaphylaxis is categorized 
as AESIs.
Subject Monitoring:
Subjects should be 
monitored for 
hypersensitivity reactions 
throughout the study, and 
the information recorded in 
the eCRF.
Any clinically significant 
event should be reported as 
an AE.
Withdrawal Criteria:
In the event of severe or 


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
serious hypersensitivity 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 and 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.
Immunogenicity
Pre-clinical Data:
ADAs to GSK3196165 were 
detected in some monkeys and 
was associated with reduced 
serum levels of GSK3196165; 
ADA associated toxicity was 
not observed.
Clinical Data:
In Study MSC1000, one 
healthy volunteer who received 
a single dose of 25 µg/kg was 
found to have an 
immunoglobulin M (IgM) ADA 
at Day 15, and in Study 
MSC1001 immunoglobulin G 
(IgG) ADA were detected at 
Week 13, but not Week 16 in 
one RA subject who received 
4 weekly doses of 1.0 mg/kg, 
with no impact on 
GSK3196165 serum 
concentrations.
Investigate Risk:
Samples (pre- and 
post-baseline) will be 
collected from all subjects 
during the study to assess 
development of anti-drug 
antibodies and will be 
analyzed at the end of the 
study.
In addition to scheduled 
immunogenicity 
assessments, 
“event-driven” testing will 
also be employed for those 
subjects that experience 
anaphylaxis, serious 
hypersensitivity or adverse 
events that deemed to be 
clinically significant in the 
opinion of the investigator, 
and related to study drug 
administration that lead to 
withdrawal from the study, 
blood samples will be taken 
for immunogenicity testing 
at the time of the event and 
again 10 weeks after.


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
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 and Clinical 
Data:
There have been no reports of 
neutropenia or decreases in 
leukocytes in the non-clinical 
and clinical GSK3196165 
program.
Subject Selection:
Subjects with significant 
leukopenia (white blood 
count (WBC) ≤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 (see Time and Events 
Table, Section 7.1).
Grade 3 or 4 neutropenia is
categorized 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, embryofetal or 
effects on fertility were noted in 
the reproductive toxicology 
studies using the surrogate rat 
anti-mouse GM-CSF 
monoclonal antibody, 22E9.
Subject Selection:
Male and female subjects 
will only be permitted to 
enter the study if they meet 
the contraception 
requirements detailed in 
inclusion criterion #8.
In addition, females of child 
bearing potential will 
undergo pregnancy testing 
at screening and at regular 
intervals during the study 
(see Time and Events 
Table, Section 7.1).
Due to concomitant use of 
methotrexate, additional 
precautions to avoid 
pregnancy in females of 
reproductive potential and 
female partners of males 
subjects enrolled in the 
study are required (see 


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
The effect on human 
pregnancy is unknown.
Clinical Data:
No healthy volunteers or RA 
subjects became pregnant 
during the studies, but one 
multiple sclerosis subject 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.
Appendix 12.2).
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 elective 
termination of a pregnancy 
will be reported as an AE or 
SAE.
Potential drug interaction with 
CYP450 substrates
Non-clinical Data:
Cytokines can produce 
concentration-dependent 
inhibition on various CYP 
isoforms at the transcription 
level or by alteration of CYP 
enzyme stability in patients 
with infection or inflammation, 
and increase the plasma 
concentrations of specific CYP 
substrate drugs.
Cytokine modulators may 
reverse the apparent 
“inhibition” effect of the 
cytokines on CYP substrates, 
resulting in a “normalization” of 
CYP activities.
GSK3196165 is a cytokine 
modulator, so has the potential 
to ‘normalise’ CYP expression 
from a suppressed state in 
patients with a pro-
inflammatory disease (RA).
Clinical Data:
Subject Selection:
Subjects of reproductive 
potential using hormonal 
contraceptives, including 
oral, injections, implants, 
and patches are required to 
use a secondary method of 
contraception.
Subjects receiving 
concomitant CYP450 
substrate with narrow
therapeutic index should be 
monitored for signs in 
changes in drug exposure 
(see Section 6.10).


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
No studies have been 
performed specifically to 
evaluate the potential for 
GSK3196165 to indirectly elicit 
a pharmacokinetic drug 
interaction through cytokine 
regulation of cytochrome P450 
(CYPs) or drug transporter 
expression.
Malignancy
The risk of malignancy is 
increased in subjects with RA.  
In addition, immunomodulatory 
therapies may increase the risk 
of malignancy.
Non-clinical and Clinical 
Data:
There have been no reports of 
malignancy in the non-clinical 
and clinical GSK3196165 
program.
Subject Selection:
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.
Gadolinium (Gd)-containing 
MRI contrast agents
Non-clinical Data:
Animal studies have shown 
reproductive toxicity of 
Gd-containing MRI contrast 
agents at repeated high doses.
Clinical Data:
Use of MRI contrast agents in 
subjects with severely impaired 
renal function (GFR 
<30mL/minute) has been 
associated with Nephrogenic 
Systemic Fibrosis (NSF).  In 
subjects with severely impaired 
renal function, the benefits of 
the use of contrast agents 
should be carefully weighed 
against the risks.
Gd contrast agents can be 
associated with 
anaphylactoid/hypersensitivity 
or other idiosyncratic reactions, 
characterized by 
cardiovascular, respiratory or 
cutaneous manifestations, and 
Subject Selection:
Pregnant or breast feeding 
females will be excluded 
from taking part in the 
study.
Subjects with impaired 
renal function (glomerular 
filtration rate (GFR) 
<60mL/minute) are 
excluded by the eligibility 
criteria.
Subjects with history of 
sensitivity to Gd-containing 
contrast agents will be 
excluded from the study.  
The MRI procedure will be 
conducted under the 
supervision of a trained and 
qualified clinical staff 
trained to appropriately 
manage an allergic 
reaction.
Sites will be responsible for 
following any additional 


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
ranging to severe reactions 
including shock.  In general, 
subjects with cardiovascular 
disease are more susceptible 
to serious or even fatal 
outcomes of severe 
hypersensitivity reactions.
The risk of hypersensitivity 
reactions may be higher in 
case of:
previous reaction to 
contrast media
history of bronchial asthma
history of allergic disorders
Most of these reactions occur 
within half an hour of 
administration.  Delayed 
reactions (after hours or 
several days) have been rarely 
observed.
safety information for the 
specific gadolinium contrast 
agent used at their site and 
not enroll subjects if 
contraindicated.
Subject Monitoring and 
Management:
MRI contrast at a dose less 
than or equal to 
0.1 mmol/kg will be used in 
the MRI protocol.
Effective contraception is 
required during the study, 
and pregnancy tests will be 
performed regularly 
throughout the study prior 
to dosing in females of child 
bearing potential.
Exposure to a high field MRI 
magnet
Certain prostheses or foreign 
bodies might be incompatible 
with the MRI scanner.
Subject Selection:
All participants will be 
screened according to local 
hospital criteria and trial 
inclusion/exclusion before 
entering the MRI room to 
ensure they are able to 
have the MRI conducted.  
Subjects with non-magnetic 
resonance compatible 
metal implants or 
implantable electronic 
devices (e.g. pacemaker, 
defibrillator) will not be 
included in this study.


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4.6.2.
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, most of whom had received prior DMARDs 
or biologics [Behrens, 2015].  In addition, mavrilimumab (an anti-GM-CSF α-subunit 
receptor mAb), in combination with MTX, has also shown substantial activity in RA 
subjects who had an inadequate response to MTX in studies of up to 2.4 years of dosing 
[Burmester, 2013; Burmester, 2014; Burmester, 2015] and namilumab (an anti-GM-CSF 
mAb) for 4 weeks [Huizinga, 2015].  These data support the clinical evaluation of 
GSK3196165 in subjects with RA.
4.6.3.
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-GM-CSF α-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 up to 
2.4 years in combination with MTX in subjects with active RA [Burmester, 2013; 
Burmester, 2014; Burmester, 2015] and namilumab [Huizinga, 2015] 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 subjects with autoimmune diseases, such 
as RA.
In addition, in accordance with routine pharmacovigilance, and internal GSK safety 
review team (SRT) will review blinded safety data, including clinical laboratory 
parameters and AEs, approximately monthly during the period of study conduct.
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).


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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.
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:
AGE
1. Age ≥18 years at the time of signing informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
2. Meets ACR/EULAR 2010 RA Classification Criteria
AND
Subject not diagnosed before age of 16 years.
3. Functional class I, II or III defined by the 1992 ACR Classification of Functional 
Status in RA.
4. Active disease as defined by:
a. Swollen joint count of ≥4 (66-joint count) and tender joint count of ≥4 (68-joint 
count) at screening and at Day 1.
AND
b. DAS28(CRP) ≥3.2 at screening.
AND
c.
CRP ≥3.0 mg/L.
5. Signs of inflammation such as synovitis in the MRI scan of the most-affected hand.
6. Must be currently taking MTX (15-25 mg weekly) (oral/injected) 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.
WEIGHT
7. Body weight ≥45 kg.


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SEX
8. 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.
INFORMED CONSENT
9. Capable of giving signed informed consent as described in Section 7.2 which includes 
compliance with the requirements and restrictions listed in the consent form and in 
this protocol.
OTHER SAFETY-RELATED
10. 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).
11. DLCO ≥60%a predicted; FEV1 ≥70% predicted.
a.
For subjects with DLCO values ≥60% - <70%, a baseline chest high-resolution 
computed tomography (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.
12. No evidence of active or latent infection with 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 at screening defined as:
i. A negative QuantiFERON Gold test or T-spot test (two successive indeterminate 
QuantiFERON tests will be considered as a positive result).
OR
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 
Bacillus Calmette-Guérin (BCG) vaccination be tested with QuantiFERON gold 
test).
c. Chest X-ray within 12 weeks of Day 1 with no evidence of current or previous 
pulmonary tuberculosis, locally read by a radiologist.
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.


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5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. Pregnant or lactating, or women planning to become pregnant or initiating 
breastfeeding.
2. History of other inflammatory rheumatologic 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 (in the opinion of the investigator) persistent cough or clinically 
significant or unstable dyspnea that is unexplained.
5. QT interval corrected for heart rate (QTc) >450msec or QTc >480 msec 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 New York Heart Association 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, endocrinologic or infectious diseases, which, 
in the 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 at screening.
11. Hereditary or acquired immunodeficiency disorder, including immunoglobulin 


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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 has required management of acute or chronic infections, 
as follows:
a. Currently taking any suppressive therapy for a chronic infection (such as TB, 
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 intramuscular (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. Contraindication to MRI scanning (as assessed by local MRI safety questionnaire) 
which includes but is not limited to:
a. Intracranial aneurysm clips (except Sugita) or other metallic objects.
b. History of intra-orbital metal fragments that have not been removed by a medical 
professional.
c. Pacemakers or other implanted cardiac rhythm management devices and non-MR 
compatible heart valves.
d. Inner ear implants.
e. History of claustrophobia which may impact participation.
f.
History of sensitivity to Gd-containing contrast agents.
CONCOMITANT MEDICATIONS
17. Use of prohibited medications:
Prior to AND throughout the study:

Any conventional DMARDs other than MTX (including hydroxychloroquine, 
sulphasalazine, minocycline, cyclosporin) must be withdrawn at least 2 weeks 
prior to Day 1.


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Subjects may require longer to discontinue leflunomide prior to randomization:
o Leflunomide must be discontinued ≥12 weeks prior to randomization (or 
≥14 days after 11 days of standard cholestyramine or activated charcoal 
washout).
For these subjects, written informed consent for the study must be obtained 
prior to beginning the screening period.  However, other screening 
assessments, other than consent, must occur within 42 days prior to 
randomization.

Azathioprine must be discontinued ≥28 days prior to randomization.

Any alkylating agents (such as cyclophosphamide or chlorambucil).

Plasmapheresis or intravenous immunoglobulin (IVIG) or use of Staph protein A 
column (Prosorba) within 26 weeks of Day 1.

Biologic agents - all must be discontinued prior to Day 1:
anakinra or etanercept (4 weeks prior);
adalimumab (6 weeks prior);
infliximab (8 weeks prior);
certolizumab pegol or golimumab (10 weeks prior);
abatacept or tocilizumab (12 weeks prior);
belimumab, rituximab, or other selective B lymphocyte depleting agents 
(1 year prior, and if CD19/20+ counts are normal by fluorescence-activated 
cell sorter (FACS) analysis).
18. Tofacitinib must be discontinued at least 2 weeks prior to Day 1.
19. Corticosteroids:

Any IM, IV or intra-articular (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).
20. Non-steroidal anti-inflammatory drugs (NSAIDs):

New or change in dose of NSAID within 14 days of Day 1.
21. Any prior investigational treatment must be discontinued for at least 4 weeks or 
5 half-lives, whichever is longer, prior to Day 1.


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RELEVANT HABITS
22. 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.
CONTRAINDICATIONS 
23. 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.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
24. Abnormal chest X-ray within 12 weeks of Day 1 (locally read and reported by a 
radiologist) judged by the investigator as clinically-significant.
25. Any Grade 3 or 4 hematology or clinical chemistry laboratory abnormality (common 
terminology criteria for adverse events [CTCAE], 2009 v4.0) at screening.
26. 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 at 
screening.  Refer to Section 5.3.1 and Section 5.3.2.
27. 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 at screening:

Subjects positive for HBsAg and/or positive for anti-HBc antibody (regardless of 
anti-HBs antibody status) are excluded.
28. Hepatitis C: Positive test for Hepatitis C virus (HCV) antibody confirmed on a 
subsequent blood sample by RNA-polymerase chain reaction (PCR) assay at 
screening.

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.
29. Positive serology for HIV 1 or 2 at screening.
5.3.
Screening/Baseline/Run-in 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 information about potential subjects who failed screening is required including 
demography, screen failure details, eligibility criteria, and SAEs.


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5.3.1.
Re-Screening
If a subject has not met all of the Eligibility Criteria within the 42-day screening period, 
re-screening is permitted.  Subjects are only allowed to be re-screened once; the entire 
screening process must be repeated.
If a blood sample has to be redrawn due to sample handling problems, breakage or 
sample integrity, this is not considered a re-screening.
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 redrawn due to sample handling problems, breakage or 
sample integrity, this is not considered a re-testing.
Further details regarding the procedure for re-testing may be found in the SRM.
5.3.2.2.
Pulmonary Function Tests
It is permitted to repeat the pulmonary function testing sessions (spirometry and/or DLCO) 
once within the screening period, i.e. subjects may undergo a total of two DLCO tests 
during the screening period).
If the screening DLCO result is ≥60% but <70% predicted, a chest HRCT must be 
performed.  If this cannot be done within the screening window, then the subject must be 
re-screened.
5.3.2.3.
Electrocardiogram (ECG) Test
The QTc is the QT interval corrected for heart rate according to Fridericia’s formula 
(QTcF).  The QTc should be based on average QTc values of triplicate ECGs obtained 
over a brief recording period (e.g., 5-10 minutes).
The triplicate electrocardiogram (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.


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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, three 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.

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”.
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, behavioral or 
administrative reasons.  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.
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 (refer to Section 4.6.1).

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.


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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 Food and Drug 
Administration (FDA) premarketing clinical liver safety guidance) [FDA, 2009].
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
The same QT correction formula must be used for each individual subject to determine 
eligibility for and discontinuation from the study.  The QTc correction formula to be used 
is the QT interval corrected for heart rate according to Fridericia’s formula (QTcF).  This 
formula may not be changed or substituted once the subject has been enrolled.
For example, if a subject is eligible for the protocol based on QTcF, then QTcF must be 
used for discontinuation of this individual subject as well.


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Once the QT correction formula has been chosen for a subject’s eligibility, the same 
formula must continue to be used for that subject for all QTc data being collected for data 
analysis.  Safety ECGs and other non-protocol specified ECGs are an exception.
The QTc should be based on a single QTc value.  The QTc is the QT interval corrected 
for heart rate according to Fridericia’s formula (QTcF).

The ECG may be repeated in triplicate if the recorded QTcF value is out of range.  
The QTc should then be based on averaged QTc values of the triplicate ECGs 
obtained over a brief recording period (e.g., 5-10 minutes).
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 QTcF.
For subjects with underlying bundle branch block, follow the discontinuation criteria 
listed below:
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 cough (common terminology criteria (CTC) grade 2 or 3) or dyspnea 
(Borg scale grade 3 or above) for three consecutive weeks.  Details on CTC and 
Borg scale are provided in the SRM.
The subject should be referred to a pulmonologist for further assessment.  The study drug 
should be suspended until the symptoms or signs that caused the 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.


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5.5.2.
Hematologic Abnormalities
The following hematological 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 ≥two sequential tests), or occur 
recurrently (on two 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.
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 (study 
treatment)
Control
Background treatment 
(started prior to and 
maintained during the 
study).
Formulation 
description:
See IB (GSK 
Document Number 
2014N190256_01
) for details.
Sterile 0.9% 
(weight/volume 
[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.


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Study Treatment
Co-medication
Dosage levels 
(volumes):
180 mg (1.2mL)
1.2 mL
MTX:7.5-25 mg/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).
[Refer to Inclusion 
criterion 6 in Section 5.1.]
Route of 
Administration:
Study treatment 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
Dosing instructions:
GSK3196165/placebo should be 
administered on the same day each week 
± 1 day for the first five weekly doses 
(with a minimum of 5 days between 
doses, for no more than two consecutive 
doses).  Following this 
GSK3196165/placebo should be 
administered on the same day every other 
week (EOW) ± 3 days (with a minimum of 
8 days between doses).
Every attempt should be made to ensure 
all doses are administered.
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.
See label for details.
Method for 
individualizing 
dosage:
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 1.2 mL 
will be drawn into a 
small (e.g. 2 or 
3 mL) syringe.
See label for details.


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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 at the entry 
into study (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 electronic case report form 
(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 (GSK3196165 or placebo) in accordance 
with the randomization schedule.  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
No dose adjustments are planned for this study.
6.4.
Blinding
This will be a double-blind study, which means that the investigator and trial staff at the 
site (apart from the unblinded administrator [study coordinator or nurse], subject and 
sponsor personnel will be blinded to the study medication allocated to each individual 
subject.


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There will be an unblinded administrator (study coordinator or nurse) that will prepare 
and administer the study medication.  The barrel of the syringe will be shielded during 
investigational product administration so that subjects are not able to see any difference 
in the color between GSK3196165 and placebo.
The following will apply:

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.  Unblinding will be done via IRTS; as described in the SRM.

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 case 
report form (CRF)
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 CRF.

GSK’s Global Clinical Safety and Pharmacovigilance 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.
6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.6.
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 coordinator 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.


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
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).

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/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.
6.7.
Compliance with Study Treatment Administration
GSK3196165 or placebo will be administered by subcutaneous injection to subjects at the 
site by the unblinded administrator (study coordinator 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.
6.8.
Treatment of Study Treatment Overdose
6.8.1.
Overdose of GSK3196165
There is very limited clinical safety data for GSK3196165 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 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 study treatment 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 3 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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6.8.2.
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 mucosal, hematological and gastrointestinal reactions.  
Leucovorin (IV) or folinic acid (oral) are specific antidotes for MTX and, following 
accidental over dosage, should be administered as soon as possible after the over dosage 
occurs, as the longer the delay in initiation of leucovorin or folinic acid, the less the 
effectiveness in counteracting the MTX toxicity.  A dosage equal to, or greater than the 
MTX dose, should be given; 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 alkalization 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 dialyzer.
6.9.
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.
6.10.
Concomitant Medications and Non-Drug Therapies
During the past decade, the ability of pro-inflammatory cytokines to alter the expression 
and activity of drug metabolizing enzymes has become increasingly evident [Lee, 2010; 
Zhou, 2011; Evers, 2013].  During inflammation, enzymes such as cytochrome P 
(CYP)450 can be downregulated leading to instances of reduced clearance and increased 
plasma concentrations of administered drugs.  The administration of GSK3196165 can 
potentially alter circulating cytokine levels in a subject whose cytokine levels have been 
elevated previously.  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, 


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lovastatin, atorvastatin.  The effect of GSK3196165 on CYP450 enzyme activity may 
persist for several weeks after stopping therapy.
6.10.1.
Permitted Medications and Non-Drug Therapies
All permitted medications and non-drug therapies will be recorded as concomitant 
medications.
6.10.1.1.
Corticosteroids
6.10.1.1.1. 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 study.  Dose reductions 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 study treatment 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.
6.10.1.1.2. NSAIDs
Continued use of a single NSAID (including cyclo-oxygenase [Cox]-2 inhibitors) (e.g.
diclofenac, ibuprofen, naproxen, celecoxib) is permitted 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 (date and time of use, number and strength of doses taken).  
However, subjects should be advised not to take any NSAIDs for breakthrough pain 
within 12 hours prior to an efficacy assessment visit.
6.10.1.1.3. Analgesics
Regular use of codeine, opium alkaloid, paracetamol/acetaminophen, propoxyphene, and 
tramadol is permitted in daily doses up to the maximum recommended according to 
locally accepted clinical practices.  If, at the time of screening 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.


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6.10.1.1.4. DMARD/Biologic Rescue Medications
The subject’s disease will be assessed regularly throughout the study (as shown in 
Section 7.1).  Rescue with DMARDs / biologics is not allowed in this study.
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.
6.10.2.
Prohibited Medications and Non-Drug Therapies
Prohibited medications and non-drug therapies are described in Exclusion Criteria 13 
through 21 in Section 5.2.  Additional requirements are detailed in Section 6.10.2.1, 
Section 6.10.2.2, and Section 6.10.2.3.
6.10.2.1.
Related to the Study

IA corticosteroids are strongly discouraged within 8 weeks prior to Day 1, and then 
through Week 12.

However, IA corticosteroids may be used in a limited fashion as treatment for severe 
RA flares.

No more than 1 joint should be injected, during the study and the total dose of IA 
corticosteroid should not exceed 40 mg of triamcinolone (or equivalent) during the 
12-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.
6.10.2.2.
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).


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
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, 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 metabolized 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.
6.10.2.3.
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
Procedures
Screening
- up to 6 
weeks
Base-
line
Treatment Period
FU
EW1
Week
1
2
3
4
6
8
10
12
22
Visit
1
2
3
4
5
6
7
8
9
10
11
Day
1
8
15
22
29
43
57
71
85
155
Written Informed Consent(s)
X
Subject Demography
X
Medical, Disease, Therapy History
X
Inclusion/Exclusion Criteria
X
PRO2 and efficacy assessments3
Patient’s Assessment of Arthritis Pain, 
Patient’s Global Assessment of Arthritis, 
Physician’s Global Assessment of Arthritis2
X
X4
X
X
X
X
X
X
X
X
X
X
HAQ-DI2
X
X4
X
X
X
X
X
X
X
X
X
X
RA Symptom and Impact Diary2
X
X4
X
X
X
X
X
Swollen (66) & Tender (68) Joint Count3
X
X4
X
X
X
X
X
X
X
X
X
X
MRI
X20
X21
X21
X21
X22
Safety Evaluations5
Concomitant Medication
X
X4
X
X
X
X
X
X
X
X
X
X
Physical Examination6
X
X4
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
12-lead ECG7
X
X
X
AEs/SAEs8
X
X
X
X
X
X
X
X
X
X
X
X
Cough, Lung Auscultation, Pulse Oximetry, 
Borg Dyspnea Scale
X
X
X
X
X
X
X
X
X
X
X
X
Chest X-ray9
X
Spirometry (FEV1, FVC), DLCO
X10
X11
X11
X11


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Procedures
Screening
- up to 6 
weeks
Base-
line
Treatment Period
FU
EW1
Week
1
2
3
4
6
8
10
12
22
Visit
1
2
3
4
5
6
7
8
9
10
11
Day
1
8
15
22
29
43
57
71
85
155
Laboratory Assessments
Hematology, Chemistry
X
X4
X
X
X
X
X
X
TB, HBsAg, HepB cAb, HepC Ab, HIV
X
CRP, ESR12
X
X4
X
X
X
X
X
X
X
X
X
X
RF, ACPA (anti-CCP)
X4
Cholesterol, triglycerides, HDL, LDL13
X4
X
X
X
Pregnancy test14
S
U
U
U
U
U
U
Urinalysis (dip stick)
X
X
X
X
X
X
Other Laboratory Assessments
PK Sampling (GSK3196165)15
X
X
X
X
X
X
X
X
X
GM-CSF & PD blood biomarkers
X
X4
X
X
X
X
X
X
X
X
Whole blood flow cytometry
X4
X
X
X
X
X
RNA
X4
X
X
X
PGx sampling DNA16
X4
Lung biomarkers17
X4
X
X
X
Anti-GM-CSF auto-antibodies17
X4
Immunogenicity18
X4
X
X
X
X
X
Study Treatment GSK3196165/placebo19
(Methotrexate and folic acid weekly 
throughout treatment with GSK3196165)
X
X
X
X
X
X
X
X
Abbreviations: ACPA=anti-cyclic citrullinated protein antibody; AE=adverse event; CCP=cyclic citrullinated peptide; CRP=C-reactive protein; DNA=deoxyribonucleic acid; 
DLCO=diffusing capacity of the lung for carbon monoxide; ECG=electrocardiogram; ESR=erythrocyte sedimentation rate; EW=early withdrawal; FEV1=forced expiratory volume in one 
second; FU=follow-up; FVC=forced vital capacity; GM-CSF=granulocyte-macrophage colony-stimulating factor; HAQ-DI=Health Assessment Questionnaire Disability Index; HDL=high 
density lipoprotein; HBsAg=hepatitis B surface antigen; HepB cAb=anti-hepatitis B core antibody; HepC Ab=hepatitis C virus antibody; HIV=human immunodeficiency virus; LDL=low 
density lipoprotein; MRI=magnetic resonance imaging; PD=pharmacodynamic; PGx=pharmacogenomic; PK=Pharmacokinetic; PRO=patient reported outcome; RA=rheumatoid 
arthritis; RF=rheumatoid factor; RNA=ribonucleic acid; S=serum; SAE=serious adverse event; TB=Mycobacterium tuberculosis; U=urine.


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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. All patient reported outcome (PRO) assessments should be conducted before any tests, procedures, assessments or consultations, to avoid influencing the subjects’ perception.
3. The same individual (where possible) should perform all disease assessments for an individual subject (with separate joint assessor).
4. Assessments may be performed up to 24h before dosing.
5. All safety evaluations should be conducted before dosing.
6. Brief physical examination (assessments of the skin, lungs, CV system, and abdomen [liver and spleen]) at visits after screening.
7. Electrocardiogram (ECG) should be performed before vital signs, blood draws and dosing (triplicate ECGs required at screening, and single thereafter unless there are safety 
concerns, in which case repeats may be required (see Section 7.6.10)).
8. AEs/SAEs reported from start of study medication until the last follow-up visit. 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.
9. Unless performed within previous 12 weeks (no repeat if subject re-screened).
10. If DLCO ≥60% but <70% predicted, a chest HRCT must be performed. If this cannot be done within the screening window, then the subject must be re-screened.
11. Consider repeat DLCO if >15% relative decrease from baseline (recommendations provided in the Pulmonary Safety Guidance document).
12. ESR measured locally.
13. >8h fasting required before blood draw.
14. For women of child-bearing potential. S=serum; U=urine.
15. Blood samples taken before dosing.
16. In consenting subjects.
17. To be analyzed at end of study or in event of pulmonary safety signal.
18. In addition to these scheduled immunogenicity assessments, “event-driven” testing (see Section 7.8) 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.
19. 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 every other week (EOW) ±3 days.
20. Subjects must have passed all screening assessments, including laboratory tests, prior to undertaking MRI scanning.
21. MRI may be performed up to 7 days after scheduled visit.
22. MRI should be performed at Early Withdrawal visit if previous MRI was done >14 days before.


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7.2.
Screening and Critical Baseline Assessments
After written, informed consent (including separate consent for genetics), 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 42 days 
of Day 1 (except for subjects being treated with leflunomide, where written informed 
consent for the 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.  This 
list does not apply to subjects 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.

The following demographic parameters will be captured at screening: year of birth, 
sex, race and ethnicity.

Medical/medication/family history will be assessed at screening, 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.

RA history – disease and symptom duration, medication history, RA functional class 
(I, II or III).

Physical examination (complete examination at screening, and brief examination at 
baseline; see Section 7.6.8).

Vital signs including temperature, systolic and diastolic blood pressure, pulse rate, 
and respiratory rate, measured in semi-supine position.

Triplicate 12-lead ECG (before blood samples are taken) (screening only).

Chest X-ray (screening only).

Spirometry FEV1, FVC, and DLCO (PFTs performed according to 2005 ATS/ERS 
recommendations, see Section 5.3.2.2 and SRM for additional details) (screening 
only).

Cough, Lung Auscultation, Pulse Oximetry, Borg Dyspnea.

AE reporting and recording of concomitant medication.

Blood samples for:

Hematology (full/complete blood count and differential).

Biochemistry.

Whole blood flow cytometry (baseline only).

Serum beta subunit human chorionic gonadotropin (βhCG) pregnancy test 
(screening only).


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
HIV antibody, HBsAg, anti-hepatitis B core antibody (anti-HepBc Ab), and 
HepC Ab testing (screening only).

CRP.

ESR.

Cholesterol, triglycerides, high density lipoprotein (HDL) and low density 
lipoprotein (LDL) (baseline only).

Autoimmune serology: RF and ACPA (i.e., anti- cyclic citrullinated peptide 
[CCP] antibodies) (baseline only).

QuantiFERON Gold or T-spot test for TB (If unavailable/unapproved, then 
tuberculin skin test is permitted) (screening only).

Exploratory GM-CSF and pharmacodynamic (PD) blood biomarkers and lung 
biomarkers and anti-GM-CSF auto-antibodies (baseline only).

PK samples and immunogenicity (baseline only).

RNA (baseline only).

Pharmacogenomic DNA (in consenting subjects) (baseline only).

Urine sample for:

Routine urinalysis (screening only).

Urine βhCG pregnancy test (baseline only).

Disease activity assessments (see Section 7.5)

Tender joint count (68 joints).

Swollen joint count (66 joints).

Patient's Assessment of Arthritis Pain.

Patient's Global Assessment of Arthritis (PtGA).

Physician's Global Assessment of Arthritis (PhGA).

Health Assessment Questionnaire Disability Index (HAQ-DI).

MRI (screening only).

Patient-reported outcome (PRO) questionnaires (see Section 7.11)

RA Symptom and Impact Diary.
Patient-reported outcomes questionnaires should be completed by subjects before any 
other assessment at a clinic visit, in the order specified in the SRM.


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7.3.
Efficacy
7.3.1.
Exploratory 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 analyzed pre- and post-GSK3196165.  In addition blood 
samples will be collected and may be analyzed for markers which may be predictive of 
lung damage.  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.
7.3.2.
Biomarkers
Pharmacodynamic biomarkers may include, but not limited to, the following:

Target engagement (TE): analysis of free soluble GM-CSF and soluble GM-CSF 
complexed to GSK3196165.

Effects of GSK3196165 on target cell populations: may include, but not limited to, 
circulating levels of T, B, NK, Th17, T regulatory cells and activated monocytes, 
dendritic cells, neutrophils.

Biomarkers which may be indicative of RA disease activity: may include, but not 
limited to 14-3-3η, ACPA, CRP, and RF.

Soluble biomarkers which may be predictive of response to GSK3196165 such as 
C1M, C2M, C3M, CRPM, VICM, MRP8/14, MMP-3, and 14-3-3η.

Pharmacodynamic biomarkers to assess response to GSK3196165 such as IL-1β, 
TNFα, IL-6, IL-8, IL15, IL-23 and IL-17A/F, and chemokines such as CCL17, 
CXCL4, CXCL7, CXCL13, CCL22; and complement proteins such as C5a, ratio 
C3/C3dg, TCC, C4, C4a, sCD163.

Biomarkers of extracellular matrix (ECM) or aggrecan degradation (e.g. may 
include, but not limited to, YKL 40, ARGS neoepitope).
Additional exploratory biomarkers in the blood/serum (RNA, DNA, protein) may include 
but will not be limited to the following:

Whole blood RNA markers of GM-CSF/macrophage signaling and response to 
GSK3196165.

Whole blood DNA analysis to explore the relationship between genetic variants in 
the host and response to GSK3196165.
Safety biomarkers which may be predictive of lung damage including, but not limited to, 
the following:


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
Analysis of KL 6, SAA, SP-D, cholestenoic acid, and measurement of GM-CSF 
autoantibodies at baseline.

These will be analyzed at the end of the study or in the event of a pulmonary safety 
signal which would require further investigation.
7.3.3.
Target Engagement (TE)
If data permits, a PK/TE modeling analysis will be conducted.  This modeling work will 
be detailed in the reporting and analysis plan (RAP).
The rationale for the selection of timepoints is:

Baseline: to measure PK and target engagement (± potential biomarkers status) at 
baseline.

Week 1 and Week 2: to characterize the increase in PK and target engagement (± 
activation of potential biomarkers) due to the loading phase.

Week 4: to measure target engagement (± biomarkers) at the maximum plasma 
concentration.

Week 6 and Week 8: to measure if a maintenance regimen administered every two 
weeks can maintain sufficient target engagement (± activation of potential 
biomarkers) at steady state.

Week 12 and Week 22: to assess the decline in PK and target engagement after the 
last dose.
7.4.
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 AEs.
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.
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 


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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 analysis of blood samples.
Measurement of the levels of a subset of RNA species on blood samples.
7.5.
Clinical Efficacy
7.5.1.
Magnetic Resonance Imaging
The most affected hand will be documented at screening and used for all imaging visits. 
If subjects report both hands are equally involved, then the subject’s dominant hand will 
be used.  Each subject’s most affected hand/wrist will be imaged by MRI at Screening, 
Week 4, Week 12 and Week 22 (see Section 7.1, Time and Events Schedule).  The 
scanning protocol will include routine localizers, T1 measurement sequences, dynamic 
DCE-MRI acquisition, and acquisitions required for OMERACT RAMRIS and RAMRIQ 
scoring.
The following will be assessed:

Change from baseline in synovitis, osteitis and erosion as assessed OMERACT 
RAMRIS and RAMRIQ in the hand/wrist.

Change from baseline in joint inflammation as measured by DCE-MRI in the 
hand/wrist:

Ktrans
.

Ve.

Vp.

IRE.

ME.
7.5.2.
Clinical assessments
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, visual analogue scale 
(VAS) (global disease) for the subject and treating physician, HAQ-DI – physical 


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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 7.11 and laboratory assessments
(CRP).  Based on these assessments ACR (20, 50 and 70), DAS28(CRP) and the EULAR 
response will be calculated.
RA symptoms will be assessed through the subject completion of an RA Symptom and 
Impact Diary (see Section 7.11.2).
7.5.3.
Joint Assessments
The procedure for joint assessments can be found in the SRM.
7.5.3.1.
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.
7.5.3.2.
Independent Joint Evaluator
One or more independent assessors, who have documented experience in performing 
joint assessments, will be designated at each study site to perform joint assessments.  
Preferably the same independent assessor will perform all joint assessment for the same 
subject throughout the study.  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 study.
The independent joint assessor should have no other contact with the subject during the 
study, 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.
7.5.4.
Patient’s Assessment of Arthritis Pain
Subjects will assess the severity of their current arthritis pain using a 100 unit 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.
7.5.5.
Patient’s Global Assessment of Arthritis
Subjects will complete a global assessment of disease activity using the PtGA item, a 
VAS with anchors “0” (very well) to “100” (very poor).
Further details of this assessment are provided in the SRM.


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7.5.6.
Physician’s Global Assessment of Arthritis
Physicians will complete a global assessment of disease activity using the PhGA, a VAS 
with anchors “0” (none) to “100” (extremely active), respectively.
Further details of this assessment are provided in the SRM.
7.5.7.
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 time point.
The components of the DAS28 arthritis assessment include:

Tender/Painful Joint Count (28).

Swollen Joint Count (28).

CRP or ESR.

PtGA.
7.5.8.
ACR Assessments
The ACR’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 time point.
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.

PtGA.

PhGA.

CRP or ESR.

HAQ-DI.
7.6.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).


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7.6.1.
Screening Visits

Chest X-ray (posterior to anterior [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.

Baseline chest HRCT for subjects with DLCO values ≥60% - <70%, and it is 
recommended that the subject will be reviewed by a local pulmonologist to exclude 
significant pre-existing respiratory disease.

Immunogenicity testing.
7.6.2.
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 AEs, 
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.
7.6.3.
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, lactate dehydrogenase [LDH], cholestenoic 
acid).

ECG measurements.

Vital signs.

Hematological and clinical chemistry parameters.

Physical examinations.

Pregnancy test (for women of child-bearing potential).


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7.6.4.
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.
7.6.4.1.
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 study medication), at the time points 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.
7.6.4.2.
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


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7.6.4.3.
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 4.6.1) 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.
7.6.4.4.
Cardiovascular and Death Events
For any cardiovascular (CV) events detailed in Appendix 12.4 and all deaths, whether or 
not they are considered SAEs, specific CV and Death sections of the eCRF will be 
required to be completed.  These sections include questions regarding CV (including 
sudden cardiac death) and non-cardiovascular death.
The CV eCRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms.  The CV information should be 
recorded in the specific CV section of the CRF within 1 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 1 week 
of when the death is reported.
Investigators will be required to fill out event specific data collection tools for CV AEs 
and SAEs detailed in Section 12.4.4, Appendix 12.4.  This information should be 
recorded in the specific cardiovascular eCRF within 1 week of when the AE/SAE(s) are 
first reported.
7.6.5.
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 judgment 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.
7.6.6.
Adverse Events of Special Interest
Please see Section 4.6.1 for a discussion of potential risks with GSK3196165.  AEs of 
special interest include:

Serious infections, including serious respiratory infections and TB.

Opportunistic infections.


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
Neutropenia (grade 3 or 4).

Respiratory events including:
Persistent (for 3 consecutive weeks) reduction in DLCO >15%
Persistent (for 3 consecutive weeks) cough and/or dyspnea
Non-life-threatening pulmonary changes related to surfactant accumulation.

PAP.

Hypersensitivity reactions, including anaphylaxis.

Injection site reactions.

Persistent cough or dyspnea.
7.6.6.1.
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 requires 
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.
7.6.6.2.
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_01and will notify the IRB/IEC, if 
appropriate according to local requirements.
7.6.7.
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.
7.6.8.
Physical Exams

A complete physical examination at screening will include, at a minimum, 
assessment of the CV, Respiratory, Gastrointestinal and Neurological systems.  
Height and weight will also be measured and recorded.

A brief physical examination at subsequent visits will include, at a minimum 
assessments of the skin, lungs, CV system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
7.6.9.
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.
7.6.10.
Electrocardiogram
See Section 5.2 regarding QTc exclusion criteria.
Single 12-lead ECGs will be obtained (before dosing, vital signs measurements and blood 
samples taken) at the time points after Day 1 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.  The ECG may be repeated in 
triplicate if the recorded QTcF value is out of range.  The QTc should then be based on 
averaged QTc values of the triplicate ECGs obtained over a brief recording period (e.g., 
5-10 minutes).  Refer to Section 5.4.2 for QTc withdrawal criteria and additional QTc 
readings that may be necessary.


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7.6.11.
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/center 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 any locally performed 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
Protocol Required Safety 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
Sodium
Potassium
Calcium
Phosphate
Urea
Creatinine
Creatinine clearance 
(calculated)
AST
ALT
γ-glutamyl transpeptidase 
Urine dipstick
Glucose
Protein
Microscopy of 
urine sediment for 
erythrocytes, 
leukocytes and 
casts if urine 
dipstick abnormal


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Hematology
Biochemistry
Urinalysis 
eosinophils
basophils
monocytes
lymphocytes
Platelets
Activated partial thromboplastin time (aPTT)
Prothrombin Time (PT)
International Normalized Ratio (INR)
Fibrinogen
ESR*
(GGT)
LDH
Alkaline phosphatase (AP)
Bilirubin (total)
Creatine Phosphokinase 
(CPK)
Total protein
Albumin
Albumin/globulin ratio
Serum Glucose
CRP
Cholesterol**
Triglycerides**
HDL**
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 7.3.2).  Baseline measurement of GM-CSF autoantibodies will be measured.
7.6.12.
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.

PFTs – spirometry (FEV1, FVC), gas transfer (DLCO).
PFTs should be performed according to 2005 ATS/ERS recommendations for lung 
function testing [MacIntyre, 2005; Miller, 2005a; Miller, 2005b].  Spirometry should be 


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performed prior to DLCO testing.  The standards for acceptable testing sessions are 
described further in the Pulmonary Safety Guidance document in the SRM.
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 treatment 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 SRT may request copies 
of any reports or images for central review.
7.7.
Pharmacokinetics
Details of PK blood sample collection, processing, storage and shipping procedures are 
provided in the central laboratory manual.
7.7.1.
Blood Sample Collection
Blood samples for PK analysis of GSK3196165 will be collected at the time points 
indicated in Section 7.1, Time and Events Table.  The actual date and time of each blood 
sample collection 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.
7.7.2.
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).
7.8.
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].


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Serum samples will be collected and tested for presence of antibodies that bind to 
GSK3196165 anti-drug antibodies (ADAs).  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.
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 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.
7.9.
Magnetic Resonance Imaging
Each subject’s most affected wrist (corresponding to the affected hand which is 
determined and documented at screening) will be imaged by MRI at Screening, Week 4, 
Week 12 and Week 22 (see Section 7.1).  If a scanning failure occurs at any visit, if 
feasible a rescan is allowed within 7 days after the failed scan after consultation and 
agreement with the Medical Monitor.  There will be a minimum of 24 hours between 
scans where gadolinium (Gd) contrast is used.  The MRI will be used in order to 
non-invasively quantify the degree of inflammation and structural changes within the 
target joint.
Each MRI total scan time should not exceed 1 hour.  For each subject, MRIs must be 
performed on the same scanner and using the same type of chelated Gd contrast agent as 
was used at screening.  If scanning cannot occur on the same scanner within the visit time 
window due to hardware failure, an alternate scanner may be used or the time window 
may be extended by 3 days only after consultation and agreement with the Medical 
Monitor.


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On attendance at the MRI department, subjects will be placed in the scanner and will be 
prepared for intravenous contrast agent administration.  The scanning protocol will 
include routine localizers, T1 measurement sequences,  DCE-MRI acquisition, and 
acquisitions required for OMERACT RAMRIS and RAMRIQ scoring.  Additional 
exploratory MRI endpoints, as detailed in the Imaging Acquisition Manual, may also be 
acquired for exploratory purposes.
Details of scanning site training procedures, acceptable Gd contrast agents, and scanning 
protocols will be provided in a dedicated Imaging Acquisition Manual.
All MRI scans will be available at site, and may be reported at the site by a radiologist 
(non-anonymized) for clinical abnormalities per local standard procedures.
7.10.
Genetics
Information regarding genetic research is included in Appendix 12.6.
7.11.
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.
7.11.1.
Health Assessment Questionnaire – Disability Index (HAQ-DI)
The functional status of the subject will be assessed by means of the 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.
7.11.2.
Rheumatoid Arthritis Symptoms and Impact Diary PRO
Symptoms associated with RA will be assessed using a novel RA Symptom and Impact 
Diary, as per the Time and Events Schedule (Section 7.1).
8.
DATA MANAGEMENT
For this study, subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data.
Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.


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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.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
No formal hypotheses are to be tested.  Differences between the treatment groups for the 
MRI synovitis data will be assessed by deriving the 95% credible interval.  The analysis 
will be performed in a Bayesian framework, making use of historical data on the placebo 
arm where appropriate.  The posterior distribution of the treatment difference will be 
computed, conditional on the observed data and the assumed prior distribution and the 
95% credible interval will be derived from the posterior distribution.
For all other endpoints, differences between the treatment groups will be assessed using 
95% confidence intervals (CIs).  Historical data may be used where available.
9.2.
Sample Size Considerations
The sample size for this study is based on feasibility.
9.2.1.
Sample Size Assumptions
For the MRI synovitis data, based on a review of results in the literature, the standard 
deviation (SD) for both treatment groups is assumed to have a value of 2.5.  Based on this 
value, assuming prior information cannot be used, with 30 subjects on GSK3196165 
180 mg and 10 subjects on placebo, aiming for 50% early and 50% established RA 
subjects, it is estimated that the lower and upper bounds of the 95% CI for the difference 
would be within 1.8 points of the difference.  This is considered the worst case precision 
and further estimates assuming different weights for the prior distribution on placebo will 
be assessed to estimate any improvement in the precision of the CI.
9.2.2.
Sample Size Sensitivity
Not applicable.
9.2.3.
Sample Size Re-estimation or Adjustment
Not applicable.


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9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
The primary population will be the Intent-to-Treat (ITT) population, defined as all 
subjects who were randomized to treatment and who received at least one dose of study 
treatment.
9.3.2.
Final Analysis
The final analysis will be conducted when all subjects have completed their last follow up 
visit.
9.3.3.
Interim Analysis
No interim analysis is planned for this study.
9.4.
Key Elements of Analysis Plan
Full details of all analyses will be provided in the analysis plan.
For the MRI data, the primary analysis will be a repeated measures Bayesian model for 
the difference between treatments over each visit.  The full details of this approach will 
be provided in the analysis plan.
The data will be analyzed across all subjects, and may also be presented for each disease 
duration subgroup (stratification factor).
For other continuous endpoints Bayesian and frequentist methods will be used as 
appropriate.
In addition, the relationship between the mechanistic / biomarker endpoints and clinical 
effects (e.g., ACR20 Response) will be graphically presented and analyzed using an 
appropriate statistical model identifying any trends.  The model will determine whether 
the mechanistic / biomarker effect significantly explains or predicts the effect on the 
clinical endpoints.  This may be conducted through comparing statistical models; 
incorporating different explanatory terms (i.e., mechanistic / biomarker endpoints) with 
the ‘null’ model (no mechanistic / biomarker endpoints); or, if deemed appropriate, 
multivariate statistical methods may also be applied to determine the relationship 
between the key endpoints.  The consistency in the changes over time between the 
endpoints will also be assessed.
Full details of all summaries and analyses will be given in the RAP.


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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 or designee will obtain favorable opinion/approval from 
the appropriate regulatory agency to conduct the study in accordance with International 
Conference on Harmonization (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 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:
IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable.
Obtaining signed informed consent.
Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC).
GSK or designee will provide full details of the above procedures, either verbally, 
in writing, or both.
Signed informed consent must be obtained for each subject prior to participation in 
the study.
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 


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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, 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.


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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.
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.


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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.


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11.
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MacIntyre N, Crapo RO, Viegi G, et al. Standardisation of the single-breath 
determination of carbon monoxide uptake in the lung. Eur Respir J 2005;26:720-35.
Mantovani A, Sica A, Locati M. New vistas on macrophage differentiation and 
activation. Eur J Immunol 2007;37:14-6.
Mantovani A, Sozzani S, Locati M, et al. Macrophage polarization: tumor-associated 
macrophages as a paradigm for polarized M2mononuclear phagocytes. Trends in 
Immunology 2002;23:549-55.
Michelson J, Easley M, Wigley FM, Hellmann D. Foot and ankle problems in rheumatoid 
arthritis. Foot Ankle Int 1994;15:608-13.
Miller MR, Crapo R, Hankinson J, et al. General considerations for lung function testing. 
Eur Respir J 2005a;26:153-61.
Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 
2005b;26:319-38.


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Mulherin D, Fitzgerald O, Bresnihan B. Synovial tissue macrophage populations and 
articular damage in rheumatoid arthritis. Arthritis Rheum 1996;39:115-24.
Nakano K, Okada Y, Saito K. Rheumatoid synovial endothelial cells produce 
macrophage colony-stimulating factor leading to osteoclastogenesis in rheumatoid 
arthritis. Rheumatology (Oxford) 2007;46:597-603.
Nam JL, Ramiro S, Gaujoux-Viala C, et al. Efficacy of biological disease-modifying 
antirheumatic drugs: a systematic literature review informing the 2013 update of the 
EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis 
2014;73:516-28.
Østergaard M, Peterfy C, Conaghan P, et al. OMERACT Rheumatoid Arthritis Magnetic 
Resonance Imaging Studies. Core set of MRI acquisitions, joint pathology definitions, 
and the OMERACT RA-MRI scoring system. J Rheumatol 2003;30:1385-6.
Piccoli L, Campo I, Fregni CS, et al. Neutralization and clearance of GM-CSF by 
autoantibodies in pulmonary alveolar proteinosis. Nat Commun 2015;6:7375.
Plater-Zyberk C, Joosten LA, Helsen MM, et al. GM-CSF neutralisation suppresses 
inflammation and protects cartilage in acute streptococcal cell wall arthritis of mice. Ann 
Rheum Dis. 2007;66:452-7.
Stanley E, Lieschke GJ, Grail D, et al. Granulocyte/macrophage colony-stimulating 
factor-deficient mice show no major perturbation of hematopoiesis but develop a 
characteristic pulmonary pathology. Proc Natl Acad Sci USA 1994;91:5592-6.
Steidl S, Ratsch O, Brocks B, et al. In vitro affinity maturation of human GM-CSF 
antibodies by targeted CDR-diversification. Mol Immunol 2008;46:135-44.
Tak PP, Smeets TJ, Daha MR, et al. Analysis of the synovial cell infiltrate in early 
rheumatoid synovial tissue in relation to local disease activity. Arthritis Rheum 
1997;40:217-25.
Uchida K, Nakata K, Carey B, et al. Standardized serum GM-CSF autoantibody testing 
for the routine clinical diagnosis of autoimmune pulmonary alveolar proteinosis. J 
Immunol Methods 2014;402:57-70.
Uchida K, Nakata K, Suzuki T, et al. Granulocyte/macrophage-colony-stimulating factor 
autoantibodies and myeloid cell immune functions in healthy subjects. Blood
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Zhou H, Mascelli MA. Mechanisms of monoclonal antibody-drug interactions. Annual 
Rev Pharmacol Toxicol 2011;51:359-72.


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12.
APPENDICES
12.1.
Appendix 12.1 – Abbreviations and Trademarks
Abbreviations
µg
micrograms
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
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine transaminase
AMD
Age-related macular degeneration
AP
Alkaline phosphatase
aPTT
Activated partial thromboplastin time
AST
Aspartate transaminase
ATS
American Thoracic Society
AUC
Area under the plasma concentration time curve
AUC(0-168)
Area under drug concentration time curve from time zero to 168 hours 
postdose
AUC(0-336)
Area under drug concentration time curve from time zero to 336 hours 
postdose
βhCG
Beta-subunit human chorionic gonadotropin
BCG
Bacillus Calmette-Guérin
C1M
MMP-2,9,13-degraded type I collagen
C2M
MMP-degraded type II collagen
C3
Complement component 3
C3dg
Complement component 3dg
C3M
MMP-9-degraded type III collagen
C4
Complement component 4
C4a
Complement component 4a
C5a
Complement component 5a
CCL17
Chemokine (C-C Motif) Ligand 17
CCL22
Chemokine (C-C Motif) Ligand 22
CCP
Cyclic citrullinated peptide
CD4
Cluster of differentiation antigen 4
CD19/20
Cluster of differentiation antigen 19/20
CD68
Cluster of differentiation antigen 68
CI
Confidence interval
CIA
Collagen-induced arthritis
ClIV/ClSC
Intravenous plasma clearance/subcutaneous plasma clearance
COPD
Chronic obstructive pulmonary disease
Cox
Cyclo-oxygenase


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CPK
Creatine phosphokinase
CRO
Contract Research Organization
CRF
Case report form
CRP
C-reactive protein
CRPM
MMP-degraded CRP
CTC
Common terminology criteria
CTCAE
Common terminology criteria for adverse events
CV
Cardiovascular
CXCL4
Chemokine (C-X-C Motif) Ligand 4
CXCL7
Chemokine (C-X-C Motif) Ligand 7
CXCL13
Chemokine (C-X-C Motif) Ligand 13
CYP450
Cytochrome P450
DAS
Disease activity score
DAS28
Disease activity score for 28 different joints
DAS28(CRP)
Disease activity score for 28 different joints with CRP value
DCE-MRI
Dynamic contrast enhanced magnetic resonance imaging
dL
Deciliter
DLCO
Diffusing capacity of the lung for carbon monoxide
DMARD
Disease modifying antirheumatic drugs
DNA
Deoxyribonucleic acid
DRC
Data Review Committee
DRE
Disease-related event
ECG
Electrocardiogram
ECM
Extracellular matrix
eCRF
Electronic case report form
EOW
Every other week
ePRO
Electronic patient reported outcome
ERS
European Respiratory Society
ESR
Erythrocyte sedimentation rate
EULAR
European League Against Rheumatism
EW
Early withdrawal
FACS
Fluorescence-activated cell sorter
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in one second
FRP
Females of reproductive potential
FSH
Follicle-stimulating hormone
FU
Follow-up
FVC
Forced vital capacity
GCP
Good Clinical Practice
Gd
Gadolinium
GFR
Glomerular filtration rate
GGT
Gamma-glutamyl transpeptidase
GM-CSF
Granulocyte-macrophage colony-stimulating factor
GSK
GlaxoSmithKline
h
Hour
HAQ-DI
Health Assessment Questionnaire Disability Index


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HBc
Hepatitis B core
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HepB cAb
Anti-hepatitis B core antibody
HepC Ab
Hepatitis C virus antibody
HC gp
Human cartilage glycoprotein
HCV
Hepatitis C virus
HDL
High-density lipoprotein
HIV
Human immunodeficiency virus
HRCT
High-resolution computed tomography
HRT
Hormone replacement therapy
IA
Intra-articular
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M 
IL
Interleukin
IL-1
Interleukin 1
IL-1β
Interleukin 1 beta
IL-6
Interleukin 6
IL-8
Interleukin 8
IL-12p70
Interleukin 12p70
IL-15
Interleukin 15
IL-17A/F
Interleukin 17A/F
IL-23
Interleukin 23
IM
Intramuscular
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board
IRE
Initial rate of enhancement
IRTS
Interactive response technology system
ITT
Intent-to-Treat
IV
Intravenous
IVIG
Intravenous immunoglobulin
Kg
Kilogram
KL-6
Krebs von den Lungen-6
Ktrans
Exchange rate
L
Litre
LDH
Lactate dehydrogenase
LDL
Low-density lipoprotein
mAb
Monoclonal antibody
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean cell volume
ME
Maximal signal intensity enhancement


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MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MHC
Major histocompatibility complex
mL
Milliliter
Mmol
millimole
MMP-3
Matrix metalloproteinase 3
MR
Magnetic resonance
MRI
Magnetic resonance imaging
MRP
Myeloid-related protein
msec
millisecond
MTX
Methotrexate
MTX-IR
Methotrexate-inadequate response
N
Number of subjects
NB
Nota bene
NK
Natural killer
NOAEL
No observed adverse effect level
NOEL
No observed effect level
NSAID
Non-steroidal anti-inflammatory drug
NSF
Nephrogenic systemic fibrosis
OMERACT
Outcome Measures in Rheumatology
PA
Posterior to anterior
PAP
Pulmonary alveolar proteinosis
PCR
Polymerase chain reaction
PD
Pharmacodynamic
PFT
Pulmonary function test
PGx
Pharmacogenomic
PtGA
Patient’s Global Assessment of Arthritis
PhGA
Physician’s Global Assessment of Arthritis
PK
Pharmacokinetic(s)
PRO
Patient reported outcome
PT
Prothrombin Time
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate according to Fridericia’s formula
QW
Once a week
RA
Rheumatoid arthritis
RAMRIQ
Rheumatoid arthritis MRI quantitative score
RAMRIS
Rheumatoid arthritis MRI scoring system
RAP
Reporting and Analysis Plan
RF
Rheumatoid factor
RNA
Ribonucleic acid
SAA
Serum amyloid A
SAE
Serious adverse event
SC
Subcutaneous
sCD163
Soluble cluster of differentiation 163 (scavenger receptor for 
hemoglobin-haptoglobin complex)
SD
Standard deviation


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SP-D
Surfactant protein D
SRM
Study Reference Manual
SRT
Safety Review Team
TB
Mycobacterium tuberculosis
TCC
Terminal complement complex
TE
Target engagement
TEAE
Treatment emergent adverse event
Th17
T helper 17 cell
TNF
Tumor necrosis factor
TNFα
Tumor necrosis factor alpha
TST
Tuberculin skin test
ULN
Upper limit of normal
VAS
Visual analogue scale
Ve
Interstitial volume
VICM
Matrix metalloproteinase-degraded fragment of vimentin
Vp
Plasma volume
WBC
White blood count
w/v
Weight/volume
YKL-40
Serum chondrex
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
MedDRA


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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 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 in the Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) 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.
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.

Intrauterine device or intrauterine system.

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011


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
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

Oral Contraceptive, either combined or progestogen alone [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

Viral hepatitis serology4

Blood sample for PK analysis, obtained 
less than 12 weeks after last dose5

Serum CPK and 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 


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MONITORING:
For bilirubin or INR criteria:

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
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct high 
performance liquid chromatography 
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 computerized 
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, stabilize 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 judgment 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 


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in the investigator’s opinion they are of greater intensity, frequency or duration than 
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.


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
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
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.


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
Acute renal failure.

Seizure.

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.


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
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 
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 


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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 
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 Contract 
Research Organization (CRO).

Site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data.


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
If a site receives a report of a new SAE from a study 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 PK 
(absorption, distribution, metabolism, and elimination), or PD (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.


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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 
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 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.


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
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.
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 Asp Med 2012; 33: 467-86.


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12.7.
Appendix 12.7: Important Study Assessment Details and 
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, and safety assessments (AEs, 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 electronic patient 
reported outcome (ePRO) device.  The subject will complete the Borg scale on paper and 
study personnel will enter the results into the eCRF.


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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 (applies to all countries)
Section 1. Protocol Synopsis for Study 205180 and Section 3. Objectives and 
Endpoints.
Classified primary and secondary objectives and endpoints.
Rationale
Previous version listed all objectives and endpoints as exploratory.
Section 1. Protocol Synopsis for Study 205180, Section 4.1. Overall Design, Section
5.3 .1. Re Screening, Section 7.1. Time and Events Table, and Section 7.2. Screening 
and Critical Baseline Assessments
Screening window extended to six weeks.
Rationale
To facilitate scheduling of screening MRI scan, which should only be performed after 
other screening assessments have been passed.
Section 4.3. Type and Number of Subjects
Estimated number of screened subjects revised.
Rationale
More conservative estimate based on recent clinical study experience.
Section 4.6.1. Risk Assessment
Deleted “>15% relative decrease in DLCO from screening” as trigger for subject to be 
withdrawn from study drug.
Rationale
Second DLCO test is at Week 12, after dosing of study drug has been completed.
Section 5.1. Inclusion Criteria, Section 5.3.2.2. DLCO test, Section 7.1. Time and 
Events Table, Section 7.2. Screening and Critical Baseline Assessments, and Section 
7.6.12. Pulmonary Assessments
Consolidated details of PFTs into additional guidance in Section 7.6.12.
Rationale
To avoid any misunderstanding of PFTs.


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Section 5.1. Inclusion Criteria
Addition of Day 1 joint count, and clarification that chest HRCT must be performed if 
DLCO ≥60% - <70% predicted.
Rationale
To ensure subjects still have active RA with the extended screening window, and to avoid 
any misunderstanding of requirement for chest HRCT.
Section 5.2. Exclusion Criteria
Addition of history of sensitivity to Gd-containing contrast agents.
Rationale
To maintain safety.
Section 5.3.1.Re-Screening
Re-screening is permitted.
Rationale
Had previously stated that re-screening is required.
Section 7.1. Time and Events Table
Revision that subjects must have passed all screening assessments, including laboratory 
tests, prior to undertaking MRI scanning, and that whole blood flow cytometry is 
scheduled at Baseline (Day 1).
Rationale
It is more appropriate that these tests are done for patients likely to be randomized.
Section 7.1. Time and Events Table and Section 7.2 Screening and Critical Baseline 
Assessments
Clarification that RNA analysis is not part of the pharmacogenetics substudy.
Rationale
RNA transcriptomics/sequencing is not proposed for this study.
Section 7.5.2. Clinical assessments
Removed “daily”.
Rationale


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Error in frequency of assessment.
Section 7.9. Magnetic Resonance Imaging
Re-worded, to indicate that all MRI scans will be available at site, and may be reported 
locally.
Rationale
Local standard procedures for reporting MRI scans may differ.
Appendix 12.1. Abbreviations and Trademarks
Added missing abbreviations.
Rationale
Some abbreviations had not been included.
Appendix 12.2. Contraception Eligibility Criteria for Female and Male Subjects
Removed requirement for two forms of complementary contraception, except when using 
hormonal contraceptives.
Rationale
Due to potential drug interaction with CYP450 substrates, a second form of contraception 
is required for subjects using hormonal contraceptives.  This requirement does not apply 
to subjects that are not using hormonal contraception, hence the contraception guidance 
has been corrected.
Appendix 12.7. Important Study Assessment Details and Study Specific Equipment
Removed “morning stiffness” assessment, and added that the Borg dyspnea scale will be 
completed on paper.
Rationale
Morning stiffness is not being recorded in the study, and an ePRO device not available 
for the Borg scale.

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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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PPD
PPD
PPD
PPD


GlaxoSmithK.line 
GSK Study 205180 (RENAISSANCE) 
Reporting and Analysis Plan 
TABLE OF CONTENTS 
1 
IN1RODUCTION .................................................................................................... 8 
2 
STUDYOBJECTIVES .......................................................................................... 10 
3 
INVESTIGATIONAL PLAN ................................................................................. 12 
3.1 Overall Study Design and Plan ......................................................................... 12 
3 .1.1 Overall Design ....................................................................................... 12 
3 .1.2 Time and Events Table ........................................................................... 13 
3 .1.3 Treatment Arms and Duration ................................................................ 16 
3 .1.4 Study Oversight ...................................................................................... 16 
3.1.5 Type and Number ofSubjects ................................................................. 16 
3.2 Exploratory Biomarkers ................................................................................... 16 
3.3 Efficacy and Safety Variables .......................................................................... 16 
3.3.1 Disease Activity Score (DAS): ............................................................... 16 
3.3.2 ACR Response Rates .............................................................................. 18 
3.3.3 Swollen and Tender/Painful Joint Count ................................................. 19 
3 .3 .4 Patient's Assessment of Arthritis Pain .................................................... 19 
3.3.5 Patient's Global Assessment of Arthritis ................................................. 19 
3.3.6 Physician's Global Assessment of Arthritis ............................................ 20 
3.3.7 SDAI ...................................................................................................... 20 
3.3.8 CDAI ..................................................................................................... 20 
3 .3.9 Index- and Boolean-based ACR/EULAR Remission Rates ..................... 20 
3.3.10 
HAQ-DI ......................................................................................... 21 
3 .3 .11 
Borg Dyspnea Scale ........................................................................ 22 
3.3.12 
RAMR.IS ........................................................................................ 22 
3.3.13 
RAMR.IQ ........................................................................................ 23 
3.3.14 
DCE-MRI ....................................................................................... 24 
4 
STATISTICAL ME1HODS ................................................................................... 25 
4.1 Data Quality Assurance .................................................................................... 25 
4.2 General Presentation Considerations ................................................................ 25 
4.3 Study Subjects ................................................................................................. 26 
4.3.1 Disposition ofSubjects ........................................................................... 26 
4.3.2 Protocol Deviations ................................................................................ 27 
4.4 General Data Handling Conventions ................................................................ 28 
4.4.1 Missing Dates ......................................................................................... 28 
4.4.2 Missing Data for Efficacy and Safety Endpoints ..................................... 29 
4.4.2.1 Missing Data for Efficacy Endpoints ......................................... 29 
4.4.2.2 Missing Data at Baseline for Safety Endpoints ........................... 30 
4.4.3 Multiple Assessments and Early Withdrawal Visits ................................ 30 
4.4.4 Visit Windows for Efficacy Parameters .................................................. 30 
4.4.5 Oral Corticosteroid Conversion .............................................................. 31 
4.5 Analysis Populations ........................................................................................ 31 
4.5.1 Analysis Datasets ................................................................................... 32 
4.6 Demographic and Other Baseline Characteristics ............................................. 33 
4.7 Medication Use ................................................................................................ 34 
4. 7.1 Extent of Exposure ................................................................................. 3 5 
TP-GDO-WW-016-04 
Effective Date: 25 Nov 15 
Related to: SOP-GDO-WW-019 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Doeument Efl'eetive Date: Date oflast signature 
Page4 of70 


GlaxoSmithK.line 
GSK Study 205180 (RENAISSANCE) 
Reporting and Analysis Plan 
4.8 Treatment Compliance ..................................................................................... 35 
4.9 Efficacy Evaluation .......................................................................................... 36 
4.9.1 Analysis and Data Conventions .............................................................. 36 
4.9.1.1 Multi-center Studies .................................................................. 36 
4.9.1.2 Adjustments for Covariates ........................................................ 36 
4.9.1.3 Multiple Comparisons/Multiplicity ............................................ 36 
4.9.1.4 Interim Analyses ....................................................................... 36 
4.9.1.5 Examination ofSubgroups ......................................................... 36 
4.9.2 Primary Efficacy Endpoint- Exploratory Biomarkers ............................ 36 
4.9.3 Secondary Efficacy Endpoints ................................................................ 38 
4.9.3.1 Inflammatory Structural Joint Damage in the Hand!Wrist .......... 38 
4.9.3.2 Exploratory MRI/Imaging Endpoints ......................................... 39 
4.9.3.3 Clinical Efficacy Variables ........................................................ 39 
4.9.4 Overview of Summaries and Analyses ofEfficacy Endpoints ................ .41 
4.10 
Safety Evaluation ................................................................................... 43 
4.10.1 
Adverse Events ............................................................................... 43 
4.1 0.2 
Disease Related Events .................................................................. .45 
4.10.3 
Respiratory Events .......................................................................... 45 
4.1 0.4 
Deaths and Serious Adverse Events ............................................... .45 
4.1 0.5 
Pulmonary assessments ................................................................... 46 
4.10.6 
Cardiovascular Events .................................................................... 46 
4.10.7 
Liver Events ................................................................................... 46 
4.10.8 
Clinical Laboratory Evaluation ...................................................... .47 
4.1 0.9 
Vital Signs, Physical Findings and Other Observations Related to 
Safety ..................................................................................................... 48 
4.10.10 
Safety Monitoring ........................................................................... 49 
4.10.10.1 Medical Monitoring .............................................................. 49 
4.10.11 
lmmunogenicity .............................................................................. 49 
4.11 
Patient Reported Outcome (PRO) Measures ........................................... 50 
4.12 
Other Analyses .................................................................... , .................. 50 
4.12.1 
Pharm.acokinetic Analysis ............................................................... 50 
4.12.2 
Pharm.acokinetic/Pharmacodynamic (PKIPD) Exploratory analysis.50 
4.12.3 
Genetic Research ........................................................................... ,50 
4.13 
Determination of Sample Size ................................................................ 50 
4.14 
Changes in the Conduct of the Study or Planned Analysis ...................... 51 
5 
REFERENCES ....................................................................................................... 51 
6 
Appendix ................................................................................................................ 53 
6.1 Appendix A: Biomarker Details ....................... , ............................................... 53 
6.2 Appendix B: Laboratory Parameters oflnterest ................................................ 57 
6.3 Appendix C: Bayesian Repeated Measures Model.. .......................................... 59 
6.3.1 Proc Mixed ............................................................................................. 59 
6.3.2 General Considerations for Bayesian Analyses (PROC MCMC) ............. 60 
6.4 Appendix D: Opportunistic Infections: MedDRA Preferred Terms ................... 63 
6.5 Appendix E: Scoring ofRAMRIS Features ...................................................... 68 
6.6 Appendix F: RAP Updates ............................................................................... 70 
TP-GDO-WW-016-04 
Effective Date: 25 Nov 15 
Related to: SOP-GDO-WW-019 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Doeument Efl'eetive Date: Date oflast signature 
Page 5 of70 


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Document ID: 393172927 - Name at Publication: 227221 RAP 20171116 2.0
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