Conditions: Arthritis, Rheumatoid
Keywords: GSK3196165 Active Rheumatoid Arthritis Methotrexate Monoclonal Antibody Efficacy Electrocardiogram Tolerability Pharmacokinetics Japanese Subjects
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 15
Healthy volunteers: no

Brief summary:
This is a randomized, double-blind, parallel group, 3 dosage level, placebo-controlled, Phase 1/2 study designed to evaluate the pharmacokinetics, safety, tolerability, and efficacy of the monoclonal antibody GSK3196165, in Japanese subjects with active moderate-severe rheumatoid arthritis (RA) despite treatment with methotrexate(MTX). The subjects will receive GSK3196165 in combination with methotrexate therapy for the 12 weeks of treatment period. Approximately 55 subjects will be screened to achieve 40 randomized subjects, so as to have approximately 10 subjects in each treatment group.

Detailed description:

Arms:
arm 1: Participants will receive GSK3196165 Dose 1 weekly as a single subcutaneous (SC) injection by an un-blinded administrator. There will be 5 weekly injections (Days 1, 8, 15, 22 and 29), then every other week (EOW) injections at Days 43, 57 and 71 (Weeks 6, 8 and 10 respectively). Participants will also receive a stable dose of methotrexate during the Treatment Period. arm 2: Participants will receive GSK3196165 Dose 2 weekly as a single SC injection by an un-blinded administrator. There will be 5 weekly injections (Days 1, 8, 15, 22 and 29), then EOW injections at Days 43, 57 and 71 (Weeks 6, 8 and 10 respectively). Participants will also receive a stable dose of methotrexate during the Treatment Period. arm 3: Participants will receive GSK3196165 Dose 3 weekly as a single SC injection by an un-blinded administrator. There will be 5 weekly injections (Days 1, 8, 15, 22 and 29), then EOW injections at Days 43, 57 and 71 (Weeks 6, 8 and 10 respectively). Participants will also receive a stable dose of methotrexate during the Treatment Period. arm 4: Participants will receive placebo weekly as a single SC injection by an un-blinded administrator. There will be 5 weekly injections (Days 1, 8, 15, 22 and 29), then EOW injections at Days 43, 57 and 71 (Weeks 6, 8 and 10 respectively). Participants will also receive a stable dose of methotrexate during the Treatment Period.

Interventions: intervention 1: GSK3196165 Dose 1 intervention 2: GSK3196165 Dose 2 intervention 3: GSK3196165 Dose 3 intervention 4: Methotrexate intervention 5: Placebo intervention 6: Folic acid
Intervention descriptions: intervention 1: GSK3196165 is supplied as liquid and will be administered as SC injection. intervention 2: GSK3196165 is supplied as liquid and will be administered as SC injection. intervention 3: GSK3196165 is supplied as liquid and will be administered as SC injection. intervention 4: Methotrexate capsule/tablet 8-16 mg per week is given orally. intervention 5: Placebo is supplied as liquid as sterile 0.9% sodium chloride solution and will be administered as SC injection. intervention 6: Folic acid tablet 5 mg per week is given orally.

Protocol document:
Prot_000.pdf: 
2016N278580_02
CONFIDENTIAL
GlaxoSmithKline group of companies
201789
1
TITLE PAGE
Division:  Worldwide Development
Information Type: Protocol Amendment
Title:
A Phase 1/2, Double-Blind, Placebo-Controlled Study of the 
Pharmacokinetics, Safety and Tolerability of GSK3196165 in 
Combination with Methotrexate Therapy, in Japanese Subjects 
with Active Moderate-Severe Rheumatoid Arthritis Despite 
Treatment with Methotrexate.
Compound Number:
GSK3196165
Development Phase
I/II
Effective Date:
19-MAY-2017
Protocol Amendment Number: 02
Author(s):
 
Revision Chronology:
GlaxoSmithKline 
Document Number
Date
Version
2016N278580_00
17-AUG-2016
Original
2016N278580_01
26-SEP-2016
Amendment Number 01
Revision contents:
This amendment addresses PMDA modifications requested during the clinical trial 
notification process. It includes an additional Inclusion Criterion for FVC in Section 5.1; 
additional Exclusion Criterion and Stopping Criterion for HBV-DNA for subjects with 
positive anti-HBs antibody in Section 5.2 and Section 5.4; addition of a preventive dose 
of co-trimoxazole in Section 4.6.1 and Section 6.10.2.2; addition of HBV-DNA test at 
Screening and addition of footnote for clarification in Section 7.1; addition of “past 
week’s pain” in Section 12.6.2.1; correction of analysis populations in Section 9.3.1; and 
deletion of unapproved contraception methods in Japan in Section 12.2.
2016N278580_02
19-MAY-2017
Amendment Number 02
Revision contents:
Change of Inclusion Criterion for CRP in Section 5.1.
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


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SPONSOR SIGNATORY:
Kihito Takahashi
Vice President, Head of Development and Medical 
Affairs Division, GlaxoSmithKline K.K.
Date


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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time 
Phone 
Number
Fax Number
Site Address
Primary Medical 
Monitor 
M.D., Ph.D
4-6-15, 
Sendagaya, 
Shibuya-ku, 
Tokyo, Japan
SAE contact  
information 
Clinical Operation 
Department
Person in charge of 
GSK3196165
4-6-15, 
Sendagaya, 
Shibuya-ku, 
Tokyo, Japan
PV Information 
Management Service 
department
4-6-15, 
Sendagaya, 
Shibuya-ku, 
Tokyo, Japan
Sponsor Legal Registered Address:
GlaxoSmithKline. K.K.
GSK Building, 6-15, Sendagaya 4-chome, Tokyo, 151-8566, Japan
Taro Kunitomi, Head of Immuno-Inflammation/Dermatology TA Office (Medicines 
Development)
Regulatory Agency Identifying Number(s): None
PPD
PPD


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INVESTIGATOR PROTOCOL AGREEMENT PAGE

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 201789........................................................9
2.
INTRODUCTION....................................................................................................11
2.1.
Study Rationale ..........................................................................................11
2.2.
Brief Background ........................................................................................11
2.2.1.
Rheumatoid Arthritis ....................................................................11
2.2.2.
GM-CSF and RA..........................................................................11
2.2.3.
GSK3196165...............................................................................12
2.2.4.
Clinical Data ................................................................................12
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................13
4.
STUDY DESIGN ....................................................................................................14
4.1.
Overall Design ............................................................................................14
4.2.
Treatment Arms and Duration.....................................................................14
4.3.
Type and Number of Subjects.....................................................................15
4.4.
Design Justification.....................................................................................15
4.5.
Dose Justification........................................................................................16
4.6.
Benefit:Risk Assessment ............................................................................18
4.6.1.
Risk Assessment .........................................................................19
4.6.2.
Benefit Assessment.....................................................................25
4.6.3.
Overall Benefit:Risk Conclusion...................................................25
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............25
5.1.
Inclusion Criteria.........................................................................................26
5.2.
Exclusion Criteria........................................................................................27
5.3.
Screening/Baseline Failures .......................................................................31
5.3.1.
Re-Screening...............................................................................31
5.3.2.
Re-Testing...................................................................................31
5.3.2.1.
Laboratory tests..........................................................31
5.3.2.2.
Pulmonary Function Tests..........................................31
5.3.2.3.
ECG test.....................................................................32
5.4.
Withdrawal/Stopping Criteria.......................................................................32
5.4.1.
Liver Chemistry Stopping Criteria ................................................33
5.4.1.1.
Liver Chemistry Stopping and Increased 
Monitoring Algorithm...................................................33
5.4.1.2.
Study Treatment Restart or Rechallenge....................33
5.4.2.
QTc Stopping Criteria ..................................................................33
5.5.
Treatment Interruption ................................................................................34
5.5.1.
Respiratory Symptoms.................................................................34
5.5.2.
Hematologic abnormalities...........................................................34
5.6.
Subject and Study Completion....................................................................35
6.
STUDY TREATMENT ............................................................................................35
6.1.
Investigational Product and Other Study Treatment....................................35
6.2.
Treatment Assignment................................................................................37
6.3.
Planned Dose Adjustments.........................................................................38
6.4.
Blinding.......................................................................................................38
6.5.
Packaging and Labeling..............................................................................39


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6.6.
Preparation/Handling/Storage/Accountability..............................................39
6.7.
Compliance with Study Treatment Administration.......................................39
6.8.
Treatment of Study Treatment Overdose....................................................40
6.8.1.
Overdose of GSK3196165...........................................................40
6.8.2.
Overdose of Methotrexate ...........................................................40
6.9.
Treatment after the End of the Study ..........................................................41
6.10.
Concomitant Medications and Non-Drug Therapies....................................41
6.10.1.
Permitted Medications and Non-Drug Therapies..........................41
6.10.1.1.
Oral Corticosteroids....................................................41
6.10.1.2.
NSAID ........................................................................42
6.10.1.3.
Analgesics..................................................................42
6.10.1.4.
Chinese traditional medicine.......................................42
6.10.2.
Prohibited Medications and Non-Drug Therapies.........................42
6.10.2.1.
Related to the Study...................................................42
6.10.2.2.
Related to Methotrexate .............................................43
6.10.2.3.
Complementary Therapies other than Chinese 
traditional medicine.....................................................43
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................44
7.1.
Time and Events Table...............................................................................45
7.2.
Screening and Critical Baseline Assessments ............................................48
7.3.
Pharmacokinetics .......................................................................................49
7.4.
Safety .........................................................................................................50
7.4.1.
Study visits ..................................................................................50
7.4.2.
Safety endpoints and other assessments.....................................50
7.4.3.
Adverse Events (AEs) and Serious Adverse Events 
(SAEs).........................................................................................51
7.4.3.1.
Time period and Frequency for collecting AE 
and SAE information...................................................51
7.4.3.2.
Method of Detecting AEs and SAEs ...........................51
7.4.3.3.
Follow-up of AEs and SAEs........................................52
7.4.3.4.
Cardiovascular and Death Events ..............................52
7.4.4.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs.........................................................52
7.4.5.
AEs of Special Interest.................................................................52
7.4.5.1.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................53
7.4.5.2.
Regulatory Reporting Requirements for SAEs............53
7.4.6.
Pregnancy ...................................................................................54
7.4.7.
Physical Exams ...........................................................................54
7.4.8.
Vital Signs....................................................................................54
7.4.9.
Electrocardiogram (ECG).............................................................54
7.4.10.
Clinical Safety Laboratory Assessments ......................................55
7.4.11.
Pulmonary Assessments .............................................................56
7.5.
Immunogenicity...........................................................................................57
7.6.
Efficacy.......................................................................................................57
7.6.1.
Joint Assessments.......................................................................58
7.6.1.1.
Excluded from Joint Assessments..............................58
7.6.1.2.
Independent Joint Evaluator.......................................58
7.6.2.
Patient’s Assessment of Arthritis Pain..........................................58
7.6.3.
Patient’s Global Assessment of Arthritis ......................................58
7.6.4.
Physician’s Global Assessment of Arthritis ..................................59


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7.6.5.
DAS Assessments.......................................................................59
7.6.5.1.
Disease activity criteria based on DAS28 score..........59
7.6.5.2.
EULAR response criteria based on DAS28 
score ..........................................................................60
7.6.6.
ACR Assessments.......................................................................60
7.6.7.
SDAI and CDAI............................................................................60
7.7.
Biomarker(s)/Pharmacodynamic Markers ...................................................61
7.8.
Pharmacogenetics......................................................................................61
7.9.
Value Evidence and Outcome.....................................................................62
7.9.1.
HAQ-DI........................................................................................62
7.9.2.
FACIT-Fatigue .............................................................................62
8.
DATA MANAGEMENT ...........................................................................................62
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................62
9.1.
Hypotheses.................................................................................................63
9.2.
Sample Size Assumptions ..........................................................................63
9.3.
Data Analysis Considerations .....................................................................63
9.3.1.
Analysis Populations....................................................................63
9.3.2.
Interim Analysis ...........................................................................64
9.4.
Key Elements of Analysis Plan ...................................................................64
9.4.1.
Primary Analyses.........................................................................64
9.4.2.
Safety Analyses...........................................................................64
9.4.3.
Immunogenicity Analyses ............................................................64
9.4.4.
Efficacy Analyses.........................................................................64
9.4.5.
Biomarker(s)/Pharmacodynamic Marker(s) Analyses ..................65
9.4.5.1.
Pharmacokinetic/Pharmacodynamic Analyses ...........65
10. STUDY GOVERNANCE CONSIDERATIONS........................................................65
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............65
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................65
10.3.
Quality Control (Study Monitoring) ..............................................................66
10.4.
Quality Assurance.......................................................................................66
10.5.
Study and Site Closure ...............................................................................66
10.6.
Records Retention......................................................................................67
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................68
11. REFERENCES.......................................................................................................69
12. APPENDICES........................................................................................................73
12.1.
Appendix 1: Abbreviations and Trademarks................................................73
12.2.
Appendix 2: Contraception eligibility criteria for female and male 
subjects ......................................................................................................76
12.2.1.
Female ........................................................................................76
12.2.2.
Male.............................................................................................77
12.3.
Appendix 3: Liver chemistry stopping criteria and required follow up 
assessments...............................................................................................78
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................81
12.4.1.
Definition of Adverse Events........................................................81


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12.4.2.
Definition of Serious Adverse Events...........................................82
12.4.3.
Recording of AEs and SAEs ........................................................83
12.4.4.
Evaluating AEs and SAEs............................................................84
12.4.5.
Reporting of SAEs to GSK...........................................................86
12.4.6.
Sentinel Events............................................................................86
12.4.7.
Definition of Cardiovascular Events .............................................87
12.5.
Appendix 5: Collection of Pregnancy Information........................................88
12.5.1.
Female ........................................................................................88
12.5.2.
Female partners of male subjects ................................................88
12.6.
Appendix 6: Assessment of Safety, Efficacy, Value Evidence and 
Outcome.....................................................................................................89
12.6.1.
Safety ..........................................................................................89
12.6.1.1.
Borg scale ..................................................................89
12.6.2.
Efficacy........................................................................................90
12.6.2.1.
Patient’s Assessment of Arthritis Pain ........................90
12.6.2.2.
Patient’s Global Assessment of Arthritis .....................91
12.6.2.3.
Physician’s Global Assessment of Arthritis .................91
12.6.3.
Value Evidence and Outcome......................................................92
12.6.3.1.
HAQ-DI.......................................................................92
12.6.3.2.
FACIT-Fatigue............................................................94
12.7.
Appendix 7: Country Specific Requirements...............................................95
12.7.1.
Study Conduct Considerations.....................................................95
12.7.1.1.
Regulatory and Ethical Considerations.......................95
12.7.1.2.
Informed Consent.......................................................95
12.7.2.
Study Period................................................................................95
12.7.3.
Study Administrative Structure.....................................................95
12.7.4.
Pharmacogenetics.......................................................................95
12.8.
Appendix 8: Protocol Changes....................................................................99


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1.
PROTOCOL SYNOPSIS FOR STUDY 201789
Rationale
Study 201789 is a Phase I/II study designed to provide the data necessary to assess the 
pharmacokinetics, safety and tolerability of GSK3196165 for 12 weeks treatment period, 
in combination with methotrexate (MTX) therapy, in Japanese subjects with active 
moderate-severe rheumatoid arthritis (RA) despite treatment with MTX.  In addition, this 
study will assess efficacy of GSK3196165 in Japanese subjects.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To assess the pharmacokinetics of 
GSK3196165 in Japanese RA subjects

Pharmacokinetic parameters of 
GSK3196165 calculated from sparse 
sampling concentrations

To assess the safety and tolerability of 
GSK3196165 in combination with MTX 
therapy in Japanese RA subjects

Incidence of adverse events, serious 
adverse events and adverse events of 
special interest
Secondary

To assess the safety other than primary 
endpoints

Vital signs, 12-lead ECG and laboratory 
assessment

Immunogenicity (anti-GSK3196165 
antibody)

To assess the efficacy in Japanese RA 
subjects

Change from baseline in disease activity 
score for 28 different joints [DAS28(CRP)]
at all assessment timepoints
Overall Design

This is a randomized, double-blind, parallel group, 3 dosage level, placebo-
controlled, Phase 1/2 study with the objective to assess pharmacokinetics (PK), 
safety, tolerability and efficacy of GSK3196165 for 12 weeks, in combination with 
MTX, in Japanese subjects with active moderate-severe RA despite treatment with 
MTX.

Approximately 40 subjects will be randomized into the study (10 subjects in each 
treatment groups).
Treatment Arms and Duration
This study is composed of up to 4 weeks screening period, 12 weeks treatment period 
(last dose Week 10), and 10 weeks follow-up period (12 weeks from last dose).
Subjects will be randomized (1:1:1:1) to placebo or one of three subcutaneous (SC) 
GSK3196165 doses at Day 1 (Week 0).


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Treatment with GSK3196165 or placebo will be given weekly as a single SC injection by 
an unblinded administrator.  There will be 5 weekly injections (Days 1, 8, 15, 22, 29), 
then every other week (EOW) injections at Days 43, 57 and 71 (Week 6, 8, 10, 
respectively).
GSK3196165/placebo must be administered on the same day each week ±1 day for the 
first 5 weekly doses.  Following this GSK3196165 or placebo must be administered on 
the same day EOW ±3 days.
Type and Number of Subjects
Target population of this study is Japanese subjects with active moderate-severe RA who 
previously received oral MTX (at a dose between 8-16 mg/week for at least 12 weeks, 
with a stable and tolerated dose for 4 weeks).
Approximately 55 subjects will be screened to achieve 40 randomized subjects.
Analysis
For serum concentrations of GSK3196165 over time, individual data will be listed and 
presented in graphical form, and summary statistics at each time point will be calculated 
by each dose level.  The following PK variables after the last dosing will be derived as 
data allowed: maximum concentration (Cmax), time to maximum concentration (tmax), 
area under the curve (AUCtau, AUC(0-inf)), and elimination half-life (t1/2).  For PK 
parameters, summary statistics will be calculated by each dose level, and scatter plots 
against the dose level will be generated.  Dose proportionality will also be assessed with 
the power model.
All adverse events will be coded using medical dictionary for regulatory activities 
(MedDRA) and summarized by System Organ Class (SOC) and Preferred Term (PT).  
The number and percentage of subjects with any adverse events will be summarized by 
dose.  The study treatment-related AEs, SAEs, AEs leading to discontinuation of study 
treatment, and AEs of special interest will be reported separately.
The ITT population with observed case dataset will be used for efficacy analyses.  Time 
course of the change from baseline in DAS28(CRP) will be analyzed by mixed model for 
repeated measurements (MMRM). The dose response analyses will be performed on the 
change from baseline in DAS28(CRP) at Week 12.


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2.
INTRODUCTION
GSK3196165 is a recombinant human monoclonal antibody (mAb) targeting 
granulocyte-macrophage colony stimulating factor (GM-CSF) and is currently under 
development as a treatment for rheumatoid arthritis (RA) subjects with inadequate 
response to methotrexate (MTX).
2.1.
Study Rationale
Study 201789 is a Phase I/II study designed to provide the data necessary to assess the 
pharmacokinetics (PK), safety and tolerability of GSK3196165 for 12 weeks treatment 
period, in combination with MTX therapy, in Japanese subjects with active moderate-
severe RA despite treatment with MTX.  In addition, this study will assess efficacy of 
GSK3196165 in Japanese subjects.
2.2.
Brief Background
2.2.1.
Rheumatoid Arthritis
RA is a chronic, systemic inflammatory autoimmune disease, characterised by a 
symmetrical polyarthritis that is associated with substantial disability and morbidity.  RA 
affects approximately 0.5-1.0% of the worldwide population (0.6-1.0% of Japanese 
population [Yamanaka, 2014]), 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 synthetic DMARDs (csDMARDs), of which MTX is the gold standard, and 
biological DMARDs which target cytokines (e.g. tumor necrosis factor [TNF] α, 
interleukin [IL] -6) or T-cells.  However, a substantial proportion of patients either fail to 
respond, or have inadequate response, to currently available RA therapies [Gaujoux-Viala, 
2014; Nam, 2014].  Therefore, there is still a medical need for more effective treatments 
choices for RA with alternative mechanisms of action.
2.2.2.
GM-CSF and RA
Accumulating evidence suggests that the GM-CSF pathway may play a central role in the 
pathogenesis of RA, via the activation and differentiation of neutrophils and macrophages 
[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, as well as chemokines and matrix degrading proteases 
[Fleetwood, 2007; Gasson, 1991; Hamilton JA, 2004; Hamilton, 2013; Hart, 1991;
Mantovani, 2007].  GM-CSF also serves as a differentiation factor for dendritic cells and 
induces upregulation of human lymphocyte antigen (HLA) class II on antigen presenting 
cells, which in turn will activate cluster of differentiation antigen (CD) 4+ T cells.  In 
addition, GM-CSF is a strong chemo-attractant factor for neutrophils and induces the 
release of activated oxygen species from neutrophils, which can directly damage cartilage 
structure [Dang, 1999; Gomez-Cambronero, 2003].


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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].  The number of 
synovial CD68+ macrophages from RA patients correlates with disease activity scores, 
therefore, it potentially serves as a biomarker for treatment response [Bresnihan, 2009; 
Haringman, 2005].  The number of macrophages in synovial tissue is correlated with 
radiographic progression [Michelson, 1994; Mulherin, 1996].  GM-CSF also contributes 
to osteoclastic bone resorption which aggravates joint damage in patients with RA 
[Nakano, 2007].    In addition, in mouse models of collagen-induced arthritis (CIA), GM-
CSF knockout or anti-GM-CSF mAb treatment reduced disease activity and prevented 
progression of established arthritis and, furthermore administration of recombinant GM-
CSF led to exacerbation of arthritis [Campbell, 1997; Cook, 2001; Plater-Zyberk, 2007].
Taken together, pre-clinical and clinical data suggest that GM-CSF is a key mediator of 
inflammatory and immune disorders and may play a role in RA pathogenesis.  This 
provides 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.
2.2.3.
GSK3196165
GSK3196165 is a high-affinity recombinant human mAb that binds specifically to human 
GM-CSF and neutralises its biological function by blocking the interaction of GM-CSF 
with its cell surface receptor [Steidl, 2008].
2.2.4.
Clinical Data
GSK3196165 has been studied overseas in 4 completed clinical trials, consisting of 2 
studies in healthy volunteers, 1 study each in subjects with RA and multiple sclerosis 
(MS) (see GSK3196165 investigator’s brochure [IB]).
MSC-1001 was a Phase1b/2a multi-center, randomized, sequential group, double-blind, 
placebo-controlled study which evaluated the safety, preliminary efficacy, and PK of 
multiple doses of GSK3196165 in subjects (N=96) with active, mild-moderate RA 
[Behrens, 2015].  Subjects received 4 IV weekly doses of GSK3196165 at 0.3 mg/kg, 
1.0 mg/kg or 1.5 mg/kg or placebo in addition to stable concomitant treatment with 
csDMARDs 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.  Other disease activity measures (e.g., American College of 
Rheumatology [ACR] response) and patient-reported outcomes were consistent with the 
results for DAS28.  GSK3196165 was generally safe and well-tolerated in this study.
Currently 3 clinical studies are on-going overseas, including 2 in RA and one in hand 
osteoarthritis.  As for the studies in RA subjects, Study 201755 (BAROQUE) is a Phase 
IIb, placebo-controlled, dose-adaptive 52-week study in approximately 210 subjects with 
active moderate-severe RA despite treatment with MTX.  Study 205180 
(RENAISSANCE) is a Phase IIa, mechanistic 12-week study in approximately 40 
subjects with active RA despite treatment with DMARDs.


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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To assess the pharmacokinetics of 
GSK3196165 in Japanese RA subjects

Pharmacokinetic parameters of 
GSK3196165 calculated from sparse 
sampling concentrations

To assess the safety and tolerability of 
GSK3196165 in combination with MTX 
therapy in Japanese RA subjects

Incidence of adverse events, serious 
adverse events and adverse events of 
special interest
Secondary

To assess the safety other than primary 
endpoints

Vital signs, 12-lead ECG and laboratory 
assessment

Immunogenicity (anti-GSK3196165 
antibody)

To assess the efficacy in Japanese RA 
subjects

Change from baseline in DAS28(CRP) at all 
assessment timepoints
Exploratory
Efficacy Endpoints
At all efficacy assessment timepoints for

ACR 20/50/70 response rate

Change from baseline in DAS28(ESR)

Proportion of subjects achieving categorical DAS28(CRP) / DAS28(ESR) response 
(moderate/good European League against Rheumatism [EULAR] response)

Proportion of subjects achieving DAS28(CRP) / DAS28(ESR) remission

Change from baseline in Simplified Disease Activity Index (SDAI) and the Clinical Disease 
Activity Index (CDAI)

Change from baseline in functional assessment of chronic illness therapy-fatigue (FACIT-
Fatigue)
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.
Biomarker Endpoints

Pharmacodynamic biomarkers to assess target engagement (e.g., serum concentration of free 
GM-CSF, GM-CSF-GSK3196165 complex)

Pharmacodynamic biomarkers which may be predictive of response to GSK3196165 (e.g. 14-
3-3η, MRP8/14, ARGS neoepitope, YKL-40)

Pharmacodynamic biomarkers to assess response to GSK3196165 (e.g. IL-6, IL-1β, TNFα, 
IL-17A, IL-17F)

Whole blood ribonucleic acid (RNA) analysis


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Objectives
Endpoints
Safety Biomarkers

Biomarkers which may be indicative of lung damage (e.g. surfactant D [SP-D], KL-6, 
cholestenoic acid)

Baseline concentrations of GM-CSF autoantibodies
Other

Pharmacogenetics (PGx): Whole blood deoxyribonucleic acid (DNA) analysis
4.
STUDY DESIGN
4.1.
Overall Design

This is a randomized, double-blind, parallel group, 3 dosage level, placebo-
controlled, Phase 1/2 study with the objective to assess pharmacokinetics, safety, 
tolerability and efficacy of GSK3196165 for 12 weeks, in combination with 
methotrexate (MTX), in Japanese subjects with active moderate-severe RA despite 
treatment with MTX.

Approximately 40 subjects will be randomized into the study (10 subjects in each 
treatment groups).
Figure 1
Study Design
4.2.
Treatment Arms and Duration
This study is composed of up to 4 weeks screening period, 12 weeks treatment period 
(last dose Week 10), and 10 weeks follow-up period (12 weeks from last dose).
Subjects will be randomized (1:1:1:1) to placebo or one of three subcutaneous (SC) 
GSK3196165 doses at Day 1 (Week 0).


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Treatment with GSK3196165 or placebo will be given weekly as a single SC injection by 
an unblinded administrator.  There will be 5 weekly injections (Day 1, 8, 15, 22, 29), then 
every other week (EOW) injections at Day 43, 57 and 71 (Week 6, 8, 10, respectively).
GSK3196165/placebo must be administered on the same day each week ±1 day for the 
first 5 weekly doses.  Following this GSK3196165 or placebo must be administered on 
the same day EOW ±3 days.
4.3.
Type and Number of Subjects
Target population of this study is Japanese subjects with active moderate-severe RA who 
previously received oral MTX (at a dose between 8-16 mg/week for at least 12 weeks, 
with a stable and tolerated dose for 4 weeks).
Approximately 55 subjects will be screened to achieve 40 randomized subjects.
4.4.
Design Justification
This is the first study of GSK3196165 in Japanese subjects, therefore the primary 
objectives of this study is to assess the pharmacokinetics, safety and tolerability of 
GSK3196165 in combination with MTX therapy in Japanese subjects.  The overall study 
design is established to achieve these objectives of this study.
Target population
The target population of this study is Japanese subjects with RA.  As GSK3196165 is 
expected to be used in combination with MTX in clinical practices, investigating PK, 
safety and efficacy of the drug by the combined use of MTX will be beneficial to further 
drug development.  With reasons presented below, it is considered that this study is able 
to be conducted as the first study of GSK3196165 in Japanese RA subjects without 
previous data in healthy volunteers.
1.
From the results of completed clinical studies in healthy volunteers, RA subjects, and 
MS subjects to date, no safety or tolerability issues have been identified with 
GSK3196165 (See Section 4.5 and GSK3196165 IB).  There was no evidence of a 
dose relationship of AEs in these clinical trials.
2.
One clinical study (MSC-1001) in non-Japanese subjects with RA has been 
completed and GSK3196165 was well tolerated in the subject population after repeat 
weekly administration of GSK3196165 for 4 weeks up to 1.5 mg/kg via IV route.  
Doses of 1.0 and 1.5 mg/kg IV weekly were associated with reduction of disease 
activity (see GSK3196165 IB).
3.
GSK3196165 is the monoclonal antibody which binds specifically to human GM-
CSF; therefore, it is not anticipated to show pharmacological effects other than the 
expected effect, inhibition of GM-CSF signaling.
Parallel-group design
In this study, GSK3196165 at doses of 45, 90 and 180 mg will be subcutaneously 
administered to Japanese subjects with RA in a parallel-group manner.  The study plan is 


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feasible to conduct with parallel groups by implementing appropriate measures to secure 
the safety of study subjects in light of;  i) the doses/exposures in this study remaining 
within a range of doses/exposures in the clinical studies conducted in the non-Japanese 
population, and ii) no results suggesting potential safety concerns of GSK3196165.
For potential risks of GSK3196165 administration to secure the safety of subjects (e.g., 
infection, pulmonary alveolar proteinosis, hypersensitive reaction, etc.), the procedures of 
inclusion criteria for eligible subjects, screening test, and safety monitoring during the 
treatment period will be set as mitigation strategies (see Section 4.6.1).  Safety 
monitoring through multiple visits will be performed for the purpose of safety evaluation 
after the initial dose.
Placebo control
Inclusion of a placebo arm will allow a more robust exploration of the safety profile of 
GSK3196165 when given in combination with MTX.  The placebo arm is included also 
to measure the absolute effect of each dose tested.
In addition, the investigator can withdraw the subject from study at any time as clinically 
indicated, so subjects having insufficient benefit will not be inadequately treated.
Methotrexate background
All subjects will continue to receive MTX.  Although MTX dosing should be kept stable 
throughout the study as far as possible, dose reduction is permitted to a minimum of 
8 mg/week due to intolerance or toxicity, and dose increase, following reduction, is 
permitted back to the subject’s dose prior to reduction (maximum dose: 16 mg/week).  
Likewise, temporary interruption of MTX dosing for the management of intolerance will 
be permitted.
4.5.
Dose Justification
A four-fold range of doses (45-180 mg), that are expected to result in largely non-
overlapping exposures, are proposed for evaluation in this study.  Study agent will be 
administered SC weekly for 5 injections, then every other week (EOW) injections.  
Dosing will use fixed doses, not based on body weight (i.e. mg/kg).  This reflects the 
change to fixed doses in the Phase IIb study (Study 201755) and the proposed future 
dosing of GSK3196165 in the clinical setting.
Two Phase I studies in non-Japanese healthy volunteers showed that GSK3196165 was 
well tolerated up to 3.0 mg/kg following single IV dose  and up to 2.0 mg/kg following 
single SC dose.  Other Phase 1b repeat dose study in subjects with MS, GSK3196165 
was also well tolerated up to 2 mg/kg following the EOW administration of the 
investigational product for 12 weeks (see GSK3196165 IB).
In case of the lowest eligible body weight in this study (i.e. 40 kg), which would be 
expected to result in the highest systemic exposure, the highest planned dose of 180 mg 
(SC) is equivalent to 4.5 mg/kg (SC).  Based on the absolute bioavailability following SC 
administration (~ 44%) (see GSK3196165 IB), the systemic exposure at 4.5 mg/kg (SC) 


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is considered to be comparable with 1.98 mg/kg (IV), which is lower than the tolerable 
dose in Study MSC-1000, 3.0 mg/kg (IV).
Furthermore, the maximum dose proposed, 180 mg SC has been selected to allow ample 
margin to the no observed adverse effect level (NOAEL), and also a margin to the no 
observed effect level (NOEL) (the dose at which foamy alveolar macrophages were not 
observed in the 26-week rhesus monkey study).  A dose of 180 mg SC is predicted to 
result in steady-state exposures which will allow a 25-fold margin to the NOAEL 
(50 mg/kg), where reversible minimal to mild foamy alveolar macrophages (considered 
non-adverse) were seen in the 26-week monkey toxicity study, with a 3-fold margin to 
the NOEL (5 mg/kg) (Table 1).
Table 1
Safety margins with 180 mg SC GSK3196165 relative to exposures to 
exposures in nonclinical toxicology studies
Study/
Species
Assessment
Dose
(mg/kg/wk)
AUC(0-168) a
(µg.hr/mL)
AUC(0-336) b
(µg.hr/mL)
Fold difference
primates to human ratio
AUC(0-168)
AUC(0-336)
Rhesus
Monkey
4 weeks IV
Week 4
5
4407
8814
2.9
NA
25
22250
44500
14.5
100c,d
55101
110201
35.9
Cynomolgus 
Monkey
13week SC
Week 13
10
3149
6298
2.1
3.3
30d
12765
25530
8.3
13.2
100c
37797
75594
24.6
39.2
Rhesus
Monkey
26 week IV
Week 26
5d
2822
5644
1.8
2.9
15
11264
22528
7.3
11.7
50c
24482
48963
15.9
25.4
Human
12 weeks SC
e
Last dose in Induction phase
(Week 4-5)
1536
-
Last dose in Maintenance 
phase
(Week10-12)
-
1930
IV intravenous; SC subcutaneous
a. AUC(0-168): As there were no significant differences on sampling occasions or gender differences 
within each primate study, the end of study mean values of AUC (0-168) in female and male [GSK3196165 
IB: Table 10 and Table 11 in Section 4.5] have been used and divided by 2.
b. AUC(0-336): AUC (0-168) have been multiplied by 2 to obtain mean concentrations over a two week 
period.
c. No observed adverse effect dose level (NOAEL).
d. No observed effect dose level (NOEL).
e. Simulated median AUC based on analysis of SC data from study MOR103C104 with a 2 compartment 
PK model.
The dose range includes doses that are anticipated to be effective or minimally effective 
based on the results as follows:


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
In the Phase 1b/2a RA study (Study MSC-1001), IV doses of 1.0 mg/kg and 
1.5 mg/kg showed activity and 0.3 mg/kg showed little to no activity after 4 weeks 
of weekly treatment (see GSK3196165 IB).

Complete inhibition of GM-CSF function by GSK3196165 has been observed in 
different assays in vitro at mean concentrations averaging 0.2 μg/mL.  Although the 
level of penetration of GSK3196165 into the inflamed synovial tissues is not known, 
it is reasonable to assume that its penetration rate is in the range as seen with other 
mAbs.  Concentration levels of mAbs in the synovium vary among patients and have 
been reported to be below 30% of the plasma values [Choy, 2000].  Based on a 30% 
penetration rate, the continuous GM-CSF production and considering patient 
heterogeneity, the minimal or sub-optimal clinical effect level is anticipated to be at 
approximately 10-fold higher (2 μg/mL) than the inhibitory concentration derived 
from in vitro studies.
Doses of 90 and 180 mg SC given EOW are anticipated to result in steady state Cmin 
concentration levels of approximately 2 μg/mL or greater (a hypothetical target to bind 
synovial GM-CSF, see GSK3196165 IB).  The weekly loading dose regimen is intended 
to achieve rapid reduction in disease activity, as supported by the completed 4-week RA 
study (Study MSC-1001) where doses of 1.0 and 1.5 mg/kg IV weekly were associated 
with reduction of DAS28 score after the first dose that continued to decrease through 
Week 10 and 6, respectively (see GSK3196165 IB).
Therefore, the dose range in this study (45, 90 and 180 mg [SC]) is considered to be safe 
and appropriate.  Also, using this range will allow us to assess linearity in 
pharmacokinetics of GSK3196165 in Japanese subjects.
4.6.
Benefit:Risk Assessment
Summaries of findings from both non-clinical and clinical studies conducted with 
GSK3196165 can be found in the GSK3196165 IB.  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-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 (26-week 
study in rhesus monkey), T-cell 
dependent B-cell primary or secondary 
response, or circulating cytokine levels 
(26-week study in rhesus monkey) 
were observed.
Studies in knock-out mice showed that 
GM-CSF deficiency (GM-CSF-/-) 
affects the ability of mice to control 
infection when infected with M. 
tuberculosis or pulmonary group B 
streptococcus [LeVine, 1999].
Clinical Data:
One healthy volunteer in study MSC-
1000 experienced septic shock 
secondary to pneumonia 29 days after 
receiving a single dose of IP at 
1.5 mg/kg.  Subject recovered after 
treatment with antibiotics, and the 
subject completed the study follow-up 
period as per protocol.
One RA subject in study MSC-1001 
experienced serious pleurisy which 
responded to antibiotics.
Subject selection (see Section 5.2):

Subjects with active infections, or a 
history of recent infections 
(hospitalization within the last six 
months) or recurrent infections are 
not permitted to enter the study.

Subjects with significant 
leukopenia are not permitted to 
enter the study.

Subjects will be screened for 
significant neutropenia, TB, HIV 
and Hepatitis B and C, and 
excluded from study participation if 
positive.

Subjects with a recent vaccination 
(live or attenuated) or a planned 
live vaccination are not permitted 
to enter the study.
Subject monitoring:

Serious infections and 
opportunistic infections are 
categorised as adverse events of 
special interest (AESIs).

Subjects will be monitored for 
infection according to standard of 
care for subjects receiving any 
immune-modulating biologic 
therapy for RA.  Appropriate 
diagnostic tests will be considered 
during the study if clinically 
indicated to secure the safety of 
subjects.

Subjects will be instructed as to 
the signs and symptoms of 
infection, and to contact site 
personnel should they develop.  
This information will also be 
contained within the patient 
Informed Consent Form.


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Potential Risk 
of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy

When subjects are considered to
be at high risk of pneumocystis 
pneumonia (PCP) after the 
initiation of treatment by the 
investigator’s judgement, 
preventive dosing of co-
trimoxazole is permitted.
Withdrawal criteria:

In the event of a serious or 
opportunistic infection, study 
medication should be discontinued 
and the subject withdrawn from 
the study.
Pulmonary 
alveolar 
proteinosis 
(PAP)
GM-CSF signalling is required to 
maintain the normal function of 
alveolar macrophages.  Long-term 
absence of GM-CSF signalling (e.g., 
via hereditary GM-CSF deficiency or 
development of anti-GM-CSF auto-
antibodies) is known to cause the 
extremely rare condition of PAP, which 
is characterized by the accumulation 
of surfactant lipids and protein in the 
alveolar spaces, with resultant 
impairment in gas exchange.
Non-clinical Data:
Non-adverse minimal to mild foamy 
alveolar macrophage accumulation 
were noted in lungs of monkeys in the
13-week SC and 26-week IV 
toxicology studies, but reversible 
following off drug period.  Dose levels 
at which foamy alveolar macrophages 
were not observed were identified in 
these studies.
Clinical Data:
No cases of PAP have been reported 
to date in the clinical development 
program.  Furthermore evaluation of 
pulmonary function has not 
demonstrated any abnormalities in 
Subject selection (see Section 5.1
and Section 5.2):

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, Diffusing capacity of 
the lung for carbon monoxide 
[DLCO] measurements) will be 
performed at screening in order to 
exclude those subjects with 
moderate-severe impairment.
Dose Duration:

The exposure duration to 
GSK3196165 in this study is 12 
weeks.  Although the time course 
of PAP development in humans is 
unknown, the published literature 
suggests that it requires full 
inhibition of GM-CSF for years 
before clinical manifestation of the 
disease can be detected (refer to 
GSK3196165 IB for further 
details).  Therefore, the risk of 
development of PAP in this study 


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Potential Risk 
of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
pulmonary functions.
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.  PAP, 
persistent cough or dyspnea 
will be categorised as AESIs.
Pulmonary function testing 
(spirometry and DLCO
measurements) will be 
performed at screening, 
Week 12 and at the follow-up 
visit.  Relative change in 
DLCO >15% from screening or 
non life threatening 
pulmonary changes related 
to surfactant accumulation
will be categorised as AESIs 
if confirmed with three 
consecutive weekly tests.

In the event of clinically-significant 
pulmonary events, the subject 
should be referred to a 
pulmonologist for further 
assessment.  The study drug 
should be suspended until the 
symptoms or signs that caused 
referral have resolved and/or the 
diagnosis has been determined 
and clinically significant events 
have been excluded by the 
pulmonologist.  Suggested 
pulmonary assessment and 
management algorithms will be 
provided in the Study Reference 
Manual (SRM).


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Potential Risk 
of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Withdrawal criteria:

In the event of a confirmed PAP, 
study medication should be 
discontinued and the subject 
withdrawn from the study.
Hypersensitivity 
reactions, 
including 
anaphylaxis
There is a potential risk of 
hypersensitivity reactions, including 
anaphylaxis, during and following the 
administration of protein-based 
products, such as GSK3196165.
Clinical Data:
No allergic or acute systemic reactions 
have been observed to date in the 
clinical development program.
Subject selection (see Section 5.2):

Subjects with a history of 
sensitivity to any of the study 
treatments, or components 
thereof, or a history of drug or 
other allergy that, in the opinion of 
the investigator or Medical 
Monitor, contraindicates their 
participation, will not be permitted 
to enter the study.
Study treatment 
administration/Subject monitoring:

All SC administrations will be 
performed at the clinical site.

Subjects will be required to remain 
monitored at the site for 1hour 
after the injection for the first 3 
injections, and then for 30minutes 
for subsequent injections.

Subjects should be informed of the 
signs and symptoms of an acute 
hypersensitivity reaction, and be 
instructed to seek immediate 
medical care should they develop.  
This information will also be 
contained within the patient 
Informed Consent Form.

Should hypersensitivity or 
anaphylaxis occur, subjects should 
be managed appropriately per 
local guidelines/medical 
judgement.

Hypersensitivity reactions, 
including anaphylaxis are 
categorised as AESIs.


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Potential Risk 
of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Withdrawal criteria:

In the event of severe or serious 
hypersensitivity reactions including
anaphylaxis, study medication 
should be discontinued and the 
subject withdrawn from the study.
Injection site 
reactions
SC injections may be associated with 
local reactions (e.g., swelling, 
induration, pain).
Non-clinical & Clinical Data:
No macroscopic or microscopic 
changes indicative of local injection 
site reactions were observed following 
IV or SC administration.
Subject monitoring:

Subjects should be monitored for 
injection site reactions throughout 
the study, and the information 
recorded in the eCRF.

Injection sites will be rotated.

Injection site reactions  are 
categorised as AESIs.
Leukopenia
Although there is a perceived 
theoretical risk that GM-CSF blockade 
may affect maturation of leukocytes 
and their precursors, mice lacking GM-
CSF do not develop neutropenia or 
show any major perturbation of 
hematopoiesis [Stanley, 1994].
Non-clinical & Clinical Data:
There have been no reports of 
neutropenia or decreases in 
leukocytes in the non-clinical and 
clinical GSK3196165 program.
Subject selection (see Section 5.2):

Subjects with significant 
leukopenia (≤3.0 x 109/L); 
thrombocytopenia (platelet count 
≤100 x 109/L); neutropenia 
(absolute neutrophil count ≤1.5 x 
109/L); lymphocytopenia (≤0.5 x 
109/L) within 4 weeks prior to 
Day 1 are not permitted to enter 
the study.
Subject monitoring:

A full blood count (with differential) 
will be performed at regular 
intervals throughout the study (ref. 
Time and Events Table, Section 
7.1).

Grade 3 or greater neutropenia is 
categorised as an AESI.
Withdrawal criteria:

In the events of significant 
leukopenia (<2.0 x 109/L); 
neutropenia (absolute neutrophil 
count <1.0 x 109/L); 
lymphocytopenia (<0.5 x 109/L), 
study medication should be 


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Potential Risk 
of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
discontinued and the subject 
withdrawn from the study.
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.
The effect on human pregnancy is 
unknown.
Clinical Data:
No HVs or RA subjects became 
pregnant during the studies, but one 
MS subject was found to be pregnant 
during study MOR103C103 and 
received four 2.0 mg/kg doses, the 
pregnancy was terminated 2 weeks 
later by elective abortion.
Subject selection (see Section 5.1):

Male and female subjects will only 
be permitted to enter the study if 
they meet the contraception 
requirements detailed in inclusion 
criterion #10 and Appendix 2.
Subject monitoring:

Females of child bearing potential 
will undergo pregnancy testing at 
screening and at regular intervals 
during the study (ref. Time and 
Events Table, Section 7.1).
Withdrawal criteria:

In the event of a pregnancy in a 
female subject in the study, study 
medication should be discontinued 
and the subject withdrawn from 
the study.
Other considerations:

Subject will be followed to 
determine the outcome of the 
pregnancy

Any pregnancy complication or 
elective termination of a 
pregnancy will be reported as an 
AE or SAE.
Malignancy
The risk of malignancy is increased in 
patients with RA.  In addition, 
immunomodulatory therapies may 
increase the risk of malignancy.
Non-clinical & Clinical Data:
There have been no reports of 
malignancy in the non-clinical and 
clinical GSK3196165 program.
Subject selection (see Section 5.2):

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.


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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 (Study MSC-1001) in subjects with active RA [Behrens, 2015].  In 
addition, mavrilimumab (an anti-GM-CSF α-subunit receptor mAb), has also shown 
substantial activity in RA subjects who had an inadequate response to MTX in studies of 
up to 24 weeks of dosing [Burmester, 2013; Burmester, 2014].  These data support the 
clinical evaluation of GSK3196165 in subjects with RA.
4.6.3.
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.
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).  Appropriate safety 
monitoring will be undertaken in studies of GSK3196165 to proactively address and 
mitigate the potential risks.  Recent data with mavrilimumab administered for 24 weeks 
in combination with MTX in subjects with active RA [Burmester, 2014] provides further 
support that targeting this pathway is associated with an acceptable benefit:risk profile.
Given the safety monitoring that has been put in place to minimize risk to subjects 
participating in clinical studies of GSK3196165, the potential risks identified are justified 
by the potential benefits that may be afforded to patients with RA.
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.
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.  


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5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. Age ≥20 years at the time of signing informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
2. Japanese RA subjects who meets ACR/EULAR 2010 RA Classification Criteria.
3. Functional class I, II or III defined by the 1992 ACR Classification of Functional 
Status in RA.
4. Disease duration of ≥12 weeks (time from onset of patient-reported symptoms of 
either pain or stiffness or swelling in hands, feet or wrists).
5. Swollen joint count of ≥4 (66-joint count) and tender joint count of ≥4 (68-joint 
count) at screening and at Day 1.
6. DAS28(CRP) ≥3.2 at screening.
7. C-Reactive Protein (CRP) ≥0.3 mg/dL at screening.
8. Must have previously received MTX (8-16 mg weekly) orally for at least 12 weeks 
before screening, with a stable and tolerated dose for ≥4 weeks prior to Day 1.
WEIGHT
9. Weight ≥40 kg.
SEX
10. Male or female subjects are eligible to participate so long as they meet and agree to 
abide by the contraceptive criteria detailed in Appendix 2.
INFORMED CONSENT
11. Written informed consent prior to any of the screening procedures including 
discontinuation of prohibited medications.


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OTHER SAFETY-RELATED
12. Willing to continue or initiate treatment with oral folic acid (5 mg/week) and be 
treated during the entire study (mandatory co-medication for MTX treatment).
13. DLCO ≥60%1) predicted; forced expiratory volume in 1 second (FEV1) ≥70% 
predicted; forced vital capacity (FVC) ≥80% predicted.
1) For subjects with DLCO values ≥60% to <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.
14. No evidence of active or latent infection with Mycobacterium tuberculosis (TB), as 
defined by all of the following:
1) No history of active or latent TB infection irrespective of treatment status.
2) A negative T-spot test within 4 weeks of baseline (Day 1).  
3) Chest X-ray within 12 weeks of Day 1, locally read by a radiologist, with no 
evidence of current or previous pulmonary tuberculosis.
NB: If there is suspicious of risk for TB infection because of 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.
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 women.
2. History of other inflammatory rheumatological or autoimmune disorders, other than 
Sjögren’s syndrome secondary to RA.
3. History of any respiratory disease which (in the opinion of the investigator) would 
compromise subject safety or the ability of the subject to complete the study (e.g. 
significant interstitial lung disease, such as pulmonary fibrosis, chronic obstructive 
pulmonary disease (COPD), moderate-severe asthma, bronchiectasis, previous PAP).
4. Clinically-significant or unstable (in the opinion of the investigator) persistent cough 
or dyspnea that is unexplained.
5. QT interval corrected for heart rate (QTc) >450msec or QTc >480msec for subjects 
with bundle branch block.


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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) ≥1.5xULN; 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. Clinically significant unstable or uncontrolled acute or chronic disease (e.g., 
cardiovascular including uncompensated congestive cardiac failure New York Heart 
Association [NYHA] III or IV, myocardial infarction within 12 months, unstable 
angina pectoris, uncontrolled hypertension, uncontrolled hypercholesterolemia) 
pulmonary, hematologic, gastrointestinal (including Crohn’s Disease or ulcerative 
colitis), hepatic, renal, neurological, psychiatric, malignancy, endocrinological or 
infectious diseases, which, in the 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/1.73 m2 (MDRD formula) or serum creatinine >1.5xULN within 4 
weeks of Day 1.
11. Hereditary or acquired immunodeficiency disorder, including immunoglobulin 
deficiency.
12. History of infected joint prosthesis at any time, with the prosthesis still in situ. 
History of leg ulcers, catheters, chronic sinusitis or recurrent chest or urinary tract 
infections.
13. Active infections, or history of recurrent infections (excluding recurrent fungal 
infections of the nail bed), or have required management of acute or chronic 
infections, as follows:
i)
Currently on any suppressive therapy for a chronic infection (such as 
tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes 
zoster and atypical mycobacteria).
OR
ii) Hospitalization for treatment of infection within 26 weeks of Day 1.
OR
iii) Use of parenteral (IV or IM) antimicrobials (antibacterials, antivirals, 
antifungals, or antiparasitic agents) within 26 weeks of Day 1 or oral 


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antimicrobials within 2 weeks of Day 1.
14. A vaccination (live or attenuated) within 30 days of Day 1 or Bacillus Calmette-
Guérin (BCG) vaccination within 1 year of Day 1, or a live vaccination planned 
during the course of the study (including follow-up period).
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 
(including follow-up period).
CONCOMITANT MEDICATIONS
16. Use of prohibited medications Prior to AND throughout thestudy:

Any conventional DMARDs other than MTX (including sulfasalazine, 
bucillamine, iguratimod, tacrolimus) should be withdrawn at least 2 weeks prior 
to Day 1.

Subjects may require longer to discontinue azathioprine or leflunomide prior 
to Day 1:
i)
Azathioprine must be discontinued ≥4 weeks prior to randomization.
ii) Leflunomide must be discontinued ≥12 weeks prior to Day 1 (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 4 weeks prior to Day 1.

Any biologic agents (such as TNF inhibitors [including adalimumab, 
etanercept, infliximab, certolizumab pegol, golimumab] or non-TNF 
inhibitors [including abatacept, rituximab, tocilizumab, belimumab]).

Any Janus kinase (JAK) inhibitors (such as tofacitinib).

Any anti-rheumatic investigational compounds.

Any alkylating agents (such as cyclophosphamide).

Plasmapheresis or intravenous immunoglobulin (IVIG) within 26 weeks of 
Day 1.
17. Corticosteroids:

Any IM, IV or IA corticosteroids within 8 weeks of Day 1.

Oral corticosteroids:

Any treatment with >10 mg/day dose oral prednisolone (or equivalent) 
within 4 weeks of Day 1.

New oral corticosteroid or changes in corticosteroid dose within the 4 weeks 
prior to Day 1.  (New topical steroids and immunosuppressive agents (e.g., 
eye drops, creams) are permitted).


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18. Non-steroidal anti-inflammatory drugs (NSAIDs):

New or change in dose of NSAID within 2 weeks of Day 1.
19. Any non-anti-rheumatic investigational treatment must be discontinued for at least 4 
weeks or 5 half-lives, whichever is longer, prior to Day 1.
RELEVANT HABITS
20. 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 
21. 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
22. Abnormal chest X-ray within 12 weeks of Day 1 (locally read and reported by a 
radiologist) judged by the investigator as clinically-significant.
23. Any Grade 3 or 4 hematology or clinical chemistry laboratory abnormality [CTCAE, 
2009 v4.0] within 4 weeks of Day 1.
24. Hemoglobin ≤9 g/dL; white blood cell count ≤3.0 x 109/L; platelet count ≤100 x 
109/L; absolute neutrophil count ≤1.5 x 109/L; lymphocyte count ≤0.5 x 109/L within 
4 weeks of Day 1.
25. Serologic evidence of current/previous Hepatitis B virus (HBV) infection based on 
the results of testing for Hepatitis B surface antigen (HBsAg) and anti-Hepatitis B 
core (anti-HBc) antibody as follows within 4 weeks of Day 1.

Subjects positive for HBsAg and/or positive for anti-HBc antibody (regardless of 
anti-HBs antibody status) are excluded.

Subjects with positive anti-HBs antibody and HBV-DNA (≥2.1 log copies/mL) 
are excluded.
26. Hepatitis C: Positive test for Hepatitis C virus (HCV) antibody confirmed on a 
subsequent blood sample by RNA-PCR assay within 4 weeks of Day 1.

Subjects who are positive for Hepatitis C antibody and negative when the 
Hepatitis C RNA-PCR assay is performed on a subsequent sample will be 
eligible to participate.  Subjects who are positive for Hepatitis C antibody and 
have a positive result for the HCV when the Hepatitis C RNA-PCR assay is 
performed on the subsequent sample will not be eligible to participate.


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27. Positive serology for human immunodeficiency virus (HIV) 1 or 2 (within 4 weeks of 
Day 1).
5.3.
Screening/Baseline Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized.  In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and any Serious Adverse Events.
5.3.1.
Re-Screening
If a subject has not met all of the Eligibility Criteria within the 28-day screening period, 
re-screening is allowed.  Subjects are only allowed to be re-screened once; the entire 
screening process must be repeated (with the exception of chest X-ray if within 12 weeks 
of the first screening period or HRCT if this was already performed within the first 
screening period).
If a blood sample has to be withdrawn due to sample handling problems, breakage or 
sample integrity, this is not considered a re-screening.
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 inclusion/exclusion criteria, the test may be 
repeated twice within the screening period.  If the subject fails the laboratory criteria for 
a third time they will be considered a screen failure; these subjects may be re-screened as 
described in Section 5.3.1.
If a blood sample has to be withdrawn due to sample handling problems, breakage or 
sample integrity, this is not considered a re-testing.
Further details regarding the procedure for laboratory re-testing may be found in the 
SRM.
5.3.2.2.
Pulmonary Function Tests
It is permitted to repeat the pulmonary function testing sessions (spirometry and/or DLCO) 
once within 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.


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5.3.2.3.
ECG test
The ECG may be repeated once within the screening period if the recorded QTcF value 
was slightly out of range, and the Investigator does not consider that there are any other 
clinically-significant ECG abnormalities that would preclude the subject from 
participating in the study.
5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible.

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study.

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and if necessary a certified letter to the subject’s last known 
mailing address).  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.
In addition, study medications will be discontinued and the subject withdrawn from the 
study in the event of any of the following:

All serious or opportunistic infections.

Pregnancy.

Confirmed PAP.

Severe or serious hypersensitivity reactions, including anaphylaxis.

If the liver chemistry stopping criteria (Section 5.4.1) or QTc stopping criteria 
(Section 5.4.2) are met.

Persistent or recurrent hematological laboratory abnormalities (see Section 5.5.2).

Detected (≥2.1 log copies/mL) HBV DNA for subjects who have positive anti-
HBs antibody.

Other serious or severe adverse events, at the discretion of the investigator, after 
consultation with the Medical Monitor.


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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 10-week 
follow-up visit (from withdrawal visit).
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance).
5.4.1.1.
Liver Chemistry Stopping and Increased Monitoring Algorithm
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 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 QT interval corrected for heart rate according to Fridericia’s formula (QTcF)
must be used to determine eligibility for and discontinuation from the study.


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
The QTcF 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 single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minutes) recording period.
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:

QTc >500 msec OR uncorrected QT >600 msec

Change from baseline of QTc >60 msec
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) for three 
consecutive weeks.

Persistent dyspnea (Borg scale grade 3 or above) for three consecutive weeks.
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.  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 the SRM.
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


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
Absolute neutrophil count < 1.0 x 109/L

Lymphocyte count < 0.5 x 109/L
Study medication should not be restarted until the parameters are above these values, and 
subjects should be followed as appropriate until resolution of the event.
If these abnormalities are persistent (present on ≥2 sequential tests), or occur recurrently 
(on 2 separate occasions), study medications will be permanently discontinued and the 
subject withdrawn from the study.
5.6.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.  The end of the study is defined as the last subject’s last visit.
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.
Table 2
Investigational Product and Other Study Treatment
Investigational Product
Co-medication
Test 
Control
Product name:
GSK3196165
Placebo
Methotrexate and folic 
acid.
Physical 
description:
Sterile, aqueous solution 
of purified monoclonal 
antibody 150 mg/mL
Sterile 0.9% 
(weight/volume [w/v]) 
sodium chloride 
solution
-
Dosage form:
Liquid (Subcutaneous 
injection preparation in a 
glass vial containing 
1.2 mL of GSK3196165)
Liquid (Injection 
preparation in plastic 
ampoule containing 
20 mL saline)
MTX: tablet, capsule
Folic acid: tablet 
Route of 
Administration:
SC injection
SC injection
Oral


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Investigational Product
Co-medication
Test 
Control
Dosage levels 
(volumes):
45 mg (0.3 mL)
90 mg (0.6 mL)
180 mg (1.2 mL)
- (0.6 mL)
MTX:8-16 mg/week
Folic acid: 5 mg/week.
Note: Folic acid dose 
may be increased to 
counteract side-effects 
of MTX (including 
nausea, mucositis, and 
headache).
Dosing 
instructions:
Investigator product (GSK3196165 or placebo) 
will be administered SC weekly for 5 injections,
and then EOW injections.  Investigational product 
should be administered SC into thigh or abdomen.  
Sites should be rotated, and it should be 
administered in different site than previous one.
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.
Subjects will be randomized as shown in Time 
and Events Table, Section 7.1, and the dosing 
schedule should be followed as closely as 
possible.  GSK3196165/placebo should be 
administered on the same day each week ± 1 day 
for the first 5 weekly doses (with a minimum of 5 
days between doses, for no more than 2 
consecutive doses).  Following this 
GSK3196165/placebo should be administered on 
the same day EOW ± 3 days (with a minimum of 
8 days between doses).
GSK3196165/placebo will be discontinued or 
interrupted as described in Section 5.4 or Section 
5.5.
MTX and folic acid
should be started prior 
to and maintained
during the study.
MTX: can be taken as a 
single weekly dose, or 
divided weekly dose, 
per investigator’s 
discretion.
Folic acid: should be 
taken within 24-48
hours following MTX 
administration.


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Investigational Product
Co-medication
Test 
Control
Storage Condition
GSK3196165 should 
be  stored under cold 
chain condition (2-8°C, 
protected from light).
Placebo should be 
stored at room 
temperature and 
protected from 
excessive heat and 
freezing.
-
Manufacturer/
Source of
procurement
GSK
Otsuka Pharmaceutical 
Factory, Inc..
(Provided by GSK)
-
Further details of study treatment information are provided in the SRM.
Co-administration drug
Investigators are responsible for ensuring that subjects continue to receive MTX and folic 
acid.
1.
MTX
Subjects will receive 8-16 mg/week MTX orally.  MTX dosing should be kept stable 
throughout the study as far as possible.  Dose reduction is permitted to a minimum of 
8 mg/week due to intolerance or toxicity, and dose increase, following reduction, is 
permitted back to the subject’s dose prior to reduction (maximum dose 16 mg/week).  
Likewise, temporary interruption of MTX dosing for the management of intolerance will 
be permitted.
Timing of MTX is unrelated to food intake, and may be changed at the investigator’s 
discretion in case of intolerability.
2.
Folic acid
Subjects will receive 5 mg/week folic acid orally.  The dosing regimen is at the discretion 
of the investigator.  Folic acid should be taken within 24-48 hours following the MTX.  
Folic acid dose may be increased to counteract side-effects of MTX (including nausea, 
mucositis, and headache).
6.2.
Treatment Assignment
Subjects will be assigned to study treatment 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.


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Randomization numbers will be assigned to subjects by patient registration center.
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.
Subjects should be randomized and receive their first dose of study medications on the 
same day (Day 1).
Further details of treatment assignment are provided in the SRM.
6.3.
Planned Dose Adjustments
This protocol does NOT allow dose adjustments of investigational product.
6.4.
Blinding
The study will be double-blind, which means that the investigator and trial staff at site 
(apart from the unblinded administrator), subject, and sponsor personnel (apart from the 
unblinded monitor and the unblinded data manager) will be blinded to the trial treatment 
allocated to each individual subject.
There will be at least one unblinded administrator that will prepare and administer the 
study treatment and will not perform any other study procedures.  A shield (e.g., eye 
mask) will be used during investigational product administration so that subjects are not 
able to see the injection volume, syringe size, or any difference in color between 
GSK3196165 and placebo.
Emergency Key Code Unblinding

The investigator or treating physician may unblind a subject’s treatment 
assignment only in the case of an emergency OR in the event of a serious medical 
condition when knowledge of the study treatment is essential for the appropriate 
clinical management or welfare of the subject as judged by the investigator.

Investigators have direct access to the subject’s individual study treatment.

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the subject’s treatment assignment.

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the treatment 
assignment of the unblinded subject, unless that information is important for the 
safety of subjects currently in the study.

The date and reason for the unblinding must be fully documented in the eCRF.
A subject will be withdrawn if the subject’s treatment code is unblinded by the 
investigator.  The primary reason for discontinuation (the event or condition which led to 
the unblinding) will be recorded in the eCRF.


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
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind 
the treatment assignment for any subject with an SAE.  If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the subject’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy.
6.5.
Packaging and Labeling
The contents of the label for GSK3196165 will be in accordance with all applicable 
regulatory requirements for clinical supplies.
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 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 unblinded administrator designated by investigator.

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 (MSDS) 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.
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.  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 and folic 
acid.  The date taken and total weekly dose will be recorded in the eCRF.


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6.8.
Treatment of Study Treatment Overdose
6.8.1.
Overdose of GSK3196165
For this study, any dose of GSK3196165 > 180 mg within one week time period will be 
considered an overdose.  There is very limited clinical safety data at this stage of 
development.  However there have been no reports of overdose with GSK3196165 to 
date.  The risk of overdose occurring is considered low because in GSK3196165 will be 
administered by an independent administrator (an unblinded site staff), and the maximum 
volume that can be withdrawn from the vial is equivalent to the highest dose (of 180 mg)
to be evaluated.  No specific treatment is recommended for an overdose of GSK3196165, 
and the investigator should treat as clinically indicated.  Details (amount of 
investigational product given and any resulting AEs/SAEs) should be recorded in the 
eCRF.
In the event of an overdose the investigator should:
1.
contact the Medical Monitor immediately.
2.
closely monitor the subject for AEs/SAEs and laboratory abnormalities.
3.
obtain a plasma sample for PK analysis at the time of the event, and three days after 
the event (unless otherwise requested by the Medical Monitor).
4.
consult with the Medical Monitor for any decisions regarding dose interruptions or 
modifications based on the clinical evaluation of the subject.
6.8.2.
Overdose of Methotrexate
Signs and symptoms:
Reports of oral overdose often indicate accidental daily administration instead of weekly 
(single or divided doses). Symptoms commonly reported following overdose include 
hematologic and gastrointestinal reaction.  For example, leukopenia, thrombocytopenia, 
anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, 
nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In some cases, no 
symptoms were reported. There have been reports of death following overdose.  In these 
cases, events such as sepsis or septic shock, renal failure, and aplastic anemia were also 
reported.  There have been reports of death following overdose. In these cases, events 
such as sepsis or septic shock, renal failure, and aplastic anemia were also reported.
Treatment:
In case of overdosage, leucovorin administration, which diminishes the toxicity and 
counteracts the effect of MTX, should begin as promptly as possible together with 
hydration and urinary alkalinization to promote elimination of MTX.  As the time interval 
between methotrexate administration and leucovorin initiation increases, the 
effectiveness of leucovorin in counteracting toxicity may decrease.


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6.9.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because the indication being studied is not life threatening or seriously debilitating 
and other treatment options are available.
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 metabolising enzymes has become increasingly evident [Lee, 2010; 
Zhou, 2011; Evers, 2013].  During inflammation, enzymes such as Cytochrome P (CYP) 
450 can be down-regulated leading to instances of reduced clearance and increased 
plasma concentrations of administered drugs.
The administration of GSK3196165 can potentially alter circulating cytokine levels to a 
patient whose cytokine levels have been elevated.  This may partially or completely 
reverse the impact of cytokines on CYP450 enzymes leading to changes in the exposure 
of co-administered drugs whose metabolism is dependent on CYP450 enzymes.  The 
reports so far suggest the magnitude of drug interaction by therapeutic proteins 
(clinically) is generally small (less than two-fold) and therefore only likely to be 
clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose 
is individually adjusted.  Upon initiation or discontinuation of GSK3196165, in subjects 
being treated with these types of medicinal products, therapeutic monitoring of effect 
(e.g., warfarin) or drug concentration (e.g. theophylline) should be performed and the 
individual dose of the medicinal product adjusted as needed.  Prescribers should exercise 
caution when GSK3196165 is co-administered with CYP3A4 substrate drugs where 
decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, 
etc.  The effect of GSK3196165 on CYP450 enzyme activity may persist for several 
weeks after stopping therapy.
6.10.1.
Permitted Medications and Non-Drug Therapies
All permitted medications, and non-drug therapies that may affect RA disease activity or 
assessments will be recorded in eCRF.
6.10.1.1.
Oral Corticosteroids
Stable use of oral corticosteroids 10 mg/day prednisone or equivalent agent is permitted 
if the dose is stable for at least 4 weeks prior to Day 1 (baseline).  This dose should 
remain constant throughout the first 12 weeks of the study.  Dose changes before Week 
12 are not permitted, unless required for safety or tolerability.


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6.10.1.2.
NSAID
Continued use of single NSAID (including cyclooxygenase [Cox]-2 inhibitors) is 
permitted (i.e. diclofenac, ibuprofen, naproxen, celecoxib) in daily doses up to the 
maximum recommended dose, if the dosage was stable for at least 14 days prior Day 1.  
The dose/type of NSAID may be changed for safety or tolerability problems.  If the 
subject is not regularly using NSAIDs, he/she may take the NSAIDs mentioned above as 
breakthrough pain management, which must be recorded in the eCRF.  However, subjects 
should be advised not to take any NSAIDs for breakthrough pain within 12 hours prior to 
an efficacy assessment visit.
6.10.1.3.
Analgesics
Regular use of codeine, opium alkaloid, paracetamol/acetaminophen and tramadol are 
permitted in daily doses up to the maximum recommended.  If the subject is not regularly 
using any analgesics, he/she may take the analgesics mentioned above as breakthrough 
pain management.  However, the subjects should be advised not to take any analgesics 
for breakthrough pain within 12hours prior to an efficacy assessment visit.
6.10.1.4.
Chinese traditional medicine
Stable use of Chinese traditional medicine that has indications for RA is permitted if the 
dose is stable for at least 4 weeks prior to Day 1 (baseline).  This dose should remain 
constant throughout the first 12 weeks of the study.
6.10.2.
Prohibited Medications and Non-Drug Therapies
6.10.2.1.
Related to the Study

Any conventional DMARDs other than MTX (including leflunomide, sulfasalazine, 
azathioprine, bucillamine, iguratimod, tacrolimus).

Any biologic agent (such as TNF inhibitors such as adalimumab, etanercept, 
infliximab, certolizumab pegol, golimumab or non-TNF inhibitors (including 
abatacept, rituximab, tocilizumab and belimumab), tofacitinib and any anti-
rheumatic investigational compounds.

Any alkylating agents (such as cyclophosphamide).

Plasmapheresis or intravenous immunoglobulin (IVIG).

Oral corticosteroid above 10 mg/day predonisone or equivalent agent.

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.


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
IV and/or IM steroids are not permitted for at least 4 weeks prior to Day 1, or 
throughout the study.

Live vaccines should not be administered for at least 30 days (or 1 year for BCG 
vaccination) prior to Day 1, or 12 weeks after the last dose of GSK3196165.  On the 
other hand, inactivated vaccines (including toxoid) can be administered throughout 
the study.  However, 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 law and guideline.
6.10.2.2.
Related to Methotrexate
Refer to prescribing information for warnings, precautions and contraindications with 
MTX treatment.

Prohibited:
Concomitant administration of folate antagonists such as co-trimoxazole*
(trimethoprim-sulfamethoxazole), triamterene and nitrous oxide are prohibited.
*: When a preventive dose is required for subjects considered at high risk of
pneumocystis pneumonia (PCP) after the initiation of treatment by the 
investigator’s judgement, the approved low dose of co-trimoxazole is allowed (1 
tablet daily or 3 times a week).
Vitamin preparations containing folic acid or its derivatives may alter response to 
MTX (although folic acid is required to reduce the side-effects of MTX, it must 
not be administered on the same day as MTX).

Caution:
The following medications may increase side-effects of MTX (including bone-
marrow suppression, hepatotoxicity, nephrotoxicity, gastrointestinal toxicity).

NSAIDs (including salicylates)

sulfonamides, tetracyclines, chloramphenicol, phenytoin, barbituric acid 
derivatives

penicillins (including piperacillin sodium), probenecid

ciprofloxacin
The following medication may photosensitivity.

porfimer sodium
6.10.2.3.
Complementary Therapies other than Chinese traditional medicine
The use of complementary therapies that may affect RA disease activity or assessments, 
including, but not limited to, traditional medicine (e.g. Acupuncture, Ayurveda) is 
prohibited.


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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).
The following points must be noted:

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order before administration of study treatment:
1）
Patient- reported outcome (PRO) assessments
2）
12-lead ECG
3）
vital signs
4）
blood draws
Note: The timing of the assessments should allow the blood draw to occur at the exact 
nominal time.


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7.1.
Time and Events Table
Procedures
Screen-
ing
Baseline
Treatment Period
FU
EW1
Last Visit
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Week
(up to 4 
weeks)
0
1
2
3
4
6
8
10
12
15
18
22
Day
1
3*
8
15
22
29
43
57
71
74*
85
106
127
155
Allowance
±1 day
±3 days
±1 day
±3 days
±1 week
Written Informed Consent(s)
X
Subject Demography
X
Medical, Disease, Therapy History
X
Inclusion/Exclusion Criteria
X
Efficacy and PRO Assessments3
Swollen (66) & Tender (68) Joint 
Count2
X
X4
X
X
X
X
X
X
X
X
Patient’s Assessment of Arthritis Pain, 
Patient’s Global Assessment of 
Arthritis, Physician’s Global 
Assessment of Arthritis3
X
X4
X
X
X
X
X
X
X
X
HAQ-DI3
X
X4
X
X
X
X
X
X
X
X
FACIT-Fatigue3
X4
X
X
X
X
Safety Evaluations5
Concomitant Medication
X
X
Record all concomitant medications
Height6, Body weight
X
X
X
X
X
Other Physical Examination7
X
X4
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG8
X
X
X
AEs/SAEs/AESIs
X9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cough, Lung Auscultation,
Pulse Oximetry,
Borg Dyspnea Scale
X
X4
X
X
X
X
X
X
X
X
X
X
Chest X-ray10
X
Spirometry (FEV1, FVC)
X
X
X
X
DLCO
X11
X
X
X


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Procedures
Screen-
ing
Baseline
Treatment Period
FU
EW1
Last Visit
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Week
(up to 4 
weeks)
0
1
2
3
4
6
8
10
12
15
18
22
Day
1
3*
8
15
22
29
43
57
71
74*
85
106
127
155
Allowance
±1 day
±3 days
±1 day
±3 days
±1 week
Laboratory Assessments
Hematology, Chemistry (except for lipid 
and pregnancy test)
X
X4
X
X
X
X
X
X
Urinalysis (dip stick)
X
X
X
X
X
X
Cholesterol, triglycerides, HDL, LDL12
X4
X
X
X
Pregnancy test13
S
U
U
U
U
U
U
TB, HBsAg, HepB cAb, HBs Ab, HepC 
Ab, HIV, HBV DNA**
X
HBV DNA monitoring (HBs Ab positive 
subject only)
X
X
X
X
X
X
X
RF, ACPA (anti-CCP)
X
ESR14
X4
X
X
X
X
X
X
X
X
CRP
X
X4
X
X
X
X
X
X
X
X
Other Laboratory Assessments
PK blood sampling (GSK3196165)15
X4
X
X
X
X
X
X
X
X
X
X
X
X
Free GM-CSF, GM-CSF-GSK3196165
complex
X4
X
X
X
X
X
X
X
X
X
PD blood biomarkers
X4
X
X
X
X
RNA blood biomarker
X4
X
X
X
PGx sampling DNA16
X4
Lung biomarkers
X4
X
X
X
Immunogenicity (anti-GSK3196165 
antibody)17
X4
X
X
X
X
X
Anti-GM-CSF auto-antibodies
X4
Study Treatment 
GSK3196165/placebo18
X
X
X
X
X
X
X
X
ACPA: Anti-cyclic citrullinated protein antibody,  CCP: Cyclic citrullinated peptide,  ESR: Erythrocyte sedimentation rate,  FVC: Forced vital capacity,  HAQ-DI: Health Assessment 
Questionnaire Disability Index,  HBV: Hepatitis B virus,  HDL: High-density lipoprotein,  LDL: Low-density lipoprotein,  RF: Rheumatoid factor.


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1. All subjects who withdraw from the study should have an early withdrawal (EW) visit as soon as possible after study agent discontinuation and then return for a follow-up visit (the 
last visit) for 10 weeks (12 weeks after last dose of study medication).
2. The same individual (where possible) should perform all disease assessments for an individual subject.
3. PRO assessments should be conducted before any tests, procedures, assessments or consultations, to avoid influencing the subjects’ perception.
4. Assessments may be performed up to 24hours before dosing GSK3196165/placebo.
5. All safety evaluations should be conducted before dosing GSK3196165/placebo.
6. Height will be measured at only screening.
7. Complete physical at screening, and then limited physical examination (see Section 7.4.7) thereafter.
8. 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 7.4.9).
9. Only SAEs related to study participation or related to a GSK product will be recorded from the time a subject consents to participate in the study.
10. Unless performed within previous 12 weeks (No need to repeat if subject re-screened).
11. Chest HRCT if DLCO ≥60% - <70% predicted (No need to repeat if subject re-screened).
12. ≥8 hours fasting required before blood draw.
13. For women of child-bearing potential. S=serum; U=urine.
14. ESR measured locally.
15. PK sampling should be collected before dosing at the visits scheduled study treatment (GSK3196165/placebo). At the visits doesn't scheduled study treatments, it may be collected 
in any time during the visit. (Day 3, 74, 85, 106, 127, 155, and early withdrawal visit).
16. In consenting subjects.
17. In addition to these scheduled immunogenicity assessments, “event-driven” testing will also be employed for those subjects that experience anaphylaxis, serious hypersensitivity, or 
adverse events related to study drug administration that led to withdrawal from the study (see Section 7.5).
18. GSK3196165 or placebo must be administered on the same day each week ±1 day for the first 5 weekly doses, thereafter on the same day EOW ±3 days for bi-weekly doses.
* The Day 3 (Visit 3) blood sample must be drawn 2 days (1 day is allowable) after the first dose, and the Day 74 (Visit 11) blood sample must be drawn 3 days (1 day is allowable) 
after the last dose.
** HBV-DNA sample will be collected from all subjects, and HBV-DNA will be tested for only subjects with HBs Ab positive.


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7.2.
Screening and Critical Baseline Assessments
After written, informed consent, 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 4 weeks of Day 1 (except for subjects being 
treated with azathioprine or leflunomide, where written informed consent for the study 
must be obtained prior to discontinuing these drugs and beginning the screening period).  
Women and men of reproductive potential must consent to use of a highly effective 
method of contraception for the period predefined in Appendix 2.

The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.

Medical/medication/family history will be assessed as related to the 
inclusion/exclusion criteria listed in Section 5.

Cardiovascular medical history/risk factors (as detailed in the eCRF) will be 
assessed at screening.

Rheumatoid arthritis history – disease duration, medication history, RA functional 
class (I, II or III) will be confirmed.

The following examination, confirmation and test will be conducted.

Physical examination (complete examination at screening, and brief examination 
at Day 1 visit; see Section 7.4.7).

Vital signs including temperature, systolic and diastolic blood pressure, pulse rate, 
and respiratory rate.

Triplicate 12-lead ECG (screening only).

Chest X-ray (posterior to anterior [PA] and lateral, or in accordance with local 
requirements) (screening only).

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.

Spirometry FEV1, FVC and DLCO (see SRM for additional details) (screening 
only).

Baseline chest HRCT for subjects with DLCO values between ≥60% - <70%, 
and it is recommended that the subject will be reviewed by a local 
pulmonologist to exclude significant pre-existing respiratory disease.

Cough, Lung Auscultation, Pulse Oximetry, Borg Dyspnea Scale.

AEs reporting and recording of concomitant medications.

Blood samples will be taken for:

Hematology.

Biochemistry.


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
Serum beta subunit human chorionic gonadotropin (βhCG) pregnancy test 
(screening only).

HIV antibody, Hepatitis B surface antigen, anti-HBc, and Hepatitis C 
antibody testing (screening only).

CRP.

ESR (baseline only).

Cholesterol, triglycerides, high density lipoprotein (HDL) and low density 
lipoprotein (LDL) (baseline only).

Autoimmune serology: RF and ACPA (i.e., anti-CCP antibodies) (screening 
only).

T-spot test for TB (screening only).

Exploratory GM-CSF, PD, lung biomarkers and anti-GM-CSF auto-
antibodies (baseline only).

PK samples and immunogenicity (anti-GSK3196165 antibody) (baseline 
only).

RNA (in consenting subjects) (baseline only).

Pharmacogenomic DNA (in consenting subjects) (baseline only).

Urine sample will be taken for:

Routine urinalysis (screening only).

Urine βhCG pregnancy test (baseline only).

Disease activity assessments (see Section 7.6) and Patient-reported outcome 
(PRO) questionnaires (see Section 7.9):

Tender joint count (68 joints).

Swollen joint count (66 joints).

Patient’s Assessment of Arthritis Pain.

Patient’s Global Assessment of Arthritis.

Physician’s Global Assessment of Arthritis.

HAQ-DI.

FACIT-Fatigue (baseline only).
Patient-reported outcomes questionnaires should be completed by subjects before any 
other assessment at a clinic visit, in the order specified in the SRM.
7.3.
Pharmacokinetics
Blood samples for pharmacokinetic analysis of GSK3196165 will be collected at the time 
points indicated in the Time and Events Table (Section 7.1).  The actual date and time of 
each blood sample will be recorded.  The timing of PK samples may be altered and/or PK 


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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 SRM.
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 for samples in GSK3196165 group, but not in placebo group.  
Raw data will be archived at the bioanalytical site (detailed in the SRM).
PK analyses are described in Section 9.4.1 and Section 9.4.5.1.
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).
7.4.1.
Study visits
Subjects will have systematic safety monitoring throughout the study.  Additional time 
points for safety tests (such as vital signs, physical exams and laboratory safety tests) 
may be added during the course of the study based on newly available data to ensure 
appropriate safety monitoring.
In addition to routine laboratory assessments, ECG monitoring, and evaluation of adverse 
events, particular attention will be paid to respiratory events and function given the 
potential risk associated with targeting GM-CSF and the effects on alveolar macrophages.  
This may result in the occurrence of the extremely rare condition of PAP, which is 
characterized by the accumulation of surfactant lipids and protein in the alveolar spaces 
(with no fibrosis), with resultant impairment in gas exchange, which may lead to increase 
a risk of secondary pulmonary infections.
All subjects will return for a follow-up visit at10 weeks after completion/withdrawal of 
treatment period.  Particular attention will be paid to withdrawal symptoms given the 
potential risk associated with release of immune suppression.
7.4.2.
Safety endpoints and other assessments

Incidence of AEs/SAEs.

Incidence of AESI (such as serious infections and opportunistic infections) (see 
Section 7.4.5).

Pulmonary events (cough, dyspnea, pulse oximetry, spirometry, DLCO).

Lung biomarkers (such as SP-D, KL-6, cholestenoic acid).

ECG measurements.

Vital signs.

Hematological and clinical chemistry parameters.


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
Physical examinations.

Pregnancy test (for women of child-bearing potential).

Immunogenicity (anti-GSK3196165 antibody).
7.4.3.
Adverse Events (AEs) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 5.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
7.4.3.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the follow-
up contact (12 weeks after the last dose of investigational product), at the timepoints 
specified in the Time and Events Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF.

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact.

All SAEs will be recorded and reported to GSK within 24hours, as indicated in 
Appendix 5.

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 5.
7.4.3.2.
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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7.4.3.3.
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 7.4.5) 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 4.
7.4.3.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 5 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF will 
be required to be completed.  These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death.
The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms.  The CV information should be recorded in the specific cardiovascular section of 
the eCRF within one week of receipt of a CV Event data query prompting its completion.
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported.  Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.4.4.
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, vital signs measurements), including those that 
worsen from baseline, and felt to be clinically significant in the medical and scientific 
judgement of the investigator are to be recorded as AEs or SAEs.
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs.
7.4.5.
AEs 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.

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.


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Non life threatening pulmonary changes related to surfactant accumulation.

PAP.

Hypersensitivity reactions, including anaphylaxis.

Injection site reactions.
7.4.5.1.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The following have been specified as disease-related events (DREs) for the study:

Events related to exacerbation of articular/peri-articular manifestations of RA, will 
not be reported as AEs, and will be recorded in the DRE eCRF.

Events related to the articular/peri-articular flare up of the disease, and that require 
hospitalization, will not be reported as SAEs.  However, such events must still be 
recorded in the DRE eCRF.
These DREs will be monitored by a Safety Review Team (SRT) on a routine basis.
NOTE: However, if either of the following conditions apply, then the event must be 
recorded and reported as an SAE (instead of a DRE):

The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual subject.
OR

The investigator considers that there is a reasonable possibility that the event was 
related to treatment with the investigational product.
New onset or worsening of extra-articular manifestations of RA should be reported as 
AEs/SAEs.
7.4.5.2.
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.
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.


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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 GSK3196165 IB and will notify the IRB/IEC, if appropriate according to local 
requirements.
7.4.6.
Pregnancy

Any pregnancy (participating females and female partners of participating males) 
that occurs from first administration of investigational product to the follow-up visit 
must be reported.

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 6.
7.4.7.
Physical Exams

A complete physical examination at the Screening visit will include, at a minimum, 
assessment of the Cardiovascular, Respiratory, Gastrointestinal and Neurological 
systems.  Height and weight will also be measured and recorded.

A brief physical examination at subsequent assessments will be performed as
indicated in the Time and Event Table (Section 7.1) and include, at a minimum 
assessments of the skin, lungs, cardiovascular system, and abdomen (liver and 
spleen).  Body weight will also be measured and recorded.

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
7.4.8.
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 after 5 minutes rest and will include temperature, 
systolic and diastolic blood pressure, pulse rate and respiratory rate.

A single set of values will be collected and recorded in the source documentation 
and eCRF.
7.4.9.
Electrocardiogram (ECG)

Triplicate 12 lead ECGs will be obtained at screening, then single 12 lead ECGs will 
be obtained 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., 5-10minutes).  Refer to Section 5.4.2 for QTc withdrawal 
criteria and additional QTc readings that may be necessary.


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7.4.10.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 3, must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedule 
(Section 7.1).  Laboratory requisition forms must be completed and samples must be 
clearly labelled with the subject number, protocol number, site/centre number, and visit 
date.  Details for the preparation and shipment of samples will be provided by the 
laboratory and are detailed in the Central Laboratory Manual.  Reference ranges for all 
safety parameters will be provided to the site by the laboratory responsible for the 
assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF.
Refer to the central laboratory manual for appropriate processing and handling of samples 
to avoid duplicate and/or additional blood draws.
All study-required laboratory assessments will be performed by a central laboratory, apart 
from:

ESR: The results of each test must be entered into the eCRF.
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 3.
Table 3
Routine Laboratory Assessments
Hematology
Biochemistry
Urinalysis 
Hemoglobin
Hematocrit
Mean corpuscular volume (MCV)
Mean corpuscular hemoglobin (MCH)
Mean corpuscular hemoglobin concentration 
(MCHC)
Erythrocyte count
Reticulocyte count
Leukocyte count
Leukocyte differential count
neutrophils
eosinophils
basophils
monocytes
lymphocytes
Platelets
Activated partial thromboplastin time (aPTT)
Prothrombin Time (PT)
Sodium
Potassium
Calcium
Phosphate
Urea nitrogen
Creatinine
Creatinine clearance 
(calculated)
Aspartate transaminase (AST)
Alanine transaminase (ALT)
γ-glutamyl transpeptidase 
(GGT)
Lactate dehydrogenase (LDH)
Alkaline phosphatase (ALP)
Bilirubin (total)
Creatine Phosphokinase 
(CPK)
Total protein
Urine dipstick
  Glucose
  Protein
  
Microscopy of urine 
sediment for 
erythrocytes, 
leukocytes and 
casts if urine 
dipstick abnormal
Urine pregnancy 
test


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Hematology
Biochemistry
Urinalysis 
International Normalised Ratio (INR)
Fibrinogen
Erythrocyte Sedimentation Rate (ESR)*
Albumin
Albumin/globulin ratio
Glucose
C-reactive protein (CRP)
Cholesterol**
Triglycerides**
High-density lipoprotein 
(HDL)**
Low-density lipoprotein 
(LDL)**
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 and cholestenoic acid (see Section 7.7).  
Baseline measurement of GM-CSF autoantibodies will be measured.
7.4.11.
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)
Further details of this assessment are provided 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), the subject should be referred to a pulmonologist for further 
assessment.  The study treatment should be suspended until the symptoms or signs that 


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caused referral have resolved and/or the underlying diagnosis has been determined and 
clinically significant events have been excluded by the pulmonologist.
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.
7.5.
Immunogenicity
Serum samples will be collected and tested for presence of antibodies that bind to 
GSK3196165.  Serum samples for testing anti-GSK3196165 antibodies will be collected 
as described in Section 7.1, Time and Events Table.  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 
Study Reference Manual (SRM).
The timing and number of planned immunogenicity samples may be altered during the 
course of the study, based on newly-available data to ensure appropriate safety 
monitoring.  In the event of a hypersensitivity reaction that is either 1) clinically-
significant in the opinion of the investigator, or 2) leads to the subject withdrawing from 
the study, blood samples should be taken from the subject for immunogenicity testing, at 
the time of the event and again 12 weeks after.  For subjects who prematurely withdraw 
from the study, immunogenicity testing will occur at withdrawal and at follow-up 12 
weeks after last dose.
Serum will be tested for the presence of anti-GSK3196165 antibodies using the currently 
approved analytical methodology using a tiered testing schema: screening, confirmation 
and titration steps.  The presence of treatment emergent anti-drug antibodies (ADA) will 
be determined using a GSK3196165 bridging style ADA assay with a bio-analytically 
determined cut point determined during assay validation.  Samples taken after dosing 
with GSK3196165 that have a value at or above the cut-point will be considered 
treatment-emergent ADA-positive.  These ADA positive samples will be further 
evaluated in a confirmatory assay, and confirmed positive samples will be further 
characterized by assessment of titer.  Results of anti-GSK3196165 antibody testing will 
be reported at the end of the study and will include incidence and titer.  The presence or 
absence of antibodies to GSK3196165 in dosed subjects will be analyzed, then 
summarized descriptively and/or graphically presented.
7.6.
Efficacy
Efficacy assessments will include:

Evaluation of all 68 joints for tenderness and 66 joints for swelling to be performed 
by an independent joint evaluator.

VAS (global disease) for the subject and treating physician.

VAS (pain) for the subject.


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
Health assessment questionnaire – disability index (HAQ-DI), as well as other PRO 
assessments described in more detail in Section 7.9.

Laboratory assessments (CRP, ESR). 
Based on these assessments DAS28(CRP), ACR (20, 50 and 70), the EULAR response, 
SDAI and CDAI will be calculated.
7.6.1.
Joint Assessments
The procedure for joint assessments can be found in the SRM.
7.6.1.1.
Excluded from Joint Assessments
Replaced or fused joint will not be included in joint evaluations.  In addition, if the 
subjects who has had an intra-articular corticosteroid injection, that joint will not be 
included in joint evaluation at Week 12.  The reason for absence of the evaluations of 
those joints must be recorded.
7.6.1.2.
Independent Joint Evaluator
One or more independent assessors, who have experience in performing joint 
assessments, will be designated at each trial site to perform joint assessments.  Preferably 
the same independent assessor will perform all joint assessment for the same subject 
throughout the trial.  The principal investigator must ensure that the independent joint 
assessor can perform joint assessment properly.  This also applies if the independent joint 
assessor is replaced during the trial.
The independent joint assessor should have no other contact with the subject during the 
trial, must not be the treating physician (investigator), should not discuss the subject's 
clinical status with the subject during the joint assessment nor with other site personnel, 
and will not be permitted to review the subject's medical records, the eCRF, nor any of 
the previous joint assessments.
7.6.2.
Patient’s Assessment of Arthritis Pain
Subjects will assess the severity of their current arthritis pain using a 10 unit visual 
analog scale (VAS) by placing a mark on the scale between “0” (no pain) and “10” (most 
severe pain), which corresponds to the magnitude of their current pain.
Subjects will also assess the severity of their past week's arthritis pain using a 100 unit 
visual analog scale (VAS) by placing a mark on the scale between “0” (no pain) and 
“100” (severe pain), which corresponds to the magnitude of their pain for the past week.
Further details of this assessment are provided in the SRM.
7.6.3.
Patient’s Global Assessment of Arthritis
Subjects will complete a global assessment of disease activity using the patient global 
assessment (PtGA) visual analog scale, a VAS with anchors “0” (very well) to “10” (very 
poor).


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Further details of this assessment are provided in the SRM.
7.6.4.
Physician’s Global Assessment of Arthritis
Physicians will complete a global assessment of disease activity using the physician 
global assessment item (PhGA), a VAS with anchors “0” (none) to “10” (extremely 
active), respectively.
Further details of this assessment are provided in the SRM.
7.6.5.
DAS Assessments
The Disease Activity Score (DAS) assessment is a derived measurement with differential 
weighting given to each component.  The DAS 28(CRP) or DAS 28(ESR) will be 
calculated at each assessment timepoint.
The components of the DAS 28 arthritis assessment include:

Tender/Painful Joint Count (28).

Swollen Joint Count (28).

CRP or ESR.

Patient’s Global Assessment of Arthritis.
Sites/investigators will not have access to ongoing DAS scores, apart from the screening 
results (needed to confirm eligibility).
The DAS28 score is calculated using the following formula, where TJC = tender joint 
count, SJC = swollen joint count, PtGA = patients global assessment (mm), CRP = C-
reactive protein (mg/L) and ESR = Erythrocyte sedimentation rate (mm/hr):
7.6.5.1.
Disease activity criteria based on DAS28 score
The disease activity is classified into the below 4 categories based on the calculated DAS 
28 score.  Remission is achieved by a DAS28 score lower than 2.6.
DAS28 score
Categories
>5.1
High disease activity
3.2~ 5.1
Moderate disease activity
<3.2
Low disease activity
<2.6
Remission


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7.6.5.2.
EULAR response criteria based on DAS28 score
The EULAR response criteria based on DAS 28 score are used to assess the response of 
the disease activity.
DAS28 score at 
timepoints
Change from baseline (Day 1) in DAS 28
>1.2
>0.6 ~ 1.2
0.6
<3.2
Good
Moderate
None
3.2～5.1
Moderate
Moderate
None
>5.1
Moderate
None
None
7.6.6.
ACR Assessments
The American College of Rheumatology’s definition for calculating improvement in RA 
(ACR20) is calculated as a 20% improvement in tender and swollen joint counts and 20% 
improvement in 3 of the 5 remaining ACR-core set measures: patient and physician 
global assessments, pain, disability, and an acute-phase reactant.  Similarly, ACR50 and 
70 are calculated with the respective percent improvement.  This efficacy measurement 
will be made at every study assessment timepoint.
The specific components of the ACR Assessments that will be used in this study are:

Tender/Painful Joint count (68).

Swollen Joint Count (66).

Patient’s Assessment of Arthritis Pain.

Patient’s Global Assessment of Arthritis.

Physician’s Global Assessment of Arthritis.

CRP or ESR.

Health Assessment Questionnaire – Disability Index (HAQ-DI).
7.6.7.
SDAI and CDAI
The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index 
(CDAI) are assessment methods for the disease activity and are determined using more 
simple formula than DAS28.  These score will be calculated at each assessment 
timepoint.
The components of the SDAI and CDAI score include:

Tender/Painful Joint Count (28).

Swollen Joint Count (28).


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
CRP (Only SDAI).

Patient’s Global Assessment of Arthritis.

Physician’s Global Assessment of Arthritis.
The SDAI and CDAI score are calculated using the following formula, where TJC = 
tender joint count, SJC = swollen joint count, PtGA = patients global assessment (cm)
and PhGA = physicians global assessment (cm):
SDAI = SJC28 ＋TJC28 ＋PtGA/10 ＋PhGA/10 ＋CRP (mg/dl)
CDAI = SJC28 ＋TJC28 ＋PtGA/10 ＋PhGA/10
7.7.
Biomarker(s)/Pharmacodynamic Markers
Blood samples for biomarker/pharmacodynamic analysis will be collected at the time 
points indicated in the Time and Events Table (Section 7.1).  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 SRM.  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.
The following biomarkers/pharmacodynamic endpoints will be assessed:

Target engagement: analysis of free soluble GM-CSF and soluble GM-CSF 
complexed to GSK3196165.

Soluble biomarkers which may be predictive of response to GSK3196165 such as 
MRP8/14, ARGS neoepitope, YKL-40 and 14-3-3η.

Serum cytokines to monitor mechanism of action of GSK3196165 such as IL-6, IL-
1β, TNFα, IL-17A and IL-17F.

Safety biomarkers which may be predictive of lung damage including the following: 
SP-D, KL-6, cholestenoic acid and measurement of GM-CSF autoantibodies at 
baseline.

These will be analysed at the end of the study or in the event of a pulmonary safety 
signal which would require further investigation.
Additional exploratory biomarkers in the blood/serum (RNA) will be collected from only 
consenting subjects and may include but will not be limited to the following:

RNA analysis of blood.
7.8.
Pharmacogenetics
Information regarding pharmacogenetic (PGx) is included in Appendix 7.


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7.9.
Value Evidence and Outcome
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.
7.9.1.
HAQ-DI
The functional status of the subject will be assessed by means of the Disability Index of 
the Health Assessment Questionnaire (HAQ-DI) (see Appendix 6).  This 20-question 
instrument assesses the degree of difficulty a person has in accomplishing tasks in eight 
functional areas[Fries, 1980; Matsuda, 2003] :

dressing and grooming, arising, eating, walking, hygiene, reach, grip, and common 
daily activities.
7.9.2.
FACIT-Fatigue
The Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue questionnaire is 
a patient-reported measure validated and developed originally to assess fatigue in 
individuals with cancer (see Appendix 6).  The FACIT-fatigue has subsequently been 
used and validated in numerous chronic conditions, including RA.
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.

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
A detailed description of any planned analyses will be documented in a Reporting and 
Analysis Plan (RAP).  Any deviations from the analyses described in the protocol will be 
documented in the RAP or the final study report.


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9.1.
Hypotheses
The primary objective of this study is to assess the PK, safety and tolerability of 
GSK3196165 in combination with MTX therapy in Japanese RA subjects.  No formal 
hypotheses to be tested.  Two-sided 90% confidence intervals will be used for PK 
estimation.
9.2.
Sample Size Assumptions
The sample size is determined based on feasibility.  A total of 40 subjects will be 
randomized in a 1:1:1:1 proportion to receive GSK3196165 doses of 45 mg, 90 mg, 
180 mg or placebo.
Table 4 provides the precision of percentage of subjects with specific adverse events in 
each group with 10 subjects.
Table 4
Precision of percentage of subjects with specific adverse events in 
each group with 10 subjects
Number of subjects
Number of particular
safety events observed
Exact 95% confidence intervals
10
1
0.3% - 44.5%
10
2
2.5% - 55.6%
10
3
6.7% - 65.2%
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations

All Screening Population: The All Screening Population consists of all subjects who 
are given subject number and whose data including demographics are collected at 
screening.

Randomized population: The randomized population is defined as all subjects who 
were randomized to treatment regardless of whether they actually receive study 
treatment.  

Intention to Treat (ITT) Population: The ITT Population consists of all randomized 
subjects who receive at least one dose of study treatment.  This population will be 
used for efficacy and safety analyses.

Pharmacokinetic (PK) population: The PK Population consists of all GSK3196165-
treated subjects from whom PK samples are collected and analyzed.
Additional populations may be defined in the RAP.


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9.3.2.
Interim Analysis
No interim analysis in midstream of the treatment period is planned.  However once all 
subjects have completed visits in the treatment period, an interim analysis may be 
performed to discuss within GSK and consult with the regulatory authority on the future 
development plan of GSK3196165.  In that case all data up to the end of treatment period 
for each subject will be frozen and then the randomization schedule will be unblinded for 
the analysis.
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
For serum concentrations of GSK3196165 over time, individual data will be listed and 
presented in graphical form, and summary statistics at each time point will be calculated 
by each dose level.  The following PK variables will be derived as data allowed: Cmax, 
tmax, AUCtau, AUC(0-inf), and t1/2.  For PK parameters, summary statistics will be 
calculated by each dose level, and scatter plots against the dose level will be generated.  
Dose proportionality will also be assessed with the power model.
A population pharmacokinetic modeling approach may be further applied to model the 
drug concentration data obtained in the study in the future.  Further details of population 
pharmacokinetic analyses will be described in a separate Reporting and Analysis Plan 
(RAP) if population PK analyses is performed.”
9.4.2.
Safety Analyses
All adverse events will be coded using MedDRA and summarized by System Organ 
Class (SOC) and Preferred Term (PT).  The number and percentage of subjects with any 
adverse events will be summarized by dose.  The study treatment-related AEs, SAEs, 
AEs leading to discontinuation of study treatment, and AEs of special interest will be 
reported separately.
For other safety parameters, such as laboratory assessment, vital signs, 12-lead ECG, and 
anti-GSK3196165 antibody, safety biomarkers, data and/or change from baseline will be 
summarized with descriptive statistics at each assessment visit by dose.
9.4.3.
Immunogenicity Analyses
Details of the statistical analysis will be provided in the RAP.
9.4.4.
Efficacy Analyses
The ITT population with observed case dataset will be used for efficacy analyses.  Time 
course of the change from baseline in DAS28(CRP) will be analyzed by mixed model for 
repeated measurements (MMRM). The dose response analyses will be performed on the 
change from baseline in DAS28(CRP) at Week 12.  Full details for all efficacy analyses 
will be given in the RAP.


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9.4.5.
Biomarker(s)/Pharmacodynamic Marker(s) Analyses
All pharmacodynamic data will be summarised, graphically represented and listed 
appropriately.  More details are included in the RAP.
9.4.5.1.
Pharmacokinetic/Pharmacodynamic Analyses
Exploratory plots will be presented for individual and/or pooled plasma GSK3196165 
concentrations versus pharmacodynamic markers or efficacy endpoints.  If data permit, 
potential association between systemic exposure of GSK3196165 and identified 
pharmacodynamic markers (e.g. CRP, MRP8/14) and efficacy endpoints (e.g. change in 
DAS28(CRP) score from baseline) will be explored.  More details are included in the 
RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable.

Signed informed consent to be obtained for each subject before participation in the 
study (and for amendments as applicable).

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC).

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.


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


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


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
The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership 
of the records in the event the investigator is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication

Where required by applicable regulatory requirements, an investigator signatory will 
be identified for the approval of the clinical study report.  The investigator will be 
provided reasonable access to statistical tables, figures, and relevant reports and will 
have the opportunity to review the complete study results at a GSK site or other 
mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study subjects, 
as appropriate.

GSK will provide the investigator with the randomization codes for their site only 
after completion of the full statistical analysis.

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.


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11.
REFERENCES
Behrens F, Tak PP, Ostergaard M, et al. MOR103, a human monoclonal antibody to 
granulocyte-macrophage colony-stimulating factor, in the treatment of patients with 
moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, 
placebo-controlled, dose-escalation trial. Ann Rheum Dis. 2015;74(6):1058-64. 
Bell AL, Magill MK, McKane WR, et al. Measurement of colony-stimulating factors in 
synovial fluid: potential clinical value. Rheumatol Int. 1995;14(5):177-82. 
Bresnihan B, Pontifex E, Thurlings RM, et al. Synovial tissue sublining CD68 expression 
is a biomarker of therapeutic response in rheumatoid arthritis clinical trials: consistency 
across centers. J Rheumatol. 2009;36(8):1800-2. 
Burmester G, McInnes IB, Kremer JM, et al. Efficacy and safety/tolerability of 
mavrilimumab, a human GM-CSFRα monoclonal antibody in patients with rheumatoid 
arthritis. Arthritis and Rheumatology. 2014;66(SUPPL. 10 ):S1231-2. 
Burmester GR, Weinblatt ME, McInnes IB, et al. Efficacy and safety of mavrilimumab in 
subjects with rheumatoid arthritis. Ann Rheum Dis. 2013;72(9):1445-52. 
Campbell IK, Bendele A, Smith DA, et al. Granulocyte-macrophage colony stimulating 
factor exacerbates collagen induced arthritis in mice. Ann Rheum Dis. 1997;56(6):364-8. 
Choy EHS, Connolly DJA, Rapson N, et al. Pharmacokinetic, pharmacodynamic and 
clinical effects of a humanized IgG1 anti-CD4 monoclonal antibody in the peripheral 
blood and synovial fluid of rheumatoid arthritis patients. Rheumatology (Oxford). 
2000;39(10):1139-46. 
Common Terminology Criteria for Adverse Events (CTCAE) Study ID v 4.0. . 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf. Report Date 28 May 2009. 
Cook AD, Braine EL, Campbell IK, et al. Blockade of collagen-induced arthritis post-
onset by antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF): 
requirement for GM-CSF in the effector phase of disease. Arthritis Res. 2001;3(5):293-8. 
Cornish AL, Campbell IK, McKenzie BS, et al. G-CSF and GM-CSF as therapeutic 
targets in rheumatoid arthritis. Nat Rev Rheumatol. 2009;5(10):554-9. 
Dang PM, Dewas C, Gaudry M, et al. Priming of human neutrophil respiratory burst by 
granulocyte/macrophage colony-stimulating factor (GM-CSF) involves partial 
phosphorylation of p47(phox). J Biol Chem. 1999;274(29):20704-8. 
Davis JM III, Knutson KL, Strausbauch MA, et al. Analysis of complex biomarkers for 
human immune-mediated disorders based on cytokine responsiveness of peripheral blood 
cells. J Immunol. 2010;184(12):7297-304. 


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Detert J, Bastian H, Listing J, et al. Induction therapy with adalimumab plus methotrexate 
for 24 weeks followed by methotrexate monotherapy up to week 48 versus methotrexate 
therapy alone for DMARD-naïve patients with early rheumatoid arthritis: HIT HARD, an 
investigator-initiated study. Ann Rheum Dis. 2013;72(6):844-50. 
Emery P, Hammoudeh M, FitzGerald O, et al. Assessing maintenance of remission with 
reduced dose etanercept plus methotrexate, methotrexate alone, or placebo in patients 
with early rheumatoid arthritis who achieved remission with etanercept and 
methotrextate: the prize study. Ann Rheum Dis. 2013;72(Suppl3):A399. 
Evers R, Dallas S, Dickmann LJ, et al. Critical review of preclinical approaches to 
investigate cytochrome P450-mediated therapeutic protein drug-drug interactions and 
recommendations for best practices: A white paper. Drug Metab Dispos. 
2013;41(9):1598-609. 
Fiehn C, Wermann M, Pezzutto A, et al. Plasma GM-CSF concentrations in rheumatoid 
arthritis, systemic lupus erythematosus and spondyloarthropathy. Z Rheumatol. 
1992;51(3):121-6. 
Fleetwood AJ, Lawrence T, Hamilton JA, et al. Granulocyte-macrophage colony-
stimulating factor (CSF) and macrophage CSF-dependent macrophage phenotypes 
display differences in cytokine profiles and transcription factor activities: implications for 
CSF blockade in inflammation. J Immunol. 2007;178(8):5245-52. 
Fries JF, Spitz P, Kraines RG, et al. Measurement of patient outcome in arthritis. Arthritis 
Rheum. 1980;23(2):137-45. 
Gasson JC. Molecular physiology of granulocyte-macrophage colony-stimulating factor. 
Blood. 1991;77(6):1131-45. 
Gaujoux-Viala C, Nam J, Ramiro S, et al. Efficacy of conventional synthetic disease-
modifying antirheumatic drugs, glucocorticoids and tofacitinib: a systematic literature 
review informing the 2013 update of the EULAR recommendations for management of 
rheumatoid arthritis. Ann Rheum Dis. 2014;73(3):510-5. 
GlaxoSmithKline Document Number 2014N190256_01 Study ID NA. GSK3196165 
Investigator’s Brochure. Report Date 26-Feb-2016. 
Goekoop-Ruiterman YPM, de Vries-Bouwstra JK, Allaart CF, et al. Clinical and 
radiographic outcomes of four different treatment strategies in patients with early 
rheumatoid arthritis (the beSt study): A randomized, controlled trial. Arthritis Rheum. 
2005;52(11):3381-90. 
Gomez-Cambronero J, Horn J, Paul CC, et al. Granulocyte-macrophage colony-
stimulating factor is a chemoattractant cytokine for human neutrophils: involvement of 
the ribosomal p70 S6 kinase signaling pathway. J Immunol. 2003;171(12):6846-55. 
Hamilton JA, Achuthan A. Colony stimulating factors and myeloid cell biology in health 
and disease. Trends Immunol. 2013;34(2):81-9. 


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Hamilton JA, Anderson GP. GM-CSF biology. Growth Factors. 2004;22(4):225-31. 
Haringman JJ, Gerlag DM, Zwinderman AH, et al. Synovial tissue macrophages: a 
sensitive biomarker for response to treatment in patients with rheumatoid arthritis. Ann 
Rheum Dis. 2005;64(6):834-8. 
Hart PH, Vitti GF, Burgess DR, et al. Activation of human monocytes by granulocyte-
macrophage colony-stimulating factor: increased urokinase-type plasminogen activator 
activity. Blood. 1991;77(4):841-8. 
Lee JI, Zhang L, Men AY, et al. CYP-mediated therapeutic protein-drug interactions: 
clinical findings, proposed mechanisms and regulatory implications. Clin Pharmacokinet. 
2010;49(5):295-310. 
LeVine AM, Reed JA, Kurak KE, et al. GM-CSF-deficient mice are susceptible to 
pulmonary group B streptococcal infection. J Clin Invest. 1999;103(4):563-9. 
Mantovani A, Sica A, Locati M. New vistas on macrophage differentiation and activation. 
Eur J Immunol. 2007;37(1):14-6. 
Mantovani A, Sozzani S, Locati M, et al. Macrophage polarization: tumor-associated 
macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 
2002;23(11):549-55. 
Matsuda Y, Singh G, Yamanaka H, et al. Validation of a Japanese Version of the 
Stanford Health Assessment Questionnaire in 3,763 Patients With Rheumatoid Arthritis. 
Arthritis & Rheumatism. 2003;49(6):784-8. 
Michelson J, Easley M, Wigley FM, et al. Foot and ankle problems in rheumatoid 
arthritis. Foot Ankle Int. 1994;15(11):608-13. 
Mulherin D, Fitzgerald O, Bresnihan B. Synovial tissue macrophage populations and 
articular damage in rheumatoid arthritis. Arthritis Rheum. 1996;39(1):115-24. 
Nakano K, Okada Y, Saito K, et al. Rheumatoid synovial endothelial cells produce 
macrophage colony-stimulating factor leading to osteoclastogenesis in rheumatoid 
arthritis. Rheumatology (Oxford). 2007;46(4):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(3):516-28. 
Plater-Zyberk C, Joosten LAB, Helsen MMA, et al. GM-CSF neutralisation suppresses 
inflammation and protects cartilage in acute streptococcal cell wall arthritis of mice. Ann 
Rheum Dis. 2007;66(4):452-7. 


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Smolen JS, Nash P, Durez P, et al. Maintenance, reduction, or withdrawal of etanercept 
after treatment with etanercept and methotrexate in patients with moderate rheumatoid 
arthritis (PRESERVE): a randomised controlled trial. Lancet. 2013;381(9870):918-29. 
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(12):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(1):135-44. 
Takeuchi T, Tanaka Y, Close D, et al. Efficacy and safety of mavrilimumab in Japanese 
subjects with rheumatoid arthritis: findings from a Phase IIa study. Mod Rheumatol. 
2015;25(1):21-30. 
Tanaka Y, Hirata S, Kubo S, et al. Discontinuation of adalimumab after achieving 
remission in patients with established rheumatoid arthritis: 1-year outcome of the 
HONOR study. Ann Rheum Dis. 2015;74(2):389-95. 
Yamanaka H, Sugiyama N, Inoue E, et al. Estimates of the prevalence of and current 
treatment practices for rheumatoid arthritis in Japan using reimbursement data from 
health insurance societies and the IORRA cohort (I). Mod Rheumatol. 2014;24(1):33-40. 
Zhou H, Mascelli MA. Mechanisms of monoclonal antibody-drug interactions. Annu Rev 
Pharmacol Toxicol. 2011;51:359-72. 


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ACPA
Anti-cyclic citrullinated protein antibody
ACR
American College of Rheumatology
ADA
Anti-drug antibody
AE
Adverse Event
AESI
Adverse events of special interest
ALP
Alkaline phosphatase
ALT
Alanine transaminase
aPTT
Activated partial thromboplastin time
AST
Aspartate transaminase
AUC
Area under the curve
BCG
Bacillus Calmette-Guérin
βhCG
Human chorionic gonadotropin β-subunit
CCP
Cyclic citrullinated peptide
CD
Cluster of differentiation antigen
CDAI
Clinical disease activity index
CIA
Collagen-induced arthritis
Cmax
Maximum concentration
Cmin
Minimum concentration
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic obstructive pulmonary disease
CPK
Creatine phosphokinase
CRP
C-reactive protein
csDMARD
Conventional synthetic disease modifying antirheumatic drugs
CT
Computer Tomography
CTCAE
Common terminology criteria for adverse events
CYP
Cytochrome P
DAS
Disease activity score
DAS28
Disease activity score for 28 different joints
DLCO
Diffusing capacity of the lung for carbon monoxide
DMARD
Disease modifying antirheumatic drugs
DNA
Deoxyribonucleic acid
DRE
Disease-related event
ESR
Erythrocyte sedimentation rate
EULAR
European League against Rheumatism
FACIT-Fatigue
Functional assessment of chronic illness therapy-Fatigue
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in one second
FRP
Females of reproductive potential
FSH
Follicle-stimulating hormone
FVC
Forced vital capacity


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GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GGT
γ-glutamyltranspeptidase
GM-CSF
Granulocyte-macrophage colony stimulating factor
GSK
GlaxoSmithKline
GSKDrug
GSKDrug
HAQ-DI
Health Assessment Questionnaire Disability Index
HBc
Hepatitis B virus core
HBs
Hepatitis B virus surface
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HDL
High-density lipoprotein
HIV
Human immunodeficiency virus
HLA
Human lymphocyte antigen
HPLC
High performance liquid chromatography
HRCT
High-resolution computed tomography
HRT
Hormone replacement therapy
IB
Investigator’s brochure
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IL
Interleukin
INR
International normalized ratio
ITT
Intent to Treat
JAK
Janus kinase
LDH
Lactate dehydrogenase
LDL
Low-density lipoprotein
mAb
Monoclonal antibody
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean cell volume
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed model for repeated measurements
MRI
Magnetic resonance imaging
MS
Multiple sclerosis
MSDS
Material Safety Data Sheet
MTX
Methotrexate
NOAEL
No observed adverse effect level
NOEL
No observed effect level
NSAID
Non-steroidal anti-inflammatory drug
NYHA
New York Heart Association
PA
Posterior to anterior
PAP
Pulmonary alveolar proteinosis


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PCR
Polymerase chain reaction
PCP
Pneumocystis pneumonia
PD
Pharmacodynamic
PGx
Pharmacogenetics
PK
Pharmacokinetics
PRO
Patient- reported outcome
PT
Prothrombin time
QTcF
QT intervals corrected by Fridericia's formula
RA
Rheumatoid arthritis
RAP
Reporting and analysis plan
RF
Rheumatoid factor
RNA
Ribonucleic acid
SAE
Serious adverse event
SC
Subcutaneous
SDAI
Simple disease activity index
SE
Sentinel event
SP-D
Surfactant D
SRM
Study Reference Manual
SRT
Safety Review Team
t1/2
Elimination half-life
tmax
Time to maximum concentration
TNF
Tumor necrosis factor
ULN
Upper limit of normal
VAS
Visual analog scale
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
InForm
MedDRA


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12.2.
Appendix 2: Contraception eligibility criteria for female and 
male subjects
12.2.1.
Female
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative serum human chorionic gonadotrophin [hCG] test), not lactating, and at least 
one of the following conditions applies:
1. 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.
2. 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.
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners, 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.

Intrauterine device or intrauterine system that meets the SOP effectiveness criteria 
including a <1% rate of failure per year, as stated in the product label

Combined estrogen and progestogen oral contraceptive [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 


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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.  The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
If using hormonal contraceptives, including oral, injections, implants, and patches, a 
secondary method of contraception must be used.
12.2.2.
Male
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.
b) Male condom plus partner use of one of the contraceptive options below that 
meets the SOP effectiveness criteria including a <1% rate of failure per year, as 
stated in the product label:

Intrauteriine device or intrauterine system

Combined estrogen and progestogen oral contraceptive [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 from the time of first dose of study medication 
until 12 weeks after the last dose of study medication.
Reference:
Hatcher RA, Trussell J, Nelson AL, et al. Contraceptive Technology. 20th edition. 
Atlanta, Georgia:Ardent Media, 2011:50. Table 3.2. 


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12.3.
Appendix 3: Liver chemistry stopping criteria and required 
follow up assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).
Phase II 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 by GSK 

Viral hepatitis serology4

Blood sample for pharmacokinetic 
(PK) analysis, obtained less than 
12 weeks after last dose5

Serum creatine phosphokinase 
(CPK) and lactate dehydrogenase 
(LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or 
worsening of clinical symptoms of 
liver injury, or hypersensitivity, on 
the AE report form


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Medical Governance, permanently 
discontinue study treatment and may 
continue subject in the study for any 
protocol specified follow up assessments
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

Record use of concomitant 
medications on the concomitant 
medications report form including 
acetaminophen, herbal remedies, 
other over the counter medications

Record alcohol use on the liver 
event alcohol intake case report 
form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin 
G (IgG or gamma globulins)

Serum acetaminophen adduct 
HPLC assay (quantifies potential 
acetaminophen contribution to 
liver injury in subjects with 
definite or likely acetaminophen 
use in the preceding week [James, 
2009])

Liver imaging (ultrasound, 
magnetic resonance, or 
computerised tomography) and /or 
liver biopsy to evaluate liver 
disease; complete Liver Imaging 
and/or Liver Biopsy CRF forms
1.
Serum bilirubin fractionation should be performed if testing is available.  If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants.
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia).


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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 or Hepatitis E RNA.
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.
Phase II 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 GSK medical monitor within 24 
hours of learning of the abnormality to 
discuss subject safety.

Subject can continue study treatment.

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return 
to within baseline.

If at any time subject meets the liver 
chemistry stopping criteria, proceed as 
described above.

If, after 4 weeks of monitoring, ALT <3xULN 
and bilirubin <2xULN, monitor subjects twice 
monthly until liver chemistries normalize or 
return to within baseline.
References
James LP, Letzig L, Simpson PM, et al. Pharmacokinetics of Acetaminophen-Protein 
Adduct in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab 
Dispos. 2009;37:1779-84. 


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12.4.
Appendix 4: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.


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
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

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 fulfills 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 


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normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (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.
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 CRF.

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 CRF page.


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
There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
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.
12.4.4.
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.


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
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 Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
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 CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.


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12.4.5.
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 PV Information Management Service 
department.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data.

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form to the PV 
Information Management Service department.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Medical Monitor /Sponsor Contact Information page.
12.4.6.
Sentinel Events
A Sentinel Event is a GSK defined SAE that is not necessarily drug-related but has been 
associated historically with adverse reactions for other drugs and is therefore worthy of 
heightened pharmacovigilance.  Medical Monitor review of all SAEs for possible 
Sentinel Events is mandated at GSK.  The Medical Monitor may request additional 
clinical information on an urgent basis if a possible Sentinel Event is identified on SAE
review.  The current GSK defined Sentinel Events are listed below:

Acquired long QT syndrome.

Agranulocytosis/Severe neutropenia.

Anaphylaxis & anaphylactoid reactions.

Hepatotoxicity.

Acute renal failure.

Seizure.

Stevens Johnson syndrome/toxic epidermal necrosis.


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12.4.7.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization


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12.5.
Appendix 5: Collection of Pregnancy Information
12.5.1.
Female

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this 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 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.  This 
applies only to subjects who are randomized to receive study medication.

After obtaining the necessary signed informed 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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12.7.
Appendix 7: Country Specific Requirements
12.7.1.
Study Conduct Considerations
12.7.1.1.
Regulatory and Ethical Considerations
The study will be conducted in accordance with “the Ministerial Ordinance on the 
Standards for the Conduct of Clinical Trials of Medicinal Products (MHW Notification 
No.28 dated 27th March, 1997)” and the Pharmaceutical Affairs Law. GSK will submit 
the CTN to the regulatory authorities in accordance with the Pharmaceutical Affairs Law 
before conclusion of any contract for the conduct of the study with study sites.
12.7.1.2.
Informed Consent
Prior to participation in the study, the investigator (or subinvestigator) should fully 
inform the potential subject of the study including the written information.  The 
investigator (or subinvestigator) should provide the subject ample time and opportunity to 
inquire about details of the study.  The subject should sign and personally date the 
consent form.  If the subject wishes to consider the content of the written information at 
home, he/she may sign the consent form at home.  The person who conducted the 
informed consent discussion and study collaborator giving supplementary explanation, 
where applicable, should sign and personally date the consent form.  If an impartial 
witness is required, the witness should sign and personally date the consent form.  The 
investigator (or subinvestigator) should retain this signed and dated form (and other 
written information) together with the source medical records, such as clinical charts (in 
accordance with the rules for records retention, if any, at each medical institution) and 
give a copy to the subject.
12.7.2.
Study Period
December 2016 ~ January 2018
12.7.3.
Study Administrative Structure
Sponsor information is included in Exhibit 1.  List of Medical Institutions and 
Investigators is included in Exhibit 2.
12.7.4.
Pharmacogenetics
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 


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development of medicines.  Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Pharmacogenetic Research Objectives and Analyses
The objective of the pharmacogenetic (PGx) research is to understand the relationship 
between genetic factors and response to GSK3196165.  To achieve this objective, the 
relationship between genetic variants and the followings are investigated.

Response to medicine, including GSK3196165 or any concomitant medicines

Rheumatoid arthritis susceptibility, severity, and progression and related conditions
PGx data may be generated while the study is underway or following completion of the 
study.  PGx evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses).  PGx 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 PGx 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate pharmacogenetic RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in PGx research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the PGx 
research.
Study Assessments and Procedures
A key component of successful PGx research is the collection of samples during clinical 
studies.  Collection of samples, even when no a priori hypothesis has been identified, 
may enable future PGx analyses to be conducted to help understand variability in disease 
and medicine response.

A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction.  A 
Blood sample is collected at the baseline visit, after the subject has been randomized 
and provided informed consent for PGx research.  Instructions for collection and 
shipping of the PGx 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 


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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 PGx 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 PGx research may still participate in the 
study.  PGx informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in PGx 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 PGx sample, if already collected:

Continue to participate in the PGx research in which case the PGx DNA sample is 
retained

Discontinue participation in the PGx research and destroy the PGx DNA sample
If a subject withdraws consent for PGx 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 PGx research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.

PGx data that has been analyzed at the time of withdrawn consent will continue to be 
stored and used, as appropriate.


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Screen and Baseline Failures
If a sample for PGx 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 PGx 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 PGx Data
GSK may summarize the PGx research results in the clinical study report, or separately 
and may publish the results in scientific journals.
GSK may share PGx research data (after deleting the subject number so that the provided 
information will not be identified) 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 PGx 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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12.8.
Appendix 8: Protocol Changes
Protocol Amendment: 01
4.6.1.Risk Assessment, Infections, Mitigation Strategy
Added the below sentence in Subject monitoring section.
1.
When subjects are considered to be at high risk of pneumocystis pneumonia (PCP) 
after the initiation of treatment by the investigator’s judgement, a preventive dose of 
co-trimoxazole is permitted.
Rationale
As Japanese RA subjects treated with biologics may be more susceptible to PCP, a
preventive dose of co-trimoxazole is allowed to ensure the safety of subjects considered 
as high risk of PCP, according to PMDA requests.
5.1.Inclusion Criteria, 13
Criteria for FVC ≥80% predicted added as below.
13.DLCO ≥60% predicted; forced expiratory volume in 1 second (FEV1) ≥70% predicted; 
forced vital capacity (FVC) ≥80% predicted.
Rationale
FVC criteria was added in Inclusion Criteria to exclude asymptomatic interstitial
pneumonia.
5.2.Exclusion Criteria, 25
Added criteria for HBV-DNA for the subjects with positive anti-HBs antibody as below.
25.Serologic evidence of current/previous Hepatitis B virus (HBV) infection based on the 
results of testing for Hepatitis B surface antigen (HBsAg) and anti-Hepatitis B core (anti-
HBc) antibody as follows within 4 weeks of Day 1.
2.
Subjects positive for HBsAg and/or positive for anti-HBc antibody (regardless of 
anti-HBs antibody status) are excluded.
3.
Subjects with positive anti-HBs antibody and HBV-DNA (≥2.1 log copies/mL) are 
excluded.
Rationale
According to the treatment guideline of HBV infection, the HBs antibody positive 
subjects require HBV-DNA testing, and will be randomised once HBV-DNA (<2.1 log 
copies/mL) is confirmed. 


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5.4.Withdrawal/Stopping Criteria
Added HBV-DNA stopping criteria.
4.
Detected (≥2.1 log copies/mL) HBV DNA for subjects who have positive anti-HBs 
antibody.
Rationale
HBV-DNA stopping criteria was clarified for subjects with positive anti-HBs antibody.
6.10.2.Prohibited Medications and Non-Drug Therapies, 6.10.2.2.Related to 
Methotrexate
Allowed a preventive dose of co-trimoxazole for subjects considered at high risk of PCP.
5.
Concomitant administration of folate antagonists such as co-trimoxazole*
(trimethoprim-sulfamethoxazole), triamterene and nitrous oxide are prohibited.
*: When a preventive dose is required for subjects considered at high risk of 
pneumocystis pneumonia (PCP) after the initiation of treatment by the investigator’s 
judgement, the approved low dose of co-trimoxazole is allowed (1 tablet daily or 3 times 
a week).
Rationale
A preventive dose of TMP-SMX is allowed to ensure the safety of subjects with high risk 
of PCP, according to PMDA requests.
7.1.Time and Events Table
Changed HBV-DNA test at Screening, and added footnote as below.
** HBV-DNA sample will be collected from all subjects, and HBV-DNA will be tested 
for only subjects with HBs Ab positive.
Rationale
To confirm the existing of HBV-DNA for HBs antibody positive subjects at Screening. 
7.6.2.Patient’s Assessment of Arthritis Pain and 12.6.Appendix 6: Assessment of 
Safety, Efficacy, Value Evidence and Outcome, 12.6.2.Efficacy
Added “Past week’s pain” VAS assessment.
Rationale
“Past week’s pain” assessment sheet was added in protocol.


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9.3.1.Analysis Populations
Analysis populations were revised as below.
•All Screening Population: The All Screening Population consists of all subjects who are 
given subject number and whose data including demographics are collected at screening.
• Randomized population: The randomized population is defined as all subjects who 
were randomized to treatment regardless of whether they actually receive study treatment. 
•Intention to Treat (ITT) Population: The ITT Population consists of all randomized 
subjects who receive at least one dose of study treatment.  This population will be used 
for efficacy and safety analyses.
•Pharmacokinetic (PK) population: The PK Population consists of all GSK3196165-
treated subjects from whom PK samples are collected and analyzed.
Rationale
To be consistent with on-going global Phase IIb study (201755).
12.2.Appendix 2: Contraception eligibility criteria for female and male subjects, 
12.2.1.Female and 12.2.2.Male
Removed the following contraception methods.
•Contraceptive subdermal implant
•Injectable progestogen
•Contraceptive vaginal ring
•Percutaneous contraceptive patches
Rationale
These contraception methods are not approved in Japan.
Protocol Amendment: 02
5.1.Inclusion Criteria
Changed the CRP criterion from ≥0.5 mg/dL to ≥0.3 mg/dL.
7.
C-Reactive Protein (CRP) ≥0.3 mg/dL at screening.
Rationale
To allow the patients with 0.3 ~ 0.5 mg/dL CRP in the study.

SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
201789 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for 201789: A Phase 1/2, 
Double-Blind, Placebo-Controlled Study of the 
Pharmacokinetics, Safety and Tolerability of GSK3196165 in 
Combination with Methotrexate Therapy, in Japanese 
Subjects with Active Moderate-Severe Rheumatoid Arthritis 
Despite Treatment with Methotrexate. 
Compound Number  : GSK3196165 
Effective Date  
: 24-JAN-2018 
 
Description : 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 201789. 
• 
This RAP is intended to describe the pharmacokinetic, safety, immunogenicity, 
efficacy, pharmacodynamic and pharmacokinetic/pharmacodynamic analyses 
required for the study.  
• 
This version includes amendments to the originally approved RAP. 
• 
This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable. 
 
RAP Author(s):  
Approver 
Date 
Approval 
Method 
 
 
 
Biostatistics Group2, Biomedical Data Sciences, 
Japan 
 
 
17-Jan-2018 
Email 
Manager, Clinical Pharmacology & Science 
Promotion Office, Medicines Development 
 
 
 
 
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
PPD
PPD


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
201789 
 
2 
 
RAP Team Approvals: 
Approver 
Date 
Approval Method 
 
18-Jan-2018 
Email 
Immuno-Inflammation, Dermatology TA Office, 
Medicines Development, Japan 
 
19-Jan-2018 
Email 
Clinical Operations Dept., Japan 
 
19-Jan-2018 
Email 
Data Practice Group, Biomedical Data Sciences 
Dept., Japan 
 
19-Jan-2018 
Email 
Medical Writing Office, Medicines 
Development, Japan 
 
19-Jan-2018 
Email 
Clinical Pharmacology & Science Promotion 
Office, Medicines Development, Japan 
 
19-Jan-2018 
Email 
Statistical Programming & Reporting Group, 
Biomedical Data Sciences, Japan 
 
 
Clinical Statistics and Clinical Programming Line Approvals:  
Approver 
Date 
Approval 
Method 
 
24-Jan-2018 
Email 
Manager, Biostatistics Group2, Biomedical Data 
Sciences, Japan 
 
23-Jan-2018 
Email 
Manager, Statistical Programming & Reporting 
Group, Biomedical Data Sciences, Japan 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
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TABLE OF CONTENTS 
PAGE 
1. 
REPORTING & ANALYSIS PLAN SYNPOSIS ......................................................... 6 
1.1. 
RAP Amendments ........................................................................................ 7 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 8 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 8 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 8 
2.3. 
Study Design ................................................................................................ 9 
2.4. 
Statistical Hypotheses................................................................................... 9 
3. 
PLANNED ANALYSES .......................................................................................... 10 
3.1. 
Final Analyses ............................................................................................ 10 
4. 
ANALYSIS POPULATIONS ................................................................................... 10 
4.1. 
Protocol Deviations ..................................................................................... 10 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 11 
6. 
STUDY POPULATION ANALYSES ....................................................................... 11 
6.1. 
Overview of Planned Analyses ................................................................... 11 
6.1.1. 
Demographic Characteristics ....................................................... 13 
6.1.2. 
Baseline Efficacy Parameters ...................................................... 13 
6.1.3. 
Rheumatoid Factor and Anti-cyclic Citrullinated Protein 
Antibody ...................................................................................... 13 
6.1.4. 
RA disease history ....................................................................... 13 
6.1.5. 
Corticosteroid use ........................................................................ 13 
6.1.6. 
Exposure ..................................................................................... 14 
6.1.6.1. 
GSK3196165 .............................................................. 14 
6.1.6.2. 
MTX ........................................................................... 14 
7. 
PRIMARY STATISTICAL ANALYSES .................................................................... 14 
7.1. 
Pharmacokinetic Analyses .......................................................................... 14 
7.1.1. 
Overview of Planned Pharmacokinetic Analyses ......................... 14 
7.1.2. 
Drug Concentration Measures ..................................................... 14 
7.1.3. 
Pharmacokinetic Parameters ....................................................... 15 
7.1.3.1. 
Deriving Pharmacokinetic Parameters ........................ 15 
7.1.3.2. 
Statistical Analysis of Pharmacokinetic 
Parameters ................................................................. 16 
7.2. 
Safety Analyses .......................................................................................... 17 
7.2.1. 
Overview of Planned Adverse Event Analyses ............................ 17 
8. 
SECONDARY STATISTICAL ANALYSES ............................................................. 18 
8.1. 
Safety Analyses .......................................................................................... 18 
8.1.1. 
Overview of Planned Other Safety Analyses ................................ 18 
8.1.1.1. 
Pulmonary assessment .............................................. 19 
8.1.1.2. 
Respiratory events...................................................... 20 
8.1.2. 
Overview of Planned Clinical Laboratory Analyses ...................... 20 


 
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8.1.3. 
Immunogenicity Analyses ............................................................ 21 
8.2. 
Efficacy Analyses ........................................................................................ 22 
8.2.1. 
Overview of Planned Efficacy Analyses ....................................... 22 
8.2.2. 
DAS28 (CRP) .............................................................................. 22 
8.2.2.1. 
Planned Efficacy Statistical Analyses ......................... 23 
9. 
EXPLORATORY STATISTICAL ANALYSES ......................................................... 25 
9.1. 
Overview of Planned Exploratory Analyses ................................................. 25 
9.1.1. 
ACR 20/50/70 response ............................................................... 26 
9.1.2. 
DAS28 (ESR) .............................................................................. 26 
9.1.3. 
SDAI, CDAI and FACIT-Fatigue ................................................... 26 
9.1.4. 
Categorical DAS28 Response ..................................................... 27 
9.1.5. 
DAS28 Remission ........................................................................ 27 
9.1.6. 
Other endpoints ........................................................................... 27 
9.2. 
Pharmacodynamic and Biomarker Analyses ............................................... 28 
9.2.1. 
Overview of Planned Pharmacodynamic and Biomarker 
Analyses ...................................................................................... 28 
9.3. 
Pharmacokinetic / Pharmacodynamic Analyses .......................................... 28 
10. REFERENCES ....................................................................................................... 30 
11. APPENDICES ........................................................................................................ 31 
11.1. 
Appendix 1: Time & Events ......................................................................... 32 
11.1.1. 
Protocol Defined Time & Events .................................................. 32 
11.2. 
Appendix 2: Assessment Windows ............................................................. 37 
11.3. 
Appendix 3: Treatment States and Phases ................................................. 38 
11.3.1.1. Treatment States for Concomitant Medications 
for Rheumatoid Arthritis (CONMEDS RA) Data .......... 38 
11.3.1.2. Treatment States for AE Data ..................................... 39 
11.4. 
Appendix 4: Data Display Standards & Handling Conventions .................... 40 
11.4.1. 
Study Treatment & Sub-group Display Descriptors ...................... 40 
11.4.2. 
Baseline Definition & Derivations ................................................. 40 
11.4.2.1. Baseline Definitions .................................................... 40 
11.4.2.2. Derivations and Handling of Missing Baseline 
Data ........................................................................... 40 
11.4.3. 
Reporting Process & Standards ................................................... 40 
11.5. 
Appendix 5: Derived and Transformed Data ............................................... 43 
11.5.1. 
General ........................................................................................ 43 
11.5.2. 
Study Population .......................................................................... 43 
11.5.3. 
Safety .......................................................................................... 45 
11.5.4. 
Efficacy ........................................................................................ 47 
11.5.5. 
Immunogenicity............................................................................ 56 
11.6. 
Appendix 6: Premature Withdrawals & Handling of Missing Data ............... 57 
11.6.1. 
Premature Withdrawals ................................................................ 57 
11.6.2. 
Handling of Missing Data ............................................................. 57 
11.6.2.1. Handling of Partial Dates ............................................ 58 
11.6.2.2. Handling of Missing Data for Statistical 
Analysis ...................................................................... 58 
11.7. 
Appendix 7: Multiple Comparisons & Multiplicity ......................................... 59 
11.8. 
Appendix 8: Model Checking and Diagnostics for Statistical 
Analyses ..................................................................................................... 60 
11.8.1. 
Statistical Analysis Assumptions .................................................. 60 


 
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11.9. 
Appendix 9 – Abbreviations & Trade Marks ................................................ 61 
11.9.1. 
Abbreviations ............................................................................... 61 
11.9.2. 
Trademarks ................................................................................. 62 
11.10. Appendix 10: List of Data Displays.............................................................. 63 
11.10.1. Data Display Numbering .............................................................. 63 
11.10.2. Deliverable ................................................................................... 63 
11.10.3. Study Population Tables .............................................................. 64 
11.10.4. Efficacy Tables ............................................................................ 66 
11.10.5. Efficacy Figures ........................................................................... 69 
11.10.6. Safety Tables ............................................................................... 72 
11.10.7. Pharmacokinetic Tables ............................................................... 75 
11.10.8. Pharmacokinetic Figures ............................................................. 76 
11.10.9. Pharmacodynamic and Biomarker Tables .................................... 77 
11.10.10. Pharmacodynamic and Biomarker Figures .................................. 79 
11.10.11. Pharmacokinetic / Pharmacodynamic Figures ............................. 82 
11.10.12. ICH Listings ................................................................................. 83 
11.10.13. Non-ICH listings ........................................................................... 92 
 


 
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1. 
REPORTING & ANALYSIS PLAN SYNPOSIS 
 Overview 
Key Elements of the RAP 
Purpose 
• 
This RAP describes all planned analyses and outputs required for the final 
Clinical Study Report (CSR) of study 201789. 
Protocol 
• 
This RAP is based on the protocol [(Dated: 27/SEP/2016) of study 201789 
(GSK Document No. : 2016N278580_01] and eCRF. 
Primary 
Objective  
• 
To assess the pharmacokinetics of GSK3196165 in Japanese rheumatoid 
arthritis (RA) subjects 
• 
To assess the safety and tolerability of GSK3196165 in combination with 
methotrexate (MTX) therapy in Japanese RA subjects. 
Primary 
Endpoint 
• 
Pharmacokinetic (PK) parameters of GSK3196165 calculated from sparse 
sampling concentrations. 
• 
Incidence of adverse events (AEs), serious adverse events (SAEs) and 
AEs of special interest. 
Study Design 
• 
This is a randomized, double-blind, parallel group, 3 dosage level, placebo-
controlled, Phase 1/2 study in Japanese subjects with active moderate-
severe RA despite treatment with MTX. 
Planned 
Analyses 
• 
Final analyses will be performed according to the steps described in 
Section 3.1. 
• 
All decisions regarding final analyses, as defined in this RAP document, will 
be made prior to Database Freeze (unblinding) of the study data. 
Analysis 
Populations 
• 
The Intent to Treat (ITT) population consists of all subjects who were 
randomized to treatment and receive at least one dose of study treatment. 
This population will be used for the efficacy and safety analyses. 
• 
PK population consists of all GSK3196165-treated subjects from whom PK 
samples are collected and analyzed. 
Hypothesis 
• 
No formal hypotheses will be tested. 
Primary 
Analyses(PK) 
• 
For serum concentration of GSK3196165 over time, individual data will be 
listed and presented in graphical form, and summary statistics at each time 
point will be calculated by each dose level. The following PK variables after 
the last dosing will be derived by non-compartmental analysis as applicable 
and as data allowed: Cmax, tmax, AUCtau, AUC(0-t), AUC(0-inf), and t1/2. 
For PK parameters, summary statistics will be calculated by each dose 
level, and scatter plots against the dose level will be generated. Dose 
proportionality will also be assessed with the power model.  
Primary 
analyses(Safety 
and Tolerability) 
• 
All AEs will be coded using MedDRA and summarized by System Organ 
Class (SOC) and Preferred Term (PT). The number and percentage of 
subjects with any AEs will be summarized by dose. The study treatment-
related AEs, SAEs, AEs leading to discontinuation of study treatment, and 
AEs of special interest will be reported separately.  
 


 
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1.1. 
RAP Amendments 
Revision chronology: 
RAP Section 
Amendment Details 
Reporting and Analysis Plan_Study201789_Final [23-MAY-2017] 
Reporting and Analysis Plan_Study201789_final_Amend 1 [04-OCT-2017] 
Section 3.1 and Section 3.2 
Removed these sections because the planned interim 
analyses have been canceled.  
Section 3.3 
Removed this section and added the unblinding process. 
Section 3.1 
Removed “(interim and final)”. 
Section 8.2.1 
Added the listing of change from baseline in DAS28(CRP) 
Section 9.1 
Added the listings of ACR response, Categorical DAS28 
response and DAS28 remission 
Section 9.1 
Added the listing of change from baseline in DAS28(ESR) 
Section 11.4.3 
Removed the Reporting area for interim analyses 
Section 11.4.3 
Amended the area for final reporting 
Section 11.10.1 
Amended the Numbering according to the change of the TLF. 
Section 11.10.2 
Removed the delivery description for interim analyses 
Section 11.10.3, Section 11.10.4, 
Section 11.10.5, Section 11.10.6 and 
Section 11.10.12 
Removed the TOC of TLF for interim analyses. 
Section 11.10.9 and Section 11.10.10 
Amended the TOC to simplify it. 
Section 11.10.11 
Amended the typos. 
Section 11.10.12 
Added the listings of ACR20/50/70, Categorical DAS28 
response and DAS28 remission 
Reporting and Analysis Plan_Study201789_final_Amend 2 [24-Jan-2018] 
Section 4. 
Removed “valid” to avoid misunderstanding.  
Section 6.1.3. 
Added the description of RF and ACPA analyses.  
Section 7.1.3.2. 
Added one pharmacokinetic parameter “AUC(0-t)” for dose 
proportionality.  
Section 7.2.1. 
Added 3 AESI listings (Infection, Hypersensitivity Reactions 
and Injection Site Reaction) 
Section 8.1.1. 
Removed the summary of change from baseline in Borg scale 
becase this variable is categorical.  
Section 8.1.3. 
Added the details of Immunogenicity analyses because of 
clarification of data in detail 
Section 11.2. 
Clarified that early withdrawal visits will be included for 
Assessment Windows. 
Section 11.5.2 
Added the reference date for Age calculation 
Section 11.5.2 
Added the definitions of Age Group and Age Category 
Section 11.5.2 
Amended the procedure for average daily dose of OCS to 
calculate it at only each scheduled visit.  
Section 11.5.3 
Amended the specification of AESI because the procedure to 
specify AESI was changed.  
Section 11.5.4 
Clarified that when calculating ACR, Patient’s Assessment for 
Arthritis Pain “at this time” will be used.  
Section 11.5.4 
Amended the typos in SJC and TJC section.  
Section 11.10. 
Amended Shell IDs and titles. 
Added some displays. 
 


 
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2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol [(Dated: 27/SEP/2016)]. 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• 
To assess the PK of GSK3196165 in 
Japanese RA subjects 
• 
PK parameters of GSK3196165 calculated from sparse 
sampling concentrations 
• 
To assess the safety and tolerability of 
GSK 3196165 in combination with 
MTX therapy in Japanese RA subjects 
• 
Incidence of AEs, SAEs and AEs of special interest 
Secondary Objectives 
Secondary Endpoints 
• 
To assess the safety other than 
primary endpoints 
• 
To assess the efficacy in Japanese 
RA subjects 
• 
Vital signs, 12-lead ECG and laboratory assessment 
• 
Immunogenicity (anti-GSK3196165 antibody) 
• 
Change from baseline in Disease Activity Score 28 
[DAS28(CRP)] at all assessment timepoints 
Exploratory 
Efficacy Endpoints 
At all efficacy assessment timepoints 
• 
ACR 20/50/70 response rate 
• 
Change from baseline in DAS28(ESR) 
• 
Proportion of subjects achieving categorical DAS28(CRP) / DAS28(ESR) response (moderate/good 
EULAR response) 
• 
Proportion of subjects achieving DAS28(CRP) / DAS28(ESR) remission. 
• 
Change from baseline in Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity 
Index (CDAI) 
• 
Change from baseline in the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue 
 
• 
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. 
Biomarker Endpoints 
• 
Pharmacodynamic biomarkers to assess target engagement (e.g., serum concentration of free GM-
CSF, GM-CSF-GSK3196165 complex) 
• 
Pharmacodynamic biomarkers which may be predictive of response to GSK3196165 (e.g., 14-3-3η, 
MRP8/15, ARGS neoepitope, YKL-40) 
• 
Pharmacodynamic biomarkers to assess response to GSK3196165 (e.g. IL-6, IL-1β, TNFα, IL-17A, IL-
17F) 
• 
Whole blood ribonucleic acid (RNA) analysis 
Safety Biomarkers 
• 
Biomarkers which may be indicative of lung damage (e.g. SP-D, KL-6, cholestenoic acid) 
• 
Baseline concentrations of GM-CSF autoantibodies 
 


 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
Design Features 
• This is a randomized, double-blind, parallel group, 3 
dosage level, placebo-controlled, Phase 1/2 study in 
Japanese RA subjects. 
Dosing 
• This study is composed of up to 4 weeks screening period, 
12 weeks treatment period (last dose Week 10), and 10 
weeks follow-up period (12 weeks from last dose). 
• Treatment with GSK3196165 or placebo will be given 
weekly as a single subcutaneous (SC) injection by an 
unblinded administrator. There will be 5 weekly injections 
(Day 1, 8, 15, 22, 29), then every other week (EOW) 
injections at Day 43, 57 and 71. 
Treatment Assignment 
• Subjects will be randomized (1:1:1:1) to placebo or one of 
three SC GSK3196165 doses at Day 1 (Week 0). 
Interim Analysis 
• No interim analysis in midstream of the treatment period is 
planned. 
• Once all subjects have completed visits in the treatment 
period, an interim analysis may be performed to discuss 
within GSK and consult with the regulatory authority on the 
future development plan of GSK3196165. 
 
2.4. 
Statistical Hypotheses 
The primary objective of this study is to assess the PK, safety and tolerability of 
GSK3196165 in combination with MTX therapy in Japanese RA subjects. No formal 
hypotheses to be tested. Two-sided 90% confidence interval (CI) will be used for PK 
estimation. 


 
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3. 
PLANNED ANALYSES 
3.1. 
Final Analyses 
The final planned analyses will be performed after the completion of the following 
sequential steps: 
1. All subjects have completed the study as defined in the protocol. 
2. All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management. 
3. all criteria for unblinding the randomisation codes have been met. 
4. Randomisation codes have been distributed according to RandAll NG prodcedures. 
 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
All Screening 
• Comprise of all subjects who are given subject 
number and of whom data are collected at 
screening. 
• Study Population 
Randomised 
• All subjects who are randomized to treatment. 
• Any subject who receives a treatment 
randomization number will be considered to 
have been randomized. 
• Study Population 
ITT 
• All subjects who are randomized to treatment 
and who receive at least one dose of study 
treatment. 
• Study Population 
• Efficacy 
• Safety 
PK 
• This population consists of all GSK3196165-
treated subjects from whom PK samples are 
collected and analyzed. 
• PK 
Immunogenicity 
• The immunogenicity population will consist of 
all subjects in the ITT population, who had at 
least one immunogenicity assessment. 
• Immunogenicity 
NOTES :  
• 
Please refer to Appendix 10: List of Data Displays which details the population to be used for each displays being 
generated. 
 
4.1. 
Protocol Deviations 
• 
Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed. 


 
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• 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan. 
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
• 
A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the eCRF. 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions.  
Table 1 
Overview of Appendices 
Section Component 
11.1 
Appendix 1: Time & Events 
11.2 
Appendix 2: Assessment Windows 
11.3 
Appendix 3: Treatment States and Phases 
11.4 
Appendix 4: Data Display Standards & Handling Conventions 
11.5 
Appendix 5: Derived and Transformed Data 
11.6 
Appendix 6: Premature Withdrawals & Handling of Missing Data 
11.7 
Appendix 7: Multiple Comparisons & Multiplicity 
11.8 
Appendix 8: Model Checking and Diagnostics for Statistical Analyses. 
 
6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Analyses 
The study population analyses will be based on the All Screening, Randomised and ITT 
population, unless otherwise specified. 
Table 2 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 10: List of Data Displays. 


 
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Table 2 
Overview of Planned Study Population Analyses 
Endpoint / Parameter / Display Type 
Data Displays Generated 
Table 
Figure 
Listing 
Subject Disposition 
Subject Disposition for the Subject Conclusion Record 
Y 
 
 
Reasons for Subject Withdrawal 
 
 
Y 
Treatment Status and Reasons for Discontinuation of Study 
Treatment 
Y 
 
Y 
Screening Status and Reasons for Screen Failure 
Y 
 
Y 
Subjects Who Were Rescreened 
 
 
Y 
Subjects Enrolled by Site ID 
Y 
 
 
Subjects for Whom the Treatment Blind was Broken 
 
 
Y 
Planned and Actual Treatments 
 
 
Y 
Protocol Deviations 
Important Protocol Deviations 
Y 
 
Y 
Subjects with Inclusion/Exclusion Criteria Deviations 
 
 
Y 
Populations Analysed 
Study Populations 
Y 
 
 
Exclusions from ITT Population 
Y 
 
 
Subjects Excluded from Any Population 
 
 
Y 
Demographic and Baseline Characteristics 
Demographic Characteristics 
Y 
 
Y 
Baseline Efficacy Parameters 
Y 
 
 
RF and ACPA 
Y 
 
Y 
Age Ranges 
Y 
 
 
Race and Racial Combinations 
Y 
 
Y [1] 
RA Disease History 
Y 
 
Y 
Substance Use 
Y 
 
Y 
Prior and Concomitant Medications 
Medical Conditions 
 
 
Y 
Medications 
Y 
 
Y 
Medications for RA prior to the Date of first dose 
Y 
 
 
Medications for RA from the Date of first dose 
Y 
 
 
Relationship of Medication Class, Dictionary Term and Verbatim 
Text 
 
 
Y 
Oral Corticosteroid by Visit 
Y 
 
 
Change from Baseline in Oral Corticosteroid by Visit 
Y 
 
 
Non-drug therapy 
 
 
Y 
Exposure and Treatment Compliance 
Exposure to Study Treatment 
Y 
 
Y 
Exposure to MTX 
Y 
 
Y 
NOTES : 
• 
Y = Yes display generated. 
 [1] Listing of race. 


 
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6.1.1. 
Demographic Characteristics 
The following items will be summarized and listed by dose group in addition to those as 
standard. 
• 
BMI 
• 
Family history for Cardiovascular risk factor 
 
6.1.2. 
Baseline Efficacy Parameters 
The following efficacy parameters at baseline will be summarized by dose group. 
• 
DAS28(CRP, ESR) 
• 
CRP, ESR 
• 
Swollen Joint Count 66 
• 
Tender Joint Count 68 
• 
SDAI, CDAI 
• 
Patient’s Global Assessment of Arthritis 
• 
Physician’s Global Assessment of Arthritis 
• 
Patient’s Assessment of Arthritis Pain (current and past week’s pain) 
• 
HAQ-DI score 
• 
FACIT-Fatigue 
6.1.3. 
Rheumatoid Factor and Anti-cyclic Citrullinated Protein Antibody 
The number and percentage of RF positives and ACPA positives will be summarized.  
 
6.1.4. 
RA disease history 
RA disease history will be summarized in form of disease duration categorical (< 2 years/ 
≥2 years) and as summary statistics (in month), RA functional class and time since start 
of RA symptoms. Disease duration and time since start of RA symptoms are defined in 
the Appendix 5. 
6.1.5. 
Corticosteroid use 
Value and change from baseline in average daily prednisolone dose will be summarized 
and listed by visit. Average daily dose is defined in the Appendix 5. 


 
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6.1.6. 
Exposure 
The extent of exposure to GSK3196165 and MTX will be evaluated by summarizing and 
listing the following items, respectively. These items are defined in the Appendix 5. 
6.1.6.1. 
GSK3196165 
• 
The number of injections 
• 
Cumulative dose in mg 
• 
The duration of drug exposure in days 
6.1.6.2. 
MTX 
• 
Overall average weekly dose 
7. 
PRIMARY STATISTICAL ANALYSES 
7.1. 
Pharmacokinetic Analyses 
7.1.1. 
Overview of Planned Pharmacokinetic Analyses 
The PK analyses will be based on the PK population, unless otherwise specified. 
Table 3 provides an overview of the planned analyses, with full details being presented in 
Appendix 10: List of Data Displays.  
Table 3 
Overview of Planned Pharmacokinetic Analyses 
Endpoint / Parameter/ 
Display Type 
Untransformed 
Log-Transformed 
Stats Analysis 
Summary Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Serum GSK3196165 Concentrations 
Serum Concentration 
 
 
 
Y 
Y 
Y 
Y 
 
 
 
 
 
 
 
PK Parameters 
Parameters 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
 
 
 
Dose Proportionality 
 
 
 
 
 
 
 
Y 
 
 
 
Y 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listings, Y = Display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.     
7.1.2. 
Drug Concentration Measures 
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 11.4.3 
Reporting Process & Standards). 


 
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7.1.3. 
Pharmacokinetic Parameters 
7.1.3.1. 
Deriving Pharmacokinetic Parameters 
• Refer to Appendix 4: Data Display Standards & Handling Conventions 
(Section 11.4.3 Reporting Process & Standards). 
• The PK parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using WinNonlin (version 6.3 or higher). 
• All calculations of non-compartmental parameters will be based on actual sampling 
times. 
• PK parameters described in Table 4 will be determined from the serum GSK3196165 
concentration-time data, as data permits. 
Table 4 
Derived Pharmacokinetic Parameters 
Parameter 
Parameter Description 
AUCtau 
Area under the concentration-time curve from time zero (pre-dose in Visit 10) to 
336 hr post-dose (Visit 12).  
If a sampling time deviation occurred at nominal time 336 hours after 
administration (and 336 < t), AUCtau will be calculated using the concentration at 
time 336 hours after administration post-dose estimated by the method of 
interpolation. 
If nominal time 336 hours after administration > t (or if the concentration at time 
336 hours after administration was below then limit of quantification), then the 
concentration (y) at time 336 hours after administration is estimated using λz and 
last observed Ct according to the formula: 
y=Ct(obser) x e-λz(336-t) 
Then the following equation will be used to calculate (AUCtau=AUC(0-336) after 
last-dosing) where t is the time of last quantifiable serum concentration. 
AUCtau = AUC(0-t) + AUC(t-336) 
If λz is not estimable, a AUC(t-336)is not calculated (when 336 > t). 
(NOTE: λz is the apparent terminal phase rate constant.) 
AUC(0-t) 
Area under the concentration-time curve from time zero (pre-dose in Visit 10) to 
the time of the last quantifiable concentration (C(t)) will be calculated by a 
combination of linear and logarithmic trapezoidal methods. The linear trapezoidal 
method will be employed for all incremental trapezoids arising from increasing 
concentrations and the logarithmic trapezoidal method will be used for those 
arising from decreasing concentrations (i.e., Linear Up/Log Down calculation 
method in Phoenix WinNonlin Professional). 
NOTE: Ct is the last observed quantifiable concentration. 
AUC(0-inf) 
Area under the concentration-time curve from time zero (pre-dose in Visit 10) 
extrapolated to infinity will be calculated as:  
AUC = AUC(0-t) + C(t) / lambda_z 
%AUCex 
The percentage of AUC(0-inf) obtained by extrapolation (%AUCex) will be 
calculated as: 
[AUC(0-inf) – AUC(0-t)] / AUC(0-inf) x 100 


 
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Parameter 
Parameter Description 
Cmax 
Maximum observed concentration after last dosing (Visit 10), determined directly 
from the concentration-time data. 
tmax 
Time to reach Cmax, determined directly from the concentration-time data. 
tlast 
The time of the last measurable (positive) concentration. 
t1/2 
Apparent terminal half-life will be calculated as:  
t1/2 = ln2 / lambda_z 
lambda_z 
The first order rate constant associated with the terminal (log-linear) portion of the 
curve. 
lambda_z_lower 
The lower limit on time for values to be included in the calculation of Lambda z. 
lambda_z_upper 
The upper limit on time for values to be included in the calculation of Lambda z. 
#pts 
The number of time points used in computing Lambda z. 
R2 
The goodness of fit statistic for the terminal elimination phase. 
NOTES: 
• 
Additional parameters may be included as required. 
 
7.1.3.2. 
Statistical Analysis of Pharmacokinetic Parameters 
The following PK statistical analyses will only be performed, if sufficient data is 
available (i.e. if subjects have well defined serum profiles).  
Pharmacokinetic Statistical Analyses 
Drug Concentration Measurements 
• Summary statistics, by dose group and nominal time point, will be calculated for the 
concentration of GSK3196165 in serum. 
• Individual serum concentration-time profiles will be plotted. Also median/mean profiles will be 
plotted. Each of the figures will contain one plot on the untransformed scale (i.e. a linear plot) 
and one plot on the loge-transformed scale (i.e. semi-log plot). 
• Mean/Median profiles by dose group will be plotted. Each of figures will contain one plot on the 
untransformed scale (i.e. a linear plot) and one plot on the log transformed scale (i.e. a log-
linear plot). 
• Individual subject serum concentrations of GSK3196165 will be listed by dose group and 
nominal time. The items to be listed are center, subject, age, sex, race, dose, date, planned 
relative time, actual time, time deviation, actual relative time and concentration by dose groups. 
Deriving and Summarizing Pharmacokinetic Parameters 
• The summary tables will be produced for the derived serum GSK3196165 PK parameter. 
Summary statistics will be calculated for each parameter by dose groups. 
• All the derived PK parameters for GSK3196165 will be listed, by subject and dose group. The 
items to be listed are center, subject, age, sex, race, dose, Cmax, Tmax, AUCtau, AUC(0-t), 
AUC(0-inf), %AUCex and t1/2. 
• Individual parameter, tlast, lamda_z, lamda_z_lower, lamda_z_upper, #pts and R2 will be 
listed. Summary statistics will not be calculated. 
• The steady-state will be examined graphically by plotting the Ctrough of Visit 2 - Visit 12 [Visit2 
(Day 1), Visit4 (Day 8), Visit5 (Day 15), Visit7 (Day 29), Visit9 (Day 57), Visit10 (Day 71), 
Visit12 (Day 85)]. 


 
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Pharmacokinetic Statistical Analyses 
Dose proportionality 
• Dose proportionality of GSK3196165 for Cmax, AUCtau, AUC(0-t) and AUC(0-inf) will be 
evaluated using the power model defined as follows. 
 
   log(Yi) = μ + β*log(Dk) + εi 
 
     Yi 
The measured response variable of PK parameter(Cmax, AUCtau, AUC(0-t) and 
AUC(0-inf)) for ith subject 
     μ  
Intercept 
     β  
Slope of loge-transformed dose 
     Dk 
Dose  (k=1: 45mg, 2: 90mg, 3: 180mg) 
     εi 
Random error following normal distribution N(0, σ2) 
 
• The power model will be fitted to loge-transformed PK parameters data using SAS Proc Mixed 
with loge-transformed dose as fixed effect. An estimate of the slope with corresponding 90% CI 
will be estimated from the power model to assess the degree of dose-proportionality (slope β 
around unity indicates dose-proportionality). Point estimates for the slopes of PK parameters 
with associated 90% CI will be presented. 
• If data permit, mean profile of Cmax, AUCtau, AUC(0-t) and AUC(0-inf) will be plotted. Each of 
the figures will contain one plot on linear and logarithmic scales. 
 
7.2. 
Safety Analyses 
The safety analyses will be based on the ITT population, unless otherwise specified. The 
summaries will be presented based on the AEs during on-treatment period. The listings 
will be presented based on the AEs during entire study. On-treatment is defined in the 
Appendix 3. 
7.2.1. 
Overview of Planned Adverse Event Analyses 
Table 5 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 10: List of Data Displays. 


 
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Table 5 
Overview of Planned Adverse Event Analyses 
Endpoint / Parameter/ Display Type 
Absolute 
Summary 
Individual 
T 
F 
L 
Adverse Events (AEs) 
All AEs by SOC and PT 
Y 
 
Y 
All AEs by SOC and PT and Maximum Intensity 
Y 
 
 
AESI 
Y 
 
 
AESI – Serious Infections and Non Serious Pulmonary or Opportunistic 
Infections 
 
 
Y 
AESI – Systemic Hypersensitivity Reactions 
 
 
Y 
AESI – Injection Site Reaction 
 
 
Y 
Adverse Events by Overall Frequency 
Y 
 
 
Drug-Related AEs by SOC and PT 
Y 
 
 
Drug-Related AEs by SOC and PT and Maximum Intensity 
Y 
 
 
Common Non-Serious Adverse Events by SOC and PT 
Y 
 
 
Subject Numbers for Individual AEs 
 
 
Y 
Relationship Between AE SOCs, PT and Verbatim Text 
 
 
Y 
AEs Leading to Withdrawal from Study 
Y 
 
 
AEs Leading to Permanent Discontinuation of Study Treatment  
Y 
 
 
AESI Leading to Permanent Discontinuation of Study Treatment 
Y 
 
 
Disease Related Events 
Y 
 
Y 
Serious AEs 
Serious AEs 
 
 
Y 
Serious AEs by SOC and PT 
Y 
 
 
NOTES: 
• 
T = Table, F = Figures, L = Listings, Y = Yes display generated, SOC = System Organ Class, PT = Preferred 
Term. 
• 
Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.  
8. 
SECONDARY STATISTICAL ANALYSES 
8.1. 
Safety Analyses 
8.1.1. 
Overview of Planned Other Safety Analyses 
The safety analyses will be based on the ITT population, unless otherwise specified. 
Table 6 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 10: List of Data Displays. 


 
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Table 6 
Overview of Planned Other Safety Analyses 
Endpoint / Parameter/ Display Type 
Absolute 
Change from BL 
Summary Individual Summary 
Individual 
T 
F 
L 
T 
F 
L 
ECG 
ECG Findings 
Y 
 
 
 
 
 
Change from Baseline in ECG Values by Visit 
 
 
 
Y 
 
 
ECG values by Visit 
Y 
 
Y 
 
 
 
Abnormal ECG Findings 
 
 
Y 
 
 
 
Vital Signs 
Change From Baseline in Vital Signs by Visit 
 
 
 
Y 
 
 
Vital Signs by Visit 
Y 
 
Y 
 
 
 
Pulmonary 
Cough by Visit and Grade 
Y 
 
Y 
 
 
 
Lung Auscultation by Visit 
Y 
 
Y 
 
 
 
Pulse Oximetry by Visit 
Y 
 
Y 
Y 
 
 
Borg Dyspnea Scale by Visit 
Y 
 
Y 
 
 
 
FEV1 by Visit 
Y 
 
Y 
Y 
 
 
FVC by Visit 
Y 
 
Y 
Y 
 
 
DLCO by Visit 
Y 
 
Y 
Y 
 
 
Respiratory events 
Persistent cough with grade 2 or greater recorded 
Y 
 
Y 
 
 
 
Persistent dyspnea with grade 3 or greater recorded 
Y 
 
Y 
 
 
 
Persistent DLCO by >15% 
Y 
 
Y 
 
 
 
Hepatic B Virus 
HBV DNA monitoring 
 
 
Y 
 
 
 
NOTES: 
 
• 
T = Table, F = Figures, L = Listings, Y = Yes display generated,  
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.  
 
8.1.1.1. 
Pulmonary assessment 
All pulmonary assessment results (Cough, Lung Auscultation, Pulse Oximetry, Borg 
Dyspnea Scale, FEV1, FVC and DLCO) will be listed. 
The values and the changes from baseline for the FEV1, FVC, DLCO and Pulse Oximetry 
will be summarized. The number and percentages of subjects having a cough for each 
grade and each Borg dyspnea scale will be summarized by visit. 


 
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8.1.1.2. 
Respiratory events 
Numbers and percentages of subjects experiencing persistent cough, or persistent 
dyspnea or persistent DLCO decrease will be reported in a table by dose group at the start 
time of the event. 
The definitions of these events are described in the Appendix 5. 
8.1.2. 
Overview of Planned Clinical Laboratory Analyses 
Table 7 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 10: List of Data Displays. 
If a subject fails any of the laboratory inclusion/exclusion criteria, laboratory test related 
to the inclusion/exclusion criteria may be repeated in screening period. The data collected 
by retests are not at screening visit but unscheduled visit. Therefore the summary at 
Screening visit will not be presented and baseline values defined in the Appendix 4 will 
be summarized. 
Table 7 
Overview of Planned Clinical Laboratory Analyses 
Endpoint / Parameter/ Display Type 
Absolute 
Change from BL 
Summary Individual Summary 
Individual 
T 
F 
L 
T 
F 
L 
Chemistry 
Chemistry Changes from Baseline 
 
 
 
Y 
 
 
Chemistry by visit 
Y 
 
Y 
 
 
 
Emergent Chemistry Results Relative to Normal Range 
Y 
 
 
 
 
 
Hematology 
Hematology Changes From Baseline 
 
 
 
Y 
 
 
Hematology by Visit 
Y 
 
Y 
 
 
 
Emergent Hematology Results Relative to Normal Range 
Y 
 
 
 
 
 
Urinalysis 
Urinalysis Dipstick Results 
Y 
 
Y 
 
 
 
Hepatobiliary (Liver) 
Liver Monitoring/Stopping Event Reporting 
 
 
Y[1] 
 
 
 
Hepatobiliary Laboratory Abnormalities 
Y[1] 
 
 
 
 
 
Medical Conditions for Subjects with Liver Stopping 
Events 
 
 
Y[1] 
 
 
 
Substance Use for Subjects with Liver Stopping Events 
 
 
Y[1] 
 
 
 
Liver Monitoring/Stopping Event Reporting 
 
 
Y[1] 
 
 
 
Liver Stopping Event Information for RUCAM Score 
 
 
Y[1] 
 
 
 
Liver Biopsy Details 
 
 
Y[1] 
 
 
 
Liver Imaging Details 
 
 
Y[1] 
 
 
 


 
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Endpoint / Parameter/ Display Type 
Absolute 
Change from BL 
Summary Individual Summary 
Individual 
T 
F 
L 
T 
F 
L 
Laboratory Tests (Antigen and Antibody) for Liver Events 
 
 
Y[1] 
 
 
 
Laboratory Tests (DNA and RNA) for Liver Events 
 
 
Y[1] 
 
 
 
Cardiovascular 
ECG Findings in Cardiovascular Events 
 
 
Y[2] 
 
 
 
Subjects who had Cardiovascular Events 
 
 
Y[2] 
 
 
 
Diagnostic Test for Cardiovascular Events 
 
 
Y[2] 
 
 
 
Findings about Cardiovascular Events 
 
 
Y[2] 
 
 
 
Healthcare Resource Utilization due to Cardiovascular 
Events 
 
 
Y[2] 
 
 
 
NYHA Functional Class for Cardiovascular Events 
 
 
Y[2] 
 
 
 
Death in Cardiovascular Events 
 
 
Y[2] 
 
 
 
NOTES: 
• 
T = Table, F = Figures, L = Listings, Y = Yes display generated 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.  
• 
RUCAM: Roussel Uclaf Causality Assessment Method 
• 
[1]: if at least one Liver event occurs, this display will be presented. 
• 
[2]: if at least one Cardiovascular event occurs, this display will be presented. 
 
8.1.3. 
Immunogenicity Analyses 
The immunogenicity analyses will be based on the Immunogenicity population, unless 
otherwise specified. 
The positive subjects of Anti-GSK3196165 Binding Antibody Detection are defined as 
those of which tests at Confirming are “positive”, and otherwise negative. The positive 
subjects of Neutralising Antibody detection are defined those of which tests at Screening 
are “positive”, and otherwise negative.  
The number and percentage of positive and negative subjects will be summarized. Shift 
table from baseline to every assessment will be produced to assess the number of subjects 
going from:  
• 
negative→negative 
• 
negative→positive 
• 
positive→negative 
• 
positive→positive 
Anti-GSK3196165 Binding Antibody Detection (posistive/negative) will be listed 
together with titre value (mL) and Rheumatoid Factor (positive/negative) for each subject 
with at least one positive result of Anti-GSK3196165 Binding Antibody Detection. 


 
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Table 8 
Overview of Immunogenicity Analyses 
[Endpoint / 
Parameter/ Display 
Type] 
Absolute 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
Immunogenicity 
 
 
 
Y 
 
 
Y 
NOTES: 
• 
T = Table, F = Figures, L = Listings, Y = Yes display generated 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.  
 
8.2. 
Efficacy Analyses 
8.2.1. 
Overview of Planned Efficacy Analyses 
The secondary efficacy analyses will be based on the ITT population, unless otherwise 
specified. 
Table 9 provides an overview of the planned efficacy analyses, with further details of 
data displays being presented in Appendix 10: List of Data Displays. 
Table 9 
Overview of Planned Efficacy Analyses 
[Endpoint / 
Parameter/ Display 
Type] 
Absolute 
Change from Baseline 
Stats Analysis 
Summary 
Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
DAS28 (CRP) 
Values 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
Y 
 
Y 
Longitudinal data 
analysis 
 
 
 
 
 
 
 
Y 
Y 
 
 
 
 
 
Dose response 
analysis at Week 12 
 
 
 
 
 
 
 
Y 
Y 
 
 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
 
8.2.2. 
DAS28 (CRP) 
DAS28(CRP) values will be listed and summarized by dose group and nominal time. 
Mean and Median change from baseline versus time profile by dose group will be plotted. 


 
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8.2.2.1. 
Planned Efficacy Statistical Analyses 
Statistical Analyses –Mixed Model with Repeated Measures– 
Endpoint(s) 
• Change from baseline in DAS28 (CRP) 
Model Specification 
• This endpoint will be analyzed using a mixed-models repeated measures (MMRM) approach. 
• Analysis will include the following fixed effects: 
• Dose group as a categorical variable 
• Visit as a categorical variable 
• Baseline DAS28(CRP) as a continuous variable 
• Dose-by-visit interaction 
• Visit-by-baseline interaction 
• An unstructured variance structure will be used to model the within-patient errors. 
• Analyses will be done with the MIXED Procedure in SAS, using the Kenward-Roger option to 
estimate denominator degrees of freedom and standard errors.  
Model Checking & Diagnostics 
• Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• LSmeans for each dose will be presented along with the associated 95% CI. 
• Point estimates and their associated 95% CI will be calculated for the differences between 
each GSK3196165 dose group and Placebo (GSK3196165 – Placebo). 
• The primary treatment comparison will be the contrast between the GSK3196165 groups to 
placebo. 
 
Statistical Analyses – Dose response Analysis – 
Endpoint(s) 
• Change from baseline in DAS28 (CRP) at Week 12. 
Model Specification 
• The following non-linear models will be fitted exploratory. 
i
i
i
i
ED
Dose
Dose
E
E
CRP
DAS
ε
+
+
+
=
50
max
0
)
(
28
 
i
B
B
i
B
i
i
ED
Dose
Dose
E
E
CRP
DAS
ε
+
+
+
=
50
max
0
)
(
28
 
i
i
i
Dose
E
E
CRP
DAS
ε
+
×
+
=
1
0
)
(
28
 
• The notation in the formula is as below: 
• Subscript i denotes i-th subject. 
• E0 : Response at dose 0 (placebo) 
• Emax : Maximum effect (for reduction, Emax≤0; for increase, Emax≥ 0) 
• ED50 : Dose at which 50% of maximum effect is reached 


 
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Statistical Analyses – Dose response Analysis – 
• B : a slope factor 
• E1 : Coefficient of a linear model. 
• 
iε  : Residual error following N(0,σ2) 
• The dose will be set to zero for all placebo data. 
• Starting values for the iterations will be chosen based on the observed data as appropriate. For 
example; 
• E0 : Mean in Placebo 
• Emax : Mean difference between 180 mg and Placebo (180 mg – Placebo) 
• ED50 : 90 (= (180 – 0) / 2) 
• B = 1 
• Each of the models will be fitted to the data and their fit compared using the Akaike information 
criteria (AIC). 
• The model with the smallest AIC will be selected as the final model for inference. 
Model Checking & Diagnostics 
• Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses. 
Calculation procedure for the 95% CIs using a bootstrap method 
• The 95% CIs will be calculated in accordance with the following procedure. 
1. Recreate the dataset by sampling with replacement from the original dataset by dose 
group. 
 Use a PROC SURVEYSELECT with SEED = 161216 to generate the 
bootstrap dataset 
2. Fit the final dose response model to the dataset in step 1. Estimate the parameters of 
interest 
1ˆθ  and compute ( )
1ˆθ
g
 {g is any arbitrary function.} 
3. Repeat steps 1-2, for b = 1, 2, ..., B (B=10,000) to obtain 
B
θ
θ
θ
ˆ
,
,
ˆ
,
ˆ
2
1

 and compute 
( ) ( )
( )
B
g
g
g
θ
θ
θ
ˆ
,
,
ˆ
,
ˆ
2
1

. 
4. Select 2.5% quantile of the 
b
θˆ  and ( )
b
g θˆ  as the lower limit and 97.5% quantile as the 
upper limit. 
Model Results Presentation 
• The result of the final model will be presented. 
• The estimates of model parameters and their 95% CI will be presented. 
• From the fitted model, predictive responses for each of the doses will be calculated along with 
95% CI. 
• The differences between each GSK3196165 dose and Placebo and their 95% CI will be 
calculated from the fitted model. 
• A plot of the residuals versus predicted values will be examined to assess distuributional 
assumptions. 
• The results of the other models will be shown as only SAS outputs. 
 


 
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9. 
EXPLORATORY STATISTICAL ANALYSES 
9.1. 
Overview of Planned Exploratory Analyses 
The exploratory analyses will be based on the ITT population, unless otherwise specified. 
Table 10 provides an overview of the planned exploratory analyses, with full details of 
data displays being presented in Appendix 10: List of Data Displays. 
Table 10 
Overview of Planned Exploratory Analyses 
[Endpoint / 
Parameter/ Display 
Type] 
Absolute 
Change from Baseline 
Stats Analysis 
Summary 
Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Efficacy Endpoints 
ACR 20/50/70 response 
Proportion at each 
assessment 
 
 
 
Y 
Y 
 
Y 
 
 
 
 
 
 
 
DAS28(ESR) 
Values 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
Y 
 
Y 
Longitudinal data 
analysis 
 
 
 
 
 
 
 
Y 
Y 
 
 
 
 
 
SDAI, CDAI and FACIT-Fatigue 
Values 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
Y 
 
 
Longitudinal data 
analysis 
 
 
 
 
 
 
 
Y 
Y 
 
 
 
 
 
Categorical DAS28(CRP) / DAS28(ESR) response 
DAS28(CRP) / DAS28(ESR) remission  
Proportion at each 
assessment 
 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
Other endpoints 
Swollen (28, 66) & 
Tender (28, 68) Joint 
Count 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
 
 
 
Patient’s Assessment 
of Arthritis Pain 
(current pain/past 
week’s pain) 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
 
 
 
Patient’s Global 
Assessment of Arthritis 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
 
 
 
Physician’s Global 
Assessment of Arthritis 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
 
 
 
CRP, ESR 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
Y 
 
 
HAQ-DI score 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
Y 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated, HAQ-DI: Health Assessment Questionnaire 
Disability Index 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (descriptive statistics) of the observed raw data.  
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 


 
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9.1.1. 
ACR 20/50/70 response 
The number and percentage of responder will be presented. The difference of response 
rate from Placebo and the associated 95% CI will be calculated. The 95% CI will be 
based on normal approximation. 
The percentage of ACR 20/50/70 responder by dose group will be plotted, respectively. 
9.1.2. 
DAS28 (ESR) 
DAS28(ESR) values will be listed and summarized by dose group and nominal time. 
Mean and median change from baseline versus time profiles by dose group will be 
plotted. 
Statistical Analyses –Mixed Model with Repeated Measures– 
Endpoint(s) 
• Change from baseline in DAS28(ESR) 
Model Specification 
• This endpoint will be analyzed using a MMRM approach. 
• Analysis will include the following fixed effects: 
• Dose group as a categorical variable 
• Visit as a categorical variable 
• Baseline DAS28(ESR) as a continuous variable 
• Dose-by-visit interaction. 
• Visit-by-baseline interaction. 
• An unstructured variance structure will be used to model the within-patient errors. 
• Analyses will be done with the MIXED Procedure in SAS, using the Kenward-Roger option to 
estimate denominator degrees of freedom and standard errors. 
Model Checking & Diagnostics 
• Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• Point estimates and their associated 95% CI will be calculated for the differences between 
each GSK3196165 dose group and Placebo (GSK3196165 – Placebo). 
• The primary treatment comparison will be the contrast between treatments at week 12. 
 
9.1.3. 
SDAI, CDAI and FACIT-Fatigue 
SDAI, CDAI and FACIT-Fatigue scores will be listed and summarized by dose group 
and nominal time. Mean and median change from baseline versus time profiles by dose 
group will be plotted. 
Statistical Analyses –Mixed Model with Repeated Measures– 
Endpoint(s) 
• Change from baseline in SDAI, CDAI and FACIT-Fatigue 
Model Specification 
• This endpoint will be analyzed using a MMRM approach. 


 
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Statistical Analyses –Mixed Model with Repeated Measures– 
• Analysis will include the following fixed effects: 
• Dose group as a categorical variable 
• Visit as a categorical variable 
• Baseline as a continuous variable 
• Dose-by-visit interaction 
• Visit-by-baseline interaction 
• An unstructured variance structure will be used to model the within-patient errors. 
• Analyses will be done with the MIXED Procedure in SAS, using the Kenward-Roger option to 
estimate denominator degrees of freedom and standard errors.  
Model Checking & Diagnostics 
• Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• LSmeans for each dose will be presented along with the associated 95% CI. 
• Point estimates and their associated 95% CI will be calculated for the differences between 
each GSK3196165 dose group and Placebo (GSK3196165 – Placebo). 
 
9.1.4. 
Categorical DAS28 Response 
A good or moderate response will be combined to form the “responder” category. The 
number and percentage of responders will be presented. The difference of response rate 
from Placebo and the associated 95% CI will be calculated. The 95% CI will be based on 
normal approximation. 
9.1.5. 
DAS28 Remission 
The number and percentage of remission from Placebo will be presented. The difference 
of remission rate and the associated 95% CI will be calculated. The 95% CI will be based 
on normal approximation. 
9.1.6. 
Other endpoints 
The other endpoints as below will be listed and summarized by dose group and nominal 
time as well as changes from baseline. Changes from baseline in only CRP, ESR and 
HAQ-DI will be plotted by dose group, respectively. 
• 
Swollen Joint Count (28 and 66) 
• 
Tender Joint Count (28 and 68) 
• 
Patient’s Assessment of Arthritis Pain 
• 
Current pain 
• 
Past week’s pain 
• 
Patient’s Global Assessment of Disease Activity 
• 
Physician’s Global Assessment of Arthritis 


 
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• 
CRP (in mg/L), ESR (in mm/hr) 
• 
Health Assessment Questionnaire-Disability Index (HAQ-DI) 
 
9.2. 
Pharmacodynamic and Biomarker Analyses 
9.2.1. 
Overview of Planned Pharmacodynamic and Biomarker Analyses 
The pharmacodynamic analyses will be based on the ITT population, unless otherwise 
specified. 
Table 11 provides an overview of the planned pharmacodynamic and Biomarker analyses, 
with full details of data displays being presented in Appendix 10: List of Data Displays. 
Table 11 
Overview of Planned Pharmacodynamic and Biomarker Analyses 
Endpoint / Parameter/ 
Display Type 
Untransformed 
Absolute 
Change from Baseline 
Stats Analysis 
Summary Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
free soluble GM-CSF and soluble GM-CSF complexed to GSK3196165 
Values 
 
 
 
Y 
Y 
 
Y 
 
 
 
Y 
Y 
 
Y 
MRP8/14, ARGS neoepitope, YKL-40 and 14-3-3η. 
Values 
 
 
 
Y 
Y 
 
Y 
 
 
 
Y 
Y 
 
Y 
IL-6, IL-1β, TNFα, IL-17A and IL-17F 
Values 
 
 
 
Y 
Y 
 
Y 
 
 
 
Y 
Y 
 
Y 
SP-D, KL-6 and cholestenoic acid 
Values 
 
 
 
Y 
Y 
 
Y 
 
 
 
Y 
Y 
 
Y 
measurement of GM-CSF autoantibodies at baseline 
Values 
 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
 
Biomarkers/pharmacodynamic endpoint values will be listed and summarized by dose 
group and nominal time. Mean and median versus time profiles by dose group will be 
plotted. 
 
9.3. 
Pharmacokinetic / Pharmacodynamic Analyses 
A graphical PK/PD exploration will be conducted to complement the statistical dose-
response analysis and to visualize the nature of the concentration-response correlation. A 
variety of graphs will be generated per subject and in overall, where GSK3196165 
concentration is characterised by the individual values, and the response is characterised 
by the individual values of the pharmacodynamic markers or efficacy.  


 
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Pharmacokinetic and pharmacodynamic data from this study may be combined with 
historical data (e.g. BAROQUE) for the purpose of further exploratory analysis 
(including population pharmacokinetic and/or PK/PD modelling as appropriate) which 
may be reported separately from the main clinical study report. 
• Linear scatterplot of change from baseline in PD values (free soluble GM-CSF, 
GM-CSF-GSK3196165 complex) at each visit versus GSK3196165 concentration 
values at corresponding visit 
• Linear scatterplot of change from baseline in CRP levels at each visit versus 
GSK3196165 concentration values at corresponding visit 
• Linear scatterplot of change from baseline in DAS28(CRP) measures at each visit 
versus GSK3196165 concentration values at corresponding visit 


 
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10. 
REFERENCES 
Aletaha D, Nell VP, Stamm T, et al. Acute phase reactants add little to composite disease 
activity indices for rheumatoid arthritis: validation of a clinical activity score. Arthritis 
Res Ther. 2005;7(4):R796-806. 
American Collenge of Rheumatology Committee to Reevaluate Improvement Criteria. A 
proposed revision to the ACR20: the hybrid measure of American College of 
Rheumatology response. Arthritis Rheum. 2007;57(2):193-202. 
Fransen J, van Riel PL,. The Disease Activity Score and the EULAR response criteria. 
Clin Exp Rheumatol. 2005;23(5 Suppl 39):S93-9. 
Fries JF, Spitz P, Kraines RG, et al. Measurement of patient outcome in arthritis. Arthritis 
Rheum. 1980;23(2):137-45.  
GlaxoSmithKline Document Number 2016N278580_01: Study Protocol of 201789: A 
Phase 1/2, Double-Blind, Placebo-Controlled Study of the Pharmacokinetics, Safety and 
Tolerability of GSK3196165 in Combination with Methotrexate Therapy, in Japanese 
Subjects with Active Moderate-Severe Rheumatoid Arthritis Despite Treatment with 
Methotrexate. Effective Date- 26-Sep-2016. 
Matsuda Y, Singh G, Yamanaka H, et al. Validation of a Japanese Version of the 
Stanford Health Assessment Questionnaire in 3,763 Patients With Rheumatoid Arthritis. 
Arthritis & Rheumatism. 2003;49(6):784-8. 
Prevoo ML, van't Hof MA, Kuper HH, et al. Modified disease activity scores that include 
twenty-eight joint counts. Development and validation in a prospective longitudinal study 
of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38(1):44-8. 
Smolen JS, Breedveld FC, Schiff MH, et al. A simplified disease activity index for 
rheumatoid arthritis for use in clinical practice. Rheumatology (Oxford). 2003;42(2):244-
57. 
Wells G, Becker JC, Teng J, et al. Validationof the 28-joint Disease Activity Score 
(DAS28) and European League Against Rheumatism response criteria based on C-
reactive protein against disease progression in patients with rheumatoid arthritis, and 
comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis. 
2009;68(6):954-60. 


 
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11. 
APPENDICES 
Section 
Appendix 
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions 
Section 11.1 
Appendix 1: Time and Events 
Section 11.2 
Appendix 2: Assessment Windows 
Section 11.3 
Appendix 3: Treatment States & Phases 
Section 11.4 
Appendix 4: Data Display Standards & Handling Conventions 
• Study Treatment & Sub-group Display Descriptors 
• Baseline Definitions & Derivations 
• Reporting Process & Standards 
Section 11.5 
Appendix 5: Derived and Transformed Data 
• General, Study Population & Safety 
• Efficacy 
• Immunogenicity 
Section 11.6 
Appendix 6: Premature Withdrawals & Handling of Missing Data 
• Premature Withdrawals 
• Handling of Missing Data 
Section 11.7 
Appendix 7: Multiple Comparisons and Multiplicity 
Section 11.8 
Appendix 8: Model Checking and Diagnostics for Statistical Analyses 
Other RAP Appendices 
Section 11.9 
Appendix 9: Abbreviations & Trade Marks 
Section 11.10 
Appendix 10: List of Data Displays 
 
 


 
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11.1. 
Appendix 1: Time & Events 
11.1.1. 
Protocol Defined Time & Events 
Procedures 
Screen-
ing 
Baseline 
Treatment Period 
FU 
 
EW1 
Last Visit 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
Week 
(up to 4 
weeks) 
0 
1 
2 
3 
4 
6 
8 
10 
12 
15 
18 
22 
 
Day 
 
1 
3* 
8 
15 
22 
29 
43 
57 
71 
74* 
85 
106 
127 
155 
 
Allowance 
 
 
±1 day 
±3 days 
±1 day 
±3 days 
±1 week 
 
Written Informed Consent(s) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, Disease, Therapy History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy and PRO Assessments3 
Swollen (66) & Tender (68) Joint 
Count2 
X 
X4 
 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
X 
X 
Patient’s Assessment of Arthritis Pain, 
Patient’s Global Assessment of 
Arthritis, Physician’s Global 
Assessment of Arthritis3 
X 
X4 
 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
X 
X 
HAQ-DI3 
X 
X4 
 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
X 
X 
FACIT-Fatigue3 
 
X4 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
X 


 
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Procedures 
Screen-
ing 
Baseline 
Treatment Period 
FU 
 
EW1 
Last Visit 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
Week 
(up to 4 
weeks) 
0 
1 
2 
3 
4 
6 
8 
10 
12 
15 
18 
22 
 
Day 
 
1 
3* 
8 
15 
22 
29 
43 
57 
71 
74* 
85 
106 
127 
155 
 
Allowance 
 
 
±1 day 
±3 days 
±1 day 
±3 days 
±1 week 
 
Safety Evaluations5 
Concomitant Medication 
X 
X 
Record all concomitant medications 
Height6, Body weight 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
Other Physical Examination7 
X 
X4 
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
Vital Signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
12-lead ECG8 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
AEs/SAEs/AESIs 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cough, Lung Auscultation, 
Pulse Oximetry, 
Borg Dyspnea Scale 
X 
X4 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
Chest X-ray10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spirometry (FEV1, FVC) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
DLCO 
X11 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Laboratory Assessments 
Hematology, Chemistry (except for lipid 
and pregnancy test) 
X 
X4 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 


 
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Procedures 
Screen-
ing 
Baseline 
Treatment Period 
FU 
 
EW1 
Last Visit 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
Week 
(up to 4 
weeks) 
0 
1 
2 
3 
4 
6 
8 
10 
12 
15 
18 
22 
 
Day 
 
1 
3* 
8 
15 
22 
29 
43 
57 
71 
74* 
85 
106 
127 
155 
 
Allowance 
 
 
±1 day 
±3 days 
±1 day 
±3 days 
±1 week 
 
Urinalysis (dip stick) 
X 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
Cholesterol, triglycerides, HDL, LDL12 
 
X4 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Pregnancy test13 
S 
U 
 
 
 
 
U 
 
U 
 
 
U 
 
 
U 
U 
TB, HBsAg, HepB cAb, HBs Ab, HepC 
Ab, HIV, HBV DNA** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV DNA monitoring (HBs Ab positive 
subject only) 
 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
RF, ACPA (anti-CCP) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ESR14 
 
X4 
 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
X 
X 
CRP 
X 
X4 
 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
X 
X 
Other Laboratory Assessments 
PK blood sampling (GSK3196165)15 
 
X4 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Free GM-CSF, GM-CSF-GSK3196165 
complex 
 
X4 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
X 
X 
PD blood biomarkers 
 
X4 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
RNA blood biomarker 
 
X4 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 


 
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Procedures 
Screen-
ing 
Baseline 
Treatment Period 
FU 
 
EW1 
Last Visit 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
Week 
(up to 4 
weeks) 
0 
1 
2 
3 
4 
6 
8 
10 
12 
15 
18 
22 
 
Day 
 
1 
3* 
8 
15 
22 
29 
43 
57 
71 
74* 
85 
106 
127 
155 
 
Allowance 
 
 
±1 day 
±3 days 
±1 day 
±3 days 
±1 week 
 
PGx sampling DNA16 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lung biomarkers 
 
X4 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Immunogenicity (anti-GSK3196165 
antibody)17 
 
X4 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
X 
Anti-GM-CSF auto-antibodies 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Treatment 
GSK3196165/placebo18 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
ACPA: Anti-cyclic citrullinated protein antibody,  CCP: Cyclic citrullinated peptide,  ESR: Erythrocyte sedimentation rate,  FVC: Forced vital capacity,  HBV: Hepatitis B virus,  
HDL: High-density lipoprotein,  LDL: Low-density lipoprotein,  RF: Rheumatoid factor. 
1. All subjects who withdraw from the study should have an early withdrawal (EW) visit as soon as possible after study agent discontinuation and then return for a follow-up visit (the 
last visit) for 10 weeks  
   (12 weeks after last dose of study medication). 
2. The same individual (where possible) should perform all disease assessments for an individual subject. 
3. PRO assessments should be conducted before any tests, procedures, assessments or consultations, to avoid influencing the subjects’ perception. 
4. Assessments may be performed up to 24hours before dosing GSK3196165/placebo. 
5. All safety evaluations should be conducted before dosing GSK3196165/placebo. 
6. Height will be measured at only screening. 
7. Complete physical at screening, and then limited physical examination (see Section 7.4.7 in the Protocol) thereafter. 


 
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8. 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 7.4.9 in the Protocol). 
9. Only SAEs related to study participation or related to a GSK product will be recorded  from the time a subject consents to participate in the study. 
10. Unless performed within previous 12 weeks (No need to repeat if subject re-screened). 
11. Chest HRCT if DLCO ≥60% - <70% predicted (No need to repeat if subject re-screened). 
12. ≥8 hours fasting required before blood draw. 
13. For women of child-bearing potential. S=serum; U=urine. 
14. ESR measured locally. 
15. PK sampling should be collected before dosing at the visits scheduled study treatment (GSK3196165/placebo). At the visits doesn't scheduled study treatments, it may be collected 
in any time during the 
  visit. (Day 3, 74, 85, 106, 127, 155, and early withdrawal visit). 
16. In consenting subjects. 
17. In addition to these scheduled immunogenicity assessments, “event-driven” testing will also be employed for those subjects that experience anaphylaxis, serious hypersensitivity, or 
AEs related 
    to study drug administration that led to withdrawal from the study (see Section 7.5 in the Protocol). 
18. GSK3196165 or placebo must be administered on the same day each week ±1 day for the first 5 weekly doses, thereafter on the same day EOW ±3 days for bi-weekly doses. 
* The Day 3 (Visit 3) blood sample must be drawn 2 days (±1 day is allowable) after the first dose, and the Day 74 (Visit 11) blood sample must be drawn 3 days (±1 day is allowable) 
after the last dose. 
** HBV-DNA sample will be collected from all subjects, and HBV-DNA will be tested for only subjects with HBs Ab positive. 
 


 
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11.2. 
Appendix 2: Assessment Windows 
Data at the scheduled visit defined by Appendix 1 will be summarized according to this 
RAP. Data out of the allowances will not be slotted to a particular time point, but will be 
listed as unscheduled and early withdrawal unless otherwise specified. 
In case that the one allowance contains more than two assessments, the first assessment 
will be treated as the scheduled and the others as the unscheduled. 
 


 
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11.3. 
Appendix 3: Treatment States and Phases 
11.3.1.1. 
Treatment States for Concomitant Medications for Rheumatoid Arthritis 
(CONMEDS RA) Data 
Treatment State 
Definition 
Prior only 
CONMEDs RA Stop Date < the Date of first dose of study medication 
Prior and 
Concomitant 
CONMEDs RA Start Date < the Date of first dose of study medication 
CONMEDs RA Stop Date ≥ the Date of first dose of study medication 
Concomitant only 
CONMEDs RA Start Date ≥ the Date of first dose of study medication 
Flowchart 
 
 


 
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11.3.1.2. 
Treatment States for AE Data 
Treatment State 
Definition 
Pre-Treatment 
AE Start Date < Study Treatment Start Date 
On-treatment 
Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date + 12 weeks 
Post-treatment 
AE Start Date > Study Treatment Stop Date + 12 weeks 
Onset Time  
Since 1st Dose 
(Days) 
If Treatment Start Date ˃ AE Onset Date, = AE Onset Date - Treatment Start Date 
If Treatment Start Date ≤ AE Onset Date, = AE Onset Date - Treatment Start Date +1 
Missing otherwise. 
Onset Time  
Since last Dose 
(Days) 
If Treatment Stop Date > AE Onset Date, = AE Onset Date - Treatment Stop Date 
If Treatment Stop Date ≤ AE Onset Date, = AE Onset Date - Treatment Stop Date + 1 
Missing otherwise 
Duration (Days)  
AE Resolution Date – AE Onset Date + 1 
Drug-related 
If relationship to GSK3196165/Placebo is marked ‘YES’ on Inform/CRF OR value is 
missing. 
MTX-related 
If relationship to Methotrexate is marked ‘YES’ on Inform/CRF OR value is missing.  
NOTES:  
• 
If the study treatment stop date is missing then the AE will be considered to be On-Treatment. 
 


 
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11.4. 
Appendix 4: Data Display Standards & Handling 
Conventions 
11.4.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
RandAll NG  
Data Displays for Reporting  
Code 
Description 
Description 
Order [1] 
A 
Placebo 
Placebo 
1 
B 
GSK3196165 45 mg 
GSK3196165 45 mg 
2 
C 
GSK3196165 90 mg 
GSK3196165 90 mg 
3 
D 
GSK3196165 180 mg 
GSK3196165 180 mg 
4 
NOTES: 
1. 
Order represents treatments being presented in TFL, as appropriate. 
 
11.4.2. 
Baseline Definition & Derivations 
11.4.2.1. 
Baseline Definitions 
For all endpoints (expect as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment. 
11.4.2.2. 
Derivations and Handling of Missing Baseline Data 
Definition 
Reporting Details 
Change from Baseline 
= Post-Dose Visit Value – Baseline 
% Change from Baseline 
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline] 
NOTES : 
• 
Unless otherwise specified, the baseline definitions specified in Section 11.4.2.1 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings. 
• 
Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing. 
• 
The baseline definition will be footnoted on all change from baseline displays. 
 
11.4.3. 
Reporting Process & Standards 
Reporting Process 
Software 
• The currently supported versions of SAS software will be used. 
Reporting Area 
HARP Server 
: uk1salx00175 
HARP Area 
: arenv\arprod\gsk3196165\mid201789\final_02 
QC Spreadsheet 
:arenv\arprod\gsk3196165\mid201789\final_02\qc 


 
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Reporting Process 
Analysis Datasets  
• Analysis datasets will be created according to Legacy GSK A&R dataset standards OR  
CDISC standards (SDTM IG Version 3.1.3 & AdaM IG Version 1.0. 
• For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM. 
Generation of RTF Files 
• RTF files will not be generated. 
 
Reporting Standards 
General 
• The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated: 
o 4.03 to 4.23: General Principles 
o 5.01 to 5.08: Principles Related to Data Listings 
o 6.01 to 6.11: Principles Related to Summary Tables 
o 7.01 to 7.13: Principles Related to Graphics  
Formats 
• All data will be reported according to the randomized group the subject received unless 
otherwise stated. 
• GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected. 
• Numeric data will be reported at the precision collected on the eCRF. 
• The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time 
• Reporting for tables, figures and formal statistical analyses : 
• Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
• The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate. 
• Reporting for Data Listings:  
• Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1). 
• Unscheduled or unplanned readings will be presented within the subject’s listings.  
• Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will 
be included in listings but omitted from figures, summaries and statistical analyses. 
Unscheduled Visits 
• Unscheduled visits will not be included in summary tables, except for the Respiratory events 
and the laboratory items which may be re-tested. 
• Unscheduled visits will not be included in figures. 
• All unscheduled visits will be included in listings. 


 
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Reporting Standards 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Reporting of Pharmacokinetic Concentration Data 
Descriptive 
Summary Statistics 
Refer to IDSL Statistical Principle 6.06.1 
Assign zero to NQ values (Refer to GUI_51487 for further details) 
Reporting of Pharmacokinetic Parameters 
Descriptive 
Summary Statistics 
(Log Transformed) 
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD) 
of logged data and [between and or within] geometric coefficient of variation 
(CVb/w (%)) will be reported. 
[1] CVb (%) = √ (exp(SD2) - 1) * 100 
(SD = SD of log transformed data)  
Parameters Not 
Being Log 
Transformed 
Tmax 
Graphical Displays 
• Refer to IDSL Statistical Principals 7.01 to 7.13. 
 


 
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11.5. 
Appendix 5: Derived and Transformed Data 
11.5.1. 
General 
Multiple Measurements at One Time Point 
• Mean of the measurements will be calculated and used in any derivation of summary statistics 
but if listed, all data will be presented. 
• If there are two values within a time window the value closest to the target day for that window 
will be used. If values are the same distance from the target then the mean will be taken. 
• Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables. 
Study Day 
• Calculated as the number of days from randomization date : 
• Ref Date = Missing                       → Study Day = Missing  
• Ref Date < Randomisation Date   → Study Day = Ref Date – Randomisation Date     
• Ref Data ≥ Randomisation Date   → Study Day = Ref Date – (Randomisation Date) + 1  
 
11.5.2. 
Study Population 
Demographics 
Age 
• GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows: 
o Any subject with a missing date and month will have this imputed as ‘30th June’. 
• Birth date will be presented in listings as ‘YYYY’. 
• Age will be calculated based on date of Screening visit as an Age reference date for Screen 
failed subjects and based on date of the initial dose date for ITT population.  
Age Group 
• The following category will be used for Summary of Demography. 
o Age ≤ 18 (years) 
o 19 < Age < 64 
o 65 ≤ Age 
Age Category 
• 
The following category will be used for Summary of Age Ranges. 
o Age < 18 (years) 
o 18 ≤ Age ≤ 64 
o 65 ≤ Age ≤ 84 
o 85 ≤ Age 
Body Mass Index (BMI) 
• Calculated as Weight (kg) / [Height (m)]2 


 
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Demographics 
RA disease history 
RA Disease Duration 
• RA disease duration will be calculated based on the formula: 
Disease Duration in Months = [Treatment Start Date – (RA Diagnosis Date)] / 30.25 
rounded to four decimals 
Disease Duration in Years = [Treatment Start Date – (RA Diagnosis Date)] / 365.25 
rounded to four decimals 
Time since start of RA symptoms 
• Time since start of RA symptoms will be calculated based on the formula: 
Time since start of RA symptoms in Months = [Treatment Start Date – (Date of first 
symptom)] / 30.25 rounded to four decimals 
Prior and Concomitant Medications 
Oral Corticosteroid 
• To assess corticosteroid use and determine average daily corticosteroid dose, all corticosteroid 
dosages will be converted to a prednisolone equivalent in milligrams by multiplying the dose of 
the steroid (using the coded term from GSKDrug) by the conversion factor to get prednisolone 
equivalent units. 
• The following table will provide the conversion factors. 
• For each scheduled visit, the average daily prednisolone dose will be calculated by summing all 
prednisolone doses since the previous visit up to and including the current visit and then 
dividing by the number of days in this period (Date of current visit – Date of previous 
scheduled visit). 
• If frequency that a subject takes the steroid is less than once daily such as QOD, the dosage 
will be converted to daily dose and then the average daily dose will be calculated. For example, 
if a subject takes 10 mg of the steroid QOD, the daily dose is 5 mg/day.  
Conversion 
Steroid 
8.333  BETAMETHASONE 
0.2  CORTISONE 
6.667  DEXAMETHASONE 
0.25  HYDROCORTISONE 
1.25  METHYLPREDNISOLONE 
1  PREDNISOLONE 
1.25  TRIAMCINOLONE 
Rheumatoid factor (RF) 
• A subject who has a value of RF > 15 IU/mL is positive. 
• Otherwise negative. 
Anti-cyclic Citrullinated Protein Antibody (ACPA) 
• A subject who has a value of ACPA ≥ 4.5 U/mL is positive. 
• Otherwise negative. 
 


 
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Extent of Exposure 
GSK3196165 
• Number of days of exposure to study drug will be calculated based on the formula:   
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1 
• Subjects who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure.  
• The cumulative dose will be based on the formula: 
Cumulative Dose = Sum of (Actual Volume x One Dosage / Expected Volume) 
• The following table provides the one dosage and the expected volume in each dose group. 
Dose group 
One Dosage (mg) 
Expected volume (mL) 
Placebo 
0 
0.6 
45 mg 
45 
0.3 
90 mg 
90 
0.6 
180 mg 
180 
1.2 
Methotrexate (MTX) 
• Overall Average Weekly MTX dose will be averaged across Week 1 - 12for each subject based 
on the formula: 
Overall Average Weekly MTX Dose = Mean of the Weekly Dosage of MTX 
11.5.3. 
Safety 
Adverse events of special interest will be derived using Common Terminology Criteria 
for Adverse Events, 2009 v4.0 (CTCAE). 
Adverse Events of Special Interest 
Adverse Events of Special Interest are defined as the AEs below. AESI will be specified by Safety 
Review Team and Japan EST.  
• Serious infections, including serious respiratory infections and TB. 
• Opportunistic infections 
• Neutropenia 
• Respiratory events as AESI 
• Pulmonary alveolar proteinosis 
• Hypersensitivity reactions, including anaphylaxis 
• Injection site reactions 
 
 
Respiratory events 
Events 
Definition 
Persistent cough with Grade 2 or greater 
recorded 
Cough grade 2 or greater recorded for 3 
consecutive weeks (15 or more days) on the 
eCRF page. 
Persistent dyspnea with Grade 3 or greater 
recorded 
Borg Scale grade 3 or greater recorded for 3 
consecutive weeks (15 or more days) on the 
eCRF page. 


 
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Respiratory events 
Events 
Definition 
Persistent decrease of DLCO by > 15% 
Relative decrease of DLCO of >15% compared to 
baseline for 3 consectuvie weeks (15 or more 
days) 
Decrease of DLCO = (%change from baseline 
in DLCO) ×-1 
A subject’s baseline DLCO value will be taken as 
the lowest value obtained from the Screening 
assessment or any unscheduled visit in between 
Screening and Day 1 visit. 
Final adjudication will be conducted by the SRT. 
 
 
Laboratory Parameters 
• If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value.  
o Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01 
o Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1 
o Example 3: 0 Significant Digits = ‘< x’ becomes x – 1     
 
 
 
 


 
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11.5.4. 
Efficacy 
ACR 20/50/70 response[American Collenge of Rheumatology Committee to Reevaluate 
Improvement Criteria, 2007]   
Procedure 
• 
The following 7 ACR-core set measures will define ACR20/50/70 response. 
• Tender/Painful Joint Count 68 (TJC68) 
• Swollen Joint Count 66 (SJC66) 
• Patient’s Assessment of Arthritis Pain at this time 
• Patient’s Global Assessment of Arthritis 
• Physician’s Global Assessment of Arthritis 
• C-reactive protein (CRP) (in mg/L) 
• Health Assessment Questionnaire-Disability Index (HAQ-DI) 
• 
The %Change from Baseline in each ACR-core set measure will be calculated. 
• 
If %Change from Baseline in both tender and swollen joint counts are less than -20% and 
those in 3 of the 5 remaining ACR-core set measures are less than -20%, ARC20 criteria is 
met. 
• 
Similarly ACR50 and 70 are calculated with the respective percent improvement. 
• 
For all visits if any of the component scores are missing, then those scores will considered as 
not having met the criteria for improvement. Therefore, if TJC68 or SJC66 or 3 or more of the 5 
remaining ACR-core set measures are missing, ACR20/ ACR50/ ACR70 will each be 
considered as “no response" 
• 
For component scores with missing Baseline values or a Baseline value of 0, the percentage 
improvement cannot be calculated and the component will be considered as not having met 
the criteria for improvement for all visits. 


 
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Flowchart 
 
 


 
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Examples 
• The subject did not met the criteria for ACR20 
Component 
Baseline 
Post-dose visit value 
%change 
TJC68 
43 
14 
-67 
SJC66 
38 
44 
16 
Patient’s Assessment of 
Arthritis Pain 
46 
20 
-57 
Patient’s Global 
Assessment of Arthritis 
85 
31 
-64 
Physician’s Global 
Assessment of Arthritis 
75 
27 
-64 
CRP 
2.8 
2.0 
-29 
HAQ-DI 
11.6 
7.2 
-38 
• The subject met the criteria for ACR50 but not ACR70 
Component 
Baseline 
Post-dose visit value 
%change 
TJC68 
43 
14 
-67 
SJC66 
38 
14 
-63 
Patient’s Assessment of 
Arthritis Pain 
46 
10 
-78 
Patient’s Global 
Assessment of Arthritis 
85 
31 
-64 
Physician’s Global 
Assessment of Arthritis 
75 
27 
-64 
CRP 
2.8 
1.0 
-64 
HAQ-DI 
11.6 
1.2 
-90 
Disease Activity Score[Prevoo, 1995; Fransen, 2005; Wells, 2009]  
• 
The DAS assessment is a derived measurement with differential weighting given to each 
component. The DAS28 (CRP) and DAS28 (ESR) will be calculated at each assessment time 
point. 
• 
The components of the DAS28 arthritis assessment include: 
• Tender Joint Count 28 (TJC28) 
• Swollen Joint Count 28 (SJC28) 
• C-reactive protein (CRP) (in mg/L) or Erythrocyte sedimentation rate (ESR) (in mm/hr) 
• Patient’s Global Assessment of Arthritis (PtGA) (visual analogue scale with values from 0 = 
best to 100 = worst) 
DAS28 (CRP) 
• 
The DAS28 (CRP) will be calculated using the following formula: 
96
.0
014
.0
)1
ln(
36
.0
28
28
.0
28
56
.0
)
(
28
+
×
+
+
×
+
×
+
×
=
PtGA
CRP
SJC
TJC
CRP
DAS
 


 
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• 
If one of the components is missing at an individual assessment point, the DAS28 (CRP) value 
for that assessment will be set to missing 
DAS28 (ESR) 
• 
The DAS28 (ESR) will be calculated using the following formula: 
PtGA
ESR
SJC
TJC
ESR
DAS
×
+
×
+
×
+
×
=
014
.0
)
ln(
70
.0
28
28
.0
28
56
.0
)
(
28
 
• 
If one of the components is missing at an individual assessment point, the DAS28 (ESR) value 
for that assessment will be set to missing. An ESR value of 0 will be substituted with ESR = 1 
for the calculation of DAS28 (ESR). 
Categorical DAS28 Response 
• 
DAS28 (CRP) and DAS28 (ESR) will be categorized using EULAR response criteria. 
Response at a given time point is defined based on the combination of current DAS28 score 
andDAS28 decrease from baseline. The definition of no response, moderate response and 
good response is captured in the following table: 
• 
DAS28 decrease from baseline value will be calculated using the following formula: 
DAS28 decrease from baseline = DAS28 Baseline – Post-Dose Visit DAS28 Value 
Current DAS28 
DAS28 decrease from baseline 
>1.2 
>0.6 to ≤1.2 
≤0.6 
≤3.2 
Good response 
Moderate response 
No response 
>3.2 to ≤5.1 
Moderate response 
Moderate response 
No response 
>5.1 
Moderate response 
No response 
No response 
• 
If the post-baseline DAS28 (CRP) or DAS28 (ESR) is missing, then the corresponding EULAR 
category will be missing. 
DAS28 Remission 
• 
DAS28 (CRP) remission is achieved by a DAS28 (CRP) value lower than 2.6. 
• 
DAS28 (ESR) remission is achieved by a DAS28 (ESR) value lower than 2.6. 
• 
Missing DAS28 values will be considered as not achieving remission. 
Health Assessment Questionnaire-Disability Index (HAQ-DI)[Fries, 1980; Matsuda, 2003]  
Procedure 
• 
The functional status of the subject will be assessed by means of the Disability Index of the 
Health Assessment Questionnaire. This 20-question instrument assesses the degree of 
difficulty a person has in accomplishing tasks in eight functional areas: 
• Dressing & grooming 
• Arising 
• Eating 
• Walking 
• Hygiene 


 
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• Reach 
• Grip 
• Activities 
• 
Each functional area contains at least two questions. For each question, there is a four level 
response set that is scored from 0 (without any difficulty) to 3 (unable to do). If aids or devices 
or physical assistance are used for a specific functional area and the maximum response of 
this functional area is 0 or 1, the according value is increased to a score of 2. 
Aid or device 
Functional area 
Devices used for dressing 
Dressing and grooming 
Special or built up chair 
Arising 
Built up or special utensils 
Eating 
Cane 
Walking 
Crutches 
Walking 
Walker 
Walking 
Wheelchair 
Walking 
Bathtub seat 
Hygiene 
Bathtub bar 
Hygiene 
Raised toilet seat 
Hygiene 
Long-handled appliances in bathroom 
Hygiene 
Long-handled appliances for reach 
Reach 
Jar opener 
Grip 
 
• 
Regarding these corrections, the highest response within each functional area determines the 
score of that specific functional area. If no questions within a given functional area were 
answered, no score will be provided for that category (even if answers on aids or equipment 
are available). 
• 
HAQ-DI is only calculated if there are at least 6 functional area scores available. 
• 
The average of these non-missing functional area scores defines the continuous HAQ-DI score 
ranging from 0 to 3. If there are less than 6 functional area scores available, no imputation will 
be done and the HAQ-DI will be set to missing for the according assessment. 


 
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Flowchart 
 
 


 
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Examples 
Value in each question 
Use of aid or device / Need for help 
No. 
Functional area 
Value 
1 
Dressing and grooming 
1 
2 
Dressing and grooming 
0 
3 
Arising 
2 
4 
Arising 
1 
5 
Eating 
3 
6 
Eating 
0 
7 
Eating 
2 
8 
Walking 
1 
9 
Walking 
0 
10 
Hygiene 
2 
11 
Hygiene 
2 
12 
Hygiene 
1 
13 
Reach 
0 
14 
Reach 
0 
15 
Grip 
3 
16 
Grip 
2 
17 
Grip 
0 
18 
Activities 
2 
19 
Activities 
1 
20 
Activities 
0 
Functional area 
Use or Need 
Dressing and 
grooming 
× 
Arising 
○ 
Eating 
× 
Walking 
○ 
Hygiene 
× 
Reach 
○ 
Grip 
× 
Activities 
× 
 
 
 
 
 
Functional area 
Score 
Use of aid 
Updated score 
Dressing and grooming 
1 
× 
1 
Arising 
2 
○ 
2 
Eating 
3 
× 
3 
Walking 
1 
○ 
2 
Hygiene 
2 
× 
2 
Reach 
0 
○ 
2 
Grip 
3 
× 
3 
Activities 
2 
× 
2 
Sum updated scores 
17 
Divide by number of functional area scored 
2.125 
Maximum value in each functional area 
This score was 
not updated 
because it was 
more than 2 
This score was 
increased to 2 
because it was 0 or 1. 


 
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FACIT-Fatigue 
Procedure 
• 
The FACIT-Fatigue questionnaire is a patient-reported measure developed to assess fatigue 
consisting 13 statements regarding feeling fatigue using a numeric rating scale ranging from 0 
(Not at all) to 4 (very much). 
• 
For only two of the items (i.e. An5 and An7) a higher value represents a lower fatigue, 11 of the 
item scores (i.e. HI7, HI12, An1, An2, An3, An4, An8, An12, An14, An15, An16) have to be 
reversed by subtracting the captured value from 4 (0 is turned to a 4, 1 into 3, 3 into 1, 4 into 
0). 
• 
After performing the reversals, the sum of the non-missing individual items will be multiplied by 
13 and divided by the number of the non-missing individual items. 
• 
The final score ranges from 0 to 52 with higher values representing a lower fatigue. 
• 
If more than 6 individual items are missing at an assessment the FACIT-Fatigue score will be 
set to missing at that assessment. 
Examples 
Item Code 
Reverse Item 
Item Response 
Item Score 
HI7 
4 
－ 
2 
= 
2 
HI12 
4 
－ 
4 
= 
0 
An1 
4 
－ 
3 
= 
1 
An2 
4 
－ 
1 
= 
3 
An3 
4 
－ 
3 
= 
1 
An4 
4 
－ 
0 
= 
4 
An5 
0 
＋ 
2 
= 
2 
An7 
0 
＋ 
1 
= 
1 
An8 
4 
－ 
2 
= 
2 
An12 
4 
－ 
3 
= 
1 
An14 
4 
－ 
1 
= 
3 
An15 
4 
－ 
2 
= 
2 
An16 
4 
－ 
3 
= 
1 
Sum individual item scores 
23 
Multiply by 13 = 
299 
Divide by number of items answered = 
23 
Fatigue Subscale Score = 
23 
SDAI[Smolen, 2003]   
• 
The Simplified Disease Activity Index (SDAI) is a composite score consisting of the sum of 
SJC28, TJC28, PtGA/10, PhGA/10, and CRP (mg/dl). 
• 
This score will be calculated based on the formula: 
SDAI = SJC28 + TJC28 + PtGA / 10 + PhGA / 10 + CRP 


 
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• 
If one of the components is missing at an individual assessment point, the SDAI value for that 
assessment will be set to missing. 
CDAI[Aletaha, 2005]  
• 
The Clinical Disease Activity Index (CDAI) is a composite score consisting of the sum of 
SJC28, TJC28, PtGA/10, PhGA/10. 
• 
This score will be calculated based on the formula: 
CDAI = SJC28 + TJC28 + PtGA / 10 + PhGA / 10 
• 
If one of the components is missing at an individual assessment point, the CDAI value for that 
assessment will be set to missing. 
Swollen and Tender/Painful Joint Count 
• 
Four different scores will be calculated to evaluate swelling and tenderness of joints.SJC28 
and TJC28 will take 28 joints into account, SJC66 and TJC68 will use 66 and 68 joints, 
respectively. 
• 
The assessment for swelling is the total number of joints with a present swelling and ranges 
from 0 to 28 for SJC28 and 0 to 66 for SJC66. 
• 
The assessment for tenderness is the total number of joints with a present tenderness and 
ranges from 0 to 28 for TJC28 and 0 to 68 for TJC68. 
• 
The following 28 joints will be taken into account for TJC28 and SJC28. 
o Shoulder (2 joints) 
o Knee (2) 
o Elbow (2) 
o Wrist (2) 
o Fingers (PIP, MCP: 20) 
• 
Additionally the following joints will be taken into account for TJC68 and SJC66. 
o Temporomandibular (2) 
o Stemoclavicular (2) 
o Acromioclavicular (2) 
o Fingers (DIP: 8) 
o Ankle (2) 
o Tarsus (2) 
o Toes (PIP, MTP: 20) 
o Hip (2, only for TJC) 
• 
If there are missing observations for tender or swollen joints then the remaining observations 
will be assessed and weighted by dividing the number presented by number of non-missing 
and by multiplying by 28/66/68 for the joint count. No imputations for individual joints will be 
done. If a joint is not evaluable at Baseline, then that joint is set missing throughout the study. 
• 
If data for more than 50% of the joints are missing at the time of a given assessment, then the 
total count will be set to missing for that visit. 


 
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Patient’s Assessment of Arthritis Pain 
• 
Subjects will assess the severity of their current arthritis pain using a continuous visual 
analogue scale (VAS) by placing a mark on the scale between “0” (no pain) and “10” (most 
severe pain), which corresponds to the magnitude of their current pain. 
• 
Subjects will also assess the severity of their past week’s arthritis pain using a continuous 
visual analogue scale (VAS) by placing a mark on the scale between “0” (no pain) and “100” 
(severe pain), which corresponds to the magnitude of their pain for the past week. 
• 
The current endpoints are collected on eCRF after converted to a 100 unit. 
• 
No imputations for missing data will be done. 
Patient’s Global Assessment of Disease Activity 
• 
Subjects will complete a global assessment of disease activity using the patient global 
assessment (PtGA) item, a continuous VAS with anchors “0” (very well) to “10” (very poor). 
• 
The current endpoints are collected on eCRF after converted to a 100 unit. 
• 
No imputations for missing data will be done. 
Physician’s Global Assessment of Arthritis 
• 
Physicians will complete a global assessment of disease activity using the physician global 
assessment item (PhGA), a continuous VAS with anchors “0” (none) to “10” (extremely active). 
• 
The current endpoints are collected on eCRF after converted to a 100 unit. 
• 
No imputations for missing data will be done. 
 
11.5.5. 
Immunogenicity 
Immunogenicity 
• Samples taken after dosing with GSK3196165 that have a value at or above the cut-point will 
be considered treatment emergent Anti-Drug-Antibody positive. 
 


 
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11.6. 
Appendix 6: Premature Withdrawals & Handling of Missing 
Data 
11.6.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• Subject study completion (i.e. as specified in the protocol) was defined as 
subjects who have completed all phases of the study including the following-up 
visit. 
• Withdrawn subjects were not replaced in the study. 
• All available data from subjects who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, 
unless otherwise specified. 
 
11.6.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument : 
o These data will be indicated by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such. 
Binary 
variable 
• Subjects with missing efficacy data or early withdrawal will be imputed as a 
failure (e.g. no DAS28(CRP) remission or no moderate/good EULAR response). 
Continuous 
variable 
• No imputation will be done. 
 


 
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11.6.2.1. 
Handling of Partial Dates 
Element 
Reporting Detail 
General 
Partial dates will be displayed as captured in subject listing displays. 
Medications 
• Missing start day, but month and year present: 
o 
If first study medication administration had been taken place in the same 
month and year as the occurrence of the medication, then the start day of 
the medication is assigned to the day of first study medication administration. 
o Otherwise the start day is set to the first day of the month (eg, XX-Sep-2010 
is considered as 01-Sep-2010). 
• Missing start day and month, but year present: 
o 
If first study medication administration had been taken in the same year as 
the occurrence of the medication, then the start date of the medication is 
assigned to the date of first study medication administration. 
o 
Otherwise the start day and month is set to 01 January (eg, XX-XXX-2010 is 
considered as 01-Jan-2010). 
• Missing stop day, but month and year present: 
o 
The day is set to the last day of the month (eg, XX-Sep-2010 is considered 
as 30-Sep-2010). 
• Missing stop day and month, but year present: 
o 
The stop day and month is set to 31 December (eg, XX-XXX-2010 is 
considered as 31-Dec-2010). 
• The recorded partial date will be displayed in listings. 
RA 
diagnosis 
and 
symptom 
onset 
• Missing day, but month and year present: 
o Date is set to the first day of the month. 
• Missing day and month, but year present: 
o Date is set to 01 January. 
11.6.2.2. 
Handling of Missing Data for Statistical Analysis 
Element 
Reporting Detail 
Continuous 
variables 
• The analysis will be considered on the assumption of Missing at Random 
(MAR) (e.g. MMRM). 
 


 
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11.7. 
Appendix 7: Multiple Comparisons & Multiplicity 
 
No multiplicity adjustment will be planned because no formal statistical hypotheses will 
be tested in this study. 


 
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11.8. 
Appendix 8: Model Checking and Diagnostics for Statistical 
Analyses 
11.8.1. 
Statistical Analysis Assumptions 
Endpoint(s) • Change from baseline in DAS28(CRP), DAS28(ESR), SDAI, CDAI and FACIT-
fatigue 
Analysis 
• MMRM 
• The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used. 
• An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on 
the REPEATED line. 
o In the event that this model fails to converge, alternative correlation structures may be 
considered such as CSH or CS.  
• Akaike's Information Criteria (AIC) will be used to assist with the selection of covariance 
structure. 
 
Endpoint(s) • Change from baseline in DAS28(CRP) at Week 12 
Analysis 
• Dose response analysis 
• Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a plot of the residuals versus the fitted values to gain confidence that the model 
assumptions are reasonable. 
 


 
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11.9. 
Appendix 9 – Abbreviations & Trade Marks 
11.9.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AIC 
Akaike's Information Criteria 
A&R 
Analysis and Reporting  
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
CTR 
Clinical Trial Register 
CVb / CVw 
Coefficient of Variation (Between) / Coefficient of Variation (Within) 
DOB 
Date of Birth 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
IA 
Interim Analysis 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
IMMS 
International Modules Management System 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
GUI 
Guidance 
LOCF 
Last Observation Carries Forward 
MMRM 
Mixed Model Repeated Measures 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
PP 
Per Protocol 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
RAMOS 
Randomization & Medication Ordering System  
SAC 
Statistical Analysis Complete 
SDTM 
Study Data Tabulation Model 
SOP 
Standard Operation Procedure 
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  
GSK 
GlaxoSmithKline 


 
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11.9.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
NONE 
 
SAS 
 
 
WinNonlin 
 
 
 
 


 
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11.10. 
Appendix 10: List of Data Displays 
11.10.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.21 
 
Efficacy 
2.1 to 2.37 
2.1 to 2.26 
Safety 
3.1 to 3.38 
 
Pharmacokinetic 
4.1 to 4.4 
4.1 to 4.8 
Pharmacodynamic and / or Biomarker 
5.1 to 5.4 
5.1 to 5.8 
Pharmacokinetic / Pharmacodynamic 
 
6.1 to 6.3 
Section 
Listings 
ICH Listings 
1 to 77 
 
11.10.2. 
Deliverable 
Delivery 
Description 
SAC 
Final Statistical Analysis Complete 
 
 


 
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11.10.3. 
Study Population Tables 
 
Study Population Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Subject Disposition 
1.1.  
ITT 
ES1 
Summary of Subject Disposition for the Subject Conclusion 
Record 
 
SAC 
1.2.  
ITT 
SD1 
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment 
 
SAC 
1.3.  
All 
Screening 
ES6 
Summary of Screening Status and Reasons for Screen Failure 
 
SAC 
1.4.  
All 
Screening 
NS1 
Summary of Subjects Enrolled by Site ID 
 
SAC 
Protocol Deviations 
1.5.  
Randomised 
DV1 
Summary of Important Protocol Deviations 
 
SAC 
Population Analysed 
1.6.  
All 
Screening 
SP1 
Summary of Study Populations 
 
SAC 
1.7.  
Randomised 
SP2A 
Summary of Exclusions from ITT Population 
 
SAC 


 
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Study Population Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Demographic and Baseline Characteristics 
1.8.  
ITT 
DM1 
Summary of Demographic Characteristics 
 
SAC 
1.9.  
ITT 
POP_T5 
Summary of Baseline Efficacy Parameters 
 
SAC 
1.10. 
ITT 
POP_T6 
Summary of Rheumatoid factor and Anti-Cyclic Citrullinated 
Protein Antibody 
 
SAC 
1.11. 
All 
Screening 
DM11 
Summary of Age Ranges 
 
SAC 
1.12. 
ITT 
DM5 
Summary of Race and Racial Combinations 
 
SAC 
1.13. 
ITT 
POP_T1 
Summary of Substance Use 
 
SAC 
1.14. 
ITT 
POP_T2 
Summary of Rheumatoid Arthritis Disease History 
 
SAC 
Prior and Concomitant Medications 
1.15. 
ITT 
CM1 
Summary of Medications 
 
SAC 
1.16. 
ITT 
CM1 
Summary of Medications for Rheumatoid Arthritis prior to the 
Date of first dose 
 
SAC 
1.17. 
ITT 
CM1 
Summary of Medications for Rheumatoid Arthritis from the Date 
of first dose 
 
SAC 
1.18. 
ITT 
POP_T3 
Summary of Oral Corticosteroid by Visit 
 
SAC 
1.19. 
ITT 
POP_T3 
Summary of Change from Baseline in Oral Corticosteroid by 
Visit 
 
SAC 
Exposure 
1.20. 
ITT 
EX1 
Summary of Exposure to Study Treatment 
 
SAC 
1.21. 
ITT 
POP_T4 
Summary of Exposure to MTX 
 
SAC 
 


 
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11.10.4. 
Efficacy Tables 
Secondary Efficacy: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
DAS28(CRP) 
2.1.  
ITT 
EFF_T1 
Summary of DAS28(CRP) Values 
 
SAC 
2.2.  
ITT 
EFF_T1 
Summary of Change from Baseline in DAS28(CRP) 
 
SAC 
Statistical Analysis for DAS28(CRP) Comparison with Placebo 
2.3.  
ITT 
EFF_T2 
Summary of Repeated Measures Analysis of Change from 
Baseline in DAS28(CRP) 
 
SAC 
Dose Response Analysis in DAS28(CRP) 
2.4.  
ITT 
EFF_T3 or 
EFF_T4 
Summary of Results of Dose Response Analysis for Change 
from Baseline in DAS28(CRP) at Week 12 
Statistician will select the final model 
among the three dose response 
models. 
SAC 
 


 
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Exploratory Efficacy: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
ACR 20/50/70 response 
2.5.  
ITT 
EFF_T5 
Summary of ACR 20 Responses 
 
SAC 
2.6.  
ITT 
EFF_T5 
Summary of ACR 50 Responses 
 
SAC 
2.7.  
ITT 
EFF_T5 
Summary of ACR 70 Responses 
 
SAC 
DAS28(ESR) 
2.8.  
ITT 
EFF_T1 
Summary of DAS28(ESR) Values 
 
SAC 
2.9.  
ITT 
EFF_T1 
Summary of Change from Baseline in DAS28(ESR) 
 
SAC 
2.10. 
ITT 
EFF_T2 
Summary of Repeated Measures Analysis of Change from 
Baseline in DAS28(ESR) 
 
SAC 
SDAI, CDAI and FACIT-Fatigue 
2.11. 
ITT 
EFF_T1 
Summary of SDAI Values 
 
SAC 
2.12. 
ITT 
EFF_T1 
Summary of CDAI Values 
 
SAC 
2.13. 
ITT 
EFF_T1 
Summary of FACIT-Fatigue 
 
SAC 
2.14. 
ITT 
EFF_T1 
Summary of Change from Baseline in SDAI 
 
SAC 
2.15. 
ITT 
EFF_T1 
Summary of Change from Baseline in CDAI 
 
SAC 
2.16. 
ITT 
EFF_T1 
Summary of Change from Baseline in FACIT-Fatigue 
 
SAC 
2.17. 
ITT 
EFF_T2 
Summary of Repeated Measures Analysis of Change from 
Baseline in SDAI 
 
SAC 
2.18. 
ITT 
EFF_T2 
Summary of Repeated Measures Analysis of Change from 
Baseline in CDAI 
 
SAC 
2.19. 
ITT 
EFF_T2 
Summary of Repeated Measures Analysis of Change from 
Baseline in FACIT-Fatigue 
 
SAC 


 
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201789 
 
68 
 
Categorical DAS28(CRP) / DAS28(ESR) Response 
2.20. 
ITT 
EFF_T5 
Summary of Categorical DAS28(CRP) Responses 
 
SAC 
2.21. 
ITT 
EFF_T5 
Summary of Categorical DAS28(ESR) Responses 
 
SAC 
DAS28(CRP) / DAS28(ESR) Remission 
2.22. 
ITT 
EFF_T5 
Summary of DAS28(CRP) Remission 
 
SAC 
2.23. 
ITT 
EFF_T5 
Summary of DAS28(ESR) Remission 
 
SAC 
The other endpoints 
2.24. 
ITT 
EFF_T6 
Summary of Swollen/Tender Joint Counts 
 
SAC 
2.25. 
ITT 
EFF_T6 
Summary of Patient’s Assessment of Arthritis Pain 
 
SAC 
2.26. 
ITT 
EFF_T1 
Summary of Patient’s Global Assessment of Arthritis 
 
SAC 
2.27. 
ITT 
EFF_T1 
Summary of Physician’s Global Assessment of Arthritis 
 
SAC 
2.28. 
ITT 
EFF_T1 
Summary of CRP 
 
SAC 
2.29. 
ITT 
EFF_T1 
Summary of ESR 
 
SAC 
2.30. 
ITT 
EFF_T1 
Summary of HAQ-DI score 
 
SAC 
2.31. 
ITT 
EFF_T6 
Summary of Change from Baseline in Swollen/Tender Joint 
Counts 
 
SAC 
2.32. 
ITT 
EFF_T6 
Summary of Change from Baseline in Patient’s Assessment of 
Arthritis Pain 
 
SAC 
2.33. 
ITT 
EFF_T1 
Summary of Change from Baseline in Patient’s Global 
Assessment of Arthritis 
 
SAC 
2.34. 
ITT 
EFF_T1 
Summary of Change from Baseline in Physician’s Global 
Assessment of Arthritis 
 
SAC 
2.35. 
ITT 
EFF_T1 
Summary of Change from Baseline in CRP 
 
SAC 
2.36. 
ITT 
EFF_T1 
Summary of Change from Baseline in ESR 
 
SAC 
2.37. 
ITT 
EFF_T1 
Summary of Change from Baseline in HAQ-DI score 
 
SAC 
 


 
CONFIDENTIAL 
 
 
 
201789 
 
69 
 
11.10.5. 
Efficacy Figures 
Secondary Efficacy: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
DAS28(CRP) 
2.1.  
ITT 
EFF_F3 
Plot of Mean (95%CI) Change from Baseline in DAS28(CRP) 
Profiles 
 
SAC 
2.2.  
ITT 
EFF_F3 
Plot of Median (Range) Change from Baseline in DAS28(CRP) 
Profiles 
 
SAC 
Statistical Analysis for DAS28(CRP) Comparison with Placebo 
2.3.  
ITT 
EFF_F3 
Plot of Predicted (95%CI) Treatment Difference from Placebo in 
DAS28(CRP) 
 
SAC 
Dose Response Analysis in DAS28(CRP) 
2.4.  
ITT 
EFF_F2 
Plot of Predicted (95%CI) Change from Baseline in 
DAS28(CRP) by the final Dose Response Model at Week 12 
Statistician will select the final model 
among the three dose response 
models. 
SAC 
2.5.  
ITT 
EFF_F1 
Plot of the Residuals versus the Predicted DAS28(CRP) by final 
Dose Response Model at Week 12 
 
SAC 
 


 
CONFIDENTIAL 
 
 
 
201789 
 
70 
 
Exploratory Efficacy: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
ACR20/50/70 
2.6.  
ITT 
EFF_F4 
Barplot of ACR20 Response Rate by Visit 
 
SAC 
2.7.  
ITT 
EFF_F4 
Barplot of ACR50 Response Rate by Visit 
 
SAC 
2.8.  
ITT 
EFF_F4 
Barplot of ACR70 Response Rate by Visit 
 
SAC 
DAS28(ESR) 
2.9.  
ITT 
EFF_F3 
Plot of Mean (95%CI) Change from Baseline in DAS28(ESR) 
Profiles 
 
SAC 
2.10. 
ITT 
EFF_F3 
Plot of Median (Range) Change from Baseline in DAS28(ESR) 
Profiles 
 
SAC 
Statistical Analysis for DAS28(CRP) Comparison with Placebo 
2.11. 
ITT 
EFF_F3 
Plot of Predicted (95%CI) Treatment Difference from Placebo in 
DAS28(ESR) 
 
SAC 
SDAI, CDAI and FACIT-Fatigue 
2.12. 
ITT 
EFF_F3 
Plot of Mean (95%CI) Change from Baseline in SDAI Profiles 
 
SAC 
2.13. 
ITT 
EFF_F3 
Plot of Median (Range) Change from Baseline in SDAI Profiles 
 
SAC 
2.14. 
ITT 
EFF_F3 
Plot of Mean (95%CI) Change from Baseline in CDAI Profiles 
 
SAC 
2.15. 
ITT 
EFF_F3 
Plot of Median (Range) Change from Baseline in CDAI Profiles 
 
SAC 
2.16. 
ITT 
EFF_F3 
Plot of Mean (95%CI) Change from Baseline in FACIT-Fatigue 
Profiles 
 
SAC 
2.17. 
ITT 
EFF_F3 
Plot of Median (Range) Change from Baseline in FACIT-Fatigue 
Profiles 
 
SAC 


 
CONFIDENTIAL 
 
 
 
201789 
 
71 
 
Exploratory Efficacy: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Statistical Analyses for SDAI, CDAI and FACIT-Fatigue Comparisons with Placebo 
2.18. 
ITT 
EFF_F3 
Plot of Predicted (95%CI) Treatment Difference from Placebo in 
SDAI 
 
SAC 
2.19. 
ITT 
EFF_F3 
Plot of Predicted (95%CI) Treatment Difference from Placebo in 
CDAI 
 
SAC 
2.20. 
ITT 
EFF_F3 
Plot of Predicted (95%CI) Treatment Difference from Placebo in 
FACIT-Fatigue 
 
SAC 
Each Components of Composite endpoints 
2.21. 
ITT 
EFF_F3 
Plot of Mean (95% CI) Change from Baseline in CRP Profiles 
 
SAC 
2.22. 
ITT 
EFF_F3 
Plot of Median (Range) Change from Baseline in CRP Profiles 
 
SAC 
2.23. 
ITT 
EFF_F3 
Plot of Mean (95% CI) Change from Baseline in ESR Profiles 
 
SAC 
2.24. 
ITT 
EFF_F3 
Plot of Median (Range) Change from Baseline in ESR Profiles 
 
SAC 
2.25. 
ITT 
EFF_F3 
Plot of Mean (95% CI) Change from Baseline in HAQ-DI score 
Profiles 
 
SAC 
2.26. 
ITT 
EFF_F3 
Plot of Median (Range) Change from Baseline in HAQ-DI score 
Profiles 
 
SAC 
 


 
CONFIDENTIAL 
 
 
 
201789 
 
72 
 
11.10.6. 
Safety Tables 
Safety : Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Adverse Events (AEs) 
3.1.  
ITT 
AE1 
Summary of All AEs by SOC and PT 
 
SAC 
3.2.  
ITT 
AE5A 
Summary of All AEs by SOC and PT and Maximum Intensity 
 
SAC 
3.3.  
ITT 
SAFE_T4 
Summary of AESI 
 
SAC 
3.4.  
ITT 
AE3 
Summary of Adverse Events by Overall Frequency 
 
SAC 
3.5.  
ITT 
AE1 
Summary of Drug-Related AEs by SOC and PT 
 
SAC 
3.6.  
ITT 
AE5A 
Summary of Drug-Related AEs by SOC and PT and Maximum 
Intensity 
 
SAC 
3.7.  
ITT 
AE15 
Summary of Common (>=5%) Non-Serious Adverse Events by 
SOC and PT 
 
SAC 
3.8.  
ITT 
AE1 
Summary of AEs Leading to Withdrawal from Study 
 
SAC 
3.9.  
ITT 
AE1 
Summary of AEs Leading to Permanent Discontinuation of 
Study Treatment 
 
SAC 
3.10. 
ITT 
SAFE_T4 
Summary of AESI Leading to Permanent Discontinuation of 
Study Treatment 
 
SAC 
3.11. 
ITT 
AE1 
Summary of Disease Related Events 
 
SAC 
Serious Adverse Events (SAEs) 
3.12. 
ITT 
AE16 
Summary of Serious Adverse Events by SOC and PT 
 
SAC 


 
CONFIDENTIAL 
 
 
 
201789 
 
73 
 
Safety : Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
ECG 
3.13. 
ITT 
EG1 
Summary of ECG Findings 
 
SAC 
3.14. 
ITT 
EG2 
Summary of Change from Baseline in ECG Values by Visit 
 
SAC 
3.15. 
ITT 
EG2 
Summary of ECG values by visit 
 
SAC 
Vital Signs 
3.16. 
ITT 
VS1 
Summary of Change from Baseline in Vital Signs by Visit 
 
SAC 
3.17. 
ITT 
VS1 
Summary of Vital Signs by Visit 
 
SAC 
Pulmonary 
3.18. 
ITT 
SAFE_T1 
Summary of Cough by Visit and Grade 
 
SAC 
3.19. 
ITT 
SAFE_T1 
Summary of Lung Auscultation by Visit 
 
SAC 
3.20. 
ITT 
SAFE_T2 
Summary of Pulse Oximetry by Visit 
 
SAC 
3.21. 
ITT 
SAFE_T1 
Summary of Borg Dyspnea Scale by Visit 
 
SAC 
3.22. 
ITT 
SAFE_T2 
Summary of Percent Predicted Normal FEV1 by Visit 
 
SAC 
3.23. 
ITT 
SAFE_T2 
Summary of Percent Predicted Normal FVC by Visit 
 
SAC 
3.24. 
ITT 
SAFE_T2 
Summary of Percent Predicted HGB Corrected DLCO by Visit 
 
SAC 
3.25. 
ITT 
SAFE_T2 
Summary of Change from Baseline in Pulse Oximetry by Visit 
 
SAC 
3.26. 
ITT 
SAFE_T2 
Summary of Change from Baseline in Percent Predicted Normal 
FEV1 by Visit 
 
SAC 
3.27. 
ITT 
SAFE_T2 
Summary of Change from Baseline in Percent Predicted Normal 
FVC by Visit 
 
SAC 
3.28. 
ITT 
SAFE_T2 
Summary of Change from Baseline in Percent Predicted HGB 
Corrected DLCO by Visit 
 
SAC 


 
CONFIDENTIAL 
 
 
 
201789 
 
74 
 
Safety : Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Respiratory events 
3.29. 
ITT 
SAFE_T5 
Summary of Persistent cough, dyspnea and DLCO decrease by 
> 15%  
 
SAC 
Chemistry 
3.30. 
ITT 
LB1 
Summary of Chemistry Changes from Baseline 
 
SAC 
3.31. 
ITT 
LB1 
Summary of Chemistry by visit 
 
SAC 
3.32. 
ITT 
LB15 
Summary of Emergent Chemistry Results Relative to Normal 
Ranges 
 
SAC 
Hematology 
3.33. 
ITT 
LB1 
Summary of Hematology Changes from Baseline 
 
SAC 
3.34. 
ITT 
LB1 
Summary of Hematology by Visit 
 
SAC 
3.35. 
ITT 
LB15 
Summary of Emergent Hematology Results Relative to Normal 
Range 
 
SAC 
Urinalysis 
3.36. 
ITT 
UR3 
Summary of Urinalysis Dipstick Results 
 
SAC 
Hepatobiliary (Liver) 
3.37. 
ITT 
LIVER10 
Summary of Hepatobiliary Laboratory Abnomalities 
 
SAC 
Immunogenicity 
3.38. 
Immunogeni
city 
SAFE_T3 
Summary of Immunogenicity 
 
SAC 
 


 
CONFIDENTIAL 
 
 
 
201789 
 
75 
 
11.10.7. 
Pharmacokinetic Tables 
Pharmacokinetic : Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Serum GSK3196165 Concentrations 
4.1.  
PK 
PK01 
Summary of Serum GSK3196165 Concentrations 
 
SAC 
PK Parameters 
4.2.  
PK 
PK03 
Summary of Derived Serum GSK3196165 Pharmacokinetic 
Parameters 
 
SAC 
4.3.  
PK 
PK05 
Summary of Log-Transformed Derived Serum GSK3196165 
Pharmacokinetic Parameters 
 
SAC 
4.4.  
PK 
PK_T1 
Summary of Power Model Analysis for Dose Proportionality of 
GSK3196165 Pharmacokinetic Parameters 
• 
Cmax 
• 
AUCtau 
• 
AUC(0-t) 
• 
AUC(0-inf) 
SAC 
 


 
CONFIDENTIAL 
 
 
 
201789 
 
76 
 
11.10.8. 
Pharmacokinetic Figures 
Pharmacokinetic : Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Serum GSK3196165 Concentrations 
4.1.  
PK 
PK_F1 
Individual Serum GSK3196165 Concentration-Time Plots 
(Linear and Semi-log) 
 
SAC 
4.2.  
PK 
PK17 
Mean Serum GSK3196165 Concentration-Time Plots (Linear 
and Semi-log) 
 
SAC 
4.3.  
PK 
PK18 
Median Serum GSK3196165 Concentration-Time Plots (Linear 
and Semi-log) 
 
SAC 
Parameters 
4.4.  
PK 
PK28 
Plot of Individual Serum GSK3196196 Pharmacokinetic 
Parameters versus Dose 
• 
Cmax 
• 
AUCtau 
• 
AUC(0-t) 
• 
AUC(0-inf) 
SAC 
4.5.  
PK 
PK_F2 
Plot of GSK3196165 Pharmacokinetic Parameter Cmax vs. 
Treatment 
 
SAC 
4.6.  
PK 
PK_F2 
Plot of GSK3196165 Pharmacokinetic Parameter AUCtau vs. 
Treatment 
 
SAC 
4.7.  
PK 
PK_F2 
Plot of GSK3196165 Pharmacokinetic Parameter AUC(0-t) vs. 
Treatment 
 
SAC 
4.8.  
PK 
PK_F2 
Plot of GSK3196165 Pharmacokinetic Parameter AUC(0-inf) vs. 
Treatment 
 
SAC 
 


 
CONFIDENTIAL 
 
 
 
201789 
 
77 
 
11.10.9. 
Pharmacodynamic and Biomarker Tables 
Pharmacodynamic and Biomarker : Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Biomarkers 
5.1.  
ITT 
PD1 
Summary of Biomarkers 
• 
free soluble GM-CSF 
• 
soluble GM-CSF complexed to 
GSK3196165 
• 
MRP8/14 
• 
ARGS neopitope 
• 
YKL-40 
• 
14-3-3η 
• 
IL-6 
• 
IL-1β 
• 
TNFα 
• 
IL-17A 
• 
IL-17F 
SAC 
5.2.  
ITT 
PD3 
Summary of Change from Baseline in Biomarkers 
• 
free soluble GM-CSF 
• 
soluble GM-CSF complexed to 
GSK3196165 
• 
MRP8/14 
• 
ARGS neopitope 
• 
YKL-40 
• 
14-3-3η 
• 
IL-6 
• 
IL-1β 
• 
TNFα 
• 
IL-17A 
• 
IL-17F 
SAC 


 
CONFIDENTIAL 
 
 
 
201789 
 
78 
 
Pharmacodynamic and Biomarker : Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Safety Biomarkers 
5.3.  
ITT 
PD1 
Summary of Safety Biomakers 
 SP-D 
 KL-6 
 Cholestenoic Acid 
 GM-CSF Autoantibodies at 
Baseline 
SAC 
5.4.  
ITT 
PD3 
Summary of Change from Baseline in Safety Biomarkers 
 SP-D 
 KL-6 
 Cholestenoic Acid 
SAC 
 


 
CONFIDENTIAL 
 
 
 
201789 
 
79 
 
11.10.10. 
Pharmacodynamic and Biomarker Figures 
Pharmacodynamic and Biomarker : Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Biomarkers 
5.1.  
ITT 
PD_F1 
Plot of Mean Biomarkers 
• 
free soluble GM-CSF 
• 
soluble GM-CSF complexed to 
GSK3196165 
• 
MRP8/14 
• 
ARGS neopitope 
• 
YKL-40 
• 
14-3-3η 
• 
IL-6 
• 
IL-1β 
• 
TNFα 
• 
IL-17A 
• 
IL-17F 
SAC 
5.2.  
ITT 
PD_F2 
Plot of Median Biomarkers 
• 
free soluble GM-CSF 
• 
soluble GM-CSF complexed to 
GSK3196165 
• 
MRP8/14 
• 
ARGS neopitope 
• 
YKL-40 
• 
14-3-3η 
• 
IL-6 
• 
IL-1β 
• 
TNFα 
• 
IL-17A 
• 
IL-17F 
SAC 


 
CONFIDENTIAL 
 
 
 
201789 
 
80 
 
Pharmacodynamic and Biomarker : Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
5.3.  
ITT 
PD_F1 
Plot of Mean Change from Baseline in Biomarkers -Time Profile 
• 
free soluble GM-CSF 
• 
soluble GM-CSF complexed to 
GSK3196165 
• 
MRP8/14 
• 
ARGS neopitope 
• 
YKL-40 
• 
14-3-3η 
• 
IL-6 
• 
IL-1β 
• 
TNFα 
• 
IL-17A 
• 
IL-17F 
SAC 
5.4.  
ITT 
PD_F2 
Plot of Median Change from Baseline in Biomarkers -Time 
Profile 
• 
free soluble GM-CSF 
• 
soluble GM-CSF complexed to 
GSK3196165 
• 
MRP8/14 
• 
ARGS neopitope 
• 
YKL-40 
• 
14-3-3η 
• 
IL-6 
• 
IL-1β 
• 
TNFα 
• 
IL-17A 
• 
IL-17F 
SAC 


 
CONFIDENTIAL 
 
 
 
201789 
 
81 
 
Pharmacodynamic and Biomarker : Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Safety Biomarkers 
5.5.  
ITT 
PD_F1 
Plot of Mean Safety Biomarkers -Time Profile 
• 
SP-D 
• 
KL-6 
• 
Cholestenoic acid 
SAC 
5.6.  
ITT 
PD_F2 
Plot of Median Safety Biomarkers -Time Profile 
• 
SP-D 
• 
KL-6 
• 
Cholestenoic acid 
SAC 
5.7.  
ITT 
PD_F1 
Plot of Mean Change from Baseline in Safety Biomarkers -Time 
Profile 
• 
SP-D 
• 
KL-6 
• 
Cholestenoic acid 
SAC 
5.8.  
ITT 
PD_F2 
Plot of Median Change from Baseline in Safety Biomarkers -
Time Profile 
• 
SP-D 
• 
KL-6 
• 
Cholestenoic acid 
SAC 
 


 
CONFIDENTIAL 
 
 
 
201789 
 
82 
 
11.10.11. 
Pharmacokinetic / Pharmacodynamic Figures 
Pharmacokinetic / Pharmacodynamic : Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
6.1.  
PK 
PKPD_F1 
Linear scatter plot of Change from Baseline in freesoluble GM-
CSF level at each visit versus GSK3196165 concentration 
values at corresponding visit 
 
SAC 
6.2.  
PK 
PKPD_F1 
Linear scatter plot of Change from Baseline in CRP levels at 
each visit versus GSK3196165 concentration values at 
corresponding visit 
 
SAC 
6.3.  
PK 
PKPD_F1 
Linear scatter plot of Change from Baseline in DAS28(CRP) 
measures at each visit versus GSK3196165 concentration 
values at corresponding visit 
 
SAC 
 


 
CONFIDENTIAL 
 
 
 
201789 
 
83 
 
11.10.12. 
ICH Listings 
ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Subject Disposition 
1.  
ITT 
ES2 
Listing of Reasons for Subject Withdrawal 
 
SAC 
2.  
ITT 
SD2 
Listing of Treatment Status and Reasons for Discontinuation of 
Study Treatment 
 
SAC 
3.  
ALL 
Screening 
ES7 
Listing of Screening Status and Reasons for Screen Failure 
 
SAC 
4.  
ALL 
Screening 
ES9 
Listing of Subjects Who Were Rescreened 
 
SAC 
5.  
Randomised 
BL1 
Listing of Subjects Whom the Treatment Blind was Broken 
 
SAC 
6.  
ITT 
TA1 
Listing of Planned and Actual Treatments 
Sort by site id 
SAC 
Protocol Deviations 
7.  
All 
Screening 
DV2 
Listing of Important Protocol Deviations 
 
SAC 
8.  
All 
Screening 
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
 
SAC 
Populations Analysed 
9.  
ITT 
SP3 
Listing of Subjects Excluded from Any Population 
 
SAC 
Demographic and Baseline Characteristics 
10.  
ITT 
DM2 
Listing of Demographic Characteristics 
 
SAC 
11.  
ITT 
POP_L4 
Listing of Rheumatoid factor and Anti-Cyclic Citrullinated Protein 
Antibody 
 
SAC 
12.  
ITT 
DM9 
Listing of Race and Racial Combinations 
 
SAC 


 
CONFIDENTIAL 
 
 
 
201789 
 
84 
 
ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
13.  
ITT 
POP_L1 
Listing of Substance Use 
 
SAC 
14.  
ITT 
POP_L2 
Listing of Rheumatoid Arthritis Disease History 
 
SAC 
Prior and Concomitant Medications 
15.  
ITT 
MH2 
Listing of Medical Conditions 
 
SAC 
16.  
ITT 
CM3 
Listing of Medications 
 
SAC 
17.  
ITT 
CM6 
Listing of Relationship of Medication Class, Dictionary Term and 
Verbatim Text 
 
SAC 
18.  
ITT 
SP1 
Listing of Non-drug therapy 
 
SAC 
Exposure and Treatment Compliance 
19.  
ITT 
POP_L3 
Listing of Exposure to Study Treatment 
 
SAC 
20.  
ITT 
EX3 
Listing of Exposure to MTX 
 
SAC 


 
CONFIDENTIAL 
 
 
 
201789 
 
85 
 
ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Adverse Events 
21.  
ITT 
AE8 
Listing of All Adverse Events 
Including the flag of whether each AE is 
related to GSK3196165/Placebo and/or 
Methotrexate 
SAC 
22.  
ITT 
SAFE_L1 
Listing of Adverse Events of Special Interest – Serious 
Infections, and Non Serious Pulmonary or Opportunistic 
Infections 
 
SAC 
23.  
ITT 
SAFE_L1 
Listing of Adverse Events of Special Interest – Systemic 
Hypersensitivity Reactions 
 
SAC 
24.  
ITT 
SAFE_L1 
Listing of Adverse Events of Special Interest – Injection Site 
Reaction 
 
SAC 
25.  
ITT 
AE7 
Listing of Subject Numbers for Individual AEs 
 
SAC 
26.  
ITT 
AE2 
Listing of Relationship Between AE SOCs, PT and Verbatim 
Text 
 
SAC 
27.  
ITT 
AE8 
Listing of Disease Related Events 
 
SAC 


 
CONFIDENTIAL 
 
 
 
201789 
 
86 
 
ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Serious AE 
28.  
ITT 
AE8 
Listing of Serious Adverse Events 
 
SAC 
ECG 
29.  
ITT 
CP_EG3 
Listing of ECG values by Visit 
 
SAC 
30.  
ITT 
CP_EG5 
Listing of Abnormal ECG Findings 
 
SAC 
Vital Signs 
31.  
ITT 
CP_VS4 
Listing of Vital Signs by Visit 
 
SAC 
Pulmonary 
32.  
ITT 
SAFE_L2 
Listing of Cough by Visit and Grade 
 
SAC 
33.  
ITT 
SAFE_L2 
Listing of Lung Auscultation by Visit 
 
SAC 
34.  
ITT 
SAFE_L2 
Listing of Pulse Oximetry by Visit 
 
SAC 
35.  
ITT 
SAFE_L2 
Listing of Borg Dyspnea Scale by Visit 
 
SAC 
36.  
ITT 
SAFE_L2 
Listing of Percent Predicted Normal FEV1 by Visit 
 
SAC 
37.  
ITT 
SAFE_L2 
Listing of Percent Predicted Normal FVC by Visit 
 
SAC 
38.  
ITT 
SAFE_L2 
Listing of Percent Predicted HGB Corrected DLCO by Visit 
 
SAC 
Respiratory events 
39.  
ITT 
SAFE_L5 
Listing of Persistent cough, dyspnea and DLCO decrease by > 
15% 
 
SAC 
Hepatic B Virus 
40.  
ITT 
SAFE_L3 
Listing of HBV DNA monitoring 
 
SAC 


 
CONFIDENTIAL 
 
 
 
201789 
 
87 
 
ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Chemistry 
41.  
ITT 
LB5 
Listing of Chemistry by Visit 
 
SAC 
Hematology 
42.  
ITT 
LB5 
Listing of Hematology by Visit 
 
SAC 
Urinalysis 
43.  
ITT 
UR2a 
listing of Emergent Urinalysis Dipstick Results 
 
SAC 
Immunogenicity 
44.  
Immunogeni
city 
SAFE_L4 
Listing of Immunogenicity 
 
SAC 
DAS28 
45.  
ITT 
EFF_L1 
Listing of DAS28 Values 
Including changes from baseline 
SAC 
ACR20/50/70 
46.  
ITT 
EFF_L2 
Listing of ACR20/50/70 
Including ACR components 
SAC 
Categorical DAS28 response / DAS28 remission 
47.  
ITT 
EFF_L3 
Listing of Categorical DAS28 response 
 
SAC 
48.  
ITT 
EFF_L4 
Listing of DAS28 remission 
 
SAC 
SDAI, CDAI and FACIT-Fatigue 
49.  
ITT 
EFF_L5 
Listing of SDAI Values 
 
SAC 
50.  
ITT 
EFF_L5 
Listing of CDAI Values 
 
SAC 
51.  
ITT 
EFF_L6 
Listing of FACIT-Fatigue Values 
Including FACIT-fatigue components 
SAC 


 
CONFIDENTIAL 
 
 
 
201789 
 
88 
 
ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Other endpoints 
52.  
ITT 
EFF_L7 
Listing of Swollen/Tender Joint Count 
include assessment status (Y or N or 
ND)  
SAC 
53.  
ITT 
EFF_L8 
Listing of Patient’s Assessment of Arthritis Pain 
 
SAC 
54.  
ITT 
EFF_L9 
Listing of Patient’s Global Assessment of Arthritis 
 
SAC 
55.  
ITT 
EFF_L9 
Listing of Physician’s Global Assessment of Arthritis 
 
SAC 
56.  
ITT 
EFF_L10 
Listing of CRP 
 
SAC 
57.  
ITT 
EFF_L10 
Listing of ESR 
 
SAC 
58.  
ITT 
EFF_L11 
Listing of HAQ-DI score 
Including HAQ-DI components 
SAC 
PK 
59.  
PK 
PK07 
Listing of serum GSK3196165 concentration 
 
SAC 
60.  
PK 
PK_L1 
Listing of GSK3196165 Pharmacokinetic parameters 
 
SAC 


 
C O N FI D E N TI A L  
 
 
 
2 0 1 7 8 9  
 
8 9  
 
I C H : Li sti n g s 
N o.  
P o p ul ati o n  
I D S L / T S T I D / 
E x a m pl e S h ell  
Titl e    
Pr o gr a m mi n g N ot e s  
D eli v er a bl e  
Bi o m ar k er s  
6 1.   
I T T 
P D 1 0  
Listi ng of Bio m arkers  
•  
fr e e s ol u bl e G M-C S F  
•  
s ol u bl e G M-C S Fc o m pl ex e d t o 
G S K 3 1 9 6 1 6 5  
•  
M R P 8/ 1 4  
•  
A R G S n e o e pit o p e  
•  
Y K L -4 0  
•  
1 4 - 3-3 η  
•  
I L- 6 
•  
I L- 1 
•  
T N F  
•  
I L-1 7 A  
•  
I L-1 7 F  
S A C  
S af et y Bi o m ar k er s  
6 2.   
I T T 
P D 1 0  
Listi ng of S afety Bi o m arkers  
•  
S P - D 
•  
K L - 6 
•  
C h ol est e n oic Aci d  
•  
G M- C S F A ut o a nti b o di es  
S A C  


 
CONFIDENTIAL 
 
 
 
201789 
 
90 
 
ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Hepatobiliary (Liver) 
63.  
ITT 
MH2 
Listing of Medical Conditions for Subjects with Liver Stopping 
Events 
 
SAC 
64.  
ITT 
SU2 
Listing of Substance Use for Subjects with Liver Stopping 
Events 
 
SAC 
65.  
ITT 
LIVER5 
Listing of Liver Monitoring/Stopping Event Reporting 
 
SAC 
66.  
ITT 
LIVER6 
Listing of Liver Stopping Event Information for RUCAM Score 
 
SAC 
67.  
ITT 
LIVER7 
Listing of Liver Biopsy Details 
 
SAC 
68.  
ITT 
LIVER8 
Listing of Liver Imaging Details 
 
SAC 
69.  
ITT 
JLE2 
Listing of Laboratory Tests (Antigen and Antibody) for Liver 
Events 
 
SAC 
70.  
ITT 
JLE3 
Listing of Laboratory Tests (DNA and RNA) for Liver Events 
 
SAC 


 
CONFIDENTIAL 
 
 
 
201789 
 
91 
 
ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Cardiovascular 
71.  
ITT 
EG5 
Listing of ECG Findings in Cardiovascular Events 
 
SAC 
72.  
ITT 
SAFE_L (CV1) 
Listing of Subjects who had Cardiovascular Events 
 
SAC 
73.  
ITT 
SAFE_L (CV2) 
Listing of Diagnostic Test for Cardiovascular Events 
 
SAC 
74.  
ITT 
SAFE_L 
(FACV1) 
Listing of Findings about Cardiovascular Events 
 
SAC 
75.  
ITT 
SAFE_L 
(HRU1) 
Listing of Healthcare Resource Utilization due to Cardiovascular 
Events 
 
SAC 
76.  
ITT 
SAFE_L 
(NYHA1) 
Listing of NYHA Functional Class for Cardiovascular Events 
 
SAC 
77.  
ITT 
SAFE_L 
(DTH1) 
Listing of Death in Cardiovascular Events 
 
SAC 
 


 
CONFIDENTIAL 
 
 
 
201789 
 
92 
 
11.10.13. Non-ICH listings 
ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Dose Response Analyses 
78.  
ITT 
EFF_L12 
SAS Output of Dose Response Analysis of Change from 
Baseline in DAS28(CRP) using Emax model with 3 parameters 
 
SAC 
79.  
ITT 
EFF_L12 
SAS Output of Dose Response Analysis of Change from 
Baseline in DAS28(CRP) using Emax model with 4 parameters 
 
SAC 
80.  
ITT 
EFF_L12 
SAS Output of Dose Response Analysis of Change from 
Baseline in DAS28(CRP) using Linear model 
 
SAC