Clinical trial NCT02858492
Conditions: Arthritis, Rheumatoid
Keywords: efficacy safety pharmacokinetics pharmacodynamics Rheumatoid Arthritis autoimmune
Sponsor: GlaxoSmithKline
Start date: 2016-10-17; Completion date: 2018-10-22
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is the first study with GSK2982772, a receptor-interacting protein-1 (RIP1) kinase inhibitor, in subjects with moderate to severe RA who are currently being treated with disease modifying anti-rheumatic drugs (DMARDs). The primary objective of the study is to investigate the safety and tolerability of repeat oral doses of GSK2982772 in subjects with moderate to severe RA. In addition to the PK, a number of experimental and clinical endpoints will be employed to obtain information on the PD, and preliminary efficacy in subjects with active RA. Although no formal hypothesis will be tested, these endpoints will enable a broader understanding of the mechanism of action and potential for clinical efficacy of GSK2982772 in RA. After a screening period of up to 30 days, approximately 24 subjects will be randomized to receive either GSK2982772 or placebo for 84 days (12 weeks), followed by a follow-up period (28 days). The total duration of participation in the study will be approximately 20 weeks from screening to the last study visit.

Detailed description:

Arms: arm 1: Enrolled subjects will receive GSK2982772 60 mg thrice daily (approximately 8 hours apart) for 84 days. arm 2: Enrolled subjects will receive placebo thrice daily (approximately 8 hours apart) for 84 days.
Interventions: intervention 1: GSK2982772 60 mg intervention 2: Placebo
Intervention descriptions: intervention 1: GSK2982772 is available as a 30 mg white to almost white, round film coated tablet which will be administered as two tablets thrice daily as directed. intervention 2: Placebo is available as a white to almost white, round film coated tablet which will be administered as two tablets thrice daily as directed.

Protocol documents:
Prot_000.pdf: 
2015N251670_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
203168
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A multicentre, randomised, double-blind (sponsor-unblinded), 
placebo-controlled study to investigate the safety and 
tolerability, pharmacokinetics, pharmacodynamics, and efficacy 
of GSK2982772 in subjects with moderate to severe rheumatoid 
arthritis.
Compound Number:
GSK2982772
Development Phase:
II
Effective Date:
20-APR-2017
Protocol Amendment Number:  03
Author (s):
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


2015N251670_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
203168
2
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N251670_00
2016-APR-01
Original
2015N251670_01
2016-MAY-25
Amendment No. 1
Protocol Amendment 01 incorporates the addition of risk text for drug interaction with P-
glycoprotein (Pgp) inhibitors and narrow therapeutic index (NTI) CYP3A4 substrates, an 
updated list of prohibited medications plus some minor protocol clarifications and 
administrative changes.
2015N251670_02
2016-JUL-14
Amendment No. 2
Protocol Amendment 02 incorporates addition of suicidal ideation and behaviour (SIB) 
withdrawal criteria plus other minor protocol clarifications and administrative changes.
2015N251670_03
2017-APR-20
Amendment No. 3
Change in dosing regimen from 60 mg BID to 60 mg TID, restrictions on JAK inhibitors,
defined non-reproductive potential criteria in Exclusion 11, change to clinical laboratory 
criteria in Exclusion 23, addition of evaluation of joint space narrowing with MRI, 
flexibility in scheduling with MRI and synovial biopsy, some minor protocol 
clarifications and administrative changes.


PPD
PPD
PPD


2015N251670_03
CONFIDENTIAL
203168
4
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager Number
Fax 
Number
Site 
Address
Primary 
Medical 
Monitor 
Telephone:  
Email: 
Mobile:  
 
NA
GSK Stockley 
Park West, 1-
3 Ironbridge 
Road, 
Uxbridge, 
Middlesex, 
UB11 1BT, 
UK
Secondary 
Medical 
Monitor
Mobile:  
Email:  
Mobile: 
NA
1250 S. 
Collegeville 
Road, 
Collegeville, 
PA USA 
19426
SAE contact  
information 
Medical 
Monitor as 
above
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.
Regulatory Agency Identifying Number(s):  EudraCT 2016-000912-13
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


2015N251670_03
CONFIDENTIAL
203168
5
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 203168
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


2015N251670_03
CONFIDENTIAL
203168
6
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 203168......................................................10
2.
INTRODUCTION....................................................................................................15
2.1.
Study Rationale ..........................................................................................15
2.2.
Brief Background ........................................................................................15
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................17
4.
STUDY DESIGN ....................................................................................................20
4.1.
Overall Design ............................................................................................20
4.2.
Treatment Arms and Duration.....................................................................20
4.2.1.
Screening ....................................................................................20
4.2.2.
Treatment Period.........................................................................21
4.2.3.
Follow-up Period..........................................................................21
4.3.
Type and Number of Subjects.....................................................................21
4.4.
Design Justification.....................................................................................21
4.5.
Dose Justification........................................................................................22
4.6.
Benefit:Risk Assessment ............................................................................23
4.6.1.
Risk Assessment .........................................................................24
4.6.2.
Benefit Assessment.....................................................................30
4.6.3.
Overall Benefit:Risk Conclusion...................................................30
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............30
5.1.
Inclusion Criteria.........................................................................................30
5.2.
Exclusion Criteria........................................................................................32
5.3.
Screening/Baseline/Run-in Failures............................................................35
5.4.
Withdrawal/Stopping Criteria.......................................................................35
5.4.1.
Individual Safety Stopping Criteria ...............................................36
5.4.2.
Group Safety Stopping Criteria ....................................................37
5.4.3.
Liver Chemistry Stopping Criteria ................................................37
5.4.3.1.
Study Treatment Restart or Rechallenge....................37
5.4.4.
QTc Stopping Criteria ..................................................................38
5.4.5.
Haematologic Stopping Criteria ...................................................38
5.5.
Subject and Study Completion....................................................................38
6.
STUDY TREATMENT ............................................................................................39
6.1.
Investigational Product and Other Study Treatment....................................39
6.2.
Treatment Assignment................................................................................39
6.3.
Planned Dose Adjustments.........................................................................40
6.4.
Blinding.......................................................................................................40
6.5.
Packaging and Labeling..............................................................................41
6.6.
Preparation/Handling/Storage/Accountability..............................................41
6.7.
Compliance with Study Treatment Administration.......................................41
6.8.
Treatment of Study Treatment Overdose....................................................42
6.9.
Treatment after the End of the Study ..........................................................42
6.10.
Lifestyle and/or Dietary Restrictions............................................................42
6.10.1.
Activity .........................................................................................42
6.11.
Concomitant Medications and Non-Drug Therapies....................................42


2015N251670_03
CONFIDENTIAL
203168
7
6.11.1.
Permitted Medications and Non-Drug Therapies..........................42
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................43
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................45
7.1.
Time and Events Table...............................................................................46
7.2.
Screening and Critical Baseline Assessments ............................................50
7.3.
Safety .........................................................................................................50
7.3.1.
Adverse Events (AEs) and Serious Adverse Events 
(SAEs).........................................................................................50
7.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................50
7.3.1.2.
Method of Detecting AEs and SAEs ...........................51
7.3.1.3.
Follow-up of AEs and SAEs........................................51
7.3.1.4.
Cardiovascular and Death Events ..............................51
7.3.1.5.
Regulatory Reporting Requirements for SAEs............52
7.3.2.
Pregnancy ...................................................................................52
7.3.3.
Physical Exams ...........................................................................52
7.3.4.
Vital Signs....................................................................................53
7.3.5.
Electrocardiogram (ECG).............................................................53
7.3.6.
Clinical Safety Laboratory Assessments ......................................53
7.3.7.
Suicidal Risk Monitoring...............................................................55
7.4.
Efficacy.......................................................................................................56
7.4.1.
Patient Reported Outcomes.........................................................56
7.4.1.1.
Rheumatoid Arthritis Symptoms and Impact 
Diary...........................................................................56
7.4.1.2.
Patient Assessment of Joint Pain ...............................56
7.4.1.3.
Patient’s Global Assessment of Disease 
(PtGA) ........................................................................56
7.4.1.4.
Disability Index of the Health Assessment 
Questionnaire (HAQ-DI) .............................................56
7.4.1.5.
Functional Assessment of Chronic Illness 
Therapy (FACIT)-Fatigue Scale..................................57
7.4.2.
Clinical Disease Assessments .....................................................57
7.4.2.1.
Disease Activity Score (DAS) Assessments ...............57
7.4.2.2.
American College of Rheumatology Criteria 
(ACR) Assessments ...................................................57
7.4.2.3.
Joint Assessments......................................................58
7.4.2.4.
Measurement of Serum CRP......................................58
7.4.2.5.
Physician’s Global Assessment of Disease 
Activity (PGA).............................................................58
7.5.
Pharmacokinetics .......................................................................................58
7.5.1.
Blood Sample Collection..............................................................58
7.5.2.
Sample Analysis ..........................................................................58
7.5.3.
Synovial Biopsy Tissue for Pharmacokinetic Assay .....................59
7.5.4.
Sample Analysis ..........................................................................59
7.6.
Biomarker(s)/Pharmacodynamic Markers ...................................................59
7.6.1.
Magnetic Resonance Imaging (MRI) of Joint ...............................59
7.6.2.
Synovial Biopsy ...........................................................................60
7.6.2.1.
Selection of Joint for Synovial Biopsy .........................60
7.6.2.2.
Synovial Biopsy Procedure.........................................60
7.6.3.
Novel Pharmacodynamic Biomarkers ..........................................61
7.6.3.1.
RIP1 Target Engagement in Blood .............................61


2015N251670_03
CONFIDENTIAL
203168
8
7.6.3.2.
RIP1 Target Engagement in Synovial Tissue..............61
7.6.3.3.
Pathway Biomarkers in Synovial Tissue .....................61
7.6.4.
Exploratory Novel Biomarkers......................................................61
7.7.
Genetics .....................................................................................................62
8.
DATA MANAGEMENT ...........................................................................................62
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................63
9.1.
Hypotheses.................................................................................................63
9.2.
Sample Size Considerations.......................................................................63
9.2.1.
Sample Size Assumptions ...........................................................63
9.2.2.
Sample Size Sensitivity................................................................64
9.2.3.
Sample Size Re-estimation or Adjustment...................................65
9.3.
Data Analysis Considerations .....................................................................65
9.3.1.
Analysis Populations....................................................................65
9.3.2.
Interim Analysis ...........................................................................65
9.4.
Key Elements of Analysis Plan ...................................................................66
9.4.1.
Primary Analyses.........................................................................66
9.4.2.
Secondary Analyses ....................................................................66
9.4.3.
Other Analyses ............................................................................67
9.4.3.1.
Exploratory Analyses..................................................67
10. STUDY GOVERNANCE CONSIDERATIONS........................................................67
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............67
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................67
10.3.
Quality Control (Study Monitoring) ..............................................................68
10.4.
Quality Assurance.......................................................................................68
10.5.
Study and Site Closure ...............................................................................69
10.6.
Records Retention......................................................................................69
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................70
11. REFERENCES.......................................................................................................71
12. APPENDICES........................................................................................................73
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................73
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................77
12.3.
Appendix 3:  Prednisolone Equivalent Dose Table......................................79
12.4.
Appendix 4- Genetic Research ...................................................................80
12.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................84
12.5.1.
Definition of Adverse Events........................................................84
12.5.2.
Definition of Serious Adverse Events...........................................85
12.5.3.
Definition of Cardiovascular Events .............................................87
12.5.4.
Recording of AEs and SAEs ........................................................87
12.5.5.
Evaluating AEs and SAEs............................................................88
12.5.6.
Reporting of SAEs to GSK...........................................................89
12.6.
Appendix 6: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................90


2015N251670_03
CONFIDENTIAL
203168
9
12.6.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............90
12.6.2.
Collection of Pregnancy Information ............................................91
12.7.
Appendix 7:  Protocol Amendment Changes...............................................93
12.7.1.
Amendment 3 (20-APR-2017) from Protocol Amendment 
2 (14- JUL-2016)..........................................................................93
12.7.2.
Amendment 2 (14-JUL-2016) from Protocol Amendment 1 
(25-MAY-2016) ..........................................................................114
12.7.3.
Protocol Amendment 1 (25-MAY-2016) from the original 
protocol (01-APR-2016).............................................................118


2015N251670_03
CONFIDENTIAL
203168
10
1.
PROTOCOL SYNOPSIS FOR STUDY 203168
Rationale
This study is the first experience with GSK2982772, a receptor-interacting protein-1 
(RIP1) kinase inhibitor, in subjects with moderate to severe rheumatoid arthritis (RA) 
who are currently being treated with disease modifying anti-rheumatic drugs (DMARDs).
The primary objective of this study has not changed with amendment 03; however the 
dosing regimen does change to GSK2982772 (60 mg three times daily for 84 days). 
The primary objective will be to investigate the safety and tolerability of repeat oral doses 
of GSK2982772 (60 mg three times daily for 84 days). In addition to the 
pharmacokinetics (PK), a number of experimental and clinical endpoints will be 
employed to obtain information on the pharmacodynamics (PD), and preliminary efficacy 
in subjects with active RA. Although no formal hypothesis will be tested, these endpoints 
will enable a broader understanding of the mechanism of action and potential for clinical 
efficacy of GSK2982772 in RA, by making full use of the information obtained from 
each subject enrolled.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To investigate the safety and tolerability 
of 60 mg three times daily doses of 
GSK2982772 in subjects with moderate 
to severe Rheumatoid Arthritis.

Adverse events.

Clinical laboratory values (clinical 
chemistry, haematology and urinalysis).

Vital sign measurements (blood pressure, 
heart rate, respiratory rate, and body 
temperature).

12-Lead ECG monitoring.
Secondary

To investigate the plasma concentrations 
of GSK2982772 following 60 mg three 
times daily doses of GSK2982772 in 
subjects with moderate to severe 
Rheumatoid Arthritis.

Pre-dose concentrations of GSK2982772 
on Days 8 and 43 (Week 6).  

Post-dose concentrations of 
GSK2982772 on Days 1, 8, and 43 
(Week 6) at 1, 2, 4 and 6 hours.

Trough concentrations on Day 85 (Week
12).

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
inflammatory biomarkers in blood 
subjects with moderate to severe 
Rheumatoid Arthritis.

Change from baseline in blood 
inflammatory markers (e.g., may include 
but not limited to CRP, IL6, MMP-1, 
MMP-3, MMP-13, TIMP-1, MCP-1, MIF, 
MRP8/14 and other markers 
encompassed by Vectra DA).


2015N251670_03
CONFIDENTIAL
203168
11
Objectives
Endpoints

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
bone and synovial parameters as 
measured by MRI and DCE-MRI in 
subjects with moderate to severe 
Rheumatoid Arthritis.

Change from baseline in Magnetic 
Resonance Imaging (MRI) parameters in 
the most affected hand/wrist.  MRI 
parameters may include assessment of 
bone erosions, synovitis, bone oedema 
and joint space narrowing as assessed 
in the OMERACT-RAMRIS (Outcome 
Measures in Rheumatology, Rheumatoid 
Arthritis Magnetic Resonance Image 
Scoring System) scoring system, the 
RAMRIQ (Rheumatoid arthritis MRI 
quantitative) scoring system, the 
modified CARLOS (Cartilage Loss 
Scoring System) and additional 
exploratory endpoints as data permit.
Change from baseline in synovial 
inflammation as measured by dynamic 
contrast enhanced (DCE)-MRI in the most 
affected hand/wrist:

Exchange rate (Ktrans)

Interstitial volume (Ve)

Plasma volume (Vp)

Initial rate of enhancement (IRE)

Maximal signal intensity enhancement 
(ME)

Joint volume

Enhancing volume

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
clinical disease activity in subjects with 
moderate to severe Rheumatoid Arthritis.

Change from baseline in Disease Activity 
Score (DAS) 28-CRP scores.

Proportion of subjects achieving 
categorical DAS28-CRP response 
(moderate/good EULAR response) at 
each assessment time points.

Proportion of subjects achieving 
categorical ACR20/50/70 response.

To investigate the effect of 60 mg three 
times daily dosing of GSK2982772 on 
methotrexate (MTX) concentrations. 

Plasma concentrations of MTX pre-dose 
GSK2982772 on Days 1, 8, and 43 
(Week 6).
Exploratory

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
inflammatory biomarkers in synovial 
tissue from subjects with moderate to 

Change from baseline in CD68+ 
macrophages, CD55+ fibroblast-like 
synoviocytes and a number of infiltrating 
CD3, CD22, CD138 inflammatory cells, 


2015N251670_03
CONFIDENTIAL
203168
12
Objectives
Endpoints
severe Rheumatoid Arthritis.
and synovial inflammatory biomarkers 
including, but not limited to VEGF, IL-1β, 
IL-6, TNFα, and MMP-1.

To investigate pathway and target 
engagement following 60 mg three times 
daily doses of GSK2982772 in blood and 
synovial biopsy tissue in subjects with 
moderate to severe Rheumatoid Arthritis.

Pharmacology biomarker endpoints may 
include, but are not limited to the 
following, pre-dose at Days 1, 43 (Week
6) and trough on Day 85 (Week 12), as 
applicable and if evaluable samples and 
data permit:
Target Engagement Assay RIP1 
(TEAR1) in blood and synovial 
tissue.
Total or phosphorylated RIP1, MLKL, 
and RIP3, cleaved and total 
caspase 3 and caspase 8 
signatures in synovial tissue.

To investigate the concentration of 
GSK2982772 and possible drug-related 
material, as well as specific distribution 
within tissue if feasible, in the synovial 
tissue after 60 mg three times daily 
doses of GSK2982772. 

Pre-dose GSK2982772 synovial tissue 
biopsies and possible drug-related 
material concentrations, as well as 
specific distribution within tissue if 
feasible, on Day 43 (Week 6), as 
evaluable samples and data permit.

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on the
quality of life of subjects with moderate 
to severe Rheumatoid Arthritis.

Change from baseline in Health 
Assessment Questionnaire Disability 
Index (HAQ-DI).

Change from baseline in RA symptom 
questionnaire score.

Change from baseline in Functional 
Assessment of Chronic Illness Therapy 
(FACIT)-Fatigue.

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
gene expression in the blood subjects 
with active moderate to severe 
Rheumatoid Arthritis.

Transcriptomic analysis of mRNA 
isolated from blood pre-dose on Days 1 
and 43 (Week 6) and trough on Day 85 
(Week 12).

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
gene expression in the synovium of 
subjects with moderate to severe 
Rheumatoid Arthritis.

Transcriptomic analysis of mRNA 
isolated from synovial tissue pre-dose on 
Days 1 and 43 (Week 6).


2015N251670_03
CONFIDENTIAL
203168
13
Overall Design
This is a multicentre, randomised, double-blind (sponsor-unblinded), placebo-controlled 
study to investigate the safety and tolerability, PK, PD, and preliminary efficacy of 
GSK2982772 in subjects with moderate to severe RA.  The study design schematic is 
depicted in Figure 1 below.
Figure 1
Study Overview
Amendment 03:
Prior to amendment 03:
Key assessments:
Safety assessments, PK samples, DAS28-CRP, 
ACR20/50/70, FACIT-fatigue, Rheumatoid Arthritis Symptom 
and Impact Diary, HAQ-DI assessments, MRI, PD samples
Treatment Arms and Duration
Each subject will participate in the study for approximately 20 weeks.  This includes a 
screening period of up to 30 days, an 84 day (12 week) treatment period, and a 28 day 
follow-up period after the last dose.
Within 30 days of the screening visit (defined as day of consent signing), subjects who 
are eligible will enter the treatment period and start treatment (or dosing) on Day 1.
The Follow-up Period is 28 days (4 weeks) long.  All visits and assessments are detailed 
in Section 7.1.


2015N251670_03
CONFIDENTIAL
203168
14
Subjects who have completed screening assessments and are eligible will be randomised 
in a 2:1 ratio (active to placebo) to one of the following treatments:
GSK2982772 60 mg three times daily (TID) 
Placebo three times daily (TID) 
Prior to amendment 03 being effective in each country, subjects have been randomised in 
a 2:1 ratio (active to placebo) to one of the following treatments:
GSK2982772 60 mg two times daily (BID) 
Placebo two times daily (BID)
Type and Number of Subjects
A sufficient number of subjects will be screened so that approximately 24 subjects with 
moderate to severe RA are randomised into the study on a TID regimen. Prior to protocol 
amendment 03 being approved in each country, no more than 18 subjects will be 
randomised into the study on a BID regimen.  Should the overall drop-out rate be higher 
than anticipated, additional or replacement subjects may be randomised (up to an overall
total maximum of 48) into the study at the discretion of the Sponsor.
Analysis
The safety and tolerability of GSK2982772 following 12 weeks of treatment will be 
based on the review and displays of adverse events, clinical laboratory values, vital sign 
measurements and 12-lead electrocardiogram (ECG) monitoring.
Ongoing reviews of available efficacy, pharmacodynamic and mechanistic endpoints will 
be conducted during the study by a Data Review Committee (DRC), consisting of a 
limited number of GlaxoSmithKline (GSK) individuals, some of who are also members 
of the GSK study team who are not involved with the day-to-day running of the study.  
The primary purpose of these reviews will be to monitor target engagement, 
inflammatory markers and Disease activity score for 28 different joints with (CRP) value 
(DAS28-CRP) for futility and internal decision making. A data review charter will 
outline in detail the activities of this review and how the integrity of the study will be 
maintained.
A formal interim analysis will be conducted during the study, when an appropriate 
number of subjects have completed 12 weeks of treatment or on the request of the DRC.  
The purpose of this interim will be to assess whether to stop the study for futility.  This 
interim analysis may also facilitate decision making regarding the subsequent clinical 
development of GSK2982772 for RA.
Comparisons between treatment groups on any changes observed will be conducted for 
the secondary endpoints if deemed appropriate, e.g. changes in the mean target 
engagement, changes in inflammatory markers and percentage change in DAS28-CRP 


2015N251670_03
CONFIDENTIAL
203168
15
will be statistically analysed using a Mixed-effect Model Repeat Measurements 
(MMRM) comparing GSK2982772 with placebo at each time point. 
The relationship between each of the mechanistic endpoints and also with the clinical 
endpoints may also be graphically presented and analysed using an appropriate statistical 
model identifying any trends. The model will determine whether the mechanistic effect 
significantly explains or predicts the effect on the other mechanistic or clinical endpoints 
(e.g DAS28-CRP).  In addition, based on the data that we observe in the study, 
probabilities of success will be determined, where the definition of success will be 
dependent on the endpoint. For example, what is the probability that we would observe a 
certain change in DAS28-CRP (i.e., comparatory rate), based on the data that we have 
observed in the study.  Further details regarding the statistical analysis will be outlined in 
the Reporting and Analysis Plan (RAP).
2.
INTRODUCTION
2.1.
Study Rationale
This study is the first experience with GSK2982772, a receptor-interacting protein-1 
(RIP1) kinase inhibitor, in subjects with moderate to severe rheumatoid arthritis (RA) 
who are currently being treated with disease modifying anti-rheumatic drugs (DMARDs).  
All subjects will be allowed to continue standard of care therapy including non-biologic 
DMARDs during the study, provided that the medication type and dose is stable 
throughout the study.
The primary objective of this study has not changed with amendment 03; however the 
dosing regimen does change to GSK2982772 (60 mg three times daily for 84 days). 
The primary objective will be to investigate the safety and tolerability of repeat oral doses 
of GSK2982772 (60 mg three times daily for 84 days).  In addition, a number of 
experimental and clinical endpoints will be employed to obtain information on the 
pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy in subjects 
with moderate to severe RA.
2.2.
Brief Background
RIP1 is a member of the receptor-interacting Serine/Threonine kinase family containing 
an amino-terminal kinase domain, an intermediate domain and a carboxy-terminal death 
domain.  RIP1 is a key signalling node which plays an essential role in inflammation and 
cell death in response to signals including tumor necrosis factor (TNF) family cytokines, 
ligands for toll-like receptor (TLR) 3/TLR4, sensors of viral infection, and interferons 
[Ofengeim, 2013].  Through tight regulation by ubiquitylation, deubiquitylation and 
interaction with its receptors, RIP1 has dual roles as a kinase and a scaffolding protein, 
and serves as an upstream checkpoint for both cell death and survival [Ofengeim, 2013]. 
Detailed understanding of RIP1 kinase function has not been fully elucidated, but it is 
known that RIP1 exerts it signalling functions through both its catalytic kinase activity 
and by acting as a scaffolding protein for signalling complexes.  Recent work has 
demonstrated that RIP1 catalytic kinase activity can regulate TNF-mediated necroptosis 


2015N251670_03
CONFIDENTIAL
203168
16
[Ofengeim, 2013] and noncanonical apoptosis [Wang, 2008, Dondelinger, 2013]. In 
addition, the production of certain inflammatory cytokines can be regulated by RIP1 
kinase activity Investigator’s Brochure (IB) [GlaxoSmithKline Document Number
2014N204126_02].  In contrast, RIP1’s scaffolding function acts to facilitate other
immune processes including TNF mediated classical apoptosis and NF-kB-signalling 
[Ofengeim, 2013, Humphries, 2015].  With this, an inhibitor of RIP1 kinase activity with 
GSK2982772 may fill a unique niche in the treatment of inflammatory conditions
through multiple mechanisms, including inhibition of inflammation-induced cell death 
(necroptosis and apoptosis) and inhibition of the production of certain pro-inflammatory 
cytokines.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by a debilitating, 
progressive polyarthritis that typically affects the small joints of the hands and feet 
[Vasanthi, 2007]. TNF is known to be one of the key cytokines that drives inflammation 
in RA [Choy, 2001].  In animal models, transgenic mice that chronically over express 
low levels of TNF develop a spontaneous polyarthritis that resembles RA in humans 
[Keffer, 1991] and blockade of NFB activation results in the development of a 
spontaneous murine polyarthritis that is RIP1-dependent [Berger, 2014].  In RA patients, 
TNF is detected in high concentrations in both blood and synovial fluid, and expression 
of TNF and its signalling intermediates, including RIP1, have been shown to be 
constitutively increased in PBMCs from RA subjects compared to healthy controls 
[Raghav, 2006].
Synthetic disease modifying antirheumatic drugs (DMARDs) including nonsteroidal anti-
inflammatory drugs, steroids, methotrexate (MTX), sulfasalazine, hydroxychloroquine, 
and leflunomide, are often used alone or in combination in moderate to severe RA; 
however, most DMARDs do not significantly impact disease progression, and may be 
hampered by poor side effect profiles.  Recently, tofacitinib, an oral small molecule 
inhibitor of JAK, was approved for moderate to severe RA, but its long term safety is still 
unknown.  TNF antagonists are used in the treatment of patients with moderate-severe 
disease who have not responded or who have intolerance to traditional DMARDs.  While 
studies have shown that they can improve symptoms and slow the progression of joint 
damage in many patients [Agarwal, 2011], only half of RA patients achieve American 
College of Rheumatology (ACR) 50 criteria, and many become refractory to anti-TNF 
treatments after several years.  In addition to the association with increased rates of 
opportunistic infections across all indications, anti-TNF therapy in RA is linked to lupus-
like syndrome and increased rates of demyelinating disease.  Other biologic therapies 
which inhibit T cell activation (abatacept) or lead to selective B cell depletion (rituximab) 
have shown clinical efficacy in anti-TNF refractory patients, although both carry 
potential risks for serious infection.  Therefore, there remains a high unmet need for safe 
and tolerable therapies that lead to improved rates of clinical remission and increased 
physical function in patients with moderate to severe RA.


2015N251670_03
CONFIDENTIAL
203168
17
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To investigate the safety and tolerability 
of 60 mg three times daily doses of 
GSK2982772 in subjects with moderate 
to severe Rheumatoid Arthritis.

Adverse events.

Clinical laboratory values (clinical 
chemistry, haematology and urinalysis).

Vital sign measurements (blood pressure, 
heart rate, respiratory rate, and body 
temperature).

12-Lead ECG monitoring.
Secondary

To investigate the plasma concentrations 
of GSK2982772 following 60 mg three 
times daily doses of GSK2982772 in 
subjects with moderate to severe 
Rheumatoid Arthritis.

Pre-dose concentrations of GSK2982772 
on Days 8, and 43 (Week 6).  

Post-dose concentrations of 
GSK2982772 on Days 1, 8, and 43 
(Week 6) at 1, 2, 4 and 6 hours.

Trough concentrations on Day 85 (Week
12).

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
inflammatory biomarkers in blood 
subjects with moderate to severe 
Rheumatoid Arthritis.

Change from baseline in blood 
inflammatory markers (e.g., may include 
but not limited to CRP, IL6, MMP-1, 
MMP-3, MMP-13, TIMP-1, MCP-1, MIF, 
MRP8/14 and other markers 
encompassed by Vectra DA).

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
bone and synovial parameters as 
measured by MRI and DCE-MRI in 
subjects with moderate to severe 
Rheumatoid Arthritis.

Change from baseline in MRI 
parameters in the most affected 
hand/wrist.  MRI parameters may include 
assessment of bone erosions, synovitis, 
bone oedema and joint space narrowing 
as assessed in the OMERACT-RAMRIS 
(Outcome Measures in Rheumatology, 
Rheumatoid Arthritis Magnetic 
Resonance Image Scoring System) 
scoring system, the RAMRIQ 
(rheumatoid arthritis MRI quantitative) 
scoring system, the modified CARLOS 
(Cartilage Loss Scoring System) and 
additional exploratory endpoints as data 
permit.
Change from baseline in synovial 
inflammation as measured by dynamic 
contrast enhanced (DCE)-MRI in the most 
affected hand/wrist:


2015N251670_03
CONFIDENTIAL
203168
18
Objectives
Endpoints

Exchange rate (Ktrans)

Interstitial volume (Ve)

Plasma volume (Vp)

Initial rate of enhancement (IRE)

Maximal signal intensity enhancement 
(ME)

Joint volume

Enhancing volume

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
clinical disease activity in subjects with 
moderate to severe Rheumatoid Arthritis.

Change from baseline in Disease Activity 
Score (DAS) 28-CRP scores.

Proportion of subjects achieving 
categorical DAS28-CRP response 
(moderate/good EULAR response) at 
each assessment time points.

Proportion of subjects achieving 
categorical ACR20/50/70 response.

To investigate the effect of 60 mg three 
times daily dosing of GSK2982772 on 
methotrexate (MTX) concentrations 

Plasma concentrations of MTX pre-dose 
GSK2982772 on Days 1, 8, and 43 
(Week 6).
Exploratory 

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
inflammatory biomarkers in synovial 
tissue in subjects with moderate to 
severe Rheumatoid Arthritis.

Change from baseline in CD68+ 
macrophages, CD55+ fibroblast-like 
synoviocytes and a number of infiltrating 
CD3, CD22, CD138 inflammatory cells, 
and synovial inflammatory biomarkers 
including, but not limited to VEGF, IL-1β, 
IL-6, TNFα, and MMP-1.

To investigate pathway and target 
engagement following 60 mg three times 
daily doses of GSK2982772 in blood and 
synovial tissue in subjects with moderate 
to severe Rheumatoid Arthritis.

Pharmacology biomarker endpoints may 
include, but are not limited to the 
following, pre-dose at Days 1, 43 (Week 
6) and trough on Day 85 (Week 12), as 
applicable and if evaluable samples and 
data permit:
Target Engagement Assay RIP1 
(TEAR1) in blood and synovial 
tissue.
Total or phosphorylated RIP1, MLKL, 
and RIP3, cleaved and total 
caspase 3 and caspase 8 
signatures in synovial tissue.


2015N251670_03
CONFIDENTIAL
203168
19
Objectives
Endpoints

To investigate the concentration of 
GSK2982772 and possible drug-related 
material, as well as specific distribution 
within tissue if feasible, in the synovial 
tissue after 60 mg three times daily 
doses of GSK2982772.

Pre-dose GSK2982772 synovial tissue 
biopsies and possible drug-related 
material concentrations, as well as 
specific distribution within tissue  if 
feasible, on Day 43 (Week 6), as 
evaluable samples and data permit

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on the 
quality of life of subjects with moderate 
to severe Rheumatoid Arthritis.

Change from baseline in Health 
Assessment Questionnaire Disability 
Index (HAQ-DI).

Change from baseline in RA symptom 
questionnaire score.

Change from baseline in Functional 
Assessment of Chronic Illness Therapy 
(FACIT)-Fatigue.

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
gene expression in the blood of subjects 
with moderate to severe Rheumatoid 
Arthritis.

Transcriptomic analysis of mRNA 
isolated from blood pre-dose on Days 1 
and 43 (Week 6) and trough on Day 85 
(Week 12).

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
gene expression in synovium of subjects 
with moderate to severe Rheumatoid 
Arthritis.

Transcriptomic analysis of mRNA 
isolated from synovial tissue pre-dose on 
Days 1 and 43 (Week 6).


2015N251670_03
CONFIDENTIAL
203168
20
4.
STUDY DESIGN
4.1.
Overall Design
This is a multicentre, randomised, double-blind (sponsor-unblinded), placebo-controlled 
study to investigate the safety and tolerability, PK, PD, and preliminary efficacy of 
GSK2982772 in subjects with moderate to severe RA.  The study design schematic is 
depicted in Figure 2 below.
Figure 2
Study Overview
Amendment 03:
Prior to amendment 03:
Key assessments:
Safety assessments, PK samples, DAS28-CRP, 
ACR20/50/70, FACIT-fatigue, Rheumatoid Arthritis Symptom 
and Impact Diary, HAQ-DI assessments, MRI, PD samples
4.2.
Treatment Arms and Duration
It is anticipated that the total duration of participation in the study will be approximately 
20 weeks from screening to the last study visit. 
4.2.1.
Screening
Within 30 days of the screening visit (defined as day of consent signing), subjects who 
are eligible will enter the treatment period and start treatment (or dosing) on Day 1.


2015N251670_03
CONFIDENTIAL
203168
21
4.2.2.
Treatment Period
Subjects will be randomly assigned to either GSK2982772 60 mg or placebo orally three 
times daily (approximately 8 hours apart) for 84 days (12 weeks).  Subjects that were 
randomised prior to protocol amendment 03 being approved in each country were 
randomly assigned to either GSK2982772 60 mg or placebo orally two times daily 
(approximately 12 hours apart) for 84 days (12 weeks). 
Further guidance and information for study treatment and dosing are provided in the 
Study Reference Manual (SRM).  
During the 84 day (12 week) treatment period, subjects will attend the clinical site for 
visits on Days 1, 8, 15, 29, 43, 57, 71 and 85.  At specific visits, subjects must not take 
study treatment prior to their scheduled visit (see Section 7.1).  On Days 22, 36, 50, 64 
and 78, each subject will be contacted by telephone and asked about their general health, 
study medication compliance and diary card completion. Subjects will be given a diary 
card at each of the visits on which they will be instructed to record their daily study 
medication and concomitant medication taken and any adverse events.
4.2.3.
Follow-up Period
After the Treatment Period, the subject will enter the Follow-up Period which lasts for 
28 days post the last administration of study medication, in order to complete follow-up
assessments per the Time and Events Table (see Section 7.1).
4.3.
Type and Number of Subjects
A sufficient number of subjects will be screened so that approximately 24 subjects with 
moderate to severe RA are randomised into the study on a TID regimen.  Prior to 
protocol amendment 3 being approved in each country, no more than 18 subjects will be 
randomised into the study on a BID regimen.  Should the overall drop-out rate be higher 
than anticipated, additional or replacement subjects may be randomised (up to an overall
maximum of 48) into the study at the discretion of the Sponsor.
4.4.
Design Justification
As this is the first trial of GSK2982772 in subjects with RA, the primary endpoint is the 
safety and tolerability of GSK2982772.  In addition, this study will include assessments 
of target engagement and downstream PD effects of GSK2982772, to understand whether 
GSK2982772 is inhibiting the pathway of interest in this disease.
The 12 week duration of treatment is based on review of previous proof of mechanism 
and proof of concept studies in RA and is limited by the supporting 13 week toxicology 
studies. It is expected that an effective therapy should cause group level changes in the 
mechanistic parameters by the 12 week time point. 
The subjects will be randomised in a 2:1 ratio to GSK2982772 60 mg three times daily 
(TID) and placebo respectively.  The primary objective of this study is to assess safety 
and tolerability, and assessment of this is most valuable in a placebo controlled study. 


2015N251670_03
CONFIDENTIAL
203168
22
The placebo group was also deemed necessary as autoimmune diseases naturally 
fluctuate in severity.  However, the size of the placebo group has been kept to a 
minimum.  All subjects will be allowed to continue standard of care therapy including 
non-biologic DMARDs during the study, provided that the medication and dose is stable 
throughout the study.
4.5.
Dose Justification
The initial selection of the 60 mg BID dose being tested in this study is based on the 
safety, PK, and PD data from the First Time in Human (FTiH) study, 200975.  
GSK2982772 administered at 60 mg BID for 14 days was well tolerated and no safety 
concerns were identified. A BID dosing regimen was initially selected over a QD dosing 
regimen due to the short half-life of GSK2982772 in humans (~2h).  Based on 
preliminary PK/PD modelling of ex-vivo RIP1 target engagement and GSK2982772 
concentrations from the multiple dose ascending part of Study 200975, a 60 mg BID dose 
was predicted to have on average 95% RIP1 target engagement in blood and 
approximately 90% of subjects will have >90% target engagement in blood at Cmin using 
a novel in-house ex-vivo PD/target engagement assay based solely on the TNF pathway 
which is believed to be a key component of the RIP1 pathway.  
However, based on final PK/PD modelling from the full repeat dose part of the Study 
200975 (up to 120 mg BID), a 60 mg BID dose is now predicted to have on average 99% 
RIP1 target engagement in blood and approximately 90% of subjects will have >85% 
target engagement at Cmin. This is lower than our target of achieving >90% target 
engagement in at least 90% of subjects at Cmin.  Therefore, a 60 mg TID cohort is now 
being proposed.  
The Cmin values at 60 mg TID are predicted to be approximately 3.5 fold higher than for 
60 mg BID.  Using the final PK/PD, a 60 mg TID dose is predicted to have on average 
99% RIP1 target engagement in blood and approximately 90% of subjects will have 
>96% target engagement at Cmin.  No data are currently available about the distribution of
GSK2892772 into the synovium.  Based on data in non-steroidal anti-inflammatory drugs 
(NSAIDs), the synovial fluid concentrations fluctuate to a much lesser extent than those 
in plasma [Netter, 1989].  Peak drug concentrations are generally lower in synovial fluid 
but are similar to plasma at later time points.  Assuming the same is true for 
GSK2982772, a 60 mg TID dose should provide similar RIP1 target engagement at the 
site of action as predicted in blood.
In addition, because of the short half-life, a modified release formulation is now being 
developed with the aim to provide a once daily dosing regimen.  By increasing the 
frequency of dosing to three times daily (TID) with the current immediate release 
formulation, this will more closely match the PK, safety and efficacy profile of a 
preferred once daily modified release formulation.
The safety of increasing the dose frequency to 60 mg TID is justified based on 
nonclinical safety findings to date with GSK2982772. It is anticipated that a human dose 
of 60 mg TID (180 mg/day) will produce AUC(0-24) and Cmax values of approximately 
9.9 ug.h/mL and 0.8 ug/mL, respectively, which are approximately 1/5th and 1/15th of the 


2015N251670_03
CONFIDENTIAL
203168
23
gender-averaged AUC (48.4 ug.h/mL) and Cmax (12.3 ug/mL) achieved in the 13 week 
monkey study at the no adverse effect level (NOAEL) dose of 30 mg/kg/day. Please see 
GSK2982772 IB [GlaxoSmithKline Document Number 2014N204126_02].
As of 03 Apr 2017, a total of approximately 93 subjects across 4 clinical studies have 
been randomised to receive GSK2982772. In Study 200975, GSK2982772 administered 
up to 120 mg BID for 14 days and was well tolerated and no safety concerns were 
identified. A total of 9 subjects had received 120 mg BID in that study.  Please see 
GSK2982772 IB [GlaxoSmithKline Document Number 2014N204126_02]. In the 
ongoing Phase 2a studies in Psoriasis [(PsO); Study 203167] and Rheumatoid Arthritis 
[(RA); Study 203168], a total of 26 subjects have been randomised to GSK2982772 60 
mg BID. GSK2982772 was well tolerated and no drug-related SAEs have been reported.  
In Study 203167, there was a death of a 19 year old male subject due to an accidental 
overdose with 3,4-methylenedioxy-methamphetamine (MDMA) that was not considered 
drug related by the Principal Investigator (PI). 
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2982772 can be found in the IB [GlaxoSmithKline Document Number
2014N204126_02].  The following section outlines the risk assessment and mitigation 
strategy for this protocol:


2015N251670_03
CONFIDENTIAL
203168
24
4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK2982772
Central Nervous System (CNS) effects
Non-clinical data: 
In the 4-week GLP toxicology study, CNS findings were 
observed in 4/12 monkeys which were administered 100 or 
300 mg/kg/day.  CNS findings included uncoordination, 
irregular gait, trembling, hunched appearance, and 
decreased activity. The clinical relevance of these findings 
in humans is not known.  The NOAEL for this study was
determined at 10 mg/kg/day.
In the 13-week GLP toxicology study, there were no CNS 
findings observed in monkeys administered 10, 30 or 100 
mg/kg/day.  The NOAEL for this study was determined at 
30 mg/kg/day.  
Clinical data:
A First Time in Human (FTiH) study with single ascending 
and multiple ascending dose study has been performed in 
67 healthy male volunteers to date.  See Investigator’s 
Brochure (IB) [GlaxoSmithKline Document Number 
2014N204126_02].  No drug-associated CNS adverse 
events were identified and no Serious Adverse Effects 
(SAEs) were reported.
Subject Selction:

Subjects with known history of significant neurologic 
disorders including but not limited to progressive 
multiple sclerosis (MS), Amyotrophic lateral sclerosis 
(ALS), Alzheimer’s and dementia will be excluded.

Individuals with potentially increased susceptibility for 
neurologic effects will be excluded based on medical 
history at screening.
Subject Monitoring:

Subjects will be monitored for standard CNS-related 
adverse events.
Immunosuppression
The possibility of immunosuppression, including an 
increase in the frequency and/or severity of infection, may 
result from the intended pharmacologic effect of 
GSK2982772.  This may be enhanced in subjects taking 
other immunomodulating drugs or corticosteroids.
Subject Selection:

Subjects with recurrent, chronic or active infections 
will be excluded from the study.

Subjects will be screened for TB, HIV, Hepatitis B and 


2015N251670_03
CONFIDENTIAL
203168
25
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Clinical data:
In the FTiH study, no SAEs were reported.  One subject 
experienced an Adverse Effect (AE) herpes zoster 
approximately 27 days after receiving his last dose with 
GSK2982772 or placebo.  The blinded Investigator 
determined this to be potentially drug-related.
C, and excluded from the study if positive.
Subject Monitoring:

Subjects will be monitored for signs of infection.

See Individual Stopping Criteria for atypical or 
opportunistic infections (Section 5.4.1).
Vaccinations
There is a theoretical risk that GSK2982772 could 
decrease an individual’s immune response to vaccines or 
allow symptoms to develop following vaccination with a live 
vaccine when administered while on therapy.
Subject Selection:

Attenuated or live vaccines should not be 
administered to subjects from 30 days prior to the first 
dose of GSK2982772, during the study and for 5 half-
lives plus 30 days (total 32 days) after GSK2982772 
is discontinued.

If indicated, non-live vaccines (e.g. inactivated 
influenza vaccines) may be administered while 
receiving GSK2982772 based on a treating physician 
assessment of the benefit:risk (e.g., risk of theoretical 
decreased responsiveness). 

Investigators will be expected to have followed local 
and/or national guidelines with respect to
vaccinations, including against influenza and 
pneumococcus, in subjects with RA.
Respiratory
Non-clinical data:
In the single dose Safety Cardiovascular (CV) and 
Respiratory Study in monkeys, a decrease in minute 
volume (MV) and respiratory rate was observed at all 
doses (10, 100, and 300 mg/kg).  These findings were 
noted to be reversible and mild in severity
In a 14-day repeat dose Safety Respiratory Study in 
monkeys, no respiratory effects on total pulmonary 
ventilation (minute volume) or respiratory rate were 
observed at doses of 1 or 10 mg/kg/day. See IB for 
GSK2982772 [GlaxoSmithKline Document Number
2014N204126_02].
Subject Monitoring:

Subjects should be monitored for standard 
respiratory-related adverse events.

Vital signs will be monitored during study visits.


2015N251670_03
CONFIDENTIAL
203168
26
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Clinical data:
In the FTiH study, repeat doses of GSK2982772 were 
administered x 14 days in 36 healthy male volunteers. 
Extensive respiratory monitoring with end-tidal CO2 
(ETCO2), oxygen saturation (SpO2) and nocturnal 
respiratory rate monitoring was performed.   No SAEs 
occurred, and no drug-associated respiratory-related 
adverse events were identified.
Suicidality
GSK2982772 is considered to be a CNS-active drug based 
upon pre-clinical studies.
Clinical data:
In the FTiH study, there have been some reports of 
lethargy, abnormal dreams, and depressed mood.  No 
events of suicidal ideation or behaviour or changes in 
behaviour were reported. 
Subject Selection:

Subjects with a current history of suicidal ideation and 
behaviour (SIB) as measured using the Columbia 
Suicide Severity Rating Scale (C-SSRS)  or a history 
of attempted suicide will be excluded from the study.
Subject Monitoring:

Subjects should be monitored appropriately and 
observed closely for suicidal ideation and behaviour 
or any other unusual changes in behaviour.

Baseline and treatment emergent assessment of 
suicidality will be conducted by trained site personnel 
using the (Columbia Suicide Severity Rating Scale) C-
SSRS in all subjects.  See Section 7.3.7.
Reproductive toxicity
Non-clinical data:
In an early rat embryofetal development study, there was 
no maternal or developmental toxicity at doses 200 
mg/kg/day.
In a rabbit embryofetal development study, GSK2982772 
was administered at doses of 0, 10, 100, 300 or 600 
mg/kg/day on gestation day 7 to 19.  No developmental 
toxicity was evident at doses up to 300 mg/kg/day.
Subject Selection:

Male and female subjects of childbearing potential will 
be included in this study only if they agree to use 
highly effective methods of contraception and avoid 
conception for defined periods of time before first 
administration of study drug until 30days (females) 
and 90 days (males) after the last administration of 
study drug (Appendix 6).

Females of childbearing potential will undergo serum 
pregnancy test at screening and then urine pregnancy 
testing at regular intervals during the study. 

Pregnant and lactating females are not eligible for 


2015N251670_03
CONFIDENTIAL
203168
27
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
inclusion in the study.
Withdrawal Criteria:

If a female subject should become pregnant during 
the study, study medication should be discontinued.  
The 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.
Drug Interaction
Non-clinical data:
In vitro studies with GSK2982772 assessing potential drug-
drug interactions with Cytochrome P450 3A4 (CYP3A4) 
substrates, P-glycoprotein (Pgp) inhibitors and OAT3 
substrates were completed.  To date, formal drug 
interaction studies in humans have not been performed 
with GSK2982772. 
There is a low risk that GSK2982772 could be a 
perpetrator of OAT3 substrates.  MTX is an OAT3 
substrate in which GSK2982772 could potentially impair 
the clearance of MTX.
There is a low risk that GSK2982772 could be an inducer 
of CYP3A4 and therefore may lower circulating levels of 
concomitant medications that are metabolised by CYP3A4 
when co administered with GSK2982772.
GSK2982772 is a Pgp substrate and therefore co 
administration with concomitant medications that are Pgp 
inhibitors could increase circulating levels of GSK2982772.
See Section 4.3.6 of the GSK2982772 IB [GlaxoSmithKline 
Document 2014N204126_02].
Subject Selections:

Subjects who are taking concomitant medications 
known to inhibit Pgp or are CYP3A4 narrow 
therapeutic index (NTI) substrates will be excluded 
from the study.  See Section 6.11.2 for a 
comprehensive list of medications.
Subject Monitoring:

Subjects’ concomitant medication usage will be 
reviewed prior to inclusion and monitored throughout 
the study.

Subjects should be monitored throughout the study 
for potential effects of interaction between 
GSK2982772 and other concomitant medications.

PK sample collection to evaluate the potential 
interaction of GSK2982772 and MTX will be 
performed throughout the study.

Subjects should be monitored for potential effects of 
interaction between GSK2982772 and MTX.

Clinical laboratory results (e.g., liver function tests) 
are routinely being monitored throughout the study.


2015N251670_03
CONFIDENTIAL
203168
28
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Procedures
Synovial Joint  Biopsy
Potential risks of the procedure include discomfort, 
infection or bleeding.
Note:  Synovial biopsies are optional and not required on 
all subjects.
Subject Selection:

Subjects with known allergy to lidocaine or other local 
anaesthetics will not be included in the biopsy portion 
of the study.

Subjects with a platelet count 100 x 109/L will be 
excluded from participation.
Subject Management:

The biopsies will be performed under ultrasound or 
arthroscopic guidance.  Subjects will be given 
instructions for aftercare and contact information 
should there be any adverse reactions after the 
procedure.

Biopsy site healing will be monitored during the study 
as part of AE safety review. 
Gadolinium (Gd) containing MRI contrast agents
Non-clinical data:
Animal studies have shown reproductive toxicity of 
gadolinium (Gd)-containing MRI contrast agents at 
repeated high doses.
Clinical data:
Use of MRI contrast agents in subjects with severely 
impaired rental function (GFR<30mL/minute) has been 
associated with Nephrogenic Systemic Fibrosis (NSF).  In 
subjects with severely impaired renal function, the benefits 
of the use of contrast agents should be carefully weighed 
against the risks.
Gadolinium (Gd) contrast agents can be associated with 
anaphylactoid/hypersensitivity or other idiosyncratic 
reactions, characterized by cardiovascular, respiratory, or 
Subject Selection:

Pregnant or lactating females will be excluded from 
taking part in the study.

Subjects with impaired renal function 
(GFR<60mL/minute) are excluded by the eligibility 
criteria.

Subjects with history of sensitivity to Gd-containing 
contrast agents will be excluded from the study.  The 
MRI procedure will be conducted under the 
supervision of trained and qualified clinical staff that is 
trained to appropriately manage an allergic reaction.

Sites will be responsible for following any additional 
safety information for the specific Gd contrast agent 
used at their site and not enroll subjects if 
contraindicated.


2015N251670_03
CONFIDENTIAL
203168
29
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
cutaneous manifestations, and ranging to severe reactions 
including shock.  In general, subjects with cardiovascular 
disease are more susceptible to serious or even fatal 
outcomes of severe hypersensitivity reactions.
The risk of hypersensitivity reactions may be higher in 
cases of:

Previous reaction to contrast media

History of bronchial asthma

History of allergic disorders
Most of these reactions occur within half an hour of 
administration.  Delayed reactions (after hours or several 
days) have been rarely observed.
Subject Monitoring and Management: 

MRI contrast at a dose less than or equal to 0.1
mmol/kg per imagining session at baseline and Days 
43 and 85 will be used in the MRI protocol.

Effective contraception is required during the study, 
and pregnancy testing will be performed regularly 
throughout the study and prior to dosing in females of 
child bearing potential.
Other 
Exposure to a high field MRI magnet
Certain prostheses or foreign bodies might be incompatible 
with the MRI scanner.
Subject Selection:

All participants will be screened according to local 
hospital criteria and study inclusion/exclusion before 
entering the MRI scanner to ensure they are able to 
have the MRI conducted.  Subjects with non-magnetic 
resonance compatible metal implants or implantable 
electronic devices (e.g., pacemaker, defibrillator) will 
not be included in this study.


2015N251670_03
CONFIDENTIAL
203168
30
4.6.2.
Benefit Assessment
There are additional treatment options available for subjects who have an inadequate 
response to current therapies for RA.  It is possible that treatment with GSK2982772 may 
be effective in the treatment of RA, as the FTiH study demonstrated that the drug 
engaged with the target and produced ex vivo PD effects in suppression of RIP1-
dependent cytokines MIP1and MIP1[GlaxoSmithKline Document Number
2014N204126_02].  There will be limited direct benefit to the subject through their 
contribution to the process of developing new therapies in an area of unmet need.  
4.6.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with GSK2982772 are justified by the 
anticipated benefits that may be afforded to patients with RA by contributing to the 
understanding of the disease and the development of new therapies for patients with these 
conditions in the future.  
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 (IP) or other study 
treatment that may impact subject eligibility is provided in the IB [GlaxoSmithKline 
Document Number 2014N204126_02].
In addition, Investigators are expected to follow local and/or national guidelines with 
respect to vaccinations, including vaccinations for influenza and pneumococcus, in 
subjects with RA.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. Between 18 and 75 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Subjects that do not have any medical conditions, other than moderate to severe RA 
that in the opinion of the Investigator put the subject at unacceptable risk or interfere 
with study assessments or integrity of the data.  These medical conditions should be 


2015N251670_03
CONFIDENTIAL
203168
31
stable at the time of screening and are expected to remain stable for the duration of 
the study. 
3. Subject has had a confirmed diagnosis of rheumatoid arthritis according to the revised 
2010 American College of Rheumatology/European League Against Rheumatism 
ACR-EULAR classification criteria.
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) at screening.
5. Swollen joint count of ≥4 (28-joint count) and tender joint count ≥4 (28-joint count) 
at screening.
6. Subject has a DAS28 CRP disease activity score of 3.2 and CRP ≥5.0 mg/L (4.76
nmol/L) at screening.
7. Subject must have received at least 12 weeks of non-biologic DMARD monotherapy 
or methotrexate (MTX)/DMARD combination therapy prior to screening AND must 
be on stable dose throughout the study.
8. Subject is naive to any biological therapies for RA 
OR
Subject may have had previous exposure to a single anti-TNF biologic agent which 
was discontinued for reasons other than primary non-response more than 8 weeks (or 
5 half lives whichever is longer) from first dose.  Note:  Exposure to a single anti-
TNF is not required in addition to Inclusion #7 above.
9. For subjects who have consented to synovial joint biopsy:
a.
Subject has an involved knee, wrist, or ankle suitable for biopsy, as assessed 
by a rheumatologist at screening.
WEIGHT
10. A body mass index (BMI) within range of 18.5 - 35 kg/m2 (inclusive) at screening.
SEX
11. Male and female subjects 
Males:
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements in Appendix 6.
Females: 
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:
a.
Non-reproductive potential defined as:
Pre-menopausal females with one of the following:

Documented tubal ligation


2015N251670_03
CONFIDENTIAL
203168
32

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 (see 
Appendix 6) if they wish to continue their HRT during the study.  Otherwise, 
they must discontinue HRT to allow confirmation of post-menopausal status 
prior to study enrolment.
b. Reproductive potential and agrees to follow one of the options listed in the Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Appendix 6) from 30 days prior to the first dose of 
study medication and until at least 30 days after the last dose of study medication and 
completion of the follow-up visit.
The Investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
INFORMED CONSENT
12. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
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. Subject with a positive anti-double stranded deoxyribonucleic acid (DNA [anti-
dsDNA]) and confirmed diagnosis of systemic lupus erythematosus (SLE).
2. Subject with current history of Suicidal Ideation Behaviour (SIB) as measured using 
the Columbia Suicide Severity Rating Scale (C-SSRS) or a history of attempted 
suicide.
3. An active infection, or a history of infections as follows:

Hospitalisation for treatment of infection within 60 days before first dose 
(Day 1).

Currently on any suppressive therapy for a chronic infection (such as 
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and 


2015N251670_03
CONFIDENTIAL
203168
33
atypical mycobacteria).

Use of parenteral (IV or intramuscular) antibiotics (antibacterials, antivirals, 
antifungals, or antiparasitic agents) for an infection within 60 days before first 
dose.

A history of opportunistic infections within 1 year of screening (e.g. 
pneumocystis jirovecii, CMV pneumonitis, aspergillosis).  This does not 
include infections that may occur in immunocompetent individuals, such as 
fungal nail infections or vaginal candidiasis, unless it is of an unusual severity 
or recurrent nature.

Recurrent or chronic infection or other active infection that, in the opinion of 
the Investigator might cause this study to be detrimental to the patient.

History of TB, irrespective of treatment status.

A positive diagnostic TB test at screening defined as a positive 
QuantiFERON-TB Gold test or T-spot test.  In cases where the QuantiFERON 
or T-spot test is indeterminate, the subject may have the test repeated once, 
but they will not be eligible for the study unless the second test is negative. In 
cases where the QuantiFERON or T-spot test is positive, but a locally-read 
follow up chest x-ray, shows no evidence of current or previous pulmonary 
tuberculosis, the subject may be eligible for the study at the discretion of the 
Investigator and GSK Medical Monitor.
4. QTc >450msec or QTc >480msec for subjects with bundle branch block at screening.
The QTc is the QT interval corrected for heart rate according to either Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), or another method, machine or manual 
over read.
The specific formula that will be used to determine eligibility and discontinuation for 
an individual subject should be determined and documented prior to initiation of the 
study. In other words, several different formulae cannot be used to calculate the QTc 
for an individual subject and then the lowest QTc value used to include or discontinue 
the subject from the trial. For purposes of data analysis, QTcB, QTcF, another QT 
correction formula, or a composite of available values of QTc will be used as 
specified in the Reporting and Analysis Plan (RAP).
5. ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%) at screening.
6. Current active or chronic history of liver or biliary disease (with the exception of 
Gilbert’s syndrome or asymptomatic gallstones).
7. Current or history of renal disease or estimated glomerular filtration rate (GFR) by 
Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) 
calculation <60 mL/min/1.73m2 at screening.
8. Hereditary or acquired immunodeficiency disorder, including immunoglobulin 
deficiency.
9. A major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem 
cell/marrow transplant.
10. Any planned surgical procedures including surgical joint procedures (e.g., intra-
articular, tendon sheath, or bursal corticosteroid injections) during the study.
11. A history of malignant neoplasm within the last 5 years, except for adequately treated 


2015N251670_03
CONFIDENTIAL
203168
34
non-metastatic cancers of the skin (basal or squamous cell) or carcinoma in situ of the 
uterine cervix that has been fully treated and shows no evidence of recurrence.
12. Has undergone surgery including synovectomy or arthroplasty on the joint chosen for 
biopsy and/or magnetic resonance imaging (MRI).  
13. The subject has a history of any other joint disease other than RA at the knee, wrist or 
ankle joint chosen for biopsy and/or MRI (e.g., gout, pseudogout, osteoarthritis).
14. Has undergone intra-articular corticosteroid injection, arthrocentesis or synovial 
biopsy on any joint within 6 weeks of screening.
15. A known allergy to lidocaine or other local anaesthetics (Note: only applies to 
subjects who consent for synovial biopsy procedures).
16. Contraindication to MRI scanning (as assessed by local MRI safety questionnaire) 
which includes but are not limited to:

Intracranial aneurysm clips (except Sugita) or other metallic objects,

History of intra-orbital metal fragments that have not been removed by a 
medical professional.

Pacemakers or other implanted cardiac rhythm management devices and non-
MR compatible heart valves,

Inner ear implants,

History of claustrophobia which may impact participation.
CONCOMITANT MEDICATIONS
17. The subject has received treatment with the therapies listed in Section 6.11.2, or 
changes to those treatments, within the prescribed timeframe.  If in doubt, or the 
therapy is not listed please consult with the medical monitor.

Other medications (including vitamins, herbal and dietary supplements) will 
be considered on a case-by-case basis, and will be allowed if in the opinion of 
the Investigator the medication will not interfere with the study procedures or 
compromise subject safety.
RELEVANT HABITS
18. History of alcohol or drug abuse that would interfere with the ability to comply with 
the study.
CONTRAINDICATIONS 
19. 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.
20. Received a live or attenuated vaccine within 30 days of randomization OR plan to 
receive a vaccination during the study until 5 half-lives (or 2 days) plus 30 days after 
receiving GSK2982772.
21. Contraindication to gadolinium contrast agent in accordance with local guidelines.
22. The subject has participated in a clinical trial and has received an investigational 


2015N251670_03
CONFIDENTIAL
203168
35
product within 30 days or 5 half-lives, whichever is longer before the first dose of 
study medication, or plans to take part in another clinical trial at the same time as 
participating in this clinical trial.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
23. Haemoglobin <9 g/dL; haematocrit <30%, white blood cell count ≤3,000/mm3 (≤3.0
x 109/L); platelet count ≤100,000/µL (≤100 x 109/L); absolute neutrophil count ≤1.5 x 
109/L at screening.
24. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of study treatment.  As 
potential for and magnitude of immunosuppression with this compound is unknown, 
subjects with presence of hepatitis B core antibody (HBcAb) should be excluded.
25. A positive serology for human immunodeficiency virus (HIV) 1 or 2 at screening. 
26. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 3 months.
27. Exposure to more than 4 investigational medicinal products within 12 months prior to 
the first dose. 
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Section 7.3.1.5).
Subjects who do not qualify to participate in the study due to a screening laboratory value 
or ECG abnormality can repeat the test once within the original screening window, if the 
Investigator believes there is a reasonable possibility that the subject would be eligible if 
re-tested. 
Subjects can be re-screened only on approval of the GSK Medical Monitor and only 
once.  Re-screening is allowed when a subject failed inclusion/exclusion criteria or some 
other screening condition initially, but the Investigator believes there is a reasonable 
probability that the subject would be eligible if re-screened. 
5.4.
Withdrawal/Stopping Criteria
Subjects may be withdrawn from the study for any of the following reasons:

A subject may withdraw from study treatment at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioural or administrative reasons.  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.  The reason for withdrawal should be 
documented in the Case Report Form (CRF).


2015N251670_03
CONFIDENTIAL
203168
36

The Sponsor’s request, for reasons such as significant protocol deviations or 
subject safety concern (and after discussion with the Investigator).

If a subject is withdrawn from study treatment, this subject is also considered to 
be withdrawn from the study.

Study is terminated by the Sponsor.
If a subject is withdrawn, the Sponsor may decide to replace that subject and this will be 
done through the Interactive Response Technology System (IRTS).
If a subject chooses to withdraw from the study after dosing then the Investigator must 
make every effort to complete the follow-up assessments detailed in the Time and Events 
Table (Section 7.1).
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the Investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

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”. 
5.4.1.
Individual Safety Stopping Criteria
Study medication will be discontinued in the event of any of the following:

If a subject experiences a serious or severe clinically significant AE that in the 
clinical judgement of the Investigator, after consultation with the medical monitor, 
is possibly, probably or definitely related to investigational product.

The subject becomes pregnant.

The subject initiates treatment with any prohibited medications for the treatment 
of RA as listed in Section 6.11.2.

The subject develops a serious opportunistic or atypical infection.

If any of the liver chemistry stopping criteria (Section 5.4.3), QTc stopping 
criteria (Section 5.4.4), or Haematologic stopping criteria (Section 5.4.5) are met.

The subject experiences any signs of suicidal ideation or behaviour 
(Section 7.3.7).


2015N251670_03
CONFIDENTIAL
203168
37
5.4.2.
Group Safety Stopping Criteria
In addition to the criteria specified above, AEs, SAEs, laboratory abnormalities, ECG 
abnormalities and changes in vital signs occurring across all randomised subjects will be 
regularly reviewed by the Sponsor Safety Review Team (SRT) in order to ensure 
appropriate subject safety.  Any changes to the study due to safety reasons will be 
promptly communicated to the appropriate Regulatory Authorities.
5.4.3.
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). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Figure 3
Phase II Liver Chemistry Stopping Criteria – Liver Stopping Events 
Algorithm
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2.
5.4.3.1.
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.
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*


2015N251670_03
CONFIDENTIAL
203168
38
5.4.4.
QTc Stopping Criteria
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 patients 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

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may 
not be changed or substituted once the subject has been enrolled.
For example, if a subject is eligible for the protocol based on QTcB, then QTcB must be 
used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the 
same formula must continue to be used for that subject for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified ECGs 
are an exception. 

The decision to withdraw a subject will be based on an average QTc value of 
triplicate ECGs.  If an ECG demonstrates a prolonged QTc, obtain 2 more ECGs 
over a brief period (5-10 minutes), and then use the averaged QTc values of the 3 
ECGs to determine whether the subject should be discontinued from the study.
5.4.5.
Haematologic Stopping Criteria
Study treatment will be stopped for a subject if any of the following haematological 
stopping criteria is met:

Haemoglobin - an absolute decrease of ≥2 g/dL from baseline (pre-dose Day 1)

Platelets <50 × 109/L
5.5.
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.


2015N251670_03
CONFIDENTIAL
203168
39
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Study Treatment
Product name:
GSK2982772
Placebo
Dosage form:
Tablet
Tablet
Unit dose 
strength(s)/Dosage level(s):
30 mg
NA
Route of Administration
For oral use only
For oral use only
Dosing instructions (with 
amendment 03):
Take TWO tablets three 
times a day as directed 
by your physician
Take TWO tablets three 
times a day as directed 
by your physician
Dosing instructions (prior 
to amendment 03):
Take TWO tablets in the 
MORNING and TWO 
tablets in the EVENING 
as directed
Take TWO tablets in the 
MORNING and TWO 
tablets in the EVENING 
as directed
Physical description:
White to almost white, 
round, film coated tablet
White to almost white, 
round, film coated tablet
Source of procurement
Study medication is 
supplied by 
GlaxoSmithKline
Placebo is supplied by 
GlaxoSmithKline
6.2.
Treatment Assignment
At Screening a unique Subject Number will be assigned to any subject who has signed a 
consent form.  The unique Subject Number will be used to identify individual subjects 
during the course of the study.  Any subject that is re-screened outside of the allowed 
screening window at the approval of the GSK Medical Monitor, must be assigned a new 
unique Subject Number.
Subjects who meet screening eligibility criteria will be randomised to a treatment group 
through an Interactive Response Technology System (IRTS).  The IRTS will confirm the 
subject’s CRF number (Subject Number) and provide the randomisation number, where:

A randomisation number will be assigned from a randomisation schedule 
generated by Clinical Statistics, prior to the start of the study, using validated 
internal software.  Once assigned, this number must not be reassigned to any other 
subject in the study.


2015N251670_03
CONFIDENTIAL
203168
40
Therefore, the randomisation is centrally controlled by the IRTS.
Subjects will be randomised to receive either GSK2982772 or placebo in a 2:1 ratio.
6.3.
Planned Dose Adjustments
No dose adjustments are allowed.
6.4.
Blinding
This will be a double blind (sponsor unblinded) study and the following will apply:

Sponsor unblinded refers only to the Data Review Committee, consisting of the 
GSK Project Physician Lead (PPL), study statistician, study pharmacokineticist, 
Pattern Recognition Receptor (PRR) Discovery Performance Unit (DPU) Head, 
Early Development Lead (EDL) and Safety Review Team (SRT) Leader, or their 
designees on an ongoing basis.  A physician external to the GSK2982772 project 
team may also be involved in the data review.  A data review charter will identify 
the specific GSK individuals involved; outline in detail the activities of this 
review, and how the integrity of the study will be maintained. The rest of the core 
GSK study team will remain blinded.

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 to his/her study staff or GSK, 
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 CRF.

A subject will be withdrawn if the subject’s treatment code is unblinded by the 
Investigator or treating physician.  The primary reason for discontinuation (the 
event or condition which led to the unblinding) will be recorded in the CRF.

GSK’s Global Clinical Safety and Pharmacovigilance (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.


2015N251670_03
CONFIDENTIAL
203168
41
6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.6.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the Investigator and authorized site staff. 

The Investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

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.  

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the Investigator, where this is required by local laws, or is available 
upon request from GSK.
6.7.
Compliance with Study Treatment Administration
When subjects are dosed at the site, they will receive study treatment directly from the 
Investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study subject identification will be confirmed at the time of dosing.  
When subjects self-administer study treatment(s) at home, compliance with GSK2982772 
and placebo will be assessed and documented through the review of the subject’s diary 
card and querying the subject during the site visits.  A record of the number of 
GSK2982772 or placebo tablets dispensed to and taken by each subject must be 
maintained and reconciled with study treatment and compliance records.  Treatment start 
and stop dates, including dates for treatment delays and/or dose reductions will also be 
recorded in the CRF.
Subjects will be given instructions on compliance and treatment with MTX (if 
applicable).  The date, time and total weekly dose will be recorded in the study diary 
cards and the CRF.


2015N251670_03
CONFIDENTIAL
203168
42
6.8.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2982772 >180 mg daily will be considered an overdose.  
GSK does not recommend specific treatment for an overdose.  The Investigator will use 
clinical judgement to treat any overdose as and when they are made aware of this.
In the event of an overdose, the Investigator or treating physician should:
1. Contact the Medical Monitor immediately.
2. Closely monitor the subject for adverse events (AEs)/serious adverse events (SAEs) 
for at least 48 hours following the last dose of GSK2982772.
3. Obtain a plasma sample for pharmacokinetic (PK) analysis if requested by the 
Medical Monitor (determined on a case-by-case basis).
4. Document all details of the overdose in the CRF.
Decisions regarding dose interruptions or modifications will be made by the Investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.9.
Treatment after the End of the Study
The Investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
Subjects will not receive any additional treatment from GSK after completion of the 
study because the 12 week duration of treatment is limited by the supporting 13 week 
toxicology studies.
6.10.
Lifestyle and/or Dietary Restrictions

Subjects must adhere to the contraceptive requirements listed in Appendix 6.
6.10.1.
Activity

Subjects will abstain from strenuous exercise more than their normal routine for 
48 hours prior to each blood collection for clinical laboratory tests.  

Subjects who have consented to synovial biopsies will abstain from strenuous 
exercise for 24 hours after synovial biopsy procedures.
6.11.
Concomitant Medications and Non-Drug Therapies
6.11.1.
Permitted Medications and Non-Drug Therapies
Selected medications for the treatment of RA may be taken, with specific requirements 
listed in Table 1, and as long as they are not prohibited (Section 6.11.2).  All concomitant 
medications taken during the study will be recorded in the source document and CRF.  
The minimum requirement is that drug name and dates of administration are recorded.


2015N251670_03
CONFIDENTIAL
203168
43
Table 1
Specific Requirements for Permitted Medications During the Study
Drug
Requirement
Methotrexate 
Stable dose regimen (up to 25 mg/week) for at 
least 12 weeks prior to screening and remain on 
this dose throughout the study (unless dose 
must be reduced because of a safety concern).  
MTX should ideally be taken on the same day of 
week and at approximately the same time of 
day throughout the study.
Sulfasalazine
Stable dose regimen for at least 12 weeks prior 
to screening and throughout the study.
Hydoxychloroquine or cholorquinine
Stable dose for at least 12 weeks prior to 
screening and throughout the study.
Leflunomide
Stable dose for at least 12 weeks prior to 
screening and throughout the study.
Folate supplements (minimum of 5 mg/week)
If a subject is on folate supplements with MTX 
treatment, they must be on a stable dose 
regimen for at least 4 weeks prior to 
randomization and throughout the study.
Other oral anti-rheumatic therapies such as 
non-steroidal anti-inflammatory drugs (NSAIDs), 
oral glucocorticords (e.g., prednisolone ≤ 10 mg 
/day.  See Appendix 3 for equivalent doses).
Stable dose regimen for at least 4 weeks prior 
to screening and throughout the study (unless 
reduction required due to adverse effects).
Omit dose on the morning prior to study visits 
until after joint assessments.
6.11.2.
Prohibited Medications and Non-Drug Therapies
Table 2 lists prohibited medications for defined periods of time before and during the 
study until after the follow up visit. 
Subjects who start prohibited medications or therapies as a treatment for RA or other 
reasons during the study will be withdrawn from study treatment for safety reasons.  If in 
any doubt, Investigators are advised to discuss medications with the medical monitor.


2015N251670_03
CONFIDENTIAL
203168
44
Table 2
Prohibited Medications
Therapy
Time period 
A change in dose of methotrexate or other DMARD.
12 weeks prior to screening until after the 
follow up visit (Day 112)
Greater than 10mg/day oral prednisolone (or 
equivalent glucocorticoid) or a change in dose of 
corticosteroid.
4 weeks prior to screening until after the 
follow up visit (Day 112)
Intramuscular glucocorticoids (e.g., 
methylprednisolone ≤120 mg/month)
4 weeks prior to screening until after the 
follow up visit (Day 112)
Intra-articular corticosteroid injections
6 weeks prior to screening and until after 
the follow up visit (Day 112).
Janus Kinase (JAK) Inhibitors
4 weeks prior to screening until after the 
follow up visit (Day 112).
P-glycoprotein (Pgp) inhibitors including but not 
limited to amiodarone, azithromycin, captopril, 
carvedilol, clarithromycin, conivaptan, cyclosporine, 
diltiazem, dronedarone, erythromycin, felodipine, 
itraconazole, ketoconazole, lopinavir, ritonavir, 
quercetin, quinidine, ranolazine, ticagrelor, 
verapamil [FDA, 2012].
4 weeks prior to first dose (Day 1) until 
after the follow up visit (Day 112).
Narrow therapeutic index (NTI) CYP3A4 substrates 
including but not limited to alfentanil, astemizole, 
cisapride, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus, terfenadine [FDA, 2012].
4 weeks prior to the first dose (Day 1)
until after the follow up visit (Day 112).
Biologic therapies for the treatment of rheumatoid 
arthritis not limited to anti-TNF biologics or other 
biologics, rituximab, anakinra, abatacept or 
tocilizumab.
At any time. 
Exposure to more than one anti-TNF biologic 
therapies for the treatment of RA including but not 
limited to anti-TNF biologics, infliximab, 
adalimumab, etanercept, certolizumab and 
golimumab.
Exception:  Exposure to a single anti-TNF-biologic 
for which the subject discontinued for a reason other 
than primary non-response is permitted.
Cannot have been exposed to more than 
one anti-TNF biologic or be on at any 
time during the study.
In the case of a single anti-TNF biologic 
for which the subject discontinued for a 
reason other than primary non-response, 
the subject must not be on for 8 weeks or 
5 half lives (whichever is longer) prior to 
first dose until after the follow up visit 
(Day 112).  
Live vaccination
Live or attenuated vaccinations are not 
permitted within 30 days of 
randomization or plan to receive a 
vaccination during the study until follow-
up visit.  If indicated, non-live vaccines 
(e.g., inactivated influenza vaccines) may 


2015N251670_03
CONFIDENTIAL
203168
45
Therapy
Time period 
be administered whilst receiving 
GSK2982772 based on an assessment 
of the benefit:risk (e.g., risk of decreased 
responsiveness).  Investigators are 
expected to follow local and/or national 
guidelines with respect to vaccinations, 
including against pneumococcus and 
influenza, in subjects with RA.
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 (Section 7.1), are essential and required for study 
conduct.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the SRM and laboratory manual.  The SRM will provide the site personnel 
with administrative and detailed technical information that does not impact subject safety.
This section lists the procedures and parameters of each planned study assessment.  The
timing of each assessment is listed in the Time and Events Table Section 7.1

At study visits, the Patient Reported Outcomes (PROs) should be completed 
prior to any other study assessments.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic/biomarker or others assessments may be 
altered during the course of the study based on newly available data (e.g., to 
obtain data closer to the time of peak concentrations) to ensure appropriate 
monitoring. 

The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment. 

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.

The Institutional Review Board/Independent Ethics Committee (IRB/IEC) will 
be informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the Informed Consent Form. 


2015N251670_03
CONFIDENTIAL
203168
46
7.1.
Time and Events Table
Procedures
Screening (-30)
Treatment Period17
Early Withdrawal18
Follow Up (3)19
Day 1 
Day 8 (3)
Day 15 (3)
Day 22 (3)
Day 29 (3)
Day 36 (3)
Day 43 (3)
(week 6)
Day 50 (3)
Day 57 (3)
Day 64 (3)
Day 71 (3)
Day 78 (3)
Day 85 (+2)
(week 12)
Site Visit
X
X
X
X
X
X
X
X
X
X
X
Phone call
X
X
X
X
X
General/Safety Assessments and Procedures
Informed Consent
X
Subject Demography
X
Full medical history1
X
Inclusion/Exclusion Criteria
X
Full physical exam2
X
X
X
X
Brief physical exam
X4
X
X
X4
X
X
Vital signs (BP, HR, RR, temperature)  
X
X4
X
X
X
X4
X
X
X
X
X
12-lead ECG
X3
X4
X
X
X
X4
X
X
X
X
X
Concomitant medication review & AE reporting/SAEs5
X---------------------------------------------------------------------------------------------------------------------------X
PROs/Questionnaires/Diaries/Disease Assessments and Procedures
Columbia Suicide Severity Rating Scale (C-SSRS)
X
X4
X4
X
X
FACIT-fatigue; RA Symptom and Impact Diary6
X4
X4
X
X
HAQ-DI; Patient Assessment of joint pain6
X4
X
X
X4
X
X
X
X
Patient Global Assessment (PtGA)6
X
X4
X
X
X4
X
X
X
X
Tender (28) & Swollen (28) joint count
X
X4
X
X
X4
X
X
X
X
Physician Global Assessment (PGA)
X4
X
X
X4
X
X
X
X
MRI/DCE-MRI7
X4, 20
X4,21
X22
X16


2015N251670_03
CONFIDENTIAL
203168
47
Procedures
Screening (-30)
Treatment Period17
Early Withdrawal18
Follow Up (3)19
Day 1 
Day 8 (3)
Day 15 (3)
Day 22 (3)
Day 29 (3)
Day 36 (3)
Day 43 (3)
(week 6)
Day 50 (3)
Day 57 (3)
Day 64 (3)
Day 71 (3)
Day 78 (3)
Day 85 (+2)
(week 12)
Study Treatment
Randomisation
X
Study medication (three times daily)8
X-------------------------------------------------------------------------------------------------------X
Dispensing of study medication
X
X
X
Dispensing of diary cards
X
X
X
X
X
X
X
Collection and review of diary cards
X
X
X
X
X
X
X
X
Laboratory (Safety) Assessments and Procedures
TB, HIV, HepB,Hep C Ab, Anti-CCP, Anti-dsDNA, RF 
X
FSH & estradiol  (if applicable)
X
Serum pregnancy test (WCBP only)
X
Urine pregnancy test (WCBP only)9
X4
X
X
X
X4
X
X
X
X
X
Haematology, chemistry, urinalysis 
X
X4
X
X
X10
X4
X10
X10
X
X
X
CRP
X
X4
X
X
X4
X
X
X
X
Blood sample for PD inflammatory biomarkers, mRNA, and 
TE11
X4
X4
X
X
PK blood samples GSK298277212
X
X4
X4
X
X
PK blood samples for MTX13
X4
X4
X4
Pharmacogenetic sample (PGx)
X14
Synovial biopsies for PK, inflammatory biomarkers, mRNA, 
target engagement & pathway engagement analysis15
X4,20
X4,21
X16


2015N251670_03
CONFIDENTIAL
203168
48
Footnotes:
1.
Full medical history (includes past and current conditions, medication history, substance usage, and family history of premature CV disease).
2.
Full physical exam (includes height/weight at screening, height not measured at later time points).
3.
Triplicate ECG to be performed at screening only.
4.
Pre-dose.
5.
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.  AEs will be collected from the start of Study Treatment until the follow-up 
contact.  On Days 22, 36, 50, 64, and 78, subjects will be questioned about their general health status via phone call.
6.
All PRO assessments should be conducted on site before any tests, procedures, or assessments, to avoid influencing the subjects’ perception.
7.
DCE-MRI will be performed on all subjects, provided that sites have DCE-MRI capability and experience (e.g., hardware and software requirements). If sites do not have DCE-MRI 
capability or experience, a regular MRI will be performed of the affected hand/wrist.  If the same joint is used for MRI and synovial biopsy, MRI should be performed before biopsy 
(if applicable).
8.
Subjects must take study medication three times a day approximately 8 hours apart. Exact time of dosing to be recorded in diary cards. On Day 1, the first study dose will be 
administered at the site.  On Days 8, 43 and 85 only, subjects must not take their medication at home in the morning. Subjects will complete pre-dose assessments and then will 
be administered their morning dose of medication at site on Days 8 and 43.  On Day 85, subjects are no longer receiving study medication.
9.
If urine pregnancy test is positive, a confirmatory serum pregnancy test must be performed.
10. Haematology and chemistry only.  No urinalysis required on Days 29, 57 and 71.  When clinical laboratory samples are taken on the same day as the MRI, the samples should be 
taken first prior to the administration of the contrast fluid with MRI.  If this is not feasible (i.e. MRI is performed first), it is recommended that a separate IV catheter or straight 
venipuncture be performed in the opposite arm to where the MRI contrast fluid was administered.
11. Blood samples for inflammatory biomarkers, mRNA and target engagement.  See laboratory manual for full details on sample collection, handling and shipment.
12. PK blood samples for GSK2982772 will be taken pre-dose on Days 8 and 43. Post-dose serial PK samples will be taken on Days 1, 8 and Day 43 at the following time points: 1, 2, 
4, and 6 hours. A trough PK sample will be taken on Day 85 or at Early Withdrawal.
13. Only applicable if subjects are on MTX: PK blood samples for MTX will be taken pre-dose GSK2982772 on Day 1 (MTX alone), on Days 8 and 43 (MTX + GSK2982772).  
Subjects who are on MTX should ideally take their MTX dose on the same day of the week at approximately the same time of the day throughout the study. In addition, the Day 1, 
8 and 43 visits should ideally be on the same day of the week.
14. A PGx blood sample is collected at the baseline visit, after the subject has been randomised and provided informed consent for genetic research.  If the sample is not collected at 
the baseline visit, it can be collected at any time during the study after randomisation.
15. Synovial biopsies are optional.
16. Biopsy (if applicable) and MRI only are required at Early Withdrawal visit if subject withdraws after at least 14 days of treatment and prior to Day 43.  If a subject withdraws 
between Days 43 and 57, an MRI is not required at the Early Withdrawal visit.  If a subject withdraws on Day 57 or after, an MRI should be performed at the Early Withdrawal visit.  
A window allowance of 3 days of Early Withdrawal visit is allowed to perform the MRI.
17. Visit windows during the treatment period are relative to Day 1.
18. If a subject withdraws from the study, every effort will be made for the subject to complete an Early Withdrawal visit prior to the Follow Up visit.
19. Follow-up visit should be completed 28 days (3 days) after the last dose of study medication.
20. MRI (and if applicable; a biopsy) may be performed during the screening window as an additional visit (if required) up to 7 days before Day 1 to allow sites flexibility in scheduling.  
The MRI must be completed prior to synovial biopsy (if performed on the same joint).  The site should be reasonably confident that the subject has fully qualified for the study 
(e.g., screening clinical labs, vital signs, physical examination, etc.) before the MRI (and if applicable: a biopsy) is/are performed. 


2015N251670_03
CONFIDENTIAL
203168
49
21. A biopsy (if applicable) and MRI may be performed on a separate day within the Day 43 window allowance (3 days).  A separate visit to perform the MRI followed by synovial 
biopsy (if applicable) is only allowed to accommodate scheduling.  If biopsy is being performed, this visit must be scheduled after the Day 43 visit where the PK, clinical laboratory 
tests and other required Day 43 procedures are performed.  Subjects must not take their study medication at home in the morning before the full Day 43 visit and also the morning 
before MRI and biopsy (if applicable) visit if being done on a separate day. 
22. For MRI performed on day 85, a visit window of up to 2 days after is allowed in order to perform the MRI.


2015N251670_03
CONFIDENTIAL
203168
50
7.2.
Screening and Critical Baseline Assessments
After written informed consent, screening assessments will be performed as outlined in 
the Time and Events Table (Section 7.1).
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/mental health and family history, ECG and laboratory tests will be 
assessed as related to the inclusion/exclusion criteria listed in Section 5.
Cardiovascular medical history/risk factors and smoking history (as detailed in the CRF) 
will be assessed at screening.
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.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  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.
The Investigator will be responsible for determining the clinical significance of any 
results that fall outside of the laboratory normal ranges.
In line with routine pharmacovigilance, an internal GSK Safety Review Team (SRT), 
which will include 203168 study team members, will review blinded safety data, 
including clinical laboratory parameters and adverse events, at appropriate intervals 
during the period of study conduct.
7.3.1.
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. 
7.3.1.1.
Time period and Frequency for collecting AE and SAE information

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. 

AEs will be collected from the start of Study Treatment until the follow-up 
contact (see Section 7.3.1.3), at the time points specified in the Time and Events 
Table (Section 7.1).


2015N251670_03
CONFIDENTIAL
203168
51

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 CRF.

All SAEs will be recorded and reported to GSK within 24 hours, 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.
7.3.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.3.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 5. 
7.3.1.4.
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 CRF will 
be required to be completed.  These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death.
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms.  The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion.


2015N251670_03
CONFIDENTIAL
203168
52
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported.  Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.3.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the Investigator to GSK of SAEs 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.
An Investigator who receives an Investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.3.2.
Pregnancy

Details of all pregnancies in female subjects and female partners of male subjects 
will be collected after the start of dosing and until 30 up to 90 days (as applicable)
after the last dose.

If a pregnancy is reported within 30 days (90 days in partners) after the last dose 
then the Investigator should inform GSK within 2 weeks of learning of the 
pregnancy and should follow the procedures outlined in Appendix 6.
7.3.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
head, eyes, ears, nose, throat, skin, thyroid, joint, lymph nodes, cardiovascular, 
respiratory, gastrointestinal and neurological systems. Height and weight will also 
be measured and recorded at the first physical examination. 

A brief physical examination will include, at a minimum assessments of the lungs, 
cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.


2015N251670_03
CONFIDENTIAL
203168
53
7.3.4.
Vital Signs

Vital signs will be measured in a supine or semi-supine position after 
approximately 5 minutes rest and will include temperature, systolic and diastolic 
blood pressure, pulse rate and respiratory rate. 
7.3.5.
Electrocardiogram (ECG)

Triplicate12-lead ECGs will be obtained at screening and single 12-lead ECGs 
obtained at every time point during the study using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc (F or 
B) intervals.  A manual over read is also allowed. Refer to Section 5.4.4 for QTc 
withdrawal criteria and additional QTc readings that may be necessary.

The QTc should be based on averaged QTc values of triplicate electrocardiograms 
obtained over a brief (e.g., 5-10 minutes) recording period.  

ECG to be measured in a semi-supine position after approximately 5 minutes rest.
7.3.6.
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 Table 
(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 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 CRF.
Refer to the 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:

Haematology, platelets and coagulation sample if they are required to be taken 
closer to the biopsies (as per local practices) than specified in Section 5.4.5.
NOTE:  Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either a treatment and/or response evaluation to be 
performed. If a local sample is required, it is important that the sample for central 
analysis be obtained at the same time.  Additionally, if the local laboratory results are 
used to make either a treatment or response evaluation, the results must be entered into 
the CRF.


2015N251670_03
CONFIDENTIAL
203168
54
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 3. 
Table 3
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
1,2
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 3
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose4
Calcium
Alkaline phosphatise
Albumin
CRP
Triglycerides4
Total Cholesterol4
Fasting HDL 
cholesterol4
Fasting LDL 
cholesterol4
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening and 
RoutineTests

HIV 1 & 2

Hepatitis B (HBsAg)

Hepatitis B core antibody (HBcAb)

Hepatitis C (Hep C antibody)

QuantiFeron Gold Test

T-spot (if QuantiFeron is indeterminant)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Urine hCG Pregnancy test (as needed for women of child bearing 
potential) 5

Serum hCG (as needed for women of child bearing potential) to be 
done at screening and if urine test positive at other time points in the 
study.

Anti-dsDNA

Rheumatoid Factor

Anti-CCP

Estimated glomerular filtration rate (eGFR) will be calculated using 
the CKD-EPI formula.
Footnotes:
1.
The subject’s CBC results from the previous scheduled visit should be checked prior to the synovial biopsy 
procedures according to local practices and may be repeated at the discretion of the investigator.


2015N251670_03
CONFIDENTIAL
203168
55
2.
Details of Haematologic Stopping Criteria are given in Section 5.4.5.
3.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after liver 
stopping or monitoring event are given in Section 5.4.3 and Appendix 2.
4.
No fasting required.  Any abnormal result for glucose or lipids (non-fasted) may be repeated at the discretion 
of the Investigator.
5.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
ethics committee.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study 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.
7.3.7.
Suicidal Risk Monitoring
GSK2982772 is considered to be a CNS-active drug. There has been some concern that 
some CNS-active drugs may be associated with an increased risk of suicidal thinking or 
behaviour when given to some patients with RA.  Although this drug has not been shown 
to be associated with an increased risk of suicidal thinking or behaviour when given to 
healthy volunteers, GSK considers it important to monitor for such events before or 
during clinical studies with compounds such as this.   
Subjects being treated with GSK2982772 should be monitored appropriately for suicidal 
ideation and behaviour or any other unusual changes in behaviour. Study medication 
must be immediately discontinued in all subjects who experience signs of suicidal 
ideation or behaviour.
Families and caregivers of subjects being treated with GSK2982772 should be alerted 
about the need to monitor subjects for the emergence of unusual changes in behaviour, as 
well as the emergence of suicidal ideation and behaviour and to report such symptoms 
immediately to the study Investigator.
At Screening and baseline (pre-dose Day 1), the ‘Baseline/Screening CSSRS’ will be 
completed.  Assessments will be done at Days 43 (Week 6) and 85 (Week 12), the ‘Since 
Last Visit CSSRS’ will be completed.  GSK Version 4.1 of both rating scales will be 
used.
Subjects who answer ‘yes’ to any suicidal behaviour or ‘yes’ to suicidal ideation 
Questions 4 or 5 will be referred to their GP or appropriate psychiatric care and be 
discontinued from study medication.  The Medical Monitor will be notified.  If 
appropriate, an AE or SAE should be reported (see Section 7.3.1 AE and SAE).  In 
addition, the Investigator should complete a Possible Suicidality Related Adverse Event 
(PSRAE) form to collect detailed information on the circumstances of the reported AEs 
which, in the Investigator’s opinion, are possibly suicidality-related.  These may include, 
but are not limited to, an event involving suicidal ideation, a preparatory act toward 
imminent suicidal behaviour, a suicide attempt, or a completed suicide.


2015N251670_03
CONFIDENTIAL
203168
56
7.4.
Efficacy
7.4.1.
Patient Reported Outcomes
Patient Reported Outcomes questionnaires should be completed by subjects before any 
other assessment at a clinic visit.
7.4.1.1.
Rheumatoid Arthritis Symptoms and Impact Diary
Symptoms associated with RA will be assessed using a novel RA Symptom and Impact 
Diary as per Section 7.1, Time and Events Table.  The study staff should not clarify any 
of the questions for the subject.
7.4.1.2.
Patient Assessment of Joint Pain
The severity of the subject’s joint pain will be assessed by completion of a numeric rating 
scale (NRS).  The subject will be asked to select a whole number (0-10 integers) that best 
reflects the intensity of their pain.  The scale is represented by a horizontal bart with “no 
pain” at the lower anchor and “most severe pain” at the upper anchor.  This questionnaire 
should take approximately 1 minute to complete.
The patient assessment of joint pain will be used to calculate ACR responders.
7.4.1.3.
Patient’s Global Assessment of Disease (PtGA)
Subjects will complete a global assessment of disease activity using the patient global 
assessment item, a visual analogue scale (VAS) with anchors “0” (very well) to “10” 
(very poor).
The patient’s global assessment of disease will be used to calculate DAS clinical scores 
and ACR responders.
7.4.1.4.
Disability Index of the Health Assessment Questionnaire (HAQ-DI)
The HAQ-DI will be utilised to assess the subject’s physical function or disability 
according to the subject.  The study staff should not clarify any of the questions for the 
subject.
This 20-question instrument assesses the degree of difficulty a person has in 
accomplishing tasks in 8 functional areas [Fries, 1980]: 

Dressing, arising, eating, walking, hygiene, reach, grip, and common daily 
activities. 
Responses are scored from 0 (no difficulty) to 3 (inability to perform a task in that area). 
The HAQ-DI will be used to calculate ACR responders.


2015N251670_03
CONFIDENTIAL
203168
57
7.4.1.5.
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue 
Scale
Subjects will complete a 13-point fatigue questionnaire using the FACIT-Fatigue 
assessment, a Likert scale from 0 to 4, to “0” (very much fatigued) to“4” (not at all 
fatigued).  This questionnaire should take a few minutes to complete and provides the 
level of fatigue with usual daily activities from the previous week. 
7.4.2.
Clinical Disease Assessments
Brief details are given below and detailed procedural instructions are given in the SRM.  
The sponsor will calculate DAS28(CRP)  and ACR (20/50/70) responses at each 
assessment time point as defined below.
7.4.2.1.
Disease Activity Score (DAS) Assessments
The DAS28 is a measure of disease activity.  It is a composite score derived measurement 
weighing given to each component.  
The components of the DAS28 assessment include:

Tender/Painful Joint Count (28)

Swollen Joint Count (28)

CRP

PtGA
7.4.2.2.
American College of Rheumatology Criteria (ACR) Assessments
The ACR Criteria is a standard criteria to measure the effectiveness of treatments from 
placebo.  The ACR’s definition for calculating improvement in RA (ACR20) is 
calculated as a 20% improvement in tender and swollen joint counts and 20% 
improvement in 3 of the 5 remaining ACR-core set measures: patient and physician 
global assessments, pain, disability, and an acute-phase reactant.  Similarly, ACR50 and 
70 are calculated with the respective percent improvement.  
The specific components of the ACR Assessments that will be used in this study are:

Tender/Painful Joint count (28)

Swollen Joint Count (28)

Patient Assessment of Joint Pain

PtGA

PGA

CRP

HAQ-DI


2015N251670_03
CONFIDENTIAL
203168
58
7.4.2.3.
Joint Assessments
Tender Joint Count Assessments
A total of 28 joints will be scored for presence or absence of tenderness.
Swollen Joint Count Assessments
A total of 28 joints will be scored for presence or absence of swelling.
Joint assessments will be used to calculate DAS28 clinical scores and ACR responders.
7.4.2.4.
Measurement of Serum CRP
Blood samples will be collected in order to measure serum CRP concentrations.  The 
CRP is a component of the DAS28, ACR, and Vectra DA clinical scores.
7.4.2.5.
Physician’s Global Assessment of Disease Activity (PGA)
The Investigator or physician designee only will complete a global assessment of disease 
activity using the physician global assessment item, a VAS with anchor’s “0” (none) to 
“10” (extremely active).
Note: 

The Investigator or physician designee should complete the PGA independently of 
the subject.

Ideally, the same Investigator or physician designee should perform all global 
assessments for each subject during the duration of the study.
7.5.
Pharmacokinetics
7.5.1.
Blood Sample Collection
Blood samples for PK analysis of GSK2982772 will be collected at the time points 
indicated in Section 7.1 Time and Events Table.  The actual date and time of each blood 
sample collection will be recorded.  The timing of PK samples may be altered and/or PK 
samples may be obtained at additional time points to ensure thorough PK monitoring.  
For subjects who are on stable doses of methotrexate (MTX), blood samples for PK 
analysis of MTX will be collected at the time points indicated in Section 7.1 Time and 
Events Table.  The actual date and time of each blood sample collection will be recorded.  
Details of blood sample collection, processing, storage and shipping procedures are 
provided in the laboratory manual. 
7.5.2.
Sample Analysis
Plasma analysis will be performed at a bioanalytical site (to be detailed in the SRM) 
under the control of Platform Technology and Science In Vitro/In Vivo Translation (PTS 
IVIVT) and Third Party Resource, GlaxoSmithKline. Concentrations of GSK2982772 


2015N251670_03
CONFIDENTIAL
203168
59
and MTX will be determined in plasma samples using the currently approved 
bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed 
in the SRM).
Once the plasma sample has been analysed for GSK2982772 any remaining plasma
sample may be analysed for other compound-related material and the results may be 
reported under a separate PTS-IVIVT, GlaxoSmithKline protocol.
7.5.3.
Synovial Biopsy Tissue for Pharmacokinetic Assay
See Section 7.6.2.2 for details on synovial tissue biopsy and procedure.  If available, 
synovial tissue samples may be analysed for concentrations of GSK2982772 and possible 
drug-related material, as well as specific tissue distribution if feasible as sample 
availability allows. 
7.5.4.
Sample Analysis
Synovial biopsy sample analysis will be performed under the control of PTS IVIVT, 
GlaxoSmithKline.  Information on processing the biopsies for the synovial 
pharmacokinetic assay will be provided in the laboratory manual.  The results may be 
reported under a separate PTS-IVIVT, GlaxoSmithKline protocol.
7.6.
Biomarker(s)/Pharmacodynamic Markers
Pharmacodynamic biomarkers will be collected at the time points in Section 7.1 Time 
and Events Table and may include, but are not limited to, the following:

Blood samples for mRNA expression e.g., IL6, MMP-1, MMP3, MMP-13, TIMP-1, 
MCP-1 and MIF.

Blood samples for biomarkers which may be indicative of RA disease activity e.g., 
MRP8/14 and markers encompassed by Vectra DA.
Details of blood sample collection, processing, storage and shipping procedures are 
provided in the laboratory manual.
7.6.1.
Magnetic Resonance Imaging (MRI) of Joint
The most affected hand will be documented at baseline and used for all imaging visits. If 
subjects report both hands are equally involved, then the subject’s dominant hand will be 
used.
DCE-MRI will be performed on all subjects, provided that sites have DCE-MRI 
capability and experience (e.g., hardware and software requirements). If sites do not have 
DCE-MRI capability, only a standard MRI will be performed.
Each subject’s most affected wrist (corresponding to the affected hand which is 
determined and documented at baseline) will be imaged by MRI at pre-dose on Days 1, 
43 and 85 (see Section 7.1).  If a scanning failure occurs at any visit, if feasible a rescan 


2015N251670_03
CONFIDENTIAL
203168
60
is allowed within 7 days after the failed scan after consultation and agreement with the 
GSK Medical Monitor.  There will be a minimum of 24 hours between scans where 
gadolinium (Gd) contrast is used.  The MRI will be used in order to non-invasively 
quantify the degree of inflammation and structural changes within the target joint.
Each MRI total scan time should be approximately 1 hour.  For each subject, MRIs must 
be performed on the same scanner and using the same type of chelated Gd contrast agent 
as was used at screening.  If scanning cannot occur on the same scanner within the visit 
time window due to hardware failure, an alternate scanner may be used or the time 
window may be extended by 3 days only after consultation and agreement with the GSK 
medical monitor.
On attendance at the MRI department, subjects will be placed in the scanner and will be 
prepared for intravenous contrast agent administration.  The scanning protocol will 
include routine localizers, T1 measurement sequences, dynamic DCE-MRI acquisition, 
and acquisitions required for OMERACT RAMRIS, RAMRIQ and CARLOS scoring.  
Additional exploratory MRI endpoints, as detailed in the Acquisition Manual, may also 
be acquired for exploratory purposes.
Details of scanning site training procedures, acceptable Gd contrast agents, and scanning 
protocols will be provided in a dedicated Imaging Manual.
All MRI scans will be reported at the site by a radiologist (non-anonymized) for clinical 
abnormalities.
7.6.2.
Synovial Biopsy
7.6.2.1.
Selection of Joint for Synovial Biopsy
Synovial biopsies are optional for subjects enrolled in this study. There is no minimum 
number of subjects with joint biopsies required, but biopsies should be performed in as 
many subjects as possible.  Synovial biopsy of a subject’s swollen and tender wrist, knee 
or ankle joint will be performed at baseline (pre-dose Day 1).  The final choice of joint is 
left to the discretion of the Investigator, although ideally it will be the most inflamed 
joint.  The same joint should be biopsied at Day 43 (Week 6).  If in the event that a repeat 
biopsy of the same joint as baseline is not possible, the joint may change if essential, after 
discussion with the GSK Medical Monitor.  Any change must be documented in the CRF.
If a subject chooses to withdraw from the study after dosing and prior to Day 43, the 
Investigator must make every effort to perform a synovial biopsy if the subject has 
received at least 14 days of treatment with GSK2982772 or placebo.  
7.6.2.2.
Synovial Biopsy Procedure
Ultrasound imaging or arthroscopy will be used to guide the collection of approximately 
(as feasible for any given subject) of 6 synovial biopsies for immunohistochemistry 
(IHC), 6 synovial biopsies for pharmacokinetics, 6 synovial biopsies for target 
engagement, and 6 synovial biopsies for RNA extraction up to a combined maximum of 
30 biopsies from the chosen joint under local anaesthesia (see SRM).


2015N251670_03
CONFIDENTIAL
203168
61
Biopsy tissue taken from synovial tissue will be divided accordingly for IHC, PK, target 
and pathway engagement, and gene expression.  Histological assessment by IHC will be 
evaluated for general appearance and total inflammatory infiltrate.  Specific cell numbers 
will also be analysed (which may include but are not limited to CD3+T-cells, CD55+ 
fibroblast-like synoviocytes, CD68+macrophages).  mRNA may be isolated from 
synovial biopsys tissue, as feasibility dictates, to determine the effect of placebo and 
GSK2982772 on markers of inflammation and tissue healing (e.g., may include and not 
be limited to VEGF, IL-1β, IL-6, TNFα, and MMP-1 and other chemokines and 
cytokines).  Biopsy tissue collected for RNA transcriptional analysis may be utilised to 
determine the effect of GSK2982772 on cytokine and receptor expression, in addition to 
other markers of inflammation and tissue healing, as feasibility allows.  For example, this 
may include but is not limited to, measurement of acute phase proteins, other chemokines 
and cytokines.  Examples of technologies that may be used for these analysis include, but 
are not limited to, quantitative PCR, microarray, RNA sequencing or mass cytometry 
(CyTOF). 
7.6.3.
Novel Pharmacodynamic Biomarkers
7.6.3.1.
RIP1 Target Engagement in Blood
Blood samples for RIP1 target engagement will be collected at the time points indicated 
in Section 7.1 to measure levels of free and drug-bound RIP1 protein.
7.6.3.2.
RIP1 Target Engagement in Synovial Tissue
Synovial tissue biopsy samples will be collected at the time points indicted in Section 7.1
to measure levels of free and drug-bound RIP1 protein if sample quantity and data allow.
7.6.3.3.
Pathway Biomarkers in Synovial Tissue
Synovial tissue biopsy samples will be collected at the time points indicated in Section 
7.1 to measure total or phosphorylated RIP1, RIP3, MLKL and cleaved or total caspase 3 
and caspase 8 if sample quantity and data allow.
7.6.4.
Exploratory Novel Biomarkers
With the subject’s consent, tissue and blood sample(s) will be collected during this study 
and may be used for the purposes of measuring novel biomarkers to identify factors that 
may influence disease/condition for study treatment, and/or medically related conditions, 
as well as the biological and clinical responses to GSK2982772.  If relevant, this 
approach will be extended to include the identification of biomarkers associated with 
adverse events.
Samples will be collected at the time points indicated in Section 7.1. The timing of the 
collections may be adjusted on the basis of emerging pharmacokinetic or 
pharmacodynamic (PD) data from this study or other new information in order to ensure 
optimal evaluation of the PD endpoints.


2015N251670_03
CONFIDENTIAL
203168
62
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with RA or medically related conditions and/or the action of 
GSK2982772 may be identified by application of:

Gene expression analysis may be conducted on the blood and/or synovial biopsies 
using microarray, RNA sequencing and/or alternative equivalent technologies, 
which facilitates the simultaneous measurement (and confirmation) of the relative 
abundances of thousands of RNA species resulting in a transcriptome profile for 
each synovial tissue sample.

Soluble inflammatory mediators in the blood may be assayed for cytokine and 
inflammatory mediators including, but not limited to, pro-inflammatory and anti-
inflammatory cytokines, chemokines, and acute phase proteins. 
These analyses may be reported under separate protocol following the completion of the 
study.  All samples will be retained for a maximum of 15 years after the last subject 
completes the trial.
7.7.
Genetics
In consenting subjects, a blood sample for pharmacogenetics (PGx) research will be 
drawn on Day 1 (or any time point post randomisation and prior to study completion) to
better characterize genetic variability that may affect efficacy or safety endpoints. 
Information regarding pharmaogenetic (PGx) research is included in Appendix 4.
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. 

CRFs (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
and date of birth will not be collected or transmitted to GSK according to GSK 
policy.


2015N251670_03
CONFIDENTIAL
203168
63
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The primary objective of the study is to investigate the safety and tolerability of 
GSK2982772 following 12 weeks of treatment. No formal statistical hypotheses will be 
conducted to assess this objective. 
If appropriate, comparisons between the GSK2982772 and the placebo arm will be made 
to investigate the secondary pharmacodynamic, mechanistic and efficacy objectives. 
Trends over time will be investigated for both treatment arms along with associations 
between each of the pharmacodynamic, mechanistic and efficacy parameters. 
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The study is not powered to detect pre-defined differences. A sufficient number of 
subjects will be screened so that approximately 24 subjects with moderate to severe RA 
are randomised into the study on a TID regimen.  Prior to protocol amendment 3 being 
approved in each country, no more than 18 subjects will be randomised into the study on 
a BID regimen.  Table 4 summarises the total planned sample sizes for BID and TID 
regimens.  Should the drop-out rate be higher than anticipated, additional or replacement 
subjects may be randomised (up to an overall total maximum of 48) into the study at the 
discretion of the Sponsor.
Table 4
Summary of Total Sample Size by Dosing Regimen
Number Randomised to 
GSK2982772 60 mg BID or 
Placebo BID
Number Randomised to 
GSK2982772 60 mg TID or 
Placebo TID
Revised 
Max 
Total 
Sample 
Size
Total + 
Additional/ 
Replacement 
Subjects
7 - 12
24
36
42
12 - 18
24
42
48
The primary objective of the study is safety and tolerability, where there will be 
20 subjects randomised to GSK2982772 60 mg TID and up to 12 subjects randomised to
GSK29827772 60 mg BID. Using a Bayesian approach to determine the confidence 
interval (CI) around an observed safety event, we would assume a flat Beta (1, 1) prior, 
and if we were to observe one safety event in 16 then the posterior distribution would be
Beta (2, 16), as outlined below in Figure 4.


2015N251670_03
CONFIDENTIAL
203168
64
Figure 4
One Event in 16 Subjects: Beta (2,16) Distribution
Thus, we can be 95% certain that the true probability of the safety event lies between 2%
and 25%. 
For supportive information, the properties of the key secondary endpoint DAS28 have 
been considered.
Based on the estimate of variability (SD=1 from historical data) it is estimated that the 
lower and upper bounds of the 95% CI for the change from baseline in DAS28-CRP 
score will be within approximately 0.693 and 0.490 of the point estimate of GSK2982772
60 mg TID (n=16) and placebo (n=8).
9.2.2.
Sample Size Sensitivity
A sample size sensitivity analysis has been conducted on the primary endpoint to 
investigate the different safety event rates.  If the number of subjects who complete the 
12 weeks is higher or lower than 16 in the GSK2982772 group, then the true incidence
rates of safety events that could not be ruled out (as outlined in Section 9.2.1) would 
change.  These changes are outlined in Table 5.
Table 5
Sample Size Sensitivity
GSK2982772 subjects 
completing the study
Number of a particular safety 
event observed with 
GSK2982772
Upper limit of exact 95% 
Credible Interval indicating 
that a true incidence rate of 
x% could not be ruled out
20
0
16.1%
20
1
23.8%
20
2
30.4%
18
0
17.6%
18
1
26.0%
18
2
33.1%
16
0
19.5%


2015N251670_03
CONFIDENTIAL
203168
65
GSK2982772 subjects 
completing the study
Number of a particular safety 
event observed with 
GSK2982772
Upper limit of exact 95% 
Credible Interval indicating 
that a true incidence rate of 
x% could not be ruled out
16
1
28.7%
16
2
36.4%
14
0
21.8%
14
1
31.9%
14
2
40.5%
12
0
24.7%
12
1
36.0%
12
2
45.4%
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation or adjustment will be conducted.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
All Subjects Population: The ‘All Subjects Population’ is defined as subjects who were 
screened for the study.  This population is used for the summary of selected 
accountability data.
Safety Population: The ‘Safety Population’ is defined as subjects who receive at least 
one dose of study medication. This population is used for the summary of all data 
including demography, safety, efficacy and exploratory data but excluding PK data.
Pharmacokinetic Population: The ‘PK Population' is defined as subjects in the ‘Safety’ 
population who received an active dose and for whom a GSK2982772 pharmacokinetic 
sample was obtained and analysed.   This population is used for the summary of PK data 
only.  Any PK-PD analysis will be conducted on the Safety population such that subjects 
receiving placebo can be included.
If 12 or more subjects are randomised to a BID regimen (i.e., ≥4 placebo and ≥8 
GSK2982772 60 mg BID) then treatment received will take into account dosing 
frequency for GSK2982772, otherwise treatment will be irrespective of dosing frequency.
9.3.2.
Interim Analysis
A formal interim analysis will be conducted during the study.  Additionally two review 
teams will monitor data on an ongoing basis for routine pharmacovigilance and decision 
making regarding the subsequent clinical development of GSK2982772 for RA.
In line with routine pharmacovigilance, an internal GSK Safety Review Team (SRT) 
which will include members of the GSK2982772 project team, will review blinded safety 


2015N251670_03
CONFIDENTIAL
203168
66
data, including clinical laboratory parameters and adverse events, at appropriate intervals 
during the period of study conduct.
Once an appropriate number of subjects have completed Day 43 (Week 6) the DAS28-
CRP data will be reviewed in an unblinded manner and on an ongoing basis by the Data 
Review Committee, consisting of the GSK Project Physician Lead (PPL), the study
statistician, the study pharmacokineticist, the PRR DPU Head, EDL and SRT Leader or 
designees on an ongoing basis.  A physician external to the GSK2982772 project team 
may also be involved in the data review. Additional inflammatory biomarkers, clinical 
and mechanistic endpoints (e.g. target engagement) may be reviewed if available. No 
other member of the GSK core study team will be unblinded to this data. The primary 
purpose of these informal reviews will be to monitor DAS28-CRP for futility.  On review 
of DAS28-CRP data, the review group may recommend an interim analysis of key 
clinical and mechanistic data is first conducted prior to any decision to terminate the 
study for futility.  A data review charter will identify the specific GSK individuals 
involved, outline in detail the activities of this review and how the integrity of the study 
will be maintained.
A formal interim analysis will be conducted during the study. The timing of this analysis 
will either be on the recommendation of the data review group to assess futility based on 
6 weeks of treatment, or when an appropriate number have completed 12 weeks of 
treatment, whichever is earliest.  The purpose of the Interim Analysis would be to assess 
whether to stop the study for futility.  This interim analysis may also facilitate decision 
making regarding the subsequent clinical development of GSK2982772 for RA. 
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
All safety evaluations will be based on the Safety population.  Clinical interpretation will 
be based on the review and displays of adverse events, clinical laboratory values, vital 
sign measurements and 12-lead ECG monitoring.
9.4.2.
Secondary Analyses
The relationship between each of the mechanistic endpoints and also with the clinical 
endpoints will be graphically presented and analysed using an appropriate statistical 
model identifying any trends. The model will determine whether the mechanistic effect 
significantly explains or predicts the effect on the other mechanistic or clinical endpoints 
(e.g., DAS28-CRP score). This may be conducted through comparing statistical models 
incorporating different explanatory terms (i.e. mechanistic endpoints) with the ‘null’ 
model (no mechanistic endpoints); or if deemed appropriate, multivariate statistical 
methods may also be applied to determine the relationship between the key endpoints. 
The consistency in the changes over time between the endpoints will also be assessed.
Each endpoint will be considered individually and at the treatment level, where 
comparisons between treatment groups would be made on any changes observed, if 
deemed appropriate. This could include change from baseline in DAS28-CRP, which will 
be statistically analysed using a MMRM analysis comparing GSK2982772 with placebo 


2015N251670_03
CONFIDENTIAL
203168
67
at each time point. Additionally this could include, the proportion of subjects achieving 
ACR20/50/70 and DAS28-CRP response, which will be statistically analysed using a 
Generalised Estimating Equation (GEE) model comparing GSK2982772 with placebo at 
each timepoint. Similar analyses will be conducted for other secondary endpoints if 
deemed appropriate.
9.4.3.
Other Analyses
In addition, based on the data that we observe in the study, probabilities of success will 
be determined, where the definition of success will be dependent on the endpoint. For 
example, what is the probability that we would observe a certain change in DAS28 (i.e., 
comparator rate), based on the data that we have observed in the study.
GSK2982772 plasma concentrations will be summarised descriptively by day and 
nominal sampling time.  
Further details regarding the statistical analysis will be outlined in the Reporting and 
Analysis Plan (RAP).
9.4.3.1.
Exploratory Analyses
All exploratory endpoints will be descriptively summarised, graphically presented and 
listed appropriately.  Further details can be found 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
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.

Obtaining signed informed consent.

Investigator reporting requirements (e.g., reporting of AEs/SAEs/protocol 
deviations to IRB/IEC).


2015N251670_03
CONFIDENTIAL
203168
68

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study.

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK 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 CRF will
serve as the source document.
GSK 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 
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.


2015N251670_03
CONFIDENTIAL
203168
69
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the Investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures (SOP).

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.


2015N251670_03
CONFIDENTIAL
203168
70

GSK will inform the Investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.  

The Investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the Investigator is no longer associated with 
the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the clinical study report.  The Investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the Investigator with the full summary of the study results.  The 
Investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the Investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.


2015N251670_03
CONFIDENTIAL
203168
71
11.
REFERENCES
Agarwal SK.  Biologic agents in rheumatoid arthritis:  An update for managed care 
professionals.  Journal of Managed Care Pharmacy, 2011;17(9-b):S14-8.
Berger SB, Kasparcova V, Hoffman S, Swift B, Dare L, Schaeffer M et al.  Cutting edge:  
RIP1 kinase activity is dispensable for normal development but is a key regulator of 
inflammation in SHARPIN-deficient mice.  The Journal of Immunology,
2014;192:5476-80.
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.
Choy EHS, Panayi GS.  Cytokine pathways and joint inflammation in rheumatoid 
arthritis.  The New England Journal of Medicine, 2001;344:907-916.
Dondelinger Y, Aguileta MA, Goossens V, Dubuisson C, Grootjans S, Dejardin E et al.  
RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions 
of cIAP1/2 depletion or TAK1 kinase inhibition.  Cell Death and Differentiation, 
2013;20:1381-92.
Fries JF, Spitz P, Kraines RG, Holman HR.  Measurement of patient outcomes in 
arthritis.  Arthritis Rheum 1980;23:137-45.
GlaxoSmithKline Document Number 2014N204126_02.  Investigator Brochure for 
GSK2982772.  Report Date 27-JAN-2017.
Gorin MB.  Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mo. Aspects Med. 2012; 33:467-486.
Hatcher RA, Trussell J,  Nelson AL, Cates W Jr, Stewart F, Kowal D, et al. 
Contraceptive Technology. 20th edition.  Atlanta, Georgia: Ardent Media, Inc., 2011: 50.  
Table 3 2.
Humphries F, Yang S, Wang B, Moynagh P N.  RIP kinases: key decision makers in cell 
death and innate immunity.  Cell Death & Differ, 2015;22:225-236.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D et al.  Transgenic
mice expressing human tumour necrosis factor:  A predictive genetic model of arthritis.  
The EMBO Journal, 1991;10:4025-31.
Netter P, Bannwarth B, Royer-Morral M-J. Recent findings on the pharmacokinetics of 
non steroidal anti-inflammatory drugs in synovial fluid. Clin Pharmaokinet, 
1989;17(3):145-162.


2015N251670_03
CONFIDENTIAL
203168
72
Ofengeim D, Yuan J.  Regulation of RIP1 kinase signaling at the crossroads of 
inflammation and cell death.  Nature Reviews Molecular Cell Biology, 2013;14:727-36.
Raghav SK, Gupta B, Agrawal C, Chaturvedi VP, and Das HR. Expression of TNF-alpha 
and related signaling molecules in the peripheral blood mononuclear cells of rheumatoid 
arthritis patients.  Mediators Inflamm. 2006(3):12682.
U.S. Department of Health and Human Services, Food and Drug Administration (FDA). 
(2012) Guidance for Industry: Drug Interaction Studies – Study Design, Data Analysis, 
Implications for Dosing, and Labeling Recommendations. Center for Drug Evaluation 
and Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM292362.pdf
Vasanthi P, Nalini G, Rajasekhar G. Role of tumor necrosis factor-alpha in rheumatoid 
arthritis: a review. Journal of Rheumatology, 2007; 10:270–274.
Wang L, Du F, Wang X. TNF-alpha induces two distinct caspase-8 activation pathways. 
Cell, 2008; 133(4):693-703.


2015N251670_03
CONFIDENTIAL
203168
73
12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
ACR
American College of Rheumatology
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
AMD
Age-related macular degeneration
Anti-CCP
Anti-Cyclic Citrullinated Peptide
Anti-dsDNA
Anti-double stranded deoxyribose nucleic acid
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
BID
Twice a day
CARLOS
Cartilage Loss Scoring System
CI
Confidence Interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration 
equation
Cmax
Maximum observed concentration
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CRF 
Case Report Form
CRP
C-Reactive Protein
C-SSRS
Columbia Suicide Severity Rating Scale
CV
Cardiovascular
CYP
Cytochrome P
DAS
Disease Activity Score
DAS28
Disease activity score for 28 different joints
DAS28(CRP)
Disease activity score for 28 different joints with CRP value
DCE
Dynamic contrast enhanced
DNA
Deoxyribose Nucleic Acid
DMARD
Disease-Modifying Antirheumatic Drugs
DPU
Discovery Performance Unit
DRC
Data Review Committee
ECG
Electrocardiogram
EDL
Early Development Lead
EMA
European Medicines Agency
ETCO2
End-tidal Carbon Dioxide
EULAR
European League Against Rheumatism
FACIT-Fatigue
Functional Assessment of Chronic Illness Therapy-Fatigue
FDA
Food and Drug Administration
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
FTiH
First Time in Human
GCP
Good Clinical Practice


2015N251670_03
CONFIDENTIAL
203168
74
Gd
Gadolinium
GEE
Generalised Estimating Equations
GFR
Glomerular Filtrate Rate
GSK
GlaxoSmithKline
HAQ-DI
Disability Index of the Healthy Assessment Questionnaire
HBcAb
Hepatitis B Core Antibody
HBsAg
Hepatitis B Surface Antigen
hCG
Human Chorionic Gonadotropin
HIV
Human Immunodeficiency Virus
HRT
Hormone Replacement Therapy
IB
Investigator Brochure
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IL
Interleukin
IP
Investigational Product
IRB
Institutional Review Board
IRE
Initial rate of enhancement
IRTS
Interactive Response Technology System
Kg
Kilogram
L
Litre
LDL
Low Density Lipoprotein
MCH
Mean corpuscular haemoglobin
MCHC
Mean corpuscular haemoglobin concentration
MCV
Mean Corpuscular Volume
MDMA
3,4-methylenedioxy-methamphetamine
ME
Maximal signal intensity enhancement
MedDRA
Medical Dictionary for Regulatory Activity
mg
Milligram
mL
Millilitre
MLKL
Mixed lineage kinase domain-like protein
mm
Millimeter
mmol
Millimole
MMP
Matrix metallopproteinase
MMRM
Mixed-effect Model Repeat Measurements
MRI
Magnetic Resonance Imaging
msec
millisecond
MRP
Myeloid-related Protein
MSDS
Material Safety Data Sheet
MTX
Methotrexate
NF-B
Nuclear factor kappa-light-chain-enhancer of activated B 
cells
NHS
National Health Service
NOAEL
No Adverse Effect Level
NONMEM
Non Linear Mixed Effect Model
NRS
Numeric Rating Scale


2015N251670_03
CONFIDENTIAL
203168
75
NSAID
Non-steroidal anti-inflammatory drug
NSF
Nephrogenic Systemic Fibrosis
OMERACT
Outcome Measures in Rheumatology
PBMC
Peripheral blood mononuclear cell
PCR
Polymerase Chain Reaction
PD
Pharmacodynamic
PGA
Physician’s Global Assessment of Disease
Pgp
P-glycoprotein
PGx
Pharmacogenetics
PK
Pharmacokinetic
PPD
Tuberculin Purified Protein Derivative
PPL
Project Physician Lead
PRO
Patient Reported Outcome
PRR
Pattern Recognition Receptor
PSRAE
Possible Suicidality Related Adverse Event
PtGA
Patient Global Assessment of Disease
PTS IVIVT
Platform Technology and Science In Vitro/In Vitro 
Translation
QTc
Electrocardiogram QT interval corrected for heart rate
QTcB
Electrocardiogram QT interval corrected for heart rate using 
Bazett’s formula
QTcF
Electrocardiogram QT interval corrected for heart rate using 
Fridericia’s formula
RA
Rheumatoid Arthritis
R&D
Research and Development
RAP
Reporting and Analysis Plan
RAMRIQ
Rheumatoid arthritis MRI quantitative
RAMRIS
Rheumatoid arthritis MRI scoring system
RBC
Red Blood Cell
RF
Rheumatoid factor
RIP1
Receptor-interacting protein-1
RIP3
Receptor-interacting protein-3
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SIB
Suicidal Ideation Behaviour
SLE
Systemic lupus erythematosus
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SOP
Standard Operating Procedure
SpO2
Peripheral Capillary Oxygen Saturation
SRM
Study Reference Manual
SRT
Safety Review Team
TB
Tuberculosis
TEAR
Target Engagement Assay RIP1
TID
Three times a day
TIMP
Tissue inhibitor of metalloproteinases


2015N251670_03
CONFIDENTIAL
203168
76
TLR
Toll-like receptor
TNF
Tumor necrosis factor
TTS
Technical Terms of Supply
UK
United Kingdom
ULN
Upper Limit of Normal
VAS
Visual Analogue Scale
VEGF
Vascular endothelial growth factor
WOCP
Women of Child Bearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
QuantiFERON
Sugita
Vectra DA


2015N251670_03
CONFIDENTIAL
203168
77
12.2.
Appendix 2: Liver Safety Required Actions and 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).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
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, permanently discontinue study 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 2 days after 
last dose5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 


2015N251670_03
CONFIDENTIAL
203168
78
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
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]). NOTE: not 
required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes:Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the laboratory manual.  


2015N251670_03
CONFIDENTIAL
203168
79
12.3.
Appendix 3:  Prednisolone Equivalent Dose Table
Drug Name
Dose Equivalent to 1 mg Oral Prednisone
Cortisone acetate
Hydrocortisone
Prednisolone
Methylprednisolone
Triamcinolone
Dexamethasone
5 mg
4 mg
1 mg
0.8 mg
0.8 mg
0.15 mg


2015N251670_03
CONFIDENTIAL
203168
80
12.4.
Appendix 4- Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including GSK2982772 or any concomitant medicines;

Rheumatoid arthritis susceptibility, severity, and progression and related 
conditions
GSK2982772 is a novel first-in-class asset being introduced to patients with moderate to 
severe RA for the first time. Currently its mechanism of action is not fully characterised 
nor understood. 
Specific genes may be studied that encode the drug targets, or drug mechanism of action 
pathways, drug metabolizing enzymes, drug transporters or which may underpin adverse 
events, disease risk or drug response. These candidate genes may include a common set 
of ADME (Absorption, Distribution, Metabolism and Excretion) genes that are studied to 
determine the relationship between gene variants or treatment response and/or tolerance. 
In addition, continuing research may identify other enzymes, transporters, proteins ore 
receptors that may be involved in response to GSK2982772. The genes that may code for 
these proteins may also be studied. Genome-wide scans involving a large number of 
polymorphic markers (e.g. single nucleotide polymorphisms) at defined locations in the 
genome, often correlated with a candidate gene, may be studied to determine the 
relationship between genetic variants and treatment response or tolerance. This approach 
is often employed when a definitive candidate gene does not exist and/or the potential 
genetic effects are not well understood.
Genetic data may be generated while the study is underway or following completion of
the study.  Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.


2015N251670_03
CONFIDENTIAL
203168
81
If applicable and genetic research is conducted, appropriate descriptive and/or statistical 
analysis methods will be used to evaluate pharmacogenetic data in the context of the 
other clinical data. A detailed description of any planned analyses will be documented in
a Reporting and Analysis Plan (RAP) prior to initiation of the analysis. Planned analyses 
and results of genetic investigations will be reported either as part of the clinical RAP and 
study report, or in a separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at the baseline visit, after the subject has been 
randomized and provided informed consent for genetic research. Instructions for 
collection and shipping of the genetic sample are described in the laboratory 
manual. The DNA from the blood sample may undergo quality control analyses to 
confirm the integrity of the sample. If there are concerns regarding the quality of 
the sample, then the sample may be destroyed. The blood sample is taken on a 
single occasion unless a duplicate sample is required due to an inability to utilize 
the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the Investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
The need to conduct PGx analysis may be identified after a study (or set of studies) of 
GSK2982772 has been completed and the study data reviewed. In some cases, the 
samples may not be studied.
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.


2015N251670_03
CONFIDENTIAL
203168
82
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained.

Discontinue participation in the genetic research and destroy the genetic DNA 
sample.
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the Investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analysed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analysed, it will not be analysed or used for future research.  

Genetic data that has been analysed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the Investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 


2015N251670_03
CONFIDENTIAL
203168
83
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.


2015N251670_03
CONFIDENTIAL
203168
84
12.5.
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.5.1.
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.

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.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.


2015N251670_03
CONFIDENTIAL
203168
85
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.

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.
12.5.2.
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:
a. Results in death
b. 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.


2015N251670_03
CONFIDENTIAL
203168
86
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 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.

Refer to Appendix 2 for the required liver chemistry follow-up instructions


2015N251670_03
CONFIDENTIAL
203168
87
12.5.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.5.4.
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.

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 PRO questionnaires and the collection of AE data are 
independent components of the study.

Responses to each question in the PRO 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.


2015N251670_03
CONFIDENTIAL
203168
88
12.5.5.
Evaluating AEs and SAEs
Assessment of Intensity
The Investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The Investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The Investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The Investigator will also consult the 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.


2015N251670_03
CONFIDENTIAL
203168
89
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.
12.5.6.
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 Medical Monitor.

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 or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


2015N251670_03
CONFIDENTIAL
203168
90
12.6.
Appendix 6: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.6.1.
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 or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1. Contraceptive subdermal implant
2. Intrauterine device or intrauterine system
3. Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]
4. Injectable progestogen [Hatcher, 2011]
5. Contraceptive vaginal ring [Hatcher, 2011]
6. Percutaneous contraceptive patches [Hatcher, 2011]
7. Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or 
semen analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The Investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception
Contraceptive requirements for male subjects with female partners of reproductive 
potential (when applicable).
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 90 days after the last dose of study medication.
1.
Vasectomy with documentation of azoospermia. The documentation on male sterility 
can come from the site personnel’s: review of subject’s medical records, medical 
examination and/or semen analysis, or medical history interview.
2.
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:

Contraceptive subdermal implant

Intrauterine device or intrauterine system


2015N251670_03
CONFIDENTIAL
203168
91

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The Investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.6.2.
Collection of Pregnancy Information

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 or be withdrawn from the study

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study and up to 
90 days after the last dose of study medication.  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.


2015N251670_03
CONFIDENTIAL
203168
92

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.


2015N251670_03
CONFIDENTIAL
203168
93
12.7.
Appendix 7:  Protocol Amendment Changes
12.7.1.
Amendment 3 (20-APR-2017) from Protocol Amendment 2 (14-
JUL-2016)
Where the Amendment Applies
This amendment applies to all subjects who will participate in this study in all countries.
Summary of Protocol Amendment Changes with Rationale
Protocol Amendment 03 incorporates change in dosing regimen from 60 mg BID to 60 
mg TID, restrictions on JAK inhibitors, defined non-reproductive potential criteria in 
Exclusion 11, change to clinical laboratory criteria in Exclusion 23, of evaluation of joint 
space narrowing with MRI, flexibility in scheduling with MRI and synovial biopsy.
GlaxoSmithKline Document Number of Investigator Brochure GSK2982772 has been 
updated to 2014N204126_02 throughout the document. Other minor protocol 
clarifications and administrative changes are also provided in this amendment.
List of Specific Changes (bold indicates text added and strikethrough indicates text 
removed):
Authors
Author (s):
 
 
 
PPD


2015N251670_03
CONFIDENTIAL
203168
94
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number and 
email address
After-hours 
Phone/Cell/
Pager Number
Fax Number
Site Address
Primary 
Medical 
Monitor 
Tel       
Email   
Mobile:  
Email: 
Mobile  
 
 
Mobile:  
N/A
GSK Stockley 
Park West, 1-3 
Ironbridge 
Road, 
Uxbridge, 
Middlesex, 
UB11 1BT, UK
UP4440
1250 S 
Collegeville, PA  
19426 USA
Secondary 
Medical 
Monitor
Mobile:
Email 
Tel: 
Mobile: 
Email:
Mobile
Mobile: 
NA
 
1250 S.
Collegeville 
Rd.
Collegeville PA 
19426, USA
Cytokine
Chemokine
DPU, GSK,
Gunnels Wood
Road,
Stevenage,
SG1 2NY, UK
SAE 
contact  
information 
Medical 
Monitor as 
above
Synopsis and Section 2.1 Study Rationale
The primary objective of this study has not changed with amendment 03; however 
the dosing regimen does change to GSK2982772 (60 mg three times daily for 84 
days). 
The primary objective will be to investigate the safety and tolerability of repeat oral doses 
of GSK2982772 (60 mg twice three times daily for 84 days). In addition to the 
pharmacokinetics (PK), a number of experimental and clinical endpoints will be 
employed to obtain information on the pharmacodynamics (PD), and preliminary efficacy 
in subjects with active RA. Although no formal hypothesis will be tested, these endpoints 
will enable a broader understanding of the mechanism of action and potential for clinical 
efficacy of GSK2982772 in RA, by making full use of the information obtained from 
each subject enrolled.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PP
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


2015N251670_03
CONFIDENTIAL
203168
95
Synopsis and Section 3 Objectives and Endpoints
Objectives
Endpoints
Primary

To investigate the safety and tolerability 
of 60 mg twice three times daily doses of 
GSK2982772 in subjects with moderate 
to severe Rheumatoid Arthritis.

Adverse events.

Clinical laboratory values (clinical 
chemistry, haematology and urinalysis).

Vital sign measurements (blood pressure, 
heart rate, respiratory rate, and body 
temperature).

12-Lead ECG monitoring.
Secondary

To investigate the plasma concentrations 
of GSK2982772 following 60 mg twice
three times daily doses of GSK2982772 
in subjects with moderate to severe 
Rheumatoid Arthritis.

Pre-dose concentrations of GSK2982772 
on Days 8 and 43 (Week 6).  

Post-dose concentrations of 
GSK2982772 on Days 1, 8, and 43 
(Week 6) at 1, 2, 4 and 6 hours.

Trough concentrations on Day 85 (Week
12).

To investigate the effect of 60 mg twice
three times daily doses of GSK2982772 
on inflammatory biomarkers in blood 
subjects with moderate to severe 
Rheumatoid Arthritis.

Change from baseline in blood 
inflammatory markers (e.g., may include 
but not limited to CRP, IL6, MMP-1, 
MMP-3, MMP-13, TIMP-1, MCP-1, MIF, 
MRP8/14 and other markers 
encompassed by Vectra DA).

To investigate the effect of 60 mg twice
three times daily doses of GSK2982772 
on bone and synovial parameters as 
measured by MRI and DCE-MRI in 
subjects with moderate to severe 
Rheumatoid Arthritis.

Change from baseline in Magnetic 
Resonance Imaging (MRI) parameters in 
the most affected hand/wrist.  MRI 
parameters may include assessment of 
bone erosions, synovitis, and bone 
oedema and joint space narrowing as 
assessed in the OMERACT-RAMRIS 
(Outcome Measures in Rheumatology, 
Rheumatoid Arthritis Magnetic 
Resonance Image Scoring System) 
scoring system, the RAMRIQ 
(Rheumatoid arthritis MRI quantitative) 
scoring system, the modified CARLOS 
(Cartilage Loss Scoring System) and 
additional exploratory endpoints as data 
permit.
Change from baseline in synovial
inflammation as measured by dynamic 
contrast enhanced (DCE)-MRI in the most 
affected hand/wrist:


2015N251670_03
CONFIDENTIAL
203168
96
Objectives
Endpoints

Exchange rate (Ktrans)

Interstitial volume (Ve)

Plasma volume (Vp)

Initial rate of enhancement (IRE)

Maximal signal intensity enhancement 
(ME)

Joint volume

Enhancing volume

To investigate the effect of 60 mg twice
three times daily doses of GSK2982772 
on clinical disease activity in subjects 
with moderate to severe Rheumatoid 
Arthritis.

Change from baseline in Disease Activity 
Score (DAS) 28-CRP scores.

Proportion of subjects achieving 
categorical DAS28-CRP response 
(moderate/good EULAR response) at 
each assessment time points.

Proportion of subjects achieving 
categorical ACR20/50/70 response.

To investigate the effect of 60 mg twice
three times daily dosing of 
GSK2982772 on methotrexate (MTX) 
concentrations. 

Plasma concentrations of MTX pre-dose 
GSK2982772 on Days 1, 8, and 43 
(Week 6).
Exploratory

To investigate the effect of 60 mg twice
three times daily doses of GSK2982772 
on inflammatory biomarkers in synovial 
tissue from subjects with moderate to 
severe Rheumatoid Arthritis.

Change from baseline in CD68+ 
macrophages, CD55+ fibroblast-like 
synoviocytes and a number of infiltrating 
CD3, CD22, CD138 inflammatory cells, 
and synovial inflammatory biomarkers 
including, but not limited to VEGF, IL-1β, 
IL-6, TNFα, and MMP-1.

To investigate pathway and target 
engagement following 60 mg twice three 
times daily doses of GSK2982772 in 
blood and synovial biopsy tissue in
subjects with moderate to severe 
Rheumatoid Arthritis.

Pharmacology biomarker endpoints may 
include, but are not limited to the 
following, pre-dose at Days 1, 43 (Week
6) and trough on Day 85 (Week 12), as 
applicable and if evaluable samples and 
data permit:
Target Engagement Assay RIP1 
(TEAR1) in blood and synovial 
tissue.
Total or phosphorylated RIP1, MLKL, 
and RIP3, cleaved and total 
caspase 3 and caspase 8
signatures in synovial tissue.

To investigate the concentration of 

Pre-dose GSK2982772 synovial tissue 


2015N251670_03
CONFIDENTIAL
203168
97
Objectives
Endpoints
GSK2982772 and possible drug-related 
material, as well as specific distribution 
within tissue if feasible, in the synovial 
tissue after 60 mg twice three times 
daily doses of GSK2982772.
biopsies and possible drug-related 
material concentrations, as well as 
specific distribution within tissue if 
feasible, on Day 43 (Week 6), as
evaluable samples and data permit.

To investigate the effect of 60 mg twice
three times daily doses of GSK2982772 
on the quality of life of subjects with 
moderate to severe Rheumatoid Arthritis.

Change from baseline in Health 
Assessment Questionnaire Disability 
Index (HAQ-DI).

Change from baseline in RA symptom 
questionnaire score.

Change from baseline in Functional 
Assessment of Chronic Illness Therapy 
(FACIT)-Fatigue.

To investigate the effect of 60 mg twice
three times daily doses of GSK2982772 
on gene expression in the blood subjects 
with active moderate to severe 
Rheumatoid Arthritis.

Transcriptomic analysis of mRNA 
isolated from blood pre-dose on Days 1 
and 43 (Week 6) and trough on Day 85 
(Week 12).

To investigate the effect of 60 mg twice
three times daily doses of GSK2982772 
on gene expression in the synovium of 
subjects with moderate to severe 
Rheumatoid Arthritis.

Transcriptomic analysis of mRNA 
isolated from synovial tissue pre-dose on 
Days 1 and 43 (Week 6).
Synopsis and Section 4.1 Overall Design
Schematic added. 
Amendment 03:
Synopsis Treatment Arms and Duration
Subjects who have completed screening assessments and are eligible will be randomised 
in a 2:1 ratio (active to placebo) to one of the following treatments:


2015N251670_03
CONFIDENTIAL
203168
98
GSK2982772 60 mg twice three times daily (BID TID) 
Placebo three times daily (BID TID) 
Prior to amendment 03 being effective in each country, subjects have been 
randomised in a 2:1 ratio (active to placebo) to one of the following treatments:
GSK2982772 60 mg two times daily (BID) 
Placebo two times daily (BID)
Synopsis and Section 4.3 Type and Number of Subjects
A sufficient number of subjects will be screened so that approximately 30 24 subjects 
with moderate to severe RA are randomised into the study on a TID regimen. Prior to 
protocol amendment 03 being approved in each country, no more than 18 subjects 
will be randomised into the study on a BID regimen.  Should the drop-out rate be 
higher than anticipated, additional or replacement subjects may be randomised (up to a
an overall total maximum of 36 48) into the study at the discretion of the Sponsor.
Section 4.2.2 Treatment Period
Subjects will be randomly assigned to either GSK2982772 60 mg or placebo orally twice
three times daily (approximately 12 8 hours apart) for 84 days (12 weeks).  Subjects 
that were randomised prior to protocol amendment 03 being approved in each 
country were randomly assigned to either GSK2982772 60 mg or placebo orally two 
times daily (approximately 12 hours apart) for 84 days (12 weeks). 
During the 84 day (12 week) treatment period, subjects will attend the clinical site for 
visits on Days 1, 8, 15, 29, 43, 57, 71 and 85.  At specific visits, subjects must not take 
study treatment prior to their scheduled visit (see Section 7.1).  On Days 22, 36, 50, 64 
and 78, each subject will be contacted by telephone and asked about their general health,
study medication compliance and diary card completion. Subjects will be given a 
diary card at each of the visits on which they will be instructed to record their daily 
study medication and concomitant medication taken and any adverse events.
Section 4.3 Type and Number of Subjects
A sufficient number of subjects will be screened so that approximately 30 24 subjects 
with moderate to severe RA are randomised into the study on a TID regimen. Prior to 
protocol amendment 3 being approved in each country, no more than 18 subjects 
will be randomised into the study on a BID regimen.  Should the overall drop-out rate 
be higher than anticipated, additional or replacement subjects may be randomised (up to a
an overall total maximum of 36 48) into the study at the discretion of the Sponsor.
Section 4.4 Design Justification
The subjects will be randomised in a 2:1 ratio to GSK2982772 60 mg twice daily (BID)
three times daily (TID) and placebo respectively.  The primary objective of this study is 


2015N251670_03
CONFIDENTIAL
203168
99
to assess safety and tolerability, and assessment of this is most valuable in a placebo 
controlled study. The placebo group was also deemed necessary as autoimmune diseases 
naturally fluctuate in severity.  However, the size of the placebo group has been kept to a 
minimum.  All subjects will be allowed to continue standard of care therapy including 
non-biologic DMARDs during the study, provided that the medication and dose is stable 
throughout the study.
Section 4.5 Dose Justification
The initial selection of the 60 mg BID dose to be being tested in this study is based on 
the safety, PK, and PD data from the First Time in Human (FTiH) study, 200975.  
GSK2982772 administered at 60 mg BID for 14 days was well tolerated and no safety 
concerns were identified. A BID dosing regimen was initially selected over a QD dosing 
regimen due to the short half-life of GSK2982772 in humans (~2h).  Based on 
preliminary PK/PD modelling of ex-vivo RIP1 target engagement and GSK2982772 
concentrations from the multiple dose ascending part of Study 200975, a 60 mg BID dose 
wasis predicted to have on average 95% RIP1 target engagement in blood and 
approximately 90% of subjects will have >90% target engagement in blood at Cmin using 
a novel in-house ex-vivo PD/target engagement assay based solely on the TNF 
pathway which is believed to be a key component of the RIP1 pathway.  
However, based on final PK/PD modelling from the full repeat dose part of the 
Study 200975 (up to 120 mg BID), a 60 mg BID dose is now predicted to have on 
average 99% RIP1 target engagement in blood and approximately 90% of subjects 
will have >85% target engagement at Cmin.  This is lower than our target of 
achieving >90% target engagement in at least 90% of subjects at Cmin.  Therefore, a 
60 mg TID cohort is now being proposed. 
The Cmin values at 60 mg TID are predicted to be approximately 3.5 fold higher than 
for 60 mg BID.  Using the final PK/PD, a 60 mg TID dose is predicted to have on 
average 99% RIP1 target engagement in blood and approximately 90% of subjects 
will have > 96% target engagement at Cmin.  No data are currently available about the 
distribution of GSK2892772 into the synovium.  Based on data in non-steroidal anti-
inflammatory drugs (NSAIDs), the synovial fluid concentrations fluctuate to a much 
lesser extent than those in plasma [Netter, 1989].  Peak drug concentrations are generally 
lower in synovial fluid but are similar to plasma at later time points.  Assuming the same 
is true for GSK2982772, a 60 mg BIDTID dose should provide similar RIP1 target 
engagement at the site of action as predicted in blood. 
In addition, because of the short half-life, a modified release formulation is now 
being developed with the aim to provide a once daily dosing regimen.  By increasing 
the frequency of dosing to three times daily (TID) with the current immediate 
release formulation, this will more closely match the PK, safety and efficacy profile 
of a preferred once daily modified release formulation.
The safety of increasing the dose frequency to 60 mg TID is justified based on 
nonclinical safety findings to date with GSK2982772. It is anticipated that a human 
dose of 60 mg TID (180 mg/day) will produce AUC(0-24) and Cmax values of 
approximately 9.9 ug.h/mL and 0.8 ug/mL, respectively, which are approximately 


2015N251670_03
CONFIDENTIAL
203168
100
1/5th and 1/15th of the gender-averaged AUC (48.4 ug.h/mL) and Cmax (12.3 ug/mL) 
achieved in the 13 week monkey study at the no adverse effect level (NOAEL) dose 
of 30 mg/kg/day. Please see GSK2982772 IB [GlaxoSmithKline Document Number 
2014N204126_02].
As of 03 Apr 2017, a total of approximately 93 subjects across 4 clinical studies have 
been randomised to receive GSK2982772. In Study 200975, GSK2982772 
administered up to 120 mg BID for 14 days and was well tolerated and no safety 
concerns were identified. A total of 9 subjects had received 120 mg BID in that 
study.  Please see GSK2982772 IB [GlaxoSmithKline Document Number 
2014N204126_02]. In the ongoing Phase 2a studies in Psoriasis [(PsO); Study 
203167] and Rheumatoid Arthritis [(RA); Study 203168], a total of 26 subjects have 
been randomised to GSK2982772 60 mg BID. GSK2982772 was well tolerated and 
no drug-related SAEs have been reported.  In Study 203167, there was a death of a 
19 year old male subject due to an accidental overdose with 3,4-methylenedioxy-
methamphetamine (MDMA) that was not considered drug related by the Principal 
Investigator (PI).  
Therefore, it is predicted that a dose of GSK2982772 60 mg BID may be clinically 
efficacious in subjects with RA.
It is anticipated that a human dose of 60 mg BID will produce area under the 
concentration-time curve (AUC[0-24]) and maximum observed concentration (Cmax) values 
of approximately 9 g.h/mL and 1 g/mL, respectively, which are approximately 1/6th  
and 1/12th of the gender-averaged AUC (48.4 g.h/mL) and Cmax (12.3 g/mL) achieved 
in the 13 week monkey study at the no adverse effect level (NOAEL) dose of 30
mg/kg/day.
Section 5.1 Inclusion Criteria
Sex
11. Male & Female subjects 
Females: 
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:
a.
Non-reproductive potential as defined as in Appendix 6:
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


2015N251670_03
CONFIDENTIAL
203168
101

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 (see Appendix 6) 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.
Section 5.2 Exclusion Criteria
Diagnostic assessments and other criteria
23. Haemoglobin <119 g/dL; haematocrit <30%, white blood cell count ≤3,000/mm3 
(≤3.0 x 109/L) or  ≥14,000/mm3 (≥14 x 109/L); platelet count ≤100,000/µL (≤100 
x 109/L); absolute neutrophil count ≤31.5 x 109/L; lymphocyte count <1 x 109/L at 
screening.
Section 5.4 Withdrawal/Stopping Criteria
Subjects may be withdrawn from the study for any of the following reasons:

A subject may withdraw from study treatment at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioural or administrative reasons.  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.  The reason for withdrawal should be 
documented in the Case Report Form (CRF).

The Sponsor’s request, for reasons such as significant protocol deviations or 
subject safety concern (and after discussion with the Investigator).

If a subject is withdrawn from study treatment, this subject is also considered to 
be withdrawn from the study.

Study is terminated by the Sponsor.
Section 5.4.5 Haematologic Stopping Rules
Study treatment will be stopped for a subject if any of the following haematological 
stopping criteria is met:

Haemoglobin - <9 g/dL (5.58 mmol/L) or an absolute decrease of ≥32 g/dL 
from baseline (pre-dose Day 1)

Neutrophils <1 × 109/L


2015N251670_03
CONFIDENTIAL
203168
102

Lymphocytes <0.5 × 109/L

Platelets <50 × 109/L
Section 6.1 Investigation Product and Other Study Treatment
Study Treamtent Treatment
Product name:
GSK2982772
Placebo
Dosage form:
Tablet
Tablet
Unit dose strength(s)/Dosage 
level(s):
30 mg
NA
Route of Administration 
For oral use only
For oral use only
Dosing instructions (with
amendment 03):
Take TWO tablets three 
times a day as directed 
by your physician
Take TWO tablets three 
times a day as directed 
by your physician
Dosing instructions (prior to 
amendment 03):
Take TWO tablets in the 
MORNING and TWO 
tablets in the EVENING 
as directed
Take TWO tablets in the 
MORNING and TWO 
tablets in the EVENING 
as directed
Physical description:
White to almost white, 
round, film coated tablet
White to almost white, 
round, film coated tablet
Source of procurement
Study medication is 
supplied by 
GlaxoSmithKline
Placebo is supplied by 
GlaxoSmithKline
Section 6.4 Blinding
Sponsor unblinded refers only to the Data Review Committee (DRC) consisting of the 
GSK study physician Project Physician Lead (PPL), the study statistician, the study
pharmacokineticist, Pattern Recognition Receptor (PRR) Discovery Performance Unit 
(DPU) Head, the Early Development Leader (EDL), the Safety Review Team (SRT) 
leader, or their designees on an ongoing basis.
Section 6.7 Compliance With Study Treatment Administration
Subjects will be given instructions on compliance and treatment with MTX (if 
applicable).  The date, time and total weekly dose will be recorded in the study diary 
cards and the CRF.
Section 6.8 Treatment of Study Treatment Overdose
For this study, any dose of GSK2982772 >120180 mg daily will be considered an 
overdose.  GSK does not recommend specific treatment for an overdose.  The 
Investigator will use clinical judgement to treat any overdose as and when they are made 
aware of this.


2015N251670_03
CONFIDENTIAL
203168
103
Section 6.11.1 Permitted Medications and Non-Drug Therapies
Table 1 
Drug
Requirement
Methotrexate 
Stable dose regimen (up to 25 mg/week) for at least 12 
weeks prior to screening and remain on this dose 
throughout the study (unless dose must be reduced 
because of a safety concern).  MTX should ideally be 
taken on the same day of week and at approximately 
the same time of day throughout the study.
Section 6.11.2 Prohibited Medications and Non-Drug Therapies
Table 2
Therapy
Time period 
A change in dose of methotrexate or other DMARD.
12 weeks prior to screening until after the 
follow up visit (Day 112)
Greater than 10mg/day oral prednisolone (or 
equivalent glucocorticoid) or a change in dose of 
corticosteroid.
4 weeks prior to screening until after the 
follow up visit (Day 112)
Intramuscular glucocorticoids (e.g., 
methylprednisolone ≤120 mg/month)
4 weeks prior to screening until after the 
follow up visit (Day 112)
Intra-articular corticosteroid injections
6 weeks prior to screening and until after 
the follow up visit (Day 112).
Janus Kinase (JAK) Inhibitors
4 weeks prior to screening until after 
the follow up visit (Day 112).
P-glycoprotein (Pgp) inhibitors including but not 
limited to amiodarone, azithromycin, captopril, 
carvedilol, clarithromycin, conivaptan, cyclosporine, 
diltiazem, dronedarone, erythromycin, felodipine, 
itraconazole, ketoconazole, lopinavir, ritonavir, 
quercetin, quinidine, ranolazine, ticagrelor, 
verapamil [FDA, 2012].
4 weeks prior to first dose (Day 1) until 
after the follow up visit (Day 112).
Narrow therapeutic index (NTI) CYP3A4 substrates 
including but not limited to alfentanil, astemizole, 
cisapride, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus, terfenadine [FDA, 2012].
4 weeks prior to the first dose (Day 1)
until after the follow up visit (Day 112).
Biologic therapies for the treatment of rheumatoid 
arthritis not limited to anti-TNF biologics or other 
biologics, rituximab, anakinra, abatacept or 
tocilizumab.
At any time. 


2015N251670_03
CONFIDENTIAL
203168
104
Therapy
Time period 
Exposure to more than one anti-TNF biologic 
therapies for the treatment of RA including but not 
limited to anti-TNF biologics, infliximab, 
adalimumab, etanercept, certolizumab and 
golimumab.
Exception:  Exposure to a single anti-TNF-biologic 
for which the subject discontinued for a reason other 
than primary non-response is permitted.
Cannot have been exposed to more than 
one anti-TNF biologic or be on at any 
time during the study.
In the case of a single anti-TNF biologic 
for which the subject discontinued for a 
reason other than primary non-response, 
the subject must not be on for 8 weeks or 
5 ½ half lives (whichever is longer) prior 
to first dose until after the follow up visit 
(Day 112).  
Live vaccination
Live or attenuated vaccinations are not 
permitted within 30 days of 
randomization or plan to receive a 
vaccination during the study until follow-
up visit.  If indicated, non-live vaccines 
(e.g., inactivated influenza vaccines) may 
be administered whilst receiving 
GSK2982772 based on an assessment 
of the benefit:risk (e.g., risk of decreased 
responsiveness).  Investigators are 
expected to follow local and/or national 
guidelines with respect to vaccinations, 
including against pneumococcus and 
influenza, in subjects with RA.


2015N251670_03
CONFIDENTIAL
203168
105
Section 7.1 Time and Events Table
Procedures
Screening (-30)
Treatment Period17
Early Withdrawal18
Follow Up (3)19
Day 1 
Day 8 (3)
Day 15 (3)
Day 22 (3)
Day 29 (3)
Day 36 (3)
Day 43 (3)
(week 6)
Day 50 (3)
Day 57 (3)
Day 64 (3)
Day 71 (3)
Day 78 (3)
Day 85 (+2)
(week 12)
Site Visit
X
X
X
X
X
X
X
X
X
X
X
Phone call
X
X
X
X
X
General/Safety Assessments and Procedures
Informed Consent
X
Subject Demography
X
Full medical history1
X
Inclusion/Exclusion Criteria
X
Full physical exam2
X
X
X
X
Brief physical exam
X4
X
X
X4
X
X
Vital signs (BP, HR, RR, temperature)  
X
X4
X
X
X
X4
X
X
X
X
X
12-lead ECG
X3
X4
X
X
X
X4
X
X
X
X
X
Concomitant medication review & AE reporting/SAEs5
X---------------------------------------------------------------------------------------------------------------------------X
PROs/Questionnaires/Diaries/Disease Assessments and Procedures
Columbia Suicide Severity Rating Scale (C-SSRS)
X
X4
X4
X
X
FACIT-fatigue; RA Symptom and Impact Diary6
X4
X4
X
X
HAQ-DI; Patient Assessment of joint pain6
X4
X
X
X4
X
X
X
X
Patient Global Assessment (PtGA)6
X
X4
X
X
X4
X
X
X
X
Tender (28) & Swollen (28) joint count
X
X4
X
X
X4
X
X
X
X
Physician Global Assessment (PGA)
X4
X
X
X4
X
X
X
X
MRI/DCE-MRI7
X4, 20
X4,2021
X22
X16


2015N251670_03
CONFIDENTIAL
203168
106
Procedures
Screening (-30)
Treatment Period17
Early Withdrawal18
Follow Up (3)19
Day 1 
Day 8 (3)
Day 15 (3)
Day 22 (3)
Day 29 (3)
Day 36 (3)
Day 43 (3)
(week 6)
Day 50 (3)
Day 57 (3)
Day 64 (3)
Day 71 (3)
Day 78 (3)
Day 85 (+2)
(week 12)
Study Treatment
Randomisation
X
Study medication (twicethree times daily)8
X-------------------------------------------------------------------------------------------------------X
Dispensing of study medication
X
X
X
Dispensing of diary cards
X
X
X
X
X
X
X
Collection and review of diary cards
X
X
X
X
X
X
X
X
Laboratory (Safety) Assessments and Procedures
TB, HIV, HepB,Hep C Ab, Anti-CCP, Anti-dsDNA, RF 
X
FSH & estradiol  (if applicable)
X
Serum pregnancy test (WCBP only)
X
Urine pregnancy test (WCBP only)9
X4
X
X
X
X4
X
X
X
X
X
Haematology, chemistry, urinalysis 
X
X4
X
X
X10
X4
X10
X10
X
X
X
CRP
X
X4
X
X
X4
X
X
X
X
Blood sample for PD inflammatory biomarkers, mRNA, and 
TE11
X4
X4
X
X
PK blood samples GSK298277212
X
X4
X4
X
X
PK blood samples for MTX13
X4
X4
X4
Pharmacogenetic sample (PGx)
X14
Synovial biopsies for PK, inflammatory biomarkers, mRNA, 
target engagement & pathway engagement analysis15
X4,20
X4,1921
X16
Footnotes:
1.
Full medical history (includes past and current conditions, medication history, substance usage, and family history of premature CV disease).


2015N251670_03
CONFIDENTIAL
203168
107
2.
Full physical exam (includes height/weight at screening, height not measured at later time points).
3.
Triplicate ECG to be performed at screening only.
4.
Pre-dose.
5.
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.  AEs will be collected from the start of Study Treatment until the follow-
up contact.  On Days 22, 36, 50, 64, and 78, subjects will be questioned about their general health status via phone call.
6.
All PRO assessments should be conducted on site before any tests, procedures, or assessments, to avoid influencing the subjects’ perception.
7.
DCE-MRI will be performed on all subjects, provided that sites have DCE-MRI capability and experience (e.g., hardware and software requirements). If sites do not have 
DCE-MRI capability or experience, a regular MRI will be performed of the affected hand/wrist.  If the same joint is used for MRI and synovial biopsy, MRI should be performed 
before biopsy (if applicable).
8.
Subjects must take study medication twicethree times a day approximately 12 8 hours apart. Exact time of dosing to be recorded in diary cards. On Day 1, the first study 
dose will be administered at the site.  On Days 8, 43 and 85 only, subjects must not take their medication at home in the morning. Subjects will complete pre-dose 
assessments and then will be administered their morning dose of medication at site on Days 8 and 43.  On Day 85, subjects are no longer receiving study medication.
9.
If urine pregnancy test is positive, a confirmatory serum pregnancy test must be performed.
10. Haematology and chemistry only.  No urinalysis required on Days 29, 57 and 71.  When clinical laboratory samples are taken on the same day as the MRI, the samples 
should be taken first prior to the administration of the contrast fluid with MRI.  If this is not feasible (i.e. MRI is performed first), it is recommended that a separate 
IV catheter or straight venipuncture be performed in the opposite arm to where the MRI contrast fluid was administered.
11. Blood samples for inflammatory biomarkers, mRNA and target engagement.  See laboratory manual for full details on sample collection, handling and shipment.
12. PK blood samples for GSK2982772 will be taken pre-dose on Days 8 and 43. Post-dose serial PK samples will be taken on Days 1, 8 and Day 43 at the following time points: 
1, 2, 4, and 6 hours. Aand trough PK sample will be taken on Day 85 or at Early Withdrawal.
13. Only applicable if subjects are on MTX: PK blood samples for MTX will be taken pre-dose GSK2982772 on Day 1 (MTX alone), on Days 8 and 43 (MTX + GSK2982772).  
Subjects who are on MTX must should ideally take their MTX dose on the same day of the week at approximately the same time of the day throughout the study. In addition, 
the Day 1, 8 and 43 visits mustshould ideally be on the same day of the week.
14. A PGx blood sample is collected at the baseline visit, after the subject has been randomised and provided informed consent for genetic research.  If the sample is not 
collected at the baseline visit, it can be collected at any time during the study after randomisation.
15. Synovial biopsies are optional.
16. Biopsy (if applicable) and MRI only are required at Early Withdrawal visit if subject withdraws after at least 14 days of treatment and prior to Day 43.  If a subject withdraws 
between Days 43 and 57, an MRI is not required at the Early Withdrawal visit.  If a subject withdraws on Day 57 or after, an MRI should be performed at the Early Withdrawal 
visit.  A window allowance of 3 days of Early Withdrawal visit is allowed to perform the MRI.
17. Visit windows during the treatment period are relative to Day 1.
18. If a subject withdraws from the study, every effort will be made for the subject to complete an Early Withdrawal visit prior to the Follow Up visit.
19. Follow-up visit should be completed 28 days (3 days) after the last dose of study medication.
20. MRI (and if applicable; a biopsy) may be performed during the screening window as an additional visit (if required) up to 7 days before Day 1 to allow sites 
flexibility in scheduling.  The MRI must be completed prior to synovial biopsy (if performed on the same joint).  The site should be reasonably confident that the 
subject has fully qualified for the study (e.g., screening clinical labs, vital signs, physical examination, etc.) before the MRI (and if applicable: a biopsy) is/are 
performed. 


2015N251670_03
CONFIDENTIAL
203168
108
21. A biopsy (if applicable) and MRI may be performed on a separate day within the Day 43 window allowance (3 days). A separate visit to perform the MRI followed by 
synovial biopsy (if applicable) is only allowed to accommodate scheduling.  If biopsy is being performed, this visit must be scheduled after the Day 43 visit where the PK, 
clinical laboratory tests and other required Day 43 procedures are performed.  Subjects must not take their study medication at home in the morning before the full Day 43 
visit and also the morning before MRI and biopsy (if applicable) visit if being done on a separate day. 
22. For MRI performed on day 85, a visit window of up to 2 days after is allowed in order to perform the MRI.


2015N251670_03
CONFIDENTIAL
203168
109
Section 7.3.5 Electrocardiogram (ECG)

Triplicate12-lead ECGs will be obtained at screening and single 12-lead ECGs 
obtained at every time point during the study using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc (F or 
B) intervals.  A manual over read is also allowed. Refer to Section 5.4.4 for QTc 
withdrawal criteria and additional QTc readings that may be necessary.
Section 7.3.7 Suicidal Risk Monitoring
Subjects being treated with GSK2982772 should be monitored appropriately for suicidal 
ideation and behaviour or any other unusual changes in behaviour. Study medication
must be immediately discontinued in all subjects who experience signs of suicidal 
ideation or behaviour must immediately be discontinued from study medication.
Section 7.6.1 Magnetic Resonance Imaging (MRI) of Joint
On attendance at the MRI department, subjects will be placed in the scanner and will be 
prepared for intravenous contrast agent administration.  The scanning protocol will 
include routine localizers, T1 measurement sequences, dynamic DCE-MRI acquisition, 
and acquisitions required for OMERACT RAMRIS, and RAMRIQ and CARLOS
scoring.  Additional exploratory MRI endpoints, as detailed in the Acquisition Manual, 
may also be acquired for exploratory purposes.
Section 9.2.1 Sample Size Assumptions
The study is not powered to detect pre-defined differences. A sufficient number of 
subjects will be screened so that approximately 2430 subjects with moderate to severe 
RA are randomised into the study on a TID regimen.  Prior to protocol amendment 3 
being approved in each country, no more than 18 subjects will be randomised into 
the study on a BID regimen.  Table 4 summarises the total planned sample sizes for 
BID and TID regimens.  Should the drop-out rate be higher than anticipated, additional 
or replacement subjects may be randomised (up to an overall maximum of 4836) into the 
study at the discretion of the Sponsor.
Table 4
Summary of Total Sample Size by Dosing Regimen
Number Randomised to 
GSK2982772 60 mg BID or 
Placebo BID
Number Randomised to 
GSK2982772 60 mg TID or 
Placebo TID
Revised 
Max 
Total 
Sample 
Size
Total + 
Additional/ 
Replacement 
Subjects
7 - 12
24
36
42
12 - 18
24
42
48


2015N251670_03
CONFIDENTIAL
203168
110
The primary objective of the study is safety and tolerability, where there will be 20
subjects randomised to GSK2982772 60 mg TID and up to 12 subjects randomised to 
GSK29827772 60 mg BID. Using a Bayesian approach to determine the confidence 
interval (CI) around an observed safety event, we would assume a flat Beta (1, 1) prior, 
and if we were to observe one safety event in 20 16 then the posterior distribution would 
be Beta (2, 2016), as outlined below in Figure 4. 
Thus, we can be 95% certain that the true probability of the safety event lies between 
0.012% and 0.2425%. 
For supportive information, the properties of the key secondary endpoint DAS28 have 
been considered.
Based on the estimate of variability (SD=1 from historical data) it is estimated that the 
lower and upper bounds of the 95% CI for the change from baseline in DAS28-CRP 
score will be within approximately 0.6940.693 and 0.4620.490 of the point estimate of 
GSK2982772 60 mg TID (n=2018) and placebo (n=108).


2015N251670_03
CONFIDENTIAL
203168
111
Section 9.2.2 Sample Size Sensitivity
A sample size sensitivity analysis has been conducted on the primary endpoint to 
investigate the different safety event rates.  If the number of subjects who complete the 
12 weeks is higher or lower than 16 in the GSK2982772 group, then the true incidence 
rates of safety events that could not be ruled out (as outlined in Section 9.2.1) would 
change.  These changes are outlined in Table 5.
Table 5
Sample Size Sensitivity
GSK2982772 subjects 
completing the study
Number of a particular safety 
event observed with
GSK2982772
Upper limit of exact 95% 
Credible Interval indicating that 
a true incidence rate of x% 
could not be ruled out
20
0
16.1%
20
1
23.8%
20
2
30.4%
18
0
17.6%
18
1
26.0%
18
2
33.1%
16
0
19.5%
16
1
28.7%
16
2
36.4%
14
0
21.8%
14
1
31.9%
14
2
40.5%
12
0
24.7%
12
1
36.0%
12
2
45.4%
Section 9.3.1 Analysis Populations
If 12 or more subjects are randomised to a BID regimen (i.e., ≥4 placebo and ≥8 
GSK2982772 60 mg BID) then treatment received will take into account dosing 
frequency for GSK2982772, otherwise treatment will be irrespective of dosing 
frequency.
Section 9.3.2 Interim Analysis
Once an appropriate number of subjects have completed Day 43 (Week 6) the DAS28-
CRP data will be reviewed in an unblinded manner and on an ongoing basis by the Data 
Review Committee, consisting of the GSK study physicianProject Physician Lead 
(PPL), the study statistician, the study pharmacokineticist, the PRR DPU Head, EDL and 
SRT Leader or designees on an ongoing basis.  A physician external to the GSK2982772 
project team may also be involved in the data review. Additional inflammatory 
biomarkers, clinical and mechanistic endpoints (e.g. target engagement) may be reviewed 
if available. No other member of the GSK core study team will be unblinded to this data.


2015N251670_03
CONFIDENTIAL
203168
112
Section 11.0
References
GlaxoSmithKline Document Number 2014N204126_02.  Investigator Brochure for 
GSK2982772.  Report Date 27-JAN-2017.
Section 12.1. Appendix 1 – Abbreviations and Trademarks
Anti-CCP
Anti-Cyclic Citrullinated Peptide
CARLOS
Cartilage Loss Scoring System
hCG
Human Chorionic Gonadotropin
LDL
Low Density Lipoprotein
MCV
Mean Corpuscular Volume
MDMA
3,4-methylenedioxy-methamphetamine
PPL
Project Physician Lead
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
TID
Three times daily
WOCP
Women of Child Bearing Potential
Section 12.4 Appendix 4 – Genetic Research
Genetic Research Objectives and Analyses
GSK2982772 is a novel first-in-class asset being introduced to patients with 
moderate to severe RA for the first time. Currently its mechanism of action is not 
fully characterised nor understood. 
Specific genes may be studied that encode the drug targets, or drug mechanism of 
action pathways, drug metabolizing enzymes, drug transporters or which may 
underpin adverse events, disease risk or drug response. These candidate genes may 
include a common set of ADME (Absorption, Distribution, Metabolism and 
Excretion) genes that are studied to determine the relationship between gene 
variants or treatment response and/or tolerance. In addition, continuing research 
may identify other enzymes, transporters, proteins ore receptors that may be 
involved in response to GSK2982772. The genes that may code for these proteins 
may also be studied. Genome-wide scans involving a large number of polymorphic 
markers (e.g. single nucleotide polymorphisms) at defined locations in the genome, 
often correlated with a candidate gene, may be studied to determine the relationship 
between genetic variants and treatment response or tolerance. This approach is 
often employed when a definitive candidate gene does not exist and/or the potential 
genetic effects are not well understood.  
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.


2015N251670_03
CONFIDENTIAL
203168
113
If applicable and genetic research is conducted, Aappropriate descriptive and/or 
statistical analysis methods will be used to evaluate pharmacogenetic data in the 
context of the other clinical data. A detailed description of any planned analyses will be 
documented in a Reporting and Analysis Plan (RAP) prior to initiation of the analysis. 
Planned analyses and results of genetic investigations will be reported either as part of the 
clinical RAP and study report, or in a separate genetics RAP and report, as appropriate.


2015N251670_03
CONFIDENTIAL
203168
114
12.7.2.
Amendment 2 (14-JUL-2016) from Protocol Amendment 1 (25-
MAY-2016)
Where the Amendment Applies
This amendment applies to all subjects who will participate in this study in all countries.
Summary of Protocol Amendment Changes with Rationale
Protocol Amendment 02 incorporates addition of suicidal ideation and behaviour (SIB) 
withdrawal criteria.
Other minor protocol clarifications and administrative changes are also provided in this 
amendment.
List of Specific Changes (bold indicates text added and strikethrough indicates text 
removed):
Authors
Author (s):
 
Author (s):
 
 
PPD
PPD


2015N251670_03
CONFIDENTIAL
203168
115
MEDICAL MONITOR/SPONSOR INFORMATION
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
Tel:  
Mobile:  
Email: 
Mobile:  
Pattern Recognition 
Receptor DPU,
UP4440
1250 S Collegeville, 
PA  19426 USA
Secondary 
Medical 
Monitor
Tel: 
Mobile:  
Email:  
Mobile: 
 
Cytokine 
Chemokine DPU, 
GSK, Gunnels 
Wood Road, 
Stevenage, SG1 
2NY, UK
SAE contact  
information 
Medical 
Monitor as 
above
Section 5.4.1 Individual Safety Stopping Criteria
Study medication will be discontinued in the event of any of the following:

If a subject experiences a serious or severe clinically significant AE that in the 
clinical judgement of the Investigator, after consultation with the medical monitor, 
is possibly, probably or definitely related to investigational product.

The subject becomes pregnant.

The subject initiates treatment with any prohibited medications for the treatment 
of RA as listed in Section 6.11.2.

The subject develops a serious opportunistic or atypical infection.

If any of the liver chemistry stopping criteria (Section 5.4.3), QTc stopping 
criteria (Section 5.4.4), or Haematologic stopping criteria (Section 5.4.5) are met.

The subject experiences any signs of suicidal ideation or behaviour (Section 
7.3.7).
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PP
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


2015N251670_03
CONFIDENTIAL
203168
116
Section 7.1 Time and Events Table
Footnotes:
1.
Full medical history (includes past and current conditions, medication history, substance usage, and family history 
of premature CV disease).
2.
Full physical exam (includes height/weight at screening, height not measured at later time points).
3.
Triplicate ECG to be performed at screening only.
4.
Pre-dose.
5.
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.  AEs will be collected from the start of Study Treatment 
until the follow-up contact. On Days 22, 36, 50, 64, and 78, subjects will be questioned about their general 
health status via phone call.
6.
All PRO assessments should be conducted before any tests, procedures, or assessments, to avoid influencing the 
subjects’ perception.
7.
DCE-MRI will be performed on all subjects, provided that sites have DCE-MRI capability and experience (e.g., 
hardware and software requirements). If sites do not have DCE-MRI capability or experience, a regular MRI will 
be performed of the affected hand/wrist.  If the same joint is used for MRI and synovial biopsy, MRI should 
be performed before biopsy (if applicable).
8.
Subjects must take study medication twice a day approximately 12 hours apart. Exact time of dosing to be 
recorded in diary cards. On Day 1, the first study dose will be administered at the site.  On Days 8, 43 and 85 
only, subjects must not take their medication at home in the morning. Subjects will complete pre-dose 
assessments and then will be administered their morning dose of medication at site on Days 8 and 43.  On Day 
85, subjects are no longer receiving study medication.
9.
If urine pregnancy test is positive, a confirmatory serum pregnancy test must be performed.
10. Haematology and chemistry only.  No urinalysis required on Days 29, 57 and 71.
11. Blood samples for inflammatory biomarkers, mRNA and target engagement.  See laboratory manual for full details 
on sample collection, handling and shipment.
12. PK blood samples for GSK2982772 will be taken pre-dose on Days 8 and 43. Post-dose serial PK samples will be 
taken on Days 1, 8 and Day 43 at the following time points: 1, 2, 4, and 6 hours and trough on Day 85 or at Early 
Withdrawal.
13. PK blood samples for MTX will be taken pre-dose GSK2982772 on Day 1 (MTX alone), on Days 8 and 43 (MTX + 
GSK2982772).  Subjects who are on MTX must take their MTX dose on the same day of the week at 
approximately the same time of the day throughout the study. In addition, the Day 1, 8 and 43 visits must be on 
the same day of the week.
14. A PGx blood sample is collected at the baseline visit, after the subject has been randomised and provided 
informed consent for genetic research.  If the sample is not collected at the baseline visit, it can be collected at 
any time during the study after randomisation.
15. Synovial biopsies are optional.
16. Biopsy (if applicable) and MRI only are required at Early Withdrawal visit if subject withdraws after at least 14 days 
of treatment and prior to Day 43.  If a subject withdraws between Days 43 and 57, an MRI is not required at the 
Early Withdrawal visit.  If a subject withdraws on Day 57 or after, an MRI should be performed at the Early 
Withdrawal visit. 
17. Visit windows during the treatment period are relative to Day 1.
18. If a subject withdraws from the study, every effort will be made for the subject to complete an Early Withdrawal 
visit prior to the Follow Up visit.
19. Follow-up visit should be completed 28 days (3 days) after the last dose of study medication.
20. A biopsy (if applicable) and MRI may be performed on a separate day within the Day 43 window allowance (3 
days). A separate visit to perform the MRI followed by synovial biopsy (if applicable) is only allowed to 
accommodate scheduling.  If biopsy is being performed, this visit must be scheduled after the Day 43 visit where 
the PK, clinical laboratory tests and other required Day 43 procedures are performed.  Subjects must not take 
their study medication at home in the morning before the full Day 43 visit and also the morning before MRI and 
biopsy (if applicable) visit if being done on a separate day. 


2015N251670_03
CONFIDENTIAL
203168
117
Section 7.2 Screening and Critical Baseline Assessments
Medical/medication/mental health and family history, ECG and laboratory tests will be 
assessed as related to the inclusion/exclusion criteria listed in Section 5.
Section 7.3.7 Suicidal Risk Monitoring
Subjects being treated with GSK2982772 should be monitored appropriately for suicidal 
ideation and behaviour or any other unusual changes in behaviour. Consideration should 
be given to discontinuing GSK2982772 in sAll subjects who experience signs of suicidal 
ideation or behaviour must immediately be discontinued from study medication.
Families and caregivers of subjects being treated with GSK2982772 should be alerted 
about the need to monitor subjects for the emergence of unusual changes in behaviour, as 
well as the emergence of suicidal ideation and behaviour and to report such symptoms 
immediately to the study Investigator.
At Screening and baseline (pre-dose Day 1), the ‘Baseline/Screening CSSRS’ will be 
completed.  Assessments will be done at At Days 43 (Week 6) and 85 (Week 12), the 
‘Since Last Visit CSSRS’ will be completed.  GSK Version 4.1 of both rating scales will 
be used.
Subjects who answer ‘yes’ to any suicidal behaviour or ‘yes’ to suicidal ideation 
Questions 4 or 5 will be referred to their GP or appropriate psychiatric care and be 
discontinued from study medication.  The Medical Monitor will be notified.  If 
appropriate, an AE or SAE should be reported (see Section 7.3.1 AE and SAE).  In 
addition, the Investigator should complete a Possible Suicidality Related Adverse Event 
(PSRAE) form to collect detailed information on the circumstances of the reported AEs 
which, in the Investigator’s opinion, are possibly suicidality-related.  These may include, 
but are not limited to, an event involving suicidal ideation, a preparatory act toward 
imminent suicidal behaviour, a suicide attempt, or a completed suicide.


2015N251670_03
CONFIDENTIAL
203168
118
12.7.3.
Protocol Amendment 1 (25-MAY-2016) from the original protocol 
(01-APR-2016)
Where the Amendment Applies
This amendment applies to all subjects who will participate in this study in all countries.
Summary of Protocol Amendment Changes with Rationale
Protocol Amendment 01 incorporates the addition of risk text for drug interaction with P-
glycoprotein (Pgp) inhibitors and narrow therapeutic index (NTI) CYP3A4 substrates, 
and an updated list of prohibited medications.
Other minor protocol clarifications and administrative changes are also provided in this 
amendment.
List of Specific Changes (bold indicates text added and strikethrough indicates text 
removed):
Section 1 Protocol synopsis, Analysis, Paragraph 2
An ongoing review of available efficacy, pharmacodynamic and mechanistic endpoints 
will be conducted during the study by a Data Review Committee (DRC), consisting of a 
limited number of GlaxoSmithKline (GSK) individuals, some of whom are also members 
of the GSK study team who are not involved in the day-to-day running of the study.  
Section 4.5 Dose Justification
It is anticipated that a human dose of 60 mg BID will produce area under the 
concentration-time curve (AUC[0-24]) and maximum observed concentration (Cmax) values 
of approximately 9 g.h/mL and 1 g/mL, respectively, which are approximately 1/6th  
and 1/12th of the gender-averaged AUC (48.4 g.h/mL) and Cmax (12.3 g/mL) achieved 
in the 13 week monkey study at the no adverse effect level (NOAEL) dose of 
30 mg/kg/day.
Section 4.6.1 Risk Assessment
Drug Interaction
Non-clinical data:
In vitro studies with GSK2982772 
assessing uptake of potential drug-
drug interactions with Cytochrome 
P450 3A4 (CYP3A4) substrates, P-
glycoprotein (Pgp) inhibitors and
OAT3 substrates were completed.  
To date, formal drug interaction 
studies in humans have not been 
performed with GSK2982772.
There is a low risk that GSK2982772 
could be a perpetrator of OAT3 
substrates.  MTX is an OAT3 
Subject Selections:

Subjects who are taking 
concomitant medications 
known to inhibit Pgp or are 
CYP3A4 narrow therapeutic 
index (NTI) substrates will be 
excluded from the study.  See 
Section 6.11.2 for a 
comprehensive list of 
medications.
Subject Monitoring:

Subjects’ concomitant 
medication usage will be 


2015N251670_03
CONFIDENTIAL
203168
119
substrate in which GSK2982772 
could potentially impair the clearance 
of MTX.
There is a low risk that 
GSK2982772 could be an inducer 
of CYP3A4 and therefore may 
lower circulating levels of 
concomitant medications that are 
metabolised by CYP3A4 when co 
administered with GSK2982772.
GSK2982772 is a Pgp substrate 
and therefore co administration 
with concomitant medications that 
are Pgp inhibitors could increase 
circulating levels of GSK2982772.
See Section 4.3.6 of the 
GSK2982772 IB [GlaxoSmithKline 
Document 2014204126_01].
reviewed prior to inclusion 
and monitored throughout the 
study.

Subjects should be monitored 
throughout the study for 
potential effects of interaction 
between GSK2982772 and 
other concomitant 
medications.

PK sample collection to evaluate 
the potential interaction of 
GSK2982772 and MTX will be 
performed throughout the study.

Subjects should be monitored 
for potential effects of interaction 
between GSK2982772 and 
MTX.

Clinical laboratory results (e.g., 
liver function tests) are routinely 
being monitored throughout the 
study.
Section 5.2 Exclusion Criteria, Contraindications
CONTRAINDICATIONS 
19. 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.
20. Received a live or attenuated vaccine within 30 days of randomization OR plan to 
receive a vaccination during the study until 5 half-lives (or 2 days) plus 30 days after 
receiving GSK2982772.
21. Contraindication to gadolinium contrast agent in accordance with local guidelines.
22. The subject has participated in a clinical trial and has received an investigational 
product within 30 days or 5 half-lives, whichever is longer before the first dose of 
study medication, or plans to take part in another clinical trial at the same time as 
participating in this clinical trial.
Section 6.4 Blinding
This will be a double blind (sponsor unblinded) study and the following will apply:

Sponsor unblinded refers only to the Data Review Committee, consisting of the 
GSK study physician, study statistician, study pharmacokineticist, Pattern 
Recognition Receptor (PRR) Discovery Performance Unit (DPU) Head, Early
Development Lead (EDL) and Safety Review Team (SRT) Leader, or their 
designees on an ongoing basis.  A physician external to the GSK2982772 project 
team may also be involved in the data review.  A data review charter will identify 
the specific GSK individuals involved; outline in detail the activities of this 


2015N251670_03
CONFIDENTIAL
203168
120
review, and how the integrity of the study will be maintained. The rest of the core 
GSK study team will remain blinded.
Section 6.11.2 Amended Prohibited Medications and Non-Drug Therapies, Table 2 
Prohibited Medications
Therapy
Time period 
A change in dose of methotrexate or other 
DMARD.
12 weeks prior to screening until after the 
follow up visit (Day 112)
Greater than 10mg/day oral prednisolone (or 
equivalent glucocorticoid) or a change in dose 
of corticosteroid.
4 weeks prior to screening until after the 
follow up visit (Day 112)
Intramuscular glucocorticoids (e.g., 
methylprednisolone ≤120 mg/month)
4 weeks prior to screening until after the 
follow up visit (Day 112)
Intra-articular corticosteroid injections
6 weeks prior to screening and until after the 
follow up visit (Day 112).
P-glycoprotein (Pgp) inhibitors including 
but not limited to amiodarone, azithromycin, 
captopril, carvedilol, clarithromycin, 
conivaptan, cyclosporine, diltiazem, 
dronedarone, erythromycin, felodipine, 
itraconazole, ketoconazole, lopinavir, 
ritonavir, quercetin, quinidine, ranolazine, 
ticagrelor, verapamil [FDA, 2012].
4 weeks prior to first dose (Day 1) until 
after the follow up visit (Day 112).
Narrow therapeutic index (NTI) CYP3A4 
substrates including but not limited to 
alfentanil, astemizole, cisapride, 
cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus, terfenadine [FDA, 
2012].
4 weeks prior to the first dose (Day1) until 
after the follow up visit (Day 112).
Biologic therapies for the treatment of 
rheumatoid arthritis not limited to anti-TNF 
biologics or other biologics, rituximab, anakinra, 
abatacept or tocilizumab.
At any time. 
Exposure to more than one anti-TNF biologic 
therapies for the treatment of RA including but 
not limited to anti-TNF biologics, infliximab, 
adalimumab, etanercept, certolizumab and 
golimumab.
Exception:  Exposure to a single anti-TNF-
biologic for which the subject discontinued for a 
reason other than primary non-response is 
permitted.
Cannot have been exposed to more than one 
anti-TNF biologic or be on at any time during 
the study.
In the case of a single anti-TNF biologic for 
which the subject discontinued for a reason 
other than primary non-response, the subject 
must not be on for 8 weeks or 5 ½ lives 
(whichever is longer) prior to first dose until 


2015N251670_03
CONFIDENTIAL
203168
121
Therapy
Time period 
after the follow up visit (Day 112).  
Live vaccination
Live or attenuated vaccinations are not 
permitted within 30 days of randomization or 
plan to receive a vaccination during the study 
until follow-up visit.  If indicated, non-live 
vaccines (e.g., inactivated influenza vaccines) 
may be administered whilst receiving 
GSK2982772 based on an assessment of the 
benefit:risk (e.g., risk of decreased 
responsiveness).  Investigators are expected 
to follow local and/or national guidelines with 
respect to vaccinations, including against 
pneumococcus and influenza, in subjects with 
RA.


2015N251670_03
CONFIDENTIAL
203168
122
Section 7.1 Time and Events Table
Procedures
Screening (-30)
Treatment Period17
Early Withdrawal18
Follow Up (3)19
Day 1 
Day 8 (3)
Day 15 (3)
Day 22 (3)
Day 29 (3)
Day 36 (3)
Day 43 (3)
(week 6)
Day 50 (3)
Day 57 (3)
Day 64 (3)
Day 71 (3)
Day 78 (3)
Day 85 (+2)
(week 12)
Site Visit
X
X
X
X
X
X
X
X
X
X
X
Phone call
X
X
X
X
X
General/Safety Assessments and Procedures
Informed Consent
X
Subject Demography
X
Full medical history1
X
Inclusion/Exclusion Criteria
X
Full physical exam2
X
X
X
X
Brief physical exam
X4
X
X
X4
X
X
Vital signs (BP, HR, RR, temperature)  
X
X4
X
X
X
X4
X
X
X
X
X
12-lead ECG
X3
X4
X
X
X
X4
X
X
X
X
X
Concomitant medication review & AE reporting/SAEs5
X---------------------------------------------------------------------------------------------------------------------------X
PROs/Questionnaires/Diaries/Disease Assessments and Procedures
Columbia Suicide Severity Rating Scale (C-SSRS)
X
X4
X4
X
X
FACIT-fatigue; RA Symptom and Impact Diary6
X4
X4
X
X
HAQ-DI; Patient Assessment of joint pain6
X4
X
X
X4
X
X
X
X
Patient Global Assessment (PtGA)6
X
X4
X
X
X4
X
X
X
X
Tender (28) & Swollen (28) joint count
X
X4
X
X
X4
X
X
X
X
Physician Global Assessment (PGA)
X4
X
X
X4
X
X
X
X
MRI/DCE-MRI7
X4
X4,20
X
X16


2015N251670_03
CONFIDENTIAL
203168
123
Procedures
Screening (-30)
Treatment Period17
Early Withdrawal18
Follow Up (3)19
Day 1 
Day 8 (3)
Day 15 (3)
Day 22 (3)
Day 29 (3)
Day 36 (3)
Day 43 (3)
(week 6)
Day 50 (3)
Day 57 (3)
Day 64 (3)
Day 71 (3)
Day 78 (3)
Day 85 (+2)
(week 12)
Study Treatment
Randomisation
X
Study medication (twice daily)8
X-------------------------------------------------------------------------------------------------------X
Dispensing of study medication
X
X
X
Dispensing of diary cards
X
X
X
X
X
X
X
Collection and review of diary cards
X
X
X
X
X
X
X
X
Laboratory (Safety) Assessments and Procedures
TB, HIV, HepB,Hep C Ab, Anti-CCP, Anti-dsDNA, Anti-
CARP, RF 
X
FSH & estradiol  (if applicable)
X
Serum pregnancy test (WCBP only)
X
Urine pregnancy test (WCBP only)9
X4
X
X
X
X4
X
X
X
X
X
Haematology, chemistry, urinalysis 
X
X4
X
X
X10
X4
X10
X10
X
X
X
CRP
X
X4
X
X
X4
X
X
X
X
Blood sample for PD inflammatory biomarkers, mRNA, and 
TE11
X4
X4
X
X
PK blood samples GSK298277212
X
X4
X4
X
X
PK blood samples for MTX13
X4
X4
X4
Pharmacogenetic sample (PGx)
X14
Synovial biopsies for PK, inflammatory biomarkers, mRNA, 
target engagement & pathway engagement analysis15
X4
X4,20
X16


2015N251670_03
CONFIDENTIAL
203168
124
Footnotes:
1.
Full medical history (includes past and current conditions, medication history, substance usage, and family history of premature CV disease).
2.
Full physical exam (includes height/weight at screening, height not measured at later time points).
3.
Triplicate ECG to be performed at screening only.
4.
Pre-dose.
5.
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.  AEs will be collected from the start of Study Treatment until the follow-up 
contact.
6.
All PRO assessments should be conducted before any tests, procedures, or assessments, to avoid influencing the subjects’ perception.
7.
DCE-MRI will be performed on all subjects, provided that sites have DCE-MRI capability and experience (e.g., hardware and software requirements). If sites do not have DCE-MRI 
capability or experience, a regular MRI will be performed of the affected hand/wrist.  
8.
Subjects must take study medication twice a day approximately 12 hours apart. Exact time of dosing to be recorded in diary cards. On Days 8, 43 and 85 only, subjects must not 
take their medication at home in the morning. Subjects will complete pre-dose assessments and then will be administered their morning dose of medication at site on Days 8 and 
43.  On Day 85, subjects are no longer receiving study medication.
9.
If urine pregnancy test is positive, a confirmatory serum pregnancy test must be performed.
10. Haematology and chemistry only.  No urinalysis required on Days 29, 57 and 71.
11. Blood samples for inflammatory biomarkers, mRNA and target engagement.  See laboratory manual for full details on sample collection, handling and shipment.
12. PK blood samples for GSK2982772 will be taken pre-dose on Days 8 and 43. Post-dose serial PK samples will be taken on Days 1, 8 and Day 43 at the following time points: 1, 2, 
4, and 6 hours and trough on Day 85 or at Early Withdrawal.
13. PK blood samples for MTX will be taken pre-dose GSK2982772 on Day 1 (MTX alone), on Days 8 and 43 (MTX + GSK2982772).  Subjects who are on MTX must take their MTX 
dose on the same day of the week at approximately the same time of the day throughout the study. In addition, the Day 1, 8 and 43 visits must be on the same day of the week.
14. A PGx blood sample is collected at the baseline visit, after the subject has been randomised and provided informed consent for genetic research.  If the sample is not collected at 
the baseline visit, it can be collected at any time during the study after randomisation.
15. Synovial biopsies are optional.
16. Biopsy (if applicable) and MRI only are required at Early Withdrawal visit if subject withdraws after at least 14 days of treatment and prior to Day 43.  If a subject withdraws 
between Days 43 and 57, an MRI is not required at the Early Withdrawal visit.  If a subject withdraws on Day 57 or after, an MRI should be performed at the Early Withdrawal visit. 
17. Visit windows during the treatment period are relative to Day 1.
18. If a subject withdraws from the study, every effort will be made for the subject to complete an Early Withdrawal visit prior to the Follow Up visit.
19. Follow-up visit should be completed 28 days (3 days) after the last dose of study medication.
20. A biopsy (if applicable) and MRI may be performed on a separate day within the Day 43 window allowance (3 days).  A separate visit to perform the MRI followed by 
synovial biopsy (if applicable) is only allowed to accommodate scheduling.  If biopsy is being performed, this visit must be scheduled after the Day 43 visit where the 
PK, clinical laboratory tests and other required Day 43 procedures are performed.  Subjects must not take their study medication at home in the morning before the 
full Day 43 visit and also the morning before MRI and biopsy (if applicable) visit if being done on a separate day.


2015N251670_03
CONFIDENTIAL
203168
125
Section 7.2 Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors and smoking history (as detailed in the 
CRF) will be assessed at screening.
Section 7.3.4 Vital Signs
Vital signs will be measured in a supine or semi-supine position after approximately 
5 minutes rest and will include temperature, systolic and diastolic blood pressure, pulse 
rate and respiratory rate.
Section 7.3.6 Clinical Safety Laboratory Assessments, Table 3 Protocol Required 
Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
1,2
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 3
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose4
Calcium
Alkaline phosphatise
Albumin
CRP
Triglycerides4
Total Cholesterol4
Fasting HDL 
cholesterol4
Fasting LDL 
cholesterol4
Routine 
Urinalysis

Specific gravitypH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening and 
RoutineTests

HIV 1 & 2

Hepatitis B (HBsAg)

Hepatitis B core antibody (HBcAb)

Hepatitis C (Hep C antibody)

QuantiFeron Gold Test

T-spot (if QuantiFeron is indeterminant)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Urine hCG Pregnancy test (as needed for women of child bearing 
potential) 5

Serum hCG (as needed for women of child bearing potential) to be 
done at screening and if urine test positive at other time points in the 


2015N251670_03
CONFIDENTIAL
203168
126
Laboratory 
Assessments
Parameters
study.

Anti-dsDNA

Rheumatoid Factor

Anti-CCP

Anti-CARP

Estimated glomerular filtration rate (eGFR) will be calculated using 
the CKD-EPI formula.
Section 9.3.2 Interim Analysis
Once an appropriate number of subjects have completed Day 43 (Week 6) the DAS28-
CRP data will be reviewed in an unblinded manner and on an ongoing basis by the Data
Review Committee, consisting of the GSK study physician, the study statistician, the 
study pharmacokineticist, the PRR DPU Head, EDL and SRT Leader or designees on an 
ongoing basis.


2015N251670_04
CONFIDENTIAL
The GlaxoSmithKline group of companies
203168
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A multicentre, randomised, double-blind (sponsor-unblinded), 
placebo-controlled study to investigate the safety and 
tolerability, pharmacokinetics, pharmacodynamics, and efficacy 
of GSK2982772 in subjects with moderate to severe rheumatoid 
arthritis.
Compound Number:
GSK2982772
Development Phase:
II
Effective Date:
03-AUG-2017
Protocol Amendment Number:  04
Author (s):
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved. 
Unauthorised copying or use of this information is prohibited.
PPD


2015N251670_04
CONFIDENTIAL
The GlaxoSmithKline group of companies
203168
2
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N251670_00
2016-APR-01
Original
2015N251670_01
2016-MAY-25
Amendment No. 1
Protocol Amendment 01 incorporates the addition of risk text for drug interaction with P-
glycoprotein (Pgp) inhibitors and narrow therapeutic index (NTI) CYP3A4 substrates, an 
updated list of prohibited medications plus some minor protocol clarifications and 
administrative changes.
2015N251670_02
2016-JUL-14
Amendment No. 2
Protocol Amendment 02 incorporates addition of suicidal ideation and behaviour (SIB) 
withdrawal criteria plus other minor protocol clarifications and administrative changes.
2015N251670_03
2017-APR-20
Amendment No. 3
Change in dosing regimen from 60 mg BID to 60 mg TID, restrictions on JAK inhibitors, 
defined non-reproductive potential criteria in Exclusion 11, change to clinical laboratory 
criteria in Exclusion 23, addition of evaluation of joint space narrowing with MRI, 
flexibility in scheduling with MRI and synovial biopsy, some minor protocol 
clarifications and administrative changes.
2015N251670_04
2017-AUG-03
Amendment No. 4
A country specific amendment for Germany which reinstates the clinical laboratory 
criteria in Exclusion 23 and Haematologic Stopping Criteria in Section 5.4.5 that was 
changed in Amendment 03.


PPD
PPD


2015N251670_04
CONFIDENTIAL
203168
4
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager Number
Fax 
Number
Site 
Address
Primary 
Medical 
Monitor 
Telephone:  
Email: 
Mobile: 
 
NA
GSK Stockley 
Park West, 1-
3 Ironbridge 
Road, 
Uxbridge, 
Middlesex, 
UB11 1BT, 
UK
Secondary 
Medical 
Monitor
Mobile:  
Email:  
Mobile: 
NA
1250 S. 
Collegeville 
Road, 
Collegeville, 
PA USA 
19426 
SAE contact 
information
Medical 
Monitor as 
above
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.
Regulatory Agency Identifying Number(s):  EudraCT 2016-000912-13
PPD
PPD
PPD
PPD
PPD
PPD
PPD


2015N251670_04
CONFIDENTIAL
203168
5
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 203168
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


2015N251670_04
CONFIDENTIAL
203168
6
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 203168......................................................10
2.
INTRODUCTION....................................................................................................15
2.1.
Study Rationale ..........................................................................................15
2.2.
Brief Background ........................................................................................15
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................17
4.
STUDY DESIGN ....................................................................................................20
4.1.
Overall Design ............................................................................................20
4.2.
Treatment Arms and Duration.....................................................................20
4.2.1.
Screening ....................................................................................20
4.2.2.
Treatment Period.........................................................................21
4.2.3.
Follow-up Period..........................................................................21
4.3.
Type and Number of Subjects.....................................................................21
4.4.
Design Justification.....................................................................................21
4.5.
Dose Justification........................................................................................22
4.6.
Benefit:Risk Assessment ............................................................................23
4.6.1.
Risk Assessment .........................................................................24
4.6.2.
Benefit Assessment.....................................................................30
4.6.3.
Overall Benefit:Risk Conclusion...................................................30
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............30
5.1.
Inclusion Criteria.........................................................................................30
5.2.
Exclusion Criteria........................................................................................32
5.3.
Screening/Baseline/Run-in Failures............................................................35
5.4.
Withdrawal/Stopping Criteria.......................................................................35
5.4.1.
Individual Safety Stopping Criteria ...............................................36
5.4.2.
Group Safety Stopping Criteria ....................................................37
5.4.3.
Liver Chemistry Stopping Criteria ................................................37
5.4.3.1.
Study Treatment Restart or Rechallenge....................38
5.4.4.
QTc Stopping Criteria ..................................................................38
5.4.5.
Haematologic Stopping Criteria ...................................................39
5.5.
Subject and Study Completion....................................................................39
6.
STUDY TREATMENT ............................................................................................40
6.1.
Investigational Product and Other Study Treatment....................................40
6.2.
Treatment Assignment................................................................................40
6.3.
Planned Dose Adjustments.........................................................................41
6.4.
Blinding.......................................................................................................41
6.5.
Packaging and Labeling..............................................................................42
6.6.
Preparation/Handling/Storage/Accountability..............................................42
6.7.
Compliance with Study Treatment Administration.......................................42
6.8.
Treatment of Study Treatment Overdose....................................................43
6.9.
Treatment after the End of the Study ..........................................................43
6.10.
Lifestyle and/or Dietary Restrictions............................................................43
6.10.1.
Activity .........................................................................................43
6.11.
Concomitant Medications and Non-Drug Therapies....................................43


2015N251670_04
CONFIDENTIAL
203168
7
6.11.1.
Permitted Medications and Non-Drug Therapies..........................43
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................44
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................46
7.1.
Time and Events Table...............................................................................47
7.2.
Screening and Critical Baseline Assessments ............................................51
7.3.
Safety .........................................................................................................51
7.3.1.
Adverse Events (AEs) and Serious Adverse Events 
(SAEs).........................................................................................51
7.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................51
7.3.1.2.
Method of Detecting AEs and SAEs ...........................52
7.3.1.3.
Follow-up of AEs and SAEs........................................52
7.3.1.4.
Cardiovascular and Death Events ..............................52
7.3.1.5.
Regulatory Reporting Requirements for SAEs............53
7.3.2.
Pregnancy ...................................................................................53
7.3.3.
Physical Exams ...........................................................................53
7.3.4.
Vital Signs....................................................................................54
7.3.5.
Electrocardiogram (ECG).............................................................54
7.3.6.
Clinical Safety Laboratory Assessments ......................................54
7.3.7.
Suicidal Risk Monitoring...............................................................56
7.4.
Efficacy.......................................................................................................57
7.4.1.
Patient Reported Outcomes.........................................................57
7.4.1.1.
Rheumatoid Arthritis Symptoms and Impact 
Diary...........................................................................57
7.4.1.2.
Patient Assessment of Joint Pain ...............................57
7.4.1.3.
Patient’s Global Assessment of Disease 
(PtGA) ........................................................................57
7.4.1.4.
Disability Index of the Health Assessment 
Questionnaire (HAQ-DI) .............................................57
7.4.1.5.
Functional Assessment of Chronic Illness 
Therapy (FACIT)-Fatigue Scale..................................58
7.4.2.
Clinical Disease Assessments .....................................................58
7.4.2.1.
Disease Activity Score (DAS) Assessments ...............58
7.4.2.2.
American College of Rheumatology Criteria 
(ACR) Assessments ...................................................58
7.4.2.3.
Joint Assessments......................................................59
7.4.2.4.
Measurement of Serum CRP......................................59
7.4.2.5.
Physician’s Global Assessment of Disease 
Activity (PGA).............................................................59
7.5.
Pharmacokinetics .......................................................................................59
7.5.1.
Blood Sample Collection..............................................................59
7.5.2.
Sample Analysis ..........................................................................59
7.5.3.
Synovial Biopsy Tissue for Pharmacokinetic Assay .....................60
7.5.4.
Sample Analysis ..........................................................................60
7.6.
Biomarker(s)/Pharmacodynamic Markers ...................................................60
7.6.1.
Magnetic Resonance Imaging (MRI) of Joint ...............................60
7.6.2.
Synovial Biopsy ...........................................................................61
7.6.2.1.
Selection of Joint for Synovial Biopsy .........................61
7.6.2.2.
Synovial Biopsy Procedure.........................................61
7.6.3.
Novel Pharmacodynamic Biomarkers ..........................................62
7.6.3.1.
RIP1 Target Engagement in Blood .............................62


2015N251670_04
CONFIDENTIAL
203168
8
7.6.3.2.
RIP1 Target Engagement in Synovial Tissue..............62
7.6.3.3.
Pathway Biomarkers in Synovial Tissue .....................62
7.6.4.
Exploratory Novel Biomarkers......................................................62
7.7.
Genetics .....................................................................................................63
8.
DATA MANAGEMENT ...........................................................................................63
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................64
9.1.
Hypotheses.................................................................................................64
9.2.
Sample Size Considerations.......................................................................64
9.2.1.
Sample Size Assumptions ...........................................................64
9.2.2.
Sample Size Sensitivity................................................................65
9.2.3.
Sample Size Re-estimation or Adjustment...................................66
9.3.
Data Analysis Considerations .....................................................................66
9.3.1.
Analysis Populations....................................................................66
9.3.2.
Interim Analysis ...........................................................................66
9.4.
Key Elements of Analysis Plan ...................................................................67
9.4.1.
Primary Analyses.........................................................................67
9.4.2.
Secondary Analyses ....................................................................67
9.4.3.
Other Analyses ............................................................................68
9.4.3.1.
Exploratory Analyses..................................................68
10. STUDY GOVERNANCE CONSIDERATIONS........................................................68
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............68
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................68
10.3.
Quality Control (Study Monitoring) ..............................................................69
10.4.
Quality Assurance.......................................................................................69
10.5.
Study and Site Closure ...............................................................................70
10.6.
Records Retention......................................................................................70
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................71
11. REFERENCES.......................................................................................................72
12. APPENDICES........................................................................................................74
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................74
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................78
12.3.
Appendix 3:  Prednisolone Equivalent Dose Table......................................80
12.4.
Appendix 4- Genetic Research ...................................................................81
12.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................85
12.5.1.
Definition of Adverse Events........................................................85
12.5.2.
Definition of Serious Adverse Events...........................................86
12.5.3.
Definition of Cardiovascular Events .............................................88
12.5.4.
Recording of AEs and SAEs ........................................................88
12.5.5.
Evaluating AEs and SAEs............................................................89
12.5.6.
Reporting of SAEs to GSK...........................................................90
12.6.
Appendix 6: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................91


2015N251670_04
CONFIDENTIAL
203168
9
12.6.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............91
12.6.2.
Collection of Pregnancy Information ............................................92
12.7.
Appendix 7: - Country Specific Requirements.............................................94
12.8.
Appendix 8:  Protocol Amendment Changes...............................................95
12.8.1.
Amendment 4 (03-AUG-2017) from Protocol Amendment 
3 (20-APR-2017)..........................................................................95
12.8.2.
Amendment 3 (20-APR-2017) from Protocol Amendment 
2 (14- JUL-2016)..........................................................................96
12.8.3.
Amendment 2 (14-JUL-2016) from Protocol Amendment 1 
(25-MAY-2016) ..........................................................................117
12.8.4.
Protocol Amendment 1 (25-MAY-2016) from the original 
protocol (01-APR-2016).............................................................121


2015N251670_04
CONFIDENTIAL
203168
10
1.
PROTOCOL SYNOPSIS FOR STUDY 203168
Rationale
This study is the first experience with GSK2982772, a receptor-interacting protein-1 
(RIP1) kinase inhibitor, in subjects with moderate to severe rheumatoid arthritis (RA) 
who are currently being treated with disease modifying anti-rheumatic drugs (DMARDs).
The primary objective of this study has not changed with amendment 03; however the 
dosing regimen does change to GSK2982772 (60 mg three times daily for 84 days). 
The primary objective will be to investigate the safety and tolerability of repeat oral doses 
of GSK2982772 (60 mg three times daily for 84 days). In addition to the 
pharmacokinetics (PK), a number of experimental and clinical endpoints will be 
employed to obtain information on the pharmacodynamics (PD), and preliminary efficacy 
in subjects with active RA. Although no formal hypothesis will be tested, these endpoints 
will enable a broader understanding of the mechanism of action and potential for clinical 
efficacy of GSK2982772 in RA, by making full use of the information obtained from 
each subject enrolled.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To investigate the safety and tolerability of 
60 mg three times daily doses of 
GSK2982772 in subjects with moderate to 
severe Rheumatoid Arthritis.

Adverse events.

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis).

Vital sign measurements (blood pressure, 
heart rate, respiratory rate, and body 
temperature).

12-Lead ECG monitoring.
Secondary

To investigate the plasma concentrations 
of GSK2982772 following 60 mg three 
times daily doses of GSK2982772 in 
subjects with moderate to severe 
Rheumatoid Arthritis.

Pre-dose concentrations of GSK2982772 
on Days 8 and 43 (Week 6).  

Post-dose concentrations of GSK2982772 
on Days 1, 8, and 43 (Week 6) at 1, 2, 4 
and 6 hours.

Trough concentrations on Day 85 (Week 
12).

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
inflammatory biomarkers in blood subjects 
with moderate to severe Rheumatoid 
Arthritis.

Change from baseline in blood 
inflammatory markers (e.g., may include 
but not limited to CRP, IL6, MMP-1, MMP-
3, MMP-13, TIMP-1, MCP-1, MIF, 
MRP8/14 and other markers encompassed 
by Vectra DA).


2015N251670_04
CONFIDENTIAL
203168
11
Objectives
Endpoints

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on bone 
and synovial parameters as measured by 
MRI and DCE-MRI in subjects with 
moderate to severe Rheumatoid Arthritis.

Change from baseline in Magnetic 
Resonance Imaging (MRI) parameters in 
the most affected hand/wrist.  MRI 
parameters may include assessment of 
bone erosions, synovitis, bone oedema 
and joint space narrowing as assessed in 
the OMERACT-RAMRIS (Outcome 
Measures in Rheumatology, Rheumatoid 
Arthritis Magnetic Resonance Image 
Scoring System) scoring system, the 
RAMRIQ (Rheumatoid arthritis MRI 
quantitative) scoring system, the modified 
CARLOS (Cartilage Loss Scoring System) 
and additional exploratory endpoints as 
data permit.
Change from baseline in synovial 
inflammation as measured by dynamic 
contrast enhanced (DCE)-MRI in the most 
affected hand/wrist:

Exchange rate (Ktrans)

Interstitial volume (Ve)

Plasma volume (Vp)

Initial rate of enhancement (IRE)

Maximal signal intensity enhancement 
(ME)

Joint volume

Enhancing volume

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
clinical disease activity in subjects with 
moderate to severe Rheumatoid Arthritis.

Change from baseline in Disease Activity 
Score (DAS) 28-CRP scores.

Proportion of subjects achieving 
categorical DAS28-CRP response 
(moderate/good EULAR response) at each 
assessment time points.

Proportion of subjects achieving 
categorical ACR20/50/70 response.

To investigate the effect of 60 mg three 
times daily dosing of GSK2982772 on 
methotrexate (MTX) concentrations. 

Plasma concentrations of MTX pre-dose 
GSK2982772 on Days 1, 8, and 43 (Week 
6).
Exploratory

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
inflammatory biomarkers in synovial tissue 
from subjects with moderate to severe 

Change from baseline in CD68+ 
macrophages, CD55+ fibroblast-like 
synoviocytes and a number of infiltrating 
CD3, CD22, CD138 inflammatory cells, 


2015N251670_04
CONFIDENTIAL
203168
12
Objectives
Endpoints
Rheumatoid Arthritis.
and synovial inflammatory biomarkers 
including, but not limited to VEGF, IL-1β, 
IL-6, TNFα, and MMP-1.

To investigate pathway and target 
engagement following 60 mg three times 
daily doses of GSK2982772 in blood and 
synovial biopsy tissue in subjects with 
moderate to severe Rheumatoid Arthritis.

Pharmacology biomarker endpoints may 
include, but are not limited to the following, 
pre-dose at Days 1, 43 (Week 6) and 
trough on Day 85 (Week 12), as applicable 
and if evaluable samples and data permit:
Target Engagement Assay RIP1 
(TEAR1) in blood and synovial tissue.
Total or phosphorylated RIP1, MLKL, 
and RIP3, cleaved and total caspase 
3 and caspase 8 signatures in 
synovial tissue.

To investigate the concentration of 
GSK2982772 and possible drug-related 
material, as well as specific distribution 
within tissue if feasible, in the synovial 
tissue after 60 mg three times daily doses 
of GSK2982772. 

Pre-dose GSK2982772 synovial tissue 
biopsies and possible drug-related material 
concentrations, as well as specific 
distribution within tissue if feasible, on Day 
43 (Week 6), as evaluable samples and 
data permit.

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on the 
quality of life of subjects with moderate to 
severe Rheumatoid Arthritis.

Change from baseline in Health 
Assessment Questionnaire Disability Index 
(HAQ-DI).

Change from baseline in RA symptom 
questionnaire score.

Change from baseline in Functional 
Assessment of Chronic Illness Therapy 
(FACIT)-Fatigue.

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on gene 
expression in the blood subjects with active 
moderate to severe Rheumatoid Arthritis.

Transcriptomic analysis of mRNA isolated 
from blood pre-dose on Days 1 and 43 
(Week 6) and trough on Day 85 (Week 12).

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on gene 
expression in the synovium of subjects with 
moderate to severe Rheumatoid Arthritis.

Transcriptomic analysis of mRNA isolated 
from synovial tissue pre-dose on Days 1 
and 43 (Week 6).


2015N251670_04
CONFIDENTIAL
203168
13
Overall Design
This is a multicentre, randomised, double-blind (sponsor-unblinded), placebo-controlled 
study to investigate the safety and tolerability, PK, PD, and preliminary efficacy of 
GSK2982772 in subjects with moderate to severe RA.  The study design schematic is 
depicted in Figure 1 below.
Figure 1
Study Overview
Amendment 03:
Prior to amendment 03:
Key assessments:
Safety assessments, PK samples, DAS28-CRP, 
ACR20/50/70, FACIT-fatigue, Rheumatoid Arthritis Symptom 
and Impact Diary, HAQ-DI assessments, MRI, PD samples
Treatment Arms and Duration
Each subject will participate in the study for approximately 20 weeks.  This includes a 
screening period of up to 30 days, an 84 day (12 week) treatment period, and a 28 day 
follow-up period after the last dose.
Within 30 days of the screening visit (defined as day of consent signing), subjects who 
are eligible will enter the treatment period and start treatment (or dosing) on Day 1.
The Follow-up Period is 28 days (4 weeks) long.  All visits and assessments are detailed 
in Section 7.1.


2015N251670_04
CONFIDENTIAL
203168
14
Subjects who have completed screening assessments and are eligible will be randomised 
in a 2:1 ratio (active to placebo) to one of the following treatments:
GSK2982772 60 mg three times daily (TID) 
Placebo three times daily (TID) 
Prior to amendment 03 being effective in each country, subjects have been randomised in 
a 2:1 ratio (active to placebo) to one of the following treatments:
GSK2982772 60 mg two times daily (BID) 
Placebo two times daily (BID)
Type and Number of Subjects
A sufficient number of subjects will be screened so that approximately 24 subjects with 
moderate to severe RA are randomised into the study on a TID regimen. Prior to protocol 
amendment 03 being approved in each country, no more than 18 subjects will be 
randomised into the study on a BID regimen.  Should the overall drop-out rate be higher 
than anticipated, additional or replacement subjects may be randomised (up to an overall
total maximum of 48) into the study at the discretion of the Sponsor.
Analysis
The safety and tolerability of GSK2982772 following 12 weeks of treatment will be 
based on the review and displays of adverse events, clinical laboratory values, vital sign 
measurements and 12-lead electrocardiogram (ECG) monitoring.
Ongoing reviews of available efficacy, pharmacodynamic and mechanistic endpoints will 
be conducted during the study by a Data Review Committee (DRC), consisting of a 
limited number of GlaxoSmithKline (GSK) individuals, some of who are also members 
of the GSK study team who are not involved with the day-to-day running of the study.  
The primary purpose of these reviews will be to monitor target engagement, 
inflammatory markers and Disease activity score for 28 different joints with (CRP) value 
(DAS28-CRP) for futility and internal decision making. A data review charter will 
outline in detail the activities of this review and how the integrity of the study will be 
maintained.
A formal interim analysis will be conducted during the study, when an appropriate 
number of subjects have completed 12 weeks of treatment or on the request of the DRC.  
The purpose of this interim will be to assess whether to stop the study for futility.  This 
interim analysis may also facilitate decision making regarding the subsequent clinical 
development of GSK2982772 for RA.
Comparisons between treatment groups on any changes observed will be conducted for 
the secondary endpoints if deemed appropriate, e.g. changes in the mean target 
engagement, changes in inflammatory markers and percentage change in DAS28-CRP 


2015N251670_04
CONFIDENTIAL
203168
15
will be statistically analysed using a Mixed-effect Model Repeat Measurements 
(MMRM) comparing GSK2982772 with placebo at each time point. 
The relationship between each of the mechanistic endpoints and also with the clinical 
endpoints may also be graphically presented and analysed using an appropriate statistical 
model identifying any trends. The model will determine whether the mechanistic effect 
significantly explains or predicts the effect on the other mechanistic or clinical endpoints 
(e.g DAS28-CRP).  In addition, based on the data that we observe in the study, 
probabilities of success will be determined, where the definition of success will be 
dependent on the endpoint. For example, what is the probability that we would observe a 
certain change in DAS28-CRP (i.e., comparatory rate), based on the data that we have 
observed in the study.  Further details regarding the statistical analysis will be outlined in 
the Reporting and Analysis Plan (RAP).
2.
INTRODUCTION
2.1.
Study Rationale
This study is the first experience with GSK2982772, a receptor-interacting protein-1 
(RIP1) kinase inhibitor, in subjects with moderate to severe rheumatoid arthritis (RA) 
who are currently being treated with disease modifying anti-rheumatic drugs (DMARDs).  
All subjects will be allowed to continue standard of care therapy including non-biologic 
DMARDs during the study, provided that the medication type and dose is stable 
throughout the study.
The primary objective of this study has not changed with amendment 03; however the 
dosing regimen does change to GSK2982772 (60 mg three times daily for 84 days). 
The primary objective will be to investigate the safety and tolerability of repeat oral doses 
of GSK2982772 (60 mg three times daily for 84 days).  In addition, a number of 
experimental and clinical endpoints will be employed to obtain information on the 
pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy in subjects 
with moderate to severe RA.
2.2.
Brief Background
RIP1 is a member of the receptor-interacting Serine/Threonine kinase family containing 
an amino-terminal kinase domain, an intermediate domain and a carboxy-terminal death 
domain.  RIP1 is a key signalling node which plays an essential role in inflammation and 
cell death in response to signals including tumor necrosis factor (TNF) family cytokines, 
ligands for toll-like receptor (TLR) 3/TLR4, sensors of viral infection, and interferons 
[Ofengeim, 2013].  Through tight regulation by ubiquitylation, deubiquitylation and 
interaction with its receptors, RIP1 has dual roles as a kinase and a scaffolding protein, 
and serves as an upstream checkpoint for both cell death and survival [Ofengeim, 2013]. 
Detailed understanding of RIP1 kinase function has not been fully elucidated, but it is 
known that RIP1 exerts it signalling functions through both its catalytic kinase activity 
and by acting as a scaffolding protein for signalling complexes.  Recent work has 
demonstrated that RIP1 catalytic kinase activity can regulate TNF-mediated necroptosis 


2015N251670_04
CONFIDENTIAL
203168
16
[Ofengeim, 2013] and noncanonical apoptosis [Wang, 2008, Dondelinger, 2013]. In 
addition, the production of certain inflammatory cytokines can be regulated by RIP1 
kinase activity Investigator’s Brochure (IB) [GlaxoSmithKline Document Number
2014N204126_02].  In contrast, RIP1’s scaffolding function acts to facilitate other
immune processes including TNF mediated classical apoptosis and NF-kB-signalling 
[Ofengeim, 2013, Humphries, 2015].  With this, an inhibitor of RIP1 kinase activity with 
GSK2982772 may fill a unique niche in the treatment of inflammatory conditions
through multiple mechanisms, including inhibition of inflammation-induced cell death 
(necroptosis and apoptosis) and inhibition of the production of certain pro-inflammatory 
cytokines.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by a debilitating, 
progressive polyarthritis that typically affects the small joints of the hands and feet 
[Vasanthi, 2007]. TNF is known to be one of the key cytokines that drives inflammation 
in RA [Choy, 2001].  In animal models, transgenic mice that chronically over express 
low levels of TNF develop a spontaneous polyarthritis that resembles RA in humans 
[Keffer, 1991] and blockade of NFB activation results in the development of a 
spontaneous murine polyarthritis that is RIP1-dependent [Berger, 2014].  In RA patients, 
TNF is detected in high concentrations in both blood and synovial fluid, and expression 
of TNF and its signalling intermediates, including RIP1, have been shown to be 
constitutively increased in PBMCs from RA subjects compared to healthy controls 
[Raghav, 2006].
Synthetic disease modifying antirheumatic drugs (DMARDs) including nonsteroidal anti-
inflammatory drugs, steroids, methotrexate (MTX), sulfasalazine, hydroxychloroquine, 
and leflunomide, are often used alone or in combination in moderate to severe RA; 
however, most DMARDs do not significantly impact disease progression, and may be 
hampered by poor side effect profiles.  Recently, tofacitinib, an oral small molecule 
inhibitor of JAK, was approved for moderate to severe RA, but its long term safety is still 
unknown.  TNF antagonists are used in the treatment of patients with moderate-severe 
disease who have not responded or who have intolerance to traditional DMARDs.  While 
studies have shown that they can improve symptoms and slow the progression of joint 
damage in many patients [Agarwal, 2011], only half of RA patients achieve American 
College of Rheumatology (ACR) 50 criteria, and many become refractory to anti-TNF 
treatments after several years.  In addition to the association with increased rates of 
opportunistic infections across all indications, anti-TNF therapy in RA is linked to lupus-
like syndrome and increased rates of demyelinating disease.  Other biologic therapies 
which inhibit T cell activation (abatacept) or lead to selective B cell depletion (rituximab) 
have shown clinical efficacy in anti-TNF refractory patients, although both carry 
potential risks for serious infection.  Therefore, there remains a high unmet need for safe 
and tolerable therapies that lead to improved rates of clinical remission and increased 
physical function in patients with moderate to severe RA.


2015N251670_04
CONFIDENTIAL
203168
17
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To investigate the safety and tolerability of 
60 mg three times daily doses of 
GSK2982772 in subjects with moderate to 
severe Rheumatoid Arthritis.

Adverse events.

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis).

Vital sign measurements (blood pressure, 
heart rate, respiratory rate, and body 
temperature).

12-Lead ECG monitoring.
Secondary

To investigate the plasma concentrations 
of GSK2982772 following 60 mg three 
times daily doses of GSK2982772 in 
subjects with moderate to severe 
Rheumatoid Arthritis.

Pre-dose concentrations of GSK2982772 
on Days 8, and 43 (Week 6).  

Post-dose concentrations of GSK2982772 
on Days 1, 8, and 43 (Week 6) at 1, 2, 4 
and 6 hours.

Trough concentrations on Day 85 (Week
12).

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
inflammatory biomarkers in blood subjects 
with moderate to severe Rheumatoid 
Arthritis.

Change from baseline in blood 
inflammatory markers (e.g., may include 
but not limited to CRP, IL6, MMP-1, MMP-
3, MMP-13, TIMP-1, MCP-1, MIF, 
MRP8/14 and other markers encompassed 
by Vectra DA).

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on bone 
and synovial parameters as measured by 
MRI and DCE-MRI in subjects with 
moderate to severe Rheumatoid Arthritis.

Change from baseline in MRI parameters 
in the most affected hand/wrist.  MRI 
parameters may include assessment of 
bone erosions, synovitis, bone oedema 
and joint space narrowing as assessed in 
the OMERACT-RAMRIS (Outcome 
Measures in Rheumatology, Rheumatoid 
Arthritis Magnetic Resonance Image 
Scoring System) scoring system, the
RAMRIQ (rheumatoid arthritis MRI 
quantitative) scoring system, the modified 
CARLOS (Cartilage Loss Scoring System) 
and additional exploratory endpoints as 
data permit.
Change from baseline in synovial 
inflammation as measured by dynamic 
contrast enhanced (DCE)-MRI in the most 
affected hand/wrist:

Exchange rate (Ktrans)


2015N251670_04
CONFIDENTIAL
203168
18
Objectives
Endpoints

Interstitial volume (Ve)

Plasma volume (Vp)

Initial rate of enhancement (IRE)

Maximal signal intensity enhancement 
(ME)

Joint volume

Enhancing volume

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
clinical disease activity in subjects with 
moderate to severe Rheumatoid Arthritis.

Change from baseline in Disease Activity 
Score (DAS) 28-CRP scores.

Proportion of subjects achieving 
categorical DAS28-CRP response 
(moderate/good EULAR response) at each 
assessment time points.

Proportion of subjects achieving 
categorical ACR20/50/70 response.

To investigate the effect of 60 mg three 
times daily dosing of GSK2982772 on 
methotrexate (MTX) concentrations 

Plasma concentrations of MTX pre-dose 
GSK2982772 on Days 1, 8, and 43 (Week 
6).
Exploratory 

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on 
inflammatory biomarkers in synovial tissue 
in subjects with moderate to severe 
Rheumatoid Arthritis.

Change from baseline in CD68+ 
macrophages, CD55+ fibroblast-like 
synoviocytes and a number of infiltrating 
CD3, CD22, CD138 inflammatory cells, 
and synovial inflammatory biomarkers 
including, but not limited to VEGF, IL-1β, 
IL-6, TNFα, and MMP-1.

To investigate pathway and target 
engagement following 60 mg three times 
daily doses of GSK2982772 in blood and 
synovial tissue in subjects with moderate to 
severe Rheumatoid Arthritis.

Pharmacology biomarker endpoints may 
include, but are not limited to the following, 
pre-dose at Days 1, 43 (Week 6) and 
trough on Day 85 (Week 12), as applicable 
and if evaluable samples and data permit:
Target Engagement Assay RIP1 
(TEAR1) in blood and synovial tissue.
Total or phosphorylated RIP1, MLKL, 
and RIP3, cleaved and total caspase 
3 and caspase 8 signatures in 
synovial tissue.


2015N251670_04
CONFIDENTIAL
203168
19
Objectives
Endpoints

To investigate the concentration of 
GSK2982772 and possible drug-related 
material, as well as specific distribution 
within tissue if feasible, in the synovial 
tissue after 60 mg three times daily doses 
of GSK2982772.

Pre-dose GSK2982772 synovial tissue 
biopsies and possible drug-related material 
concentrations, as well as specific 
distribution within tissue  if feasible, on Day 
43 (Week 6), as evaluable samples and 
data permit

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on the 
quality of life of subjects with moderate to 
severe Rheumatoid Arthritis.

Change from baseline in Health 
Assessment Questionnaire Disability Index 
(HAQ-DI).

Change from baseline in RA symptom 
questionnaire score.

Change from baseline in Functional 
Assessment of Chronic Illness Therapy 
(FACIT)-Fatigue.

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on gene 
expression in the blood of subjects with 
moderate to severe Rheumatoid Arthritis.

Transcriptomic analysis of mRNA isolated 
from blood pre-dose on Days 1 and 43 
(Week 6) and trough on Day 85 (Week 12).

To investigate the effect of 60 mg three 
times daily doses of GSK2982772 on gene 
expression in synovium of subjects with 
moderate to severe Rheumatoid Arthritis.

Transcriptomic analysis of mRNA isolated 
from synovial tissue pre-dose on Days 1 
and 43 (Week 6).


2015N251670_04
CONFIDENTIAL
203168
20
4.
STUDY DESIGN
4.1.
Overall Design
This is a multicentre, randomised, double-blind (sponsor-unblinded), placebo-controlled 
study to investigate the safety and tolerability, PK, PD, and preliminary efficacy of 
GSK2982772 in subjects with moderate to severe RA.  The study design schematic is 
depicted in Figure 2 below.
Figure 2
Study Overview
Amendment 03:
Prior to amendment 03:
Key assessments:
Safety assessments, PK samples, DAS28-CRP, 
ACR20/50/70, FACIT-fatigue, Rheumatoid Arthritis Symptom 
and Impact Diary, HAQ-DI assessments, MRI, PD samples
4.2.
Treatment Arms and Duration
It is anticipated that the total duration of participation in the study will be approximately 
20 weeks from screening to the last study visit. 
4.2.1.
Screening
Within 30 days of the screening visit (defined as day of consent signing), subjects who 
are eligible will enter the treatment period and start treatment (or dosing) on Day 1.


2015N251670_04
CONFIDENTIAL
203168
21
4.2.2.
Treatment Period
Subjects will be randomly assigned to either GSK2982772 60 mg or placebo orally three 
times daily (approximately 8 hours apart) for 84 days (12 weeks).  Subjects that were 
randomised prior to protocol amendment 03 being approved in each country were 
randomly assigned to either GSK2982772 60 mg or placebo orally two times daily 
(approximately 12 hours apart) for 84 days (12 weeks). 
Further guidance and information for study treatment and dosing are provided in the 
Study Reference Manual (SRM).  
During the 84 day (12 week) treatment period, subjects will attend the clinical site for 
visits on Days 1, 8, 15, 29, 43, 57, 71 and 85.  At specific visits, subjects must not take 
study treatment prior to their scheduled visit (see Section 7.1).  On Days 22, 36, 50, 64 
and 78, each subject will be contacted by telephone and asked about their general health, 
study medication compliance and diary card completion. Subjects will be given a diary 
card at each of the visits on which they will be instructed to record their daily study 
medication and concomitant medication taken and any adverse events.
4.2.3.
Follow-up Period
After the Treatment Period, the subject will enter the Follow-up Period which lasts for 
28 days post the last administration of study medication, in order to complete follow-up 
assessments per the Time and Events Table (see Section 7.1).
4.3.
Type and Number of Subjects
A sufficient number of subjects will be screened so that approximately 24 subjects with 
moderate to severe RA are randomised into the study on a TID regimen.  Prior to 
protocol amendment 3 being approved in each country, no more than 18 subjects will be 
randomised into the study on a BID regimen.  Should the overall drop-out rate be higher 
than anticipated, additional or replacement subjects may be randomised (up to an overall
maximum of 48) into the study at the discretion of the Sponsor.
4.4.
Design Justification
As this is the first trial of GSK2982772 in subjects with RA, the primary endpoint is the 
safety and tolerability of GSK2982772.  In addition, this study will include assessments 
of target engagement and downstream PD effects of GSK2982772, to understand whether 
GSK2982772 is inhibiting the pathway of interest in this disease.
The 12 week duration of treatment is based on review of previous proof of mechanism 
and proof of concept studies in RA and is limited by the supporting 13 week toxicology 
studies. It is expected that an effective therapy should cause group level changes in the 
mechanistic parameters by the 12 week time point. 
The subjects will be randomised in a 2:1 ratio to GSK2982772 60 mg three times daily 
(TID) and placebo respectively.  The primary objective of this study is to assess safety 
and tolerability, and assessment of this is most valuable in a placebo controlled study. 


2015N251670_04
CONFIDENTIAL
203168
22
The placebo group was also deemed necessary as autoimmune diseases naturally 
fluctuate in severity.  However, the size of the placebo group has been kept to a 
minimum.  All subjects will be allowed to continue standard of care therapy including 
non-biologic DMARDs during the study, provided that the medication and dose is stable 
throughout the study.
4.5.
Dose Justification
The initial selection of the 60 mg BID dose being tested in this study is based on the 
safety, PK, and PD data from the First Time in Human (FTiH) study, 200975.  
GSK2982772 administered at 60 mg BID for 14 days was well tolerated and no safety 
concerns were identified. A BID dosing regimen was initially selected over a QD dosing 
regimen due to the short half-life of GSK2982772 in humans (~2h).  Based on 
preliminary PK/PD modelling of ex-vivo RIP1 target engagement and GSK2982772 
concentrations from the multiple dose ascending part of Study 200975, a 60 mg BID dose 
was predicted to have on average 95% RIP1 target engagement in blood and 
approximately 90% of subjects will have >90% target engagement in blood at Cmin using 
a novel in-house ex-vivo PD/target engagement assay based solely on the TNF pathway 
which is believed to be a key component of the RIP1 pathway.  
However, based on final PK/PD modelling from the full repeat dose part of the Study 
200975 (up to 120 mg BID), a 60 mg BID dose is now predicted to have on average 99% 
RIP1 target engagement in blood and approximately 90% of subjects will have >85% 
target engagement at Cmin. This is lower than our target of achieving >90% target 
engagement in at least 90% of subjects at Cmin.  Therefore, a 60 mg TID cohort is now 
being proposed.  
The Cmin values at 60 mg TID are predicted to be approximately 3.5 fold higher than for 
60 mg BID.  Using the final PK/PD, a 60 mg TID dose is predicted to have on average 
99% RIP1 target engagement in blood and approximately 90% of subjects will have 
>96% target engagement at Cmin.  No data are currently available about the distribution of
GSK2892772 into the synovium.  Based on data in non-steroidal anti-inflammatory drugs 
(NSAIDs), the synovial fluid concentrations fluctuate to a much lesser extent than those 
in plasma [Netter, 1989].  Peak drug concentrations are generally lower in synovial fluid 
but are similar to plasma at later time points.  Assuming the same is true for 
GSK2982772, a 60 mg TID dose should provide similar RIP1 target engagement at the 
site of action as predicted in blood.
In addition, because of the short half-life, a modified release formulation is now being 
developed with the aim to provide a once daily dosing regimen.  By increasing the 
frequency of dosing to three times daily (TID) with the current immediate release 
formulation, this will more closely match the PK, safety and efficacy profile of a 
preferred once daily modified release formulation.
The safety of increasing the dose frequency to 60 mg TID is justified based on 
nonclinical safety findings to date with GSK2982772. It is anticipated that a human dose 
of 60 mg TID (180 mg/day) will produce AUC(0-24) and Cmax values of approximately 
9.9 ug.h/mL and 0.8 ug/mL, respectively, which are approximately 1/5th and 1/15th of the 


2015N251670_04
CONFIDENTIAL
203168
23
gender-averaged AUC (48.4 ug.h/mL) and Cmax (12.3 ug/mL) achieved in the 13 week 
monkey study at the no adverse effect level (NOAEL) dose of 30 mg/kg/day. Please see 
GSK2982772 IB [GlaxoSmithKline Document Number 2014N204126_02].
As of 03 Apr 2017, a total of approximately 93 subjects across 4 clinical studies have 
been randomised to receive GSK2982772. In Study 200975, GSK2982772 administered 
up to 120 mg BID for 14 days and was well tolerated and no safety concerns were 
identified. A total of 9 subjects had received 120 mg BID in that study.  Please see 
GSK2982772 IB [GlaxoSmithKline Document Number 2014N204126_02]. In the 
ongoing Phase 2a studies in Psoriasis [(PsO); Study 203167] and Rheumatoid Arthritis 
[(RA); Study 203168], a total of 26 subjects have been randomised to GSK2982772 60 
mg BID. GSK2982772 was well tolerated and no drug-related SAEs have been reported.  
In Study 203167, there was a death of a 19 year old male subject due to an accidental 
overdose with 3,4-methylenedioxy-methamphetamine (MDMA) that was not considered 
drug related by the Principal Investigator (PI). 
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2982772 can be found in the IB [GlaxoSmithKline Document Number
2014N204126_02].  The following section outlines the risk assessment and mitigation 
strategy for this protocol:


2015N251670_04
CONFIDENTIAL
203168
24
4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK2982772 
Central Nervous System (CNS) effects
Non-clinical data: 
In the 4-week GLP toxicology study, CNS findings were 
observed in 4/12 monkeys which were administered 100 or 
300 mg/kg/day.  CNS findings included uncoordination, 
irregular gait, trembling, hunched appearance, and 
decreased activity. The clinical relevance of these findings 
in humans is not known.  The NOAEL for this study was
determined at 10 mg/kg/day.
In the 13-week GLP toxicology study, there were no CNS 
findings observed in monkeys administered 10, 30 or 100 
mg/kg/day.  The NOAEL for this study was determined at 
30 mg/kg/day.  
Clinical data:
A First Time in Human (FTiH) study with single ascending 
and multiple ascending dose study has been performed in 
67 healthy male volunteers to date.  See Investigator’s 
Brochure (IB) [GlaxoSmithKline Document Number 
2014N204126_02].  No drug-associated CNS adverse 
events were identified and no Serious Adverse Effects 
(SAEs) were reported.
Subject Selction:

Subjects with known history of significant neurologic 
disorders including but not limited to progressive 
multiple sclerosis (MS), Amyotrophic lateral sclerosis 
(ALS), Alzheimer’s and dementia will be excluded.

Individuals with potentially increased susceptibility for 
neurologic effects will be excluded based on medical 
history at screening.
Subject Monitoring:

Subjects will be monitored for standard CNS-related 
adverse events.
Immunosuppression
The possibility of immunosuppression, including an 
increase in the frequency and/or severity of infection, may 
result from the intended pharmacologic effect of 
GSK2982772.  This may be enhanced in subjects taking 
Subject Selection:

Subjects with recurrent, chronic or active infections 
will be excluded from the study.

Subjects will be screened for TB, HIV, Hepatitis B and 


2015N251670_04
CONFIDENTIAL
203168
25
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
other immunomodulating drugs or corticosteroids.
Clinical data:
In the FTiH study, no SAEs were reported.  One subject 
experienced an Adverse Effect (AE) herpes zoster 
approximately 27 days after receiving his last dose with 
GSK2982772 or placebo.  The blinded Investigator 
determined this to be potentially drug-related.
C, and excluded from the study if positive.
Subject Monitoring:

Subjects will be monitored for signs of infection.

See Individual Stopping Criteria for atypical or 
opportunistic infections (Section 5.4.1).
Vaccinations
There is a theoretical risk that GSK2982772 could 
decrease an individual’s immune response to vaccines or 
allow symptoms to develop following vaccination with a live 
vaccine when administered while on therapy.
Subject Selection:

Attenuated or live vaccines should not be 
administered to subjects from 30 days prior to the first 
dose of GSK2982772, during the study and for 5 half-
lives plus 30 days (total 32 days) after GSK2982772 
is discontinued.

If indicated, non-live vaccines (e.g. inactivated 
influenza vaccines) may be administered while 
receiving GSK2982772 based on a treating physician 
assessment of the benefit:risk (e.g., risk of theoretical 
decreased responsiveness). 

Investigators will be expected to have followed local 
and/or national guidelines with respect to 
vaccinations, including against influenza and 
pneumococcus, in subjects with RA.
Respiratory
Non-clinical data:
In the single dose Safety Cardiovascular (CV) and 
Respiratory Study in monkeys, a decrease in minute 
volume (MV) and respiratory rate was observed at all 
doses (10, 100, and 300 mg/kg).  These findings were 
noted to be reversible and mild in severity
In a 14-day repeat dose Safety Respiratory Study in 
monkeys, no respiratory effects on total pulmonary 
Subject Monitoring:

Subjects should be monitored for standard 
respiratory-related adverse events.

Vital signs will be monitored during study visits.


2015N251670_04
CONFIDENTIAL
203168
26
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
ventilation (minute volume) or respiratory rate were 
observed at doses of 1 or 10 mg/kg/day. See IB for
GSK2982772 [GlaxoSmithKline Document Number
2014N204126_02].
Clinical data:
In the FTiH study, repeat doses of GSK2982772 were 
administered x 14 days in 36 healthy male volunteers. 
Extensive respiratory monitoring with end-tidal CO2 
(ETCO2), oxygen saturation (SpO2) and nocturnal 
respiratory rate monitoring was performed.   No SAEs 
occurred, and no drug-associated respiratory-related 
adverse events were identified.
Suicidality
GSK2982772 is considered to be a CNS-active drug based 
upon pre-clinical studies.
Clinical data:
In the FTiH study, there have been some reports of 
lethargy, abnormal dreams, and depressed mood.  No 
events of suicidal ideation or behaviour or changes in 
behaviour were reported. 
Subject Selection:

Subjects with a current history of suicidal ideation and 
behaviour (SIB) as measured using the Columbia 
Suicide Severity Rating Scale (C-SSRS) or a history 
of attempted suicide will be excluded from the study.
Subject Monitoring:

Subjects should be monitored appropriately and 
observed closely for suicidal ideation and behaviour 
or any other unusual changes in behaviour.

Baseline and treatment emergent assessment of 
suicidality will be conducted by trained site personnel 
using the (Columbia Suicide Severity Rating Scale) C-
SSRS in all subjects.  See Section 7.3.7.
Reproductive toxicity
Non-clinical data:
In an early rat embryofetal development study, there was 
no maternal or developmental toxicity at doses 200 
mg/kg/day.
In a rabbit embryofetal development study, GSK2982772 
was administered at doses of 0, 10, 100, 300 or 600 
mg/kg/day on gestation day 7 to 19.  No developmental 
toxicity was evident at doses up to 300 mg/kg/day.
Subject Selection:

Male and female subjects of childbearing potential will 
be included in this study only if they agree to use 
highly effective methods of contraception and avoid 
conception for defined periods of time before first 
administration of study drug until 30days (females) 
and 90 days (males) after the last administration of 
study drug (Appendix 6).


2015N251670_04
CONFIDENTIAL
203168
27
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy

Females of childbearing potential will undergo serum 
pregnancy test at screening and then urine pregnancy 
testing at regular intervals during the study. 

Pregnant and lactating females are not eligible for 
inclusion in the study.
Withdrawal Criteria:

If a female subject should become pregnant during 
the study, study medication should be discontinued.  
The 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.
Drug Interaction
Non-clinical data:
In vitro studies with GSK2982772 assessing potential drug-
drug interactions with Cytochrome P450 3A4 (CYP3A4) 
substrates, P-glycoprotein (Pgp) inhibitors and OAT3 
substrates were completed.  To date, formal drug 
interaction studies in humans have not been performed 
with GSK2982772. 
There is a low risk that GSK2982772 could be a 
perpetrator of OAT3 substrates.  MTX is an OAT3 
substrate in which GSK2982772 could potentially impair 
the clearance of MTX.
There is a low risk that GSK2982772 could be an inducer 
of CYP3A4 and therefore may lower circulating levels of 
concomitant medications that are metabolised by CYP3A4 
when co administered with GSK2982772.
GSK2982772 is a Pgp substrate and therefore co 
administration with concomitant medications that are Pgp 
Subject Selections:

Subjects who are taking concomitant medications 
known to inhibit Pgp or are CYP3A4 narrow 
therapeutic index (NTI) substrates will be excluded 
from the study.  See Section 6.11.2 for a 
comprehensive list of medications.
Subject Monitoring:

Subjects’ concomitant medication usage will be 
reviewed prior to inclusion and monitored throughout 
the study.

Subjects should be monitored throughout the study 
for potential effects of interaction between 
GSK2982772 and other concomitant medications.

PK sample collection to evaluate the potential 
interaction of GSK2982772 and MTX will be 
performed throughout the study.

Subjects should be monitored for potential effects of 
interaction between GSK2982772 and MTX.

Clinical laboratory results (e.g., liver function tests) 


2015N251670_04
CONFIDENTIAL
203168
28
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
inhibitors could increase circulating levels of GSK2982772.
See Section 4.3.6 of the GSK2982772 IB [GlaxoSmithKline 
Document 2014N204126_02].
are routinely being monitored throughout the study.
Study Procedures
Synovial Joint  Biopsy
Potential risks of the procedure include discomfort, 
infection or bleeding.
Note:  Synovial biopsies are optional and not required on 
all subjects.
Subject Selection:

Subjects with known allergy to lidocaine or other local 
anaesthetics will not be included in the biopsy portion 
of the study.

Subjects with a platelet count 100 x 109/L will be 
excluded from participation.
Subject Management:

The biopsies will be performed under ultrasound or 
arthroscopic guidance.  Subjects will be given 
instructions for aftercare and contact information 
should there be any adverse reactions after the 
procedure.

Biopsy site healing will be monitored during the study 
as part of AE safety review. 
Gadolinium (Gd) containing MRI contrast agents
Non-clinical data:
Animal studies have shown reproductive toxicity of 
gadolinium (Gd)-containing MRI contrast agents at 
repeated high doses.
Clinical data:
Use of MRI contrast agents in subjects with severely 
impaired rental function (GFR<30mL/minute) has been 
associated with Nephrogenic Systemic Fibrosis (NSF).  In 
subjects with severely impaired renal function, the benefits 
of the use of contrast agents should be carefully weighed 
Subject Selection:

Pregnant or lactating females will be excluded from 
taking part in the study.

Subjects with impaired renal function 
(GFR<60mL/minute) are excluded by the eligibility 
criteria.

Subjects with history of sensitivity to Gd-containing 
contrast agents will be excluded from the study.  The 
MRI procedure will be conducted under the 
supervision of trained and qualified clinical staff that is 
trained to appropriately manage an allergic reaction.

Sites will be responsible for following any additional 


2015N251670_04
CONFIDENTIAL
203168
29
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
against the risks.
Gadolinium (Gd) contrast agents can be associated with 
anaphylactoid/hypersensitivity or other idiosyncratic 
reactions, characterized by cardiovascular, respiratory, or 
cutaneous manifestations, and ranging to severe reactions 
including shock.  In general, subjects with cardiovascular 
disease are more susceptible to serious or even fatal 
outcomes of severe hypersensitivity reactions.
The risk of hypersensitivity reactions may be higher in 
cases of:

Previous reaction to contrast media

History of bronchial asthma

History of allergic disorders
Most of these reactions occur within half an hour of 
administration.  Delayed reactions (after hours or several 
days) have been rarely observed.
safety information for the specific Gd contrast agent 
used at their site and not enroll subjects if 
contraindicated.
Subject Monitoring and Management: 

MRI contrast at a dose less than or equal to 
0.1 mmol/kg per imagining session at baseline and 
Days 43 and 85 will be used in the MRI protocol.

Effective contraception is required during the study, 
and pregnancy testing will be performed regularly 
throughout the study and prior to dosing in females of 
child bearing potential.
Other 
Exposure to a high field MRI magnet
Certain prostheses or foreign bodies might be incompatible 
with the MRI scanner.
Subject Selection:

All participants will be screened according to local 
hospital criteria and study inclusion/exclusion before 
entering the MRI scanner to ensure they are able to 
have the MRI conducted.  Subjects with non-magnetic 
resonance compatible metal implants or implantable 
electronic devices (e.g., pacemaker, defibrillator) will 
not be included in this study.


2015N251670_04
CONFIDENTIAL
203168
30
4.6.2.
Benefit Assessment
There are additional treatment options available for subjects who have an inadequate 
response to current therapies for RA.  It is possible that treatment with GSK2982772 may 
be effective in the treatment of RA, as the FTiH study demonstrated that the drug 
engaged with the target and produced ex vivo PD effects in suppression of RIP1-
dependent cytokines MIP1and MIP1[GlaxoSmithKline Document Number
2014N204126_02].  There will be limited direct benefit to the subject through their 
contribution to the process of developing new therapies in an area of unmet need.  
4.6.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with GSK2982772 are justified by the 
anticipated benefits that may be afforded to patients with RA by contributing to the 
understanding of the disease and the development of new therapies for patients with these 
conditions in the future.  
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 (IP) or other study 
treatment that may impact subject eligibility is provided in the IB [GlaxoSmithKline 
Document Number 2014N204126_02].
In addition, Investigators are expected to follow local and/or national guidelines with 
respect to vaccinations, including vaccinations for influenza and pneumococcus, in 
subjects with RA.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. Between 18 and 75 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Subjects that do not have any medical conditions, other than moderate to severe RA 
that in the opinion of the Investigator put the subject at unacceptable risk or interfere 
with study assessments or integrity of the data.  These medical conditions should be 


2015N251670_04
CONFIDENTIAL
203168
31
stable at the time of screening and are expected to remain stable for the duration of 
the study. 
3. Subject has had a confirmed diagnosis of rheumatoid arthritis according to the revised 
2010 American College of Rheumatology/European League Against Rheumatism 
ACR-EULAR classification criteria.
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) at screening.
5. Swollen joint count of ≥4 (28-joint count) and tender joint count ≥4 (28-joint count) 
at screening.
6. Subject has a DAS28 CRP disease activity score of 3.2 and CRP ≥5.0 mg/L 
(4.76 nmol/L) at screening.
7. Subject must have received at least 12 weeks of non-biologic DMARD monotherapy 
or methotrexate (MTX)/DMARD combination therapy prior to screening AND must 
be on stable dose throughout the study.
8. Subject is naive to any biological therapies for RA 
OR
Subject may have had previous exposure to a single anti-TNF biologic agent which 
was discontinued for reasons other than primary non-response more than 8 weeks (or 
5 half-lives whichever is longer) from first dose.  Note:  Exposure to a single anti-
TNF is not required in addition to Inclusion #7 above.
9. For subjects who have consented to synovial joint biopsy:
a.
Subject has an involved knee, wrist, or ankle suitable for biopsy, as assessed 
by a rheumatologist at screening.
WEIGHT
10. A body mass index (BMI) within range of 18.5 - 35 kg/m2 (inclusive) at screening.
SEX
11. Male and female subjects 
Males:
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements in Appendix 6.
Females: 
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:
a.
Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation


2015N251670_04
CONFIDENTIAL
203168
32
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 (see 
Appendix 6) if they wish to continue their HRT during the study.  Otherwise, 
they must discontinue HRT to allow confirmation of post-menopausal status 
prior to study enrolment.
b. Reproductive potential and agrees to follow one of the options listed in the Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Appendix 6) from 30 days prior to the first dose of 
study medication and until at least 30 days after the last dose of study medication and 
completion of the follow-up visit.
The Investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
INFORMED CONSENT
12. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
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. Subject with a positive anti-double stranded deoxyribonucleic acid (DNA [anti-
dsDNA]) and confirmed diagnosis of systemic lupus erythematosus (SLE).
2.
Subject with current history of Suicidal Ideation Behaviour (SIB) as 
measured using the Columbia Suicide Severity Rating Scale (C-SSRS) or a history of 
attempted suicide.
3. An active infection, or a history of infections as follows:

Hospitalisation for treatment of infection within 60 days before first dose 
(Day 1).

Currently on any suppressive therapy for a chronic infection (such as 
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and 


2015N251670_04
CONFIDENTIAL
203168
33
atypical mycobacteria).

Use of parenteral (IV or intramuscular) antibiotics (antibacterials, antivirals, 
antifungals, or antiparasitic agents) for an infection within 60 days before first 
dose.

A history of opportunistic infections within 1 year of screening (e.g. 
pneumocystis jirovecii, CMV pneumonitis, aspergillosis).  This does not 
include infections that may occur in immunocompetent individuals, such as 
fungal nail infections or vaginal candidiasis, unless it is of an unusual severity 
or recurrent nature.

Recurrent or chronic infection or other active infection that, in the opinion of 
the Investigator might cause this study to be detrimental to the patient.

History of TB, irrespective of treatment status.

A positive diagnostic TB test at screening defined as a positive 
QuantiFERON-TB Gold test or T-spot test.  In cases where the QuantiFERON 
or T-spot test is indeterminate, the subject may have the test repeated once, 
but they will not be eligible for the study unless the second test is negative. In 
cases where the QuantiFERON or T-spot test is positive, but a locally-read 
follow up chest x-ray, shows no evidence of current or previous pulmonary 
tuberculosis, the subject may be eligible for the study at the discretion of the 
Investigator and GSK Medical Monitor.
4. QTc >450msec or QTc >480msec for subjects with bundle branch block at screening.
The QTc is the QT interval corrected for heart rate according to either Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), or another method, machine or manual 
over read.
The specific formula that will be used to determine eligibility and discontinuation for 
an individual subject should be determined and documented prior to initiation of the 
study. In other words, several different formulae cannot be used to calculate the QTc 
for an individual subject and then the lowest QTc value used to include or discontinue 
the subject from the trial. For purposes of data analysis, QTcB, QTcF, another QT 
correction formula, or a composite of available values of QTc will be used as 
specified in the Reporting and Analysis Plan (RAP).
5. ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%) at screening.
6. Current active or chronic history of liver or biliary disease (with the exception of 
Gilbert’s syndrome or asymptomatic gallstones).
7. Current or history of renal disease or estimated glomerular filtration rate (GFR) by 
Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) 
calculation <60 mL/min/1.73m2 at screening.
8. Hereditary or acquired immunodeficiency disorder, including immunoglobulin 
deficiency.
9. A major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem 
cell/marrow transplant.
10. Any planned surgical procedures including surgical joint procedures (e.g., intra-
articular, tendon sheath, or bursal corticosteroid injections) during the study.
11. A history of malignant neoplasm within the last 5 years, except for adequately treated 


2015N251670_04
CONFIDENTIAL
203168
34
non-metastatic cancers of the skin (basal or squamous cell) or carcinoma in situ of the 
uterine cervix that has been fully treated and shows no evidence of recurrence.
12. Has undergone surgery including synovectomy or arthroplasty on the joint chosen for 
biopsy and/or magnetic resonance imaging (MRI).  
13. The subject has a history of any other joint disease other than RA at the knee, wrist or 
ankle joint chosen for biopsy and/or MRI (e.g., gout, pseudogout, osteoarthritis).
14. Has undergone intra-articular corticosteroid injection, arthrocentesis or synovial 
biopsy on any joint within 6 weeks of screening.
15. A known allergy to lidocaine or other local anaesthetics (Note: only applies to 
subjects who consent for synovial biopsy procedures).
16. Contraindication to MRI scanning (as assessed by local MRI safety questionnaire) 
which includes but are not limited to:

Intracranial aneurysm clips (except Sugita) or other metallic objects,

History of intra-orbital metal fragments that have not been removed by a 
medical professional.

Pacemakers or other implanted cardiac rhythm management devices and non-
MR compatible heart valves,

Inner ear implants,

History of claustrophobia which may impact participation.
CONCOMITANT MEDICATIONS
17. The subject has received treatment with the therapies listed in Section 6.11.2, or 
changes to those treatments, within the prescribed timeframe.  If in doubt, or the 
therapy is not listed please consult with the medical monitor.

Other medications (including vitamins, herbal and dietary supplements) will 
be considered on a case-by-case basis, and will be allowed if in the opinion of 
the Investigator the medication will not interfere with the study procedures or 
compromise subject safety.
RELEVANT HABITS
18. History of alcohol or drug abuse that would interfere with the ability to comply with 
the study.
CONTRAINDICATIONS 
19. 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.
20. Received a live or attenuated vaccine within 30 days of randomization OR plan to 
receive a vaccination during the study until 5 half-lives (or 2 days) plus 30 days after 
receiving GSK2982772.
21. Contraindication to gadolinium contrast agent in accordance with local guidelines.
22. The subject has participated in a clinical trial and has received an investigational 


2015N251670_04
CONFIDENTIAL
203168
35
product within 30 days or 5 half-lives, whichever is longer before the first dose of 
study medication, or plans to take part in another clinical trial at the same time as 
participating in this clinical trial.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
23. Haemoglobin <9 g/dL; haematocrit <30%, white blood cell count ≤3,000/mm3 
(≤3.0 x 109/L); platelet count ≤100,000/µL (≤100 x 109/L); absolute neutrophil count 
≤1.5 x 109/L at screening. For subjects recruited in Germany:   Haemoglobin <11 
g/dL; haematocrit <30%, white blood cell count ≤3,000/mm3 (≤3.0 x 109/L); platelet 
count ≤100,000/µL (≤100 x 109/L); absolute neutrophil count ≤1.5 x 109/L at 
screening.
24. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of study treatment.  As 
potential for and magnitude of immunosuppression with this compound is unknown, 
subjects with presence of hepatitis B core antibody (HBcAb) should be excluded.
25. A positive serology for human immunodeficiency virus (HIV) 1 or 2 at screening. 
26. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 3 months.
27. Exposure to more than 4 investigational medicinal products within 12 months prior to 
the first dose. 
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Section 7.3.1.5).
Subjects who do not qualify to participate in the study due to a screening laboratory value 
or ECG abnormality can repeat the test once within the original screening window, if the 
Investigator believes there is a reasonable possibility that the subject would be eligible if 
re-tested. 
Subjects can be re-screened only on approval of the GSK Medical Monitor and only 
once.  Re-screening is allowed when a subject failed inclusion/exclusion criteria or some 
other screening condition initially, but the Investigator believes there is a reasonable 
probability that the subject would be eligible if re-screened. 
5.4.
Withdrawal/Stopping Criteria
Subjects may be withdrawn from the study for any of the following reasons:

A subject may withdraw from study treatment at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioural or administrative reasons.  If a subject withdraws from the study, 
he/she may request destruction of any samples taken, and the Investigator must 


2015N251670_04
CONFIDENTIAL
203168
36
document this in the site study records.  The reason for withdrawal should be 
documented in the Case Report Form (CRF).

The Sponsor’s request, for reasons such as significant protocol deviations or 
subject safety concern (and after discussion with the Investigator).

If a subject is withdrawn from study treatment, this subject is also considered to 
be withdrawn from the study.

Study is terminated by the Sponsor.
If a subject is withdrawn, the Sponsor may decide to replace that subject and this will be 
done through the Interactive Response Technology System (IRTS).
If a subject chooses to withdraw from the study after dosing then the Investigator must 
make every effort to complete the follow-up assessments detailed in the Time and Events 
Table (Section 7.1).
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the Investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

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”. 
5.4.1.
Individual Safety Stopping Criteria
Study medication will be discontinued in the event of any of the following:

If a subject experiences a serious or severe clinically significant AE that in the 
clinical judgement of the Investigator, after consultation with the medical monitor, 
is possibly, probably or definitely related to investigational product.

The subject becomes pregnant.

The subject initiates treatment with any prohibited medications for the treatment 
of RA as listed in Section 6.11.2.

The subject develops a serious opportunistic or atypical infection.

If any of the liver chemistry stopping criteria (Section 5.4.3), QTc stopping 
criteria (Section 5.4.4), or Haematologic stopping criteria (Section 5.4.5) are met.


2015N251670_04
CONFIDENTIAL
203168
37

The subject experiences any signs of suicidal ideation or behaviour 
(Section 7.3.7).
5.4.2.
Group Safety Stopping Criteria
In addition to the criteria specified above, AEs, SAEs, laboratory abnormalities, ECG 
abnormalities and changes in vital signs occurring across all randomised subjects will be 
regularly reviewed by the Sponsor Safety Review Team (SRT) in order to ensure 
appropriate subject safety.  Any changes to the study due to safety reasons will be 
promptly communicated to the appropriate Regulatory Authorities.
5.4.3.
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). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf


2015N251670_04
CONFIDENTIAL
203168
38
Figure 3
Phase II Liver Chemistry Stopping Criteria – Liver Stopping Events 
Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2.
5.4.3.1.
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.
5.4.4.
QTc Stopping Criteria
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 patients 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


2015N251670_04
CONFIDENTIAL
203168
39

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may 
not be changed or substituted once the subject has been enrolled.
For example, if a subject is eligible for the protocol based on QTcB, then QTcB must be 
used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the 
same formula must continue to be used for that subject for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified ECGs 
are an exception. 

The decision to withdraw a subject will be based on an average QTc value of 
triplicate ECGs.  If an ECG demonstrates a prolonged QTc, obtain 2 more ECGs 
over a brief period (5-10 minutes), and then use the averaged QTc values of the 3 
ECGs to determine whether the subject should be discontinued from the study.
5.4.5.
Haematologic Stopping Criteria
Study treatment will be stopped for a subject if any of the following haematological 
stopping criteria is met:

Haemoglobin - an absolute decrease of ≥2 g/dL from baseline (pre-dose Day 1).  For 
subjects enrolled in Germany:  Haemoglobin <9 g/dL (5.58 mmol/L) or an absolute 
decrease of ≥2 g/dL from baseline (pre-dose Day 1).  

Platelets <50 × 109/L
5.5.
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.


2015N251670_04
CONFIDENTIAL
203168
40
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Study Treatment
Product name:
GSK2982772
Placebo
Dosage form:
Tablet
Tablet
Unit dose strength(s)/Dosage 
level(s):
30 mg
NA
Route of Administration
For oral use only
For oral use only
Dosing instructions (with 
amendment 03):
Take TWO tablets three 
times a day as directed by 
your physician
Take TWO tablets three 
times a day as directed by 
your physician
Dosing instructions (prior to 
amendment 03):
Take TWO tablets in the 
MORNING and TWO tablets 
in the EVENING as directed
Take TWO tablets in the 
MORNING and TWO tablets 
in the EVENING as directed
Physical description:
White to almost white, round, 
film coated tablet
White to almost white, round, 
film coated tablet
Source of procurement
Study medication is supplied 
by GlaxoSmithKline
Placebo is supplied by 
GlaxoSmithKline
6.2.
Treatment Assignment
At Screening a unique Subject Number will be assigned to any subject who has signed a 
consent form.  The unique Subject Number will be used to identify individual subjects 
during the course of the study.  Any subject that is re-screened outside of the allowed 
screening window at the approval of the GSK Medical Monitor, must be assigned a new 
unique Subject Number.
Subjects who meet screening eligibility criteria will be randomised to a treatment group 
through an Interactive Response Technology System (IRTS).  The IRTS will confirm the 
subject’s CRF number (Subject Number) and provide the randomisation number, where:

A randomisation number will be assigned from a randomisation schedule 
generated by Clinical Statistics, prior to the start of the study, using validated 
internal software.  Once assigned, this number must not be reassigned to any other 
subject in the study.


2015N251670_04
CONFIDENTIAL
203168
41
Therefore, the randomisation is centrally controlled by the IRTS.
Subjects will be randomised to receive either GSK2982772 or placebo in a 2:1 ratio.
6.3.
Planned Dose Adjustments
No dose adjustments are allowed.
6.4.
Blinding
This will be a double blind (sponsor unblinded) study and the following will apply:

Sponsor unblinded refers only to the Data Review Committee, consisting of the 
GSK Project Physician Lead (PPL), study statistician, study pharmacokineticist, 
Pattern Recognition Receptor (PRR) Discovery Performance Unit (DPU) Head, 
Early Development Lead (EDL) and Safety Review Team (SRT) Leader, or their 
designees on an ongoing basis.  A physician external to the GSK2982772 project 
team may also be involved in the data review.  A data review charter will identify 
the specific GSK individuals involved; outline in detail the activities of this 
review, and how the integrity of the study will be maintained. The rest of the core 
GSK study team will remain blinded.

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 to his/her study staff or GSK, 
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 CRF.

A subject will be withdrawn if the subject’s treatment code is unblinded by the 
Investigator or treating physician.  The primary reason for discontinuation (the 
event or condition which led to the unblinding) will be recorded in the CRF.

GSK’s Global Clinical Safety and Pharmacovigilance (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.


2015N251670_04
CONFIDENTIAL
203168
42
6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.6.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the Investigator and authorized site staff. 

The Investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

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.  

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the Investigator, where this is required by local laws, or is available 
upon request from GSK.
6.7.
Compliance with Study Treatment Administration
When subjects are dosed at the site, they will receive study treatment directly from the 
Investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study subject identification will be confirmed at the time of dosing.  
When subjects self-administer study treatment(s) at home, compliance with GSK2982772 
and placebo will be assessed and documented through the review of the subject’s diary 
card and querying the subject during the site visits.  A record of the number of 
GSK2982772 or placebo tablets dispensed to and taken by each subject must be 
maintained and reconciled with study treatment and compliance records.  Treatment start 
and stop dates, including dates for treatment delays and/or dose reductions will also be 
recorded in the CRF.
Subjects will be given instructions on compliance and treatment with MTX (if 
applicable).  The date, time and total weekly dose will be recorded in the study diary 
cards and the CRF.


2015N251670_04
CONFIDENTIAL
203168
43
6.8.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2982772 >180 mg daily will be considered an overdose.  
GSK does not recommend specific treatment for an overdose.  The Investigator will use 
clinical judgement to treat any overdose as and when they are made aware of this.
In the event of an overdose, the Investigator or treating physician should:
1. Contact the Medical Monitor immediately.
2. Closely monitor the subject for adverse events (AEs)/serious adverse events (SAEs) 
for at least 48 hours following the last dose of GSK2982772.
3. Obtain a plasma sample for pharmacokinetic (PK) analysis if requested by the 
Medical Monitor (determined on a case-by-case basis).
4. Document all details of the overdose in the CRF.
Decisions regarding dose interruptions or modifications will be made by the Investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.9.
Treatment after the End of the Study
The Investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
Subjects will not receive any additional treatment from GSK after completion of the 
study because the 12 week duration of treatment is limited by the supporting 13 week 
toxicology studies.
6.10.
Lifestyle and/or Dietary Restrictions

Subjects must adhere to the contraceptive requirements listed in Appendix 6.
6.10.1.
Activity

Subjects will abstain from strenuous exercise more than their normal routine for 
48 hours prior to each blood collection for clinical laboratory tests.  

Subjects who have consented to synovial biopsies will abstain from strenuous 
exercise for 24 hours after synovial biopsy procedures.
6.11.
Concomitant Medications and Non-Drug Therapies
6.11.1.
Permitted Medications and Non-Drug Therapies
Selected medications for the treatment of RA may be taken, with specific requirements 
listed in Table 1, and as long as they are not prohibited (Section 6.11.2).  All concomitant 
medications taken during the study will be recorded in the source document and CRF.  
The minimum requirement is that drug name and dates of administration are recorded.


2015N251670_04
CONFIDENTIAL
203168
44
Table 1
Specific Requirements for Permitted Medications During the Study
Drug
Requirement
Methotrexate 
Stable dose regimen (up to 25 mg/week) for at 
least 12 weeks prior to screening and remain on 
this dose throughout the study (unless dose 
must be reduced because of a safety concern).  
MTX should ideally be taken on the same day of 
week and at approximately the same time of 
day throughout the study.
Sulfasalazine
Stable dose regimen for at least 12 weeks prior 
to screening and throughout the study.
Hydoxychloroquine or cholorquinine
Stable dose for at least 12 weeks prior to 
screening and throughout the study.
Leflunomide
Stable dose for at least 12 weeks prior to 
screening and throughout the study.
Folate supplements (minimum of 5 mg/week)
If a subject is on folate supplements with MTX 
treatment, they must be on a stable dose 
regimen for at least 4 weeks prior to 
randomization and throughout the study.
Other oral anti-rheumatic therapies such as 
non-steroidal anti-inflammatory drugs (NSAIDs), 
oral glucocorticords (e.g., prednisolone ≤ 10 mg 
/day.  See Appendix 3 for equivalent doses).
Stable dose regimen for at least 4 weeks prior 
to screening and throughout the study (unless 
reduction required due to adverse effects).
Omit dose on the morning prior to study visits 
until after joint assessments.
6.11.2.
Prohibited Medications and Non-Drug Therapies
Table 2 lists prohibited medications for defined periods of time before and during the 
study until after the follow up visit. 
Subjects who start prohibited medications or therapies as a treatment for RA or other 
reasons during the study will be withdrawn from study treatment for safety reasons.  If in 
any doubt, Investigators are advised to discuss medications with the medical monitor.


2015N251670_04
CONFIDENTIAL
203168
45
Table 2
Prohibited Medications
Therapy
Time period 
A change in dose of methotrexate or other DMARD.
12 weeks prior to screening until after the 
follow up visit (Day 112)
Greater than 10mg/day oral prednisolone (or 
equivalent glucocorticoid) or a change in dose of 
corticosteroid.
4 weeks prior to screening until after the 
follow up visit (Day 112)
Intramuscular glucocorticoids (e.g., 
methylprednisolone ≤120 mg/month)
4 weeks prior to screening until after the 
follow up visit (Day 112)
Intra-articular corticosteroid injections
6 weeks prior to screening and until after 
the follow up visit (Day 112).
Janus Kinase (JAK) Inhibitors
4 weeks prior to screening until after the 
follow up visit (Day 112).
P-glycoprotein (Pgp) inhibitors including but not 
limited to amiodarone, azithromycin, captopril, 
carvedilol, clarithromycin, conivaptan, cyclosporine, 
diltiazem, dronedarone, erythromycin, felodipine, 
itraconazole, ketoconazole, lopinavir, ritonavir, 
quercetin, quinidine, ranolazine, ticagrelor, verapamil 
[FDA, 2012].
4 weeks prior to first dose (Day 1) until 
after the follow up visit (Day 112).
Narrow therapeutic index (NTI) CYP3A4 substrates 
including but not limited to alfentanil, astemizole, 
cisapride, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus, terfenadine [FDA, 2012].
4 weeks prior to the first dose (Day 1) until 
after the follow up visit (Day 112).
Biologic therapies for the treatment of rheumatoid 
arthritis not limited to anti-TNF biologics or other 
biologics, rituximab, anakinra, abatacept or 
tocilizumab.
At any time. 
Exposure to more than one anti-TNF biologic 
therapies for the treatment of RA including but not 
limited to anti-TNF biologics, infliximab, adalimumab, 
etanercept, certolizumab and golimumab.
Exception:  Exposure to a single anti-TNF-biologic 
for which the subject discontinued for a reason other 
than primary non-response is permitted.
Cannot have been exposed to more than 
one anti-TNF biologic or be on at any time 
during the study.
In the case of a single anti-TNF biologic 
for which the subject discontinued for a 
reason other than primary non-response, 
the subject must not be on for 8 weeks or 
5 half lives (whichever is longer) prior to 
first dose until after the follow up visit (Day 
112).  
Live vaccination
Live or attenuated vaccinations are not 
permitted within 30 days of randomization 
or plan to receive a vaccination during the 
study until follow-up visit.  If indicated, 
non-live vaccines (e.g., inactivated 
influenza vaccines) may be administered 


2015N251670_04
CONFIDENTIAL
203168
46
Therapy
Time period 
whilst receiving GSK2982772 based on an 
assessment of the benefit:risk (e.g., risk of 
decreased responsiveness).  Investigators 
are expected to follow local and/or 
national guidelines with respect to 
vaccinations, including against 
pneumococcus and influenza, in subjects 
with RA.
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 (Section 7.1), are essential and required for study 
conduct.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the SRM and laboratory manual.  The SRM will provide the site personnel 
with administrative and detailed technical information that does not impact subject safety.
This section lists the procedures and parameters of each planned study assessment.  The
timing of each assessment is listed in the Time and Events Table Section 7.1

At study visits, the Patient Reported Outcomes (PROs) should be completed 
prior to any other study assessments.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic/biomarker or others assessments may be 
altered during the course of the study based on newly available data (e.g., to 
obtain data closer to the time of peak concentrations) to ensure appropriate 
monitoring. 

The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment. 

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.

The Institutional Review Board/Independent Ethics Committee (IRB/IEC) will 
be informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the Informed Consent Form. 


2015N251670_04
CONFIDENTIAL
203168
47
7.1.
Time and Events Table
Procedures
Screening (-30)
Treatment Period17
Early Withdrawal18
Follow Up (3)19
Day 1 
Day 8 (3)
Day 15 (3)
Day 22 (3)
Day 29 (3)
Day 36 (3)
Day 43 (3)
(week 6)
Day 50 (3)
Day 57 (3)
Day 64 (3)
Day 71 (3)
Day 78 (3)
Day 85 (+2)
(week 12)
Site Visit
X
X
X
X
X
X
X
X
X
X
X
Phone call
X
X
X
X
X
General/Safety Assessments and Procedures
Informed Consent
X
Subject Demography
X
Full medical history1
X
Inclusion/Exclusion Criteria
X
Full physical exam2
X
X
X
X
Brief physical exam
X4
X
X
X4
X
X
Vital signs (BP, HR, RR, temperature)  
X
X4
X
X
X
X4
X
X
X
X
X
12-lead ECG
X3
X4
X
X
X
X4
X
X
X
X
X
Concomitant medication review & AE reporting/SAEs5
X---------------------------------------------------------------------------------------------------------------------------X
PROs/Questionnaires/Diaries/Disease Assessments and Procedures
Columbia Suicide Severity Rating Scale (C-SSRS)
X
X4
X4
X
X
FACIT-fatigue; RA Symptom and Impact Diary6
X4
X4
X
X
HAQ-DI; Patient Assessment of joint pain6
X4
X
X
X4
X
X
X
X
Patient Global Assessment (PtGA)6
X
X4
X
X
X4
X
X
X
X
Tender (28) & Swollen (28) joint count
X
X4
X
X
X4
X
X
X
X
Physician Global Assessment (PGA)
X4
X
X
X4
X
X
X
X
MRI/DCE-MRI7
X4, 20
X4,21
X22
X16


2015N251670_04
CONFIDENTIAL
203168
48
Procedures
Screening (-30)
Treatment Period17
Early Withdrawal18
Follow Up (3)19
Day 1 
Day 8 (3)
Day 15 (3)
Day 22 (3)
Day 29 (3)
Day 36 (3)
Day 43 (3)
(week 6)
Day 50 (3)
Day 57 (3)
Day 64 (3)
Day 71 (3)
Day 78 (3)
Day 85 (+2)
(week 12)
Study Treatment
Randomisation
X
Study medication (three times daily)8
X-------------------------------------------------------------------------------------------------------X
Dispensing of study medication
X
X
X
Dispensing of diary cards
X
X
X
X
X
X
X
Collection and review of diary cards
X
X
X
X
X
X
X
X
Laboratory (Safety) Assessments and Procedures
TB, HIV, HepB,Hep C Ab, Anti-CCP, Anti-dsDNA, RF 
X
FSH & estradiol  (if applicable)
X
Serum pregnancy test (WCBP only)
X
Urine pregnancy test (WCBP only)9
X4
X
X
X
X4
X
X
X
X
X
Haematology, chemistry, urinalysis 
X
X4
X
X
X10
X4
X10
X10
X
X
X
CRP
X
X4
X
X
X4
X
X
X
X
Blood sample for PD inflammatory biomarkers, mRNA, and 
TE11
X4
X4
X
X
PK blood samples GSK298277212
X
X4
X4
X
X
PK blood samples for MTX13
X4
X4
X4
Pharmacogenetic sample (PGx)
X14
Synovial biopsies for PK, inflammatory biomarkers, mRNA, 
target engagement & pathway engagement analysis15
X4,20
X4,21
X16


2015N251670_04
CONFIDENTIAL
203168
49
Footnotes:
1.
Full medical history (includes past and current conditions, medication history, substance usage, and family history of premature CV disease).
2.
Full physical exam (includes height/weight at screening, height not measured at later time points).
3.
Triplicate ECG to be performed at screening only.
4.
Pre-dose.
5.
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.  AEs will be collected from the start of Study Treatment until the follow-up 
contact.  On Days 22, 36, 50, 64, and 78, subjects will be questioned about their general health status via phone call.
6.
All PRO assessments should be conducted on site before any tests, procedures, or assessments, to avoid influencing the subjects’ perception.
7.
DCE-MRI will be performed on all subjects, provided that sites have DCE-MRI capability and experience (e.g., hardware and software requirements). If sites do not have DCE-MRI 
capability or experience, a regular MRI will be performed of the affected hand/wrist.  If the same joint is used for MRI and synovial biopsy, MRI should be performed before biopsy 
(if applicable).
8.
Subjects must take study medication three times a day approximately 8 hours apart. Exact time of dosing to be recorded in diary cards. On Day 1, the first study dose will be 
administered at the site.  On Days 8, 43 and 85 only, subjects must not take their medication at home in the morning. Subjects will complete pre-dose assessments and then will 
be administered their morning dose of medication at site on Days 8 and 43.  On Day 85, subjects are no longer receiving study medication.
9.
If urine pregnancy test is positive, a confirmatory serum pregnancy test must be performed.
10. Haematology and chemistry only.  No urinalysis required on Days 29, 57 and 71.  When clinical laboratory samples are taken on the same day as the MRI, the samples should be 
taken first prior to the administration of the contrast fluid with MRI.  If this is not feasible (i.e. MRI is performed first), it is recommended that a separate IV catheter or straight 
venipuncture be performed in the opposite arm to where the MRI contrast fluid was administered.
11. Blood samples for inflammatory biomarkers, mRNA and target engagement.  See laboratory manual for full details on sample collection, handling and shipment.
12. PK blood samples for GSK2982772 will be taken pre-dose on Days 8 and 43. Post-dose serial PK samples will be taken on Days 1, 8 and Day 43 at the following time points: 1, 2, 
4, and 6 hours. A trough PK sample will be taken on Day 85 or at Early Withdrawal.
13. Only applicable if subjects are on MTX: PK blood samples for MTX will be taken pre-dose GSK2982772 on Day 1 (MTX alone), on Days 8 and 43 (MTX + GSK2982772).  
Subjects who are on MTX should ideally take their MTX dose on the same day of the week at approximately the same time of the day throughout the study. In addition, the Day 1, 
8 and 43 visits should ideally be on the same day of the week.
14. A PGx blood sample is collected at the baseline visit, after the subject has been randomised and provided informed consent for genetic research.  If the sample is not collected at 
the baseline visit, it can be collected at any time during the study after randomisation.
15. Synovial biopsies are optional.
16. Biopsy (if applicable) and MRI only are required at Early Withdrawal visit if subject withdraws after at least 14 days of treatment and prior to Day 43.  If a subject withdraws 
between Days 43 and 57, an MRI is not required at the Early Withdrawal visit.  If a subject withdraws on Day 57 or after, an MRI should be performed at the Early Withdrawal visit.  
A window allowance of 3 days of Early Withdrawal visit is allowed to perform the MRI.
17. Visit windows during the treatment period are relative to Day 1.
18. If a subject withdraws from the study, every effort will be made for the subject to complete an Early Withdrawal visit prior to the Follow Up visit.
19. Follow-up visit should be completed 28 days (3 days) after the last dose of study medication.
20. MRI (and if applicable; a biopsy) may be performed during the screening window as an additional visit (if required) up to 7 days before Day 1 to allow sites flexibility in scheduling.  
The MRI must be completed prior to synovial biopsy (if performed on the same joint).  The site should be reasonably confident that the subject has fully qualified for the study 
(e.g., screening clinical labs, vital signs, physical examination, etc.) before the MRI (and if applicable: a biopsy) is/are performed. 


2015N251670_04
CONFIDENTIAL
203168
50
21. A biopsy (if applicable) and MRI may be performed on a separate day within the Day 43 window allowance (3 days).  A separate visit to perform the MRI followed by synovial 
biopsy (if applicable) is only allowed to accommodate scheduling.  If biopsy is being performed, this visit must be scheduled after the Day 43 visit where the PK, clinical laboratory 
tests and other required Day 43 procedures are performed.  Subjects must not take their study medication at home in the morning before the full Day 43 visit and also the morning 
before MRI and biopsy (if applicable) visit if being done on a separate day. 
22. For MRI performed on day 85, a visit window of up to 2 days after is allowed in order to perform the MRI.


2015N251670_04
CONFIDENTIAL
203168
51
7.2.
Screening and Critical Baseline Assessments
After written informed consent, screening assessments will be performed as outlined in 
the Time and Events Table (Section 7.1).
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/mental health and family history, ECG and laboratory tests will be 
assessed as related to the inclusion/exclusion criteria listed in Section 5.
Cardiovascular medical history/risk factors and smoking history (as detailed in the CRF) 
will be assessed at screening.
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.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  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.
The Investigator will be responsible for determining the clinical significance of any 
results that fall outside of the laboratory normal ranges.
In line with routine pharmacovigilance, an internal GSK Safety Review Team (SRT), 
which will include 203168 study team members, will review blinded safety data, 
including clinical laboratory parameters and adverse events, at appropriate intervals 
during the period of study conduct.
7.3.1.
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. 
7.3.1.1.
Time period and Frequency for collecting AE and SAE information

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. 

AEs will be collected from the start of Study Treatment until the follow-up 
contact (see Section 7.3.1.3), at the time points specified in the Time and Events 
Table (Section 7.1).


2015N251670_04
CONFIDENTIAL
203168
52

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 CRF.

All SAEs will be recorded and reported to GSK within 24 hours, 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.
7.3.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.3.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 5. 
7.3.1.4.
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 CRF will 
be required to be completed.  These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death.
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms.  The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion.


2015N251670_04
CONFIDENTIAL
203168
53
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported.  Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.3.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the Investigator to GSK of SAEs 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.
An Investigator who receives an Investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.3.2.
Pregnancy

Details of all pregnancies in female subjects and female partners of male subjects 
will be collected after the start of dosing and until 30 up to 90 days (as applicable)
after the last dose.

If a pregnancy is reported within 30 days (90 days in partners) after the last dose 
then the Investigator should inform GSK within 2 weeks of learning of the 
pregnancy and should follow the procedures outlined in Appendix 6.
7.3.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
head, eyes, ears, nose, throat, skin, thyroid, joint, lymph nodes, cardiovascular, 
respiratory, gastrointestinal and neurological systems. Height and weight will also 
be measured and recorded at the first physical examination. 

A brief physical examination will include, at a minimum assessments of the lungs, 
cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.


2015N251670_04
CONFIDENTIAL
203168
54
7.3.4.
Vital Signs

Vital signs will be measured in a supine or semi-supine position after 
approximately 5 minutes rest and will include temperature, systolic and diastolic 
blood pressure, pulse rate and respiratory rate. 
7.3.5.
Electrocardiogram (ECG)

Triplicate12-lead ECGs will be obtained at screening and single 12-lead ECGs 
obtained at every time point during the study using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc (F or 
B) intervals.  A manual over read is also allowed. Refer to Section 5.4.4 for QTc 
withdrawal criteria and additional QTc readings that may be necessary.

The QTc should be based on averaged QTc values of triplicate electrocardiograms 
obtained over a brief (e.g., 5-10 minutes) recording period.  

ECG to be measured in a semi-supine position after approximately 5 minutes rest.
7.3.6.
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 Table 
(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 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 CRF.
Refer to the 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:

Haematology, platelets and coagulation sample if they are required to be taken 
closer to the biopsies (as per local practices) than specified in Section 5.4.5.
NOTE:  Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either a treatment and/or response evaluation to be 
performed. If a local sample is required, it is important that the sample for central 
analysis be obtained at the same time.  Additionally, if the local laboratory results are 
used to make either a treatment or response evaluation, the results must be entered into 
the CRF.


2015N251670_04
CONFIDENTIAL
203168
55
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 3. 
Table 3
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
1,2
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 3
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose4
Calcium
Alkaline phosphatise
Albumin
CRP
Triglycerides4
Total Cholesterol4
Fasting HDL 
cholesterol4
Fasting LDL 
cholesterol4
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening and 
RoutineTests

HIV 1 & 2

Hepatitis B (HBsAg)

Hepatitis B core antibody (HBcAb)

Hepatitis C (Hep C antibody)

QuantiFeron Gold Test

T-spot (if QuantiFeron is indeterminant)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Urine hCG Pregnancy test (as needed for women of child bearing 
potential) 5

Serum hCG (as needed for women of child bearing potential) to be 
done at screening and if urine test positive at other time points in the 
study.

Anti-dsDNA

Rheumatoid Factor

Anti-CCP

Estimated glomerular filtration rate (eGFR) will be calculated using 
the CKD-EPI formula.
Footnotes:
1.
The subject’s CBC results from the previous scheduled visit should be checked prior to the synovial biopsy 
procedures according to local practices and may be repeated at the discretion of the investigator.


2015N251670_04
CONFIDENTIAL
203168
56
2.
Details of Haematologic Stopping Criteria are given in Section 5.4.5.
3.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after liver 
stopping or monitoring event are given in Section 5.4.3 and Appendix 2.
4.
No fasting required.  Any abnormal result for glucose or lipids (non-fasted) may be repeated at the discretion 
of the Investigator.
5.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
ethics committee.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study 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.
7.3.7.
Suicidal Risk Monitoring
GSK2982772 is considered to be a CNS-active drug. There has been some concern that 
some CNS-active drugs may be associated with an increased risk of suicidal thinking or 
behaviour when given to some patients with RA.  Although this drug has not been shown 
to be associated with an increased risk of suicidal thinking or behaviour when given to 
healthy volunteers, GSK considers it important to monitor for such events before or 
during clinical studies with compounds such as this.   
Subjects being treated with GSK2982772 should be monitored appropriately for suicidal 
ideation and behaviour or any other unusual changes in behaviour. Study medication 
must be immediately discontinued in all subjects who experience signs of suicidal 
ideation or behaviour.
Families and caregivers of subjects being treated with GSK2982772 should be alerted 
about the need to monitor subjects for the emergence of unusual changes in behaviour, as 
well as the emergence of suicidal ideation and behaviour and to report such symptoms 
immediately to the study Investigator.
At Screening and baseline (pre-dose Day 1), the ‘Baseline/Screening CSSRS’ will be 
completed.  Assessments will be done at Days 43 (Week 6) and 85 (Week 12), the ‘Since 
Last Visit CSSRS’ will be completed.  GSK Version 4.1 of both rating scales will be 
used.
Subjects who answer ‘yes’ to any suicidal behaviour or ‘yes’ to suicidal ideation 
Questions 4 or 5 will be referred to their GP or appropriate psychiatric care and be 
discontinued from study medication.  The Medical Monitor will be notified.  If 
appropriate, an AE or SAE should be reported (see Section 7.3.1 AE and SAE).  In 
addition, the Investigator should complete a Possible Suicidality Related Adverse Event 
(PSRAE) form to collect detailed information on the circumstances of the reported AEs 
which, in the Investigator’s opinion, are possibly suicidality-related.  These may include, 
but are not limited to, an event involving suicidal ideation, a preparatory act toward 
imminent suicidal behaviour, a suicide attempt, or a completed suicide.


2015N251670_04
CONFIDENTIAL
203168
57
7.4.
Efficacy
7.4.1.
Patient Reported Outcomes
Patient Reported Outcomes questionnaires should be completed by subjects before any 
other assessment at a clinic visit.
7.4.1.1.
Rheumatoid Arthritis Symptoms and Impact Diary
Symptoms associated with RA will be assessed using a novel RA Symptom and Impact 
Diary as per Section 7.1, Time and Events Table.  The study staff should not clarify any 
of the questions for the subject.
7.4.1.2.
Patient Assessment of Joint Pain
The severity of the subject’s joint pain will be assessed by completion of a numeric rating 
scale (NRS).  The subject will be asked to select a whole number (0-10 integers) that best 
reflects the intensity of their pain.  The scale is represented by a horizontal bart with “no 
pain” at the lower anchor and “most severe pain” at the upper anchor.  This questionnaire 
should take approximately 1 minute to complete.
The patient assessment of joint pain will be used to calculate ACR responders.
7.4.1.3.
Patient’s Global Assessment of Disease (PtGA)
Subjects will complete a global assessment of disease activity using the patient global 
assessment item, a visual analogue scale (VAS) with anchors “0” (very well) to “10” 
(very poor).
The patient’s global assessment of disease will be used to calculate DAS clinical scores 
and ACR responders.
7.4.1.4.
Disability Index of the Health Assessment Questionnaire (HAQ-DI)
The HAQ-DI will be utilised to assess the subject’s physical function or disability 
according to the subject.  The study staff should not clarify any of the questions for the 
subject.
This 20-question instrument assesses the degree of difficulty a person has in 
accomplishing tasks in 8 functional areas [Fries, 1980]: 

Dressing, arising, eating, walking, hygiene, reach, grip, and common daily 
activities. 
Responses are scored from 0 (no difficulty) to 3 (inability to perform a task in that area). 
The HAQ-DI will be used to calculate ACR responders.


2015N251670_04
CONFIDENTIAL
203168
58
7.4.1.5.
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue 
Scale
Subjects will complete a 13-point fatigue questionnaire using the FACIT-Fatigue 
assessment, a Likert scale from 0 to 4, to “0” (very much fatigued) to“4” (not at all 
fatigued).  This questionnaire should take a few minutes to complete and provides the 
level of fatigue with usual daily activities from the previous week. 
7.4.2.
Clinical Disease Assessments
Brief details are given below and detailed procedural instructions are given in the SRM.  
The sponsor will calculate DAS28(CRP) and ACR (20/50/70) responses at each 
assessment time point as defined below.
7.4.2.1.
Disease Activity Score (DAS) Assessments
The DAS28 is a measure of disease activity.  It is a composite score derived measurement 
weighing given to each component.  
The components of the DAS28 assessment include:

Tender/Painful Joint Count (28)

Swollen Joint Count (28)

CRP

PtGA
7.4.2.2.
American College of Rheumatology Criteria (ACR) Assessments
The ACR Criteria is a standard criteria to measure the effectiveness of treatments from 
placebo.  The ACR’s definition for calculating improvement in RA (ACR20) is 
calculated as a 20% improvement in tender and swollen joint counts and 20% 
improvement in 3 of the 5 remaining ACR-core set measures: patient and physician 
global assessments, pain, disability, and an acute-phase reactant.  Similarly, ACR50 and 
70 are calculated with the respective percent improvement.  
The specific components of the ACR Assessments that will be used in this study are:

Tender/Painful Joint count (28)

Swollen Joint Count (28)

Patient Assessment of Joint Pain

PtGA

PGA

CRP

HAQ-DI


2015N251670_04
CONFIDENTIAL
203168
59
7.4.2.3.
Joint Assessments
Tender Joint Count Assessments
A total of 28 joints will be scored for presence or absence of tenderness.
Swollen Joint Count Assessments
A total of 28 joints will be scored for presence or absence of swelling.
Joint assessments will be used to calculate DAS28 clinical scores and ACR responders.
7.4.2.4.
Measurement of Serum CRP
Blood samples will be collected in order to measure serum CRP concentrations.  The 
CRP is a component of the DAS28, ACR, and Vectra DA clinical scores.
7.4.2.5.
Physician’s Global Assessment of Disease Activity (PGA)
The Investigator or physician designee only will complete a global assessment of disease 
activity using the physician global assessment item, a VAS with anchor’s “0” (none) to 
“10” (extremely active).
Note: 

The Investigator or physician designee should complete the PGA independently of 
the subject.

Ideally, the same Investigator or physician designee should perform all global 
assessments for each subject during the duration of the study.
7.5.
Pharmacokinetics
7.5.1.
Blood Sample Collection
Blood samples for PK analysis of GSK2982772 will be collected at the time points 
indicated in Section 7.1 Time and Events Table.  The actual date and time of each blood 
sample collection will be recorded.  The timing of PK samples may be altered and/or PK 
samples may be obtained at additional time points to ensure thorough PK monitoring.  
For subjects who are on stable doses of methotrexate (MTX), blood samples for PK 
analysis of MTX will be collected at the time points indicated in Section 7.1 Time and 
Events Table.  The actual date and time of each blood sample collection will be recorded.  
Details of blood sample collection, processing, storage and shipping procedures are 
provided in the laboratory manual. 
7.5.2.
Sample Analysis
Plasma analysis will be performed at a bioanalytical site (to be detailed in the SRM) 
under the control of Platform Technology and Science In Vitro/In Vivo Translation (PTS 
IVIVT) and Third Party Resource, GlaxoSmithKline. Concentrations of GSK2982772 


2015N251670_04
CONFIDENTIAL
203168
60
and MTX will be determined in plasma samples using the currently approved 
bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed 
in the SRM).
Once the plasma sample has been analysed for GSK2982772 any remaining plasma
sample may be analysed for other compound-related material and the results may be 
reported under a separate PTS-IVIVT, GlaxoSmithKline protocol.
7.5.3.
Synovial Biopsy Tissue for Pharmacokinetic Assay
See Section 7.6.2.2 for details on synovial tissue biopsy and procedure.  If available, 
synovial tissue samples may be analysed for concentrations of GSK2982772 and possible 
drug-related material, as well as specific tissue distribution if feasible as sample 
availability allows. 
7.5.4.
Sample Analysis
Synovial biopsy sample analysis will be performed under the control of PTS IVIVT, 
GlaxoSmithKline.  Information on processing the biopsies for the synovial 
pharmacokinetic assay will be provided in the laboratory manual.  The results may be 
reported under a separate PTS-IVIVT, GlaxoSmithKline protocol.
7.6.
Biomarker(s)/Pharmacodynamic Markers
Pharmacodynamic biomarkers will be collected at the time points in Section 7.1 Time 
and Events Table and may include, but are not limited to, the following:

Blood samples for mRNA expression e.g., IL6, MMP-1, MMP3, MMP-13, TIMP-1, 
MCP-1 and MIF.

Blood samples for biomarkers which may be indicative of RA disease activity e.g., 
MRP8/14 and markers encompassed by Vectra DA.
Details of blood sample collection, processing, storage and shipping procedures are 
provided in the laboratory manual.
7.6.1.
Magnetic Resonance Imaging (MRI) of Joint
The most affected hand will be documented at baseline and used for all imaging visits. If 
subjects report both hands are equally involved, then the subject’s dominant hand will be 
used.
DCE-MRI will be performed on all subjects, provided that sites have DCE-MRI 
capability and experience (e.g., hardware and software requirements). If sites do not have 
DCE-MRI capability, only a standard MRI will be performed.
Each subject’s most affected wrist (corresponding to the affected hand which is 
determined and documented at baseline) will be imaged by MRI at pre-dose on Days 1, 
43 and 85 (see Section 7.1).  If a scanning failure occurs at any visit, if feasible a rescan 


2015N251670_04
CONFIDENTIAL
203168
61
is allowed within 7 days after the failed scan after consultation and agreement with the 
GSK Medical Monitor.  There will be a minimum of 24 hours between scans where 
gadolinium (Gd) contrast is used.  The MRI will be used in order to non-invasively 
quantify the degree of inflammation and structural changes within the target joint.
Each MRI total scan time should be approximately 1 hour.  For each subject, MRIs must 
be performed on the same scanner and using the same type of chelated Gd contrast agent 
as was used at screening.  If scanning cannot occur on the same scanner within the visit 
time window due to hardware failure, an alternate scanner may be used or the time 
window may be extended by 3 days only after consultation and agreement with the GSK 
medical monitor.
On attendance at the MRI department, subjects will be placed in the scanner and will be 
prepared for intravenous contrast agent administration.  The scanning protocol will 
include routine localizers, T1 measurement sequences, dynamic DCE-MRI acquisition, 
and acquisitions required for OMERACT RAMRIS, RAMRIQ and CARLOS scoring.  
Additional exploratory MRI endpoints, as detailed in the Acquisition Manual, may also 
be acquired for exploratory purposes.
Details of scanning site training procedures, acceptable Gd contrast agents, and scanning 
protocols will be provided in a dedicated Imaging Manual.
All MRI scans will be reported at the site by a radiologist (non-anonymized) for clinical 
abnormalities.
7.6.2.
Synovial Biopsy
7.6.2.1.
Selection of Joint for Synovial Biopsy
Synovial biopsies are optional for subjects enrolled in this study. There is no minimum 
number of subjects with joint biopsies required, but biopsies should be performed in as 
many subjects as possible.  Synovial biopsy of a subject’s swollen and tender wrist, knee 
or ankle joint will be performed at baseline (pre-dose Day 1).  The final choice of joint is 
left to the discretion of the Investigator, although ideally it will be the most inflamed 
joint.  The same joint should be biopsied at Day 43 (Week 6).  If in the event that a repeat 
biopsy of the same joint as baseline is not possible, the joint may change if essential, after 
discussion with the GSK Medical Monitor.  Any change must be documented in the CRF.
If a subject chooses to withdraw from the study after dosing and prior to Day 43, the 
Investigator must make every effort to perform a synovial biopsy if the subject has 
received at least 14 days of treatment with GSK2982772 or placebo.  
7.6.2.2.
Synovial Biopsy Procedure
Ultrasound imaging or arthroscopy will be used to guide the collection of approximately 
(as feasible for any given subject) of 6 synovial biopsies for immunohistochemistry 
(IHC), 6 synovial biopsies for pharmacokinetics, 6 synovial biopsies for target 
engagement, and 6 synovial biopsies for RNA extraction up to a combined maximum of 
30 biopsies from the chosen joint under local anaesthesia (see SRM).


2015N251670_04
CONFIDENTIAL
203168
62
Biopsy tissue taken from synovial tissue will be divided accordingly for IHC, PK, target 
and pathway engagement, and gene expression.  Histological assessment by IHC will be 
evaluated for general appearance and total inflammatory infiltrate.  Specific cell numbers 
will also be analysed (which may include but are not limited to CD3+T-cells, CD55+ 
fibroblast-like synoviocytes, CD68+macrophages).  mRNA may be isolated from 
synovial biopsys tissue, as feasibility dictates, to determine the effect of placebo and 
GSK2982772 on markers of inflammation and tissue healing (e.g., may include and not 
be limited to VEGF, IL-1β, IL-6, TNFα, and MMP-1 and other chemokines and 
cytokines).  Biopsy tissue collected for RNA transcriptional analysis may be utilised to 
determine the effect of GSK2982772 on cytokine and receptor expression, in addition to 
other markers of inflammation and tissue healing, as feasibility allows. For example, this 
may include but is not limited to, measurement of acute phase proteins, other chemokines 
and cytokines.  Examples of technologies that may be used for these analysis include, but 
are not limited to, quantitative PCR, microarray, RNA sequencing or mass cytometry 
(CyTOF). 
7.6.3.
Novel Pharmacodynamic Biomarkers
7.6.3.1.
RIP1 Target Engagement in Blood
Blood samples for RIP1 target engagement will be collected at the time points indicated 
in Section 7.1 to measure levels of free and drug-bound RIP1 protein.
7.6.3.2.
RIP1 Target Engagement in Synovial Tissue
Synovial tissue biopsy samples will be collected at the time points indicted in Section 7.1
to measure levels of free and drug-bound RIP1 protein if sample quantity and data allow.
7.6.3.3.
Pathway Biomarkers in Synovial Tissue
Synovial tissue biopsy samples will be collected at the time points indicated in Section 
7.1 to measure total or phosphorylated RIP1, RIP3, MLKL and cleaved or total caspase 3 
and caspase 8 if sample quantity and data allow.
7.6.4.
Exploratory Novel Biomarkers
With the subject’s consent, tissue and blood sample(s) will be collected during this study 
and may be used for the purposes of measuring novel biomarkers to identify factors that 
may influence disease/condition for study treatment, and/or medically related conditions, 
as well as the biological and clinical responses to GSK2982772.  If relevant, this 
approach will be extended to include the identification of biomarkers associated with 
adverse events.
Samples will be collected at the time points indicated in Section 7.1. The timing of the 
collections may be adjusted on the basis of emerging pharmacokinetic or 
pharmacodynamic (PD) data from this study or other new information in order to ensure 
optimal evaluation of the PD endpoints.


2015N251670_04
CONFIDENTIAL
203168
63
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with RA or medically related conditions and/or the action of 
GSK2982772 may be identified by application of:

Gene expression analysis may be conducted on the blood and/or synovial biopsies 
using microarray, RNA sequencing and/or alternative equivalent technologies, 
which facilitates the simultaneous measurement (and confirmation) of the relative 
abundances of thousands of RNA species resulting in a transcriptome profile for 
each synovial tissue sample.

Soluble inflammatory mediators in the blood may be assayed for cytokine and 
inflammatory mediators including, but not limited to, pro-inflammatory and anti-
inflammatory cytokines, chemokines, and acute phase proteins. 
These analyses may be reported under separate protocol following the completion of the 
study.  All samples will be retained for a maximum of 15 years after the last subject 
completes the trial.
7.7.
Genetics
In consenting subjects, a blood sample for pharmacogenetics (PGx) research will be 
drawn on Day 1 (or any time point post randomisation and prior to study completion) to
better characterize genetic variability that may affect efficacy or safety endpoints. 
Information regarding pharmaogenetic (PGx) research is included in Appendix 4.
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.  

CRFs (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
and date of birth will not be collected or transmitted to GSK according to GSK 
policy.


2015N251670_04
CONFIDENTIAL
203168
64
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The primary objective of the study is to investigate the safety and tolerability of 
GSK2982772 following 12 weeks of treatment. No formal statistical hypotheses will be 
conducted to assess this objective. 
If appropriate, comparisons between the GSK2982772 and the placebo arm will be made 
to investigate the secondary pharmacodynamic, mechanistic and efficacy objectives. 
Trends over time will be investigated for both treatment arms along with associations 
between each of the pharmacodynamic, mechanistic and efficacy parameters. 
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The study is not powered to detect pre-defined differences. A sufficient number of 
subjects will be screened so that approximately 24 subjects with moderate to severe RA 
are randomised into the study on a TID regimen.  Prior to protocol amendment 3 being 
approved in each country, no more than 18 subjects will be randomised into the study on 
a BID regimen.  Table 4 summarises the total planned sample sizes for BID and TID 
regimens.  Should the drop-out rate be higher than anticipated, additional or replacement 
subjects may be randomised (up to an overall total maximum of 48) into the study at the 
discretion of the Sponsor.
Table 4
Summary of Total Sample Size by Dosing Regimen
Number Randomised to 
GSK2982772 60 mg BID or 
Placebo BID
Number Randomised to 
GSK2982772 60 mg TID or 
Placebo TID
Revised 
Max 
Total 
Sample 
Size
Total + 
Additional/ 
Replacement 
Subjects
7 - 12
24
36
42
12 - 18
24
42
48
The primary objective of the study is safety and tolerability, where there will be 
20 subjects randomised to GSK2982772 60 mg TID and up to 12 subjects randomised to 
GSK29827772 60 mg BID. Using a Bayesian approach to determine the confidence 
interval (CI) around an observed safety event, we would assume a flat Beta (1, 1) prior, 
and if we were to observe one safety event in 16 then the posterior distribution would be 
Beta (2, 16), as outlined below in Figure 4.


2015N251670_04
CONFIDENTIAL
203168
65
Figure 4
One Event in 16 Subjects: Beta (2,16) Distribution
Thus, we can be 95% certain that the true probability of the safety event lies between 2%
and 25%. 
For supportive information, the properties of the key secondary endpoint DAS28 have 
been considered.
Based on the estimate of variability (SD=1 from historical data) it is estimated that the 
lower and upper bounds of the 95% CI for the change from baseline in DAS28-CRP 
score will be within approximately 0.693 and 0.490 of the point estimate of GSK2982772
60 mg TID (n=16) and placebo (n=8).
9.2.2.
Sample Size Sensitivity
A sample size sensitivity analysis has been conducted on the primary endpoint to 
investigate the different safety event rates.  If the number of subjects who complete the 
12 weeks is higher or lower than 16 in the GSK2982772 group, then the true incidence
rates of safety events that could not be ruled out (as outlined in Section 9.2.1) would 
change.  These changes are outlined in Table 5.
Table 5
Sample Size Sensitivity
GSK2982772 subjects 
completing the study
Number of a particular safety
event observed with 
GSK2982772
Upper limit of exact 95% 
Credible Interval indicating 
that a true incidence rate of 
x% could not be ruled out
20
0
16.1%
20
1
23.8%
20
2
30.4%
18
0
17.6%
18
1
26.0%
18
2
33.1%
16
0
19.5%


2015N251670_04
CONFIDENTIAL
203168
66
GSK2982772 subjects 
completing the study
Number of a particular safety
event observed with 
GSK2982772
Upper limit of exact 95% 
Credible Interval indicating 
that a true incidence rate of 
x% could not be ruled out
16
1
28.7%
16
2
36.4%
14
0
21.8%
14
1
31.9%
14
2
40.5%
12
0
24.7%
12
1
36.0%
12
2
45.4%
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation or adjustment will be conducted.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
All Subjects Population: The ‘All Subjects Population’ is defined as subjects who were 
screened for the study.  This population is used for the summary of selected 
accountability data.
Safety Population: The ‘Safety Population’ is defined as subjects who receive at least 
one dose of study medication. This population is used for the summary of all data 
including demography, safety, efficacy and exploratory data but excluding PK data.
Pharmacokinetic Population: The ‘PK Population' is defined as subjects in the ‘Safety’ 
population who received an active dose and for whom a GSK2982772 pharmacokinetic 
sample was obtained and analysed.   This population is used for the summary of PK data 
only.  Any PK-PD analysis will be conducted on the Safety population such that subjects 
receiving placebo can be included.
If 12 or more subjects are randomised to a BID regimen (i.e., ≥4 placebo and ≥8 
GSK2982772 60 mg BID) then treatment received will take into account dosing 
frequency for GSK2982772, otherwise treatment will be irrespective of dosing frequency.
9.3.2.
Interim Analysis
A formal interim analysis will be conducted during the study.  Additionally, two review 
teams will monitor data on an ongoing basis for routine pharmacovigilance and decision 
making regarding the subsequent clinical development of GSK2982772 for RA.
In line with routine pharmacovigilance, an internal GSK Safety Review Team (SRT) 
which will include members of the GSK2982772 project team, will review blinded safety 


2015N251670_04
CONFIDENTIAL
203168
67
data, including clinical laboratory parameters and adverse events, at appropriate intervals 
during the period of study conduct.
Once an appropriate number of subjects have completed Day 43 (Week 6) the DAS28-
CRP data will be reviewed in an unblinded manner and on an ongoing basis by the Data 
Review Committee, consisting of the GSK Project Physician Lead (PPL), the study
statistician, the study pharmacokineticist, the PRR DPU Head, EDL and SRT Leader or 
designees on an ongoing basis.  A physician external to the GSK2982772 project team 
may also be involved in the data review. Additional inflammatory biomarkers, clinical 
and mechanistic endpoints (e.g. target engagement) may be reviewed if available. No 
other member of the GSK core study team will be unblinded to this data. The primary 
purpose of these informal reviews will be to monitor DAS28-CRP for futility.  On review 
of DAS28-CRP data, the review group may recommend an interim analysis of key 
clinical and mechanistic data is first conducted prior to any decision to terminate the 
study for futility.  A data review charter will identify the specific GSK individuals 
involved, outline in detail the activities of this review and how the integrity of the study 
will be maintained.
A formal interim analysis will be conducted during the study. The timing of this analysis 
will either be on the recommendation of the data review group to assess futility based on 
6 weeks of treatment, or when an appropriate number have completed 12 weeks of 
treatment, whichever is earliest.  The purpose of the Interim Analysis would be to assess 
whether to stop the study for futility.  This interim analysis may also facilitate decision 
making regarding the subsequent clinical development of GSK2982772 for RA. 
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
All safety evaluations will be based on the Safety population.  Clinical interpretation will 
be based on the review and displays of adverse events, clinical laboratory values, vital 
sign measurements and 12-lead ECG monitoring.
9.4.2.
Secondary Analyses
The relationship between each of the mechanistic endpoints and also with the clinical 
endpoints will be graphically presented and analysed using an appropriate statistical 
model identifying any trends. The model will determine whether the mechanistic effect 
significantly explains or predicts the effect on the other mechanistic or clinical endpoints 
(e.g., DAS28-CRP score). This may be conducted through comparing statistical models 
incorporating different explanatory terms (i.e. mechanistic endpoints) with the ‘null’ 
model (no mechanistic endpoints); or if deemed appropriate, multivariate statistical 
methods may also be applied to determine the relationship between the key endpoints. 
The consistency in the changes over time between the endpoints will also be assessed.
Each endpoint will be considered individually and at the treatment level, where 
comparisons between treatment groups would be made on any changes observed, if 
deemed appropriate. This could include change from baseline in DAS28-CRP, which will 
be statistically analysed using a MMRM analysis comparing GSK2982772 with placebo 


2015N251670_04
CONFIDENTIAL
203168
68
at each time point. Additionally, this could include, the proportion of subjects achieving 
ACR20/50/70 and DAS28-CRP response, which will be statistically analysed using a 
Generalised Estimating Equation (GEE) model comparing GSK2982772 with placebo at 
each timepoint. Similar analyses will be conducted for other secondary endpoints if 
deemed appropriate.
9.4.3.
Other Analyses
In addition, based on the data that we observe in the study, probabilities of success will 
be determined, where the definition of success will be dependent on the endpoint. For 
example, what is the probability that we would observe a certain change in DAS28 (i.e., 
comparator rate), based on the data that we have observed in the study.
GSK2982772 plasma concentrations will be summarised descriptively by day and 
nominal sampling time.  
Further details regarding the statistical analysis will be outlined in the Reporting and 
Analysis Plan (RAP).
9.4.3.1.
Exploratory Analyses
All exploratory endpoints will be descriptively summarised, graphically presented and 
listed appropriately.  Further details can be found 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
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.

Obtaining signed informed consent.

Investigator reporting requirements (e.g., reporting of AEs/SAEs/protocol 
deviations to IRB/IEC).


2015N251670_04
CONFIDENTIAL
203168
69

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study.

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK 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 CRF will
serve as the source document.
GSK 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 
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.


2015N251670_04
CONFIDENTIAL
203168
70
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the Investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures (SOP).

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.


2015N251670_04
CONFIDENTIAL
203168
71

GSK will inform the Investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.  

The Investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the Investigator is no longer associated with 
the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the clinical study report.  The Investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the Investigator with the full summary of the study results.  The 
Investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the Investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.


2015N251670_04
CONFIDENTIAL
203168
72
11.
REFERENCES
Agarwal SK.  Biologic agents in rheumatoid arthritis:  An update for managed care 
professionals.  Journal of Managed Care Pharmacy, 2011;17(9-b):S14-8.
Berger SB, Kasparcova V, Hoffman S, Swift B, Dare L, Schaeffer M et al.  Cutting edge:  
RIP1 kinase activity is dispensable for normal development but is a key regulator of 
inflammation in SHARPIN-deficient mice.  The Journal of Immunology,
2014;192:5476-80.
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.
Choy EHS, Panayi GS.  Cytokine pathways and joint inflammation in rheumatoid 
arthritis.  The New England Journal of Medicine, 2001;344:907-916.
Dondelinger Y, Aguileta MA, Goossens V, Dubuisson C, Grootjans S, Dejardin E et al.  
RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions 
of cIAP1/2 depletion or TAK1 kinase inhibition.  Cell Death and Differentiation, 
2013;20:1381-92.
Fries JF, Spitz P, Kraines RG, Holman HR.  Measurement of patient outcomes in 
arthritis.  Arthritis Rheum 1980;23:137-45.
GlaxoSmithKline Document Number 2014N204126_02.  Investigator Brochure for 
GSK2982772.  Report Date 27-JAN-2017.
Gorin MB.  Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mo. Aspects Med. 2012; 33:467-486.
Hatcher RA, Trussell J,  Nelson AL, Cates W Jr, Stewart F, Kowal D, et al. 
Contraceptive Technology. 20th edition.  Atlanta, Georgia: Ardent Media, Inc., 2011: 50.  
Table 3 2.
Humphries F, Yang S, Wang B, Moynagh P N.  RIP kinases: key decision makers in cell 
death and innate immunity.  Cell Death & Differ, 2015;22:225-236.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D et al.  Transgenic 
mice expressing human tumour necrosis factor:  A predictive genetic model of arthritis.  
The EMBO Journal, 1991;10:4025-31.
Netter P, Bannwarth B, Royer-Morral M-J. Recent findings on the pharmacokinetics of 
non-steroidal anti-inflammatory drugs in synovial fluid. Clin Pharmaokinet, 
1989;17(3):145-162.


2015N251670_04
CONFIDENTIAL
203168
73
Ofengeim D, Yuan J.  Regulation of RIP1 kinase signaling at the crossroads of 
inflammation and cell death.  Nature Reviews Molecular Cell Biology, 2013;14:727-36.
Raghav SK, Gupta B, Agrawal C, Chaturvedi VP, and Das HR. Expression of TNF-alpha 
and related signaling molecules in the peripheral blood mononuclear cells of rheumatoid 
arthritis patients.  Mediators Inflamm. 2006(3):12682.
U.S. Department of Health and Human Services, Food and Drug Administration (FDA). 
(2012) Guidance for Industry: Drug Interaction Studies – Study Design, Data Analysis, 
Implications for Dosing, and Labeling Recommendations. Center for Drug Evaluation 
and Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM292362.pdf
Vasanthi P, Nalini G, Rajasekhar G. Role of tumor necrosis factor-alpha in rheumatoid 
arthritis: a review. Journal of Rheumatology, 2007; 10:270–274.
Wang L, Du F, Wang X. TNF-alpha induces two distinct caspase-8 activation pathways. 
Cell, 2008; 133(4):693-703.


2015N251670_04
CONFIDENTIAL
203168
74
12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
ACR
American College of Rheumatology
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
AMD
Age-related macular degeneration
Anti-CCP
Anti-Cyclic Citrullinated Peptide
Anti-dsDNA
Anti-double stranded deoxyribose nucleic acid
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
BID
Twice a day
CARLOS
Cartilage Loss Scoring System
CI
Confidence Interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration 
equation
Cmax
Maximum observed concentration
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CRF 
Case Report Form
CRP
C-Reactive Protein
C-SSRS
Columbia Suicide Severity Rating Scale
CV
Cardiovascular
CYP
Cytochrome P
DAS
Disease Activity Score
DAS28
Disease activity score for 28 different joints
DAS28(CRP)
Disease activity score for 28 different joints with CRP value
DCE
Dynamic contrast enhanced
DNA
Deoxyribose Nucleic Acid
DMARD
Disease-Modifying Antirheumatic Drugs
DPU
Discovery Performance Unit
DRC
Data Review Committee
ECG
Electrocardiogram
EDL
Early Development Lead
EMA
European Medicines Agency
ETCO2
End-tidal Carbon Dioxide
EULAR
European League Against Rheumatism
FACIT-Fatigue
Functional Assessment of Chronic Illness Therapy-Fatigue
FDA
Food and Drug Administration
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
FTiH
First Time in Human
GCP
Good Clinical Practice


2015N251670_04
CONFIDENTIAL
203168
75
Gd
Gadolinium
GEE
Generalised Estimating Equations
GFR
Glomerular Filtrate Rate
GSK
GlaxoSmithKline
HAQ-DI
Disability Index of the Healthy Assessment Questionnaire
HBcAb
Hepatitis B Core Antibody
HBsAg
Hepatitis B Surface Antigen
hCG
Human Chorionic Gonadotropin
HIV
Human Immunodeficiency Virus
HRT
Hormone Replacement Therapy
IB
Investigator Brochure
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IL
Interleukin
IP
Investigational Product
IRB
Institutional Review Board
IRE
Initial rate of enhancement
IRTS
Interactive Response Technology System
Kg
Kilogram
L
Litre
LDL
Low Density Lipoprotein
MCH
Mean corpuscular haemoglobin
MCHC
Mean corpuscular haemoglobin concentration
MCV
Mean Corpuscular Volume
MDMA
3,4-methylenedioxy-methamphetamine
ME
Maximal signal intensity enhancement
MedDRA
Medical Dictionary for Regulatory Activity
mg
Milligram
mL
Millilitre
MLKL
Mixed lineage kinase domain-like protein
mm
Millimeter
mmol
Millimole
MMP
Matrix metallopproteinase
MMRM
Mixed-effect Model Repeat Measurements
MRI
Magnetic Resonance Imaging
msec
millisecond
MRP
Myeloid-related Protein
MSDS
Material Safety Data Sheet
MTX
Methotrexate
NF-B
Nuclear factor kappa-light-chain-enhancer of activated B 
cells
NHS
National Health Service
NOAEL
No Adverse Effect Level
NONMEM
Non Linear Mixed Effect Model
NRS
Numeric Rating Scale


2015N251670_04
CONFIDENTIAL
203168
76
NSAID
Non-steroidal anti-inflammatory drug
NSF
Nephrogenic Systemic Fibrosis
OMERACT
Outcome Measures in Rheumatology
PBMC
Peripheral blood mononuclear cell
PCR
Polymerase Chain Reaction
PD
Pharmacodynamic
PGA
Physician’s Global Assessment of Disease
Pgp
P-glycoprotein
PGx
Pharmacogenetics
PK
Pharmacokinetic
PPD
Tuberculin Purified Protein Derivative
PPL
Project Physician Lead
PRO
Patient Reported Outcome
PRR
Pattern Recognition Receptor
PSRAE
Possible Suicidality Related Adverse Event
PtGA
Patient Global Assessment of Disease
PTS IVIVT
Platform Technology and Science In Vitro/In Vitro 
Translation
QTc
Electrocardiogram QT interval corrected for heart rate
QTcB
Electrocardiogram QT interval corrected for heart rate using 
Bazett’s formula
QTcF
Electrocardiogram QT interval corrected for heart rate using 
Fridericia’s formula
RA
Rheumatoid Arthritis
R&D
Research and Development
RAP
Reporting and Analysis Plan
RAMRIQ
Rheumatoid arthritis MRI quantitative
RAMRIS
Rheumatoid arthritis MRI scoring system
RBC
Red Blood Cell
RF
Rheumatoid factor
RIP1
Receptor-interacting protein-1
RIP3
Receptor-interacting protein-3
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SIB
Suicidal Ideation Behaviour
SLE
Systemic lupus erythematosus
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SOP
Standard Operating Procedure
SpO2
Peripheral Capillary Oxygen Saturation
SRM
Study Reference Manual
SRT
Safety Review Team
TB
Tuberculosis
TEAR
Target Engagement Assay RIP1
TID
Three times a day
TIMP
Tissue inhibitor of metalloproteinases


2015N251670_04
CONFIDENTIAL
203168
77
TLR
Toll-like receptor
TNF
Tumor necrosis factor
TTS
Technical Terms of Supply
UK
United Kingdom
ULN
Upper Limit of Normal
VAS
Visual Analogue Scale
VEGF
Vascular endothelial growth factor
WOCP
Women of Child Bearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
QuantiFERON
Sugita
Vectra DA


2015N251670_04
CONFIDENTIAL
203168
78
12.2.
Appendix 2: Liver Safety Required Actions and 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).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
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, permanently discontinue study 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 2 days after
last dose5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 


2015N251670_04
CONFIDENTIAL
203168
79
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
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]). NOTE: not 
required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody 
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the laboratory manual.  


2015N251670_04
CONFIDENTIAL
203168
80
12.3.
Appendix 3:  Prednisolone Equivalent Dose Table
Drug Name
Dose Equivalent to 1 mg Oral Prednisone
Cortisone acetate
Hydrocortisone
Prednisolone
Methylprednisolone
Triamcinolone
Dexamethasone
5 mg
4 mg
1 mg
0.8 mg
0.8 mg
0.15 mg


2015N251670_04
CONFIDENTIAL
203168
81
12.4.
Appendix 4- Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including GSK2982772 or any concomitant medicines;

Rheumatoid arthritis susceptibility, severity, and progression and related 
conditions
GSK2982772 is a novel first-in-class asset being introduced to patients with moderate to 
severe RA for the first time. Currently its mechanism of action is not fully characterised 
nor understood. 
Specific genes may be studied that encode the drug targets, or drug mechanism of action 
pathways, drug metabolizing enzymes, drug transporters or which may underpin adverse 
events, disease risk or drug response. These candidate genes may include a common set 
of ADME (Absorption, Distribution, Metabolism and Excretion) genes that are studied to 
determine the relationship between gene variants or treatment response and/or tolerance. 
In addition, continuing research may identify other enzymes, transporters, proteins ore 
receptors that may be involved in response to GSK2982772. The genes that may code for 
these proteins may also be studied. Genome-wide scans involving a large number of 
polymorphic markers (e.g. single nucleotide polymorphisms) at defined locations in the 
genome, often correlated with a candidate gene, may be studied to determine the 
relationship between genetic variants and treatment response or tolerance. This approach 
is often employed when a definitive candidate gene does not exist and/or the potential 
genetic effects are not well understood.
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.


2015N251670_04
CONFIDENTIAL
203168
82
If applicable and genetic research is conducted, appropriate descriptive and/or statistical 
analysis methods will be used to evaluate pharmacogenetic data in the context of the 
other clinical data. A detailed description of any planned analyses will be documented in
a Reporting and Analysis Plan (RAP) prior to initiation of the analysis. Planned analyses 
and results of genetic investigations will be reported either as part of the clinical RAP and 
study report, or in a separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at the baseline visit, after the subject has been 
randomized and provided informed consent for genetic research. Instructions for 
collection and shipping of the genetic sample are described in the laboratory 
manual. The DNA from the blood sample may undergo quality control analyses to 
confirm the integrity of the sample. If there are concerns regarding the quality of 
the sample, then the sample may be destroyed. The blood sample is taken on a 
single occasion unless a duplicate sample is required due to an inability to utilize 
the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the Investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
The need to conduct PGx analysis may be identified after a study (or set of studies) of 
GSK2982772 has been completed and the study data reviewed. In some cases, the 
samples may not be studied.
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.


2015N251670_04
CONFIDENTIAL
203168
83
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained.

Discontinue participation in the genetic research and destroy the genetic DNA 
sample.
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the Investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analysed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analysed, it will not be analysed or used for future research.  

Genetic data that has been analysed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the Investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 


2015N251670_04
CONFIDENTIAL
203168
84
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.


2015N251670_04
CONFIDENTIAL
203168
85
12.5.
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.5.1.
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.

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.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.


2015N251670_04
CONFIDENTIAL
203168
86
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.

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.
12.5.2.
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:
a. Results in death
b. 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.


2015N251670_04
CONFIDENTIAL
203168
87
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 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.

Refer to Appendix 2 for the required liver chemistry follow-up instructions


2015N251670_04
CONFIDENTIAL
203168
88
12.5.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.5.4.
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.

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 PRO questionnaires and the collection of AE data are 
independent components of the study.

Responses to each question in the PRO 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.


2015N251670_04
CONFIDENTIAL
203168
89
12.5.5.
Evaluating AEs and SAEs
Assessment of Intensity
The Investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The Investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The Investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The Investigator will also consult the 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.


2015N251670_04
CONFIDENTIAL
203168
90
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.
12.5.6.
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 Medical Monitor.

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 or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


2015N251670_04
CONFIDENTIAL
203168
91
12.6.
Appendix 6: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.6.1.
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 or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1. Contraceptive subdermal implant
2. Intrauterine device or intrauterine system
3. Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]
4. Injectable progestogen [Hatcher, 2011]
5. Contraceptive vaginal ring [Hatcher, 2011]
6. Percutaneous contraceptive patches [Hatcher, 2011]
7. Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or 
semen analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The Investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception
Contraceptive requirements for male subjects with female partners of reproductive 
potential (when applicable).
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 90 days after the last dose of study medication.
1.
Vasectomy with documentation of azoospermia. The documentation on male sterility 
can come from the site personnel’s: review of subject’s medical records, medical 
examination and/or semen analysis, or medical history interview.
2.
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:

Contraceptive subdermal implant

Intrauterine device or intrauterine system


2015N251670_04
CONFIDENTIAL
203168
92

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The Investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.6.2.
Collection of Pregnancy Information

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 or be withdrawn from the study

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study and up to 
90 days after the last dose of study medication.  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.


2015N251670_04
CONFIDENTIAL
203168
93

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.


2015N251670_04
CONFIDENTIAL
203168
94
12.7.
Appendix 7: - Country Specific Requirements
Protocol Amendment 04 (03-AUG-2017) is a country specific amendment for Germany 
which reinstates specific clinical laboratory criteria in Exclusion Criteria 23 and 
Haematologic Stopping Criteria in Section 5.4.5 that was changed in Amendment 03 (20-
APR-2017).
The following applies to subjects recruited and enrolled in Germany:
Section 5.2 Exclusion Criteria
Diagnostic assessments and other criteria
23. Haemoglobin <11 g/dL; haematocrit <30%, white blood cell count ≤3,000/mm3 
(≤3.0 x 109/L); platelet count ≤100,000/µL (≤100 x 109/L); absolute neutrophil count 
≤1.5 x 109/L at screening.
Section 5.4.5 Haematologic Stopping Rules
Study treatment will be stopped for a subject if any of the following haematological 
stopping criteria is met:

Haemoglobin <9 g/dL (5.58 mmol/L) or an absolute decrease of ≥2 g/dL from 
baseline (pre-dose Day 1).  

Platelets <50 × 109/L


2015N251670_04
CONFIDENTIAL
203168
95
12.8.
Appendix 8:  Protocol Amendment Changes
12.8.1.
Amendment 4 (03-AUG-2017) from Protocol Amendment 3 (20-
APR-2017)
Where the Amendment Applies
This amendment applies to all subjects who will participate in this study in Germany 
only.
Summary of Protocol Amendment Changes with Rationale
Protocol Amendment 04 is a country specific amendment for Germany which reinstates 
the clinical laboratory criteria in Exclusion 23 and Haematologic Stopping Criteria in 
Section 5.4.5 that was changed in Amendment 03.
List of Specific Changes (bold indicates text added and strikethrough indicates text 
removed):
Section 5.2 Exclusion Criteria
Diagnostic assessments and other criteria
23. Haemoglobin <9 g/dL; haematocrit <30%, white blood cell count ≤3,000/mm3 
(≤3.0 x 109/L); platelet count ≤100,000/µL (≤100 x 109/L); absolute neutrophil count 
≤1.5 x 109/L at screening. For subjects recruited in Germany:   Haemoglobin <11 
g/dL; haematocrit <30%, white blood cell count ≤3,000/mm3 (≤3.0 x 109/L); platelet 
count ≤100,000/µL (≤100 x 109/L); absolute neutrophil count ≤1.5 x 109/L at 
screening.
Section 5.4.5 Haematologic Stopping Rules
Study treatment will be stopped for a subject if any of the following haematological 
stopping criteria is met:

Haemoglobin - an absolute decrease of ≥2 g/dL from baseline (pre-dose Day 1). For 
subjects enrolled in Germany:  Haemoglobin <9 g/dL (5.58 mmol/L) or an 
absolute decrease of ≥2 g/dL from baseline (pre-dose Day 1).  

Platelets <50 × 109/L


2015N251670_04
CONFIDENTIAL
203168
96
12.8.2.
Amendment 3 (20-APR-2017) from Protocol Amendment 2 (14-
JUL-2016)
Where the Amendment Applies
This amendment applies to all subjects who will participate in this study in all countries.
Summary of Protocol Amendment Changes with Rationale
Protocol Amendment 03 incorporates change in dosing regimen from 60 mg BID to 60 
mg TID, restrictions on JAK inhibitors, defined non-reproductive potential criteria in 
Exclusion 11, change to clinical laboratory criteria in Exclusion 23, of evaluation of joint 
space narrowing with MRI, flexibility in scheduling with MRI and synovial biopsy.
GlaxoSmithKline Document Number of Investigator Brochure GSK2982772 has been 
updated to 2014N204126_02 throughout the document. Other minor protocol 
clarifications and administrative changes are also provided in this amendment.
List of Specific Changes (bold indicates text added and strikethrough indicates text 
removed):
Authors
Author (s):
 
 
 
PPD


2015N251670_04
CONFIDENTIAL
203168
97
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number and 
email address
After-hours 
Phone/Cell/
Pager Number
Fax Number
Site Address
Primary 
Medical 
Monitor 
Tel       
Email   
Mobile:  
Email: 
Mobile  
 
 
Mobile:  
N/A
GSK Stockley 
Park West, 1-3 
Ironbridge 
Road, 
Uxbridge, 
Middlesex, 
UB11 1BT, UK
UP4440
1250 S 
Collegeville, PA  
19426 USA
Secondary 
Medical 
Monitor
Mobile:
Email 
Tel: 
Mobile: 
Email:
Mobile
Mobile: 
NA
 
1250 S. 
Collegeville 
Rd.
Collegeville PA 
19426, USA
Cytokine
Chemokine
DPU, GSK,
Gunnels Wood
Road,
Stevenage,
SG1 2NY, UK
SAE 
contact  
information 
Medical 
Monitor as 
above
Synopsis and Section 2.1 Study Rationale
The primary objective of this study has not changed with amendment 03; however 
the dosing regimen does change to GSK2982772 (60 mg three times daily for 84 
days). 
The primary objective will be to investigate the safety and tolerability of repeat oral doses 
of GSK2982772 (60 mg twice three times daily for 84 days). In addition to the 
pharmacokinetics (PK), a number of experimental and clinical endpoints will be 
employed to obtain information on the pharmacodynamics (PD), and preliminary efficacy 
in subjects with active RA. Although no formal hypothesis will be tested, these endpoints 
will enable a broader understanding of the mechanism of action and potential for clinical 
efficacy of GSK2982772 in RA, by making full use of the information obtained from 
each subject enrolled.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PP
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


2015N251670_04
CONFIDENTIAL
203168
98
Synopsis and Section 3 Objectives and Endpoints
Objectives
Endpoints
Primary

To investigate the safety and tolerability 
of 60 mg twice three times daily doses of 
GSK2982772 in subjects with moderate 
to severe Rheumatoid Arthritis.

Adverse events.

Clinical laboratory values (clinical 
chemistry, haematology and urinalysis).

Vital sign measurements (blood pressure, 
heart rate, respiratory rate, and body 
temperature).

12-Lead ECG monitoring.
Secondary

To investigate the plasma concentrations 
of GSK2982772 following 60 mg twice
three times daily doses of GSK2982772 
in subjects with moderate to severe 
Rheumatoid Arthritis.

Pre-dose concentrations of GSK2982772 
on Days 8 and 43 (Week 6).  

Post-dose concentrations of 
GSK2982772 on Days 1, 8, and 43 
(Week 6) at 1, 2, 4 and 6 hours.

Trough concentrations on Day 85 (Week
12).

To investigate the effect of 60 mg twice
three times daily doses of GSK2982772 
on inflammatory biomarkers in blood 
subjects with moderate to severe 
Rheumatoid Arthritis.

Change from baseline in blood 
inflammatory markers (e.g., may include 
but not limited to CRP, IL6, MMP-1, 
MMP-3, MMP-13, TIMP-1, MCP-1, MIF, 
MRP8/14 and other markers 
encompassed by Vectra DA).

To investigate the effect of 60 mg twice
three times daily doses of GSK2982772 
on bone and synovial parameters as 
measured by MRI and DCE-MRI in 
subjects with moderate to severe 
Rheumatoid Arthritis.

Change from baseline in Magnetic 
Resonance Imaging (MRI) parameters in 
the most affected hand/wrist.  MRI 
parameters may include assessment of 
bone erosions, synovitis, and bone 
oedema and joint space narrowing as 
assessed in the OMERACT-RAMRIS 
(Outcome Measures in Rheumatology, 
Rheumatoid Arthritis Magnetic 
Resonance Image Scoring System) 
scoring system, the RAMRIQ 
(Rheumatoid arthritis MRI quantitative) 
scoring system, the modified CARLOS 
(Cartilage Loss Scoring System) and 
additional exploratory endpoints as data 
permit.
Change from baseline in synovial
inflammation as measured by dynamic 
contrast enhanced (DCE)-MRI in the most 
affected hand/wrist:


2015N251670_04
CONFIDENTIAL
203168
99
Objectives
Endpoints

Exchange rate (Ktrans)

Interstitial volume (Ve)

Plasma volume (Vp)

Initial rate of enhancement (IRE)

Maximal signal intensity enhancement 
(ME)

Joint volume

Enhancing volume

To investigate the effect of 60 mg twice
three times daily doses of GSK2982772 
on clinical disease activity in subjects 
with moderate to severe Rheumatoid 
Arthritis.

Change from baseline in Disease Activity 
Score (DAS) 28-CRP scores.

Proportion of subjects achieving 
categorical DAS28-CRP response 
(moderate/good EULAR response) at 
each assessment time points.

Proportion of subjects achieving 
categorical ACR20/50/70 response.

To investigate the effect of 60 mg twice
three times daily dosing of 
GSK2982772 on methotrexate (MTX) 
concentrations. 

Plasma concentrations of MTX pre-dose 
GSK2982772 on Days 1, 8, and 43 
(Week 6).
Exploratory

To investigate the effect of 60 mg twice
three times daily doses of GSK2982772 
on inflammatory biomarkers in synovial 
tissue from subjects with moderate to 
severe Rheumatoid Arthritis.

Change from baseline in CD68+ 
macrophages, CD55+ fibroblast-like 
synoviocytes and a number of infiltrating 
CD3, CD22, CD138 inflammatory cells, 
and synovial inflammatory biomarkers 
including, but not limited to VEGF, IL-1β, 
IL-6, TNFα, and MMP-1.

To investigate pathway and target 
engagement following 60 mg twice three 
times daily doses of GSK2982772 in 
blood and synovial biopsy tissue in
subjects with moderate to severe 
Rheumatoid Arthritis.

Pharmacology biomarker endpoints may 
include, but are not limited to the 
following, pre-dose at Days 1, 43 (Week
6) and trough on Day 85 (Week 12), as 
applicable and if evaluable samples and 
data permit:
Target Engagement Assay RIP1 
(TEAR1) in blood and synovial 
tissue.
Total or phosphorylated RIP1, MLKL, 
and RIP3, cleaved and total 
caspase 3 and caspase 8
signatures in synovial tissue.

To investigate the concentration of 

Pre-dose GSK2982772 synovial tissue 


2015N251670_04
CONFIDENTIAL
203168
100
Objectives
Endpoints
GSK2982772 and possible drug-related 
material, as well as specific distribution 
within tissue if feasible, in the synovial 
tissue after 60 mg twice three times 
daily doses of GSK2982772.
biopsies and possible drug-related 
material concentrations, as well as 
specific distribution within tissue if 
feasible, on Day 43 (Week 6), as
evaluable samples and data permit.

To investigate the effect of 60 mg twice
three times daily doses of GSK2982772 
on the quality of life of subjects with 
moderate to severe Rheumatoid Arthritis.

Change from baseline in Health 
Assessment Questionnaire Disability 
Index (HAQ-DI).

Change from baseline in RA symptom 
questionnaire score.

Change from baseline in Functional 
Assessment of Chronic Illness Therapy 
(FACIT)-Fatigue.

To investigate the effect of 60 mg twice
three times daily doses of GSK2982772 
on gene expression in the blood subjects 
with active moderate to severe 
Rheumatoid Arthritis.

Transcriptomic analysis of mRNA 
isolated from blood pre-dose on Days 1 
and 43 (Week 6) and trough on Day 85 
(Week 12).

To investigate the effect of 60 mg twice
three times daily doses of GSK2982772 
on gene expression in the synovium of 
subjects with moderate to severe 
Rheumatoid Arthritis.

Transcriptomic analysis of mRNA 
isolated from synovial tissue pre-dose on 
Days 1 and 43 (Week 6).
Synopsis and Section 4.1 Overall Design
Schematic added. 
Amendment 03:
Synopsis Treatment Arms and Duration
Subjects who have completed screening assessments and are eligible will be randomised 
in a 2:1 ratio (active to placebo) to one of the following treatments:


2015N251670_04
CONFIDENTIAL
203168
101
GSK2982772 60 mg twice three times daily (BID TID) 
Placebo three times daily (BID TID) 
Prior to amendment 03 being effective in each country, subjects have been 
randomised in a 2:1 ratio (active to placebo) to one of the following treatments:
GSK2982772 60 mg two times daily (BID) 
Placebo two times daily (BID)
Synopsis and Section 4.3 Type and Number of Subjects
A sufficient number of subjects will be screened so that approximately 30 24 subjects 
with moderate to severe RA are randomised into the study on a TID regimen. Prior to 
protocol amendment 03 being approved in each country, no more than 18 subjects 
will be randomised into the study on a BID regimen.  Should the drop-out rate be 
higher than anticipated, additional or replacement subjects may be randomised (up to a
an overall total maximum of 36 48) into the study at the discretion of the Sponsor.
Section 4.2.2 Treatment Period
Subjects will be randomly assigned to either GSK2982772 60 mg or placebo orally twice
three times daily (approximately 12 8 hours apart) for 84 days (12 weeks).  Subjects 
that were randomised prior to protocol amendment 03 being approved in each 
country were randomly assigned to either GSK2982772 60 mg or placebo orally two 
times daily (approximately 12 hours apart) for 84 days (12 weeks). 
During the 84 day (12 week) treatment period, subjects will attend the clinical site for 
visits on Days 1, 8, 15, 29, 43, 57, 71 and 85.  At specific visits, subjects must not take 
study treatment prior to their scheduled visit (see Section 7.1).  On Days 22, 36, 50, 64 
and 78, each subject will be contacted by telephone and asked about their general health,
study medication compliance and diary card completion. Subjects will be given a 
diary card at each of the visits on which they will be instructed to record their daily 
study medication and concomitant medication taken and any adverse events.
Section 4.3 Type and Number of Subjects
A sufficient number of subjects will be screened so that approximately 30 24 subjects 
with moderate to severe RA are randomised into the study on a TID regimen. Prior to 
protocol amendment 3 being approved in each country, no more than 18 subjects 
will be randomised into the study on a BID regimen. Should the overall drop-out rate 
be higher than anticipated, additional or replacement subjects may be randomised (up to a
an overall total maximum of 36 48) into the study at the discretion of the Sponsor.
Section 4.4 Design Justification
The subjects will be randomised in a 2:1 ratio to GSK2982772 60 mg twice daily (BID)
three times daily (TID) and placebo respectively.  The primary objective of this study is 


2015N251670_04
CONFIDENTIAL
203168
102
to assess safety and tolerability, and assessment of this is most valuable in a placebo 
controlled study. The placebo group was also deemed necessary as autoimmune diseases 
naturally fluctuate in severity.  However, the size of the placebo group has been kept to a 
minimum.  All subjects will be allowed to continue standard of care therapy including 
non-biologic DMARDs during the study, provided that the medication and dose is stable 
throughout the study.
Section 4.5 Dose Justification
The initial selection of the 60 mg BID dose to be being tested in this study is based on 
the safety, PK, and PD data from the First Time in Human (FTiH) study, 200975.  
GSK2982772 administered at 60 mg BID for 14 days was well tolerated and no safety 
concerns were identified. A BID dosing regimen was initially selected over a QD dosing 
regimen due to the short half-life of GSK2982772 in humans (~2h).  Based on 
preliminary PK/PD modelling of ex-vivo RIP1 target engagement and GSK2982772 
concentrations from the multiple dose ascending part of Study 200975, a 60 mg BID dose 
wasis predicted to have on average 95% RIP1 target engagement in blood and 
approximately 90% of subjects will have >90% target engagement in blood at Cmin using 
a novel in-house ex-vivo PD/target engagement assay based solely on the TNF 
pathway which is believed to be a key component of the RIP1 pathway.  
However, based on final PK/PD modelling from the full repeat dose part of the 
Study 200975 (up to 120 mg BID), a 60 mg BID dose is now predicted to have on 
average 99% RIP1 target engagement in blood and approximately 90% of subjects 
will have >85% target engagement at Cmin.  This is lower than our target of 
achieving >90% target engagement in at least 90% of subjects at Cmin.  Therefore, a 
60 mg TID cohort is now being proposed. 
The Cmin values at 60 mg TID are predicted to be approximately 3.5 fold higher than 
for 60 mg BID.  Using the final PK/PD, a 60 mg TID dose is predicted to have on 
average 99% RIP1 target engagement in blood and approximately 90% of subjects 
will have > 96% target engagement at Cmin.  No data are currently available about the 
distribution of GSK2892772 into the synovium.  Based on data in non-steroidal anti-
inflammatory drugs (NSAIDs), the synovial fluid concentrations fluctuate to a much 
lesser extent than those in plasma [Netter, 1989].  Peak drug concentrations are generally 
lower in synovial fluid but are similar to plasma at later time points.  Assuming the same 
is true for GSK2982772, a 60 mg BIDTID dose should provide similar RIP1 target 
engagement at the site of action as predicted in blood. 
In addition, because of the short half-life, a modified release formulation is now 
being developed with the aim to provide a once daily dosing regimen.  By increasing 
the frequency of dosing to three times daily (TID) with the current immediate 
release formulation, this will more closely match the PK, safety and efficacy profile 
of a preferred once daily modified release formulation.
The safety of increasing the dose frequency to 60 mg TID is justified based on 
nonclinical safety findings to date with GSK2982772. It is anticipated that a human 
dose of 60 mg TID (180 mg/day) will produce AUC(0-24) and Cmax values of 
approximately 9.9 ug.h/mL and 0.8 ug/mL, respectively, which are approximately 


2015N251670_04
CONFIDENTIAL
203168
103
1/5th and 1/15th of the gender-averaged AUC (48.4 ug.h/mL) and Cmax (12.3 ug/mL) 
achieved in the 13 week monkey study at the no adverse effect level (NOAEL) dose 
of 30 mg/kg/day. Please see GSK2982772 IB [GlaxoSmithKline Document Number 
2014N204126_02].
As of 03 Apr 2017, a total of approximately 93 subjects across 4 clinical studies have 
been randomised to receive GSK2982772. In Study 200975, GSK2982772 
administered up to 120 mg BID for 14 days and was well tolerated and no safety 
concerns were identified. A total of 9 subjects had received 120 mg BID in that 
study.  Please see GSK2982772 IB [GlaxoSmithKline Document Number 
2014N204126_02]. In the ongoing Phase 2a studies in Psoriasis [(PsO); Study 
203167] and Rheumatoid Arthritis [(RA); Study 203168], a total of 26 subjects have 
been randomised to GSK2982772 60 mg BID. GSK2982772 was well tolerated and 
no drug-related SAEs have been reported.  In Study 203167, there was a death of a 
19 year old male subject due to an accidental overdose with 3,4-methylenedioxy-
methamphetamine (MDMA) that was not considered drug related by the Principal 
Investigator (PI).  
Therefore, it is predicted that a dose of GSK2982772 60 mg BID may be clinically 
efficacious in subjects with RA.
It is anticipated that a human dose of 60 mg BID will produce area under the 
concentration-time curve (AUC[0-24]) and maximum observed concentration (Cmax) values 
of approximately 9 g.h/mL and 1 g/mL, respectively, which are approximately 1/6th  
and 1/12th of the gender-averaged AUC (48.4 g.h/mL) and Cmax (12.3 g/mL) achieved 
in the 13 week monkey study at the no adverse effect level (NOAEL) dose of 30
mg/kg/day.
Section 5.1 Inclusion Criteria
Sex
11. Male & Female subjects 
Females: 
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:
a.
Non-reproductive potential as defined as in Appendix 6:
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


2015N251670_04
CONFIDENTIAL
203168
104
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 (see Appendix 6) 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.
Section 5.2 Exclusion Criteria
Diagnostic assessments and other criteria
23. Haemoglobin <119 g/dL; haematocrit <30%, white blood cell count ≤3,000/mm3 
(≤3.0 x 109/L) or  ≥14,000/mm3 (≥14 x 109/L); platelet count ≤100,000/µL (≤100 
x 109/L); absolute neutrophil count ≤31.5 x 109/L; lymphocyte count <1 x 109/L at 
screening.
Section 5.4 Withdrawal/Stopping Criteria
Subjects may be withdrawn from the study for any of the following reasons:

A subject may withdraw from study treatment at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioural or administrative reasons.  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.  The reason for withdrawal should be 
documented in the Case Report Form (CRF).

The Sponsor’s request, for reasons such as significant protocol deviations or 
subject safety concern (and after discussion with the Investigator).

If a subject is withdrawn from study treatment, this subject is also considered to 
be withdrawn from the study.

Study is terminated by the Sponsor.
Section 5.4.5 Haematologic Stopping Rules
Study treatment will be stopped for a subject if any of the following haematological 
stopping criteria is met:

Haemoglobin - <9 g/dL (5.58 mmol/L) or an absolute decrease of ≥32 g/dL 
from baseline (pre-dose Day 1)

Neutrophils <1 × 109/L


2015N251670_04
CONFIDENTIAL
203168
105

Lymphocytes <0.5 × 109/L

Platelets <50 × 109/L
Section 6.1 Investigation Product and Other Study Treatment
Study Treamtent Treatment
Product name:
GSK2982772
Placebo
Dosage form:
Tablet
Tablet
Unit dose strength(s)/Dosage 
level(s):
30 mg
NA
Route of Administration 
For oral use only
For oral use only
Dosing instructions (with 
amendment 03):
Take TWO tablets three 
times a day as directed 
by your physician
Take TWO tablets three 
times a day as directed 
by your physician
Dosing instructions (prior to 
amendment 03):
Take TWO tablets in the 
MORNING and TWO 
tablets in the EVENING 
as directed
Take TWO tablets in the 
MORNING and TWO 
tablets in the EVENING 
as directed
Physical description:
White to almost white, 
round, film coated tablet
White to almost white, 
round, film coated tablet
Source of procurement
Study medication is 
supplied by 
GlaxoSmithKline
Placebo is supplied by 
GlaxoSmithKline
Section 6.4 Blinding
Sponsor unblinded refers only to the Data Review Committee (DRC) consisting of the 
GSK study physician Project Physician Lead (PPL), the study statistician, the study 
pharmacokineticist, Pattern Recognition Receptor (PRR) Discovery Performance Unit 
(DPU) Head, the Early Development Leader (EDL), the Safety Review Team (SRT) 
leader, or their designees on an ongoing basis.
Section 6.7 Compliance With Study Treatment Administration
Subjects will be given instructions on compliance and treatment with MTX (if 
applicable).  The date, time and total weekly dose will be recorded in the study diary 
cards and the CRF.
Section 6.8 Treatment of Study Treatment Overdose
For this study, any dose of GSK2982772 >120180 mg daily will be considered an 
overdose.  GSK does not recommend specific treatment for an overdose.  The 
Investigator will use clinical judgement to treat any overdose as and when they are made 
aware of this.


2015N251670_04
CONFIDENTIAL
203168
106
Section 6.11.1 Permitted Medications and Non-Drug Therapies
Table 1 
Drug
Requirement
Methotrexate 
Stable dose regimen (up to 25 mg/week) for at least 12 
weeks prior to screening and remain on this dose 
throughout the study (unless dose must be reduced 
because of a safety concern).  MTX should ideally be 
taken on the same day of week and at approximately 
the same time of day throughout the study.
Section 6.11.2 Prohibited Medications and Non-Drug Therapies
Table 2
Therapy
Time period 
A change in dose of methotrexate or other DMARD.
12 weeks prior to screening until after the 
follow up visit (Day 112)
Greater than 10mg/day oral prednisolone (or 
equivalent glucocorticoid) or a change in dose of 
corticosteroid.
4 weeks prior to screening until after the 
follow up visit (Day 112)
Intramuscular glucocorticoids (e.g., 
methylprednisolone ≤120 mg/month)
4 weeks prior to screening until after the 
follow up visit (Day 112)
Intra-articular corticosteroid injections
6 weeks prior to screening and until after 
the follow up visit (Day 112).
Janus Kinase (JAK) Inhibitors
4 weeks prior to screening until after 
the follow up visit (Day 112).
P-glycoprotein (Pgp) inhibitors including but not 
limited to amiodarone, azithromycin, captopril, 
carvedilol, clarithromycin, conivaptan, cyclosporine, 
diltiazem, dronedarone, erythromycin, felodipine, 
itraconazole, ketoconazole, lopinavir, ritonavir, 
quercetin, quinidine, ranolazine, ticagrelor, 
verapamil [FDA, 2012].
4 weeks prior to first dose (Day 1) until 
after the follow up visit (Day 112).
Narrow therapeutic index (NTI) CYP3A4 substrates 
including but not limited to alfentanil, astemizole, 
cisapride, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus, terfenadine [FDA, 2012].
4 weeks prior to the first dose (Day 1) 
until after the follow up visit (Day 112).
Biologic therapies for the treatment of rheumatoid 
arthritis not limited to anti-TNF biologics or other 
biologics, rituximab, anakinra, abatacept or 
tocilizumab.
At any time. 


2015N251670_04
CONFIDENTIAL
203168
107
Therapy
Time period 
Exposure to more than one anti-TNF biologic 
therapies for the treatment of RA including but not 
limited to anti-TNF biologics, infliximab, 
adalimumab, etanercept, certolizumab and 
golimumab.
Exception:  Exposure to a single anti-TNF-biologic 
for which the subject discontinued for a reason other 
than primary non-response is permitted.
Cannot have been exposed to more than 
one anti-TNF biologic or be on at any 
time during the study.
In the case of a single anti-TNF biologic 
for which the subject discontinued for a 
reason other than primary non-response, 
the subject must not be on for 8 weeks or 
5 ½ half lives (whichever is longer) prior 
to first dose until after the follow up visit 
(Day 112).  
Live vaccination
Live or attenuated vaccinations are not 
permitted within 30 days of 
randomization or plan to receive a 
vaccination during the study until follow-
up visit.  If indicated, non-live vaccines 
(e.g., inactivated influenza vaccines) may 
be administered whilst receiving 
GSK2982772 based on an assessment 
of the benefit:risk (e.g., risk of decreased 
responsiveness).  Investigators are 
expected to follow local and/or national 
guidelines with respect to vaccinations, 
including against pneumococcus and 
influenza, in subjects with RA.


2015N251670_04
CONFIDENTIAL
203168
108
Section 7.1 Time and Events Table
Procedures
Screening (-30)
Treatment Period17
Early Withdrawal18
Follow Up (3)19
Day 1 
Day 8 (3)
Day 15 (3)
Day 22 (3)
Day 29 (3)
Day 36 (3)
Day 43 (3)
(week 6)
Day 50 (3)
Day 57 (3)
Day 64 (3)
Day 71 (3)
Day 78 (3)
Day 85 (+2)
(week 12)
Site Visit
X
X
X
X
X
X
X
X
X
X
X
Phone call
X
X
X
X
X
General/Safety Assessments and Procedures
Informed Consent
X
Subject Demography
X
Full medical history1
X
Inclusion/Exclusion Criteria
X
Full physical exam2
X
X
X
X
Brief physical exam
X4
X
X
X4
X
X
Vital signs (BP, HR, RR, temperature)  
X
X4
X
X
X
X4
X
X
X
X
X
12-lead ECG
X3
X4
X
X
X
X4
X
X
X
X
X
Concomitant medication review & AE reporting/SAEs5
X---------------------------------------------------------------------------------------------------------------------------X
PROs/Questionnaires/Diaries/Disease Assessments and Procedures
Columbia Suicide Severity Rating Scale (C-SSRS)
X
X4
X4
X
X
FACIT-fatigue; RA Symptom and Impact Diary6
X4
X4
X
X
HAQ-DI; Patient Assessment of joint pain6
X4
X
X
X4
X
X
X
X
Patient Global Assessment (PtGA)6
X
X4
X
X
X4
X
X
X
X
Tender (28) & Swollen (28) joint count
X
X4
X
X
X4
X
X
X
X
Physician Global Assessment (PGA)
X4
X
X
X4
X
X
X
X
MRI/DCE-MRI7
X4, 20
X4,2021
X22
X16


2015N251670_04
CONFIDENTIAL
203168
109
Procedures
Screening (-30)
Treatment Period17
Early Withdrawal18
Follow Up (3)19
Day 1 
Day 8 (3)
Day 15 (3)
Day 22 (3)
Day 29 (3)
Day 36 (3)
Day 43 (3)
(week 6)
Day 50 (3)
Day 57 (3)
Day 64 (3)
Day 71 (3)
Day 78 (3)
Day 85 (+2)
(week 12)
Study Treatment
Randomisation
X
Study medication (twicethree times daily)8
X-------------------------------------------------------------------------------------------------------X
Dispensing of study medication
X
X
X
Dispensing of diary cards
X
X
X
X
X
X
X
Collection and review of diary cards
X
X
X
X
X
X
X
X
Laboratory (Safety) Assessments and Procedures
TB, HIV, HepB,Hep C Ab, Anti-CCP, Anti-dsDNA, RF 
X
FSH & estradiol  (if applicable)
X
Serum pregnancy test (WCBP only)
X
Urine pregnancy test (WCBP only)9
X4
X
X
X
X4
X
X
X
X
X
Haematology, chemistry, urinalysis 
X
X4
X
X
X10
X4
X10
X10
X
X
X
CRP
X
X4
X
X
X4
X
X
X
X
Blood sample for PD inflammatory biomarkers, mRNA, and 
TE11
X4
X4
X
X
PK blood samples GSK298277212
X
X4
X4
X
X
PK blood samples for MTX13
X4
X4
X4
Pharmacogenetic sample (PGx)
X14
Synovial biopsies for PK, inflammatory biomarkers, mRNA, 
target engagement & pathway engagement analysis15
X4,20
X4,1921
X16
Footnotes:
1.
Full medical history (includes past and current conditions, medication history, substance usage, and family history of premature CV disease).


2015N251670_04
CONFIDENTIAL
203168
110
2.
Full physical exam (includes height/weight at screening, height not measured at later time points).
3.
Triplicate ECG to be performed at screening only.
4.
Pre-dose.
5.
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.  AEs will be collected from the start of Study Treatment until the follow-
up contact.  On Days 22, 36, 50, 64, and 78, subjects will be questioned about their general health status via phone call.
6.
All PRO assessments should be conducted on site before any tests, procedures, or assessments, to avoid influencing the subjects’ perception.
7.
DCE-MRI will be performed on all subjects, provided that sites have DCE-MRI capability and experience (e.g., hardware and software requirements). If sites do not have 
DCE-MRI capability or experience, a regular MRI will be performed of the affected hand/wrist.  If the same joint is used for MRI and synovial biopsy, MRI should be performed 
before biopsy (if applicable).
8.
Subjects must take study medication twicethree times a day approximately 12 8 hours apart. Exact time of dosing to be recorded in diary cards. On Day 1, the first study 
dose will be administered at the site.  On Days 8, 43 and 85 only, subjects must not take their medication at home in the morning. Subjects will complete pre-dose 
assessments and then will be administered their morning dose of medication at site on Days 8 and 43.  On Day 85, subjects are no longer receiving study medication.
9.
If urine pregnancy test is positive, a confirmatory serum pregnancy test must be performed.
10. Haematology and chemistry only.  No urinalysis required on Days 29, 57 and 71.  When clinical laboratory samples are taken on the same day as the MRI, the samples 
should be taken first prior to the administration of the contrast fluid with MRI.  If this is not feasible (i.e. MRI is performed first), it is recommended that a separate 
IV catheter or straight venipuncture be performed in the opposite arm to where the MRI contrast fluid was administered.
11. Blood samples for inflammatory biomarkers, mRNA and target engagement.  See laboratory manual for full details on sample collection, handling and shipment.
12. PK blood samples for GSK2982772 will be taken pre-dose on Days 8 and 43. Post-dose serial PK samples will be taken on Days 1, 8 and Day 43 at the following time points: 
1, 2, 4, and 6 hours. Aand trough PK sample will be taken on Day 85 or at Early Withdrawal.
13. Only applicable if subjects are on MTX: PK blood samples for MTX will be taken pre-dose GSK2982772 on Day 1 (MTX alone), on Days 8 and 43 (MTX + GSK2982772).  
Subjects who are on MTX must should ideally take their MTX dose on the same day of the week at approximately the same time of the day throughout the study. In addition, 
the Day 1, 8 and 43 visits mustshould ideally be on the same day of the week.
14. A PGx blood sample is collected at the baseline visit, after the subject has been randomised and provided informed consent for genetic research.  If the sample is not 
collected at the baseline visit, it can be collected at any time during the study after randomisation.
15. Synovial biopsies are optional.
16. Biopsy (if applicable) and MRI only are required at Early Withdrawal visit if subject withdraws after at least 14 days of treatment and prior to Day 43.  If a subject withdraws 
between Days 43 and 57, an MRI is not required at the Early Withdrawal visit.  If a subject withdraws on Day 57 or after, an MRI should be performed at the Early Withdrawal 
visit.  A window allowance of 3 days of Early Withdrawal visit is allowed to perform the MRI.
17. Visit windows during the treatment period are relative to Day 1.
18. If a subject withdraws from the study, every effort will be made for the subject to complete an Early Withdrawal visit prior to the Follow Up visit.
19. Follow-up visit should be completed 28 days (3 days) after the last dose of study medication.
20. MRI (and if applicable; a biopsy) may be performed during the screening window as an additional visit (if required) up to 7 days before Day 1 to allow sites 
flexibility in scheduling.  The MRI must be completed prior to synovial biopsy (if performed on the same joint).  The site should be reasonably confident that the 
subject has fully qualified for the study (e.g., screening clinical labs, vital signs, physical examination, etc.) before the MRI (and if applicable: a biopsy) is/are 
performed. 


2015N251670_04
CONFIDENTIAL
203168
111
21. A biopsy (if applicable) and MRI may be performed on a separate day within the Day 43 window allowance (3 days). A separate visit to perform the MRI followed by 
synovial biopsy (if applicable) is only allowed to accommodate scheduling.  If biopsy is being performed, this visit must be scheduled after the Day 43 visit where the PK, 
clinical laboratory tests and other required Day 43 procedures are performed.  Subjects must not take their study medication at home in the morning before the full Day 43 
visit and also the morning before MRI and biopsy (if applicable) visit if being done on a separate day. 
22. For MRI performed on day 85, a visit window of up to 2 days after is allowed in order to perform the MRI.


2015N251670_04
CONFIDENTIAL
203168
112
Section 7.3.5 Electrocardiogram (ECG)

Triplicate12-lead ECGs will be obtained at screening and single 12-lead ECGs 
obtained at every time point during the study using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc (F or 
B) intervals.  A manual over read is also allowed. Refer to Section 5.4.4 for QTc 
withdrawal criteria and additional QTc readings that may be necessary.
Section 7.3.7 Suicidal Risk Monitoring
Subjects being treated with GSK2982772 should be monitored appropriately for suicidal 
ideation and behaviour or any other unusual changes in behaviour. Study medication
must be immediately discontinued in all subjects who experience signs of suicidal 
ideation or behaviour must immediately be discontinued from study medication.
Section 7.6.1 Magnetic Resonance Imaging (MRI) of Joint
On attendance at the MRI department, subjects will be placed in the scanner and will be 
prepared for intravenous contrast agent administration.  The scanning protocol will 
include routine localizers, T1 measurement sequences, dynamic DCE-MRI acquisition, 
and acquisitions required for OMERACT RAMRIS, and RAMRIQ and CARLOS
scoring.  Additional exploratory MRI endpoints, as detailed in the Acquisition Manual, 
may also be acquired for exploratory purposes.
Section 9.2.1 Sample Size Assumptions
The study is not powered to detect pre-defined differences. A sufficient number of 
subjects will be screened so that approximately 2430 subjects with moderate to severe 
RA are randomised into the study on a TID regimen.  Prior to protocol amendment 3 
being approved in each country, no more than 18 subjects will be randomised into 
the study on a BID regimen.  Table 4 summarises the total planned sample sizes for 
BID and TID regimens.  Should the drop-out rate be higher than anticipated, additional 
or replacement subjects may be randomised (up to an overall maximum of 4836) into the 
study at the discretion of the Sponsor.
Table 4
Summary of Total Sample Size by Dosing Regimen
Number Randomised to 
GSK2982772 60 mg BID or 
Placebo BID
Number Randomised to 
GSK2982772 60 mg TID or 
Placebo TID
Revised 
Max 
Total 
Sample 
Size
Total + 
Additional/ 
Replacement 
Subjects
7 - 12
24
36
42
12 - 18
24
42
48


2015N251670_04
CONFIDENTIAL
203168
113
The primary objective of the study is safety and tolerability, where there will be 20
subjects randomised to GSK2982772 60 mg TID and up to 12 subjects randomised to 
GSK29827772 60 mg BID. Using a Bayesian approach to determine the confidence 
interval (CI) around an observed safety event, we would assume a flat Beta (1, 1) prior, 
and if we were to observe one safety event in 20 16 then the posterior distribution would 
be Beta (2, 2016), as outlined below in Figure 4. 
Thus, we can be 95% certain that the true probability of the safety event lies between 
0.012% and 0.2425%. 
For supportive information, the properties of the key secondary endpoint DAS28 have 
been considered.
Based on the estimate of variability (SD=1 from historical data) it is estimated that the 
lower and upper bounds of the 95% CI for the change from baseline in DAS28-CRP 
score will be within approximately 0.6940.693 and 0.4620.490 of the point estimate of 
GSK2982772 60 mg TID (n=2018) and placebo (n=108).


2015N251670_04
CONFIDENTIAL
203168
114
Section 9.2.2 Sample Size Sensitivity
A sample size sensitivity analysis has been conducted on the primary endpoint to 
investigate the different safety event rates.  If the number of subjects who complete the 
12 weeks is higher or lower than 16 in the GSK2982772 group, then the true incidence 
rates of safety events that could not be ruled out (as outlined in Section 9.2.1) would 
change.  These changes are outlined in Table 5.
Table 5
Sample Size Sensitivity
GSK2982772 subjects 
completing the study
Number of a particular safety 
event observed with 
GSK2982772
Upper limit of exact 95%
Credible Interval indicating that 
a true incidence rate of x% 
could not be ruled out
20
0
16.1%
20
1
23.8%
20
2
30.4%
18
0
17.6%
18
1
26.0%
18
2
33.1%
16
0
19.5%
16
1
28.7%
16
2
36.4%
14
0
21.8%
14
1
31.9%
14
2
40.5%
12
0
24.7%
12
1
36.0%
12
2
45.4%
Section 9.3.1 Analysis Populations
If 12 or more subjects are randomised to a BID regimen (i.e., ≥4 placebo and ≥8 
GSK2982772 60 mg BID) then treatment received will take into account dosing 
frequency for GSK2982772, otherwise treatment will be irrespective of dosing 
frequency.
Section 9.3.2 Interim Analysis
Once an appropriate number of subjects have completed Day 43 (Week 6) the DAS28-
CRP data will be reviewed in an unblinded manner and on an ongoing basis by the Data 
Review Committee, consisting of the GSK study physicianProject Physician Lead 
(PPL), the study statistician, the study pharmacokineticist, the PRR DPU Head, EDL and 
SRT Leader or designees on an ongoing basis.  A physician external to the GSK2982772 
project team may also be involved in the data review. Additional inflammatory 
biomarkers, clinical and mechanistic endpoints (e.g. target engagement) may be reviewed 
if available. No other member of the GSK core study team will be unblinded to this data.


2015N251670_04
CONFIDENTIAL
203168
115
Section 11.0
References
GlaxoSmithKline Document Number 2014N204126_02.  Investigator Brochure for 
GSK2982772.  Report Date 27-JAN-2017.
Section 12.1. Appendix 1 – Abbreviations and Trademarks
Anti-CCP
Anti-Cyclic Citrullinated Peptide
CARLOS
Cartilage Loss Scoring System
hCG
Human Chorionic Gonadotropin
LDL
Low Density Lipoprotein
MCV
Mean Corpuscular Volume
MDMA
3,4-methylenedioxy-methamphetamine
PPL
Project Physician Lead
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
TID
Three times daily
WOCP
Women of Child Bearing Potential
Section 12.4 Appendix 4 – Genetic Research
Genetic Research Objectives and Analyses
GSK2982772 is a novel first-in-class asset being introduced to patients with 
moderate to severe RA for the first time. Currently its mechanism of action is not 
fully characterised nor understood. 
Specific genes may be studied that encode the drug targets, or drug mechanism of 
action pathways, drug metabolizing enzymes, drug transporters or which may 
underpin adverse events, disease risk or drug response. These candidate genes may 
include a common set of ADME (Absorption, Distribution, Metabolism and 
Excretion) genes that are studied to determine the relationship between gene 
variants or treatment response and/or tolerance. In addition, continuing research 
may identify other enzymes, transporters, proteins ore receptors that may be 
involved in response to GSK2982772. The genes that may code for these proteins 
may also be studied. Genome-wide scans involving a large number of polymorphic 
markers (e.g. single nucleotide polymorphisms) at defined locations in the genome, 
often correlated with a candidate gene, may be studied to determine the relationship 
between genetic variants and treatment response or tolerance. This approach is 
often employed when a definitive candidate gene does not exist and/or the potential 
genetic effects are not well understood.  
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.


2015N251670_04
CONFIDENTIAL
203168
116
If applicable and genetic research is conducted, Aappropriate descriptive and/or 
statistical analysis methods will be used to evaluate pharmacogenetic data in the 
context of the other clinical data. A detailed description of any planned analyses will be 
documented in a Reporting and Analysis Plan (RAP) prior to initiation of the analysis. 
Planned analyses and results of genetic investigations will be reported either as part of the 
clinical RAP and study report, or in a separate genetics RAP and report, as appropriate.


2015N251670_04
CONFIDENTIAL
203168
117
12.8.3.
Amendment 2 (14-JUL-2016) from Protocol Amendment 1 (25-
MAY-2016)
Where the Amendment Applies
This amendment applies to all subjects who will participate in this study in all countries.
Summary of Protocol Amendment Changes with Rationale
Protocol Amendment 02 incorporates addition of suicidal ideation and behaviour (SIB) 
withdrawal criteria.
Other minor protocol clarifications and administrative changes are also provided in this 
amendment.
List of Specific Changes (bold indicates text added and strikethrough indicates text 
removed):
Authors
Author (s):
 
Author (s):
 
 
PPD
PPD


2015N251670_04
CONFIDENTIAL
203168
118
MEDICAL MONITOR/SPONSOR INFORMATION
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
Tel:  
Mobile:  
Email: 
Mobile:  
Pattern Recognition 
Receptor DPU,
UP4440
1250 S Collegeville, 
PA  19426 USA
Secondary 
Medical 
Monitor
Tel: 
Mobile:  
Email:  
Mobile: 
 
Cytokine 
Chemokine DPU, 
GSK, Gunnels 
Wood Road, 
Stevenage, SG1 
2NY, UK
SAE contact  
information 
Medical 
Monitor as 
above
Section 5.4.1 Individual Safety Stopping Criteria
Study medication will be discontinued in the event of any of the following:

If a subject experiences a serious or severe clinically significant AE that in the 
clinical judgement of the Investigator, after consultation with the medical monitor, 
is possibly, probably or definitely related to investigational product.

The subject becomes pregnant.

The subject initiates treatment with any prohibited medications for the treatment 
of RA as listed in Section 6.11.2.

The subject develops a serious opportunistic or atypical infection.

If any of the liver chemistry stopping criteria (Section 5.4.3), QTc stopping 
criteria (Section 5.4.4), or Haematologic stopping criteria (Section 5.4.5) are met.

The subject experiences any signs of suicidal ideation or behaviour (Section 
7.3.7).
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PP
PPD
PPD
PPD
PPD
PPD
PPD
PPD


2015N251670_04
CONFIDENTIAL
203168
119
Section 7.1 Time and Events Table
Footnotes:
1.
Full medical history (includes past and current conditions, medication history, substance usage, and family history 
of premature CV disease).
2.
Full physical exam (includes height/weight at screening, height not measured at later time points).
3.
Triplicate ECG to be performed at screening only.
4.
Pre-dose.
5.
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.  AEs will be collected from the start of Study Treatment 
until the follow-up contact. On Days 22, 36, 50, 64, and 78, subjects will be questioned about their general 
health status via phone call.
6.
All PRO assessments should be conducted before any tests, procedures, or assessments, to avoid influencing the 
subjects’ perception.
7.
DCE-MRI will be performed on all subjects, provided that sites have DCE-MRI capability and experience (e.g., 
hardware and software requirements). If sites do not have DCE-MRI capability or experience, a regular MRI will 
be performed of the affected hand/wrist.  If the same joint is used for MRI and synovial biopsy, MRI should 
be performed before biopsy (if applicable).
8.
Subjects must take study medication twice a day approximately 12 hours apart. Exact time of dosing to be 
recorded in diary cards. On Day 1, the first study dose will be administered at the site.  On Days 8, 43 and 85 
only, subjects must not take their medication at home in the morning. Subjects will complete pre-dose 
assessments and then will be administered their morning dose of medication at site on Days 8 and 43.  On Day 
85, subjects are no longer receiving study medication.
9.
If urine pregnancy test is positive, a confirmatory serum pregnancy test must be performed.
10. Haematology and chemistry only.  No urinalysis required on Days 29, 57 and 71.
11. Blood samples for inflammatory biomarkers, mRNA and target engagement.  See laboratory manual for full details 
on sample collection, handling and shipment.
12. PK blood samples for GSK2982772 will be taken pre-dose on Days 8 and 43. Post-dose serial PK samples will be 
taken on Days 1, 8 and Day 43 at the following time points: 1, 2, 4, and 6 hours and trough on Day 85 or at Early 
Withdrawal.
13. PK blood samples for MTX will be taken pre-dose GSK2982772 on Day 1 (MTX alone), on Days 8 and 43 (MTX + 
GSK2982772).  Subjects who are on MTX must take their MTX dose on the same day of the week at 
approximately the same time of the day throughout the study. In addition, the Day 1, 8 and 43 visits must be on 
the same day of the week.
14. A PGx blood sample is collected at the baseline visit, after the subject has been randomised and provided 
informed consent for genetic research.  If the sample is not collected at the baseline visit, it can be collected at 
any time during the study after randomisation.
15. Synovial biopsies are optional.
16. Biopsy (if applicable) and MRI only are required at Early Withdrawal visit if subject withdraws after at least 14 days 
of treatment and prior to Day 43.  If a subject withdraws between Days 43 and 57, an MRI is not required at the 
Early Withdrawal visit.  If a subject withdraws on Day 57 or after, an MRI should be performed at the Early 
Withdrawal visit. 
17. Visit windows during the treatment period are relative to Day 1.
18. If a subject withdraws from the study, every effort will be made for the subject to complete an Early Withdrawal 
visit prior to the Follow Up visit.
19. Follow-up visit should be completed 28 days (3 days) after the last dose of study medication.
20. A biopsy (if applicable) and MRI may be performed on a separate day within the Day 43 window allowance (3 
days).  A separate visit to perform the MRI followed by synovial biopsy (if applicable) is only allowed to 
accommodate scheduling.  If biopsy is being performed, this visit must be scheduled after the Day 43 visit where 
the PK, clinical laboratory tests and other required Day 43 procedures are performed.  Subjects must not take 
their study medication at home in the morning before the full Day 43 visit and also the morning before MRI and 
biopsy (if applicable) visit if being done on a separate day. 


2015N251670_04
CONFIDENTIAL
203168
120
Section 7.2 Screening and Critical Baseline Assessments
Medical/medication/mental health and family history, ECG and laboratory tests will be 
assessed as related to the inclusion/exclusion criteria listed in Section 5.
Section 7.3.7 Suicidal Risk Monitoring
Subjects being treated with GSK2982772 should be monitored appropriately for suicidal 
ideation and behaviour or any other unusual changes in behaviour. Consideration should 
be given to discontinuing GSK2982772 in sAll subjects who experience signs of suicidal 
ideation or behaviour must immediately be discontinued from study medication.
Families and caregivers of subjects being treated with GSK2982772 should be alerted 
about the need to monitor subjects for the emergence of unusual changes in behaviour, as 
well as the emergence of suicidal ideation and behaviour and to report such symptoms 
immediately to the study Investigator.
At Screening and baseline (pre-dose Day 1), the ‘Baseline/Screening CSSRS’ will be 
completed.  Assessments will be done at At Days 43 (Week 6) and 85 (Week 12), the 
‘Since Last Visit CSSRS’ will be completed.  GSK Version 4.1 of both rating scales will 
be used.
Subjects who answer ‘yes’ to any suicidal behaviour or ‘yes’ to suicidal ideation 
Questions 4 or 5 will be referred to their GP or appropriate psychiatric care and be 
discontinued from study medication.  The Medical Monitor will be notified.  If 
appropriate, an AE or SAE should be reported (see Section 7.3.1 AE and SAE).  In 
addition, the Investigator should complete a Possible Suicidality Related Adverse Event 
(PSRAE) form to collect detailed information on the circumstances of the reported AEs 
which, in the Investigator’s opinion, are possibly suicidality-related.  These may include, 
but are not limited to, an event involving suicidal ideation, a preparatory act toward 
imminent suicidal behaviour, a suicide attempt, or a completed suicide.


2015N251670_04
CONFIDENTIAL
203168
121
12.8.4.
Protocol Amendment 1 (25-MAY-2016) from the original protocol 
(01-APR-2016)
Where the Amendment Applies
This amendment applies to all subjects who will participate in this study in all countries.
Summary of Protocol Amendment Changes with Rationale
Protocol Amendment 01 incorporates the addition of risk text for drug interaction with P-
glycoprotein (Pgp) inhibitors and narrow therapeutic index (NTI) CYP3A4 substrates, 
and an updated list of prohibited medications.
Other minor protocol clarifications and administrative changes are also provided in this 
amendment.
List of Specific Changes (bold indicates text added and strikethrough indicates text 
removed):
Section 1 Protocol synopsis, Analysis, Paragraph 2
An ongoing review of available efficacy, pharmacodynamic and mechanistic endpoints 
will be conducted during the study by a Data Review Committee (DRC), consisting of a 
limited number of GlaxoSmithKline (GSK) individuals, some of whom are also members 
of the GSK study team who are not involved in the day-to-day running of the study.  
Section 4.5 Dose Justification
It is anticipated that a human dose of 60 mg BID will produce area under the 
concentration-time curve (AUC[0-24]) and maximum observed concentration (Cmax) values 
of approximately 9 g.h/mL and 1 g/mL, respectively, which are approximately 1/6th
and 1/12th of the gender-averaged AUC (48.4 g.h/mL) and Cmax (12.3 g/mL) achieved 
in the 13 week monkey study at the no adverse effect level (NOAEL) dose of 
30 mg/kg/day.
Section 4.6.1 Risk Assessment
Drug Interaction
Non-clinical data:
In vitro studies with GSK2982772 
assessing uptake of potential drug-
drug interactions with Cytochrome 
P450 3A4 (CYP3A4) substrates, P-
glycoprotein (Pgp) inhibitors and
OAT3 substrates were completed.  
To date, formal drug interaction 
studies in humans have not been 
performed with GSK2982772.
There is a low risk that GSK2982772 
could be a perpetrator of OAT3 
substrates.  MTX is an OAT3 
Subject Selections:

Subjects who are taking 
concomitant medications 
known to inhibit Pgp or are 
CYP3A4 narrow therapeutic 
index (NTI) substrates will be 
excluded from the study.  See 
Section 6.11.2 for a 
comprehensive list of 
medications.
Subject Monitoring:

Subjects’ concomitant 
medication usage will be 


2015N251670_04
CONFIDENTIAL
203168
122
substrate in which GSK2982772 
could potentially impair the clearance 
of MTX.
There is a low risk that 
GSK2982772 could be an inducer 
of CYP3A4 and therefore may 
lower circulating levels of 
concomitant medications that are 
metabolised by CYP3A4 when co 
administered with GSK2982772.
GSK2982772 is a Pgp substrate 
and therefore co administration 
with concomitant medications that 
are Pgp inhibitors could increase 
circulating levels of GSK2982772.
See Section 4.3.6 of the 
GSK2982772 IB [GlaxoSmithKline 
Document 2014204126_01].
reviewed prior to inclusion 
and monitored throughout the 
study.

Subjects should be monitored 
throughout the study for 
potential effects of interaction 
between GSK2982772 and 
other concomitant 
medications.

PK sample collection to evaluate 
the potential interaction of 
GSK2982772 and MTX will be 
performed throughout the study.

Subjects should be monitored 
for potential effects of interaction 
between GSK2982772 and 
MTX.

Clinical laboratory results (e.g., 
liver function tests) are routinely 
being monitored throughout the 
study.
Section 5.2 Exclusion Criteria, Contraindications
CONTRAINDICATIONS 
19. 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.
20. Received a live or attenuated vaccine within 30 days of randomization OR plan to 
receive a vaccination during the study until 5 half-lives (or 2 days) plus 30 days after 
receiving GSK2982772.
21. Contraindication to gadolinium contrast agent in accordance with local guidelines.
22. The subject has participated in a clinical trial and has received an investigational 
product within 30 days or 5 half-lives, whichever is longer before the first dose of 
study medication, or plans to take part in another clinical trial at the same time as 
participating in this clinical trial.
Section 6.4 Blinding
This will be a double blind (sponsor unblinded) study and the following will apply:

Sponsor unblinded refers only to the Data Review Committee, consisting of the 
GSK study physician, study statistician, study pharmacokineticist, Pattern 
Recognition Receptor (PRR) Discovery Performance Unit (DPU) Head, Early
Development Lead (EDL) and Safety Review Team (SRT) Leader, or their 
designees on an ongoing basis.  A physician external to the GSK2982772 project 
team may also be involved in the data review.  A data review charter will identify 
the specific GSK individuals involved; outline in detail the activities of this 


2015N251670_04
CONFIDENTIAL
203168
123
review, and how the integrity of the study will be maintained. The rest of the core 
GSK study team will remain blinded.
Section 6.11.2 Amended Prohibited Medications and Non-Drug Therapies, Table 2 
Prohibited Medications
Therapy
Time period 
A change in dose of methotrexate or other 
DMARD.
12 weeks prior to screening until after the 
follow up visit (Day 112)
Greater than 10mg/day oral prednisolone (or 
equivalent glucocorticoid) or a change in dose 
of corticosteroid.
4 weeks prior to screening until after the 
follow up visit (Day 112)
Intramuscular glucocorticoids (e.g., 
methylprednisolone ≤120 mg/month)
4 weeks prior to screening until after the 
follow up visit (Day 112)
Intra-articular corticosteroid injections
6 weeks prior to screening and until after the 
follow up visit (Day 112).
P-glycoprotein (Pgp) inhibitors including 
but not limited to amiodarone, azithromycin, 
captopril, carvedilol, clarithromycin, 
conivaptan, cyclosporine, diltiazem, 
dronedarone, erythromycin, felodipine, 
itraconazole, ketoconazole, lopinavir, 
ritonavir, quercetin, quinidine, ranolazine, 
ticagrelor, verapamil [FDA, 2012].
4 weeks prior to first dose (Day 1) until 
after the follow up visit (Day 112).
Narrow therapeutic index (NTI) CYP3A4 
substrates including but not limited to 
alfentanil, astemizole, cisapride, 
cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus, terfenadine [FDA, 
2012].
4 weeks prior to the first dose (Day1) until 
after the follow up visit (Day 112).
Biologic therapies for the treatment of 
rheumatoid arthritis not limited to anti-TNF 
biologics or other biologics, rituximab, anakinra, 
abatacept or tocilizumab.
At any time. 
Exposure to more than one anti-TNF biologic 
therapies for the treatment of RA including but 
not limited to anti-TNF biologics, infliximab, 
adalimumab, etanercept, certolizumab and 
golimumab.
Exception:  Exposure to a single anti-TNF-
biologic for which the subject discontinued for a 
reason other than primary non-response is 
permitted.
Cannot have been exposed to more than one 
anti-TNF biologic or be on at any time during 
the study.
In the case of a single anti-TNF biologic for 
which the subject discontinued for a reason 
other than primary non-response, the subject 
must not be on for 8 weeks or 5 ½ lives 
(whichever is longer) prior to first dose until 


2015N251670_04
CONFIDENTIAL
203168
124
Therapy
Time period 
after the follow up visit (Day 112).  
Live vaccination
Live or attenuated vaccinations are not 
permitted within 30 days of randomization or 
plan to receive a vaccination during the study 
until follow-up visit.  If indicated, non-live 
vaccines (e.g., inactivated influenza vaccines) 
may be administered whilst receiving 
GSK2982772 based on an assessment of the 
benefit:risk (e.g., risk of decreased 
responsiveness).  Investigators are expected 
to follow local and/or national guidelines with 
respect to vaccinations, including against 
pneumococcus and influenza, in subjects with 
RA.


2015N251670_04
CONFIDENTIAL
203168
125
Section 7.1 Time and Events Table
Procedures
Screening (-30)
Treatment Period17
Early Withdrawal18
Follow Up (3)19
Day 1 
Day 8 (3)
Day 15 (3)
Day 22 (3)
Day 29 (3)
Day 36 (3)
Day 43 (3)
(week 6)
Day 50 (3)
Day 57 (3)
Day 64 (3)
Day 71 (3)
Day 78 (3)
Day 85 (+2)
(week 12)
Site Visit
X
X
X
X
X
X
X
X
X
X
X
Phone call
X
X
X
X
X
General/Safety Assessments and Procedures
Informed Consent
X
Subject Demography
X
Full medical history1
X
Inclusion/Exclusion Criteria
X
Full physical exam2
X
X
X
X
Brief physical exam
X4
X
X
X4
X
X
Vital signs (BP, HR, RR, temperature)  
X
X4
X
X
X
X4
X
X
X
X
X
12-lead ECG
X3
X4
X
X
X
X4
X
X
X
X
X
Concomitant medication review & AE reporting/SAEs5
X---------------------------------------------------------------------------------------------------------------------------X
PROs/Questionnaires/Diaries/Disease Assessments and Procedures
Columbia Suicide Severity Rating Scale (C-SSRS)
X
X4
X4
X
X
FACIT-fatigue; RA Symptom and Impact Diary6
X4
X4
X
X
HAQ-DI; Patient Assessment of joint pain6
X4
X
X
X4
X
X
X
X
Patient Global Assessment (PtGA)6
X
X4
X
X
X4
X
X
X
X
Tender (28) & Swollen (28) joint count
X
X4
X
X
X4
X
X
X
X
Physician Global Assessment (PGA)
X4
X
X
X4
X
X
X
X
MRI/DCE-MRI7
X4
X4,20
X
X16


2015N251670_04
CONFIDENTIAL
203168
126
Procedures
Screening (-30)
Treatment Period17
Early Withdrawal18
Follow Up (3)19
Day 1 
Day 8 (3)
Day 15 (3)
Day 22 (3)
Day 29 (3)
Day 36 (3)
Day 43 (3)
(week 6)
Day 50 (3)
Day 57 (3)
Day 64 (3)
Day 71 (3)
Day 78 (3)
Day 85 (+2)
(week 12)
Study Treatment
Randomisation
X
Study medication (twice daily)8
X-------------------------------------------------------------------------------------------------------X
Dispensing of study medication
X
X
X
Dispensing of diary cards
X
X
X
X
X
X
X
Collection and review of diary cards
X
X
X
X
X
X
X
X
Laboratory (Safety) Assessments and Procedures
TB, HIV, HepB,Hep C Ab, Anti-CCP, Anti-dsDNA, Anti-
CARP, RF 
X
FSH & estradiol  (if applicable)
X
Serum pregnancy test (WCBP only)
X
Urine pregnancy test (WCBP only)9
X4
X
X
X
X4
X
X
X
X
X
Haematology, chemistry, urinalysis 
X
X4
X
X
X10
X4
X10
X10
X
X
X
CRP
X
X4
X
X
X4
X
X
X
X
Blood sample for PD inflammatory biomarkers, mRNA, and 
TE11
X4
X4
X
X
PK blood samples GSK298277212
X
X4
X4
X
X
PK blood samples for MTX13
X4
X4
X4
Pharmacogenetic sample (PGx)
X14
Synovial biopsies for PK, inflammatory biomarkers, mRNA, 
target engagement & pathway engagement analysis15
X4
X4,20
X16


2015N251670_04
CONFIDENTIAL
203168
127
Footnotes:
1.
Full medical history (includes past and current conditions, medication history, substance usage, and family history of premature CV disease).
2.
Full physical exam (includes height/weight at screening, height not measured at later time points).
3.
Triplicate ECG to be performed at screening only.
4.
Pre-dose.
5.
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.  AEs will be collected from the start of Study Treatment until the follow-up 
contact.
6.
All PRO assessments should be conducted before any tests, procedures, or assessments, to avoid influencing the subjects’ perception.
7.
DCE-MRI will be performed on all subjects, provided that sites have DCE-MRI capability and experience (e.g., hardware and software requirements). If sites do not have DCE-MRI 
capability or experience, a regular MRI will be performed of the affected hand/wrist.  
8.
Subjects must take study medication twice a day approximately 12 hours apart. Exact time of dosing to be recorded in diary cards. On Days 8, 43 and 85 only, subjects must not 
take their medication at home in the morning. Subjects will complete pre-dose assessments and then will be administered their morning dose of medication at site on Days 8 and 
43.  On Day 85, subjects are no longer receiving study medication.
9.
If urine pregnancy test is positive, a confirmatory serum pregnancy test must be performed.
10. Haematology and chemistry only.  No urinalysis required on Days 29, 57 and 71.
11. Blood samples for inflammatory biomarkers, mRNA and target engagement.  See laboratory manual for full details on sample collection, handling and shipment.
12. PK blood samples for GSK2982772 will be taken pre-dose on Days 8 and 43. Post-dose serial PK samples will be taken on Days 1, 8 and Day 43 at the following time points: 1, 2, 
4, and 6 hours and trough on Day 85 or at Early Withdrawal.
13. PK blood samples for MTX will be taken pre-dose GSK2982772 on Day 1 (MTX alone), on Days 8 and 43 (MTX + GSK2982772).  Subjects who are on MTX must take their MTX 
dose on the same day of the week at approximately the same time of the day throughout the study. In addition, the Day 1, 8 and 43 visits must be on the same day of the week.
14. A PGx blood sample is collected at the baseline visit, after the subject has been randomised and provided informed consent for genetic research.  If the sample is not collected at 
the baseline visit, it can be collected at any time during the study after randomisation.
15. Synovial biopsies are optional.
16. Biopsy (if applicable) and MRI only are required at Early Withdrawal visit if subject withdraws after at least 14 days of treatment and prior to Day 43.  If a subject withdraws 
between Days 43 and 57, an MRI is not required at the Early Withdrawal visit.  If a subject withdraws on Day 57 or after, an MRI should be performed at the Early Withdrawal visit. 
17. Visit windows during the treatment period are relative to Day 1.
18. If a subject withdraws from the study, every effort will be made for the subject to complete an Early Withdrawal visit prior to the Follow Up visit.
19. Follow-up visit should be completed 28 days (3 days) after the last dose of study medication.
20. A biopsy (if applicable) and MRI may be performed on a separate day within the Day 43 window allowance (3 days).  A separate visit to perform the MRI followed by 
synovial biopsy (if applicable) is only allowed to accommodate scheduling.  If biopsy is being performed, this visit must be scheduled after the Day 43 visit where the 
PK, clinical laboratory tests and other required Day 43 procedures are performed.  Subjects must not take their study medication at home in the morning before the 
full Day 43 visit and also the morning before MRI and biopsy (if applicable) visit if being done on a separate day.


2015N251670_04
CONFIDENTIAL
203168
128
Section 7.2 Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors and smoking history (as detailed in the 
CRF) will be assessed at screening.
Section 7.3.4 Vital Signs
Vital signs will be measured in a supine or semi-supine position after approximately 
5 minutes rest and will include temperature, systolic and diastolic blood pressure, pulse 
rate and respiratory rate.
Section 7.3.6 Clinical Safety Laboratory Assessments, Table 3 Protocol Required 
Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
1,2
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 3
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose4
Calcium
Alkaline phosphatise
Albumin
CRP
Triglycerides4
Total Cholesterol4
Fasting HDL 
cholesterol4
Fasting LDL 
cholesterol4
Routine 
Urinalysis

Specific gravitypH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening and 
RoutineTests

HIV 1 & 2

Hepatitis B (HBsAg)

Hepatitis B core antibody (HBcAb)

Hepatitis C (Hep C antibody)

QuantiFeron Gold Test

T-spot (if QuantiFeron is indeterminant)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Urine hCG Pregnancy test (as needed for women of child bearing 
potential) 5

Serum hCG (as needed for women of child bearing potential) to be 
done at screening and if urine test positive at other time points in the 


2015N251670_04
CONFIDENTIAL
203168
129
Laboratory 
Assessments
Parameters
study.

Anti-dsDNA

Rheumatoid Factor

Anti-CCP

Anti-CARP

Estimated glomerular filtration rate (eGFR) will be calculated using 
the CKD-EPI formula.
Section 9.3.2 Interim Analysis
Once an appropriate number of subjects have completed Day 43 (Week 6) the DAS28-
CRP data will be reviewed in an unblinded manner and on an ongoing basis by the Data 
Review Committee, consisting of the GSK study physician, the study statistician, the 
study pharmacokineticist, the PRR DPU Head, EDL and SRT Leader or designees on an 
ongoing basis.


2015N251670_00
CONFIDENTIAL
The GlaxoSmithKline group of companies
203168
1
TITLE PAGE
Division:  Worldwide Development
Information Type: Clinical Protocol
Title:
A multicentre, randomised, double-blind (sponsor-unblinded), 
placebo-controlled study to investigate the safety and 
tolerability, pharmacokinetics, pharmacodynamics, and efficacy 
of GSK2982772 in subjects with moderate to severe rheumatoid 
arthritis.
Compound Number:
GSK2982772
Development Phase
II
Effective Date:
01-APR-2016
Author(s):
 
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


PPD
PPD


2015N251670_00
CONFIDENTIAL
203168
3
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor
Tel:  
Mobile:  
Email: 
Mobile:  
Pattern Recognition 
Receptor DPU, 
UP4440
1250 S Collegeville, 
PA  19426 USA
Secondary 
Medical 
Monitor
Tel: 
Mobile:  
Email:  
Mobile:
 
Cytokine 
Chemokine DPU, 
GSK, Gunnels 
Wood Road, 
Stevenage, SG1 
2NY, UK
SAE contact  
information 
Medical 
Monitor as 
above
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.
Regulatory Agency Identifying Number(s): EudraCT 2016-000912-13
PPD
PPD
PPD
PPD
PPD
PP
PPD
PPD
PPD
PPD


2015N251670_00
CONFIDENTIAL
203168
4
INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

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


2015N251670_00
CONFIDENTIAL
203168
5
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 203168........................................................9
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................13
2.2.
Brief Background ........................................................................................14
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................15
4.
STUDY DESIGN ....................................................................................................18
4.1.
Overall Design ............................................................................................18
4.2.
Treatment Arms and Duration.....................................................................18
4.2.1.
Screening ....................................................................................18
4.2.2.
Treatment Period.........................................................................18
4.2.3.
Follow-up Period..........................................................................19
4.3.
Type and Number of Subjects.....................................................................19
4.4.
Design Justification.....................................................................................19
4.5.
Dose Justification........................................................................................19
4.6.
Benefit:Risk Assessment ............................................................................20
4.6.1.
Risk Assessment .........................................................................21
4.6.2.
Benefit Assessment.....................................................................27
4.6.3.
Overall Benefit:Risk Conclusion...................................................27
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............27
5.1.
Inclusion Criteria.........................................................................................27
5.2.
Exclusion Criteria........................................................................................29
5.3.
Screening/Baseline/Run-in Failures............................................................32
5.4.
Withdrawal/Stopping Criteria.......................................................................32
5.4.1.
Individual Safety Stopping Criteria ...............................................33
5.4.2.
Group Safety Stopping Criteria ....................................................33
5.4.3.
Liver Chemistry Stopping Criteria ................................................33
5.4.3.1.
Study Treatment Restart or Rechallenge....................34
5.4.4.
QTc Stopping Criteria ..................................................................34
5.4.5.
Haematologic Stopping Criteria ...................................................35
5.5.
Subject and Study Completion....................................................................35
6.
STUDY TREATMENT ............................................................................................35
6.1.
Investigational Product and Other Study Treatment....................................35
6.2.
Treatment Assignment................................................................................36
6.3.
Planned Dose Adjustments.........................................................................36
6.4.
Blinding.......................................................................................................37
6.5.
Packaging and Labeling..............................................................................37
6.6.
Preparation/Handling/Storage/Accountability..............................................38
6.7.
Compliance with Study Treatment Administration.......................................38
6.8.
Treatment of Study Treatment Overdose....................................................38
6.9.
Treatment after the End of the Study ..........................................................39
6.10.
Lifestyle and/or Dietary Restrictions............................................................39
6.10.1.
Activity .........................................................................................39
6.11.
Concomitant Medications and Non-Drug Therapies....................................39
6.11.1.
Permitted Medications and Non-Drug Therapies..........................39


2015N251670_00
CONFIDENTIAL
203168
6
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................40
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................42
7.1.
Time and Events Table...............................................................................43
7.2.
Screening and Critical Baseline Assessments ............................................46
7.3.
Safety .........................................................................................................46
7.3.1.
Adverse Events (AEs) and Serious Adverse Events 
(SAEs).........................................................................................46
7.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................46
7.3.1.2.
Method of Detecting AEs and SAEs ...........................47
7.3.1.3.
Follow-up of AEs and SAEs........................................47
7.3.1.4.
Cardiovascular and Death Events ..............................47
7.3.1.5.
Regulatory Reporting Requirements for SAEs............48
7.3.2.
Pregnancy ...................................................................................48
7.3.3.
Physical Exams ...........................................................................48
7.3.4.
Vital Signs....................................................................................49
7.3.5.
Electrocardiogram (ECG).............................................................49
7.3.6.
Clinical Safety Laboratory Assessments ......................................49
7.3.7.
Suicidal Risk Monitoring...............................................................51
7.4.
Efficacy.......................................................................................................52
7.4.1.
Patient Reported Outcomes.........................................................52
7.4.1.1.
Rheumatoid Arthritis Symptoms and Impact 
Diary...........................................................................52
7.4.1.2.
Patient Assessment of Joint Pain ...............................52
7.4.1.3.
Patient’s Global Assessment of Disease 
(PtGA) ........................................................................52
7.4.1.4.
Disability Index of the Health Assessment 
Questionnaire (HAQ-DI) .............................................52
7.4.1.5.
Functional Assessment of Chronic Illness 
Therapy (FACIT)-Fatigue Scale..................................53
7.4.2.
Clinical Disease Assessments .....................................................53
7.4.2.1.
Disease Activity Score (DAS) Assessments ...............53
7.4.2.2.
American College of Rheumatology Criteria 
(ACR) Assessments ...................................................53
7.4.2.3.
Joint Assessments......................................................54
7.4.2.4.
Measurement of Serum CRP......................................54
7.4.2.5.
Physician’s Global Assessment of Disease 
Activity (PGA).............................................................54
7.5.
Pharmacokinetics .......................................................................................54
7.5.1.
Blood Sample Collection..............................................................54
7.5.2.
Sample Analysis ..........................................................................54
7.5.3.
Synovial Biopsy Tissue for Pharmacokinetic Assay .....................55
7.5.4.
Sample Analysis ..........................................................................55
7.6.
Biomarker(s)/Pharmacodynamic Markers ...................................................55
7.6.1.
Magnetic Resonance Imaging (MRI) of Joint ...............................55
7.6.2.
Synovial Biopsy ...........................................................................56
7.6.2.1.
Selection of Joint for Synovial Biopsy .........................56
7.6.2.2.
Synovial Biopsy Procedure.........................................56
7.6.3.
Novel Pharmacodynamic Biomarkers ..........................................57
7.6.3.1.
RIP1 Target Engagement in Blood .............................57
7.6.3.2.
RIP1 Target Engagement in Synovial Tissue..............57


2015N251670_00
CONFIDENTIAL
203168
7
7.6.3.3.
Pathway Biomarkers in Synovial Tissue .....................57
7.6.4.
Exploratory Novel Biomarkers......................................................57
7.7.
Genetics .....................................................................................................58
8.
DATA MANAGEMENT ...........................................................................................58
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................59
9.1.
Hypotheses.................................................................................................59
9.2.
Sample Size Considerations.......................................................................59
9.2.1.
Sample Size Assumptions ...........................................................59
9.2.2.
Sample Size Sensitivity................................................................60
9.2.3.
Sample Size Re-estimation or Adjustment...................................60
9.3.
Data Analysis Considerations .....................................................................60
9.3.1.
Analysis Populations....................................................................60
9.3.2.
Interim Analysis ...........................................................................61
9.4.
Key Elements of Analysis Plan ...................................................................61
9.4.1.
Primary Analyses.........................................................................61
9.4.2.
Secondary Analyses ....................................................................62
9.4.3.
Other Analyses ............................................................................62
9.4.3.1.
Exploratory Analyses..................................................62
10. STUDY GOVERNANCE CONSIDERATIONS........................................................62
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............62
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................63
10.3.
Quality Control (Study Monitoring) ..............................................................63
10.4.
Quality Assurance.......................................................................................64
10.5.
Study and Site Closure ...............................................................................64
10.6.
Records Retention......................................................................................64
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................65
11. REFERENCES.......................................................................................................67
12. APPENDICES........................................................................................................69
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................69
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................73
12.3.
Appendix 3:  Prednisolone Equivalent Dose Table......................................75
12.4.
Appendix 4- Genetic Research ...................................................................76
12.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................79
12.5.1.
Definition of Adverse Events........................................................79
12.5.2.
Definition of Serious Adverse Events...........................................80
12.5.3.
Definition of Cardiovascular Events .............................................81
12.5.4.
Recording of AEs and SAEs ........................................................82
12.5.5.
Evaluating AEs and SAEs............................................................83
12.5.6.
Reporting of SAEs to GSK...........................................................84
12.6.
Appendix 6: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................85
12.6.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............85


2015N251670_00
CONFIDENTIAL
203168
8
12.6.2.
Collection of Pregnancy Information ............................................86


2015N251670_00
CONFIDENTIAL
203168
9
1.
PROTOCOL SYNOPSIS FOR STUDY 203168
Rationale
This study is the first experience with GSK2982772, a receptor-interacting protein-1 
(RIP1) kinase inhibitor, in subjects with moderate to severe rheumatoid arthritis (RA) 
who are currently being treated with disease modifying anti-rheumatic drugs (DMARDs).
The primary objective will be to investigate the safety and tolerability of repeat oral doses 
of GSK2982772 (60 mg twice daily for 84 days). In addition to the pharmacokinetics
(PK), a number of experimental and clinical endpoints will be employed to obtain 
information on the pharmacodynamics (PD), and preliminary efficacy in subjects with 
active RA. Although no formal hypothesis will be tested, these endpoints will enable a 
broader understanding of the mechanism of action and potential for clinical efficacy of 
GSK2982772 in RA, by making full use of the information obtained from each subject 
enrolled.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To investigate the safety and tolerability 
of 60 mg twice daily doses of 
GSK2982772 in subjects with moderate 
to severe Rheumatoid Arthritis.

Adverse events.

Clinical laboratory values (clinical 
chemistry, haematology and urinalysis).

Vital sign measurements (blood pressure, 
heart rate, respiratory rate, and body 
temperature).

12-Lead ECG monitoring.
Secondary

To investigate the plasma concentrations
of GSK2982772 following 60 mg twice 
daily doses of GSK2982772 in subjects 
with moderate to severe Rheumatoid
Arthritis.

Pre-dose concentrations of GSK2982772 
on Days 8 and 43 (Week 6).  

Post-dose concentrations of 
GSK2982772 on Days 1, 8, and 43
(Week 6) at 1, 2, 4 and 6 hours.

Trough concentrations on Day 85 (Week 
12).

To investigate the effect of 60 mg twice 
daily doses of GSK2982772 on 
inflammatory biomarkers in blood 
subjects with moderate to severe 
Rheumatoid Arthritis.

Change from baseline in blood 
inflammatory markers (e.g., may include 
but not limited to CRP, IL6, MMP-1, 
MMP-3, MMP-13, TIMP-1, MCP-1, MIF, 
MRP8/14 and other markers 
encompassed by Vectra DA).

To investigate the effect of 60 mg twice 
daily doses of GSK2982772 on bone and 
synovial parameters as measured by

Change from baseline in Magnetic 
Resonance Imaging (MRI) parameters in 
the most affected hand/wrist.  MRI 


2015N251670_00
CONFIDENTIAL
203168
10
Objectives
Endpoints
MRI and DCE-MRI in subjects with 
moderate to severe Rheumatoid Arthritis.
parameters may include assessment of 
bone erosions, synovitis, and bone 
oedema as assessed in the OMERACT-
RAMRIS (Outcome Measures in 
Rheumatology, Rheumatoid Arthritis 
Magnetic Resonance Image Scoring 
System) scoring system RAMRIQ 
(Rheumatoid arthritis MRI quantitative) 
scoring system, and additional 
exploratory endpoints as data permit.
Change from baseline in synovial
inflammation as measured by dynamic 
contrast enhanced (DCE)-MRI in the most 
affected hand/wrist:

Exchange rate (Ktrans)

Interstitial volume (Ve)

Plasma volume (Vp)

Initial rate of enhancement (IRE)

Maximal signal intensity enhancement 
(ME)

Joint volume

Enhancing volume

To investigate the effect of 60 mg twice 
daily doses of GSK2982772 on clinical 
disease activity in subjects with 
moderate to severe Rheumatoid Arthritis.

Change from baseline in Disease Activity 
Score (DAS) 28-CRP scores.

Proportion of subjects achieving 
categorical DAS28-CRP response 
(moderate/good EULAR response) at 
each assessment time points.

Proportion of subjects achieving 
categorical ACR20/50/70 response.

To investigate the effect of 60 mg twice 
daily dosing of GSK2982772 on 
methotrexate (MTX) concentrations.

Plasma concentrations of MTX pre-dose 
GSK2982772 on Days 1, 8, and 43 
(Week 6).
Exploratory

To investigate the effect of 60 mg twice 
daily doses of GSK2982772 on 
inflammatory biomarkers in synovial 
tissue from subjects with moderate to 
severe Rheumatoid Arthritis.

Change from baseline in CD68+ 
macrophages, CD55+ fibroblast-like 
synoviocytes and a number of infiltrating 
CD3, CD22, CD138 inflammatory cells, 
and synovial inflammatory biomarkers 
including, but not limited to VEGF, IL-1β, 
IL-6, TNFα, and MMP-1.

To investigate pathway and target 
engagement following 60 mg twice daily 

Pharmacology biomarker endpoints may 
include, but are not limited to the 


2015N251670_00
CONFIDENTIAL
203168
11
Objectives
Endpoints
doses of GSK2982772 in blood and 
synovial biopsy tissue in subjects with 
moderate to severe Rheumatoid Arthritis.
following, pre-dose at Days 1, 43 (Week 
6) and trough on Day 85 (Week 12), as 
applicable and if evaluable samples and 
data permit:
Target Engagement Assay RIP1 
(TEAR1) in blood and synovial 
tissue.
Total or phosphorylated RIP1, MLKL, 
and RIP3, cleaved and total 
caspase 3 and caspase 8
signatures in synovial tissue.

To investigate the concentration of 
GSK2982772 and possible drug-related 
material, as well as specific distribution 
within tissue if feasible, in the synovial 
tissue after 60 mg twice daily doses of 
GSK2982772.

Pre-dose GSK2982772 synovial tissue 
biopsies and possible drug-related 
material concentrations, as well as 
specific distribution within tissue  if 
feasible, on Day 43 (Week 6), as
evaluable samples and data permit.

To investigate the effect of 60 mg twice 
daily doses of GSK2982772 on the 
quality of life of subjects with moderate 
to severe Rheumatoid Arthritis.

Change from baseline in Health 
Assessment Questionnaire Disability 
Index (HAQ-DI).

Change from baseline in RA symptom
questionnaire score.

Change from baseline in Functional 
Assessment of Chronic Illness Therapy 
(FACIT)-Fatigue.

To investigate the effect of 60 mg twice 
daily doses of GSK2982772 on gene 
expression in the blood subjects with 
active moderate to severe Rheumatoid 
Arthritis.

Transcriptomic analysis of mRNA 
isolated from blood pre-dose on Days 1
and 43 (Week 6) and trough on Day 85 
(Week 12).

To investigate the effect of 60 mg twice 
daily doses of GSK2982772 on gene 
expression in the synovium of subjects 
with moderate to severe Rheumatoid 
Arthritis.

Transcriptomic analysis of mRNA 
isolated from synovial tissue pre-dose on 
Days 1 and 43 (Week 6).
Overall Design
This is a multicentre, randomised, double-blind (sponsor-unblinded), placebo-controlled 
study to investigate the safety and tolerability, PK, PD, and preliminary efficacy of 
GSK2982772 in subjects with moderate to severe RA.  The study design schematic is 
depicted in Figure 1 below.


2015N251670_00
CONFIDENTIAL
203168
12
Figure 1
Study Overview
Key assessments:
Safety assessments, PK samples, DAS28-CRP, 
ACR20/50/70, FACIT-fatigue, Rheumatoid Arthritis Symptom 
and Impact Diary, HAQ-DI assessments, MRI, PD samples
Treatment Arms and Duration
Each subject will participate in the study for approximately 20 weeks.  This includes a 
screening period of up to 30 days, an 84 day (12 week) treatment period, and a 28 day
follow-up period after the last dose.
Within 30 days of the screening visit (defined as day of consent signing), subjects who 
are eligible will enter the treatment period and start treatment (or dosing) on Day 1.
The Follow-up Period is 28 days (4 weeks) long.  All visits and assessments are detailed 
in Section 7.1.
Subjects who have completed screening assessments and are eligible will be randomised 
in a 2:1 ratio (active to placebo) to one of the following treatments:
GSK2982772 60 mg twice daily (BID) 
Placebo twice daily (BID) 
Type and Number of Subjects
A sufficient number of subjects will be screened so that approximately 30 subjects with 
moderate to severe RA are randomised into the study.  Should the drop-out rate be higher 
than anticipated, additional or replacement subjects may be randomised (up to a 
maximum of 36) into the study at the discretion of the Sponsor.
Analysis
The safety and tolerability of GSK2982772 following 12 weeks of treatment will be 
based on the review and displays of adverse events, clinical laboratory values, vital sign 
measurements and 12-lead electrocardiogram (ECG) monitoring.


2015N251670_00
CONFIDENTIAL
203168
13
Ongoing reviews of available efficacy, pharmacodynamic and mechanistic endpoints will 
be conducted during the study by a Data Review Committee (DRC), consisting of a 
limited number of GlaxoSmithKline (GSK) individuals, some of who are also members 
of the GSK study team.  The primary purpose of these reviews will be to monitor target 
engagement, inflammatory markers and Disease activity score for 28 different joints with 
CRP value (DAS28-CRP) for futility and internal decision making. A data review charter 
will outline in detail the activities of this review and how the integrity of the study will be 
maintained.
A formal interim analysis will be conducted during the study, when an appropriate 
number of subjects have completed 12 weeks of treatment or on the request of the DRC.  
The purpose of this interim will be to assess whether to stop the study for futility.  This 
interim analysis may also facilitate decision making regarding the subsequent clinical 
development of GSK2982772 for RA.
Comparisons between treatment groups on any changes observed will be conducted for 
the secondary endpoints if deemed appropriate, e.g. changes in the mean target 
engagement, changes in inflammatory markers and percentage change in DAS28-CRP 
will be statistically analysed using a Mixed-effect Model Repeat Measurements
(MMRM) comparing GSK2982772 with placebo at each time point.
The relationship between each of the mechanistic endpoints and also with the clinical 
endpoints may also be graphically presented and analysed using an appropriate statistical 
model identifying any trends. The model will determine whether the mechanistic effect 
significantly explains or predicts the effect on the other mechanistic or clinical endpoints 
(e.g DAS28-CRP).  In addition, based on the data that we observe in the study, 
probabilities of success will be determined, where the definition of success will be 
dependent on the endpoint. For example, what is the probability that we would observe a 
certain change in DAS28-CRP (i.e., comparatory rate), based on the data that we have 
observed in the study.  Further details regarding the statistical analysis will be outlined in 
the Reporting and Analysis Plan (RAP).
2.
INTRODUCTION
2.1.
Study Rationale
This study is the first experience with GSK2982772, a receptor-interacting protein-1 
(RIP1) kinase inhibitor, in subjects with moderate to severe rheumatoid arthritis (RA) 
who are currently being treated with disease modifying anti-rheumatic drugs (DMARDs).  
All subjects will be allowed to continue standard of care therapy including non-biologic 
DMARDs during the study, provided that the medication type and dose is stable 
throughout the study.
The primary objective will be to investigate the safety and tolerability of repeat oral doses 
of GSK2982772 (60 mg twice daily for 84 days).  In addition, a number of experimental 
and clinical endpoints will be employed to obtain information on the pharmacokinetics 
(PK), pharmacodynamics (PD) and preliminary efficacy in subjects with moderate to 
severe RA.


2015N251670_00
CONFIDENTIAL
203168
14
2.2.
Brief Background
RIP1 is a member of the receptor-interacting Serine/Threonine kinase family containing 
an amino-terminal kinase domain, an intermediate domain and a carboxy-terminal death 
domain.  RIP1 is a key signalling node which plays an essential role in inflammation and 
cell death in response to signals including tumor necrosis factor (TNF) family cytokines, 
ligands for toll-like receptor (TLR) 3/TLR4, sensors of viral infection, and interferons 
[Ofengeim, 2013].  Through tight regulation by ubiquitylation, deubiquitylation and 
interaction with its receptors, RIP1 has dual roles as a kinase and a scaffolding protein, 
and serves as an upstream checkpoint for both cell death and survival [Ofengeim, 2013]. 
Detailed understanding of RIP1 kinase function has not been fully elucidated, but it is 
known that RIP1 exerts it signalling functions through both its catalytic kinase activity 
and by acting as a scaffolding protein for signalling complexes.  Recent work has 
demonstrated that RIP1 catalytic kinase activity can regulate TNF-mediated necroptosis 
[Ofengeim, 2013] and noncanonical apoptosis [Wang, 2008, Dondelinger, 2013]. In 
addition, the production of certain inflammatory cytokines can be regulated by RIP1
kinase activity Investigator’s Brochure (IB) [GlaxoSmithKline Document Number 
2014N204126_01].  In contrast, RIP1’s scaffolding function acts to facilitate other 
immune processes including TNF mediated classical apoptosis and NF-kB-signalling 
[Ofengeim, 2013, Humphries, 2015].  With this, an inhibitor of RIP1 kinase activity with 
GSK2982772 may fill a unique niche in the treatment of inflammatory conditions
through multiple mechanisms, including inhibition of inflammation-induced cell death 
(necroptosis and apoptosis) and inhibition of the production of certain pro-inflammatory 
cytokines.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by a debilitating, 
progressive polyarthritis that typically affects the small joints of the hands and feet 
[Vasanthi, 2007]. TNF is known to be one of the key cytokines that drives inflammation 
in RA [Choy, 2001].  In animal models, transgenic mice that chronically over express 
low levels of TNF develop a spontaneous polyarthritis that resembles RA in humans 
[Keffer, 1991] and blockade of NFB activation results in the development of a 
spontaneous murine polyarthritis that is RIP1-dependent [Berger, 2014].  In RA patients, 
TNF is detected in high concentrations in both blood and synovial fluid, and expression 
of TNF and its signalling intermediates, including RIP1, have been shown to be 
constitutively increased in PBMCs from RA subjects compared to healthy controls 
[Raghav, 2006].
Synthetic disease modifying antirheumatic drugs (DMARDs) including nonsteroidal anti-
inflammatory drugs, steroids, methotrexate (MTX), sulfasalazine, hydroxychloroquine, 
and leflunomide, are often used alone or in combination in moderate to severe RA; 
however, most DMARDs do not significantly impact disease progression, and may be 
hampered by poor side effect profiles.  Recently, tofacitinib, an oral small molecule 
inhibitor of JAK, was approved for moderate to severe RA, but its long term safety is still 
unknown.  TNF antagonists are used in the treatment of patients with moderate-severe 
disease who have not responded or who have intolerance to traditional DMARDs.  While 
studies have shown that they can improve symptoms and slow the progression of joint 
damage in many patients [Agarwal, 2011], only half of RA patients achieve American 
College of Rheumatology (ACR)50 criteria, and many become refractory to anti-TNF 


2015N251670_00
CONFIDENTIAL
203168
15
treatments after several years.  In addition to the association with increased rates of 
opportunistic infections across all indications, anti-TNF therapy in RA is linked to lupus-
like syndrome and increased rates of demyelinating disease.  Other biologic therapies 
which inhibit T cell activation (abatacept) or lead to selective B cell depletion (rituximab) 
have shown clinical efficacy in anti-TNF refractory patients, although both carry 
potential risks for serious infection.  Therefore, there remains a high unmet need for safe 
and tolerable therapies that lead to improved rates of clinical remission and increased 
physical function in patients with moderate to severe RA.
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To investigate the safety and tolerability 
of 60 mg twice daily doses of 
GSK2982772 in subjects with moderate 
to severe Rheumatoid Arthritis.

Adverse events.

Clinical laboratory values (clinical 
chemistry, haematology and urinalysis).

Vital sign measurements (blood pressure, 
heart rate, respiratory rate, and body 
temperature).

12-Lead ECG monitoring.
Secondary

To investigate the plasma concentrations 
of GSK2982772 following 60 mg twice 
daily doses of GSK2982772 in subjects 
with moderate to severe Rheumatoid
Arthritis.

Pre-dose concentrations of GSK2982772 
on Days 8, and 43 (Week 6).  

Post-dose concentrations of 
GSK2982772 on Days 1, 8, and 43 
(Week 6) at 1, 2, 4 and 6 hours.

Trough concentrations on Day 85 (Week 
12).

To investigate the effect of 60 mg twice 
daily doses of GSK2982772 on 
inflammatory biomarkers in blood 
subjects with moderate to severe 
Rheumatoid Arthritis.

Change from baseline in blood 
inflammatory markers (e.g., may include 
but not limited to CRP, IL6, MMP-1, 
MMP-3, MMP-13, TIMP-1, MCP-1, MIF, 
MRP8/14 and other markers 
encompassed by Vectra DA).

To investigate the effect of 60 mg twice 
daily doses of GSK2982772 on bone and 
synovial parameters as measured by 
MRI and DCE-MRI in subjects with 
moderate to severe Rheumatoid Arthritis.

Change from baseline in MRI 
parameters in the most affected 
hand/wrist.  MRI parameters may include
assessment of bone erosions, synovitis, 
and bone oedema as assessed in the 
OMERACT-RAMRIS (Outcome 
Measures in Rheumatology, Rheumatoid 
Arthritis Magnetic Resonance Image 
Scoring System) scoring system 
RAMRIQ (rheumatoid arthritis MRI 
quantitative) scoring system, and 


2015N251670_00
CONFIDENTIAL
203168
16
Objectives
Endpoints
additional exploratory endpoints as data 
permit.
Change from baseline in synovial
inflammation as measured by dynamic 
contrast enhanced (DCE)-MRI in the most 
affected hand/wrist:

Exchange rate (Ktrans)

Interstitial volume (Ve)

Plasma volume (Vp)

Initial rate of enhancement (IRE)

Maximal signal intensity enhancement 
(ME)

Joint volume

Enhancing volume

To investigate the effect of 60 mg twice 
daily doses of GSK2982772 on clinical 
disease activity in subjects with 
moderate to severe Rheumatoid Arthritis.

Change from baseline in Disease Activity 
Score (DAS) 28-CRP scores.

Proportion of subjects achieving 
categorical DAS28-CRP response 
(moderate/good EULAR response) at 
each assessment time points.

Proportion of subjects achieving 
categorical ACR20/50/70 response.

To investigate the effect of 60 mg twice 
daily dosing of GSK2982772 on 
methotrexate (MTX) concentrations 

Plasma concentrations of MTX pre-dose 
GSK2982772 onDays 1, 8, and 43 
(Week 6).
Exploratory 

To investigate the effect of 60 mg twice 
daily doses of GSK2982772 on 
inflammatory biomarkers in synovial 
tissue in subjects with moderate to 
severe Rheumatoid Arthritis.

Change from baseline in CD68+ 
macrophages, CD55+ fibroblast-like 
synoviocytes and a number of infiltrating 
CD3, CD22, CD138 inflammatory cells, 
and synovial inflammatory biomarkers 
including, but not limited to VEGF, IL-1β, 
IL-6, TNFα, and MMP-1.

To investigate pathway and target 
engagement following 60 mg twice daily 
doses of GSK2982772 in blood and 
synovial tissue in subjects with moderate 
to severe Rheumatoid Arthritis.

Pharmacology biomarker endpoints may 
include, but are not limited to the 
following, pre-dose at Days 1, 43 (Week 
6) and trough on Day 85 (Week 12), as 
applicable and if evaluable samples and 
data permit:
Target Engagement Assay RIP1 
(TEAR1) in blood and synovial 
tissue.


2015N251670_00
CONFIDENTIAL
203168
17
Objectives
Endpoints
Total or phosphorylated RIP1, MLKL, 
andRIP3, cleaved and total caspase 
3 and caspase 8 signatures in 
synovial tissue.

To investigate the concentration of 
GSK2982772 and possible drug-related 
material, as well as specific distribution 
within tissue  if feasible, in the synovial 
tissue after 60 mg twice daily doses of 
GSK2982772.

Pre-dose GSK2982772 synovial tissue 
biopsies and possible drug-related 
material concentrations, as well as 
specific distribution within tissue  if 
feasible, on Day 43 (Week 6), as
evaluable samples and data permit

To investigate the effect of 60 mg twice 
daily doses of GSK2982772 on the 
quality of life of subjects with moderate 
to severe Rheumatoid Arthritis.

Change from baseline in Health 
Assessment Questionnaire Disability 
Index (HAQ-DI).

Change from baseline in RA symptom 
questionnaire score.

Change from baseline in Functional 
Assessment of Chronic Illness Therapy 
(FACIT)-Fatigue.

To investigate the effect of 60 mg twice 
daily doses of GSK2982772 on gene 
expression in the blood of subjects with 
moderate to severe Rheumatoid Arthritis.

Transcriptomic analysis of mRNA 
isolated from blood pre-dose on Days 1 
and 43 (Week 6) and trough on Day 85 
(Week 12).

To investigate the effect of 60 mg twice 
daily doses of GSK2982772 on gene 
expression in synovium of subjects with 
moderate to severe Rheumatoid Arthritis.

Transcriptomic analysis of mRNA 
isolated from synovial tissue pre-dose on 
Days 1 and 43 (Week 6).


2015N251670_00
CONFIDENTIAL
203168
18
4.
STUDY DESIGN
4.1.
Overall Design
This is a multicentre, randomised, double-blind (sponsor-unblinded), placebo-controlled 
study to investigate the safety and tolerability, PK, PD, and preliminary efficacy of 
GSK2982772 in subjects with moderate to severe RA.  The study design schematic is 
depicted in Figure 2 below.
Figure 2
Study Overview
Key assessments:
Safety assessments, PK samples, DAS28-CRP, 
ACR20/50/70, FACIT-fatigue, Rheumatoid Arthritis Symptom 
and Impact Diary, HAQ-DI assessments, MRI, PD samples
4.2.
Treatment Arms and Duration
It is anticipated that the total duration of participation in the study will be approximately 
20 weeks from screening to the last study visit.
4.2.1.
Screening
Within 30 days of the screening visit (defined as day of consent signing), subjects who 
are eligible will enter the treatment period and start treatment (or dosing) on Day 1.
4.2.2.
Treatment Period
Subjects will be randomly assigned to either GSK2982772 60 mg or placebo orally twice 
daily (approximately 12 hours apart) for 84 days (12 weeks).  Further guidance and 
information for study treatment and dosing are provided in the Study Reference Manual 
(SRM).  
During the 84 day (12 week) treatment period, subjects will attend the clinical site for 
visits on Days 1, 8, 15, 29, 43, 57, 71 and 85.  At specific visits, subjects must not take 
study treatment prior to their scheduled visit (see Section 7.1).  On Days 22, 36, 50, 64 
and 78, each subject will be contacted by telephone and asked about their general health. 
Subjects will be given a diary card at each of the visits on which they will be instructed to 


2015N251670_00
CONFIDENTIAL
203168
19
record their daily study medication and concomitant medication taken and any adverse 
events.
4.2.3.
Follow-up Period
After the Treatment Period, the subject will enter the Follow-up Period which lasts for 28 
days post the last administration of study medication, in order to complete follow-up 
assessments per the Time and Events Table (see Section 7.1).
4.3.
Type and Number of Subjects
A sufficient number of subjects will be screened so that approximately 30 subjects with 
moderate to severe RA are randomised into the study.  Should the drop-out rate be higher 
than anticipated, additional or replacement subjects may be randomised (up to a 
maximum of 36) into the study at the discretion of the Sponsor.
4.4.
Design Justification
As this is the first trial of GSK2982772 in subjects with RA, the primary endpoint is the 
safety and tolerability of GSK2982772.  In addition, this study will include assessments 
of target engagement and downstream PD effects of GSK2982772, to understand whether 
GSK2982772 is inhibiting the pathway of interest in this disease.
The 12 week duration of treatment is based on review of previous proof of mechanism 
and proof of concept studies in RA and is limited by the supporting 13 week toxicology 
studies. It is expected that an effective therapy should cause group level changes in the 
mechanistic parameters by the 12 week time point. 
The subjects will be randomised in a 2:1 ratio to GSK2982772 60 mg twice daily (BID)
and placebo respectively.  The primary objective of this study is to assess safety and 
tolerability, and assessment of this is most valuable in a placebo controlled study. The 
placebo group was also deemed necessary as autoimmune diseases naturally fluctuate in 
severity.  However, the size of the placebo group has been kept to a minimum.  All 
subjects will be allowed to continue standard of care therapy including non-biologic 
DMARDs during the study, provided that the medication and dose is stable throughout 
the study.
4.5.
Dose Justification
The selection of the 60 mg BID dose to be tested in this study is based on the safety, PK, 
and PD data from the First Time in Human (FTiH) study, 200975.  GSK2982772 
administered at 60 mg BID for 14 days was well tolerated and no safety concerns were 
identified. A BID dosing regimen was selected over a QD dosing regimen due to the 
short half-life of GSK2982772 in humans (~2h).  Based on preliminary PK/PD modelling 
of ex-vivo RIP1 target engagement and GSK2982772 concentrations from the  multiple 
dose ascending part of Study 200975, a 60 mg BID dose is predicted to have on average 
95% RIP1 target engagement in blood and approximately 90% of subjects will have  
>90% target engagement in blood at Cmin.  No data are currently available about the 
distribution of GSK2892772 into the synovium.  Based on data in non-steroidal anti-


2015N251670_00
CONFIDENTIAL
203168
20
inflammatory drugs (NSAIDs), the synovial fluid concentrations fluctuate to a much 
lesser extent than those in plasma [Netter, 1989].  Peak drug concentrations are generally 
lower in synovial fluid but are similar to plasma at later time points.  Assuming the same 
is true for GSK2982772, a 60 mg BID dose should provide similar RIP1 target 
engagement at the site of action as predicted in blood.
Therefore, it is predicted that a dose of GSK2982772 60 mg BID may be clinically 
efficacious in subjects with RA.
It is anticipated that a human dose of 60 mg will produce area under the concentration-
time curve (AUC[0-24]) and maximum observed concentration (Cmax) values of
approximately 9 g.h/mL and 1 g/mL, respectively, which are approximately 1/6th  and 
1/12th of the gender-averaged AUC (48.4 g.h/mL) and Cmax (12.3 g/mL) achieved in 
the 13 week monkey study at the no adverse effect level (NOAEL) dose of 30 mg/kg/day.
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2982772 can be found in the IB [GlaxoSmithKline Document Number 
2014N204126_01].  The following section outlines the risk assessment and mitigation 
strategy for this protocol: 


2015N251670_00
CONFIDENTIAL
203168
21
4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK2982772
Central Nervous System (CNS) effects
Non-clinical data: 
In the 4-week GLP toxicology study, CNS findings were 
observed in 4/12 monkeys which were administered 100 or 
300 mg/kg/day.  CNS findings included uncoordination, 
irregular gait, trembling, hunched appearance, and 
decreased activity. The clinical relevance of these findings 
in humans is not known.  The NOAEL for this study was
determined at 10 mg/kg/day.
In the 13-week GLP toxicology study, there were no CNS 
findings observed in monkeys administered 10, 30 or 100 
mg/kg/day.  The NOAEL for this study was determined at 
30 mg/kg/day.  
Clinical data:
A First Time in Human (FTiH) study with single ascending 
and multiple ascending dose study has been performed in 
67 healthy male volunteers to date.  See Investigator’s 
Brochure (IB) [GlaxoSmithKline Document Number 
2014N204126_01].  No drug-associated CNS adverse 
events were identified and no Serious Adverse Effects 
(SAEs) were reported.
Subject Selction:

Subjects with known history of significant neurologic 
disorders including but not limited to progressive 
multiple sclerosis (MS), Amyotrophic lateral sclerosis 
(ALS), Alzheimer’s and dementia will be excluded.

Individuals with potentially increased susceptibility for 
neurologic effects will be excluded based on medical 
history at screening.
Subject Monitoring:

Subjects will be monitored for standard CNS-related 
adverse events.
Immunosuppression
The possibility of immunosuppression, including an 
increase in the frequency and/or severity of infection, may 
result from the intended pharmacologic effect of 
GSK2982772.  This may be enhanced in subjects taking 
other immunomodulating drugs or corticosteroids.
Subject Selection:

Subjects with recurrent, chronic or active infections 
will be excluded from the study.

Subjects will be screened for TB, HIV, Hepatitis B and 
C, and excluded from the study if positive.


2015N251670_00
CONFIDENTIAL
203168
22
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Clinical data:
In the FTiH study, no SAEs were reported.  One subject 
experienced an Adverse Effect (AE) herpes zoster 
approximately 27 days after receiving his last dose with 
GSK2982772 or placebo.  The blinded Investigator 
determined this to be potentially drug-related.
Subject Monitoring:

Subjects will be monitored for signs of infection.

See Individual Stopping Criteria for atypical or 
opportunistic infections (Section 5.4.1).
Vaccinations
There is a theoretical risk that GSK2982772 could 
decrease an individual’s immune response to vaccines or 
allow symptoms to develop following vaccination with a live 
vaccine when administered while on therapy.
Subject Selection:

Attenuated or live vaccines should not be 
administered to subjects from 30 days prior to the first 
dose of GSK2982772, during the study and for 5 half-
lives plus 30 days (total 32 days) after GSK2982772 
is discontinued.

If indicated, non-live vaccines (e.g. inactivated 
influenza vaccines) may be administered while 
receiving GSK2982772 based on a treating physician 
assessment of the benefit:risk (e.g., risk of theoretical 
decreased responsiveness). 

Investigators will be expected to have followed local 
and/or national guidelines with respect to 
vaccinations, including against influenza and 
pneumococcus, in subjects wtih RA.
Respiratory
Non-clinical data:
In the single dose Safety Cardiovascular (CV) and 
Respiratory Study in monkeys, a decrease in minute 
volume (MV) and respiratory rate was observed at all 
doses (10, 100, and 300 mg/kg).  These findings were 
noted to be reversible and mild in severity
In a 14-day repeat dose Safety Respiratory Study in 
monkeys, no respiratory effects on total pulmonary 
ventilation (minute volume) or respiratory rate were 
observed at doses of 1 or 10 mg/kg/day. See IB for 
Subject Monitoring:

Subjects should be monitored for standard 
respiratory-related adverse events.

Vital signs will be monitored during study visits.


2015N251670_00
CONFIDENTIAL
203168
23
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
GSK2982772 [GlaxoSmithKline Document Number 
2014N204126_01].
Clinical data:
In the FTiH study, repeat doses of GSK2982772 were 
administered x 14 days in 36 healthy male volunteers. 
Extensive respiratory monitoring with end-tidal CO2 
(ETCO2), oxygen saturation (SpO2) and nocturnal 
respiratory rate monitoring was performed.   No SAEs 
occurred, and no drug-associated respiratory-related 
adverse events were identified.
Suicidality
GSK2982772 is considered to be a CNS-active drug based 
upon pre-clinical studies.
Clinical data:
In the FTiH study, there have been some reports of 
lethargy, abnormal dreams, and depressed mood.  No 
events of suicidal ideation or behaviour or changes in 
behaviour were reported.
Subject Selection:

Subjects with a current history of suicidal ideation and 
behaviour (SIB) as measured using the Columbia 
Suicide Severity Rating Scale (C-SSRS)  or a history 
of attempted suicide will be excluded from the study.
Subject Monitoring:

Subjects should be monitored appropriately and 
observed closely for suicidal ideation and behaviour 
or any other unusual changes in behaviour.

Baseline and treatment emergent assessment of 
suicidality will be conducted by trained site personnel 
using the (Columbia Suicide Severity Rating Scale) C-
SSRS in all subjects.  See Section 7.3.7.
Reproductive toxicity
Non-clinical data:
In an early rat embryofetal development study, there was 
no maternal or developmental toxicity at doses 200 
mg/kg/day.
In a rabbit embryofetal development study, GSK2982772 
was administered at doses of 0, 10, 100, 300 or 600 
mg/kg/day on gestation day 7 to 19.  No developmental 
toxicity was evident at doses up to 300 mg/kg/day.
Subject Selection:

Male and female subjects of childbearing potential will 
be included in this study only if they agree to use 
highly effective methods of contraception and avoid 
conception for defined periods of time before first 
administration of study drug until 30 days (females) 
and 90 days (males) after the last administration of 
study drug (Appendix 6).


2015N251670_00
CONFIDENTIAL
203168
24
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy

Females of childbearing potential will undergo serum 
pregnancy test at screening and then urine pregnancy 
testing at regular intervals during the study. 

Pregnant and lactating females are not eligible for 
inclusion in the study.
Withdrawal Criteria:

If a female subject should become pregnant during 
the study, study medication should be discontinued.  
The 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.
Drug Interaction
Non-clinical data:
In vitro studies with GSK2982772 assessing uptake of 
OAT3 were completed.  There is a low risk that 
GSK2982772 could be a perpetrator of OAT3 substrates.  
MTX is an OAT3 substrate in which GSK2982772 could 
potentially impair the clearance of MTX. 
Subject Monitoring:

PK sample collection to evaluate the potential 
interaction of GSK2982772 and MTX will be 
performed thoroughout the study.

Subjects should be monitored for potential effects of 
interaction between GSK2982772 and MTX.

Clinical laboratory results (e.g., liver function tests) 
are routinely being monitored throughout the study.
Study Procedures
Synovial Joint  Biopsy
Potential risks of the procedure include discomfort, 
infection or bleeding.
Note:  Synovial biopsies are optional and not required on 
all subjects.
Subject Selection:

Subjects with known allergy to lidocaine or other local 
anaesthetics will not be included in the biopsy portion 
of the study.

Subjects with a platelet count 100 x 109/L will be 
excluded from participation.
Subject Management:


2015N251670_00
CONFIDENTIAL
203168
25
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy

The biopsies will be performed under ultrasound or 
arthroscopic guidance.  Subjects will be given 
instructions for aftercare and contact information 
should there be any adverse reactions after the 
procedure.

Biopsy site healing will be monitored during the study 
as part of AE safety review. 
Gadolinium (Gd) containing MRI contrast agents
Non-clinical data:
Animal studies have shown reproductive toxicity of 
gadolinium (Gd)-containing MRI contrast agents at 
repeated high doses.
Clinical data:
Use of MRI contrast agents in subjects with severely 
impaired rental function (GFR<30mL/minute) has been 
associated with Nephrogenic Systemic Fibrosis (NSF).  In 
subjects with severely impaired renal function, the benefits 
of the use of contrast agents should be carefully weighed 
against the risks.
Gadolinium (Gd) contrast agents can be associated with 
anaphylactoid/hypersensitivity or other idiosyncratic 
reactions, characterized by cardiovascular, respiratory, or 
cutaneous manifestations, and ranging to severe reactions 
including shock.  In general, subjects with cardiovascular 
disease are more susceptible to serious or even fatal 
outcomes of severe hypersensitivity reactions.
The risk of hypersensitivity reactions may be higher in 
cases of:

Previous reaction to contrast media

History of bronchial asthma

History of allergic disorders
Subject Selection:

Pregnant or lactating females will be excluded from 
taking part in the study.

Subjects with impaired renal function 
(GFR<60mL/minute) are excluded by the eligibility 
criteria.

Subjects with history of sensitivity to Gd-containing 
contrast agents will be excluded from the study.  The 
MRI procedure will be conducted under the 
supervision of trained and qualified clinical staff that is
trained to appropriately manage an allergic reaction.

Sites will be responsible for following any additional 
safety information for the specific Gd contrast agent 
used at their site and not enroll subjects if 
contraindicated.
Subject Monitoring and Management: 

MRI contrast at a dose less than or equal to 0.1 
mmol/kg per imagining session at baseline and Days
43 and 85 will be used in the MRI protocol.

Effective contraception is required during the study, 
and pregnancy testing will be performed regularly 
throughout the study and prior to dosing in females of 
child bearing potential.


2015N251670_00
CONFIDENTIAL
203168
26
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Most of these reactions occur within half an hour of 
administration.  Delayed reactions (after hours or several 
days) have been rarely observed.
Other 
Exposure to a high field MRI magnet
Certain prostheses or foreign bodies might be incompatible 
with the MRI scanner.
Subject Selection:

All participants will be screened according to local 
hospital criteria and study inclusion/exclusion before 
entering the MRI scanner to ensure they are able to 
have the MRI conducted.  Subjects with non-magnetic 
resonance compatible metal implants or implantable 
electronic devices (e.g., pacemaker, defibrillator) will 
not be included in this study.


2015N251670_00
CONFIDENTIAL
203168
27
4.6.2.
Benefit Assessment
There are additional treatment options available for subjects who have an inadequate 
response to current therapies for RA.  It is possible that treatment with GSK2982772 may 
be effective in the treatment of RA, as the FTiH study demonstrated that the drug 
engaged with the target and produced ex vivo PD effects in suppression of RIP1-
dependent cytokines MIP1and MIP1[GlaxoSmithKline Document Number 
2014N204126_01].  There will be limited direct benefit to the subject through their 
contribution to the process of developing new therapies in an area of unmet need.  
4.6.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with GSK2982772 are justified by the 
anticipated benefits that may be afforded to patients with RA by contributing to the 
understanding of the disease and the development of new therapies for patients with these 
conditions in the future.  
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 (IP) or other study 
treatment that may impact subject eligibility is provided in the IB [GlaxoSmithKline
Document Number 2014N204126_01].
In addition, Investigators are expected to follow local and/or national guidelines with 
respect to vaccinations, including vaccinations for influenza and pneumococcus, in 
subjects with RA.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. Between 18 and 75 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Subjects that do not have any medical conditions, other than moderate to severe RA, 
that in the opinion of the Investigator put the subject at unacceptable risk or interfere 
with study assessments or integrity of the data.  These medical conditions should be 


2015N251670_00
CONFIDENTIAL
203168
28
stable at the time of screening and are expected to remain stable for the duration of 
the study. 
3. Subject has had a confirmed diagnosis of rheumatoid arthritis according to the revised 
2010 American College of Rheumatology/European League Against Rheumatism 
ACR-EULAR classification criteria.
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) at screening.
5. Swollen joint count of ≥4 (28-joint count) and tender joint count ≥ 4 (28-joint count) 
at screening.
6. Subject has a DAS28 CRP disease activity score of 3.2 and CRP ≥ 5.0 mg/L (4.76 
nmol/L) at screening.
7. Subject must have received at least 12 weeks of non-biologic DMARD monotherapy 
or methotrexate (MTX)/DMARD combination therapy prior to screening AND must 
be on stable dose throughout the study.
8. Subject is naive to any biological therapies for RA
OR
Subject may have had previous exposure to a single anti-TNF biologic agent which 
was discontinued for reasons other than primary non-response more than 8 weeks (or 
5 half lives whichever is longer) from first dose.  Note:  Exposure to a single anti-
TNF is not required in addition to Inclusion #7 above.
9. For subjects who have consented to synovial joint biopsy:
a.
Subject has an involved knee, wrist, or ankle suitable for biopsy, as assessed 
by a rheumatologist at screening.
WEIGHT
10. A body mass index (BMI) within range of 18.5 - 35 kg/m2 (inclusive) at screening.
SEX
11. Male and female subjects
Males:
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements in Appendix 6.
Females: 
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:
a.
Non-reproductive potential as defined in Appendix 6.
b.
Reproductive potential and agrees to follow one of the options listed in the Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Appendix 6) from 30 days prior to the first dose 


2015N251670_00
CONFIDENTIAL
203168
29
of study medication and until at least 30 days after the last dose of study medication 
and completion of the follow-up visit.
The Investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
INFORMED CONSENT
12. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
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. Subject with a positive anti-double stranded deoxyribonucleic acid (DNA [anti-
dsDNA]) and confirmed diagnosis of systemic lupus erythematosus (SLE).
2. Subject with current history of Suicidal Ideation Behaviour (SIB) as measured using 
the Columbia Suicide Severity Rating Scale (C-SSRS) or a history of attempted 
suicide.
3. An active infection, or a history of infections as follows:

Hospitalisation for treatment of infection within 60 days before first dose 
(Day 1).

Currently on any suppressive therapy for a chronic infection (such as 
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and 
atypical mycobacteria).

Use of parenteral (IV or intramuscular) antibiotics (antibacterials, antivirals, 
antifungals, or antiparasitic agents) for an infection within 60 days before first 
dose.

A history of opportunistic infections within 1 year of screening (e.g. 
pneumocystis jirovecii, CMV pneumonitis, aspergillosis).  This does not 
include infections that may occur in immunocompetent individuals, such as 
fungal nail infections or vaginal candidiasis, unless it is of an unusual severity 
or recurrent nature.

Recurrent or chronic infection or other active infection that, in the opinion of 
the Investigator might cause this study to be detrimental to the patient.

History of TB, irrespective of treatment status.

A positive diagnostic TB test at screening defined as a positive 
QuantiFERON-TB Gold test or T-spot test.  In cases where the QuantiFERON 
or T-spot test is indeterminate, the subject may have the test repeated once, 
but they will not be eligible for the study unless the second test is negative. In 
cases where the QuantiFERON or T-spot test is positive, but a locally-read 
follow up chest x-ray, shows no evidence of current or previous pulmonary 


2015N251670_00
CONFIDENTIAL
203168
30
tuberculosis, the subject may be eligible for the study at the discretion of the 
Investigator and GSK Medical Monitor.
4. QTc > 450msec or QTc > 480msec for subjects with bundle branch block at 
screening.
The QTc is the QT interval corrected for heart rate according to either Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), or another method, machine or manual 
over read.
The specific formula that will be used to determine eligibility and discontinuation for 
an individual subject should be determined and documented prior to initiation of the 
study. In other words, several different formulae cannot be used to calculate the QTc 
for an individual subject and then the lowest QTc value used to include or discontinue 
the subject from the trial. For purposes of data analysis, QTcB, QTcF, another QT 
correction formula, or a composite of available values of QTc will be used as 
specified in the Reporting and Analysis Plan (RAP).
5. ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%) at screening.
6. Current active or chronic history of liver or biliary disease (with the exception of 
Gilbert’s syndrome or asymptomatic gallstones).
7. Current or history of renal disease or estimated glomerular filtration rate (GFR) by 
Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) 
calculation <60 mL/min/1.73m2  at screening.
8. Hereditary or acquired immunodeficiency disorder, including immunoglobulin 
deficiency.
9. A major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem 
cell/marrow transplant.
10. Any planned surgical procedures including surgical joint procedures (e.g., intra-
articular, tendon sheath, or bursal corticosteroid injections) during the study.
11. A history of malignant neoplasm within the last 5 years, except for adequately treated 
non-metastatic cancers of the skin (basal or squamous cell) or carcinoma in situ of the 
uterine cervix that has been fully treated and shows no evidence of recurrence.
12. Has undergone surgery including synovectomy or arthroplasty on the joint chosen for 
biopsy and/or magnetic resonance imaging (MRI).  
13. The subject has a history of any other joint disease other than RA at the knee, wrist or 
ankle joint chosen for biopsy and/or MRI (e.g., gout, pseudogout, osteoarthritis).
14. Has undergone intra-articular corticosteroid injection, arthrocentesis or synovial 
biopsy on any joint within 6 weeks of screening.
15. A known allergy to lidocaine or other local anaesthetics (Note: only applies to 
subjects who consent for synovial biopsy procedures).
16. Contraindication to MRI scanning (as assessed by local MRI safety questionnaire)
which includes but are not limited to:

Intracranial aneurysm clips (except Sugita™) or other metallic objects,

History of intra-orbital metal fragments that have not been removed by a 
medical professional.

Pacemakers or other implanted cardiac rhythm management devices and non-
MR compatible heart valves,


2015N251670_00
CONFIDENTIAL
203168
31

Inner ear implants,

History of claustrophobia which may impact participation.
CONCOMITANT MEDICATIONS
17. The subject has received treatment with the therapies listed in Section 6.11.2, or 
changes to those treatments, within the prescribed timeframe.  If in doubt, or the 
therapy is not listed please consult with the medical monitor.

Other medications (including vitamins, herbal and dietary supplements) will 
be considered on a case-by-case basis, and will be allowed if in the opinion of 
the Investigator the medication will not interfere with the study procedures or 
compromise subject safety.
RELEVANT HABITS
18. History of alcohol or drug abuse that would interfere with the ability to comply with 
the study.
CONTRAINDICATIONS 
19. 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.
20. Received a live or attenuated vaccine within 30 days of randomization OR plan to 
receive a vaccination during the study until  half-lives (or 2 days) plus 30 days after 
receiving GSK2982772.
21. Contraindication to gadolinium contrast agent in accordance with local guidelines.
22. The subject has participated in a clinical trial and has received an investigational 
product within 30 days or 5 half-lives, whichever is longer before the first dose of
study medication, or plans to take part in another clinical trial at the same time as 
participating in this clinical trial.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
23. Haemoglobin <11 g/dL;haematocrit <30%, white blood cell count ≤3,000/mm3 (≤3.0 
x 109/L) or ≥14,000/mm3 (≥14 x 109/L); platelet count ≤ 100,000/µL (≤100 x 109/L); 
absolute neutrophil count ≤3 x 109/L; lymphocyte count <1 x 109/L at screening.
24. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of study treatment.  As 
potential for and magnitude of immunosuppression with this compound is unknown, 
subjects with presence of hepatitis B core antibody (HBcAb) should be excluded.
25. A positive serology for human immunodeficiency virus (HIV) 1 or 2 at screening. 
26. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 3 months.
27. Exposure to more than 4 investigational medicinal products within 12 months prior to 
the first dose.


2015N251670_00
CONFIDENTIAL
203168
32
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events and protocol deviations (see 
Section 7.3.1.5).
Subjects who do not qualify to participate in the study due to a screening laboratory value 
or ECG abnormality can repeat the test once within the original screening window, if the 
Investigator believes there is a reasonable possibility that the subject would be eligible if 
re-tested.
Subjects can be re-screened only on approval of the GSK Medical Monitor and only
once.  Re-screening is allowed when a subject failed inclusion/exclusion criteria or some 
other screening condition initially, but the Investigator believes there is a reasonable 
probability that the subject would be eligible if re-screened. 
5.4.
Withdrawal/Stopping Criteria
Subjects may be withdrawn from the study for any of the following reasons:

A subject may withdraw from study treatment at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioural or administrative reasons.  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.  The reason for withdrawal should be 
documented in the Case Report Form (CRF).

The Sponsor’s request, for reasons such as significant protocol deviations (and 
after discussion with the Investigator).

If a subject is withdrawn from study treatment, this subject is also considered to 
be withdrawn from the study.

Study is terminated by the Sponsor.
If a subject is withdrawn, the Sponsor may decide to replace that subject and this will be 
done through the Interactive Response Technology System (IRTS).
If a subject chooses to withdraw from the study after dosing then the Investigator must 
make every effort to complete the follow-up assessments detailed in the Time and Events 
Table (Section 7.1).
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. 


2015N251670_00
CONFIDENTIAL
203168
33

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the Investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

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”. 
5.4.1.
Individual Safety Stopping Criteria
Study medication will be discontinued in the event of any of the following:

If a subject experiences a serious or severe clinically significant AE that in the 
clinical judgement of the Investigator, after consultation with the medical monitor, 
is possibly, probably or definitely related to investigational product.

The subject becomes pregnant.

The subject initiates treatment with any prohibited medications for the treatment
of RA as listed in Section 6.11.2.

The subject develops a serious opportunistic or atypical infection.

If any of the liver chemistry stopping criteria (Section 5.4.3), QTc stopping 
criteria (Section 5.4.4), or Haematologic stopping criteria (Section 5.4.5) are met.
5.4.2.
Group Safety Stopping Criteria
In addition to the criteria specified above, AEs, SAEs, laboratory abnormalities, ECG 
abnormalities and changes in vital signs occurring across all randomised subjects will be 
regularly reviewed by the Sponsor Safety Review Team (SRT) in order to ensure 
appropriate subject safety.  Any changes to the study due to safety reasons will be 
promptly communicated to the appropriate Regulatory Authorities.
5.4.3.
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). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf


2015N251670_00
CONFIDENTIAL
203168
34
Figure 3
Phase II Liver Chemistry Stopping Criteria – Liver Stopping Events 
Algorithm
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2.
5.4.3.1.
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.
5.4.4.
QTc Stopping Criteria
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 patients 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
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*


2015N251670_00
CONFIDENTIAL
203168
35

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may 
not be changed or substituted once the subject has been enrolled.
For example, if a subject is eligible for the protocol based on QTcB, then QTcB 
must be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the 
same formula must continue to be used for that subject for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified ECGs 
are an exception. 

The decision to withdraw a subject will be based on an average QTc value of 
triplicate ECGs.  If an ECG demonstrates a prolonged QTc, obtain 2 more ECGs 
over a brief period (5-10 minutes), and then use the averaged QTc values of the 3 
ECGs to determine whether the subject should be discontinued from the study.
5.4.5.
Haematologic Stopping Criteria
Study treatment will be stopped for a subject if any of the following haematological 
stopping criteria is met:

Haemoglobin <9 g/dL (5.58 mmol/L) or an absolute decrease of ≥3 g/dL from 
baseline (pre-dose Day 1)

Neutrophils <1 × 109/L

Lymphocytes <0.5 × 109/L

Platelets <50 × 109/L
5.5.
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.


2015N251670_00
CONFIDENTIAL
203168
36
Study Treamtent
Product name:
GSK2982772
Placebo
Dosage form:
Tablet
Tablet
Unit dose 
strength(s)/Dosage level(s):
30 mg
NA
Route of Administration
For oral use only
For oral use only
Dosing instructions:
Take TWO tablets in the 
MORNING and TWO 
tablets in the EVENING 
as directed
Take TWO tablets in the 
MORNING and TWO 
tablets in the EVENING 
as directed
Physical description:
White to almost white, 
round, film coated tablet
White to almost white, 
round, film coated tablet
Source of procurement
Study medication is 
supplied by 
GlaxoSmithKline
Placebo is supplied by 
GlaxoSmithKline
6.2.
Treatment Assignment
At Screening a unique Subject Number will be assigned to any subject who has signed a 
consent form.  The unique Subject Number will be used to identify individual subjects 
during the course of the study.  Any subject that is re-screened outside of the allowed 
screening window at the approval of the GSK Medical Monitor, must be assigned a new 
unique Subject Number .
Subjects who meet screening eligibility criteria will be randomised to a treatment group 
through an Interactive Response Technology System (IRTS).  The IRTS will confirm the 
subject’s CRF number (Subject Number) and provide the randomisation number, where:

A randomisation number will be assigned from a randomisation schedule 
generated by Clinical Statistics, prior to the start of the study, using validated 
internal software.  Once assigned, this number must not be reassigned to any other 
subject in the study.
Therefore, the randomisation is centrally controlled by the IRTS.
Subjects will be randomised to receive either GSK2982772 or placebo in a 2:1 ratio.
6.3.
Planned Dose Adjustments
No dose adjustments are allowed.


2015N251670_00
CONFIDENTIAL
203168
37
6.4.
Blinding
This will be a double blind (sponsor unblinded) study and the following will apply:

Sponsor unblinded refers only to the Data Review Committee, consisting of the 
GSK study physician, study statistician, study pharmacokineticist, Early 
Development Lead (EDL) and Safety Review Team (SRT) Leader, or their 
designees on an ongoing basis.  A physician external to the GSK2982772 project
team may also be involved in the data review.  A data review charter will identify 
the specific GSK individuals involved; outline in detail the activities of this 
review, and how the integrity of the study will be maintained. The rest of the core 
GSK study team will remain blinded.

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 to his/her study staff or GSK, 
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 CRF.

A subject will be withdrawn if the subject’s treatment code is unblinded by the 
Investigator or treating physician.  The primary reason for discontinuation (the 
event or condition which led to the unblinding) will be recorded in the CRF.

GSK’s Global Clinical Safety and Pharmacovigilance (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 will be in accordance with all applicable regulatory 
requirements.


2015N251670_00
CONFIDENTIAL
203168
38
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 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the Investigator and authorized site staff. 

The Investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

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.  

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the Investigator, where this is required by local laws, or is available 
upon request from GSK.
6.7.
Compliance with Study Treatment Administration
When subjects are dosed at the site, they will receive study treatment directly from the 
Investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study subject identification will be confirmed at the time of dosing.  
When subjects self-administer study treatment(s) at home, compliance with GSK2982772 
and placebo will be assessed and documented through the review of the subject’s diary 
card and querying the subject during the site visits.  A record of the number of 
GSK2982772 or placebo tablets dispensed to and taken by each subject must be 
maintained and reconciled with study treatment and compliance records.  Treatment start 
and stop dates, including dates for treatment delays and/or dose reductions will also be 
recorded in the CRF.
Subjects will be given instructions on compliance and treatment with MTX (if 
applicable).  The date, time and total weekly dose will be recorded in the CRF.
6.8.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2982772 > 120 mg daily will be considered an overdose.  
GSK does not recommend specific treatment for an overdose.  The Investigator will use 
clinical judgement to treat any overdose as and when they are made aware of this.


2015N251670_00
CONFIDENTIAL
203168
39
In the event of an overdose, the Investigator or treating physician should:
1. Contact the Medical Monitor immediately.
2. Closely monitor the subject for adverse events (AEs)/serious adverse events (SAEs) 
for at least 48 hours following the last dose of GSK2982772.
3. Obtain a plasma sample for pharmacokinetic (PK) analysis if requested by the 
Medical Monitor (determined on a case-by-case basis).
4. Document all details of the overdose in the CRF.
Decisions regarding dose interruptions or modifications will be made by the Investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.9.
Treatment after the End of the Study
The Investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
Subjects will not receive any additional treatment from GSK after completion of the 
study because the 12 week duration of treatment is limited by the supporting 13 week 
toxicology studies.
6.10.
Lifestyle and/or Dietary Restrictions

Subjects must adhere to the contraceptive requirements listed in Appendix 6.
6.10.1.
Activity

Subjects will abstain from strenuous exercise more than their normal routine for 
48 hours prior to each blood collection for clinical laboratory tests.  

Subjects who have consented to synovial biopsies will abstain from strenuous 
exercise for 24 hours after synovial biopsy procedures.
6.11.
Concomitant Medications and Non-Drug Therapies
6.11.1.
Permitted Medications and Non-Drug Therapies
Selected medications for the treatment of RA may be taken, with specific requirements 
listed in Table 1, and as long as they are not prohibited (Section 6.11.2).  All concomitant 
medications taken during the study will be recorded in the source document and CRF.  
The minimum requirement is that drug name and dates of administration are recorded.


2015N251670_00
CONFIDENTIAL
203168
40
Table 1
Specific Requirements for Permitted Medications During the Study
Drug
Requirement
Methotrexate 
Stable dose regimen (up to 25 mg/week) for at 
least 12 weeks prior to screening and remain on 
this dose throughout the study (unless dose 
must be reduced because of a safety concern).  
MTX should be taken on the same day of week 
and at approximately the same time of day 
throughout the study.
Sulfasalazine
Stable dose regimen for at least 12 weeks prior 
to screening and throughout the study.
Hydoxychloroquine or cholorquinine
Stable dose for at least 12 weeks prior to 
screening and throughout the study.
Leflunomide
Stable dose for at least 12 weeks prior to 
screening and throughout the study.
Folate supplements (minimum of 5 mg/week)
If a subject is on folate supplements with MTX 
treatment, they must be on a stable dose 
regimen for at least 4 weeks prior to 
randomization and throughout the study.
Other oral anti-rheumatic therapies such as 
non-steroidal anti-inflammatory drugs (NSAIDs), 
oral glucocorticords (e.g., prednisolone ≤ 10 mg 
/day.  See Appendix 3 for equivalent doses).
Stable dose regimen for at least 4 weeks prior 
to screening and throughout the study (unless 
reduction required due to adverse effects).
Omit dose on the morning prior to study visits 
until after joint assessments.
6.11.2.
Prohibited Medications and Non-Drug Therapies
Table 2 lists prohibited medications for defined periods of time before and during the 
study until after the follow up visit. 
Subjects who start prohibited medications or therapies as a treatment for RA or other 
reasons during the study will be withdrawn from study treatment for safety reasons.  If in 
any doubt, Investigators are advised to discuss medications with the medical monitor.


2015N251670_00
CONFIDENTIAL
203168
41
Table 2
Prohibited Medications
Therapy
Time period 
A change in dose of methotrexate or other 
DMARD.
12 weeks prior to screening until after the 
follow up visit (Day 112)
Greater than 10mg/day oral prednisolone (or 
equivalent glucocorticoid) or a change in dose 
of corticosteroid.
4 weeks prior to screening until after the 
follow up visit (Day 112)
Intramuscular glucocorticoids (e.g., 
methylprednisolone ≤120 mg/month)
4 weeks prior to screening until after the 
follow up visit (Day 112)
Intra-articular corticosteroid injections
6 weeks prior to screening and until after the 
follow up visit (Day 112).
Biologic therapies for the treatment of 
rheumatoid arthritis not limited to anti-TNF
biologics or other biologics, rituximab, anakinra, 
abatacept or tocilizumab.
At any time 
Exposure to more than one anti-TNF biologic 
therapies for the treatment of RA including but 
not limited to anti-TNF biologics, infliximab, 
adalimumab, etanercept, certolizumab and 
golimumab.
Exception:  Exposure to a single anti-TNF-
biologic for which the subject discontinued for a 
reason other than primary non-response is 
permitted.
Cannot have been exposed to more than one
anti-TNF biologic or be on at any time during 
the study.
In the case of a single anti-TNF biologic for 
which the subject discontinued for a reason 
other than primary non-response, the subject 
must not be on for 8 weeks or 5 ½ lives 
(whichever is longer) prior to first dose until 
after the follow up visit (Day 112).  
Live vaccination
Live or attenuated vaccinations are not 
permitted within 30 days of randomization or 
plan to receive a vaccination during the study 
until follow-up visit.  If indicated, non-live 
vaccines (e.g., inactivated influenza vaccines) 
may be administered whilst receiving 
GSK2982772 based on an assessment of the 
benefit:risk (e.g., risk of decreased 
responsiveness).  Investigators are expected 
to follow local and/or national guidelines with 
respect to vaccinations, including against 
pneumococcus and influenza, in subjects with 
RA.


2015N251670_00
CONFIDENTIAL
203168
42
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 (Section 7.1), are essential and required for study 
conduct.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the SRM and laboratory manual.  The SRM will provide the site personnel 
with administrative and detailed technical information that does not impact subject safety.
This section lists the procedures and parameters of each planned study assessment.  The
timing of each assessment is listed in the Time and Events Table Section 7.1

At study visits, the Patient Reported Outcomes (PROs) should be completed 
prior to any other study assessments.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic/biomarker or others assessments may be 
altered during the course of the study based on newly available data (e.g., to 
obtain data closer to the time of peak concentrations) to ensure appropriate 
monitoring. 

The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment. 

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.

The Institutional Review Board/Independent Ethics Committee (IRB/IEC) will 
be informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the Informed Consent Form. 


2015N251670_00
CONFIDENTIAL
203168
43
7.1.
Time and Events Table
Procedures
Screening (-30)
Treatment Period17
Early Withdrawal18
Follow Up (3)19
Day 1 
Day 8 (3)
Day 15 (3)
Day 22 (3)
Day 29 (3)
Day 36 (3)
Day 43 (3)
(week 6)
Day 50 (3)
Day 57 (3)
Day 64 (3)
Day 71 (3)
Day 78 (3)
Day 85 (+2)
(week 12)
Site Visit
X
X
X
X
X
X
X
X
X
X
X
Phone call
X
X
X
X
X
General/Safety Assessments and Procedures
Informed Consent
X
Subject Demography
X
Full medical history1
X
Inclusion/Exclusion Criteria
X
Full physical exam2
X
X
X
X
Brief physical exam
X4
X
X
X4
X
X
Vital signs (BP, HR, RR, temperature)  
X
X4
X
X
X
X4
X
X
X
X
X
12-lead ECG
X3
X4
X
X
X
X4
X
X
X
X
X
Concomitant medication review & AE reporting/SAEs5
X---------------------------------------------------------------------------------------------------------------------------X
PROs/Questionnaires/Diaries/Disease Assessments and Procedures
Columbia Suicide Severity Rating Scale (C-SSRS)
X
X4
X4
X
X
FACIT-fatigue; RA Symptom and Impact Diary6
X4
X4
X
X
HAQ-DI; Patient Assessment of joint pain6
X4
X
X
X4
X
X
X
X
Patient Global Assessment (PtGA)6
X
X4
X
X
X4
X
X
X
X
Tender (28) & Swollen (28) joint count
X
X4
X
X
X4
X
X
X
X
Physician Global Assessment (PGA)
X4
X
X
X4
X
X
X
X
MRI/DCE-MRI7
X4
X4
X
X16


2015N251670_00
CONFIDENTIAL
203168
44
Procedures
Screening (-30)
Treatment Period17
Early Withdrawal18
Follow Up (3)19
Day 1 
Day 8 (3)
Day 15 (3)
Day 22 (3)
Day 29 (3)
Day 36 (3)
Day 43 (3)
(week 6)
Day 50 (3)
Day 57 (3)
Day 64 (3)
Day 71 (3)
Day 78 (3)
Day 85 (+2)
(week 12)
Study Treatment
Randomisation
X
Study medication (twice daily)8
X-------------------------------------------------------------------------------------------------------X
Dispensing of study medication
X
X
X
Dispensing of diary cards
X
X
X
X
X
X
X
Collection and review of diary cards
X
X
X
X
X
X
X
X
Laboratory (Safety) Assessments and Procedures
TB, HIV, HepB,Hep C Ab, Anti-CCP, Anti-dsDNA, Anti-
CARP, RF 
X
FSH & estradiol  (if applicable)
X
Serum pregnancy test (WCBP only)
X
Urine pregnancy test (WCBP only)9
X4
X
X
X
X4
X
X
X
X
X
Haematology, chemistry, urinalysis 
X
X4
X
X
X10
X4
X10
X10
X
X
X
CRP
X
X4
X
X
X4
X
X
X
X
Blood sample for PD inflammatory biomarkers, mRNA, and 
TE11
X4
X4
X
X
PK blood samples GSK298277212
X
X4
X4
X
X
PK blood samples for MTX13
X4
X4
X4
Pharmacogenetic sample (PGx)
X14
Synovial biopsies for PK, inflammatory biomarkers, mRNA, 
target engagement & pathway engagement analysis15
X4
X4
X16


2015N251670_00
CONFIDENTIAL
203168
45
Footnotes:
1.
Full medical history (includes past and current conditions, medication history, substance usage, and family history of premature CV disease).
2.
Full physical exam (includes height/weight at screening, height not measured at later time points).
3.
Triplicate ECG to be performed at screening only.
4.
Pre-dose.
5.
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.  AEs will be collected from the start of Study Treatment until the follow-up 
contact.
6.
All PRO assessments should be conducted before any tests, procedures, or assessments, to avoid influencing the subjects’ perception.
7.
DCE-MRI will be performed on all subjects, provided that sites have DCE-MRI capability and experience (e.g., hardware and software requirements). If sites do not have DCE-MRI 
capability or experience, a regular MRI will be performed of the affected hand/wrist.
8.
Subjects must take study medication twice a day approximately 12 hours apart. Exact time of dosing to be recorded in diary cards. On Days 8,43 and 85 only, subjects must not 
take their medication at home in the morning. Subjects will complete pre-dose assessments and then will be administered their morning dose of medication at site on Days 8 and 
43.  On Day 85, subjects are no longer receiving study medication.
9.
If urine pregnancy test is positive, a confirmatory serum pregnancy test must be performed.
10. Haematology and chemistry only.  No urinalysis required on Days 29, 57 and 71.
11. Blood samples for inflammatory biomarkers, mRNA and target engagement .  See laboratory manual for full details on sample collection, handling and shipment.
12. PK blood samples for GSK2982772 will be taken pre-dose on Days 8 and 43. Post-dose serial PK samples will be taken on Days 1, 8 and Day 43 at the following time points: 1, 2, 
4, and 6 hours and trough on Day 85 or at Early Withdrawal .
13. PK blood samples for MTX will be taken pre-dose GSK2982772 on Day 1 (MTX alone), on Days 8 and 43 (MTX + GSK2982772).  Subjects who are on MTX must take their MTX
dose on the same day of the week at approximately the same time of the day throughout the study. In addition, the Day 1, 8 and 43 visits must be on the same day of the week.
14. A PGx blood sample is collected at the baseline visit, after the subject has been randomised and provided informed consent for genetic research.  If the sample is not collected at 
the baseline visit, it can be collected at any time during the study after randomisation.
15. Synovial biopsies are optional.
16. Biopsy (if applicable) and MRI only are required at Early Withdrawal visit if subject withdraws after at least 14 days of treatment and prior to Day 43.  If a subject withdraws 
between Days 43 and 57, an MRI is not required at the Early Withdrawal visit.  If a subject withdraws on Day 57 or after, an MRI should be performed at the Early Witdrawal visit .
17. Visit windows during the treatment period are relative to Day 1.
18. If a subject withdraws from the study, every effort will be made for the subject to complete an Early Withdrawal visit prior to the Follow Up visit.
19. Follow-up visit should be completed 28 days (3 days) after the last dose of study medication.


2015N251670_00
CONFIDENTIAL
203168
46
7.2.
Screening and Critical Baseline Assessments
After written informed consent, screening assessments will be performed as outlined in 
the Time and Events Table (Section 7.1).
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history, ECG and laboratory tests will be assessed as related 
to the inclusion/exclusion criteria listed in Section 5.
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
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.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  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.
The Investigator will be responsible for determining the clinical significance of any 
results that fall outside of the laboratory normal ranges.
In line with routine pharmacovigilance, an internal GSK Safety Review Team (SRT), 
which will include 203168 study team members, will review blinded safety data, 
including clinical laboratory parameters and adverse events, at appropriate intervals 
during the period of study conduct.
7.3.1.
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. 
7.3.1.1.
Time period and Frequency for collecting AE and SAE information

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. 

AEs will be collected from the start of Study Treatment until the follow-up 
contact (see Section 7.3.1.3), at the time points specified in the Time and Events 
Table (Section 7.1).


2015N251670_00
CONFIDENTIAL
203168
47

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 CRF.

All SAEs will be recorded and reported to GSK within 24 hours, 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.
7.3.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.3.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 5. 
7.3.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 5and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed.  These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death.
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms.  The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion.


2015N251670_00
CONFIDENTIAL
203168
48
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported.  Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.3.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the Investigator to GSK of SAEs 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.
An Investigator who receives an Investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.3.2.
Pregnancy

Details of all pregnancies in female subjects and female partners of male subjects 
will be collected after the start of dosing and until 30 up to 90 days (as applicable)
after the last dose.

If a pregnancy is reported within 30 days (90 days in partners) after the last dose 
then the Investigator should inform GSK within 2 weeks of learning of the 
pregnancy and should follow the procedures outlined in Appendix 6.
7.3.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
head, eyes, ears, nose, throat, skin, thyroid, joint, lymph nodes, cardiovascular, 
respiratory, gastrointestinal and neurological systems. Height and weight will also 
be measured and recorded at the first physical examination.

A brief physical examination will include, at a minimum assessments of the lungs, 
cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.


2015N251670_00
CONFIDENTIAL
203168
49
7.3.4.
Vital Signs

Vital signs will be measured in semi-supine position after approximately 5 
minutes rest and will include temperature, systolic and diastolic blood pressure, 
pulse rate and respiratory rate. 
7.3.5.
Electrocardiogram (ECG)

Triplicate12-lead ECGs will be obtained at screening and single 12-lead ECGs 
obtained at every time point during the study using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc (F or 
B) intervals.  Refer to Section 5.4.4 for QTc withdrawal criteria and additional 
QTc readings that may be necessary.

The QTc should be based on averaged QTc values of triplicate electrocardiograms 
obtained over a brief (e.g., 5-10 minutes) recording period.  

ECG to be measured in a semi-supine position after approximately 5 minutes rest.
7.3.6.
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 Table (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 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 CRF.
Refer to the 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:

Haematology, platelets and coagulation sample if they are required to be taken 
closer to the biopsies (as per local practices) than specified in Section 5.4.5.
NOTE: Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either a treatment and/or response evaluation to be 
performed. If a local sample is required, it is important that the sample for central 
analysis be obtained at the same time.  Additionally, if the local laboratory results are 
used to make either a treatment or response evaluation, the results must be entered into 
the CRF.


2015N251670_00
CONFIDENTIAL
203168
50
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 3.
Table 3
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
1,2
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 3
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose4
Calcium
Alkaline phosphatise
Albumin
CRP
Triglycerides4
Total Cholesterol4
Fasting HDL 
cholesterol4
Fasting LDL 
cholesterol4
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening and 
RoutineTests

HIV 1 & 2

Hepatitis B (HBsAg)

Hepatitis B core antibody (HBcAb)

Hepatitis C (Hep C antibody)

QuantiFeron Gold Test

T-spot (if QuantiFeron is indeterminant)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Urine hCG Pregnancy test (as needed for women of child bearing 
potential) 5

Serum hCG (as needed for women of child bearing potential) to be 
done at screening and if urine test positive at other time points in the 
study.

Anti-dsDNA

Rheumatoid Factor

Anti-CCP

Anti-CARP

Estimated glomerular filtration rate (eGFR) will be calculated using 
the CKD-EPI formula.
Footnotes:
1.
The subject’s CBC results from the previous scheduled visit should be checked prior to the synovial biopsy 


2015N251670_00
CONFIDENTIAL
203168
51
procedures according to local practices and may be repeated at the discretion of the investigator.
2.
Details of Haematologic Stopping Criteria are given in Section 5.4.5.
3.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after liver 
stopping or monitoring event are given in Section 5.4.3 and Appendix 2.
4.
No fasting required.  Any abnormal result for glucose or lipids (non-fasted) may be repeated at the discretion 
of the Investigator.
5.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
ethics committee.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study 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.
7.3.7.
Suicidal Risk Monitoring
GSK2982772 is considered to be a CNS-active drug. There has been some concern that 
some CNS-active drugs may be associated with an increased risk of suicidal thinking or 
behaviour when given to some patients with RA.  Although this drug has not been shown 
to be associated with an increased risk of suicidal thinking or behaviour when given to 
healthy volunteers, GSK considers it important to monitor for such events before or 
during clinical studies with compounds such as this.   
Subjects being treated with GSK2982772 should be monitored appropriately for suicidal 
ideation and behaviour or any other unusual changes in behaviour. Consideration should 
be given to discontinuing GSK2982772 in subjects who experience signs of suicidal 
ideation or behaviour.
Families and caregivers of subjects being treated with GSK2982772 should be alerted 
about the need to monitor subjects for the emergence of unusual changes in behaviour, as 
well as the emergence of suicidal ideation and behaviour and to report such symptoms 
immediately to the study Investigator.
At Screening and baseline (pre-dose Day 1), the ‘Baseline/Screening CSSRS’ will be 
completed.  At Days 43 (Week 6) and 85 (Week 12), the ‘Since Last Visit CSSRS’ will 
be completed.  GSK Version 4.1 of both rating scales will be used.
Subjects who answer ‘yes’ to any suicidal behaviour or ‘yes’ to suicidal ideation 
Questions 4 or 5 will be referred to their GP or appropriate psychiatric care.  The Medical 
Monitor will be notified.  If appropriate, an AE or SAE should be reported (see 
Section 7.3.1 AE and SAE).  In addition, the Investigator should complete a Possible 
Suicidality Related Adverse Event (PSRAE) form to collect detailed information on the 
circumstances of the reported AEs which, in the Investigator’s opinion, are possibly 
suicidality-related.  These may include, but are not limited to, an event involving suicidal 
ideation, a preparatory act toward imminent suicidal behaviour, a suicide attempt, or a 
completed suicide.


2015N251670_00
CONFIDENTIAL
203168
52
7.4.
Efficacy
7.4.1.
Patient Reported Outcomes
Patient Reported Outcomes questionnaires should be completed by subjects before any 
other assessment at a clinic visit.
7.4.1.1.
Rheumatoid Arthritis Symptoms and Impact Diary
Symptoms associated with RA will be assessed using a novel RA Symptom and Impact 
Diary as per Section 7.1, Time and Events Table.  The study staff should not clarify any 
of the questions for the subject.
7.4.1.2.
Patient Assessment of Joint Pain
The severity of the subject’s joint pain will be assessed by completion of a numeric rating 
scale (NRS).  The subject will be asked to select a whole number (0-10 integers) that best 
reflects the intensity of their pain.  The scale is represented by a horizontal bart with “no 
pain” at the lower anchor and “most severe pain” at the upper anchor.  This questionnaire 
should take approximately 1 minute to complete.
The patient assessment of joint pain will be used to calculate ACR responders.
7.4.1.3.
Patient’s Global Assessment of Disease (PtGA)
Subjects will complete a global assessment of disease activity using the patient global 
assessment item, a visual analogue scale (VAS) with anchors “0” (very well) to “10” 
(very poor).
The patient’s global assessment of disease will be used to calculate DAS clinical scores 
and ACR responders.
7.4.1.4.
Disability Index of the Health Assessment Questionnaire (HAQ-DI)
The HAQ-DI will be utilised to assess the subject’s physical function or disability 
according to the subject.  The study staff should not clarify any of the questions for the 
subject.
This 20-question instrument assesses the degree of difficulty a person has in 
accomplishing tasks in 8 functional areas [Fries, 1980]: 

Dressing, arising, eating, walking, hygiene, reach, grip, and common daily 
activities. 
Responses are scored from 0 (no difficulty) to 3 (inability to perform a task in that area).
The HAQ-DI will be used to calculate ACR responders.


2015N251670_00
CONFIDENTIAL
203168
53
7.4.1.5.
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue
Scale
Subjects will complete a 13-point fatigue questionnaire using the FACIT-Fatigue 
assessment, a Likert scale from 0 to 4, to “0” (very much fatigued) to“4” (not at all 
fatigued).  This questionnaire should take a few minutes to complete and provides the 
level of fatigue with usual daily activities from the previous week. 
7.4.2.
Clinical Disease Assessments
Brief details are given below and detailed procedural instructions are given in the SRM.  
The sponsor will calculate DAS28(CRP)  and ACR (20/50/70) responses at each 
assessment time point as defined below.
7.4.2.1.
Disease Activity Score (DAS) Assessments
The DAS28 is a measure of disease activity.  It is a composite score derived measurement 
weighing given to each component.  
The components of the DAS28 assessment include:

Tender/Painful Joint Count (28)

Swollen Joint Count (28)

CRP

PtGA
7.4.2.2.
American College of Rheumatology Criteria (ACR) Assessments
The ACR Criteria is a standard criteria to measure the effectiveness of treatments from 
placebo.  The ACR’s definition for calculating improvement in RA (ACR20) is 
calculated as a 20% improvement in tender and swollen joint counts and 20% 
improvement in 3 of the 5 remaining ACR-core set measures: patient and physician 
global assessments, pain, disability, and an acute-phase reactant.  Similarly, ACR50 and 
70 are calculated with the respective percent improvement.  
The specific components of the ACR Assessments that will be used in this study are:

Tender/Painful Joint count (28)

Swollen Joint Count (28)

Patient Assessment of Joint Pain

PtGA

PGA

CRP

HAQ-DI


2015N251670_00
CONFIDENTIAL
203168
54
7.4.2.3.
Joint Assessments
Tender Joint Count Assessments
A total of 28 joints will be scored for presence or absence of tenderness.
Swollen Joint Count Assessments
A total of 28 joints will be scored for presence or absence of swelling.
Joint assessments will be used to calculate DAS28 clinical scores and ACR responders.
7.4.2.4.
Measurement of Serum CRP
Blood samples will be collected in order to measure serum CRP concentrations.  The 
CRP is a component of the DAS28, ACR, and Vectra DA clinical scores.
7.4.2.5.
Physician’s Global Assessment of Disease Activity (PGA)
The Investigator or physician designee only will complete a global assessment of disease 
activity using the physician global assessment item, a VAS with anchor’s “0” (none) to 
“10” (extremely active).
Note: 

The Investigator or physician designee should complete the PGA independently of 
the subject.

Ideally, the same Investigator or physician designee should perform all global 
assessments for each subject during the duration of the study.
7.5.
Pharmacokinetics
7.5.1.
Blood Sample Collection
Blood samples for PK analysis of GSK2982772 will be collected at the time points 
indicated in Section 7.1 Time and Events Table.  The actual date and time of each blood 
sample collection will be recorded.  The timing of PK samples may be altered and/or PK 
samples may be obtained at additional time points to ensure thorough PK monitoring.  
For subjects who are on stable doses of methotrexate (MTX), blood samples for PK
analysis of MTX will be collected at the time points indicated in Section 7.1 Time and 
Events Table.  The actual date and time of each blood sample collection will be recorded.  
Details of blood sample collection, processing, storage and shipping procedures are 
provided in the laboratory manual.
7.5.2.
Sample Analysis
Plasma analysis will be performed at a bioanalytical site (to be detailed in the SRM) 
under the control of Platform Technologies and Science In vivo In vitro Technology 
(PTS IVIVT) and Third Party Resource, GlaxoSmithKline. Concentrations of 


2015N251670_00
CONFIDENTIAL
203168
55
GSK2982772 and MTX will be determined in plasma samples using the currently
approved bioanalytical methodology. Raw data will be archived at the bioanalytical site 
(detailed in the SRM).
Once the plasma sample has been analysed for GSK2982772 any remaining plasma
sample may be analysed for other compound-related material and the results may be 
reported under a separate PTS-IVIVT, GlaxoSmithKline protocol.
7.5.3.
Synovial Biopsy Tissue for Pharmacokinetic Assay
See Section 7.6.2.2 for details on synovial tissue biopsy and procedure.  If available, 
synovial tissue samples may be analysed for concentrations of GSK2982772 and possible 
drug-related material, as well as specific tissue distribution if feasible as sample 
availability allows.
7.5.4.
Sample Analysis
Synovial biopsy sample analysis will be performed under the control of PTS IVIVT, 
GlaxoSmithKline.  Information on processing the biopsies for the synovial 
pharmacokinetic assay will be provided in the laboratory manual.  The results may be 
reported under a separate PTS-IVIVT, GlaxoSmithKline protocol.
7.6.
Biomarker(s)/Pharmacodynamic Markers
Pharmacodynamic biomarkers will be collected at the time points in Section 7.1 Time 
and Events Table and may include, but are not limited to, the following:
Blood samples for mRNA expression e.g., IL6, MMP-1, MMP3, MMP-13, TIMP-
1, MCP-1 and MIF.
Blood samples for biomarkers which may be indicative of RA disease activity e.g., 
MRP8/14 and markers encompassed by Vectra DA.
Details of blood sample collection, processing, storage and shipping procedures are 
provided in the laboratory manual.
7.6.1.
Magnetic Resonance Imaging (MRI) of Joint
The most affected hand will be documented at baseline and used for all imaging visits. If 
subjects report both hands are equally involved, then the subject’s dominant hand will be 
used.
DCE-MRI will be performed on all subjects, provided that sites have DCE-MRI 
capability and experience (e.g., hardware and software requirements). If sites do not have 
DCE-MRI capability, only a standard MRI will be performed.
Each subject’s most affected wrist (corresponding to the affected hand which is 
determined and documented at baseline) will be imaged by MRI at pre-dose on Days 1, 
43 and 85 (see Section 7.1).  If a scanning failure occurs at any visit, if feasible a rescan 
is allowed within 7 days after the failed scan after consultation and agreement with the 


2015N251670_00
CONFIDENTIAL
203168
56
GSK Medical Monitor.  There will be a minimum of 24 hours between scans where 
gadolinium (Gd) contrast is used.  The MRI will be used in order to non-invasively 
quantify the degree of inflammation and structural changes within the target joint.
Each MRI total scan time should be approximately 1 hour.  For each subject, MRIs must 
be performed on the same scanner and using the same type of chelated Gd contrast agent 
as was used at screening.  If scanning cannot occur on the same scanner within the visit 
time window due to hardware failure, an alternate scanner may be used or the time 
window may be extended by 3 days only after consultation and agreement with the GSK 
medical monitor.
On attendance at the MRI department, subjects will be placed in the scanner and will be 
prepared for intravenous contrast agent administration.  The scanning protocol will 
include routine localizers, T1 measurement sequences, dynamic DCE-MRI acquisition, 
and acquisitions required for OMERACT RAMRIS and RAMRIQ scoring.  Additional 
exploratory MRI endpoints, as detailed in the Acquisition Manual, may also be acquired 
for exploratory purposes.
Details of scanning site training procedures, acceptable Gd contrast agents, and scanning 
protocols will be provided in a dedicated Imaging Manual.
All MRI scans will be reported at the site by a radiologist (non-anonymized) for clinical 
abnormalities.
7.6.2.
Synovial Biopsy
7.6.2.1.
Selection of Joint for Synovial Biopsy
Synovial biopsies are optional for subjects enrolled in this study. There is no minimum 
number of subjects with joint biopsies required, but biopsies should be performed in as 
many subjects as possible.  Synovial biopsy of a subject’s swollen and tender wrist, knee 
or ankle joint will be performed at baseline (pre-dose Day 1).  The final choice of joint is
left to the discretion of the Investigator, although ideally it will be the most inflamed 
joint.  The same joint should be biopsied at Day 43 (Week 6).  If in the event that a repeat 
biopsy of the same joint as baseline is not possible, the joint may change if essential, after 
discussion with the GSK Medical Monitor.  Any change must be documented in the CRF.
If a subject chooses to withdraw from the study after dosing and prior to Day 43, the 
Investigator must make every effort to perform a synovial biopsy if the subject has 
received at least 14 days of treatment with GSK2982772 or placebo.  
7.6.2.2.
Synovial Biopsy Procedure
Ultrasound imaging or arthroscopy will be used to guide the collection of approximately
(as feasible for any given subject) of 6 synovial biopsies for immunohistochemistry
(IHC), 6 synovial biopsies for pharmacokinetics, 6 synovial biopsies for target 
engagement, and 6 synovial biopsies for RNA extraction up to a combined maximum of 
30 biopsies from the chosen joint under local anaesthesia (see SRM).


2015N251670_00
CONFIDENTIAL
203168
57
Biopsy tissue taken from synovial tissue will be divided accordingly for IHC, PK, target 
and pathway engagement, and gene expression.  Histological assessment by IHC will be 
evaluated for general appearance and total inflammatory infiltrate.  Specific cell numbers 
will also be analysed (which may include but are not limited to CD3+T-cells, CD55+ 
fibroblast-like synoviocytes, CD68+macrophages).  mRNA may be isolated from 
synovial biopsys tissue, as feasibility dictates, to determine the effect of placebo and 
GSK2982772 on markers of inflammation and tissue healing (e.g., may include and not
be limited to VEGF, IL-1β, IL-6, TNFα, and MMP-1 and other chemokines and 
cytokines).  Biopsy tissue collected for RNA transcriptional analysis may be utilised to 
determine the effect of GSK2982772 on cytokine and receptor expression, in addition to 
other markers of inflammation and tissue healing, as feasibility allows.  For example, this 
may include but is not limited to, measurement of acute phase proteins, other chemokines 
and cytokines.  Examples of technologies that may be used for these analysis include, but 
are not limited to, quantitative PCR, microarray, RNA sequencing or mass cytometry 
(CyTOF).
7.6.3.
Novel Pharmacodynamic Biomarkers
7.6.3.1.
RIP1 Target Engagement in Blood
Blood samples for RIP1 target engagement will be collected at the time points indicated 
in Section 7.1 to measure levels of free and drug-bound RIP1 protein.
7.6.3.2.
RIP1 Target Engagement in Synovial Tissue
Synovial tissue biopsy samples will be collected at the time points indicted in Section 7.1
to measure levels of free and drug-bound RIP1 protein if sample quantity and data allow.
7.6.3.3.
Pathway Biomarkers in Synovial Tissue
Synovial tissue biopsy samples will be collected at the time points indicated in Section 
7.1 to measure total or phosphorylated RIP1, RIP3, MLKL and cleaved or total caspase 3 
and caspase 8 if sample quantity and data allow.
7.6.4.
Exploratory Novel Biomarkers
With the subject’s consent, tissue and blood sample(s) will be collected during this study 
and may be used for the purposes of measuring novel biomarkers to identify factors that 
may influence disease/condition for study treatment, and/or medically related conditions, 
as well as the biological and clinical responses to GSK2982772.  If relevant, this 
approach will be extended to include the identification of biomarkers associated with 
adverse events.
Samples will be collected at the time points indicated in Section 7.1. The timing of the 
collections may be adjusted on the basis of emerging pharmacokinetic or 
pharmacodynamic (PD) data from this study or other new information in order to ensure 
optimal evaluation of the PD endpoints.


2015N251670_00
CONFIDENTIAL
203168
58
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with RA or medically related conditions and/or the action of 
GSK2982772 may be identified by application of:

Gene expression analysis may be conducted on the blood and/or synovial biopsies 
using microarray, RNA sequencing and/or alternative equivalent technologies, 
which facilitates the simultaneous measurement (and confirmation) of the relative 
abundances of thousands of RNA species resulting in a transcriptome profile for 
each synovial tissue sample.

Soluble inflammatory mediators in the blood may be assayed for cytokine and 
inflammatory mediators including, but not limited to, pro-inflammatory and anti-
inflammatory cytokines, chemokines, and acute phase proteins. 
These analyses may be reported under separate protocol following the completion of the 
study.  All samples will be retained for a maximum of 15 years after the last subject 
completes the trial.
7.7.
Genetics
In consenting subjects, a blood sample for pharmacogenetics (PGx) research will be 
drawn on Day 1 (or any time point post randomisation and prior to study completion) to
better characterize genetic variability that may affect efficacy or safety endpoints. 
Information regarding pharmaogenetic (PGx) research is included in Appendix 4.
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.  

CRFs (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
and date of birth will not be collected or transmitted to GSK according to GSK 
policy.


2015N251670_00
CONFIDENTIAL
203168
59
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The primary objective of the study is to investigate the safety and tolerability of 
GSK2982772 following 12 weeks of treatment. No formal statistical hypotheses will be 
conducted to assess this objective. 
If appropriate, comparisons between the GSK2982772 and the placebo arm will be made 
to investigate the secondary pharmacodynamic, mechanistic and efficacy objectives. 
Trends over time will be investigated for both treatment arms along with associations 
between each of the pharmacodynamic, mechanistic and efficacy parameters. 
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The study is not powered to detect pre-defined differences. A sufficient number of 
subjects will be screened so that approximately 30 subjects with moderate to severe RA
are randomised into the study.  Should the drop-out rate be higher than anticipated, 
additional or replacement subjects may be randomised (up to a maximum of 36) into the 
study at the discretion of the Sponsor.
The primary objective of the study is safety and tolerability, where there will be 20 
subjects randomised to GSK2982772. Using a Bayesian approach to determine the 
confidence interval (CI) around an observed safety event, we would assume a flat Beta 
(1, 1) prior, and if we were to observe one safety event in 20 then the posterior 
distribution would be Beta (2, 20), as outlined below in Figure 4. 
Figure 4
One Event in 20 Subjects: Beta (2,20) Distribution


2015N251670_00
CONFIDENTIAL
203168
60
Thus, we can be 95% certain that the true probability of the safety event lies between 
0.01 and 0.24. 
For supportive information, the properties of the key secondary endpoint DAS28 have 
been considered.
Based on the estimate of variability (SD=1 from historical data) it is estimated that the 
lower and upper bounds of the 95% CI for the change from baseline in DAS28-CRP 
score will be within approximately 0.694 and 0.462 of the point estimate of GSK2982772 
(n=20) and placebo (n=10).
9.2.2.
Sample Size Sensitivity
A sample size sensitivity analysis has been conducted on the primary endpoint to 
investigate the different safety event rates.  If the number of subjects who complete the 
12 weeks is lower than 20 in the GSK2982772 group, then the true incidence rates of 
safety events that could not be ruled out (as outlined in Section 9.2.1) would change.  
These changes are outlined in Table 4.
Table 4
Sample Size Sensitivity
GSK2982772 subjects 
completing the study
Number of a particular safety 
event observed with
GSK2982772
Upper limit of exact 95% 
Credible Interval indicating that 
a true incidence rate of x% 
could not be ruled out
20
0
16.1%
20
1
23.8%
20
2
30.4%
18
0
17.6%
18
1
26.0%
18
2
33.1%
16
0
19.5%
16
1
28.7%
16
2
36.4%
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation or adjustment will be conducted.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
All Subjects Population: The ‘All Subjects Population’ is defined as subjects who were 
screened for the study.  This population is used for the summary of selected 
accountability data.


2015N251670_00
CONFIDENTIAL
203168
61
Safety Population: The ‘Safety Population’ is defined as subjects who receive at least 
one dose of study medication. This population is used for the summary of all data 
including demography, safety, efficacy and exploratory data but excluding PK data.
Pharmacokinetic Population: The ‘PK Population' is defined as subjects in the ‘Safety’ 
population who received an active dose and for whom a GSK2982772 pharmacokinetic 
sample was obtained and analysed.   This population is used for the summary of PK data 
only.  Any PKPD analysis will be conducted on the Safety population such that subjects 
receiving placebo can be included.
9.3.2.
Interim Analysis
A formal interim analysis will be conducted during the study.  Additionally two review 
teams will monitor data on an ongoing basis for routine pharmacovigilance and decision 
making regarding the subsequent clinical development of GSK2982772 for RA.
In line with routine pharmacovigilance, an internal GSK Safety Review Team (SRT)
which will include members of the GSK2982772 project team, will review blinded safety 
data, including clinical laboratory parameters and adverse events, at appropriate intervals 
during the period of study conduct.
Once an appropriate number of subjects have completed Day 43 (Week 6) the DAS28-
CRP data will be reviewed in an unblinded manner and on an ongoing basis by the Data 
Review Committee, consisting of the GSK study physician, the study statistician, the 
study pharmacokineticist, the EDL and SRT Leader or designees on an ongoing basis.  A 
physician external to the GSK2982772 project team may also be involved in the data 
review. Additional inflammatory biomarkers, clinical and mechanistic endpoints (e.g. 
target engagement) may be reviewed if available. No other member of the GSK core 
study team will be unblinded to this data. The primary purpose of these informal reviews 
will be to monitor DAS28-CRP for futility.  On review of DAS28-CRP data, the review 
group may recommend an interim analysis of key clinical and mechanistic data is first 
conducted prior to any decision to terminate the study for futility.  A data review charter 
will identify the specific GSK individuals involved, outline in detail the activities of this 
review and how the integrity of the study will be maintained.
A formal interim analysis will be conducted during the study. The timing of this analysis 
will either be on the recommendation of the data review group to assess futility based on 
6 weeks of treatment, or when an appropriate number have completed 12 weeks of 
treatment, whichever is earliest.  The purpose of the Interim Analysis would be to assess 
whether to stop the study for futility.  This interim analysis may also facilitate decision 
making regarding the subsequent clinical development of GSK2982772 for RA. 
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
All safety evaluations will be based on the Safety population.  Clinical interpretation will 
be based on the review and displays of adverse events, clinical laboratory values, vital 
sign measurements and 12-lead ECG monitoring.


2015N251670_00
CONFIDENTIAL
203168
62
9.4.2.
Secondary Analyses
The relationship between each of the mechanistic endpoints and also with the clinical 
endpoints will be graphically presented and analysed using an appropriate statistical 
model identifying any trends. The model will determine whether the mechanistic effect 
significantly explains or predicts the effect on the other mechanistic or clinical endpoints 
(e.g., DAS28-CRP score). This may be conducted through comparing statistical models 
incorporating different explanatory terms (i.e. mechanistic endpoints) with the ‘null’ 
model (no mechanistic endpoints); or if deemed appropriate, multivariate statistical 
methods may also be applied to determine the relationship between the key endpoints. 
The consistency in the changes over time between the endpoints will also be assessed.
Each endpoint will be considered individually and at the treatment level, where 
comparisons between treatment groups would be made on any changes observed, if 
deemed appropriate. This could include change from baseline in DAS28-CRP, which will 
be statistically analysed using a MMRM analysis comparing GSK2982772 with placebo 
at each time point. Additionally this could include, the proportion of subjects achieving 
ACR20/50/70 and DAS28-CRP response, which will be statistically analysed using a a 
Generalised Estimating Equation (GEE) model comparing GSK2982772 with placebo at 
each timepoint. Similar analyses will be conducted for other secondary endpoints if 
deemed appropriate.
9.4.3.
Other Analyses
In addition, based on the data that we observe in the study, probabilities of success will 
be determined, where the definition of success will be dependent on the endpoint. For 
example, what is the probability that we would observe a certain change in DAS28 (i.e., 
comparator rate), based on the data that we have observed in the study.
GSK2982772 plasma concentrations will be summarised descriptively by day and 
nominal sampling time.  
Further details regarding the statistical analysis will be outlined in the Reporting and 
Analysis Plan (RAP).
9.4.3.1.
Exploratory Analyses
All exploratory endpoints will be descriptively summarized, graphically presented and 
listed appropriately.  Further details can be found 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.


2015N251670_00
CONFIDENTIAL
203168
63
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
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.

Obtaining signed informed consent

Investigator reporting requirements (e.g., reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study.

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK 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 CRF will
serve as the source document.
GSK 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.


2015N251670_00
CONFIDENTIAL
203168
64

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 
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 monitor will 
conduct site closure activities with the Investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures (SOP).

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 


2015N251670_00
CONFIDENTIAL
203168
65
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The Investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the Investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the Investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements. 

The Investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the Investigator is no longer associated with
the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the clinical study report.  The Investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the Investigator with the full summary of the study results.  The 
Investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
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.


2015N251670_00
CONFIDENTIAL
203168
66
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.


2015N251670_00
CONFIDENTIAL
203168
67
11.
REFERENCES
Agarwal SK.  Biologic agents in rheumatoid arthritis:  An update for managed care 
professionals.  Journal of Managed Care Pharmacy, 2011;17(9-b):S14-8.
Berger SB, Kasparcova V, Hoffman S, Swift B, Dare L, Schaeffer M et al.  Cutting edge:  
RIP1 kinase activity is dispensable for normal development but is a key regulator of 
inflammation in SHARPIN-deficient mice.  The Journal of Immunology,
2014;192:5476-80.
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.
Choy EHS, Panayi GS.  Cytokine pathways and joint inflammation in rheumatoid 
arthritis.  The New England Journal of Medicine, 2001;344:907-916.
Dondelinger Y, Aguileta MA, Goossens V, Dubuisson C, Grootjans S, Dejardin E et al.  
RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions 
of cIAP1/2 depletion or TAK1 kinase inhibition.  Cell Death and Differentiation, 
2013;20:1381-92.
Fries JF, Spitz P, Kraines RG, Holman HR.  Measurement of patient outcomes in 
arthritis.  Arthritis Rheum 1980;23:137-45.
GlaxoSmithKline Document Number 2014N204126_01.  Investigator Brochure for 
GSK2982772.  Report Date 08-MAR-2016.
Gorin MB.  Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mo. Aspects Med. 2012; 33:467-486.
Hatcher RA, Trussell J,  Nelson AL, Cates W Jr, Stewart F, Kowal D, et al. 
Contraceptive Technology. 20th edition.  Atlanta, Georgia: Ardent Media, Inc., 2011: 50.  
Table 3 2.
Humphries F, Yang S, Wang B, Moynagh P N.  RIP kinases: key decision makers in cell 
death and innate immunity.  Cell Death & Differ, 2015;22:225-236.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D et al.  Transgenic 
mice expressing human tumour necrosis factor:  A predictive genetic model of arthritis.  
The EMBO Journal, 1991;10:4025-31.
Netter P, Bannwarth B, Royer-Morral M-J. Recent findings on the pharmacokinetics of 
non steroidal anti-inflammatory drugs in synovial fluid. Clin Pharmaokinet, 
1989;17(3):145-162.


2015N251670_00
CONFIDENTIAL
203168
68
Ofengeim D, Yuan J.  Regulation of RIP1 kinase signaling at the crossroads of 
inflammation and cell death.  Nature Reviews Molecular Cell Biology, 2013;14:727-36.
Raghav SK, Gupta B, Agrawal C, Chaturvedi VP, and Das HR. Expression of TNF-alpha 
and related signaling molecules in the peripheral blood mononuclear cells of rheumatoid 
arthritis patients.  Mediators Inflamm. 2006(3):12682.
Vasanthi P, Nalini G, Rajasekhar G. Role of tumor necrosis factor-alpha in rheumatoid
arthritis: a review. Journal of Rheumatology, 2007; 10:270–274.
Wang L, Du F, Wang X. TNF-alpha induces two distinct caspase-8 activation pathways. 
Cell, 2008; 133(4):693-703.


2015N251670_00
CONFIDENTIAL
203168
69
12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
ACR
American College of Rheumatology
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
AMD
Age-related macular degeneration
Anti-dsDNA
Anti-double stranded deoxyribose nucleic acid
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
BID
Twice a day
CI
Confidence Interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration 
equation
Cmax
Maximum observed concentration
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CRF 
Case Report Form
CRP
C-Reactive Protein
C-SSRS
Columbia Suicide Severity Rating Scale
CV
Cardiovascular
CYP
Cytochrome P
DAS
Disease Activity Score
DAS28
Disease activity score for 28 different joints
DAS28(CRP)
Disease activity score for 28 different joints with CRP value
DCE
Dynamic contrast enhanced
DNA
Deoxyribose Nucleic Acid
DMARD
Disease-Modifying Antirheumatic Drugs
DRC
Data Review Committee
ECG
Electrocardiogram
EDL
Early Development Lead
EMA
European Medicines Agency
ETCO2
End-tidal Carbon Dioxide
EULAR
European League Against Rheumatism
FACIT-Fatigue
Functional Assessment of Chronic Illness Therapy-Fatigue
FDA
Food and Drug Administration
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
FTiH
First Time in Human
GCP
Good Clinical Practice
Gd
Gadolinium
GEE
Generalised Estimating Equations
GFR
Glomerular Filtrate Rate


2015N251670_00
CONFIDENTIAL
203168
70
GSK
GlaxoSmithKline
HAQ-DI
Disability Index of the Healthy Assessment Questionnaire
HBcAb
Hepatitis B Core Antibody
HBsAg
Hepatitis B Surface Antigen
HIV
Human Immunodeficiency Virus
HRT
Hormone Replacement Therapy
IB
Investigator Brochure
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IL
Interleukin
IP
Investigational Product
IRB
Institutional Review Board
IRE
Initial rate of enhancement
IRTS
Interactive Response Technology System
Kg
Kilogram
L
Litre
MCH
Mean corpuscular haemoglobin
MCHC
Mean corpuscular haemoglobin concentration
ME
Maximal signal intensity enhancement
MedDRA
Medical Dictionary for Regulatory Activity
mg
Milligram
mL
Millilitre
MLKL
Mixed lineage kinase domain-like protein
mm
Millimeter
mmol
Millimole
MMP
Matrix metallopproteinase
MMRM
Mixed-effect Model Repeat Measurements
MRI
Magnetic Resonance Imaging
msec
millisecond
MRP
Myeloid-related Protein
MSDS
Material Safety Data Sheet
MTX
Methotrexate
NF-B
Nuclear factor kappa-light-chain-enhancer of activated B 
cells
NHS
National Health Service
NOAEL
No Adverse Effect Level
NONMEM
Non Linear Mixed Effect Model
NRS
Numeric Rating Scale
NSAID
Non-steroidal anti-inflammatory drug
NSF
Nephrogenic Systemic Fibrosis
OMERACT
Outcome Measures in Rheumatology
PBMC
Peripheral blood mononuclear cell
PCR
Polymerase Chain Reaction
PD
Pharmacodynamic
PGA
Physician’s Global Assessment of Disease


2015N251670_00
CONFIDENTIAL
203168
71
PGx
Pharmacogenetics
PK
Pharmacokinetic
PPD
Tuberculin Purified Protein Derivative
PRO
Patient Reported Outcome
PSRAE
Possible Suicidality Related Adverse Event
PtGA
Patient Global Assessment of Disease
PTS IVIVT
Platform Technologies and Science In vivo In vitro 
Technology
QTc
Electrocardiogram QT interval corrected for heart rate
QTcB
Electrocardiogram QT interval corrected for heart rate using 
Bazett’s formula
QTcF
Electrocardiogram QT interval corrected for heart rate using 
Fridericia’s formula
RA
Rheumatoid Arthritis
R&D
Research and Development
RAP
Reporting and Analysis Plan
RAMRIQ
Rheumatoid arthritis MRI quantitative
RAMRIS
Rheumatoid arthritis MRI scoring system
RBC
Red Blood Cell
RF
Rheumatoid factor
RIP1
Receptor-interacting protein-1
RIP3
Receptor-interacting protein-3
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SIB
Suicidal Ideation Behaviour
SOP
Standard Operating Procedure
SpO2
Peripheral Capillary Oxygen Saturation
SRM
Study Reference Manual
SRT
Safety Review Team
TB
Tuberculosis
TEAR
Target Engagement Assay RIP1
TIMP
Tissue inhibitor of metalloproteinases
TLR
Toll-like receptor
TNF
Tumor necrosis factor
TTS
Technical Terms of Supply
UK
United Kingdom
ULN
Upper Limit of Normal
VAS
Visual Analogue Scale
VEGF
Vascular endothelial growth factor


2015N251670_00
CONFIDENTIAL
203168
72
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
QuantiFERON
Sugita
Vectra DA


2015N251670_00
CONFIDENTIAL
203168
73
12.2.
Appendix 2: Liver Safety Required Actions and 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).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
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, permanently discontinue study 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 2 days after 
last dose5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 


2015N251670_00
CONFIDENTIAL
203168
74
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
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]). NOTE: not 
required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes:Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the laboratory manual.  


2015N251670_00
CONFIDENTIAL
203168
75
12.3.
Appendix 3:  Prednisolone Equivalent Dose Table
Drug Name
Dose Equivalent to 1 mg Oral Prednisone
Cortisone acetate
Hydrocortisone
Prednisolone
Methylprednisolone
Triamcinolone
Dexamethasone
5 mg
4 mg
1 mg
0.8 mg
0.8 mg
0.15 mg


2015N251670_00
CONFIDENTIAL
203168
76
12.4.
Appendix 4- Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including GSK2982772 or any concomitant medicines;

Rheumatoid arthritis susceptibility, severity, and progression and related 
conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.


2015N251670_00
CONFIDENTIAL
203168
77
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at the baseline visit, after the subject has been 
randomized and provided informed consent for genetic research. Instructions for 
collection and shipping of the genetic sample are described in the laboratory
manual. The DNA from the blood sample may undergo quality control analyses to 
confirm the integrity of the sample. If there are concerns regarding the quality of 
the sample, then the sample may be destroyed. The blood sample is taken on a 
single occasion unless a duplicate sample is required due to an inability to utilize 
the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the Investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
The need to conduct PGx analysis may be identified after a study (or set of studies) of 
GSK2982772 has been completed and the study data reviewed. In some cases, the 
samples may not be studied.
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained.


2015N251670_00
CONFIDENTIAL
203168
78

Discontinue participation in the genetic research and destroy the genetic DNA 
sample.
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the Investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analysed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analysed, it will not be analysed or used for future research.  

Genetic data that has been analysed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the Investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.


2015N251670_00
CONFIDENTIAL
203168
79
12.5.
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.5.1.
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.

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.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes 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 


2015N251670_00
CONFIDENTIAL
203168
80
Investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 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.
12.5.2.
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:
a. Results in death
b.
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.
c.
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.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 


2015N251670_00
CONFIDENTIAL
203168
81
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
e.
Is a congenital anomaly/birth defect
f.
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
g.
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.

Refer to Appendix 2 for the required liver chemistry follow-up instructions
12.5.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias


2015N251670_00
CONFIDENTIAL
203168
82

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.5.4.
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.

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 PRO questionnaires and the collection of AE data are 
independent components of the study.

Responses to each question in the PRO 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.


2015N251670_00
CONFIDENTIAL
203168
83
12.5.5.
Evaluating AEs and SAEs
Assessment of Intensity
The Investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The Investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The Investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The Investigator will also consult the 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.


2015N251670_00
CONFIDENTIAL
203168
84
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.
12.5.6.
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 Medical Monitor.

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 or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


2015N251670_00
CONFIDENTIAL
203168
85
12.6.
Appendix 6: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.6.1.
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 or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1. Contraceptive subdermal implant
2. Intrauterine device or intrauterine system
3. Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]
4. Injectable progestogen [Hatcher, 2011]
5. Contraceptive vaginal ring [Hatcher, 2011]
6. Percutaneous contraceptive patches [Hatcher, 2011]
7. Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or 
semen analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The Investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception
Contraceptive requirements for male subjects with female partners of reproductive 
potential (when applicable).
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 90 days after the last dose of study medication.
1.
Vasectomy with documentation of azoospermia. The documentation on male sterility 
can come from the site personnel’s: review of subject’s medical records, medical 
examination and/or semen analysis, or medical history interview.
2.
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:

Contraceptive subdermal implant

Intrauterine device or intrauterine system


2015N251670_00
CONFIDENTIAL
203168
86

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The Investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.6.2.
Collection of Pregnancy Information

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 or be withdrawn from the study

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study and up to 
90 days after the last dose of study medication.  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.


2015N251670_00
CONFIDENTIAL
203168
87

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.

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
203168
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for A multicentre, randomised, 
double-blind (sponsor-unblinded), placebo-controlled study 
to investigate the safety and tolerability, pharmacokinetics, 
pharmacodynamics, and efficacy of GSK2982772 in subjects 
with moderate to severe rheumatoid arthritis.
Compound Number 
:
GSK2982772
Effective Date 
:
17-DEC-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 2015N251670_03 and 2015
2015N251670_04 in Germany.

This RAP is intended to describe the safety, tolerability, PK, PD, and efficacy 
analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.


CONFIDENTIAL
203168
2
Author(s)
Author
Lead
Statistics Leader (Biostatistics)
Co-author
Principal Statistician (Biostatistics)
RAP Team Review Confirmation 
(Method: E-mail)
Reviewer 
Date
04- DEC-2018
Principal Programmer/Analyst (Clinical Programming)
11- DEC-2018
Director (CPMS)
Clinical Development Director (R&D Immuno-Inflammation)
06-DEC-2018
Clinical Statistics & Clinical Programming Line Approvals 
(Method: Pharma TMF eSignature)
Approver
Date
17-DEC-2018
Senior Statistics Director (Biostatistics)
17-DEC-2018
Programming Manager (Clinical Programming)
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
203168
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ..............................................................................................10
2.4.
Statistical Hypotheses / Statistical Analyses ...............................................10
3.
PLANNED ANALYSES ..........................................................................................11
3.1.
Interim Analyses .........................................................................................11
3.2.
Final Analyses ............................................................................................11
4.
ANALYSIS POPULATIONS ...................................................................................11
4.1.
Protocol Deviations.....................................................................................12
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................13
5.1.
Study Treatment & Sub-group Display Descriptors.....................................13
5.2.
Baseline Definitions ....................................................................................13
5.2.1.
Derivations and Handling of Missing Baseline Data.....................15
5.3.
Multicentre Studies .....................................................................................15
5.4.
Examination of Covariates, Other Strata and Subgroups............................15
5.4.1.
Covariates and Other Strata ........................................................15
5.4.2.
Examination of Subgroups...........................................................15
5.5.
Multiple Comparisons and Multiplicity .........................................................15
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................15
6.
STUDY POPULATION ANALYSES .......................................................................16
6.1.
Overview of Planned Study Population Analyses........................................16
7.
SAFETY ANALYSES .............................................................................................16
7.1.
Adverse Events Analyses ...........................................................................16
7.2.
Clinical Laboratory Analyses.......................................................................16
7.3.
Other Safety Analyses ................................................................................16
7.4.
Cardiovascular Events................................................................................16
8.
EFFICACY ANALYSES..........................................................................................17
8.1.
Efficacy Endpoints ......................................................................................17
8.1.1.
Population of Interest...................................................................18
8.1.2.
Statistical Analyses / Methods .....................................................18
8.1.2.1.
Statistical Methodology Specification..........................18
8.2.
Exploratory Posterior Probabilities ..............................................................19
9.
PHARMACOKINETIC ANALYSES.........................................................................20
9.1.
Primary Pharmacokinetic Analyses.............................................................20
9.1.1.
Endpoint / Variables.....................................................................20
9.1.1.1.
Drug Concentration Measures....................................20


CONFIDENTIAL
203168
4
9.1.2.
Population of Interest...................................................................20
9.2.
Population PK Analyses..............................................................................20
9.3.
PK/PD.........................................................................................................20
10. BIOMARKER ANALYSES......................................................................................21
10.1.
Biomarker ...................................................................................................21
10.1.1.
Endpoint / Variables.....................................................................21
10.1.2.
Population of Interest...................................................................21
10.1.3.
Statistical Analyses / Methods .....................................................21
10.1.3.1.
Statistical Methodology Specification..........................21
10.2.
Target Engagement....................................................................................23
10.2.1.
Endpoint / Variables.....................................................................23
10.2.2.
Population of Interest...................................................................23
10.2.3.
Statistical Analyses / Methods .....................................................23
10.2.3.1.
Statistical Methodology Specification..........................23
10.3.
Transcriptomics Analyses- mRNA from Blood ............................................24
10.3.1.
Endpoint / Variables.....................................................................25
10.3.2.
Population of Interest...................................................................25
10.3.3.
Statistical Analyses / Methods .....................................................25
10.3.3.1.
Fold Change Analysis.................................................26
10.3.3.2.
Microarray: Percentage inhibition ...............................27
11. REFERENCES.......................................................................................................28
12. APPENDICES........................................................................................................29
12.1.
Appendix 1: Protocol Deviation Management and Definitions for Per
Protocol Population.....................................................................................29
12.1.1.
Exclusions from Per Protocol Population .....................................29
12.2.
Appendix 2: Schedule of Activities ..............................................................30
12.2.1.
Protocol Defined Schedule of Events...........................................30
12.3.
Appendix 3: Assessment Windows .............................................................34
12.3.1.
Definitions of Assessment Windows for Analyses........................34
12.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................35
12.4.1.
Study Phases ..............................................................................35
12.4.1.1.
Study Phases for Concomitant Medication .................35
12.4.2.
Treatment Emergent Flag for Adverse Events .............................36
Treatment States for AE Data......................................................36
12.5.
Appendix 5: Data Display Standards & Handling Conventions....................36
12.5.1.
Reporting Process .......................................................................36
12.5.2.
Reporting Standards....................................................................36
12.5.3.
Reporting Standards for Pharmacokinetic....................................38
12.6.
Appendix 6: Derived and Transformed Data ...............................................39
12.6.1.
General........................................................................................39
12.6.2.
Study Population..........................................................................39
12.6.3.
Efficacy........................................................................................40
12.6.3.1.
HAQ-DI.......................................................................40
12.6.3.2.
Patient Global Assessment.........................................42
12.6.3.3.
Physician Global Assessment (PGA)..........................42
12.6.3.4.
Disease Activity Score (DAS28): ................................42
12.6.3.5.
ACR Response Rates ................................................43
12.6.3.6.
Swollen and Tender/Painful Joint Count.....................44


CONFIDENTIAL
203168
5
12.6.3.7.
FACIT-Fatigue............................................................45
12.6.3.8.
DCE-MRI....................................................................45
12.6.3.9.
CDAI and SDAI ..........................................................46
12.6.4.
Safety ..........................................................................................46
12.6.5.
Biomarker ....................................................................................47
12.6.6.
PK................................................................................................47
12.7.
Appendix 7: Reporting Standards for Missing Data.....................................49
12.7.1.
Premature Withdrawals................................................................49
12.7.2.
Handling of Missing Data.............................................................49
12.7.2.1.
Handling of Missing and Partial Dates ........................49
12.8.
Appendix 8: Values of Potential Clinical Importance ...................................50
12.8.1.
Laboratory Values........................................................................50
12.8.2.
ECG.............................................................................................51
12.8.3.
Vital Signs....................................................................................51
12.9.
Appendix 11: Abbreviations & Trade Marks ................................................52
12.9.1.
Abbreviations...............................................................................52
12.9.2.
Trademarks .................................................................................54
12.10. Appendix 12: List of Data Displays..............................................................55
12.10.1. Data Display Numbering..............................................................55
12.10.2. Mock Example Shell Referencing ................................................55
12.10.3. Deliverables.................................................................................55
12.10.4. Study Population Tables..............................................................56
12.10.5. Efficacy Tables ............................................................................59
12.10.6. Efficacy Figures ...........................................................................65
12.10.7. Safety Tables...............................................................................68
12.10.8. Safety Figures .............................................................................71
12.10.9. Pharmacokinetic Tables...............................................................71
12.10.10.Pharmacokinetic Figures .............................................................72
12.10.11.Pharmacokinetic/Pharmacodynamic Figures ...............................74
12.10.12.Biomarker Tables.........................................................................75
12.10.13.Biomarker Figures .......................................................................77
12.10.14.ICH Listings .................................................................................79
12.10.15.Non-ICH Listings..........................................................................83
12.11. Appendix 13: Example Mock Shells for Data Displays ................................86


CONFIDENTIAL
203168
6
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol:
Revision Chronology:
2015N251670_00
01-APR-2016
Original
2015N251670_01
25-MAY-2016
Protocol Amendment 1 incorporates the addition of risk 
text for drug interaction with Pglycoprotein (Pgp) 
inhibitors and narrow therapeutic index (NTI) CYP3A4 
substrates, an updated list of prohibited medications 
plus some minor protocol clarifications and 
administrative changes.
2015N251670_02
14-JUL-2016
Protocol Amendment 02 incorporates the addition of 
suicidal ideation and behaviour (SIB) withdrawal criteria 
plus other minor protocol clarifications and 
administrative changes.
2015N251670_03
20-APR-2017
Protocol Amendment 03 incorporates the change in 
dosing regimen from 60 mg BID to 60 mg TID, 
restrictions on JAK inhibitors, defined non-reproductive 
potential criteria in Exclusion 11, change to clinical 
laboratory criteria in Exclusion 23, change in 
Haematologic Stopping Criteria in Section 5.4.5, 
addition of evaluation of joint space narrowing with MRI, 
flexibility in scheduling with MRI and synovial biopsy, 
some minor protocol clarifications and administrative 
changes.
2015N251670_04
03-AUG-2017
Protocol Amendment 04 incorporates a country specific 
amendment for Germany which reinstates the clinical 
laboratory criteria in Exclusion 23 and Haematologic 
Stopping Criteria in Section 5.4.5 that was changed in 
Amendment 03.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
A formal interim analysis will 
be conducted during the study. 
The timing of this analysis will 
either be on the 
recommendation of the data 
review group to assess futility 
A formal interim analysis will no 
longer be conducted based on 
review of recruitment 
information and 
recommendation by the DRC
Quick recruitment towards the 
end of the study meant that 
timelines for the interim analysis 
would occur after all subjects 
had completed the treatment 
phase of the study, therefore 
leaving no ability to stop the 


CONFIDENTIAL
203168
7
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
based on 6 weeks of treatment, 
or when an appropriate 
number have completed 12 
weeks of treatment, whichever 
is earliest.  The purpose of the 
Interim Analysis would be to 
assess whether to stop the 
study for futility.  This interim 
analysis may also facilitate 
decision making regarding the 
subsequent clinical 
development of GSK2982772 
for RA. 
study for futility
Exploratory endpoint defined 
as change from baseline in RA 
symptom questionnaire score
An overall score will not be 
provided due no available rules 
for how to combine these 
questions together, instead 
each item will be summarised 
separately
Development of the 
questionnaire still in progress 
and no scoring system currently 
in place. Therefore no overall 
questionnaire score can be 
calculated.
Exploratory endpoints: 
Inflammatory biomarkers, 
pathway engagement and 
mRNA in synovial tissue. 
These endpoints will not be 
analysed due to very small 
sample size and therefore lack 
of sufficient data to enable 
statistical analysis to be 
conducted. 
Uptake from subjects in the 
study to provide the optional 
synovial tissue samples was 
very limited. Only 5 subjects 
consented with only three of 
these providing a baseline and 
end of treatment sample. The 
decision therefore was made by 
the team not to perform the lab 
analysis of these samples, 
therefore planned analysis 
cannot be conducted. Synovial 
tissue samples will still be used 
to explore PK concentration and 
Target engagement
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To investigate the safety and 
tolerability of 60 mg three times 
daily doses of GSK2982772 in 
subjects with moderate to severe 
Rheumatoid Arthritis.

Adverse events.

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis).

Vital sign measurements (blood pressure, heart rate, 
respiratory rate, and body temperature).

12-Lead ECG monitoring.


CONFIDENTIAL
203168
8
Objectives
Endpoints
Secondary Objectives
Secondary Endpoints

To investigate the plasma 
concentrations of GSK2982772 
following 60 mg three times daily 
doses of GSK2982772 in subjects 
with moderate to severe
Rheumatoid Arthritis.

Pre-dose concentrations of GSK2982772 on Days 
8, and 43 (Week 6).  

Post-dose concentrations of GSK2982772 on Days 
1, 8, and 43 (Week 6) at 1, 2, 4 and 6 hours.

Trough concentrations on Day 85 (Week 12).

To investigate the effect of 60 mg 
three times daily doses of 
GSK2982772 on inflammatory 
biomarkers in blood subjects with 
moderate to severe Rheumatoid 
Arthritis.

Change from baseline in blood inflammatory markers 
(e.g., may include but not limited to CRP, IL6, MMP-
1, MMP-3, MMP-13, TIMP-1, MCP-1, MIF, MRP8/14 
and other markers encompassed by Vectra DA).

To investigate the effect of 60 mg 
three times daily doses of 
GSK2982772 on bone and 
synovial parameters as measured 
by MRI and DCE-MRI in subjects 
with moderate to severe 
Rheumatoid Arthritis.

Change from baseline in MRI parameters in the 
most affected hand/wrist.  MRI parameters may 
include assessment of bone erosions, synovitis, 
bone oedema and joint space narrowing as 
assessed in the OMERACT-RAMRIS (Outcome 
Measures in Rheumatology, Rheumatoid Arthritis 
Magnetic Resonance Image Scoring System) 
scoring system, the RAMRIQ (rheumatoid arthritis 
MRI quantitative) scoring system, the modified 
CARLOS (Cartilage Loss Scoring System) and 
additional exploratory endpoints as data permit.
Change from baseline in synovial inflammation as 
measured by dynamic contrast enhanced (DCE)-MRI 
in the most affected hand/wrist:

Exchange rate (Ktrans)

Interstitial volume (Ve)

Plasma volume (Vp)

Initial rate of enhancement (IRE)

Maximal signal intensity enhancement (ME)

Joint volume

Enhancing volume

To investigate the effect of 60 mg 
three times daily doses of 
GSK2982772 on clinical disease 
activity in subjects with moderate 
to severe Rheumatoid Arthritis.

Change from baseline in Disease Activity Score 
(DAS) 28-CRP scores.

Proportion of subjects achieving categorical DAS28-
CRP response (moderate/good EULAR response) 
at each assessment time points.

Proportion of subjects achieving categorical 
ACR20/50/70 response.

To investigate the effect of 60 mg 
three times daily dosing of 
GSK2982772 on methotrexate 
(MTX) concentrations 

Plasma concentrations of MTX pre-dose 
GSK2982772 on Days 1, 8, and 43 (Week 6).


CONFIDENTIAL
203168
9
Objectives
Endpoints
Exploratory Objectives
Exploratory Endpoints

To investigate the effect of 60 mg 
three times daily doses of 
GSK2982772 on inflammatory 
biomarkers in synovial tissue in 
subjects with moderate to severe 
Rheumatoid Arthritis.

Change from baseline in CD68+ macrophages, 
CD55+ fibroblast-like synoviocytes and a number of 
infiltrating CD3, CD22, CD138 inflammatory cells, 
and synovial inflammatory biomarkers including, but 
not limited to VEGF, IL-1β, IL-6, TNFα, and MMP-1.

To investigate pathway and target 
engagement following 60 mg three 
times daily doses of GSK2982772 
in blood and synovial tissue in 
subjects with moderate to severe 
Rheumatoid Arthritis.

Pharmacology biomarker endpoints may include, 
but are not limited to the following, pre-dose at Days 
1, 43 (Week 6) and trough on Day 85 (Week 12), as 
applicable and if evaluable samples and data 
permit:
Target Engagement Assay RIP1 (TEAR1) in 
blood and synovial tissue.

Total or phosphorylated RIP1, MLKL, and RIP3, 
cleaved and total caspase 3 and caspase 8 
signatures in synovial tissue.

To investigate the concentration of 
GSK2982772 and possible drug-
related material, as well as specific 
distribution within tissue if feasible, 
in the synovial tissue after 60 mg 
three times daily doses of 
GSK2982772.

Pre-dose GSK2982772 synovial tissue biopsies and 
possible drug-related material concentrations, as 
well as specific distribution within tissue  if feasible, 
on Day 43 (Week 6), as evaluable samples and data 
permit

To investigate the effect of 60 mg 
three times daily doses of 
GSK2982772 on the quality of life 
of subjects with moderate to 
severe Rheumatoid Arthritis.

Change from baseline in Health Assessment 
Questionnaire Disability Index (HAQ-DI).

Change from baseline in RA symptom questionnaire 
score.

Change from baseline in Functional Assessment of 
Chronic Illness Therapy (FACIT)-Fatigue.

To investigate the effect of 60 
mg three times daily doses of 
GSK2982772 on gene 
expression in the blood of 
subjects with moderate to 
severe Rheumatoid Arthritis.

Transcriptomic analysis of mRNA isolated 
from blood pre-dose on Days 1 and 43 
(Week 6) and trough on Day 85 (Week 12).

To investigate the effect of 60 
mg three times daily doses of 
GSK2982772 on gene 
expression in synovium of 
subjects with moderate to 
severe Rheumatoid Arthritis.

Transcriptomic analysis of mRNA isolated 
from synovial tissue pre-dose on Days 1 
and 43 (Week 6).


CONFIDENTIAL
203168
10
2.3.
Study Design
Overview of Study Design and Key Features
Key assessments:
Safety assessments, PK samples, DAS28, ACR20/50/70, 
FACIT-fatigue, Rheumatoid Arthritis Symptom Questionnaire
Score, HAQ-DI assessments, MRI, PD samples
Design Features
This is a multicentre, randomised, double-blind (sponsor-unblinded), placebo-controlled 
study to investigate the safety and tolerability, PK, PD, and preliminary efficacy of 
GSK2982772 in subjects with moderate to severe RA.
Dosing

60mg GSK2982772 three times daily or placebo. Prior to protocol amendment 3 
this was twice daily dosing.
Time & Events

[Refer to Appendix 2: Schedule of Activities]
Treatment 
Assignment

Subjects will be randomised across the two treatment arms, to receive 
either GSK2982772 or placebo in a 2:1 ratio.

8 of the subjects were randomised to the BID dosing, all others randomised 
to TID 
Interim Analysis

Blinded safety, clinical and adverse event data will be reviewed at 
appropriate intervals by the GSK Safety Review Team (SRT).

Once an appropriate number of subjects have completed Day 43 (Week 6) 
the DAS28-CRP data will be reviewed in an unblinded manner and on an 
ongoing basis by the Data Review Committee. Additional inflammatory 
biomarkers, clinical and mechanistic endpoints (e.g. target engagement) 
may be reviewed if available.

No formal interim analysis will be conducted
2.4.
Statistical Hypotheses / Statistical Analyses
The primary objective of the study is to investigate the safety and tolerability of 
GSK2982772 following 12 weeks of treatment. No formal statistical hypotheses will be 
conducted to assess this objective.
If appropriate, comparisons between the GSK2982772 and the placebo arm will be made 
to investigate the secondary pharmacodynamic, mechanistic and efficacy objectives. 
Trends over time will be investigated for both treatment arms along with associations 
between each of the pharmacodynamic, mechanistic and efficacy parameters.


CONFIDENTIAL
203168
11
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No formal interim analysis will be conducted. Details of decision to not conduct the 
planned interim analysis provided in Section 2.1.
Unblinded biomarker, efficacy and pharmacodynamic analyses will be conducted and 
delivered to the data review committee (DRC) according to the DRC charter. Safety will 
also be evaluated in the context of the pharmacodynamic, biomarkers and efficacy 
observed. 
3.2.
Final Analyses
The final planned primary 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 (DBR) and database freeze (DBF) has been declared by Data Management.
3.
All criteria for unblinding the randomization codes have been met. 
4.
Randomization codes have been distributed according to RandAll NG procedures.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Subjects

Comprises of all subjects who were screened for 
the study

Selected 
Accountability 
data
Randomised

Comprises of all subjects who were randomised

All listings unless 
specified
Safety

Comprise of all subjects who receive at least one 
dose of study treatment.

This population will be based on the treatment the 
subject was randomised to.

Demography

Safety

Efficacy

Exploratory

Biomarker
Pharmacokinetic
GSK298772 
(PK772)

Subjects in the ‘Safety’ population who received 
an active dose and for whom a GSK2982772 
pharmacokinetic sample was obtained and 
analysed.

GSK2982772 PK
Pharmacokinetic 
Methotrexate 
(PKMeth)

Subjects in the ‘Safety’ population who received 
an active dose and for whom a Methotrexate 
pharmacokinetic sample was obtained and 
analysed.

Methotrexate PK
Per-Protocol (PP)

Subjects in the ‘Safety’ population with those who 
had an important deviation with potential to 

DAS28-CRP


CONFIDENTIAL
203168
12
Population
Definition / Criteria
Analyses Evaluated
impact the analysis excluded. Please see Section 
12.1.1 for definition of deviations that lead to 
exclusion from this population.
PP completers

All subjects in the PP population who also 
complete the study. [1]

DAS28-CRP
Refer to Appendix 12: List of Data Displays which details the population used for each display.
[1] Completion of the study as defined from the eCRF study conclusion page. 
Note: “Subjects” is used to refer to “Participants” in all data displays to reflect GSK Display Standards and CDISC 
SDTM/ADaM standards
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.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan [02OCT18 and Version 3].
o Data will be reviewed prior to freezing the database to ensure all important are 
captured and categorised on the protocol deviations dataset. This dataset will also 
be reviewed to ensure exclusions from any populations are documented 
appropriately.
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.


CONFIDENTIAL
203168
13
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
[RandAll NG / FSO Randomization 
System]
Data Displays for Reporting 
Code
Description
Description in 
tables/figures
(TRTGRP)
Order in 
TF 
Description in Listings
(ATRTGRP)
Order 
in 
Outputs
A
GSK2982772 BID 60 
mg
GSK2982772 60mg
2
GSK2982772 60mg 
BID
3
C
GSK2982772 60mg 
TID
GSK2982772 60mg
2
GSK2982772 60mg 
TID
4
P
Placebo
Placebo
1
Placebo BID
1
Q
Placebo TID
Placebo
1
Placebo TID
2
Treatment comparisons will be displayed as follows using the descriptors as specified:
1.
GSK2982772 60mg vs Placebo
If a subject is found to have received incorrect medication at all during their study 
duration all of their data will be analysed/summarised according to the treatment group,
they were randomised to. A listing of planned and actual treatments will be provided 
identifying any subjects who did indeed receive incorrect medication.
A couple of the key efficacy endpoints will be summarised separately for the BID and 
TID treatment regimens, details are provided in Appendix 12: List of Data Displays.
5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment. 
Parameter
Study Assessments Considered As 
Baseline
Baseline Used in 
Data Display
Screening
Day 1 (Pre-Dose)
Safety 
Vital Signs[1,2]
X
X
Day 1 (Pre-Dose)
12-Lead ECG[2]
X[3]
X
Day 1 (Pre-Dose)
Clinical Laboratory 
Values[2,4]
X
X
Day 1 (Pre-Dose)
Columbia Suicide 
Severity Rating Scale (C-
SSRS)
X
X
Day 1 (Pre-Dose)


CONFIDENTIAL
203168
14
Parameter
Study Assessments Considered As 
Baseline
Baseline Used in 
Data Display
Screening
Day 1 (Pre-Dose)
Secondary
Plasma concentrations of 
GSK2982772/MTX
X
Day 1 (Pre-Dose)
Inflammatory Biomarkers 
in Blood
X
Day 1 (Pre-Dose)
MRI/DCE-MRI
X
Day 1 (Pre-Dose)
DAS28(CRP)
X
Day 1 (Pre-Dose)
ACR20/50/70
X
Day 1 (Pre-Dose)
Exploratory
Pharmacology 
Biomarkers in Blood 
X
Day 1 (Pre-Dose)
Concentration of 
GSK2982772 and 
Possible Drug-Related 
Material in the Synovial 
Tissue 
X
Day 1 (Pre-Dose)
HAQ-DI
X
Day 1 (Pre-Dose)
RA Symptom 
Questionnaire
X
Day 1 (Pre-Dose)
(FACIT)-Fatigue
X
Day 1 (Pre-Dose)
Physician Global 
Assessment
X
Day 1 (Pre-Dose)
Patient Global 
Assessment
X
Day 1 (Pre-Dose)
mRNA in Blood
X
Day 1 (Pre-Dose)
NOTES:

Unless otherwise stated, the mean of replicate assessments at any given time point will be used as the value for 
that time point.

[1] Vital sign measurements include Blood Pressure, Heart Rate, Respiratory Rate, and Body Temperature.

[2] Where both screening and pre-dose are available, the value closest to first dose will be used.

[3] ECG recordings will be performed in triplicate at screening. Use the mean of the triplicate measurements.

[4] Clinical Laboratory measurements include Clinical Chemistry, Haematology and Urinalysis.

For Safety Data, If Day 1 pre-dose is missing then Screening will be used as baseline

For Safety Data, If Day 1 is Post Dose, Screening will be used as baseline


CONFIDENTIAL
203168
15
5.2.1.
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 5.2 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.
5.3.
Multicentre Studies
There are no planned adjustments for multiple centres or regions due to the size of the 
study. For all analyses all sites, countries and regions will be pooled.
5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata
Category
Details
Strata
Not applicable for this study
Covariates
Baseline measure will be included as a covariate
5.4.2.
Examination of Subgroups
There are no planned subgroup analyses to be conducted on this study.
5.5.
Multiple Comparisons and Multiplicity
Unless specified no adjustments will be made for multiple comparisons or multiplicity.
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
12.3
Appendix 3: Assessment Windows
12.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
12.5
Appendix 5: Data Display Standards & Handling Conventions
12.6
Appendix 6: Derived and Transformed Data
12.7
Appendix 7: Reporting Standards for Missing Data
12.8
Appendix 8: Values of Potential Clinical Importance


CONFIDENTIAL
203168
16
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the Safety population, unless otherwise 
specified.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 12: List of Data Displays.
Note: “Subjects” is used to refer to “Participants” in all data displays to reflect GSK 
Display Standards and CDISC SDTM/ADaM standards
7.
SAFETY ANALYSES
The safety analyses will be based on the safety population, unless otherwise specified.
7.1.
Adverse Events Analyses
Adverse event analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 12: List of Data Displays.
7.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 12: List of Data Displays.
7.3.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 12: List of Data Displays.
7.4.
Cardiovascular Events
If any of the following events are recorded in the eCRF as a CV event during the study 
further patient profiles will be generated according to IDSL and provided to the GCSP 
department: Arrhythmias, Congestive heart failure, Cerebrovascular events/stroke and 
Transient ischemic attack (TIA), Deep vein thrombosis (DVT)/Pulmonary embolism 
(PE), Myocardial Infarction/Unstable Angina, Peripheral arterial thromboembolism, 
Pulmonary Hypertension, Revascularisation, Valvulopathy.


CONFIDENTIAL
203168
17
8.
EFFICACY ANALYSES
8.1.
Efficacy Endpoints
Table 2
Overview of Planned Efficacy Analyses
Endpoint 
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
FACIT-Fatigue
Y
Y
Y
Y
Y
Y
HAQ-DI
Y
Y
Y
Y
Y
Y
Patient Global 
assessment
Y
Y
Y
Y
Y
Y
Physician Global 
Assessment
Y
Y
Y
Y
Y
Y
DAS28-CRP
Y
Y
Y
Y
Y
Y
DAS28-CRP EULAR 
response 
Y
Y
ACR Response Rates
Y
Y
TJC28
Y
Y
Y
Y
Y
Y
SJC28
Y
Y
Y
Y
Y
Y
MRI parameters2 in 
most affected wrist
Y
Y
Y
Y
Y
Y
DCE-MRI 3
Y
Y
Y
Y
Y
Y
Patient assessment of 
joint Pain
Y
Y
Y
Y
Y
Y
RA symptom 
questionnaire 
Y
Y
CRP
Y
Y
Y
Y
Y
Y
CDAI 4
Y
Y
Y
Y
Y
Y
SDAI 4
Y
Y
Y
Y
Y
Y
1.
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 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

2: Bone erosions, synovitis, bone oedema, joint space narrowing (Based on RAMRIS/RAMRIQ and 
CARLOS)

3: Exchange rate, Interstitial volume, plasma volume, initial rate of enhancement, maximal signal intensity 
enhancement, joint volume, enhancing volume

4: Although not listed in the protocol as endpoints, these were added to aide decision making at the 
administrative review and the end of the study.


CONFIDENTIAL
203168
18
8.1.1.
Population of Interest 
The efficacy analyses will be based on the safety population, unless otherwise 
specified.
8.1.2.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: List of Data Displays 
and will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
8.1.2.1.
Statistical Methodology Specification
Statistical Analyses (cts endpoints with mmrm analysis)
Secondary/exploratory Endpoint(s)

Change from baseline (pre-dose Day 1) in FACIT-Fatigue score at Days 43 (pre-dose), and 
85.

Change from baseline (pre-dose Day 1) in HAQ-DI at days 15, 29, 43 (pre-dose), 57, 71, 85.

Change from baseline (pre-dose Day 1) in Patient Global Assessment at days 15, 29, 43 
(pre-dose), 57, 71, 85.

Change from baseline (pre-dose Day 1) in Physician Global Assessment at days 15, 29, 43 
(pre-dose), 57, 71, 85.

Change from baseline (pre-dose Day 1) in DAS28-CRP at days 15, 29, 43 (pre-dose), 57, 71, 
85.

Change from baseline (pre-dose Day 1) in TJC28 at days 15, 29, 43 (pre-dose), 57, 71, 85.

Change from baseline (pre-dose Day 1) in SJC28 at days 15, 29, 43 (pre-dose), 57, 71, 85.

Change from baseline (pre-dose Day 1) in MRI parameters based on RAMRIS at days 43 
(pre-dose) and 85.

Change from baseline (pre-dose Day 1) in MRI parameters based on RAMRIQ at days 43 
(pre-dose) and 85.

Change from baseline (pre-dose Day 1) in MRI parameters based on CARLOS at days 43 
(pre-dose) and 85.

Change from baseline (pre-dose Day 1) in MRI parameters based on DCE-MRI at days 43 
(pre-dose) and 85.

Change from baseline (pre-dose Day 1) in patient assessment of pain at days 15, 29, 43 (pre-
dose), 57, 71, 85.

Change from baseline (pre-dose Day 1) in CRP on days 15, 29, 43 (pre-dose), 57, 71, 85.

Change from baseline (pre-dose Day 1) in CDAI on days 15, 29, 43 (pre-dose), 57, 71, 85.

Change from baseline (pre-dose Day 1) in SDAI on days 15, 29, 43 (pre-dose), 57, 71, 85.
Model Specification

Endpoints will be statistically analyzed using a mixed models repeated measures (MMRM) 
approach. 

Terms fitted in the MMRM model will include:
o
Fixed Category                           : Treatment, Day, Treatment*Day


CONFIDENTIAL
203168
19
o
Fixed Continuous Covariates     : Baseline Score, baseline*Day
o
Repeated Effect                                 : Day

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 with a subject=SUBJID option.
Note: Other covariates maybe explored, if deemed appropriate for sensitivity analyses.
Model Checking & Diagnostics

For the MMRM, model assumptions will be applied, but appropriate adjustments may be 
applied based on the data.

In the unlikely circumstance that there are convergence problems with the MMRM analysis, 
this will be explored. For example the SCORING=4 option could be used in the MIXED 
statement, which makes SAS use Fisher scoring for the first 4 iterations. If the convergence 
problem cannot be resolved, the unstructured covariance matrix will be replaced by ANTE(1) 
covariance structure in combination with a random subject effect.

In the event that this model fails to converge, alternative correlation structures may be 
considered such as CSH or CS. 
Distributional assumptions underlying the model used for analysis will be examined by obtaining a 
normal probability plot of the residuals and a plot of the residuals versus the fitted values (i.e. 
checking the normality assumption and constant variance assumption of the model respectively) 
to gain confidence that the model assumptions are reasonable. 
If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data.
Model Results Presentation

LS means and corresponding standard error of means (SEs) and 95% confidence intervals 
will be presented for each treatment by time interaction, together with estimated treatment 
differences (GSK2982772 – Placebo) and the corresponding 95% confidence intervals will be 
produced.

Observed Margins will be specified to produce the LS means.

Plots of LS means and standard errors from the model will be generated over time by 
treatment. 
8.2.
Exploratory Posterior Probabilities 
Decision criteria for this study will be based on posterior probabilities of treatment 
differences (GSK2982772 vs Placebo) for the following endpoints; DAS28 (CRP), 
ACR20 and ACR50. Posterior probabilities will explore the likelihood that the treatment 
difference is greater than X based on the data observed.
A Bayesian approach will be employed to determine a 95% credible confidence interval 
and the posterior probabilities assuming a noninformative prior: Beta (1, 1) for ACR 
analyses and N [0, 1.E36).for the analysis of the DAS28-CRP. Any such analyses will be 
done by GSK II Clinical Statistics for both the administrative review and SAC.


CONFIDENTIAL
203168
20
9.
PHARMACOKINETIC ANALYSES
9.1.
Primary Pharmacokinetic Analyses
9.1.1.
Endpoint / Variables
9.1.1.1.
Drug Concentration Measures
Plasma Concentration data for GSK2982772 will be summarised and listed, no statistical 
analysis will be conducted. Summary statistics of GSK2982772 concentration by Day (1, 
8, 43 and 85) and nominal blood sampling time (pre-dose, and 1, 2, 4 and 6 hours post-
dose) will be determined. 
Plasma concentration data for methotrexate will be summarised and listed, no statistical 
analysis will be conducted.  Summary statistics of methotrexate pre-dose concentrations 
by Day (1, 8 and 43) will be determined. 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 12.5.3
Reporting Standards for Pharmacokinetic).
9.1.2.
Population of Interest 
All PK statistical displays will be based on the [“PK772”] population, unless otherwise 
specified.
9.2.
Population PK Analyses
GSK2982772 plasma concentrations from this study may be included in a cross-study 
population pharmacokinetic analysis after SAC.   To support this analysis a NONMEM 
datafile will be generated.   The details for the dataset specifications will be provided by 
CPMS after SAC, if needed.
9.3.
PK/PD
Concentration data and blood/synovial fluid target engagement will be explored 
graphically.
Concentration data will also be presented graphically against change from baseline in 
DAS28 (CRP) by visit.


CONFIDENTIAL
203168
21
10.
BIOMARKER ANALYSES
10.1.
Biomarker
10.1.1.
Endpoint / Variables
Overview of Planned Biomarker Analyses
Endpoint 
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
Secondary Biomarkers
Inflammatory 
biomarkers in blood1
Y
Y
Y
Y
Y
Y
Y
1.
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

1: Markers including CRP, CHI3L1, EGF, IL6, Leptin, MCP-1, MIF, MMP-1, MMP-3, MMP-13, Resistin, SAA,
S100A8/S100A9, TIMP-1, TNF-RI, VCAM-1, VEGFA and unadjusted Vectra DA
10.1.2.
Population of Interest
The biomarker analyses will be based on the “Safety” population, unless otherwise 
specified. 
10.1.3.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 10.1.1.will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
10.1.3.1.
Statistical Methodology Specification
Inflammatory Blood Biomarkers
Endpoint(s)
Change from baseline on log transformed inflammatory biomarkers in blood on Day 43 and 85 
pre-dose: Loge Change = Loge (Visit) – loge (Baseline)
1.
Markers: CRP, CHI3L1, EGF, IL6, Leptin, MCP-1, MIF, MMP-1, MMP-3, MMP-13, Resistin, SAA, 
S100A8/S100A9, TIMP-1, TNF-RI, VCAM-1, VEGFA and unadjusted Vectra DA
Model Specification

Endpoints will be statistically analyzed using a mixed models repeated measures (MMRM) 
approach. 


CONFIDENTIAL
203168
22

Terms fitted in the MMRM model will include:
o
Fixed Category                           : Treatment, Day, Treatment*Day
o
Fixed Continuous Covariates     : Baseline Score, baseline*Day
o
Repeated Effect                                 : Day

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 with a subject=SUBJID option.
Model Checking & Diagnostics

For the MMRM, model assumptions will be applied, but appropriate adjustments may be 
applied based on the data.

In the unlikely circumstance that there are convergence problems with the MMRM analysis, 
this will be explored. For example, the SCORING=4 option could be used in the MIXED 
statement, which makes SAS use Fisher scoring for the first 4 iterations. If the convergence 
problem cannot be resolved, the unstructured covariance matrix will be replaced by ANTE(1) 
covariance structure in combination with a random subject effect.

In the event that this model fails to converge, alternative correlation structures may be 
considered such as CSH or CS. 
Distributional assumptions underlying the model used for analysis will be examined by obtaining a 
normal probability plot of the residuals and a plot of the residuals versus the fitted values (i.e. 
checking the normality assumption and constant variance assumption of the model respectively) to 
gain confidence that the model assumptions are reasonable. 
If there are any departures from the distributional assumptions, alternative models will be explored 
using appropriate transformed data.
Presentation of results
Adjusted geometric means for each treatment group at each timepoint and associated 95% 
confidence interval will be constructed by back transforming the LS means from the model.
The treatment ratios and 95% CI will be calculated by back-transforming the difference in the 
LS means (GSK2982772 – Placebo) and associated 95% CI
Percentage change from baseline at each timepoint will be calculated using the formula:
100% x (exp(LS mean)- 1)
Plots of LS means and standard errors from the model will be generated over time by treatment.


CONFIDENTIAL
203168
23
10.2.
Target Engagement
10.2.1.
Endpoint / Variables
Table 3
Overview of Planned Target Analyses
Endpoint 
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
Target Engagement
target engagement in 
blood3
Y
Y
Y
Y
Y
Y
Y
target engagement in 
synovial tissue3
Y
1.
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

3: TEAR1 in blood and synovial tissue, Free RIP1 and Total RIP1.
1.
10.2.2.
Population of Interest
The target/pathway engagement analyses will be based on the “Safety” population, unless 
otherwise specified. 
10.2.3.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 10.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
10.2.3.1.
Statistical Methodology Specification
Target Engagement 
Endpoints

Log Ratio = Log (free TEAR1) – log (total TEAR1)
1.
Model Specification
A mixed effect model will be fitted with treatment, time (i.e. planned relative time) and 
treatment * time as a fixed effect and subject as a random effect.  Baseline log ratio will be 
fitted as a continuous covariate along with Baseline log ratio* time.
The Kenward and Roger method for approximating the denominator degrees of freedom and 


CONFIDENTIAL
203168
24
Target Engagement 
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 with a subject=SUBJID option.
Model Checking

For the MMRM, model assumptions will be applied, but appropriate adjustments may be 
applied based on the data.

In the unlikely circumstance that there are convergence problems with the MMRM analysis, 
this will be explored. For example, the SCORING=4 option could be used in the MIXED 
statement, which makes SAS use Fisher scoring for the first 4 iterations. If the convergence 
problem cannot be resolved, the unstructured covariance matrix will be replaced by ANTE(1) 
covariance structure in combination with a random subject effect.

In the event that this model fails to converge, alternative correlation structures may be 
considered such as CSH or CS. 
Distributional assumptions underlying the model used for analysis will be examined by obtaining a 
normal probability plot of the residuals and a plot of the residuals versus the fitted values (i.e. 
checking the normality assumption and constant variance assumption of the model respectively) to 
gain confidence that the model assumptions are reasonable. 
If there are any departures from the distributional assumptions, alternative models will 
be explored using appropriate transformed data.
Presentation of Results
Engagement ratio relative to baseline and associated 95% confidence interval will be calculated 
for each post-baseline timepoint, using the formula exp(ln(ratiopost/ratiobaseline) +1).
Percentage target engagement at each timepoint will be calculated from the adjusted geometric 
means using the formula (1-engagment ratio)*100%.
The treatment engagement ratios and 95% CI will be calculated by back-transforming the 
difference between the least square means and associated 95% CI
The treatment difference percentage target engagement is (1 – treatment engagement ratio) * 
100%
10.3.
Transcriptomics Analyses- mRNA from Blood
RNA will be extracted and hybridised using a balanced batch design by Epistem. 
Microarray mRNA data will be normalised using gcRMA or RMA in Array Studio v5.0 
or later. After normalisation, the data will be quality assessed and any samples deemed as 
QC fails will be excluded from any further analysis. This quality assessment will involve 
looking for outlying signals in both the normalised expression data and the MAS5 QC 
metrics generated from each sample. If any samples are excluded, the remaining data 
will be re-normalised. The output from the normalisation will be log2 transformed mRNA 
intensity data (measured in arbitrary units).
Microarray data consists of expression values (log2-transformed) derived from individual 
probesets designed against coding regions of individual genes. More than one probeset 


CONFIDENTIAL
203168
25
can exist per gene. This analysis will be conducted at the probeset level. The probeset, 
gene or gene description will be included in the outputs.
In order to identify the most robustly expressed probesets, the data can be filtered to 
remove low intensity probesets, low quality and control probe sets prior to analysis. This 
could be done simply by excluding all probesets where all observations are <6 (on the 
log2 scale). Note it has been observed empirically that when you get below 100 (6.6 on 
the log2 scale) you are into the noise of the assay. Other more stringent methods of 
filtering the data could be used. In total there are 53,617 probesets that could be analysed.  
mRNA data is available from blood samples only as described in Section 2.1. mRNA 
summaries and listings will be the responsibility of the GSK stats and programming team 
and will be delivered at an agreed date after SAC.
10.3.1.
Endpoint / Variables
Overview of Planned Biomarker Analyses
Endpoint 
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
Transcriptomics
mRNA from blood 4
Y
Y
Y
Y
Y
Y
Y
1.
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

4: Data to be provided by Epistem and analysed by the GSK stats and programming team
1.
10.3.2.
Population of Interest
The transcriptomic analyses will be based on the “Safety” population, unless otherwise 
specified. 
10.3.3.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 10.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. Note that probeset ID is required to be included in analyses and outputs if there is 
more than one probeset per gene.  


CONFIDENTIAL
203168
26
Primary Statistical Analyses
Endpoint(s)

Log2(intensity) mRNA expression of inflammatory gene transcripts 

Percentage inhibition of inflammatory gene transcripts
Model Specification

Endpoints will be statistically analyzed using a linear repeated measures mixed effects model. 

Terms fitted in the linear repeated measures mixed effects model will include:
o
Fixed Category                           : Treatment, Visit, Treatment * Visit
o
Random Effect                            : Subject
Model Checking & Diagnostics

For the MMRM, model assumptions will be applied, but appropriate adjustments may be 
applied based on the data.

In the unlikely circumstance that there are convergence problems with the MMRM analysis, 
this will be explored. For example, the SCORING=4 option could be used in the MIXED 
statement, which makes SAS use Fisher scoring for the first 4 iterations. If the convergence 
problem cannot be resolved, the unstructured covariance matrix will be replaced by ANTE(1) 
covariance structure in combination with a random subject effect.

In the event that this model fails to converge, alternative correlation structures may be 
considered such as CSH or CS. 
Distributional assumptions underlying the model used for analysis will be examined by obtaining a 
normal probability plot of the residuals and a plot of the residuals versus the fitted values (i.e. 
checking the normality assumption and constant variance assumption of the model respectively) to 
gain confidence that the model assumptions are reasonable. 
If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data.
Presentation of Results

For each probeset analysed, adjusted means with corresponding 95% CI and fold changes (for 
Log2(intensity)) or difference in LS means (for Percentage inhibition) with corresponding 95% 
CI’s can be outputted. The fold change is derived from the ratio of the back-transformed 
estimate of the difference between LS means.

Plots of LS means and standard errors from the model will be generated for each treatment by 
time.
10.3.3.1.
Fold Change Analysis
The log2 normalised copy numbers (also referred to as log2(intensity)) received from the 
normalised process will be listed and summarised appropriately.
As the data will be log2 transformed prior to the analysis the treatment effects will be 
expressed as ratios after back transformation to the original scale. These ratios can be 
converted from treatment ratios to fold change values as follows:  


CONFIDENTIAL
203168
27

If ratio ≥ 1 then fold change = ratio

If ratio < 1 then fold change = -1/ratio
To compare the expression value for each probeset, the following linear repeated 
measures mixed effects model will be fitted to each probeset that passes any pre-filtering, 
with log2 (intensity) as the response variable as outlined in Section 10.3.3. Where 
appropriate, particularly with microarray data, multiple testing will be taken into account 
using the Benjamini-Hochberg correction [Benjamini, 1995] to calculate FDR adjusted p-
values. A summary may be generated, including probeset ID, gene ID, time point, 
adjusted means with corresponding 95% CI for each treatment group, Benjamini-
Hochberg FDR adjusted p-value and fold changes corresponding 95% CI from each 
comparison for probesets found to be significant after the applying the Benjamini-
Hochberg correction.
For each comparison, subsets of probesets will be identified based on an appropriate fold-
change, for example, fold changes >1.5 or <-1.5. The proportion of probesets with fold 
changes >1.5 or <-1.5 will be summarised in a frequency table.
Exploratory graphical reporting on the back-transformed scale can include:

Log2 (intensity) plotted against time point separately for individual subjects, 
grouped by treatment group

Adjusted mean intensity and 95 CI% plotted by treatment group and time point
10.3.3.2.
Microarray: Percentage inhibition
Based on results from the fold change analyses, the selected probesets will be further 
explored through percentage inhibition. The log2 normalised data is back transformed and 
the percentage inhibition is derived on a subject level on the back transformed data for 
each probeset. The percentage inhibition will be determined for each probeset per subject, 
where it is defined as the reduction from baseline. For example: 
Day X – baseline = -40% would be a 40% reduction (i.e. -40% change from baseline) 
which in turn is defined as a 40% inhibition. 
So the percentage inhibition would be calculated as:
[ (Day x – Baseline) / Baseline ] * -100 = % inhibition
A subset of probesets may be identified and individual subject mRNA intensities and 
percentage inhibitions may be listed, summarised and plotted appropriately for each 
selected probeset. The selected probesets will be statistically analysed appropriately, and 
the output from the mixed effects model (outlined in Section 10.3.3) summarised. 


CONFIDENTIAL
203168
28
11.
REFERENCES
Benjamini Y and Hochberg Y. Controlling the False Discovery Rate: A Practical and 
Powerful Approach to Multiple Testing. J Royal Stat Soc 1995;57:289-300


CONFIDENTIAL
203168
29
12.
APPENDICES
12.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
12.1.1.
Exclusions from Per Protocol Population
Criteria for exclusion from the per protocol population are detailed in the protocol 
deviation management plan (PDMP). The stats and programming team will use the 
information in the protocol deviations dataset to select subjects who have deviations that 
are flagged as important and that should be removed from the per protocol population. 


CONFIDENTIAL
203168
30
12.2.
Appendix 2: Schedule of Activities
12.2.1.
Protocol Defined Schedule of Events
Procedures
Screening (-30)
Treatment Period17
Early Withdrawal18
Follow Up (3)19
Day 1 
Day 8 (3)
Day 15 (3)
Day 22 (3)
Day 29 (3)
Day 36 (3)
Day 43 (3)
(week 6)
Day 50 (3)
Day 57 (3)
Day 64 (3)
Day 71 (3)
Day 78 (3)
Day 85 (+2)
(week 12)
Site Visit
X
X
X
X
X
X
X
X
X
X
X
Phone call
X
X
X
X
X
General/Safety Assessments and Procedures
Informed 
Consent
X
Subject 
Demography
X
Full medical 
history1
X
Inclusion/Exclusi
on Criteria
X
Full physical 
exam2
X
X
X
X
Brief physical 
exam
X4
X
X
X4
X
X
Vital signs (BP, 
HR, RR, 
temperature)  
X
X4
X
X
X
X4
X
X
X
X
X
12-lead ECG
X3
X4
X
X
X
X4
X
X
X
X
X
Concomitant 
medication 
review & AE 
reporting/SAEs5
X-----------------------------------------------------------------------------------------------------------------------
----X
PROs/Questionnaires/Diaries/Disease Assessments and Procedures
Columbia 
Suicide Severity 
Rating Scale (C-
SSRS)
X
X4
X4
X
X
FACIT-fatigue; 
RA Symptom 
and Impact 
Diary6
X4
X4
X
X
HAQ-DI; Patient 
Assessment of 
joint pain6
X4
X
X
X4
X
X
X
X
Patient Global 
Assessment 
(PtGA)6
X
X4
X
X
X4
X
X
X
X


CONFIDENTIAL
203168
31
Procedures
Screening (-30)
Treatment Period17
Early Withdrawal18
Follow Up (3)19
Day 1 
Day 8 (3)
Day 15 (3)
Day 22 (3)
Day 29 (3)
Day 36 (3)
Day 43 (3)
(week 6)
Day 50 (3)
Day 57 (3)
Day 64 (3)
Day 71 (3)
Day 78 (3)
Day 85 (+2)
(week 12)
Tender (28) & 
Swollen (28) 
joint count
X
X4
X
X
X4
X
X
X
X
Physician Global 
Assessment 
(PGA)
X4
X
X
X4
X
X
X
X
MRI/DCE-MRI7
X4, 
20
X4,21
X22
X16
Study Treatment
Randomisation
X
Study 
medication 
(three times 
daily)8
X-----------------------------------------------------------------------------------------------
--------X
Dispensing of 
study medication
X
X
X
Dispensing of 
diary cards
X
X
X
X
X
X
X
Collection and 
review of diary 
cards
X
X
X
X
X
X
X
X
Laboratory (Safety) Assessments and Procedures
TB, HIV, HepB,
Hep C Ab, Anti-
CCP, Anti-
dsDNA, RF 
X
FSH & estradiol  
(if applicable)
X
Serum 
pregnancy test 
(WCBP only)
X
Urine pregnancy 
test (WCBP 
only)9
X4
X
X
X
X4
X
X
X
X
X
Haematology, 
chemistry, 
urinalysis 
X
X4
X
X
X10
X4
X10
X10
X
X
X
CRP
X
X4
X
X
X4
X
X
X
X
Blood sample for 
PD inflammatory 
biomarkers, 
X4
X4
X
X


CONFIDENTIAL
203168
32
Procedures
Screening (-30)
Treatment Period17
Early Withdrawal18
Follow Up (3)19
Day 1 
Day 8 (3)
Day 15 (3)
Day 22 (3)
Day 29 (3)
Day 36 (3)
Day 43 (3)
(week 6)
Day 50 (3)
Day 57 (3)
Day 64 (3)
Day 71 (3)
Day 78 (3)
Day 85 (+2)
(week 12)
mRNA, and TE11
PK blood 
samples 
GSK298277212
X
X
4
X4
X
X
PK blood 
samples for 
MTX13
X4
X
4
X4
Pharmacogeneti
c sample (PGx)
X14
Synovial 
biopsies for PK, 
inflammatory 
biomarkers, 
mRNA, target 
engagement & 
pathway 
engagement 
analysis15
X4,2
0
X4,21
X16
Footnotes:
1.
Full medical history (includes past and current conditions, medication history, substance usage, and family history 
of premature CV disease).
2.
Full physical exam (includes height/weight at screening, height not measured at later time points).
3.
Triplicate ECG to be performed at screening only.
4.
Pre-dose.
5.
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.  AEs will be collected from the start of Study Treatment 
until the follow-up contact.  On Days 22, 36, 50, 64, and 78, subjects will be questioned about their general health 
status via phone call.
6.
All PRO assessments should be conducted on site before any tests, procedures, or assessments, to avoid 
influencing the subjects’ perception.
7.
DCE-MRI will be performed on all subjects, provided that sites have DCE-MRI capability and experience (e.g., 
hardware and software requirements). If sites do not have DCE-MRI capability or experience, a regular MRI will
be performed of the affected hand/wrist.  If the same joint is used for MRI and synovial biopsy, MRI should be 
performed before biopsy (if applicable).
8.
Subjects must take study medication three times a day approximately 8 hours apart. Exact time of dosing to be 
recorded in diary cards. On Day 1, the first study dose will be administered at the site.  On Days 8, 43 and 85 
only, subjects must not take their medication at home in the morning. Subjects will complete pre-dose 
assessments and then will be administered their morning dose of medication at site on Days 8 and 43.  On Day 
85, subjects are no longer receiving study medication.
9.
If urine pregnancy test is positive, a confirmatory serum pregnancy test must be performed.
10. Haematology and chemistry only.  No urinalysis required on Days 29, 57 and 71.  When clinical laboratory 
samples are taken on the same day as the MRI, the samples should be taken first prior to the administration of the 
contrast fluid with MRI.  If this is not feasible (i.e. MRI is performed first), it is recommended that a separate IV 
catheter or straight venipuncture be performed in the opposite arm to where the MRI contrast fluid was 
administered.


CONFIDENTIAL
203168
33
11. Blood samples for inflammatory biomarkers, mRNA and target engagement.  See laboratory manual for full details 
on sample collection, handling and shipment.
12. PK blood samples for GSK2982772 will be taken pre-dose on Days 8 and 43. Post-dose serial PK samples will be 
taken on Days 1, 8 and Day 43 at the following time points: 1, 2, 4, and 6 hours.  A trough PK sample will be taken 
on Day 85 or at Early Withdrawal.
13. Only applicable if subjects are on MTX: PK blood samples for MTX will be taken pre-dose GSK2982772 on Day 1 
(MTX alone), on Days 8 and 43 (MTX + GSK2982772).  Subjects who are on MTX should ideally take their MTX 
dose on the same day of the week at approximately the same time of the day throughout the study. In addition, 
the Day 1, 8 and 43 visits should ideally be on the same day of the week.
14. A PGx blood sample is collected at the baseline visit, after the subject has been randomised and provided 
informed consent for genetic research.  If the sample is not collected at the baseline visit, it can be collected at 
any time during the study after randomisation.
15. Synovial biopsies are optional.
16. Biopsy (if applicable) and MRI only are required at Early Withdrawal visit if subject withdraws after at least 14 days 
of treatment and prior to Day 43.  If a subject withdraws between Days 43 and 57, an MRI is not required at the 
Early Withdrawal visit.  If a subject withdraws on Day 57 or after, an MRI should be performed at the Early 
Withdrawal visit.  A window allowance of 3 days of Early Withdrawal visit is allowed to perform the MRI. 
17. Visit windows during the treatment period are relative to Day 1.
18. If a subject withdraws from the study, every effort will be made for the subject to complete an Early Withdrawal 
visit prior to the Follow Up visit. 
19. Follow-up visit should be completed 28 days (3 days) after the last dose of study medication.
20. MRI (and if applicable; a biopsy) may be performed during the screening window as an additional visit (if required) 
up to 7 days before Day 1 to allow sites flexibility in scheduling.  The MRI must be completed prior to synovial 
biopsy (if performed on the same joint).  The site should be reasonably confident that the subject has fully 
qualified for the study (e.g., screening clinical labs, vital signs, physical examination, etc.) before the MRI (and if 
applicable: a biopsy) is/are performed. 
21. A biopsy (if applicable) and MRI may be performed on a separate day within the Day 43 window allowance (3 
days).  A separate visit to perform the MRI followed by synovial biopsy (if applicable) is only allowed to 
accommodate scheduling.  If biopsy is being performed, this visit must be scheduled after the Day 43 visit where 
the PK, clinical laboratory tests and other required Day 43 procedures are performed.  Subjects must not take 
their study medication at home in the morning before the full Day 43 visit and also the morning before MRI and 
biopsy (if applicable) visit if being done on a separate day. 
22. For MRI performed on day 85, a visit window of up to 2 days after is allowed in order to perform the MRI.


CONFIDENTIAL
203168
34
12.3.
Appendix 3: Assessment Windows
12.3.1.
Definitions of Assessment Windows for Analyses
No Assessment Windows will be defined for Analysis, and summaries and analyses will 
be based on nominal visits.


CONFIDENTIAL
203168
35
12.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
12.4.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
study treatment unless otherwise specified.  Treatment phases are to be included on A&R 
datasets.
Study Phase
Definition
Pre-Treatment 
Date ≤ Study Treatment Start Date
On-Treatment
Study Treatment Start Date < Date ≤ Study Treatment Stop Date +1
Post-Treatment
Date > Study Treatment Stop Date +1
12.4.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before 28 days prior to screening visit
Concomitant
Any medication that is not a prior
Post-Treatment
Any medication that is started >= Study Treatment Stop Date +1
1.
NOTES: 

Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.
1.


CONFIDENTIAL
203168
36
12.4.2.
Treatment Emergent Flag for Adverse Events
Treatment States for AE Data
Treatment State
Definition
AE = Pre-Treatment
AE Start Date < Study Treatment Start Date
AE = On-Treatment
If AE onset date is on or after treatment start date & on or before treatment stop date
+1.
Study Treatment Start Date  ≤ AE Start Date ≤ Study Treatment Stop Date +1
AE = Post-Treatment
If AE onset date is after the treatment stop date+1.
AE Start Date > Study Treatment Stop Date +1
AE 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.
AE Duration (Days) 
AE Resolution Date – AE Onset Date + 1
AE = Drug-related
If relationship 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.
12.5.
Appendix 5: Data Display Standards & Handling 
Conventions
12.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
UK1SALX00175
HARP Area
arenv \ arprod \ gsk2982772 \ mid203168 \ final
QC Spreadsheet
arenv \ arwork \ gsk2982772 \ mid203168 \ final \ documents
Analysis Datasets 

Analysis datasets will be created according to Integrated Data Standards Library (IDSL) GSK 
A&R dataset standards.
Generation of RTF Files

RTF files will be generated for all tables at the time of the SAC.
12.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 


CONFIDENTIAL
203168
37

Subject level listings will not be provided in the main body of the GSK Clinical Study Report. All subject 
level listings will be located in the modular appendices as ICH or non-ICH listings
Formats

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, unless otherwise stated.

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. 


CONFIDENTIAL
203168
38
Unscheduled Visits

Unscheduled visits will not be included in summary tables or figures, unless otherwise stated.

All unscheduled visits will be listed.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
Placebo in graphs to be shown in Blue and GSK2982772 in Red
         style graphdata1/ color=BLUE      contrastcolor=BLUE      
linestyle=1  markersymbol="circlefilled";
         style graphdata2/ color=RED       contrastcolor=RED       
linestyle=34 markersymbol="trianglefilled";
For outputs which are displayed for all 4 treatment groups (ie by regimen)
         style graphdata1/ color=BLUE      contrastcolor=BLUE      
linestyle=1  markersymbol="circlefilled";
         style graphdata2/ color=BLACK     contrastcolor=BLACK     
linestyle=1  markersymbol="circlefilled";
         style graphdata3/ color=RED       contrastcolor=RED       
linestyle=34 markersymbol="squarefilled";
         style graphdata4/ color=DARKGREEN contrastcolor=DARKGREEN 
linestyle=2  markersymbol="trianglefilled";
12.5.3.
Reporting Standards for Pharmacokinetic
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)
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
NONMEM/Pop PK 
File
Not applicable.
NONMEM/PK/PD 
File
Not applicable.
Pharmacokinetic Parameter Derivation
PK Parameter to be 
Derived by 
Programmer
Not applicable


CONFIDENTIAL
203168
39
12.6.
Appendix 6: Derived and Transformed Data
12.6.1.
General
Multiple Measurements at One Analysis 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 (as per Section 12.3.1) 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 visit (including 
unscheduled 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 First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
12.6.2.
Study Population
Demographics
Date of Birth 

Only the year of birth will be captured, and therefore the date of birth is then derived as follows:
Year of birth = YYYY → Date of birth = 
 YYYY
Age

Calculated as the integer part of (date of screening – date of birth)
Age = integer part (date of screening –
 YYYY)

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2
Race category 

White: ‘White: Arabic/North African Heritage’ and ‘White: White/Caucasian/European Heritage’, 
or both of these, but no other category checked

African descent: ‘African American/African Heritage’, and no other category checked

Asian: ‘Asian – Central/South Asian Heritage’, ‘Asian – East Asian Heritage’, ‘Asian – Japanese 
Heritage’, and ‘Asian – South East Asian Heritage’, or any combination of these, but no other 
category checked

Other: Any combination that has not been categorized above (‘mixed race’)
Disease History
Time since formal diagnosis= date of visit - date of formal diagnosis-
Time since onset of first musculoskeletal symptoms= date of visit - date of first musculoskeletal 
symptoms-
PPD
PPD


CONFIDENTIAL
203168
40
Demographics
If date of visit is missing use screening date.
Treatment Compliance

Subject compliance will be based on the number of expected tablets to be taken and the number 
actually taken and will depend on whether a subject was taking investigational product (two 30mg 
tablets) twice a day or three times according to the regimen they were randomized to:

Total tablets taken is (Total number of Tablets Dispensed-Total Tablets Returned)

Duration of exposure is calculated as described in extent of exposure section below

Total Tablets expected to be taken is duration of exposure*4 for BID subjects and *6 for TID 
subjects
Note: if any of the tablets dispensed/returned contain missing number of tablets total tablets taken will be set 
to missing.

Treatment compliance will be calculated based on the formula:  
Treatment Compliance = (Total tablets taken/total tablets expected to be taken)*100
where 
Note compliance will only be calculated for subjects who took at least one dose (i.e.) number of 
tablets taken is >=1
Extent of Exposure

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 = Total Tablets taken*30 for GSK2982772 subjects
Cumulative dose will be 0 for placebo subjects.
Note: If the total tablets taken is missing cumulative dose will be set to missing.
12.6.3.
Efficacy
12.6.3.1.
HAQ-DI
The functional status of the subject will be assessed by means of the Disability Index of 
the Stanford Health Assessment Questionnaire (HAQ-DI).  This 20-question instrument 
assesses the degree of difficulty a person has in accomplishing tasks in eight functional 
areas:

dressing & grooming, rising, eating, walking, hygiene, reach, grip, and common daily 
activities.


CONFIDENTIAL
203168
41
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.
HAQ-DI Aids
Aid or equipment
Will be associated with category score
Walking stick/frame, crutches, wheelchair
Walking
Aids used for dressing
Dressing and grooming
Specially adapted utensils
Eating
Specially adapted chair
Rising
Raised toilet seat, bath rail, bath seat
Hygiene
Long-handled appliance in bathroom
Hygiene
Long-handled appliance for reaching
Reach
Jar opener
Grip
Other (1)
Dressing & grooming, rising, eating, 
walking
Other (2)
hygiene, reach, grip, common daily 
activities
If “other” is marked as an aid or equipment, then this can be assigned to a group of four 
functional areas and will be handled as an aid or equipment for each of the four 
functional areas.  Therefore, if the maximum score of a functional area is 0 or 1 that value 
is increased to a score of 2 for each of the four functional areas.
Regarding these corrections, the highest response within each functional area determines 
the score of that specific functional area.  If no questions within a given functional area 
were answered, no score will be provided for that category (even if answers on aids or 
equipment are available).
HAQ-DI is only calculated if there are at least 6 functional area scores available.
The average of these non-missing functional area scores defines the continuous HAQ-DI 
score ranging from 0 to 3.  If there are less than 6 functional area scores available, no 
imputation will be done and the HAQ-DI will be set to missing for the according 
assessment.


CONFIDENTIAL
203168
42
12.6.3.2.
Patient Global Assessment
The patient global assessment of arthritis disease activity (PtGA) is measured on a 10cm 
visual analogue scale (VAS) with values 0=very well to 10=very poor. More commonly 
this measurement is reported as measured off the 10cm VAS in mm. For reporting 
purposes, the VAS measurement from the eCRF will be converted from cm to mm by 
multiplying values by 10. All listings and summaries of the PtGA will be using mm.
12.6.3.3.
Physician Global Assessment (PGA)
The physician global assessment of arthritis disease activity (PGA) is measured on a 
10cm visual analogue scale (VAS) with values 0=none to 10=extremely active. More 
commonly this measurement is reported as measured off the 10cm VAS in mm. For 
reporting purposes, the VAS measurement from the eCRF will be converted from cm to 
mm by multiplying values by 10. All listings and summaries of the PGA will be using 
mm.
12.6.3.4.
Disease Activity Score (DAS28):
Disease activity Score (DAS28 CRP) is a numeric outcome based on Tender joint count 
28 (TJC28), swollen joint count 28 (SJC28), C-reactive protein (CRP) and patient global 
assessment (PtGA). CRP values will be taken from the clinical chemistry data within the 
lab dataset.
The joint counts will be based on 28 joints as follows (both left and right sides): 
Shoulder, elbow, wrist, metacarpophalangeal (first (thumb), second, third, fourth, fifth), 
proximal interphalangeal (thumb (interphalangeal), index, middle, ring, little) and knee.
The DAS28-CRP score will be calculated using the following formula:

If one of the components is missing at an individual assessment point, the 
DAS28-CRP value for that assessment will be set to missing.

Note PtGA must be measured in mm for this calculation as described in Section 
12.6.3.2
Categorical DAS28 Response
DAS28-CRP scores will each be categorized using EULAR response criteria.  Response 
at a given time point is defined based on the combination of current DAS28 score and the 
improvement in the current DAS28 score relative to baseline.  The definition of no 
response, moderate response and good response is captured in the following table:


CONFIDENTIAL
203168
43
Table 4
EULAR Response Criteria
Current
DAS28
DAS28 decrease from baseline value
>1.2
>0.6 to ≤1.2
≤ 0.6
≤ 3.2
Good response
Moderate response
No response
> 3.2 to ≤ 5.1
Moderate response
Moderate response
No response
> 5.1
Moderate response
No response
No response
If the post-baseline DAS28-CRP score is missing, then the corresponding EULAR 
category will be missing.  If the baseline DAS28-CRP is missing, then all post-baseline 
EULAR response values will be missing.
DAS28 Low Disease Activity (LDA)
DAS28-CRP Low Disease Activity is defined as a DAS28 score of <3.2.
DAS28 Remission
DAS28-CRP remission is achieved by a DAS28-CRP value <= 2.6.  
12.6.3.5.
ACR Response Rates
The American College of Rheumatology’s (ACR) definition for calculating improvement 
in RA is calculated as a 20% improvement (ACR20) in both tender and swollen joint 
counts and 20% improvement in at least 3 of the 5 remaining ACR-core set measures: 
patient and physician global assessments, patient’s assessment of arthritis pain, disability 
(HAQ-DI), and an acute-phase reactant (i.e. CRP value). Similarly, ACR50 and ACR70 
are calculated with the respective percent improvement. This efficacy measurement will 
be made at every post-baseline study assessment time point.
The specific components of the ACR Assessments that will be used in this study are as 
follows and can be grouped into three components:

Tender/Painful Joint count (28)

Swollen Joint Count (28)

5 Remaining ACR-Core Set Measures:
Patient Assessment of Joint Pain
PtGA


CONFIDENTIAL
203168
44
PGA
CRP
HAQ-DI
For all visits, if any of the component scores are missing, meaning ACR20/50/70 
responder definitions cannot be properly assessed, then those scores will be considered as 
not having met the criteria for improvement. Therefore, if TJC28 or SJC28 or 3 or more 
of the 5 remaining ACR-core set measures are missing, ACR20/ ACR50/ ACR70 will 
each be considered as “no response” in the DAS_ACR dataset.
For missing Baseline values or a Baseline value of 0, the percentage improvement can’t 
be calculated and the ACR will be considered as not having met the criteria for 
improvement
e.g. 
if TJC28 or SJC28 is missing or 0 at baseline then ACR20/50/70 will be 
considered as ‘no response’
if TJC28 and SJC28 are non-missing and >0 at baseline but there are < 3 of the 5 
remaining core set measures that are non-missing and >0 at baseline then 
ACR20/50/70 will be considered as ‘no response’
Data from the screening visit will not be used to impute baseline.
12.6.3.6.
Swollen and Tender/Painful Joint Count
Four different scores will be calculated to evaluate swelling and tenderness of joints.  
TJC28 and SJC28 will take 28 joints into account.
The assessment for swelling is the total number of joints with a present swelling and 
ranges from 0 to 28 for SJC28 .
The assessment for tenderness is the total number of joints with a present tenderness and 
ranges from 0 to 28 for TJC28.
The following 28 joints will be taken into account for TJC28 and SJC28: Shoulder (2 
joints), Knee (2), Elbow (2), Wrist (2), Fingers (PIP, MCP: 20).
Artificial, ankylosed and missing joints are excluded from swelling and tenderness 
assessment.
If there are missing or excluded 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 for the joint count.  No imputations 
for individual joints will be done.  If a joint is not evaluable at Baseline, then that joint is 
set to missing throughout the study.
If data for more than 50% of the joints are missing at the time of a given assessment, then 
the total count will be set to missing for that visit.
Observed joint states will be listed without any modification for every subject and visit.


CONFIDENTIAL
203168
45
12.6.3.7.
FACIT-Fatigue
The FACT-G scoring guide identifies those items which must be reversed before being 
added to obtain subscale totals. Items are scored using a Likert scale from 0 to 4, to “0” 
(not at all) to“4” (very much).
In order to calculate a total score negatively stated items are reversed by subtracting the 
response from "4". After reversing proper items, all subscale items are summed to a total, 
which is the subscale score. For all FACIT scales and symptom indices, the higher the 
score the better the QOL.
Negatively stated items refer to all statements asked except (‘I have energy’ and ‘I am 
able to do my usual activities’)
Fatigue Score = [sum of Item Scores] x [13] / [number of items answered].
A Fatigue score will only be calculated if at least 7 responses have been provided.
12.6.3.8.
DCE-MRI
Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) parameters are 
measured at each individual joint and consist of:

Exchange Rate (Ktrans)

Interstitial Volume (Ve)

Plasma Volume (Vp)

Initial Rate of Enhancement (IRE)

Maximum signal intensity enhancement (ME).
All DCE-MRI parameters will be presented as a total measure over all joints at each time 
point.
DCI-MRI parameters will be calculated as:
Parameters will also be presented normalized by the VEP.
Normalized DCE-MRI parameters will be calculated as:
If parameters are missing for individual joints, these joints will be excluded from the 
numerator and denominator of the calculation.


CONFIDENTIAL
203168
46
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.  This threshold might be altered after 
review of the actual raw data.
12.6.3.9.
CDAI and SDAI
Although not specified in the protocol as endpoints both the Simple Disease Activity 
Index (SDAI) and clinical disease activity index (CDAI) will be calculated and 
summarised. 
SDAI
SDAI is a composite score calculated using the formula:
SDAI= SJC28 + TJC28+ PtGA + PGA+ CRP 
Where PtGA and PGA is measured 0-10 and CRP is measured in (mg/dl). Higher values 
represent higher disease activity.
If one of the components is missing at an individual assessment point, the SDAI value for 
that assessment will be set to missing.
SDAI Remission                                 SDAI <= 3.3
SDAI Low Disease Activity     3.3 < SDAI <= 11
CDAI
CDAI is a composite score calculated using the following formula:
CDAI= SJC28+ TJC28 + PtGA+ PGA
Where PtGA and PGA are measured 0-10.  CDAI ranges from 0 to 76 with higher values 
representing higher disease activity.  
Remission is achieved for a non-missing CDAI value ≤2.8 and 
Low Disease Activity     2.8 < CDAI <= 10
If one of the components is missing at an individual assessment point, no imputations 
will be done and the CDAI value for that assessment will be set to missing.
12.6.4.
Safety
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    


CONFIDENTIAL
203168
47
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as :
[1] If QTcB is machine read & QTcF is not provided, then :
[2] If QTcF is machine read and QTcB is not provided, then: 

If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
collected value THEN do not derive.
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of other 
measurements.

IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as : 
12.6.5.
Biomarker
TEAR
Target Engagement

Ratio = free / total

Target Engagement = 100 – (ratio post/ratio baseline) * 100))

BIOMARK dataset:
BICAT = TRIPK1 (total) or FRIPK1 (free) for the same smpty
12.6.6.
PK
Synovial Tissue Pharmacokinetic Concentrations
Synovial Tissue PK Conc

The density of human synovial tissue is 1.184 g/mL per Gastroplus V9.0.

The volume of solvent added to each tissue sample was 0.5 mL.

For actual tissue weights, please refer to the Excel spreadsheet
Synovial PK Concentration (ng/mL)


CONFIDENTIAL
203168
48
1.
PK Conc in Weight of Tissue Sample = SMS PK Conc in Soln (ng/mL) X [0.5 mL + (Tissue 
Weight (g) / 1.184 g/mL)] 
2.
PK Conc in tissue as concentration (ng/g) = PK Conc in Weight of Tissue Sample / Tissue 
Weight
3.
PK Conc in tissue as concentration (ng/mL) = PK Conc in tissue as concentration (ng/g)  
1.184 g/mL 
Example (fictitious) data:
SMS tissue homogenate concentration = 2 ng/mL
Tissue weight = 0.014 g
SMS plasma concentration= 400 ng/mL
Example Calculations:
1.
Convert GSK2982772 concentration in the homogenate to GSK2982772 concentration in 
the tissue sample as follows:
2 ng/mL X [0.5 mL + (0.014 g/1.184 g/mL)] = 2ng/mL X 0.512 mL = 1.024 ng GSK2982772 in a 
0.014 g tissue sample
2.
Convert absolute amount of GSK2982772 in this skin tissue sample to a tissue 
concentration as follows:
1.024 ng / 0.014 g tissue = 73.1 ng GSK2982772/g tissue = 73.1 ng/g
3.
Convert ng/g tissue to ng/mL tissue as follows:
73.1 ng/g X 1.184 g/mL = 86.5 ng GSK2982772/mL tissue = 86.5 ng/mL
4.
Determine the ratio of GSK2982772 tissue concentration to GSK2982772 plasma 
concentration for a given patient as follows:
86.5 ng/mL / 400 ng/mL = 0.216


CONFIDENTIAL
203168
49
12.7.
Appendix 7: Reporting Standards for Missing Data
12.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion was defined as one who has completed all phases of 
the study including the follow-up visit. 

Withdrawn subjects may be replaced in the study at the discretion of the 
investigator.

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. Withdrawal visits will not be summarised and will be 
listed only.
12.7.2.
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.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
12.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to 
be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the 
start date of study treatment; in this case the study treatment start date will 
be used and hence the event is considered On-treatment as per Appendix 
4: Study Phases and Treatment Emergent Adverse Events.
o
Missing Stop Day: Last day of the month will be used, unless this is after 
the stop date of study treatment; in this case the study treatment stop date 
will be used.

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing.
Concomitant 
Medications/Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.


CONFIDENTIAL
203168
50
12.8.
Appendix 8: Values of Potential Clinical Importance
12.8.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 
1
Male
0.54
Female
0.54
∆from BL
↓0.075
Hemoglobin 
g/L
Male
180
Female
180
∆from BL
↓25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
While Blood Cell Count (WBC)
x109/ L
3
20
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
mmol/L
30
Calcium
mmol/L
2
2.75
Creatinine
mmol/L
∆from BL
↑ 44.2
Glucose
mmol/L
3
9
Magnesium
mmol/L
0.5
1.23
Phosphorus
mmol/L
0.8
1.6
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Total CO2
mmol/L
18
32
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
2x ULN
AST/SGOT 
U/L
High
2x ULN
AlkPhos 
U/L
High
2x ULN
T Bilirubin 
µmol/L
High
1.5xULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
U/L
2x ULN ALT


CONFIDENTIAL
203168
51
12.8.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450 
< 480
≥ 480 
<500
≥ 500 
Absolute PR Interval
msec
< 110 
> 220 
Absolute QRS Interval
msec
< 75 
> 110
Change from Baseline
Increase from Baseline QTc
msec
> 30 
≤ 59
msec
≥ 60 
12.8.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
Bpm
< 40
> 110
Vital Sign Parameter
(Change from Baseline)
Units
Clinical Concern Range
Decrease
Increase
Lower
Upper
Lower
Upper
Systolic Blood Pressure
mmHg
≥ 20
≥ 40
≥ 20
≥ 40
Diastolic Blood Pressure
mmHg
≥ 10
≥ 20
≥ 10
≥ 20
Heart Rate
Bpm
≥ 15
≥ 30
≥ 15
≥ 30


CONFIDENTIAL
203168
52
12.9.
Appendix 11: Abbreviations & Trade Marks
12.9.1.
Abbreviations
Abbreviation
Description
ACR
American College of Rheumatology
ADaM
Analysis Data Model
AE
Adverse Event
A&R
Analysis and Reporting 
CARLOS
Cartilage Loss Scoring System
CDAI
Clinical Disease Activity Index
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CRP
C-reactive protein 
CS
Compound symmetry
CSH
Heterogenous compound symmetry
CSR
Clinical Study Report
CV
Cardiovascular
CVb
Coefficient of Variation (Between)
DAS 28-CRP
Disease Activity Score 28-CRP
DBF
Database Freeze
DBR
Database Release
DCE-MRI
Dynamic Contrast-Enhanced Magnetic Resonance Imaging 
DOB
Date of Birth
DP
Decimal Places
DRC
Data Review Committee
DVT
Deep vein thrombosis
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GCSP
Global Clinical Safety & Pharmacovigilence
GSK
GlaxoSmithKline
HAQ-DI
Disability Index of the Stanford Health Assessment Questionnaire
IA
Interim Analysis
ICH
International Conference on Harmonization
IDSL
Integrated Data Standards Library
II
Immuno-Inflammation
IRE
Initial rate of enhancement
Ktrans
Exchange rate
LS
Least squared
ME
Maximal signal intensity enhancement
MMRM
Mixed Model Repeated Measures
MRI
Magnetic Resonance Imaging
MTX
Methotrexate


CONFIDENTIAL
203168
53
Abbreviation
Description
OMERACT-
RAMRIS
Outcome Measures in Rheumatology, Rheumatoid Arthritis Magnetic 
Resonance Image Scoring System
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PE
Pulmonary embolism 
PGA
Physician Global Assessment
PK
Pharmacokinetic
PK772
Pharmacokinetic GSK298772 
PKMeth
Pharmacokinetic Methotrexate 
PP
Per Protocol
PopPK
Population PK
PtGA
Patient Global Assessment
QC
Quality Control
QOL
Quality of Life
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RA
Rheumatoid Arthritis
RAMOS
Randomization & Medication Ordering System 
RAMRIQ
Rheumatoid Arthritis MRI Quantitative
RAP
Reporting & Analysis Plan
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SDAI
Simple Disease Activity Index
SDTM
Study Data Tabulation Model
SE
Standard Error
SJC28
Swollen Joint Count 28
SRT
Safety Review Team
TA
Therapeutic Area
TEAR1
Target Engagement Assay RIP1
TIA
Transient ischemic attack
TFL
Tables, Figures & Listings 
TJC28
Tender Joint Count 28
VAS
Visual Analogue Scale
Ve
Interstitial volume
Vep
Volume of enhancing Pannus
Vp
Plasma volume


CONFIDENTIAL
203168
54
12.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
ADVAIR
NONMEM
SAS
WinNonlin


CONFIDENTIAL
203168
55
12.10.
Appendix 12: List of Data Displays
12.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.18
NA
Efficacy
2.1 to 2.67
2.1 to 2.23
Safety
3.1 to 3.24
3.1 to 3.3
Pharmacokinetic
4.1 to 4.2
4.1 to 4.7
Pharmacokinetic / Pharmacodynamic
NA
5.1 to 5.3
Biomarker
6.1 to 6.14
6.1 to 6.7
Section
Listings
ICH Listings
1 to 40, and 85
Other Listings
41 to 84  
12.10.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 13: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Population Pharmacokinetic (PopPK)
POPPK_Fn
POPPK_Tn
POPPK_Ln
Pharmacodynamic and / or Biomarker
PD_Fn
PD_Tn
PD_Ln
Pharmacokinetic / Pharmacodynamic
PKPD_Fn
PKPD_Tn
PK/PD_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
12.10.3.
Deliverables
Delivery [Priority] [1]
Description
AR
Administrative review, delivered by the GSK stats and programming team
SAC [1]
Final Statistical Analysis Complete responsibility of Quanticate
SAC2 [1]
Post SAC and delivered by the GSK stats and programming team
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort


CONFIDENTIAL
203168
56
12.10.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Safety
ES1 
Summary of Subject Disposition for the Study Conclusion 
Record
ICH E3, FDAAA, EudraCT
Add footnote: Note: “Subjects” is 
used to refer to “Participants” in 
all data displays to reflect GSK 
Display Standards and CDISC 
SDTM/ADaM standards.
AR
SAC[1]
1.2.
Safety
SD1 /
SD4
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
ICH E3
AR
SAC[1]
1.3.
All subjects
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
SAC[1]
1.4.
Randomised
NS1
Summary of Number of Subjects by Country and Site ID
EudraCT/Clinical Operations
Please add footnote to say 
that randomised 
population=enrolled 
population
SAC[1]
Protocol Deviation
1.5.
Safety
DV1
Summary of Important Protocol Deviations
ICH E3
SAC[1]


CONFIDENTIAL
203168
57
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Population Analysed
1.6.
All subjects
SP1
Summary of Study Populations 
IDSL
SAC[1]
Demographic and Baseline Characteristics
1.7.
Safety
DM1 
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
Include summary of time since formal 
diagnosis of RA and time since onset of 
first musculoskeletal symptoms
SAC[1]
1.8.
Randomised
DM11
Summary of Age Ranges
EudraCT
Please add footnote to say that 
randomised population=enrolled 
population
SAC[1]
1.9.
Safety
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
SAC[1]
1.10.
Safety
SU1
Summary of Tobacco Use
IDSL
SAC[1]
Prior and Concomitant Medications
1.11.
Safety
MH1 
Summary of Past Medical Conditions
ICH E3 
SAC[1]
1.12.
Safety
MH1 
Summary of Current Medical Conditions
ICH E3 
SAC[1]
1.13.
Safety
MH1 
Summary of Past Cardiovascular Risk Factors 
ICH E3
Include only pre-defined list
SAC[1]
1.14.
Safety
MH1 
Summary of Current Cardiovascular Risk Factors
ICH E3 
Include only pre-defined list
SAC[1]


CONFIDENTIAL
203168
58
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.15.
Safety 
FH1
Summary of Family History: Cardiovascular Risk Factors
IDSL
SAC[1]
1.16.
Safety
CM1
Summary of Prior Medications
ICH E3
AR
SAC[1]
1.17.
Safety
CM1
Summary of Concomitant Medications
ICH E3
AR
SAC[1]
Exposure and Treatment Compliance
1.18.
Safety
EX1 / 
EX5
Summary of Exposure to Study Treatment
ICH E3
SAC[1]


CONFIDENTIAL
203168
59
12.10.5.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Efficacy
2.1.
Safety
EFF_T1
Summary of FACIT-Fatigue by Visit
AR
SAC [1]
2.2.
Safety
EFF_T2
Summary of Change from Baseline in FACIT-Fatigue by Visit
AR
SAC [1]
2.3.
Safety
EFF_T3
Summary of Statistical Analysis Results for Change from 
Baseline in FACIT-Fatigue 
AR
SAC [1]
2.4.
Safety
EFF_T1
Summary of HAQ-DI by Visit
AR
SAC [1]
2.5.
Safety
EFF_T2
Summary of Change from Baseline in HAQ-DI by Visit
AR
SAC [1]
2.6.
Safety
EFF_T3
Summary of Statistical Analysis Results for Change from 
Baseline in HAQ-DI
AR
SAC [1]
2.7.
Safety
EFF_T1
Summary of Patient Global Assessment by Visit
SAC [1]
2.8.
Safety
EFF_T2
Summary of Change from Baseline in Patient Global 
Assessment by Visit
SAC [1]
2.9.
Safety
EFF_T3
Summary of Statistical Analysis Results for Change from 
Baseline in Patient Global Assessment 
SAC [1]
2.10.
Safety
EFF_T1
Summary of Physician Global Assessment by Visit
SAC [1]
2.11.
Safety
EFF_T2
Summary of Change from Baseline in Physician Global 
Assessment by Visit
SAC [1]


CONFIDENTIAL
203168
60
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.12.
Safety
EFF_T3
Summary of Statistical Analysis Results for Change from 
Baseline in Physician Global Assessment 
SAC [1]
2.13.
Safety
EFF_T1
Summary of DAS28(CRP) by Visit
AR
SAC [1]
2.14.
Safety
EFF_T2
Summary of Change from Baseline in DAS28(CRP) by Visit
AR
SAC [1]
2.15.
Safety
EFF_T3
Summary of Statistical Analysis Results for Change from 
Baseline in DAS28(CRP)
AR
SAC [1]
2.16.
Safety
EFF_T1
Summary of DAS28(CRP) by Visit and Dosing Regimen
Separate page for BID and TID
AR
SAC [1]
2.17.
Safety
EFF_T2
Summary of Change from Baseline in DAS28(CRP) by Visit and 
Dosing Regimen
Separate page for BID and TID
AR
SAC [1]
2.18.
Safety
EFF_T3
Summary of Statistical Analysis Results for Change from 
Baseline in DAS28(CRP) and Dosing Regimen
Separate page for BID and TID
AR
SAC [1]
2.19.
Safety
EFF_T4
DAS28-CRP EULAR Response Categories
AR
SAC [1]
2.20.
Safety
EFF_T4
DAS28-CRP Remission and Low Disease Activity
Update column for EULAR response to 
be summarise number and percent of 
subjects meeting remission and LDA 
criteria by visit
AR
SAC [1]
2.21.
Safety
EFF_T5
ACR Response Rates by Visit
AR
SAC [1]
2.22.
Safety
EFF_T4
DAS28-CRP EULAR Response Categories and Dosing 
Regimen
Separate page for BID and TID
AR
SAC [1]


CONFIDENTIAL
203168
61
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.23.
Safety
EFF_T4
DAS28-CRP Remission and Low Disease Activity and Dosing 
Regimen
Separate page for BID and TID
Update column for EULAR response to 
be summarise number and percent of 
subjects meeting remission and LDA 
criteria by visit
AR
SAC [1]
2.24.
Safety
EFF_T5
ACR Response Rates by Visit and Dosing Regimen
Separate page for BID and TID
AR
SAC [1]
2.25.
Safety
EFF_T1
Summary of Tender Joint Count (28 Joints) by Visit
AR
SAC [1]
2.26.
Safety
EFF_T2
Summary of Change from Baseline in Tender Joint Count (28 
Joints) by Visit
AR
SAC [1]
2.27.
Safety
EFF_T3
Summary of Statistical Analysis Results for Change from 
Baseline in Tender Joint Count (28 Joints)
AR
SAC [1]
2.28.
Safety
EFF_T1
Summary of Swollen Joint Count (28 Joints) by Visit
AR
SAC [1]
2.29.
Safety
EFF_T2
Summary of Change from Baseline in Swollen Joint Count (28 
Joints) by Visit
AR
SAC [1]
2.30.
Safety
EFF_T3
Summary of Statistical Analysis Results for Change from 
Baseline in Swollen Joint Count (28 Joints)
AR
SAC [1]
2.31.
Safety
EFF_T1
Summary of MRI parameters: RAMRIS scoring system
Separate page for each parameter
SAC [1]
2.32.
Safety
EFF_T2
Summary of Change from Baseline in MRI parameters: RAMRIS 
scoring system
Separate page for each parameter
SAC [1]
2.33.
Safety
EFF_T3
Summary of Statistical Analysis Results for Change from 
Baseline in MRI parameters: RAMRIS scoring system
Separate page for each parameter
SAC [1]


CONFIDENTIAL
203168
62
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.34.
Safety
EFF_T1
Summary of MRI parameters: RAMRIQ scoring system
Separate page for each parameter
SAC [1]
2.35.
Safety
EFF_T2
Summary of Change from Baseline in MRI parameters: RAMRIQ 
scoring system
Separate page for each parameter
SAC [1]
2.36.
Safety
EFF_T3
Summary of Statistical Analysis Results for Change from 
Baseline in MRI parameters: RAMRIQ scoring system
Separate page for each parameter
SAC [1]
2.37.
Safety
EFF_T1
Summary of MRI parameters: CARLOS scoring system
Separate page for each parameter
SAC [1]
2.38.
Safety
EFF_T2
Summary of Change from Baseline in MRI parameters: 
CARLOS scoring system
Separate page for each parameter
SAC [1]
2.39.
Safety
EFF_T3
Summary of Statistical Analysis Results for Change from 
Baseline in MRI parameters: CARLOS scoring system
Separate page for each parameter
SAC [1]
2.40.
Safety
EFF_T1
Summary of synovial inflammation DCE-MRI
Separate page for each parameter
SAC [1]
2.41.
Safety
EFF_T2
Summary of Change from Baseline in synovial inflammation 
DCE-MRI
Separate page for each parameter
SAC [1]
2.42.
Safety
EFF_T3
Summary of Statistical Analysis Results for Change from 
Baseline in synovial inflammation DCE-MRI
Separate page for each parameter
SAC [1]
2.43.
Safety
EFF_T1
Summary of synovial inflammation DCE-MRI by Dosing 
Regimen
Separate page for each 
parameter/Dosing regimen
SAC [1]
2.44.
Safety
EFF_T2
Summary of Change from Baseline in synovial inflammation 
DCE-MRI by Dosing Regimen
Separate page for each 
parameter/Dosing regimen
SAC [1]
2.45.
Safety
EFF_T3
Summary of Statistical Analysis Results for Change from 
Baseline in synovial inflammation DCE-MRI by Dosing Regimen
Separate page for each 
parameter/Dosing regimen
SAC [1]
2.46.
Safety
EFF_T1
Summary of Patient Assessment of joint Pain by Visit
AR
SAC [1]
2.47.
Safety
EFF_T2
Summary of Change from Baseline in Patient Assessment of 
joint pain by Visit
AR
SAC [1]


CONFIDENTIAL
203168
63
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.48.
Safety
EFF_T3
Summary of Statistical Analysis Results for Change from 
Baseline in Patient Assessment of joint pain
AR
SAC [1]
2.49.
Safety
DM1
Summary of RA symptom Questionnaire
Add column for visit 
Summary statistics for numeric 
responses and number (%) in each 
category for each other question
SAC [1]
2.50.
Safety
EFF_T1
Summary of CRP by Visit
SAC [1]
2.51.
Safety
EFF_T2
Summary of Change from Baseline in CRP by Visit
SAC [1]
2.52.
Safety
EFF_T3
Summary of Statistical Analysis Results for Change from 
Baseline in CRP
SAC [1]
2.53.
PP
EFF_T1
Summary of DAS28(CRP) by Visit
SAC [1]
2.54.
PP
EFF_T2
Summary of Change from Baseline in DAS28(CRP) by Visit
SAC [1]
2.55.
PP
EFF_T3
Summary of Statistical Analysis Results for Change from 
Baseline in DAS28(CRP)
SAC [1]
2.56.
PP-
completer
EFF_T1
Summary of DAS28(CRP) by Visit-Per protocol Completers
Include subjects who completed the 
study and are in PP population
SAC [1]
2.57.
PP-
completer
EFF_T2
Summary of Change from Baseline in DAS28(CRP) by Visit--Per 
protocol Completers
Include subjects who completed the 
study and are in PP population
SAC [1]
2.58.
PP-
completer
EFF_T3
Summary of Statistical Analysis Results for Change from 
Baseline in DAS28(CRP)- -Per protocol Completers
Include subjects who completed the 
study and are in PP population
SAC [1]
2.59.
Safety
EFF_T1
Summary of Clinical Disease Activity Index by Visit
AR
SAC [1]
2.60.
Safety
EFF_T2
Summary of Change from Baseline in Clinical Disease Activity 
Index by Visit
AR
SAC [1]


CONFIDENTIAL
203168
64
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.61.
Safety
EFF_T3
Summary of Statistical Analysis Results for Change from 
Baseline in Clinical Disease Activity Index
AR
SAC [1]
2.62.
Safety
EFF_T1
Summary of Simple Disease Activity Index by Visit
AR
SAC [1]
2.63.
Safety
EFF_T2
Summary of Change from Baseline in Simple Disease Activity 
Index by Visit
AR
SAC [1]
2.64.
Safety
EFF_T3
Summary of Statistical Analysis Results for Change from 
Baseline in Simple Disease Activity Index
AR
SAC [1]
2.65.
Safety
EFF_T6
Summary of Bayesian Analysis of Change from Baseline in 
DAS28-CRP at day 85
GSK Responsibility
seed=5235 thin=50 
nbi=1000 nmc=500000
AR
SAC [1]
2.66.
Safety
EFF_T7
Summary of Bayesian Analysis of ACR20 at day 85
GSK Responsibility
Seed=240, nbi=1000 
nmc=100000 thin=10
AR
SAC [1]
2.67.
Safety
EFF_T7
Summary of Bayesian Analysis of ACR50 at day 85
GSK Responsibility
Seed=241, nbi=1000 
nmc=100000 thin=10
AR
SAC [1]
Note for MRI parameters, a list of expected bones/joints for DCE and RAMRIS can be provided in an excel file on request.


CONFIDENTIAL
203168
65
12.10.6.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Efficacy
2.1.
Safety
EFF_F1
FACIT-Fatigue, Adjusted Mean (SE) Change from Baseline
and Box and Whisker Plot of Unadjusted Change from Baseline 
by Treatment over Time
AR
SAC [1]
2.2.
Safety
EFF_F1
HAQ-DI, Adjusted Mean (SE) Change from Baseline and Box 
and Whisker Plot of Unadjusted Change from Baseline by 
Treatment over Time
AR
SAC [1]
2.3.
Safety
EFF_F1
Patient Global Assessment, Adjusted Mean (SE) Change from 
Baseline and Box and Whisker Plot of Unadjusted Change from 
Baseline by Treatment over Time
SAC [1]
2.4.
Safety
EFF_F1
Physician Global Assessment, Adjusted Mean (SE) Change 
from Baseline and Box and Whisker Plot of Unadjusted Change 
from Baseline by Treatment over Time
SAC [1]
2.5.
Safety
EFF_F1
DAS28-CRP, Adjusted Mean (SE) Change from Baseline and 
Box and Whisker Plot of Unadjusted Change from Baseline by 
Treatment over Time
AR
SAC [1]
2.6.
Safety
EFF_F2
Individual Subject Profiles for DAS28-CRP
SAC [1]
2.7.
Safety
EFF_F1
DAS28-CRP, Adjusted Mean (SE) Change from Baseline and 
Box and Whisker Plot of Unadjusted Change from Baseline by 
Treatment and Dosing regimen over Time
Separate page for each dosing regimen
AR
SAC [1]
2.8.
Safety
EFF_F3
Proportion (SE) of subjects in each DAS28-CRP EULAR
Response Category
Separate page for each EULAR 
response category
AR
SAC [1]


CONFIDENTIAL
203168
66
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.9.
Safety
EFF_F4
Proportion (SE) of subjects achieving ACR20/50/70
Separate page for AC20/50 and 70
AR
SAC [1]
2.10.
Safety
EFF_F1
Tender Joint Count (28), Adjusted Mean (SE) Change from 
Baseline and Box and Whisker Plot of Unadjusted Change from 
Baseline by Treatment over Time
AR
SAC [1]
2.11.
Safety
EFF_F1
Swollen Joint Count (28), Adjusted Mean (SE) Change from 
Baseline and Box and Whisker Plot of Unadjusted Change from 
Baseline by Treatment over Time
AR
SAC [1]
2.12.
Safety
EFF_F1
MRI parameters: RAMRIS scoring, Adjusted Mean (SE) 
Change from Baseline and Box and Whisker Plot of Unadjusted 
Change from Baseline by Treatment over Time
Separate page for each parameter
SAC [1]
2.13.
Safety
EFF_F1
MRI parameters: RAMRIQ scoring, Adjusted Mean (SE) 
Change from Baseline and Box and Whisker Plot of Unadjusted 
Change from Baseline by Treatment over Time
Separate page for each parameter
SAC [1]
2.14.
Safety
EFF_F1
MRI parameters: CARLOS scoring, Adjusted Mean (SE) 
Change from Baseline and Box and Whisker Plot of Unadjusted 
Change from Baseline by Treatment over Time
Separate page for each parameter
SAC [1]
2.15.
Safety
EFF_F1
DCE-MRI, Adjusted Mean (SE) Change from Baseline and Box 
and Whisker Plot of Unadjusted Change from Baseline by 
Treatment over Time
Separate page for each parameter
SAC [1]
2.16.
Safety
EFF_F2
Individual Subject Profiles for DCE-MRI
Separate page for each parameter
SAC [1]
2.17.
Safety
EFF_F1
DCE-MRI, Adjusted Mean (SE) Change from Baseline and Box 
and Whisker Plot of Unadjusted Change from Baseline by 
Treatment and Dosing Regimen over Time
Separate page for each 
parameter/dosing regimen
SAC [1]


CONFIDENTIAL
203168
67
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.18.
Safety
EFF_F1
Patient Assessment of Joint Pain, Adjusted Mean (SE) Change 
from Baseline and Box and Whisker Plot of Unadjusted Change 
from Baseline by Treatment over Time
Separate page for each parameter
AR
SAC [1]
2.19.
Safety
EFF_F1
CRP, Adjusted Mean (SE) Change from Baseline and Box and 
Whisker Plot of Unadjusted Change from Baseline by Treatment 
over Time
AR
SAC [1]
2.20.
PP
EFF_F1
DAS28-CRP, Adjusted Mean (SE) Change from Baseline and 
Box and Whisker Plot of Unadjusted Change from Baseline by 
Treatment over Time
SAC [1]
2.21.
PP-
Completer
EFF_F1
DAS28-CRP, Adjusted Mean (SE) Change from Baseline and 
Box and Whisker Plot of Unadjusted Change from Baseline by 
Treatment over Time
Include subjects who completed the 
study and are in PP population
SAC [1]
2.22.
Safety
EFF_F1
Clinical Disease Activity Index, Adjusted Mean (SE) Change 
from Baseline and Box and Whisker Plot of Unadjusted Change 
from Baseline by Treatment over Time
AR
SAC [1]
2.23.
Safety
EFF_F1
Simple Disease Activity Index, Adjusted Mean (SE) Change 
from Baseline and Box and Whisker Plot of Unadjusted Change 
from Baseline by Treatment over Time
AR
SAC [1]


CONFIDENTIAL
203168
68
12.10.7.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
[Safety]
AE1
Summary of Adverse Events by System Organ Class and 
Preferred Term
IDSL
SAC [1]
3.2.
[Safety]
AE5A
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term
ICH E3
SAC [1]
3.3.
[Safety]
AE3
Summary of Common (10%) Adverse Events by Overall 
Frequency
ICH E3
Common defined as >= 10% within 
either treatment group
SAC [1]
3.4.
[Safety]
AE5A
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity
ICH E3
SAC [1]
3.5.
[Safety]
AE15
Summary of Common (10%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects
and Occurrences)
FDAAA, EudraCT
SAC [1]
3.6.
[Safety]
AE3
Summary of Common (10%) Drug-Related Adverse Events by 
Overall Frequency
ICH E3
SAC [1]
Serious and Other Significant Adverse Events
3.7.
[Safety]
AE1
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences)
FDAAA, EudraCT
SAC [1]
3.8.
[Safety]
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term /by Overall Frequency
IDSL
SAC [1]


CONFIDENTIAL
203168
69
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.9.
Safety
AE16
Summary of Subjects and Number of Occurrences of Serious, 
Drug-Related Serious, Fatal Serious, and Drug-Related Fatal 
Serious Adverse Events
FDAAA, EudraCT
SAC [1]
Laboratory: Chemistry 
3.10.
[Safety]
LB1
Summary of Chemistry Changes from Baseline 
ICH E3
SAC [1]
3.11.
[Safety]
LB17
Summary of Worst Case Chemistry Results by PCI Criteria 
Post-Baseline Relative to Baseline
ICH E3
SAC [1]
3.12.
[Safety]
LB17
Summary of Worst Case Lipids Results by NR Criteria Post-
Baseline Relative to Baseline by Randomised Treatment
ICH E3 (i.e. treatment emergent)
Lipids parameters = LDL, HDL 
Recommended for larger studies, could 
be covered by listings for smaller 
studies.
The specific criteria to be defined by the 
study/project team.
Values could be categorized by:
[1] Above/below reference range (e.g., 
normal range, clinical concern range).
[2] Graded toxicity scales.
[3] Changes from baseline to reference 
range category.
Or
[1] On-treatment.
[2] Post-baseline (i.e., anything after 
first dose and not necessarily while On-
treatment).
[3] Through IP end + X days, etc.
SAC [1]
Laboratory: Hematology


CONFIDENTIAL
203168
70
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.13.
[Safety]
LB1
Summary of Hematology Changes from Baseline
ICH E3
SAC[1]
3.14.
[Safety]
LB17
Summary of Worst Case Hematology Results by PCI Criteria 
Post-Baseline Relative to Baseline
ICH E3
SAC[1]
Laboratory: Urinalysis
3.15.
[Safety]
LB1
Summary of Urine Concentration Changes from Baseline
ICH E3
SAC[1]
3.16.
[Safety]
UR1
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline
ICH E3
SAC[1]
Laboratory: Hepatobiliary (Liver)
3.17.
[Safety]
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
IDSL
SAC[1]
3.18.
[Safety]
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
IDSL
SAC[1]
ECG
3.19.
[Safety]
EG1
Summary of ECG Findings 
IDSL
SAC[1]
3.20.
[Safety]
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category
IDSL
SAC[1]
3.21.
[Safety]
EG2
Summary of Change from Baseline in ECG Values by Visit
IDSL
SAC[1]
3.22.
[Safety]
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category
IDSL
SAC[1]
Vital Signs
3.23.
[Safety]
VS1
Summary of Change from Baseline in Vital Signs
ICH E3
SAC[1]
3.24.
[Safety]
VS7
Summary of Worst Case Vital Signs by PCI Criteria Post-
Baseline Relative to Baseline
IDSL
SAC[1]


CONFIDENTIAL
203168
71
12.10.8.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
3.1.
[Safety]
AE10
Plot of Common (10%) Adverse Events and Relative Risk
IDSL
SAC[1]
Laboratory
3.2.
[Safety]
LIVER14
Scatter Plot of Maximum vs. Baseline for ALT
IDSL
SAC[1]
3.3.
[Safety]
LIVER9
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin
IDSL
SAC[1]
12.10.9.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Concentration
4.1.
PK772
PK01
Summary of Plasma GSK2982772 Concentration-Time Data 
(ng/mL) by Dosing Regimen
Pre-dose, Day 1, 8, 43 and 85.
Day 1, 8 and 43  at 1, 2, 4 and 6 h 
post dose
AR
SAC [1]
4.2.
PKMeth
PK01
Summary of Plasma Methotrexate Concentration Data (ng/mL)
by Dosing Regimen
Pre-dose Day 1, 8 and 43
SAC[1]


CONFIDENTIAL
203168
72
12.10.10. Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Concentration
4.1.
PK772
PK_F1
Spaghetti plot of GSK2982772 Individual Plasma Concentration 
Data by Study Day
Spaghetti plot of individual trough 
concentrations vs day (8, 43 and 85).  
Separate panels for each per regimen 
(bid and tid)
SAC [1]
4.2.
PK772
PK_F2
GSK2982772 Trough Plasma Concentration Data by Study Day
Plot of individual trough concentrations 
vs day (8, 43 and 85) and overlaid with 
box and whisker plot. Separate panels 
for each regimen (bid and tid) 
AR
SAC [1]
4.3.
PK772
PK_F3
GSK2982772 Plasma Concentration Data by time relative to 
dose
Spaghetti plot of observed plasma 
concentration versus time (pre-dose =0, 
1, 2, 4, and 6 hours post dose). One 
panel for each regimen and separate 
pages for each day (1, 8, and 43)
AR
SAC [1]
4.4.
PK772
PK_F4
Mean (SE) GSK2982772 Plasma Concentration Data by time
Relative to Dose by Study Day
Mean concentration vs time (pre-dose 
=0, 1, 2, 4, and 6 hours post dose) for 
Day 1, 8 and 43.  One plot/panel per 
regimen (bid and tid)
SAC [1]
4.5.
PK772
PK_F5
Mean  (SE)  GSK2982772 Plasma Concentration Data by Time 
relative to Dose, by Dosing Regimen
Mean concentration vs time for bid and 
tid regimen on one plot.  One panel per 
day (1, 8 and 43)
AR
SAC [1]


CONFIDENTIAL
203168
73
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.6.
PK772
PK_F1
GSK2982772 Trough Concentrations in Plasma and Synovial 
Fluid by Study Day
Spaghetti Plot of observed trough 
concentrations by body fluid (plasma 
and synovial fluid) on Day 43 and D85.  
One panel each for BID and TID 
Just present subjects who have both 
plasma and synovia concentrations and 
update x-axis label to say concentration 
use legend to distinguish between 
synovial and plasma concentration
SAC [1]
4.7.
PK772
PK_F6
GSK2982772 Trough Concentrations Plasma vs Synovial Fluid 
Scatter plot of GSK2982772 Trough 
Plasma Concentration on X-axis and 
synovial fluid concentration on Y-Axis.  
All data, one symbol each for bid and 
tid
Only include subjects who have both 
plasma and synovial concentration data
AR
SAC [1]


CONFIDENTIAL
203168
74
12.10.11. Pharmacokinetic/Pharmacodynamic Figures
PK/PD Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.1.
PK772
PK_F6
GSK2982772 Plasma Trough Concentration vs Blood TEAR1% 
Target engagement by Study Day 
Scatter plot of GSK2982772 Trough 
Plasma Concentration vs Blood 
TEAR1.  All data on one plot, one 
symbol each for bid and tid
SAC [1]
5.2.
PK772
PK_F6
GSK2982772 Synovial Fluid Trough Concentration vs Synovial 
Fluid TEAR1% Target engagement
Scatter plot of GSK2982772 Trough 
Synovial Fluid Trough Concentration vs 
Synovial Fluid TEAR1.  All data on one 
plot, one symbol each for bid and tid
SAC [1]
5.3.
PK772
PK_F6
GSK2982772 Plasma Trough Concentration vs DAS28 (CRP) 
Change from baseline
Scatter plot of GSK2982772 Trough 
Plasma Concentration vs DAS28 
change from baseline.  All data on one 
plot, one symbol each for bid and tid, 
separate page for each relevant visit
SAC [1]


CONFIDENTIAL
203168
75
12.10.12. Biomarker Tables
Pharmacodynamic (and or Biomarker): Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Inflammatory Biomarkers in blood
6.1.
Safety
PD_T1
Summary of Blood Inflammatory Biomarkers
One page for each cell type/measure 
by visit/time and treatment
SAC [1]
6.2.
Safety
PD_T2
Summary of Percentage Change from Baseline in Blood 
Inflammatory Biomarkers
One page for each cell type/measure 
by visit/time and treatment
SAC [1]
6.3.
Safety
PD_T3
Adjusted Mean (95% CI) Percentage Change in Blood 
Inflammatory Biomarkers  
Present %CVb instead of SE
SAC [1]
6.4.
Safety
PD_T1
Summary of Blood Inflammatory Biomarkers by Dosing Regimen
One page for each cell type/measure 
by visit/time and treatment/dosing 
regimen
SAC [1]
6.5.
Safety
PD_T2
Summary of Percentage Change from Baseline in Blood 
Inflammatory Biomarkers by Dosing Regimen
One page for each cell type/measure 
by visit/time and treatment/dosing 
regimen
SAC [1]
6.6.
Safety
PD_T3
Adjusted Mean (95% CI) Percentage Change in Blood 
Inflammatory Biomarkers by Dosing Regimen
Present %CVb instead of SE
Separate page for each dosing regimen
SAC [1]
Pathway and Target engagement
6.7.
Safety
EFF_T1
Summary of TEAR1 % Target Engagement in Blood
SAC [1]
6.8.
Safety
PD_T4
Adjusted Mean (95% CI) TEAR1 % Target Engagement in Blood
SAC [1]
6.9.
Safety
EFF_T1
Summary of Pathway Engagement in Blood
No longer being produced due to 
limited sample size
SAC [1]


CONFIDENTIAL
203168
76
Pharmacodynamic (and or Biomarker): Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
mRNA
6.10.
Safety
PD_T2
Summary of mRNA Intensity of Inflammatory Gene 
Transcripts in Blood 
GSK to produce
Only to be produced for significant 
probsets based on adjusted p-values.
SAC2 [1]
6.11.
Safety
PD_T5
Frequency Table Summarising the Number of Probe Sets with 
Various Fold Change in Blood  
GSK to produce
Only to be produced for significant 
probsets based on adjusted p-values.
Use cut-offs 1.5 and -1.5 initially.  
Change to -1.25 and 1.5 if no one 
achieves the initial cut-offs
SAC2 [1]
6.12.
Safety
PD_T6
Summary of Analysis for Microaray mRNA Intensity Data in 
Blood  
GSK to produce 
Only to be produced for significant 
probsets based on adjusted p-values.
If Adj Mean FC lies between -1 and 1 
then do not include on table
SAC2 [1]
6.13.
Safety
PD_T2
Summary of mRNA Percentage Inhibition of Inflammatory 
Gene Transcripts in Blood 
GSK to produce
Only to be produced for significant 
probsets based on adjusted p-values.
SAC2 [1]
6.14.
Safety
PD_T6
Summary of Analysis for Microaray mRNA Percentage Inhibition 
Data in Blood  
GSK to produce 
Only to be produced for significant
probsets based on adjusted p-values.
If Adj Mean FC lies between -1 and 1 
then do not include on table
SAC2 [1]


CONFIDENTIAL
203168
77
12.10.13. Biomarker Figures
Pharmacodynamic (and or Biomarker): Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.1.
Safety
EFF_F1
Inflammatory Blood Biomarkers, Adjusted Mean (SE) Change 
from Baseline in and Box and Whisker Plot of Unadjusted 
Change from Baseline by Treatment over Time
One page for each cell type/measure 
by visit/time and treatment
SAC [1]
6.2.
Safety
EFF_F2
Individual Subject Profiles of Inflammatory Biomarkers
Separate page for each cell 
type/measure
SAC [1]
6.3.
Safety
EFF_F1
Inflammatory Blood Biomarkers, Adjusted Mean (SE) Change 
from Baseline in and Box and Whisker Plot of Unadjusted 
Change from Baseline by Treatment and Dosing regimen over 
Time
One page for each cell type/measure 
by visit/time and treatment/dosing 
regimen
SAC [1]
6.4.
Safety
EFF_F1
TEAR1 % Target Engagement in Blood, Adjusted Mean (SE) 
Change from Baseline in and Box and Whisker Plot of 
Unadjusted Change from Baseline by Treatment over Time
SAC [1]
6.5.
Safety
PD_F1
Individual Subject Profiles for mRNA Expression of 
Inflammatory Gene Transcripts in Blood  
GSK to produce
Only to be produced for significant 
probsets based on adjusted p-values.
Line plot by subjid coloured by 
treatment group for each probeset / 
gene.
SAC2 [1]
6.6.
Safety
PD_F2
Adjusted Mean Intensities for mRNA Expression of 
Inflammatory Gene Transcripts in Blood  
GSK to produce
Only to be produced for significant 
probsets based on adjusted p-values.
Y xais – log2 scale
SAC2 [1]


CONFIDENTIAL
203168
78
Pharmacodynamic (and or Biomarker): Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.7.
Safety
PD_F3
Adjusted Mean (SE) Fold Change in mRNA Expression of 
Inflammatory Gene Transcripts in Blood
GSK to produce 
Only to be produced for significant 
probsets based on adjusted p-values.
If Adj Mean FC lies between -1 and 1 
then do not include on table
Include band from FC -1 to 1, 
transparency 0.5
SAC2 [1]


CONFIDENTIAL
203168
79
12.10.14. ICH Listings
ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC[1]
2.
Randomised
ES2
Listing of Reasons for Study Withdrawal
ICH E3
SAC[1]
3.
Randomised
BL1 
Listing of Subjects for Whom the Treatment Blind was Broken
ICH E3
SAC[1]
4.
Randomised
TA1 
Listing of Planned and Actual Treatments
IDSL
SAC[1]
Protocol Deviations
5.
Randomised
DV2
Listing of Important Protocol Deviations 
ICH E3
SAC[1]
6.
Randomised
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
ICH E3
SAC[1]
Populations Analysed
7.
All Subjects
SP3/SP3a
Listing of Subjects Excluded from Any Population
ICH E3
SAC[1]
Demographic and Baseline Characteristics
8.
Randomised
DM2 
Listing of Demographic Characteristics
ICH E3
SAC[1]
9.
Randomised
POP_L1
Listing of Rheumatoid Arthritis Disease History
Include time since formal diagnosis of 
RA and time since onset of first 
musculoskeletal symptoms
SAC[1]
10.
Randomised
DM9 
Listing of Race
ICH E3
SAC[1]
11.
Randomised
MH2
Listing of Medical History (including CV risk factors)
IDSL
SAC[1]
Prior and Concomitant Medications
12.
Randomised
CP_CM3 
Listing of Concomitant Medications
IDSL
SAC[1]


CONFIDENTIAL
203168
80
ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure and Treatment Compliance
13.
Randomised
EX3
Listing of Exposure Data
ICH E3
Please add a column for study 
treatment to differentiate between 
dates/times for IP and Methotrexate
SAC[1]
14.
Randomised
POP_L2
Listing of Dispensing Data
Listing of container number, number of 
tablets dispensed, returned and then 
%compliance
SAC[1]
Adverse Events
15.
Randomised
AE8 
Listing of All Adverse Events
ICH E3
SAC[1]
16.
Randomised
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC[1]
17.
Randomised
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
SAC[1]
Serious and Other Significant Adverse Events
18.
Randomised
AE8 
Listing of Fatal Serious Adverse Events
ICH E3
SAC[1]
19.
Randomised
AE8 
Listing of Non-Fatal Serious Adverse Events
ICH E3
SAC[1]
20.
Randomised
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
SAC[1]
21.
Randomised
AE8 
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
ICH E3
SAC[1]
22.
Randomised
PSRAE1
Listing of Possible Suicidality-Related Adverse Event Data:
Event and Description (Section 1- Section 2)
IDSL
SAC [1]
23.
Randomised
PSRAE3
Listing of Possible Suicidality-Related Adverse Event Data: 
Possible Cause(s) (Section 3)
IDSL
SAC [1]


CONFIDENTIAL
203168
81
ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
24.
Randomised
PSRAE4
Listing of Possible Suicidality-Related Adverse Event Data 
(Section 4)
IDSL
SAC [1]
25.
Randomised
PSRAE5
Listing of Possible Suicidality-Related Adverse Event Data 
(Section 5- Section 8)
IDSL
SAC [1]
Hepatobiliary (Liver)
26.
Randomised
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events
IDSL
SAC[1]
27.
Randomised
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events
IDSL
SAC[1]
All Laboratory
28.
Randomised
LB5 
Listing of All Laboratory Data for Subjects with Any Value of 
Potential Clinical Importance
ICH E3
SAC[1]
29.
Randomised
LB5 
Listing of Laboratory Values of Potential Clinical Importance
SAC[1]
30.
Randomised
LB14
Listing of Laboratory Data with Character Results
ICH E3
SAC[1]
31.
Randomised
UR2A
Listing of Urinalysis Data for Subjects with Any Value of 
Potential Clinical Importance
ICH E3
SAC[1]
32.
Randomised
LB5 
Listing of Lipids Outside of the Normal Range
Include fasted status. 
IA [1], SAC[1]
ECG
33. Randomised
EG3 
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance
IDSL
Include absolute PCI subjects. 
Footnote:
H=High absolute, L= Low absolute
SAC[1]


CONFIDENTIAL
203168
82
ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
34.
Randomised
EG3
Listing of All ECG Changes for Subjects with a Value of 
Potential Clinical Importance
Include change from baseline PCI 
subjects. 
Footnote:
H=High change from baseline value, 
L= Low change from baseline value
SAC[1]
35.
Randomised
EG3 
Listing of ECG Values of Potential Clinical Importance
"Include absolute PCIs. 
Footnote:
H=High absolute, L= Low absolute."
SAC[1]
36.
Randomised
EG3
Listing of ECG Changes of Potential Clinical Importance
"Include change from baseline PCIs. 
Footnote:
H=High change, L= Low change."
37.
Randomised
EG5
Listing of All ECG Findings for Subjects with an Abnormal ECG 
Finding
IDSL
SAC[1]
38.
Randomised
EG5 
Listing of Abnormal ECG Findings
IDSL
SAC[1]
Vital Signs
39.
Randomised
VS4 
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance
IDSL
SAC[1]
40.
Randomised
VS4 
Listing of Vital Signs of Potential Clinical Importance
IDSL
SAC[1]
ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
85
Safety
SD2
Listing of Reasons for Study Treatment Discontinuation
ICH E3
SAC[1]


CONFIDENTIAL
203168
83
12.10.15. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
CSSRS
41.
Randomised
ECSSRS4
Listing of C-SSRS suicidal Ideation and Behaviour Data
SAC[1]
42.
Randomised
ECSSRS5
Listing of C-SSRS Suicidal Behaviour Details
SAC[1]
PK
43.
PK772
PK07
Listing of GSK2982772 Pharmacokinetic Concentration-Time 
Data
SAC[1]
44.
PKMeth
PK07
Listing of Methotrexate Pharmacokinetic Concentration-Time 
Data
SAC[1]
Efficacy
45.
Randomised
EFF_L11
Listing of FACIT-Fatigue 
SAC[1]
46.
Randomised
EFF_L8
Listing of HAQ-DI
SAC[1]
47.
Randomised
EFF_L10
Listing of Patient and Physician Global Assessment
SAC[1]
48.
Randomised
EFF_L6
Listing of DAS28-CRP, EULAR response and Joint Counts
SAC[1]
49.
Randomised
EFF_L7
Listing of ACR Response Rates and ACR Components
SAC[1]
50.
Randomised
EFF_L1
Listing of MRI Data, Inflammatory Structural Joint Damage: 
RAMRIS
SAC[1]
51.
Randomised
EFF_L2
Listing of MRI, Inflammatory Structural Joint Damage: RAMRIQ
SAC[1]
52.
Randomised
EFF_L3
Listing of MRI, Inflammatory Structural Joint Damage: CARLOS
SAC[1]
53.
Randomised
EFF_L4
Listing of Joint Inflammation: DCE-MRI
SAC[1]
54.
Randomised
EFF_L5
Listing of Swollen and Tender Joint States
SAC[1]
55.
Randomised
EFF_L12
Listing of Patient Assessment of Joint Pain
SAC[1]


CONFIDENTIAL
203168
84
Non-ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
56.
Randomised
EFF_L9
Listing of RA Symptom and Impact Diary
SAC[1]
57.
Safety
n/a
Raw SAS Output of Statistical Analysis of FACIT-Fatigue
SAC[1]
58.
Safety
n/a
Raw SAS Output of Statistical Analysis of HAQ-DI
SAC[1]
59.
Safety
n/a
Raw SAS Output of Statistical Analysis of Patient Global 
Assessment
SAC[1]
60.
Safety
n/a
Raw SAS Output of Statistical Analysis of Physician Global 
Assessment
SAC[1]
61.
Safety
n/a
Raw SAS Output of Statistical Analysis of DAS28(CRP)
SAC[1]
62.
Safety
n/a
Raw SAS Output of Statistical Analysis of DAS28(CRP) by 
dosing regimen
SAC[1]
63.
Safety
n/a
Raw SAS Output of Statistical Analysis of TJC(28)
SAC[1]
64.
Safety
n/a
Raw SAS Output of Statistical Analysis of SJC(28)
SAC[1]
65.
Safety
n/a
Raw SAS Output of Statistical Analysis of MRI:RAMRIS
SAC[1]
66.
Safety
n/a
Raw SAS Output of Statistical Analysis of MRI:RAMRIQ
SAC[1]
67.
Safety
n/a
Raw SAS Output of Statistical Analysis of MRI:CARLOS
SAC[1]
68.
Safety
n/a
Raw SAS Output of Statistical Analysis of DCE-MRI
SAC[1]
69.
Safety
n/a
Raw SAS Output of Statistical Analysis of DCE-MRI by Dosing 
Regimen
SAC[1]
70.
Safety
n/a
Raw SAS Output of Statistical Analysis of Patient Assessment 
of joint pain
SAC[1]
71.
Safety
n/a
Raw SAS Output of Statistical Analysis of CRP
SAC[1]
72.
PP
n/a
Raw SAS Output of Statistical Analysis of DAS28(CRP)
SAC[1]


CONFIDENTIAL
203168
85
Non-ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
73.
PP-completers
n/a
Raw SAS Output of Statistical Analysis of DAS28(CRP)-PP 
completers
Include subjects that complete the 
study and are in the PP population 
SAC[1]
74.
Safety
n/a
Raw SAS Output of Statistical Analysis of CDAI
AR, SAC[1]
75.
Safety
n/a
Raw SAS Output of Statistical Analysis of SDAI
AR, SAC[1]
Biomarker
76.
Randomised
PD_L1
Listing of Inflammatory Biomarkers in Blood
SAC[1]
77.
Randomised
PD_L3
Listing of TEAR1 % Target Engagement in Blood
SAC[1]
78.
Randomised
PD_L3
Listing of TEAR1 % Target Engagement in Synovial Tissue
SAC[1]
79.
Randomised
Listing of Pathway Engagement in Blood
No longer being produced due to 
limited sample size
SAC[1]
80.
Randomised
PD_L2
Listing of mRNA Expression of Inflammatory Gene 
Transcripts in Blood
Only to be produced for significant 
probsets based on adjusted p-values.
GSK To produce
SAC2[1]
81.
Safety
n/a
Raw SAS Output of Statistical Analysis of Blood Inflammatory 
Biomarkers
SAC[1]
82.
Safety
n/a
Raw SAS Output of Statistical Analysis of Blood Inflammatory 
Biomarkers by Dosing Regimen
SAC[1]
83.
Safety
n/a
Raw SAS Output of Statistical Analysis of TEAR1 Target 
Engagement in Blood
SAC[1]
84.
Safety
n/a
Raw SAS Output of Statistical Analysis of mRNA in Blood
GSK To produce
SAC2[1]


CONFIDENTIAL
203168
86
12.11.
Appendix 13: Example Mock Shells for Data Displays
Example: 
POP_L1 
Page 1 of n
Protocol: 203168                                                           
Population: Randomised
Listing of RA Disease History
Treatment Group
Site ID/ Unique 
Subject ID
Date of formal 
diagnosis
Time since formal 
diagnosis (years)
Date of onset of first 
musculoskeletal symptoms
Time since onset of 
first 
musculoskeletal 
symptoms (years)
GSK2982772
XX/XXXXX
DDMMMYYY
xx.x
DDMMMYYY
xx.x
XX/XXXXX
DDMMMYYY
xx.x
DDMMMYYY
xx.x
XX/XXXXX
DDMMMYYY
xx.x
DDMMMYYY
xx.x
…
…
…
…
…
…
PPD


CONFIDENTIAL
203168
87
Example:POP_L2 
Page 1 of 
n
Protocol: 203168                                                           
Population: Randomised
Listing of Dispensing Data
Treatment Group
Site ID/ Unique 
Subject ID
Visit
Container number
Number of 
tablets 
dispensed
Number of 
tablets 
returned
Treatment 
Compliance 
(%)1
GSK2928772
XX/XXXXX
Day 1
XXXXXX
xx
xx
XXXXXX
xx
xx
XXXXXX
xx
xx
XXXXXX
xx
xx
XXXXXX
xx
xx
XXXXXX
xx
xx
Day 29
XXXXXX
xx
xx
XXXXXX
xx
xx
XXXXXX
xx
xx
XXXXXX
xx
xx
XXXXXX
xx
xx
XXXXXX
xx
xx
Day 57
XXXXXX
xx
xx
XXXXXX
xx
xx
XXXXXX
xx
xx


CONFIDENTIAL
203168
88
XXXXXX
xx
xx
XXXXXX
xx
xx
XXXXXX
xx
xx
xx.x
XX/XXXXX
Day 1
XXXXXX
xx
xx
….
….
….
1 Compliance = (Total tablets taken/total tablets expected to be taken)*100.
Note: Compliance will only be calculated for subjects who took at least one dose.
PPD


CONFIDENTIAL
203168
89
Example EFF_T1
Page 1 of 1
Protocol: 203168                                                          
Population: Safety
Table XX:  Summary Statistics for [Continuous Parameter] by Treatment and Visit
Treatment
N
Visit
n
Mean
{95% CI
(Lower,Upper)}
SD
Median
Min.
Max.
Placebo
18
Day X
18
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xxx
xxxx.xx
xxxx.x
xxxx.x
Day Y
18
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xxx
xxxx.xx
xxxx.x
xxxx.x
Day Z
18
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xxx
xxxx.xx
xxxx.x
xxxx.x
...
GSK2982772
6
Day X
6
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xxx
xxxx.xx
xxxx.x
xxxx.x
Day Y
6
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xxx
xxxx.xx
xxxx.x
xxxx.x
Day Z
6
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xxx
xxxx.xx
xxxx.x
xxxx.x
...
PPD


CONFIDENTIAL
203168
90
Example EFF_T2
Page 1 of 1
Protocol: 203168                                                          
Population: Safety
Table XX:  Summary Statistics for Change from Baseline in [Continuous Parameter] by 
Treatment and Visit 
Treatment
N
Visit
n
Mean
{95% CI
(Lower,Upper)}
SD
Median
Min.
Max.
Placebo
18
Day X
18
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xxx
xxxx.xx
xxxx.x
xxxx.x
Day Y
18
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xxx
xxxx.xx
xxxx.x
xxxx.x
Day Z
18
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xxx
xxxx.xx
xxxx.x
xxxx.x
...
GSK2982772
6
Day X
6
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xxx
xxxx.xx
xxxx.x
xxxx.x
Day Y
6
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xxx
xxxx.xx
xxxx.x
xxxx.x
Day Z
6
xxxx.xx
(xxxx.xx,xxxx.xx)
xx.xxx
xxxx.xx
xxxx.x
xxxx.x
...
PPD


CONFIDENTIAL
203168
91
Example: EFF_T3
Protocol: 203168                                                                     Page 1 of x
Population: Safety
                                                 Table x.x:
               Repeated Measures Analysis of the Change from Baseline in [Continuous Parameter] 
                                                                   95% CI for     Difference    95% CI for
                             Treatment                    Standard    LSMean       from         Difference
                    Visit    Group       N  n   LSMean[1]     Error (Lower, Upper)  Placebo     (Lower,Upper)
                   ----------------------------------------------------------------------
                    Day XX   Placebo     xx x    x.xx     x.xxx   (x.xx, x.xx)
                             GSK2982772  xx x    x.xx    
x.xxx    (x.xx, x.xx)       x.xx       (x.xx, x.xx)
                             
                    Day XX   Placebo     xx x    x.xx     x.xxx   (x.xx, x.xx)
                             GSK2982772  xx x    x.xx     x.xxx   (x.xx, x.xx)       x.xx       (x.xx, x.xx)
                             
                     ...
Repeated Measures Analysis adjusted for Baseline Score, Treatment Group, Visit, Baseline Score by Visit and 
Treatment Group
by Visit Interaction
[1] LSMean is least squares adjusted mean.


CONFIDENTIAL
203168
92
Example: EFF_T4
Protocol: 203168                                                                     Page 1 of x
Population: Safety
Summary of DAS28(CRP) EULAR Response Categories
Visit
EULAR Category [1]
Treatment AN=xx
n   % (SE)
Treatment B
N=xx
n    % (SE)
Day X
n
No response
XX
Xx   xx (xx)
      xx
xx   xx (xx)
Moderate Response
xx   xx (xx)
xx   xx (xx)
Good Response
xx   xx(xx)
xx   xx (xx)
…
[1] Response at a given time point is defined based on the combination of current DAS28 score and the 
improvement in the current DAS28 score relative to baseline.
PPD


CONFIDENTIAL
203168
93
Example: EFF_T5
Protocol: 203168                                                                     Page 1 of x
Population: Safety
ACR20
Summary of ACR Response Rates [1]
Visit
Treatment A
N=xx
n    % (SE)
Treatment B
N=xx
n    % (SE)
Day X
n
No Response
Response
XX
xx   xx (xx)
xx   xx (xx)
XX  xx   xx (xx)
  xx   xx (xx)
DAY Y
n
No Response
xx
xx   xx (xx)
     xx
xx   xx (xx)
Response
xx   xx (xx)
xx   xx (xx)
[1] The American College of Rheumatology’s (ACR) definition for calculating improvement in RA is calculated as 
a 20% improvement (ACR20) in both tender and swollen joint counts and 20% improvement in at least 3 of the 5 
remaining ACR-core set measures: patient and physician global assessments, patient’s assessment of arthritis 
pain, disability (HAQ-DI), and an acute-phase reactant (i.e. CRP value).  Similarly, ACR50 and ACR70 are 
calculated with the respective percent improvement.  
Example: EFF_T6
Protocol: 203168                                                                     Page 1 of x
PPD


CONFIDENTIAL
203168
94
Population: Safety
Table XX
                Summary of Bayesian Analysis of Change from Baseline in DAS28-CRP at day 85
                                                            Probability (treatment difference > x),
     Treatment    SD of Treatment      95% Credible                        where x =
     Difference      Difference        Interval [1]            0       0.3       0.5       0.7         1
    ----------------------------------------------------------------------------------------------------
      x.xx          x.xx           (  x.xx,   x.xx)         xx.xx     xx.xx     xx.xx     xx.xx     xx.xx
A non-informative prior for the change in DAS28-CRP score from baseline in each treatment group was used,
thus maximising the information provided by the observed data; the prior follows a Normal(0,10^36)
distribution.
Note: A reduction in score on the DAS28-CRP scale is associated with disease improvement. The probability
statements above are shown on the positive scale, representing a difference in decline, therefore the larger
the difference in decline the greater the improvement over placebo.
[1] Interval is defined as the 2.5th and 97.5th percentiles of the posterior distribution.
PPD


CONFIDENTIAL
203168
95
Example: EFF_T7
Protocol: 203168                                                                     Page 1 of x
Population: Safety
Table XX
                              Summary of Bayesian Analysis of ACR20 at day 85
                                                            Probability (treatment difference > x),
     Treatment    SD of Treatment      95% Credible                        where x =
     Difference      Difference        Interval [1]            0         5        10        20        30
    ----------------------------------------------------------------------------------------------------
        xx.x         xx.xx           ( xx.xx,  xx.xx)     xx.xx     xx.xx     xx.xx      xx.xx      xx.xx
An non-informative prior for the probability of acheiving ACR 20 in each treatment group was used, thus
maximising the information provided by the observed data; the prior follows a Beta(1,1) distribution.
[1] Credible Interval is defined as the 2.5th and 97.5th percentiles of the posterior distribution.
PPD


CONFIDENTIAL
203168
96
Example: EFF_F1
Page 1 of 1
Protocol: 203168                                                           
Population: Safety
[Continuous Parameter,] Adjusted Mean (+/-SE) Change from Baseline and
Box and Whisker Plot of Unadjusted Change from Baseline by Treatment over Time


CONFIDENTIAL
203168
97
Example: EFF_F2
Page 1 of 1
Protocol: 203168                                                           
Population: Safety
Individual Subject Profiles for DAS28-CRP
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
203168
98
Example: EFF_F3
Page 1 of 1
Protocol: 203168                                                           
Population: Safety
Proportion of subjects in each DAS28-CRP EULAR Response Category
PPD


CONFIDENTIAL
203168
99
Example: EFF_F4
Page 1 of 1
Protocol: 203168                                                           
Population: Safety
Proportion of subjects achieving ACR20/50/70
PPD


CONFIDENTIAL
203168
100
Example: PD_T1
Protocol: 203167                                                                                 Page 1 of 7
Population: Safety
                                                 Table X.X
                            Summary Statistics of Blood Inflammatory Biomarkers
Parameter: X (Units)
                                   Planned
                                   Relative               {95% CI
Treatment            N Visit      Time       n   Mean    (Lower,Upper)}    SD       Median  Min.   Max.
-----------------------------------------------------------------------------------------------------------
Placebo              XX DAY 1      PRE-DOSE   XX   X.XX   ( X.XX, X.XX)      X.XXX    X.XX    X.X    XX.X
                        DAY 43     PRE-DOSE   XX   X.XX   ( X.XX, X.XX)      X.XXX    X.XX    X.X    XX.X
                        DAY 85     DAY 85     XX   X.XX   ( X.XX, X.XX)      X.XXX    X.XX    X.X    XX.X
GSK2982772           XX DAY 1      PRE-DOSE   XX   X.XX   ( X.XX, X.XX)      X.XXX    X.XX    X.X    XX.X
                        DAY 43     PRE-DOSE   XX   X.XX   ( X.XX, X.XX)      X.XXX    X.XX    X.X    XX.X
                        DAY 85     DAY 85     XX   X.XX   ( X.XX, X.XX)      X.XXX    X.XX    X.X    XX.X
PPD


CONFIDENTIAL
203168
101
Example: PD_T2
Protocol: 203168                                                                                 Page 1 of 7
Population: Safety
                                                 Table X.X
                       Summary of Percentage Change in Blood Inflammatory Biomarkers
Parameter: X (Units)
                      Mean     Planned
                      Baseline Relative              {95% CI
Treatment  N  Visit  [1]      Time       n  Mean    (Lower,Upper)}       SD        Median  Min.   Max.
---------------------------------------------------------------------------------------------------------
Placebo    XX DAY 43    X.XXX PRE-DOSE   XX  XX.XXX ( XX.XXX,XX.XXX)   XXX.XXXX    X.XXX    XX.XX  XX.XX
               DAY 85    X.XXX DAY 85     XX  XX.XXX ( XX.XXX,XX.XXX)   XXX.XXXX    X.XXX    XX.XX  XX.XX
GSK2982772 XX DAY 43    X.XXX PRE-DOSE   XX  XX.XXX ( XX.XXX,XX.XXX)   XXX.XXXX    X.XXX    XX.XX  XX.XX
               DAY 85    X.XXX DAY 85     XX  XX.XXX ( XX.XXX,XX.XXX)   XXX.XXXX    X.XXX    XX.XX  XX.XX
[1] Baseline is taken as the mean of the planned pre-dose measurements.


CONFIDENTIAL
203168
102
Example: PD_T3
Protocol: 203163                                                                                 Page 1 of 7
Population: Safety
                                                 Table X.X
                Adjusted Mean (95% CI) Percentage Change in Blood Inflammatory Biomarkers
Parameter: X (Units)
                                                                               Difference 95% CI for
                                                                                From        Difference
Visit     N  Treatment               n  Geometric            95% CI for        Placebo     Lower, Upper)
                                          LSMean    %CVb      LSMean            
----------------------------------------------------------------------------------------------------------
DAY 43   XX  Placebo                XX   XX.XX    XX.XXX    (XX.XX, XX.XX)
          XX  GSK2982772             XX   XX.XX    XX.XXX    (XX.XX, XX.XX)    XX.XX       (XX.XX, XX.XX)
DAY 85   XX  Placebo                XX   XX.XX    XX.XXX    (XX.XX, XX.XX)
          XX  GSK2982772             XX   XX.XX    XX.XXX    (XX.XX, XX.XX)    XX.XX       (XX.XX, XX.XX)
Note: Baseline is defined as the latest pre-dose assessment.
Note: Analysis performed using a MMRM model, adjusting for the following covariates: treatment, baseline,
Visit, baseline by visit and an interaction between treatment and visit.


CONFIDENTIAL
203168
103
Example: PD_T4
Protocol: 203168                                                                     Page 1 of x
Population: Safety
                                                 Table x.x:
               Adjusted Mean (95% CI) TEAR1 % Target Engagement in Blood
                               ___GSK LSMean___  _Placebo LSMean_
                               ___Engagement___  ___Engagement___  Treatment Ratio     Diff % Engagement
Visit   Comparison            Ratio    %        Ratio   %         (95% CI)            (95% CI)
----------------------------------------------------------------------------------------------------------
DAY 43  GSK2982772            X.XX      X      X.XX     X         X.XX (X.XX, X.XX)     X.X (X.X, X.X)
         vs Placebo
DAY 85  GSK2982772            X.XX      X      X.XX     X         X.XX (X.XX, X.XX)     X.X (X.X, X.X)
         vs Placebo
        
Note: Baseline is defined as the latest pre-dose assessment.
Note: Percentage target engagement = (1 - engagement ratio) * 100.
Repeated Measures Analysis adjusted for log baseline, Treatment Group, Visit, log baseline by Visit and 
Treatment Group by Visit Interaction


CONFIDENTIAL
203168
104
Example: PD_T5
Protocol: 203168                                                                     Page 1 of x
Population: Safety
Table XX.XX : 
Frequency table summarising the number of probe sets in various fold change 
                                                          Fold Change in Blood        
Probeset  Gene   Visit      N     n   Treatment           < 1.5        >1.5     
XXXXXX    XXXXXX Baseline  XX    XX
Placebo            xx (xx.xx)   xx (xx.xx)   
          
  
GSKXXXXXX XXmg     xx (xx.xx)   xx (xx.xx)
                 WEEK xx   XX    XX
Placebo            xx (xx.xx)   xx (xx.xx) 
          
  
GSKXXXXXX XXmg     xx (xx.xx)   xx (xx.xx) 
                 WEEK xx   XX    XX
Placebo            xx (xx.xx)   xx (xx.xx)
          
  
GSKXXXXXX XXmg     xx (xx.xx)   xx (xx.xx) 


CONFIDENTIAL
203168
105
Example: PD_T6
Protocol: 203168                                                                     Page 1 of x
Note: Fold change from baseline is defined as ratio to baseline if the ratio is >= 1, otherwise it is
defined as -1/ratio to baseline.
Programming note: Please present SE not 95% CI


CONFIDENTIAL
203168
106
Example: PD_F1                                                                               Page 1 of 1
Protocol: 203168                                                        
Population: Safety
Figure X
Individual [Continuous Parameter] Scores over Time by Treatment 
PPD
PPD
PPD
PPD


CONFIDENTIAL
203168
107
Example: PD_F2
Protocol: 203168                                                                     Page 1 of x
Population: Safety
Figure XX.XX: 
Adjusted mean probe set intensity values (+/- SE) by time from xxxx
Gene ID: XXXX


CONFIDENTIAL
203168
108
Example: PD_F3
Protocol: 203168                                                                     Page 1 of x
Population: Safety
Figure XX.XX: 
Adjusted Fold Change in mRNA Expression
Gene ID: XXXX
Programming note to present SE’s not 95% CI


CONFIDENTIAL
203168
109
Example: EFF_L1
Page 1 of n
Protocol: 203168                                                           
Population: Safety
Listing of MRI Data, Inflammatory Structural Joint Damage: RAMRIS
Treatment Group: Treatment A
Site ID/ 
Unique 
Subject ID
Visit
Number of 
Available 
Joints
Synovitis
Bone Erosion
Bone Edema/Osteitis
Cartilage Loss
XXXX/ XXXXX
Baseline 
xx
xxx
xxx
Xxx
xxx
Week X
xx
xxx
xxx
Xxx
xxx
Etc. 
XXXX/ XXXXX
Baseline 
xx
xxx
xxx
Xxx
xxx
Week X
xx
xxx
xxx
Xxx
xxx
Etc. 
PPD


CONFIDENTIAL
203168
110
Example: EFF_L2
Page 1 of n
Protocol: 203168                                                           
Population: Safety
Listing xx
Listing of MRI Data, Inflammatory Structural Joint Damage: RAMRIQ
Treatment Group: Treatment A
Site ID/ 
Unique 
Subject ID
Visit
Synovitis
Synovitis 
Normalized
Erosive Damage 
(Normalized)
Cartilage Space Loss
Bone Marrow 
Lesions
XXXX/ XXXXX
Baseline 
Week X
Etc. 
XXXX/ XXXXX
Baseline 
Week X
Etc. 
PPD


CONFIDENTIAL
203168
111
Example: EFF_L3
Page 1 of n
Protocol: 203168                                                           
Population: Safety
Listing xx
Listing of MRI Data, Inflammatory Structural Joint Damage: CARLOS
Treatment Group: Treatment A
Site ID/ 
Unique 
Subject ID
Visit
Result
XXXX/ XXXXX
Baseline 
Complete cartilage denuding or diffuse bone-on-bone contact 
Week X
Complete ankylosis
Etc. 
XXXX/ XXXXX
Baseline 
Week X
Etc. 
PPD


CONFIDENTIAL
203168
112
Example: EFF_L4
Page 1 of n
Protocol: 203168                                                           
Population: Safety
Listing of Joint Inflammation: DCE-MRI
Treatment Group: Treatment A
Site 
ID/ 
Uniqu
e 
Subje
ct ID
Visit
Exchan
ge 
Rate
Interstitial 
Volume
Plasma 
Volume
Joint 
Volume
Enhancing
Volumne
Initial Rate 
of Enhancement
Maximum signal 
intensity 
enhancement
XXXX/ 
XXXXX
Baseli
ne 
Week X
Etc. 
XXXX/ 
XXXXX
Baseli
ne 
Week X
Etc. 
PPD


CONFIDENTIAL
203168
113
Example: EFF_L5
Page 1 of n
Protocol: 203168                                                           
Population: Safety
Listing of Observed Swollen and Tender Joint States
Treatment Group: Treatment A
Site ID/Unique Subject ID: <Site ID/Subject ID>
Visit
Joints of Left 
Extremities
Joints of Right  
Extremities
Baseline Tender
Shoulder, Wrist, 
MCP3, PIP5
Elbow, 
Sternoclavicular, 
Hip, DIP3
PIP5
Swollen
Not available
Week X
…
…
Etc. 
Baseline 
Week X
Etc. 
PPD


CONFIDENTIAL
203168
114
Example: EFF_L6
Page 1 of n
Protocol: 203168                                                           
Population: Safety
Listing of DAS28-CRP, EULAR response and Joint Counts
Treatment Group: Treatment A
Site ID/ 
Unique Subject 
ID
Remission? 
Low disease 
Activity?
TJC28/ TJC68
SJC28/ SJC66
Visit
XXXX/ XXXXX
Yes
xx.x/ xx.xx
xx.x/ xx.xx
Baseline 
xx.x/ xx.xx
xx.x/ xx.xx
Week X
Etc.
Etc.
Etc. 
XXXX/ XXXXX
No
xx.x/ xx.xx
xx.x/ xx.xx
Baseline 
xx.x/ xx.xx
xx.x/ xx.xx
Week X
Etc.
Etc.
Etc. 
Note: DAS28(CRP) remission is achieved by a DAS28(CRP) value lower than 2.6 and DAS28(CRP) Low Disease Activity is 
defined as a DAS28 score of <3.2.
PPD


CONFIDENTIAL
203168
115
Example: EFF_L7
Page 1 of n
Protocol: 203168                                                           
Population: Safety
Listing of ACR Response Rates and ACR Components
Treatment Group: Treatment A
Site ID/ Unique 
Subject ID
Visit
TJC68
SJC66
PtGA
PhGA
Pt Pain
CRP Value
HAQ-DI
ACR 
20/50/70 
Response
XXXX/ XXXXX
Week 1
Xx
xx
xx
xx
xx
xx
xx
ACR 50
Week 2
Xx
xx
xx
xx
Xx
xx
xx
Etc. 
Xx
xx
xx
xx
Xx
xx
xx
ACR 20
Xx
XXXX/ XXXXX
Week 1
Xx
xx
xx
xx
Xx
xx
xx
Week 2
Xx
xx
xx
xx
Xx
xx
xx
Etc. 
Note: Listing shows percentage change from Baseline. For all components, negative values represent improvement. 
Note: ACR20 is achieved for a 20% improvement in both TJC68 and SJC66 and 20% improvement in 3 of the 5 remaining 
components. ACR50 and ACR70 are defined accordingly.
PPD


CONFIDENTIAL
203168
116
Example: EFF_L8
Page 
1 of n
Protocol: 203168                                                           
Population: Safety
Listing of HAQ-DI
Treatment Group: Treatment A
Site ID/Unique Subject ID: <Site ID/Subject ID>
Dress & 
Groom
Rising
Eating
Walking
Hygiene
Reach
Grip
Activity.
Visit
Dress/ 
Wash 
hair
Stand 
up/ Get 
in Bed
Cut 
meat/ 
Lift 
Cup/ 
Open 
Milk
Walk/ 
Climb 
stairs
Wash 
Body/ 
Have 
Bath/ 
Toilet
Reach/ 
Bend
Open 
Car/ 
Open 
Jar/ 
Turn Tap
Shop/ 
Car/ 
Chores
Aids or 
Equipment
Help 
from 
another 
Person
HAQ-DI 
SCore
Baseline 
1/3
0/2
0/2/2
1/3
0/2/2
2/2
0/2/1
0/2/2
Crutches
Eating, 
Rising
XX
Week X
x/x
x/x
x/x/x
x/x
x/x/x
x/x
x/x/x
x/x/x
XXXXX
XXXXX, 
XXXXX
Etc. 
…
…
…
…
…
…
…
…
…
…
Note: 0 = Without any difficulty. 1 = With some difficulty. 2 = With much difficulty. 3 = Unable to do.
Note: HAQ-DI Pain Sore can be found in Listing 20.
Note: Functional areas in order of the columns are: Dress & Groom, Rising, Eating, Walking, Hygiene, Reach, Grip, 
Activity
PPD


CONFIDENTIAL
203168
117
Example: EFF_L9
Page 1 of n
Protocol: 203168                                                           
Population: Safety
Listing of RA Symptom and Impact Diary [1]
Treatment Group: Treatment A
Site ID/ 
Unique 
Subject 
ID
Visit
Joint Pain 
Sitting/ 
Lying/ 
Moving
Joint Pain 
Walking/ 
Standing/ 
Lifting
Joint 
Paint 
at its 
Worst
Energy/ 
Tired
Stiffness/ 
Morning 
Stiffness
Morning 
Stiffness 
Duration
Joint 
Stiffness 
Severity
Had 
to 
Rest
Sleep 
Quality/ 
Affection
XX/XXXXX
Day X
2/ 5/ 5
4/ 3/ 4
3
No 
Energy/ 
A little 
of the 
time 
All of the 
time/ Mild
Less than 
30 Minutes
Mild
All 
of 
the 
time
Bad/ A 
little
XX/XXXXX 
Day Y
0/ 4/ 10
2/ 5/ 5
10
Some 
Energy/ 
All of 
the time
None of the 
time/ Very 
severe
No morning 
stiffness
Severe
Most 
of 
the 
time
Very 
Good/ 
Somewhat
XX/XXXXX
Day Z
2-4 Hours
XX/XXXXX
[1] Symptoms rated relative to the last 24 hours
PPD


CONFIDENTIAL
203168
118
Example: EFF_L10
Page 1 of n
Protocol: 203168                                                           
Population: Safety
Listing of Patient and Physician Global Assessment [1]
Treatment Group: Treatment A
Site ID/ 
Unique 
Subject 
ID
Visit
Actual Date
Study Day
Physician 
Assessment [1]
Patient 
Assessment
[2]
XX/XXXXX
Day X
XX
XX
XX/XXXXX 
Day Y
XX/XXXXX
Day Z
XX/XXXXX
[1]  Physician assessment of disease activity using the visual analogue scale with anchor’s “0” (none) to “10” (extremely active).
[2]  Patients assessment of how they feel today, using the visual analogue scale with anchor’s “0” (Very good)” to “10” (very poor).
PPD


CONFIDENTIAL
203168
119
Example: EFF_L11
Page 1 of n
Protocol: 203168                                                           
Population: Safety
Listing of Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale [1]
Treatment Group: Treatment A
Site ID/ 
Unique 
Subject 
ID
Visit
Actual Date
Study Day
Category
Response
      
Total 
Score
XX/XXXXX
Day X
I feel fatigued
Not at all
    XX
XX/XXXXX 
I feel weak all over
I feel listless (“washed out”)
I feel tired
I have trouble starting things because I 
am tired
I have trouble finishing things because I 
am tired
I have energy
I am able to do my usual activities
I need to sleep during the day
I am too tired to eat
I need help doing my usual activities
I am frustrated by being too tired to do 
the things I want to do
I have to limit my social activity because 
I am tired
A little bit
Somewhat
Quite a bit
Very much
A little bit
Somewhat
Not at all
A little bit
A little bit
Somewhat
Quite a bit
Not at all
Somewhat
XX/XXXXX
Day Z
XX/XXXXX


CONFIDENTIAL
203168
120
[1]  A global assessment of disease activity using the a visual analogue scale with anchor’s “0” (none) to “10” (extremely active).
Example: EFF_L12
Page 1 of n
Protocol: 203168                                                           
Population: Safety
Listing of Patient Assessment of Joint Pain [1]
Treatment Group: Treatment A
Site ID/ 
Unique 
Subject 
ID
Visit
Actual Date
Study Day
Patient 
Assessment
XX/XXXXX
Day X
XX
XX/XXXXX 
Day Y
XX/XXXXX
Day Z
XX/XXXXX
[1]   RA pain on average over the past 24 hours: using a visual analogue scale with anchor’s “0” (no pain) to “10” (most severe pain).
PPD
PPD


CONFIDENTIAL
203168
121
Example 
: PD_L1
Page 1 of n
Protocol
: 203168
Population
: Safety
                                                 Listing XX: 
Listing of Raw, Change from baseline and Percent Change in [variable}


CONFIDENTIAL
203168
122
Example 
: PD_L2
Page 1 of n
Protocol
: 203168
Population
: Safety
                                                 Listing XX: 
  Listing of Absolute, Percentage Inhibition and Maximum Percentage Inhibition in mRNA Expression
                                                            CT1/CT2/                            Maximum
                                                            CTAVG/                Percentage    Percentage
                                                            Copy                  Inhibition    Inhibition
Gene        Treatment              Subject   Visit          Number         Value  [1]           [2]
------------------------------------------------------------------------------------------------------------
XXXXGENE    GSKXXXXXX XXmg         XXXX      Screening      CT1           XX.XXX
                                                            CT2           XX.XXX
                                                            CTAVG         XX.XXX
                                                            NORMALISED    XX.XXX
                                             Baseline       CT1           XX.XXX
                                                            CT2           XX.XXX
                                                            CTAVG         XX.XXX
                                                            NORMALISED    XX.XXX     x.xxx
                                             Week X         CT1           XX.XXX
                                                            CT2           XX.XXX
                                                            CTAVG         XX.XXX
                                                            NORMALISED    XX.XXX     x.xxx


CONFIDENTIAL
203168
123
Example PD_L3
Protocol: 203168                                                                                Page 1 of 64
Population: All Subjects
                                                 Listing 79
                      Listing of TEAR1 Concentrations and % Target Engagement: Part B
Treatment: Treatment A
                                                    Planned                                     % Target
    Inv./                  Actual                   Relative                  Conc            Engagement
    Subj.         Date      Time    Visit           Time                   (pg/mL)  Ratio[1]         [2]
    ----------------------------------------------------------------------------------------------------
   
   
    9:42   DAY 1          PRE-DOSE    Free       9.31504    0.4670
   
               
                                       Total     19.94849
   
               
   11:51   DAY 1           1.5 HR      Free       5.11583    0.3894      16.605
               
                                       Total     13.13721
               
   18:20   DAY 1
    8 HR        Free       8.01224    0.3926      15.929
               
                                       Total     20.40949
               
   10:09   DAY 1
    24 HR       Free       7.82238    0.3761      19.456
               
                                       Total     20.79845
               
    9:11   DAY 14
   PRE-DOSE    Free       8.06836    0.3705      20.666
                                                                Total     21.77966
                            10:50   DAY 14  
   1.5 HR      Free       8.44182    0.4155      11.012
                                                                Total     20.31552
                            17:21   DAY XX
   8 HR        Free       7.80388    0.3734      20.033
                                                                Total     20.89901
Note: Only Tru Culture results are included.
[1] Ratio=Free/Total
[2] %Target Engagement = 100 - ((ratio post/ ratio pre-dose)* 100).
PPD
PPD
PPD


CONFIDENTIAL
203168
124
Example: PK_F1
Protocol: 203168                                                                                  Page 1 f x
Population: PK772
Figure XX.XX:  GSK2982772 Trough Plasma Concentration by Study Day
PPD
PPD


CONFIDENTIAL
203168
125
USE THIS SHELL FOR FIG. 4.6 AS WELL.
Example: PK_F2
Protocol: 203168                                                                                   Page 1 of x
Population: PK772
Figure XX.XX:  GSK2982772 Trough Plasma Concentration by Study Day
Trough Plasma Concentration (ng/mL)
PPD


CONFIDENTIAL
203168
126
Example: PK_F3
Protocol: 203168                                                                                   Page 1 of x
Population: PK772
Figure XX.XX:  GSK2982772 Plasma Concentration by Time relative to Dose
Plasma Concentration (ng/mL)
PPD
PPD


CONFIDENTIAL
203168
127
Include Day1, 8 and 43 as separate pages
Example: PK_F4
Protocol: 203168                                                                                  Page 1 of x
Population: PK772
Figure XX.XX:  Mean GSK2982772 Plasma Concentration Data by Time Relative to Dose by Study Day
PPD


CONFIDENTIAL
203168
128
Example: PK_F5
Protocol: 203168                                                                                   Page 1 of x
Population: PK772
Figure XX.XX:  Mean GSK2982772 Plasma Concentration Data by Time Relative to Dose by Randomized Regimen
PPD


CONFIDENTIAL
203168
129
Example: PK_F6
Protocol: 203168                                                                                   Page 1 of x
Population: PK772
Figure XX.XX:  GSK2982772 Plasma Trough Concentration vs Blood TEAR1% Target engagement
Blood TEAR1% Target Engagement
PPD