Conditions: Arthritis, Rheumatoid
Keywords: pharmacodynamics tolerability GSK3117391 safety efficacy rheumatoid arthritis pharmacokinetics
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3
Healthy volunteers: no

Brief summary:
GSK3117391 has the potential to complement existing therapies in the treatment of chronic inflammatory disorders such as rheumatoid arthritis (RA). This study will evaluate the efficacy, safety and tolerability of oral GSK3117391 (Dose A) administered to subjects with severe RA despite treatment with disease-modifying anti-rheumatic drugs (DMARDs). This is a randomised, double-blind (sponsor open), multicentre, placebo-controlled, parallel group study. The total maximum study duration is approximately 10 weeks. Following a screening period of up to 28 days, subjects will be randomized (1:1) to placebo or GSK3117391 (Dose A) administered orally for a period of 28 days. Subjects will be followed up for 7 to 14 days post final dose. Approximately 40 subjects with severe RA will be randomised into the study.

Detailed description:

Arms:
arm 1: Subjects will receive GSK3117391 (Dose A) for 28 days. arm 2: Subjects will receive placebo for 28 days.

Interventions: intervention 1: GSK3117391 intervention 2: Placebo
Intervention descriptions: intervention 1: GSK3117391 (Dose A) is a white, opaque, gelatin capsule. intervention 2: Placebo is a white, opaque, gelatin capsule.

Protocol document:
Prot_000.pdf: 
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A randomised, multi-center, double blind (sponsor open), 
placebo-controlled study to assess the efficacy, safety, 
tolerability, pharmacokinetics and pharmacodynamics of 
GSK3117391 in subjects with severe, active rheumatoid arthritis
Compound Number:
GSK3117391
Development Phase:
II
Effective Date:
01-JUN-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.
 
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Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2016N270377_00
2016-APR-25
Original
2016N270377_01
2016-JUN-02
Re-Published
Changes made to remove synovial tissue biopsy & correct typographical errors
2016N270377_02
2016-SEP-15
Amendment No. 1
The changes in this amendment are to address typographical errors and inconsistency 
between the Time and Events tables (Table 2, Table 3) and the protocol text, particularly 
with respect to lab parameters (MetHb, coagulation, requirement for clinical 
chemistry/urinalysis at day 7,14 and 21 and PD biomarkers)
2016N270377_03
2016-DEC-08
Amendment No. 2
The changes in this amendment are to combine the iSRC and DRC interim review 
committees, in addition to changes for clarification between the Time and Events table 
and the text of the protocol.
2016N270377_04
2017-JUN-01
Amendment No. 3
This amendment has been created to provide clarity regarding extension to the screening 
window for the washout of background DMARDs, ensuring blinding of the monocyte 
count during the study conduct, and other study requirements throughout the protocol. In 
addition, further detail has been added to some of the inclusion/exclusion criteria and 
assessment requirements for clarification.
 
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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 
GSK Clinical unit 
Cambridge
Hills Road , 
Cambridge, 
Cambridgeshire, 
CB2 2 GG
Secondary 
Medical 
Monitor
GSK, Gunnels 
Wood Road, 
Stevenage, Herts, 
SG1 2NY
SAE 
contact  
information 
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 2015-005800-27
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol 204957
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 204957......................................................10
2.
INTRODUCTION....................................................................................................12
2.1.
Study Rationale ..........................................................................................12
2.2.
Brief Background ........................................................................................12
3.
OBJECTIVES AND ENDPOINTS...........................................................................13
4.
STUDY DESIGN ....................................................................................................14
4.1.
Overall Design ............................................................................................14
4.2.
Treatment Arms and Duration.....................................................................15
4.2.1.
Screening ....................................................................................15
4.2.2.
Treatment Period.........................................................................15
4.2.3.
Follow up period ..........................................................................15
4.3.
Type and Number of Subjects.....................................................................15
4.4.
Design Justification.....................................................................................15
4.5.
Dose Justification........................................................................................16
4.6.
Benefit: Risk Assessment ...........................................................................18
4.6.1.
Risk Assessment .........................................................................18
4.6.2.
Benefit Assessment.....................................................................21
4.6.3.
Overall Benefit:Risk Conclusion...................................................21
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............21
5.1.
Inclusion Criteria.........................................................................................21
5.2.
Exclusion Criteria........................................................................................24
5.3.
Screen Failures...........................................................................................27
5.3.1.
Re-Screening...............................................................................27
5.3.2.
Re-Testing...................................................................................27
5.3.2.1.
Laboratory Tests ........................................................27
5.3.2.2.
Electrocardiogram (ECG) Test ...................................28
5.4.
Withdrawal/Stopping Criteria.......................................................................29
5.4.1.
Individual Safety Stopping Criteria ...............................................29
5.4.2.
Liver Chemistry Stopping Criteria ................................................30
5.4.2.1.
Study Treatment Restart or Rechallenge....................30
5.4.3.
QTc Stopping Criteria ..................................................................31
5.4.3.1.
Study Treatment Restart or Rechallenge....................31
5.4.4.
Haematologic Stopping Criteria ...................................................31
5.4.4.1.
Study Treatment Restart or Rechallenge....................32
5.5.
Subject and Study Completion....................................................................32
6.
STUDY TREATMENT ............................................................................................32
6.1.
Investigational Product and Other Study Treatment....................................32
6.2.
Treatment Assignment................................................................................32
6.3.
Planned Dose Adjustments.........................................................................33
6.4.
Blinding.......................................................................................................33
6.5.
Packaging and Labeling..............................................................................34
6.6.
Preparation/Handling/Storage/Accountability..............................................34
6.7.
Compliance with Study Treatment Administration.......................................35
 
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6.8.
Treatment of Study Treatment Overdose....................................................35
6.9.
Treatment after the End of the Study ..........................................................36
6.10.
Lifestyle and/or Dietary Restrictions............................................................36
6.10.1.
Meals and Dietary Restrictions ....................................................36
6.10.2.
Caffeine, Alcohol, and Tobacco ...................................................36
6.11.
Concomitant Medications and Non-Drug Therapies....................................36
6.11.1.
Permitted Medications and Non-Drug Therapies..........................36
6.11.1.1.
Oral Corticosteroids....................................................36
6.11.1.2.
NSAIDs ......................................................................37
6.11.1.3.
Analgesics..................................................................37
6.11.1.4.
Other ..........................................................................37
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................37
6.11.2.1.
Complementary Therapies .........................................39
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................39
7.1.
Time and Events Tables .............................................................................40
7.2.
Screening and Critical Baseline Assessments ............................................44
7.3.
Efficacy.......................................................................................................45
7.3.1.
Patient Reported Outcomes.........................................................45
7.3.1.1.
Disability Index of the Health Assessment 
Questionnaire (HAQ-DI) .............................................45
7.3.1.2.
Patient’s Assessment of Arthritis Pain (PtAAP)...........45
7.3.1.3.
Patient’s Global Assessment of Arthritis (PtGA) .........45
7.3.2.
Joint assessments .......................................................................46
7.3.2.1.
Replaced or Fused Joints...........................................46
7.3.2.2.
Independent Joint Evaluator.......................................46
7.3.3.
Physician’s Global Assessment of Arthritis (PhGA)......................46
7.3.4.
Measurement of Serum CRP.......................................................46
7.4.
Derived measurements...............................................................................47
7.4.1.
DAS28 measurements.................................................................47
7.4.2.
ACR measurements ....................................................................47
7.5.
Safety .........................................................................................................47
7.5.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........48
7.5.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................48
7.5.1.2.
Method of Detecting AEs and SAEs ...........................48
7.5.1.3.
Follow-up of AEs and SAEs........................................49
7.5.1.4.
Cardiovascular and Death Events ..............................49
7.5.1.5.
Regulatory Reporting Requirements for SAEs............49
7.5.2.
Pregnancy ...................................................................................49
7.5.3.
Physical Exams ...........................................................................50
7.5.4.
Vital Signs....................................................................................50
7.5.5.
Electrocardiogram (ECG).............................................................50
7.5.6.
Clinical Safety Laboratory Assessments ......................................50
7.6.
Pharmacokinetics .......................................................................................52
7.6.1.
Blood Sample Collection..............................................................52
7.6.2.
Urine Sample Collection ..............................................................53
7.6.3.
Monocyte isolation.......................................................................53
7.6.4.
Sample Analysis ..........................................................................53
7.7.
Pharmacodynamic Biomarkers ...................................................................54
7.7.1.
PD Biomarkers.............................................................................54
7.7.2.
RA disease biomarkers................................................................54
 
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7.7.2.1.
Blood Biomarkers .......................................................54
7.7.3.
Novel biomarkers.........................................................................54
7.8.
Genetics .....................................................................................................55
8.
DATA MANAGEMENT ...........................................................................................55
9.
STATISTICAL CONSIDERATIONS AND DATA.....................................................55
9.1.
Hypotheses.................................................................................................55
9.2.
Sample Size Considerations.......................................................................55
9.2.1.
Sample Size Assumptions ...........................................................55
9.2.2.
Sample Size Sensitivity................................................................56
9.2.3.
Sample Size Re-estimation or Adjustment...................................56
9.3.
Data Analysis Considerations .....................................................................56
9.3.1.
Analysis Populations and Datasets..............................................56
9.3.2.
Interim Analysis ...........................................................................57
9.4.
Key Elements of Analysis Plan ...................................................................57
9.4.1.
Primary Analyses.........................................................................57
9.4.2.
Secondary Analyses ....................................................................57
9.4.2.1.
Safety Analyses..........................................................57
9.4.2.2.
Secondary Efficacy Analyses .....................................58
9.4.2.3.
Pharmacokinetic Analysis...........................................58
9.4.2.4.
Pharmacokinetic/Pharmacodynamic Analyses ...........59
9.4.3.
Other Analyses ............................................................................59
10. STUDY GOVERNANCE CONSIDERATIONS........................................................59
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............59
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................59
10.3.
Quality Control (Study Monitoring) ..............................................................60
10.4.
Quality Assurance.......................................................................................60
10.5.
Study and Site Closure ...............................................................................61
10.6.
Records Retention......................................................................................61
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................63
10.8.
Review Committees....................................................................................63
10.8.1.
Safety Review Team....................................................................63
10.8.2.
Data Review Committee ..............................................................63
11. REFERENCES.......................................................................................................64
12. APPENDICES........................................................................................................65
12.1.
Appendix 1: Abbreviations and Trademarks................................................65
12.2.
Appendix 2: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................68
12.2.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............68
12.2.2.
Collection of Pregnancy Information ............................................69
12.2.3.
References ..................................................................................71
12.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................73
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................76
 
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12.4.1.
Definition of Adverse Events........................................................76
12.4.2.
Definition of Serious Adverse Events...........................................77
12.4.3.
Definition of Cardiovascular Events .............................................78
12.4.4.
Recording of AEs and SAEs ........................................................79
12.4.5.
Evaluating AEs and SAEs............................................................79
12.4.6.
Reporting of SAEs to GSK...........................................................81
12.5.
Appendix 5: Genetic Research ...................................................................82
12.6.
Appendix 6: Country Specific Requirements...............................................85
12.7.
Appendix 7: Protocol Changes....................................................................86
 
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1.
PROTOCOL SYNOPSIS FOR STUDY 204957
Rationale
GSK3117391 is a Histone deacetylase (HDAC) inhibitor that uses Esterase Sensitive 
Motif (ESM) technology to specifically target cells of the mononuclear myeloid lineage.  
The administered ester is hydrolysed by an intracellular esterase (human carboxy-
esterase-1, hCE-1) to its acid GSK3339189 in myeloid cells as a result of the preferential 
expression of hCE-1 in these lineages. Such targeting of myeloid cells, which play a key 
role in inflammatory disease, and the consequent reduction in non-myeloid-related side 
effects should lead to a large therapeutic window.  As a result, GSK3117391 has the 
potential to complement existing therapies in the treatment of chronic inflammatory 
disorders such as rheumatoid arthritis (RA).  This study will evaluate the efficacy, safety 
and tolerability of 40 mg oral GSK3117391 every other day in subjects with severe RA 
despite treatment with disease-modifying anti-rheumatic drugs (DMARDs). 
Objectives/Endpoints
Objectives
Endpoints
Primary
To assess the efficacy of GSK3117391 in 
subjects with severe RA following every other 
day dosing
Change from baseline in Disease Activity Score 
DAS28-CRP at Day 28
Secondary
To assess the safety and tolerability of 
GSK3117391 following every other day dosing
Adverse events
Vital signs (HR, BP & Temperature)
ECGs
Clinical laboratory tests (haematology, 
biochemistry and urinalysis)
To assess the efficacy of GSK3117391 on other 
clinical endpoints following every other day 
dosing
ACR responders (ACR20, ACR50, ACR70)
Number of swollen joints assessed using 28-
joint counts
Number of tender/painful joints assessed using 
28-joint counts
Change from baseline in DAS28-CRP over time
To assess the pharmacokinetics following every 
other day dosing of GSK3117391
Plasma concentrations and derived 
pharmacokinetics (PK) parameters of 
GSK3117391 and GSK3339189 
To investigate the monocyte numbers after 
every other day dosing with GSK3117391
Changes in monocyte numbers over time
To assess the effects of GSK3117391 on 
biomarkers of inflammation in the blood 
Changes from baseline in blood biomarkers, 
including but not limited to:
C-reactive protein (CRP),
Soluble cytokine and inflammatory mediators
Myeloid-related protein 8/14 (MRP8/14)
 
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Overall Design
This is a randomised, double-blind (sponsor open), multicentre, placebo-controlled, 
parallel group study to evaluate the efficacy, safety and tolerability, PK and PD of 
GSK3117391 in subjects with RA resistant to DMARD therapy. 
Treatment Arms and Duration
The total maximum study duration is approximately 10 weeks (not including any 
rescreen). Following a screening period of up to 28 days, or up to 56 days, if required 
only for the washout of background DMARD therapy, subjects will be randomised (1:1) 
to placebo or 40 mg GSK3117391 orally-administered every other day for a period of 28 
days. Subjects will be followed up for 7-14 days post final dose.
Type and Number of Subjects
Approximately 40 subjects with severe RA despite treatment with DMARDs will be 
randomised into the study. 
Analysis
Hypotheses and Treatment Comparisons: The study will evaluate the effect of 
GSK3117391 relative to placebo on the change from baseline in DAS28-CRP after 4 
weeks of treatment.  The primary analysis will test the null hypothesis of no treatment 
effect against the alternative hypothesis that that there is a difference in DAS28-CRP 
change from baseline between the active and placebo groups using a Mixed effect Model 
for Repeated Measures (MMRM), adjusting for baseline DAS28-CRP score. A secondary 
analysis of the primary endpoint will use the Bayesian framework to determine posterior 
probabilities of the difference in DAS28-CRP change from baseline between the 
treatment groups.
Sample Size Calculations:The properties of DAS28-CRP based on historical variability 
data and the 20 subjects randomised to each study arm are outlined in Section 9.2.
Interim analysis: An interim analysis of difference in change in DAS28-CRP may lead 
to a decision to stop the study for futility.
 
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2.
INTRODUCTION
2.1.
Study Rationale
This study will evaluate the efficacy, safety and tolerability of 40 mg oral GSK3117391 
every other day in subjects with severe RA. In addition, the effects on monocytes seen in 
the first time in human study (201302) will be evaluated further. Furthermore, this study 
will enable the exploration of pharmacokinetics (PK) and pharmacodynamics (PD) using 
every other day dosing, as results from study 201302 have shown that once daily dosing 
appears to result in higher levels of the acid form of GSK3117391 (defined as 
GSK3339189) being retained in monocytes than may be necessary for maximal 
pharmacological engagement. 
2.2.
Brief Background
Histone deacetylase (HDAC) inhibitors have been shown to be active in various models 
of inflammation (Lin, 2007; Nishida, 2004; Joosten, 2011; Glauben, 2008) and to have 
anti-inflammatory activity in clinical studies (Vojinovic, 2011; Furlan, 2011). However 
there is a concern that, because of their pleiotropic activity, it may be challenging to 
obtain a therapeutic window wide enough to allow their extensive use in the treatment of 
inflammatory disorders such as RA. 
GSK3117391 is an HDAC inhibitor that uses Esterase Sensitive Motif (ESM) 
technology, whereby an ester is hydrolysed by an intracellular esterase to a more polar 
acid which accumulates in cells that express carboxy-esterase-1 (hCE-1).  GSK3117391 
is selectively hydrolysed to the active acid, GSK3339189 by hCE-1, which is 
predominantly expressed in myeloid cells, leading to selective accumulation of 
GSK3339189 in cells of that lineage (such as monocytes, macrophages and dendritic 
cells). Using ESM technology to target myeloid cells, which play a key role in 
inflammatory disease, should lead to consequent reduction in non-myeloid-related side 
effects allowing a greater therapeutic window. As a result, GSK3117391 has the potential 
to become an extremely important agent in the treatment of chronic inflammatory 
disorders such as RA. 
RA is an inflammatory joint disease where macrophages and monocytes become 
activated and infiltrate the synovial membranes, secreting inflammatory cytokines such 
as tumour necrosis factor (TNF) α and interleukins (IL) -1, -6 and -8 (Li, 2013).   These 
cytokines activate fibroblast-like synoviocytes which produce enzymes that damage the 
bones and cartilage.  DMARDs are the fundamental treatment for patients with RA. 
Methotrexate (MTX) is the gold standard treatment and it effectively reduces clinical 
disease measures in a large proportion of patients.  However, only 30% of RA patients 
will have low disease activity with MTX alone and in the population failing to respond, 
combination treatment with biological DMARDs targeted to cytokines, B-cells or T-cells, 
is the preferred option (O'Dell, 2013).  A subset of these patients will still fail to achieve 
meaningful responses to treatment, or experience adverse events (AEs), and will continue 
to experience severely debilitating symptoms (Rubbert-Roth, 2009).  Therefore, there 
continues to be a current unmet need for more effective treatments for RA with novel 
mechanisms of action in patients refractory to conventional and biological DMARDs.  As 
 
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an orally active, myeloid-targeted small molecule, GSK3117391 represents an attractive 
alternative to the currently approved anti-cytokine antibodies and non-selective, oral anti-
inflammatory agents, such as Janus Kinase (JAK) inhibitors.
In the first clinical study with GSK3117391 (201302; GlaxoSmithKline Document 
Number 2014N193968_00 26-MAY-2015   A Phase I Double-Blind, Randomised, 
Placebo-controlled, Dose Escalating Study to Assess the Safety and Tolerability of Single 
and Multiple Oral Doses of CHR-5154 and the Effect of the Fasted and Fed State on 
Pharmacokinetics of CHR-5154 and CHR-5426 in Healthy Male Volunteers), cohorts of 
healthy volunteers received oral doses of GSK3117391 either as single ascending doses 
up to 60 mg or as multiple ascending doses of up to 40 mg once daily for 7 days. This 
study characterised the PK of GSK3117391 and its acid GSK3339189. No clinically 
significant adverse events were observed and GSK3117391 was well tolerated. A 
decision was made to stop the study prior to proceeding to the final repeat dose cohort 
following the emergence of an unexpected PD effect, namely a depletion of circulating 
monocytes that was observed following both single and multiple doses. Importantly, this 
effect was transient and reversible with no observed clinical effects and was not 
associated with any adverse events or Dose Limiting Toxicities (DLTs). 
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To assess the efficacy of GSK3117391 in 
subjects with severe RA following every other 
day dosing
Change from baseline in DAS28-CRP at Day 28
Secondary
To assess the safety and tolerability of 
GSK3117391 following every other day dosing
Adverse events
Vital signs (HR, BP & Temperature)
ECGs
Clinical laboratory tests (haematology, 
biochemistry and urinalysis)
To assess the efficacy of GSK3117391 on other 
clinical endpoints following every other day 
dosing
ACR responders (ACR20, ACR50, ACR70)
Number of swollen joints assessed using 28-
joint counts
Number of tender/painful joints assessed using 
28-joint counts
Change from baseline in DAS28-CRP over time
Note that components of composite endpoints 
(ACR response, DAS28-CRP) at all assessment 
timepoints will also be reported separately.
To assess the pharmacokinetics following every 
other day dosing of GSK3117391
Plasma concentrations and derived 
pharmacokinetics (PK) parameters of 
GSK3117391 and GSK3339189 
To investigate the monocyte numbers after 
every other day dosing with GSK3117391
Changes in monocyte numbers over time
 
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Objectives
Endpoints
To assess the effects of GSK3117391 on 
biomarkers of inflammation in the blood 
Changes from baseline in blood biomarkers, 
including but not limited to:
C-reactive protein (CRP),
Soluble cytokine and inflammatory mediators
Myeloid-related protein 8/14 (MRP8/14)
Exploratory 
To assess the intracellular pharmacokinetics 
following every other day dosing of 
GSK3117391
Where possible, intracellular concentrations and 
derived PK parameters of GSK3339189 
following every other day repeat doses
To evaluate the PD of GSK3117391 following 
every other day dosing
Acetylation levels in monocytes, lymphocytes 
and granulocytes in peripheral blood
To explore the effects of GSK3117391 on the 
leukocyte population
Cell marker quantification using flow cytometry
To investigate the effect of GSK3117391 on 
inflammatory gene expression in blood 
Change from baseline in inflammatory gene 
expression in blood
4.
STUDY DESIGN
4.1.
Overall Design
This is a randomised, double-blind (sponsor open), multicentre, placebo-controlled, 
parallel group study to evaluate the efficacy, safety and tolerability, PK and PD of 
GSK3117391 in subjects with severe RA resistant to DMARD therapy. Approximately 
40 subjects will be randomised to either GSK3117391 or placebo to be taken every other 
day for 28 days of treatment. In addition to weekly visits for safety and efficacy 
assessments, subjects will be intensively sampled after the first and final doses to allow 
for thorough investigation of the PK and PD effects of GSK3117391. The maximum total 
duration of the study is approximately 10 weeks from screening to the last study visit. See 
Figure 1 for a study schematic.
Figure 1
Study schematic
1  The screening window can be extended for up to 56 days to allow only for the washout of background 
DMARD therapy if necessary
 
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4.2.
Treatment Arms and Duration
4.2.1.
Screening
All subjects must provide written informed consent for the study prior to the start of 
screening period. Subjects will be screened up to 28 days prior to the Day 1 visit 
(randomisation and start of the treatment period). The screening window can be extended 
for up to 56 days to allow only for the washout of background DMARD therapy if 
necessary (see Section 6.11.2 for washout periods for DMARD therapies and other 
medications). Subjects on medications requiring longer washout than 56 days prior to 
Day 1 must have discontinued medication for the stated washout time in Section 6.11.2
before being considered for eligibility in this study.
All other screening assessments must be performed within 28 days prior to Day 1(dosing 
Day 1).
4.2.2.
Treatment Period
Subjects will be randomised to either GSK3117391 or placebo in a 1:1 ratio, i.e. 20 
subjects per arm. Treatment will be taken once every other day for a period of 28 days 
(14 doses), in accordance with the randomisation schedule generated prior to the start of 
the study using validated internal software.
During the treatment period, subjects will return to the clinical site for visits on Days 1-3, 
7, 14, 21, 27, 28 and 30. On these visit days, subjects should not take study treatment 
prior to the visit. Subjects will be given a diary card and instructed to take study 
medication every other day, recording this and any adverse event in the diary card.
4.2.3.
Follow up period
After the treatment period, the subject enters the follow up period for 7 to 14 days.
4.3.
Type and Number of Subjects
Approximately 40 subjects will be randomised. This assumes a dropout rate of 
approximately 15%.  
4.4.
Design Justification
This study is designed to assess the efficacy, safety and tolerability of alternate day 
dosing of GSK3117391 in RA subjects. This is the first study of GSK3117391 in 
patients. An additional objective of this study will be to characterise the pharmacokinetic 
profile of GSK3117391 and its acid, GSK3339189, and to determine pharmacodynamic 
effects in this population.
Subjects in this study are not currently benefiting from DMARD therapy therefore such 
DMARD therapies will be excluded for the duration of the study.  Any subject currently 
deriving benefit from DMARD therapy will not be included in this study.
 
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Inclusion of a placebo group is to provide a control for comparison of subjects treated 
with GSK3117391 and to allow robust exploration of the safety profile of GSK3117391.  
Inclusion of placebo will also allow measurement of the comparable effect of 
GSK3117391 and determination of DAS28 reduction and the ACR20 response rates. The 
treatment duration of 28 days will minimise the exposure to placebo in the study. If a 
subject experiences an unacceptable level of disease activity during the study, the 
investigator may withdraw the subject from further study treatment at any point. The 
subject is then to enter the follow up period, where subject will be able to receive 
standard of care treatment at the discretion of the investigator as early as 7 days after the 
last dose of study medication. 
The study is sponsor open to enable members of the Data Review Committee (DRC) to 
be unblinded for the planned interim analyses of safety data (including clinical laboratory 
parameters and AEs), monocyte counts and efficacy (see Section 9.3.2 and Section 
10.8.2).  The interim analysis of efficacy will be conducted once an appropriate number 
of subjects complete day 30 assessments. As a consequence of this efficacy analysis the 
study may be stopped for futility, according to the futility criteria outlined in the DRC 
charter.  However it is not planned to stop the study as a result of the interim analysis of 
monocyte counts.
4.5.
Dose Justification
Subjects in this study will be treated with 40 mg of GSK3117391 every other day for a 28 
day period.  This dose is justified by the safety, PK and PD profile of the molecule:
In Study 201302, the PK of GSK3117391 was well characterised. The plasma half-life 
where could be estimated, was consistent across doses (i.e. 20, 40, 50 and 60 mg), with 
the geometric mean in single administration ranging between 0.343h and 0.500h, while 
the geometric mean of the half-life of its acid, GSK3339189, in plasma ranged between 
0.604h and 0.767h. Small to minimal accumulation ratios were observed in repeat 
administration regimens. The plasma half-life of both GSK3117391 and GSK3339189 
were found to be shorter than their sustained intracellular effect (manifested as prolonged 
increases in both cellular acetylation and inhibition of cytokine production after ex vivo
LPS stimulation of sampled blood).
After single dose administration, sustained average intracellular concentrations of acid 
GSK3339189 within monocytes were observed above its IC50 (18.0 ng/mL or 53.83nM) 
at 12h post-dose with doses of 10 mg or higher (minimum average concentration 134.6 
ng/mL for the10mg dose). In addition, the intracellular acid levels were also above  the 
IC90 (308.35 ng/mL or 920.45nM) for at least 4h following doses of 40 mg and above 
(average concentrations of 429.7ng/mL of monocytes at 4h post-dose for the 40mg dose). 
Consistent with this intracellular target engagement, selective acetylation of monocytes 
was maintained for at least 12 hours in this study. 
In Study 201302, a decrease in the monocyte count was observed 4 hours post-dose and 
was enhanced by repeat administration, but the count had returned to baseline in all but 
one subject by the post-study follow up visit which was performed between 4 and 7 days 
after the last study drug administration. Monocytopaenia was not accompanied by any 
 
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clinical signs or symptoms and was not associated with any AEs or DLTs. There were no 
other clinically significant myeloid or non-myeloid adverse events observed in subjects 
after repeat doses up to 40 mg.
Therefore, a dose of 40 mg administered with a less frequent regimen than the one 
investigated in the previous clinical study has the potential to maintain efficacy while 
also allowing a higher extent of monocyte recovery during each dosing interval. An every 
other day dosing strategy for a 28 day period has been proposed, which limits the number 
of doses to 14.  An appropriate sampling scheme will be utilised to fully characterise the 
monocyte profile as well as levels of acetylation and other mechanistic biomarkers.
 
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4.6.
Benefit: Risk Assessment
4.6.1.
Risk Assessment
Potential Risk of clinical significance
Mitigation Strategy
Potential haematologic toxicity (Including monocytopaenia)
Following single doses of up to 60 mg GSK3117391 and repeat doses up to 40 mg 
GSK3117391 in healthy volunteers there was a trend for a decrease in the absolute 
monocyte counts. Levels generally returned to baseline values by 4-7 days post-
dose. There was no evidence from the FTIH study 201392 in healthy volunteers of 
an increased incidence of infection. In a study in healthy volunteers, one subject had 
minor changes in haemoglobin.
No changes in monocyte numbers were observed in definitive 4 week studies in rat 
and cynomolgus monkey. 
In contrast, increased monocyte numbers were observed in cynomologus monkeys 
at higher dose levels in the dose range finding studies.  
Monocytopaenia was observed in hCE1/Es1e-BP8 transgenic mice which express a 
complementary copy of the human carboxyesterase-1 gene under the control of the 
CD68 promoter.
Minor haematological changes were observed in rats and cynomolgus monkeys. 
Where assessed, effects were not observed after an off-dose period. Effects on the 
thymus were observed in the rat dose range finding study (decreased cellularity) 
and 28 day monkey study (decreased thymic weight and thymic atrophy).
Subject selection – Subjects with abnormal haematological parameters will be excluded from 
the study. In addition, subjects with active infections, or a history of recurrent infections, or with 
previous exposure or past infection with Mycobacterium tuberculosis, HIV or Hepatitis B or C 
will also be excluded.
Subject Monitoring – Monocyte and other white blood cell numbers will be monitored during 
the study. There will also be close monitoring of the subjects for infections..
Withdrawal Criteria -Haematological stopping criteria have been added to the protocol. 
Subjects who develop a serious infection will also be withdrawn from study treatment.
 
 
 
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Potential Risk of clinical significance
Mitigation Strategy
Reproductive and development
In preliminary embryofoetal development studies, dose-related reproductive and 
developmental toxicity (up to complete pre- and post-implantation loss, and 
decreased foetal body weight) was seen in the rat and rabbit. At all doses, there 
were skeletal abnormalities/variations and delayed ossification (both species), with 
foetal malformations (predominantly cardiovascular) being observed in the rabbit.  
Systemic exposure at the lowest effect levels are below/approximately at parity to 
the anticipated exposure for a 40 mg dose of GSK3117391.
Evaluation in a number of studies concluded that GSK3117391 is an aneugen with a 
NOEL at 60 mg/kg (sc) in the rat bone marrow micronucleus study. The rat NOEL 
for aneugenicity provides 35-fold and 10.6 fold cover for the anticipated AUC and 
Cmax, respectively, for a 40 mg dose in human.
Syncytia in the seminiferous tubules was observed in one male at 10 mg/kg/day. 
Although this could be a background finding, the severity suggests it is treatment 
related.
Subject Selection – In this study, subjects must agree to specific contraceptive guidelines and 
precautions for males and females which are provided in the protocol. In addition, the informed 
consent will include potential reproductive risks and precautions in addition to recommendations 
for the maintenance of the fertility potential. Male subjects will be required to avoid donating 
sperm or conceiving a child for the duration of the study until 91 days after the last dose.
Subject Monitoring – Female subjects will be tested for pregnancy before during and after the 
study. In additon, pregnancies of female partners of male subjects in the study will be followed if 
consent is given.
Withdrawal Criteria – Any female subject who becomes pregnant will be withdrawn from the 
study.
Clotting disorders
Minor changes relating to coagulation (increase in activated partial thromboplastin 
time and prothrombin time) were evident in rats.
Not seen to date with GSK3117391 clinically.
Subject Selection – Subjects with a history of clotting, or on current anti-coagulant treatment 
e.g.warfarin, will be excluded from the study.
Subject Monitoring – The protocol includes monitoring of clotting parameters e.g. INR/APTT & 
platelet count will occur throughout the study. Supportive therapy will be provided according to 
standard medical practice.
Withdrawal Criteria – Platelet number stopping criteria have been added to this protocol. 
Gastrointestinal events
Rats and monkeys exhibited reduced food consumption and body weight loss. In the 
rats non-adverse histological effects (minimal to mild in severity) were observed in 
the duodenum (inflammation, mucosal atrophy, degeneration of villous epithelium 
and increase in mitotic figures). 
Marked ulcerative inflammation was found in the oesophagus of two monkeys given 
10 mg/kg/day in the 4 week study. Both had loss of condition (dehydration, body 
Subject Selection – A body weight of 45 kg is required for subjects to be included in this 
study. Appropriate exclusion criterion regarding a history of pre-existing gastrooesophageal 
ulcers is included in this study protocol.
Subject Monitoring – During clinical studies clinical history, physical examination (including 
weight) and clinical laboratory assessments will be used to identify and assess toxicity in the 
gastrointestinal tract. Gastrointestinal AE/SAEs will be monitored. 
Withdrawal Criteria – In the event of clinically significant GI toxicity, study treatment will be 
 
 
 
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Potential Risk of clinical significance
Mitigation Strategy
weight loss, subdued) and one of these animals was terminated on Day 9 as a 
result. The oesophageal ulceration was likely a contributing factor in the demise of 
this animal. These effects may be due to dosing trauma and/or irritation from 
formulation, although were not seen in the vehicle control group.
discontinued and supportive therapy provided according to standard medical practice.
Potential drug-drug interactions
GSK3117391 has been shown to be an inhibitor of CYP2C8 and CYP3A4 in vitro. A 
risk assessment using physiological based pharmacokinetic modeling suggests the 
clinical risk of DDI with CYP2C8 substrates is negligible. A similar assessment with 
for CYP3A4 suggests risk of DDI is weak.
In vitro, GSK3117391 is cleared predominately via CYP3A4 and esterases with the 
latter playing the predominate role in vivo. The clinical risk of CYP mediated DDIs is 
low.
Use of concomitant medications, herbal medicines and fruit juices that are strong CYP3A4 
inhibitors or inducers will be prohibited.
Exacerbations of RA
Common risk for this patient population is the recurrent exacerbations of RA (these 
may vary in severity). 
Subjects will be monitored & treated by qualified investigators for any AEs/SAEs/exacerbations 
using permitted medications as per protocol.  If appropriate, subjects will be withdrawn from the 
study in consultation with the Medical Monitor and referred to their respective GP/specialist 
consultant and/or Rheumatology clinics at the discretion of the Investigator or Designee.
 
 
 
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4.6.2.
Benefit Assessment
Histone deacetylase (HDAC) inhibitors have been shown to be active in various models 
of inflammation (Lin, 2007; Nishida, 2004; Joosten, 2011; Glauben, 2008) and to have 
anti-inflammatory activity in clinical studies (Vojinovic, 2011; Furlan, 2011); therefore it 
is anticipated that GSK3117391 may show some benefit in subjects with RA. In addition, 
the FTIH study demonstrated that the drug engaged with the target and produced ex vivo
PD effects in inflammatory cytokines as detailed in the Investigator Brochure (GSK 
Document Number 2014N201956_00 GSK3117391 Investigator’s Brochure. 22-APR-
2016) . There is an unmet need for therapies in the RA population.  Subjects will benefit 
from thorough medical assessments as part of the study procedures and will have regular 
access to medical care for the duration of the study.
4.6.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimise risk to subjects participating in this 
study, the potential risks identified in association with GSK3117391 are justified by the 
anticipated benefits that may be afforded to subjects with RA.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardise the scientific integrity of the study, regulatory acceptability and/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. Age ≥18 years at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. The subject must have a diagnosis of RA as an adult (≥18 years) according to the 
2010 ACR/EULAR classification criteria for RA. 
3.
Functional class I, II or III defined by the 1992 ACR Classification of Functional 
Status in RA
4. The subject must have a EULAR DAS28-CRP of greater than 5.1 at screening.
5. Disease duration of >6 months (time from onset of patient-reported symptoms of 
either pain or stiffness or swelling in hands, feet or wrists).
 
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TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
6. Swollen joint count of ≥6 (66-joint count) and tender joint count of ≥8 (68-joint 
count) at screening and at day 1
7. The subject must have a CRP serum level of 5 mg/L at screening 
8. The subject has had an inadequate response or intolerance of DMARDs (due to 
lack of efficacy or toxicity, after at least 8 weeks treatment).
WEIGHT
9. Body weight 45 kg and body mass index (BMI) within the 18.5 - 35 kg/m2
inclusive.
SEX
10. Male or female requirements. 
Males:
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
91 days after the last dose of study medication.
Male condom plus recommendation for partner to use of one of the contraceptive options 
as detailed in Appendix 2. This is an all-inclusive list of those methods that meet the 
following GSK definition of highly effective: having a failure rate of less than 1% 
per year when used consistently and correctly and, when applicable, in accordance 
with the product label. For non-product methods (e.g. male sterility), the investigator 
determines what is consistent and correct use. The GSK definition is based on that 
provided by the ICH [ICH M3 (R2), 2009].”
In addition male subjects must not donate sperm for 91 days after the last dose of study 
medication.
The investigator is responsible for ensuring that subjects understand how to use these 
methods of contraception properly.
Females: 
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative 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.
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion. 
 
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SEX
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]).  
NB - Females on hormone replacement therapy (HRT) and whose menopausal status 
is in doubt will be required to use one of the highly effective contraception 
methods if they wish to continue their HRT during the study.  Otherwise, they 
must discontinue HRT to allow confirmation of post-menopausal status prior to 
study enrolment.
b.
Females of reproductive potential must have proper and established use of a Highly 
Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential 
(FRP) (see Appendix 2) from 28 days prior to the first dose of study medication and 
until 15 weeks after the last dose of study medication and completion of the follow-
up visit. In addition subjects will be required to utilise a barrier method of 
contraception.
A negative serum hCG pregnancy test at the first screening visit and urine hCG 
pregnancy test (with a sensitivity of at least 25 IU/L) at the following visits: between 
Day-7 to -4, on Day 1 prior to first study medication dose administration, at the 
weekly study visits, and the follow up visit. 
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception and receive continued guidance with respect to the 
avoidance of pregnancy and sperm donation as part of the study procedures. 
INFORMED CONSENT
11. 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.
 
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5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1.
Pregnant or lactating women.
2.
Subjects who meet diagnostic criteria for any other rheumatic disease (e.g., lupus 
erythematosus, gout, psoriatic arthritis).
3.
Subjects who have previously been treated with more than 1 biologic agent (such as 
TNF inhibitors and their biosimilars eg. adalimumab, etanercept, infliximab, 
certolizumab, golimumab or non-TNF inhibitors and their biosimilars eg.abatacept, 
rituximab, tociluzimab) or any investigational biologic.
4.
Subjects with past history of granulomatous disease eg leprosy, sarcoidosis.
5.
Subjects with current symptoms of severe, progressive, or uncontrolled renal, 
hepatic, haematological (including clotting disorders), gastrointestinal (including 
gastrooesophageal ulcers), pulmonary, cardiac (including ischemic heart disease), 
neurological, or cerebral disease, or other medical conditions that, in the opinion of 
the Investigator, might place the subject at unacceptable risk for participation in this 
study.
6.
Subjects with any values for monocytes are below the lower limit of normal (LLN) 
at screening.
7.
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 ≤2 x 109/L; lymphocyte count <1 x 109/L at 
screening.
8.
ALT and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin 
is fractionated and direct bilirubin <35%) at screening.
9.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
10. QTcF or QTcB > 450 msec (based on the average of triplicate ECGs) at screening.
11. Abnormal findings on ECG considered clinically significant by the investigator.
12. A history of carcinoma in situ and malignant disease, except for adequately treated 
non-invasive cancers of the skin (basal or squamous cell) or carcinoma in situ of the 
uterine cervix.
13. Hereditary or acquired immunodeficiency disorder, including immunoglobulin 
deficiency.
14. Abnormal chest X-ray within 12 weeks of Day 1 (locally read and reported by a 
radiologist) judged by the investigator as clinically-significant.
15. History of infected joint prosthesis at any time, with the prosthesis still in situ.  
 
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History of leg ulcers, catheters, chronic sinusitis or recurrent chest or urinary tract 
infections.
16. Active infections, or history of recurrent infections (excluding recurrent fungal 
infections of the nail bed), or have required management of acute or chronic 
infections as follows:

Currently on any suppressive therapy for a chronic infection (such as tuberculosis, 
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical 
mycobacteria).

Hospitalisation for treatment of infection within 12 weeks of Day 1.

Use of parenteral (IV or IM) antimicrobials (antibacterials, antivirals, antifungals, or 
antiparasitic agents) within 12 weeks of Day 1 or oral antimicrobials within 14 days 
of Day 1.
17. Any surgical procedure, including bone or joint surgery/synovectomy within 12 
weeks prior to Day 1 or any planned surgery within the duration of the study or 
follow-up period.
18. A vaccination (live or attenuated) within 30 days of Day 1 or BCG vaccination 
within 365 days of Day 1, or a live vaccination planned during the course of the 
study.
CONCOMITANT MEDICATIONS
19. The subject has received treatment with the therapies listed in Section 6.11.2 or 
changes to those treatments in the prescribed timeframe. Subjects who have 
previously taken >1 biologic therapy for RA are excluded from this study. Note: 
Subjects who have taken one biologic therapy only with a documented lack of 
response are eligible.
20. 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
21. History of regular alcohol consumption within 6 months of the study defined as an 
average weekly intake of >21 units for males or >14 units for females. One unit is 
equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine 
or 1 (25 mL) measure of spirits. 
22. Smokers who would not be able to refrain from smoking whilst in the clinic.
23. Subjects who cannot refrain from consuming any of the following fruits or juices 
(alone or in combination): seville oranges, grapefruit, pummelos, or any citrus fruits 
from 7 days prior to the first dose of study medication until their discharge from the 
unit after their last dose of study medication.
 
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CONTRAINDICATIONS 
24. History of sensitivity to any components of the study medication, or a history of drug 
or other allergy that, in the opinion of the Investigator or Medical Monitor, 
contraindicates their participation.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
25. Serologic evidence of current/previous Hepatitis B virus (HBV) infection based on 
the results of testing for Hepatitis B surface antigen (HBsAg) and anti-Hepatitis B 
core (anti-HBc) antibody as follows within 6 weeks of Day 1: Subjects positive for 
HBsAg and/or positive for anti-HBc antibody (regardless of anti-HBs antibody 
status) are excluded
26. Hepatitis C: Positive test for Hepatitis C virus (HCV) antibody confirmed on a 
subsequent blood sample by RNA-polymerase chain reaction (PCR) assay within 6 
weeks of Day 1. Subjects who are positive for Hepatitis C antibody and negative for 
Hepatitis C RNA-PCR assay performed on a subsequent sample will be eligible to 
participate. Subjects who are positive for Hepatitis C antibody and have a positive 
result for Hepatitis C RNA-PCR assay performed on the subsequent sample,will not 
be eligible to participate.
27. A positive test for HIV 1 or 2 at screening.
28. Evidence of active or latent infection with Mycobacterium tuberculosis (TB), as 
defined by all of the following:
a.
No history of active or latent TB infection irrespective of treatment status
b. A negative diagnostic TB test within 28 days of baseline (Day 1) defined as:
i. A negative QuantiFERON Gold test or T-spot test (two successive 
indeterminate QuantiFERON tests will be considered as a positive result).
OR
ii.
If QuantiFERON gold or T-spot test not approved or registered in country 
of participation, then a negative tuberculin skin test (TST) reaction as per 
local guidelines is required (it is strongly recommended that subjects with a 
history of Bacillus Calmette-Guérin (BCG) vaccination be tested with 
QuantiFERON gold test).
c.
Chest X-ray within 12 weeks of Day 1 with no evidence of current or previous 
pulmonary tuberculosis, locally read by a radiologist.
29. Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
30. Participation in a trial with any investigational drug within 3 months or 5 half-lives
(whichever is longer) before the start of the study and within 4 months if the study 
drug was new chemical entity. Exposure to more than 3 new chemical entities in a 
clinical study setting within 12 months prior to the first dosing day.
31. Donation of blood in excess of 500 mL within a 56 day period prior to dosing.
 
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5.3.
Screen Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomised. In order to ensure transparent reporting of screen 
failure subjects, to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and to 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 (SAE’s) (see Section 
7.5.1.5).
5.3.1.
Re-Screening
Re-screening is permitted with the approval of the medical monitor if a subject has not 
met the Eligibility Criteria within the screening period with the following exception:

If a subject fails screening due to Exclusion Criteria 6 and/or 7 in Section 5.2, 
rescreening is not permitted. 
Subjects are only allowed to be re-screened once; the entire screening process must be 
repeated.
Chest X-ray does not need to be repeated during re-screening, if one was conducted 
within 12 weeks of re-screening Day 1 and showed no evidence of current or previous 
pulmonary tuberculosis, locally read by a radiologist.
Repeat testing of glucose-6-phosphate dehydrogenase (G6PD) deficiency during 
rescreening is not needed, if test result during original screening was negative.
If a blood sample has to be redrawn due to sample handling problems, breakage or 
sample integrity, this is not considered a re-screening. Further details regarding the 
procedure for re-screening may be found in the Study Reference Manual (SRM).
5.3.2.
Re-Testing
5.3.2.1.
Laboratory Tests
If the investigator is not able to assess subject’s eligibility for any of the laboratory 
exclusion criteria in cases of (a) technical malfunction (e.g. loss of laboratory specimen); 
(b) an indeterminate result or (c) if there is reason to believe the result may be false (i.e. 
contradicts recent result for the same parameter) the test may be repeated once within the 
screening period after consultation with the medical monitor. If the original result was 
exclusionary and is confirmed by repeat testing then the subject is to be considered a 
screen failure; these subjects may be re-screened as described in Section 5.3.1.
Further details regarding the procedure for re-testing may be found in the SRM.
 
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5.3.2.2.
Electrocardiogram (ECG) Test
The QTc is the QT interval corrected for heart rate according to Frediricia’s formula 
(QTcF) or Bhecettes formula (QTcB). The QTc should be based on average QTc values 
of triplicate ECGs obtained over a brief recording period (e.g., 5-10 minutes).
The triplicate electrocardiogram (ECG) may be repeated once within the screening period 
if the recorded QTc value was slightly out of range, and the Investigator does not 
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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 
eCRF.

The Sponsor’s request, for reasons such as significant protocol deviations (and after 
discussion with the investigator).

Study is terminated by the Sponsor.
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, three telephone calls and if necessary a certified letter to the subject’s 
last known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
Any subject who does not complete the study will have a follow up visit, to occur 7-14 
days post withdrawal. 
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 medication for the treatment of RA 
as listed in Section 6.11.2.

The subject develops a serious infection.

If the liver chemistry stopping criteria (Section 5.4.2), QTc stopping criteria (Section 
5.4.3), or Haematologic stopping criteria (Section 5.4.4) are met Group Safety 
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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) and/or the DRC 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.
5.4.2.
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
Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 3
5.4.2.1.
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.
 
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5.4.3.
QTc Stopping Criteria

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 QTc should be based on averaged QTc values of triplicate electrocardiograms 
obtained over a brief (e.g., 5-10 minute) recording period.  
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:

QTc > 500 msec OR Uncorrected QT > 600 msec

Change from baseline of QTc > 60 msec
For 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
5.4.3.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after QTc stopping criteria are met by any subject 
participating in this study is not allowed.
5.4.4.
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 x 109/L

Lymphocytes < 0.5 × 109/L

Platelets < 50 × 109/L
 
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5.4.4.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after haematologic stopping criteria are met by any 
subject participating in this study is not allowed.
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 trial is defined as the last clinic visit (follow up visit) of the last subject in 
the trial. Completion of the trial globally is required in order to provide sufficient subjects 
as defined in Section 9.2, Sample Size Determination.
A subject who withdraws from treatment will be withdrawn from the study, and will 
attend a follow up clinic visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Study Treatment
Product name:
GSK3117391
Placebo 
Dosage form:
Capsule
Capsule
Unit dose strength(s)/Dosage 
level(s):
20mg
N/A
Storage requirements
Store refrigerated (2 – 8oC)
Store refrigerated (2 – 8oC)
Route of Administration
Oral
Oral
Dosing instructions:
2 capsules in the morning 
every other day
2 capsules in the morning 
every other day
Physical description:
White opaque, gelatin 
capsule
White opaque, gelatin 
capsule
Method for individualising dosage:
Capsule packed in separate 
HDPE bottles
Capsule packed in 
separate HDPE bottles
6.2.
Treatment Assignment
At Screening a unique CRF number (subject number) will be assigned to any subject who 
has at least one Screening procedure performed, other than informed consent. The unique
subject number will be used to identify individual subjects during the course of the study.
 
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Subjects who meet screening eligibility criteria and complete the pre-treatment 
assessments will be randomised to a treatment group through an Interactive Response
Technology (IRT). The IRT will confirm the subject’s CRF number (subject number) and 
provide the randomisation number using the randomisation schedule.  
The study will use central randomisation and the randomisation schedule will assign 
subjects to GSK3117391 or placebo in a ratio of 1:1.  The randomisation schedule will be 
generated by Clinical Statistics, prior to the start of the study, using validated internal 
software. 
Once a randomisation number has been assigned to a subject, it cannot be assigned to 
another subject in the study even if the original subject withdraws before taking study 
medication.
6.3.
Planned Dose Adjustments
There will be no dose adjustments in this study.
6.4.
Blinding
The study will be double-blind (sponsor open), where the investigator and trial staff at 
site, subject and most sponsor personnel will be blinded to the trial treatment allocated to 
each individual subject and interim results. Sponsor open refers only to the DRC (a 
limited set of central GSK study team members who will be involved in the review of 
data as defined in Section 10.8.2) and senior GSK stakeholders.  A limited number of 
project team members may be informed of the results of interim analyses where relevant 
to their activities. The DRC charter will identify the specific GSK individuals involved 
and will outline in detail the activities of these reviews, and how the integrity of the study 
will be maintained.  The rest of the central GSK study and project team members will 
remain blinded.
The trial will be blinded by means of allocation via IxRS, and using a placebo to match 
which will be kept in cold chain conditions as per active IP.
The anticipated effect of GSK3117391 on monocyte count and CRP may unblind a 
subject’s treatment allocation to any reviewer.  As a consequence, monocyte count data
and CRP (both of which will be analysed in a central laboratory) will not be available to 
the site during the study after screening. Investigators will, therefore, be blinded to the 
monoctye count but will be able to view other WBC counts. Summary monocyte counts 
for all subjects will be reviewed by the SRT once sufficient subjects have been recruited 
to avoid unblinding. Individual level monocyte count and CRP data will only be reviewed 
by the DRC. 
PK, PD, biomarker and exploratory leukocyte data will also not be available to the central 
study team until the end of study apart from for the DRC specified in Section 10.8.2. 
To prevent potential unblinding because of observed efficacy changes, a “dual assessor” 
approach will be used with different assessors evaluating efficacy and safety (as specified 
in Section 7.3.2.2.
 
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Although a subject may be withdrawn from the study if that subject’s treatment 
assignment is unblinded, data collected prior to the unblinding event may be used in 
analysis.  
Unblinding of individual subjects may occur to ensure appropriate management of 
subject, eg if an SAE is considered by the PI as being causally related to study drug, 
taking account of the points below. 

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. 

However, it is preferred (but not required) that the investigator first contacts the 
Medical Monitor or appropriate GSK study personnel to discuss options before 
unblinding the subject’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the 
treatment assignment of the unblinded subject, unless that information is 
important for the safety of subjects currently in the study. 

The date and reason for the unblinding must be fully documented in the 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. 
6.6.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required. The study treatment must be stored 
refrigerated (2-8oC) at site, and at subject’s home.

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.

Only subjects enrolled in the study may receive study treatment and only 
authorised 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 authorised site staff. 
 
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
The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment 
are provided in the Study Reference Manual (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 will be provided to 
the investigator, where required by local laws, or is otherwise available upon 
request from GSK.
6.7.
Compliance with Study Treatment Administration
When subjects self-administer study treatment(s) at home, compliance with every other 
day administration of the assigned GSK3117391 or placebo capsules will be assessed 
through querying the subject during the site visits and documented in the source 
documents and CRF. Sites will call subjects on non clinic visit dosing days to remind 
them to take their study treatment. A record of the number of GSK3117391 /placebo 
capsules dispensed to and taken by each subject must be maintained and reconciled with 
study treatment and compliance records.  Treatment start and stop dates and times, 
including dates for treatment delays and/or dose reductions will also be recorded in the 
patient diary.  If a subject misses a dose, they will be instructed to take it as soon as 
possible within 24 hours of the scheduled dose.  If they have not taken it within 24 hours 
of the scheduled dosing time then they should continue with future doses as scheduled 
(i.e. they should not alter their planned dosing time).
Only subjects with appropriate compliance will be included in the per-protocol
population for the primary analysis.  To be compliant the subject must not miss more than 
one dose per interval between site visits.  If a subject misses a dose in more than two 
between-visit intervals then they will be considered non-compliant.  Subjects who take 
one additional dose on more than one occasion will also be considered non-compliant 
with the protocol.
6.8.
Treatment of Study Treatment Overdose
For this study, more than 4 capsules of the study medication within a 26 hour time period 
will be considered an overdose.
GSK does not recommend specific treatment for an overdose.
In the event of an overdose the investigator or treating physician should:

Contact the Medical Monitor immediately to determine whether the subject 
may continue in the trial and what (if any) additional assessments need to be 
made.
 
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
Closely monitor the subject for adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities until the end of the study.

Document the quantity of the excess dose as well as the duration of the 
overdosing 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
Subjects will not receive any additional treatment from GSK after completion of the 
study because other treatment options are available. 
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition.
6.10.
Lifestyle and/or Dietary Restrictions
6.10.1.
Meals and Dietary Restrictions
Subjects must refrain from consuming any of the following fruits or juices (alone or in 
combination): seville oranges, grapefruit, pummelos, or any citrus fruits from 7 days 
prior to the first dose of study medication until their discharge from the unit after their 
last dose of study medication.
6.10.2.
Caffeine, Alcohol, and Tobacco
Subjects who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) may not be permitted while they are in the clinic.
6.11.
Concomitant Medications and Non-Drug Therapies
All medications and non-drug therapies will be recorded as concomitant medication.
Rescue with conventional DMARDs or biologics is not allowed in this study. Every 
effort should be made to keep the subject on study treatment with no change in 
background medication unless the subject experiences an excessive disease flare that, in 
the investigator’s opinion, warrants a change in therapy.
6.11.1.
Permitted Medications and Non-Drug Therapies
The following medications are permitted for the treatment of RA.
6.11.1.1.
Oral Corticosteroids
Continued use of oral corticosteroids 10 mg/day prednisone or equivalent is allowed if 
the dosage was stable for at least 4 weeks prior to screening. 
 
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6.11.1.2.
NSAIDs
Continued use of NSAIDs is permitted (i.e. diclofenac, ibuprofen, ketoprofen, naproxen, 
celecoxib and etoricoxib etc) in daily doses up to the maximum recommended according 
to locally accepted clinical practices if the dosage was stable for at least 2 weeks before 
screening. The concomitant use of proton pump inhibitors, e.g. omeprazole or
pantoprazole, is strongly recommended in order to lower the risk of complications 
affecting the gastrointestinal tract caused by NSAIDs.
If the patient is not regularly using NSAIDs, he/she may take the NSAIDs mentioned 
above as breakthrough pain management. However, subjects should be advised not to 
take any NSAIDs within 12 hours prior to attending a trial visit.
6.11.1.3.
Analgesics
Regular use of codeine, opium alkaloid, paracetamol/acetaminophen, propoxyphene, and 
tramadol are permitted in daily doses up to the maximum recommended according to 
locally accepted clinical practices. If the subject is not regularly using any analgesics, 
he/she may take the analgesics mentioned above as breakthrough pain management. 
However, the patients should be advised not to take any analgesics within 12 hours prior 
to attending a trial visit.
6.11.1.4.
Other
Medications used to treat conditions other than RA (and not listed in Table 1 below, or in 
the eligibility criteria) may be used at the discretion of the investigator, in consultation 
with the Medical Monitor if needed.
6.11.2.
Prohibited Medications and Non-Drug Therapies
Table 1
Prohibited throughout the study, from the time periods stated until 
after 7 days from the last dose of the study medication:
Drug class
Examples
Washout time prior to dosing
Any conventional 
DMARDs (if not listed 
here please contact 
medical monitor)
Hydroxychloroquine, 
sulphasalazine, minocycline, 
cyclosporin 
At least 2 weeks prior to Day 1
Methotrexate, azathioprine
Discontinue ≥28 days prior to Day 1
Leflunomide
Leflunomide must be discontinued ≥8 
weeks prior to Day1 if no elimination 
procedure is followed. Or discontinued with 
the following elimination procedure ≥4 
weeks prior to Day 1: Cholestyramine at a 
dosage of 8 g three times daily for at least 
24 hours, or activated charcoal at a dosage 
of 50 g 4 times a day for at least 24 hours.
Gold salts
26 weeks prior to Day 1
Targeted biological 
DMARDs
Anakinra 
1 week prior to Day 1
 
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Drug class
Examples
Washout time prior to dosing
Etanercept
Discontinue  for at least 2 weeks prior to 
Day 1
Adalimumab, infliximab 
Discontinue for at least 8 weeks prior to 
Day 1
Certolizumab pegol, golimumab 
Discontinue for at least 10 weeks prior to 
Day 1
Abatacept, tocilizumab
12 weeks prior to day 1
Rituximab, belimumab and other B 
cell depleting agents
1 year and a normal CD19/20 cell count as 
measured by flow cytometry.
Targeted synthetic 
DMARDs
Tofacitinib
Baricitinib
At least 2 weeks prior to Day 1
NSAIDS
Diclofenac, ibuprofen, ketoprofen, 
naproxen
New or change of dose within 14 days of 
Day 1
Corticosteroids
Prednisolone, dexamethasone
IM, IV, IA
PO 
Within 8 weeks of Day 1
Any treatment with >10 mg/day dose oral 
prednisolone (or equivalent) within 28 days 
of Day 1. New oral corticosteroid or 
changes in corticosteroid dose within the 
28 days prior to Day 1.
Plasmapheresis or intravenous 
immunoglobulin (IVIg) or use of 
Staph protein A column (Prosorba)
26 weeks prior to Day 1
Any  investigational 
treatment
Must be discontinued for at least 4 weeks 
or 5 half-lives, whichever is longer, prior to 
Day 1
Strong inhibitors and 
inducers of CYP3A4 
(unless in the opinion 
of the Investigator and 
sponsor the medication 
will not interfere with 
the study.)
Rifampicin, phenytoin, 
carbamazepine, St Johns Wort, 
amprenavir, atazanavir, 
clarithomycin, conivaptan, 
itraconazole, ketoconazole, 
ritonavir, nelfinavir, fosamprenavir, 
grapefruit juice, indinavir, 
voriconazole, telithromycin, 
saquinavir.
Within 7 days prior to the first dose; or 14 
days if the drug is a potential enzyme 
inducer prior to first dose
Alkylating agents
Cyclophosphamide or chlorambucil
Discontinue >=8 weeks prior to Day 1
Agents which may 
cause haemolytic 
anaemia 
Methyldopa
Subjects taking methyldopa are not eligible 
for this study
Cephalosporin
From 7 days prior to Day 1 and throughout 
the study until follow up
Anticoagulant therapy
Warfarin
Subjects taking Warfarin will not be eligible 
for this study
 
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6.11.2.1.
Complementary Therapies
The use of complementary therapies that may affect RA disease activity or assessments, 
including, but not limited to, traditional medicine (e.g. Chinese, acupuncture, Ayurvedic) 
is prohibited.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Tables, is essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Tables Section 7.1
The following points must be noted: 

If assessments are scheduled for the same nominal time, then the assessments 
should, where possible, occur in the following order:
1.
12-lead ECG
2.
Vital signs
3.
Blood draws.  
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

The timing and number of planned study 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 plasma 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. 

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. 

No more than 600 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.
 
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7.1.
Time and Events Tables
Table 2
Screening and Follow-up Assessments
Procedure
Screening
(up to 28 days prior 
to Day 11)
Follow-up Visit (7-14 
days post last dose or 
EW2)
Notes
1.
Screening period can be extended to 56 days to allow ONLY the washout of 
background DMARD therapy where necessary. All other assessments must 
be completed within 28 days prior to Day 1. Some assessment can occur on 
separate visit
2.
For EW (Early Withdrawal) visit, assessments are to be conducted as 
deemed necessary based on PI’s judgment and to be recorded as a 
unscheduled visit in the subject’s CRF 
Outpatient Visit
X
X
Additional screening visit needed for FRP pregnancy test 4 to 7 days before day 1
Informed Consent
X
Informed consent must be obtained prior to any study procedures being 
conducted including DMARD therapy washout period.
Medical/medication/drug/alcohol history
X
Demographics
X
Height and weight
X
Full Physical Examination
X
Additional examinations may be performed, or brief examinations made full 
examinations, by the Investigator, as deemed necessary (e.g. where safety or 
laboratory findings indicate).
Brief Physical Examination
X
Eligibility criteria
X
12-lead ECG and vital signs
X
X
Vital signs include HR, BP and temp. 
Pregnancy test
X
X
First test in screening is serum pregnancy test, all subsequent testing urine. An 
additional pregnancy test during screening visit (urine) is required 4-7 days prior to 
Day 1. FRP only.
Contraception use compliance 
X
X
HIV, Hep B and Hep C screen, TB, G6PD
X
RF, ACPA (i.e. aCCP)
X
Haem/Chem/Urinalysis tests
X
X
Including INR/APTT (coagulation) and MetHb (MetHb, performed locally)
PK blood sample and MetID
X
Sample to be collected only if the 24h-post last dose sample (at D28) has not 
been collected
PD biomarker sample
X
This includes biomarkers for RA disease and exploratory PD, acetylation
HAQ-DI, PtGA, PtAAP
X
X
Complete before any other assessment at a clinic visit
 
 
 
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Procedure
Screening
(up to 28 days prior 
to Day 11)
Follow-up Visit (7-14 
days post last dose or 
EW2)
Notes
1.
Screening period can be extended to 56 days to allow ONLY the washout of 
background DMARD therapy where necessary. All other assessments must 
be completed within 28 days prior to Day 1. Some assessment can occur on 
separate visit
2.
For EW (Early Withdrawal) visit, assessments are to be conducted as 
deemed necessary based on PI’s judgment and to be recorded as a 
unscheduled visit in the subject’s CRF 
Joint counts: TJC(68), SJC(66)
X
X
Independent joint assessor
Physician Global Assessment of Arthritis 
(PhGA)
X
X
Where possible, the same physician should perform all disease assessments for 
an individual subject. 
hs-CRP
X
X
Chest x-ray
X
Only required at screening if no CXR performed within 12 weeks of Day 1 visit
Adverse Event Review
X
Concomitant Medication Review
X
Gene expression blood
X
 
 
 
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Table 3
Day 1 to Day 30 On-Study Assessments
D1
D2
D3
D72 D143
D212
D27
D28
D30
Study treatment every 
other day including clinic 
visit days as shown
X
X
X
X
X
Time in relation to dose1
pre
0.25h 0.5h 1h
2h 4h 6h 10h 24h4
pre
0.25h 0.5h 1h 4h 8h pre
pre
pre 0.25h
0.5h 1h 2h 4h 6h 10h 24h4
72h4
12 lead ECG and vital 
signs
X
X
X
X
X
X
X
X
X
Brief physical examination
X
X
X
X
X
X
X
X
Pregnancy test (FRP)
X
X
X
X
X
Contraception use 
compliance
X
X
X
X
X
X
X
X
X
Haematology test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chem/Urinalysis test
X
X
X
X
X
X
X
X
Coagulation (INR/IPTT)
X
X
X
X
X
X
X
X
X
X
Joint counts: TJC(68), 
SJC(66)
X
X
X
X
X
Patient reported outcomes5
PtGA, PtAAP, HAQ-DI
X
X
X
X
X
PhGA
X
X
X
X
X
hs-CRP
X
X
X
X
X
RF, ACPA
X
MetHb
X
X
RA disease biomarker 
blood
X
X6
X
6
X6
X6
X6
X
6
X
X
X
X
6
X
Exploratory PD and 
acetylation blood
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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D1
D2
D3
D72 D143
D212
D27
D28
D30
Study treatment every 
other day including clinic 
visit days as shown
X
X
X
X
X
Time in relation to dose1
pre
0.25h 0.5h 1h
2h 4h 6h 10h 24h4
pre
0.25h 0.5h 1h 4h 8h pre
pre
pre 0.25h
0.5h 1h 2h 4h 6h 10h 24h4
72h4
PK blood
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MET ID blood
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Isolated monocyte PK7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Gene expression blood
X
PK urine sample
X
Collect urine for 24h after dose
PGx
X
Drug compliance 
assessment8
X
X
X
X
AE and concurrent med 
review
Collect AE's from D1 to end of follow up visit
FRP, Females of reproductive potential; HAQ-DI, Health Assessment Questionnaire Disability Index; hs-CRP, high sensitivity C-reactive protein; INR/IPTT, International normalised 
ratio/partial thromboplastin time; PhGA, Physician Global Assessment of Arthritis;  PtGA, Patient Global Assessment of Arthritis; TJC, Tender Joint Count; SJC, Swollen Joint Count; 
PtAAP, Patient Assessment of Arthritis Pain; ACPA, Anti-citrullinated protein antibodies; RF, rheumatoid factor; PK, pharmacokinetics ; PGx, pharmacogenomics.
1. Sample collection and assessments to be conducted in accordance with the time and events table.
2. Visits may be conducted on previous or next DOSING day.
3. The D14 visit has a 2 day window and may be on a DOSING or NON DOSING day. If on a dosing day, assessments should be 
per formed pre-dose.
4. Blood samples to be collected within a ±1h window of the scheduled time.
5. Patient Reported Outcomes questionnaires should be completed by subjects before any other assessment at a clinic visit.
6. Sample will be collected and stored for future analysis.
7. Applicable to selected sites only.
8. Record number of capsules in bottle and check patient diary. On non-visit days, phone subject to remind them to take dose .
 
 
 
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7.2.
Screening and Critical Baseline Assessments
Screening and eligibility criteria are as listed in T&E Tables and Section 5, respectively. 
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
Critical baseline measures include: DAS28-CRP score, ACR criteria, HAQ-DI, and 
exploratory biomarkers.
Disease activity assessments (screening and baseline):

Patient reported outcomes
o
HAQ-DI which includes an item on pain severity during the past week
o
Patient’s Assessment of Arthritis Pain.
o
Patient’s Global Assessment of Arthritis.

Tender/Painful Joint Count (68 joints).

Swollen Joint Count (66 joints).

Physician’s Global Assessment of Arthritis.
Patient Reported Outcomes questionnaires should be completed by subjects before any 
other assessment at a clinic visit, in the order specified above.
Procedures conducted as part of the subject’s routine clinical management, e.g. blood 
count or chest X-ray and obtained prior to signing of informed consent may be utilised 
for screening or baseline purposes provided the procedure meets the protocol-defined 
criteria and has been performed within the timeframe defined in the Time and Events 
Schedule.
The investigator is responsible for ensuring that subjects understand how to properly use 
contraception methods detailed in Appendix 2 and receive continued guidance during 
screening and study conduct with respect to the avoidance of pregnancy and sperm 
donation as part of the study procedures. Such guidance should include a reminder of the 
followings:

Contraceptive requirements of the study

Assessment of subject compliance through questions such as
o
Have you forgotten to use contraception since the last visit? 
o
Is there a chance you could be pregnant?
 
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7.3.
Efficacy
Efficacy assessments will be performed at the time points presented in the Time and 
Events Tables (Section 7.1).
Efficacy assessments will include Health Assessment Questionnaire – Disability Index 
(HAQ-DI – physical function,), Patient’s assessment of Arthritis Pain, Patient’s Global 
Assessment of Arthritis, evaluation of all 68 joints for tenderness and 66 joints for 
swelling (to be performed by an independent joint evaluator), Physician’s Global 
Assessment of Arthritis and laboratory assessments (including CRP).  Based on these 
assessments ACR (20, 50 and 70), DAS28-CRP and the EULAR response will be 
calculated by the central GSK team.
7.3.1.
Patient Reported Outcomes
Patient Reported Outcomes questionnaires should be completed by subjects before any 
other assessment at a clinic visit.
7.3.1.1.
Disability Index of the Health Assessment Questionnaire (HAQ-DI)
The functional status of the subject will be assessed by means of the Disability Index of 
the Stanford Health Assessment Questionnaire (HAQ-DI).  This 20-question instrument 
assesses the degree of difficulty a person has in accomplishing tasks in eight functional 
areas [Fries, 1980]: dressing and grooming, arising, eating, walking, hygiene, reach, grip, 
and common daily activities.
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.  
The HAQ-DI will be used to calculate ACR responders.
7.3.1.2.
Patient’s Assessment of Arthritis Pain (PtAAP)
Subjects will assess the severity of their current arthritis pain using a 100 unit visual 
analog scale (VAS) by placing a mark on the scale between “0” (no pain) and “100” 
(most severe pain), which corresponds to the magnitude of their pain. This forms part of 
the ACR response assessment.
Further details of this assessment are provided in the SRM. 
7.3.1.3.
Patient’s Global Assessment of Arthritis (PtGA)
Subjects will complete a global assessment of disease activity using the patient global 
assessment (PtGA) item, a VAS with anchors “0” (very well) to “100” (very poor). This 
forms part of the ACR response and DAS28 assessments. This assessment will be used to 
calculate ACR responders. 
Further details of this assessment are provided in the SRM. 
 
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7.3.2.
Joint assessments
The procedure for joint assessments can be found in the SRM. Tender Joint Counts (TJC) 
and Swollen Joint Counts (SJC) form part of the ACR and DAS28 measurements.
7.3.2.1.
Replaced or Fused Joints
Replaced or fused joint will not be included in joint evaluations.  The reason for absence 
of the evaluations of those joints must be recorded.
7.3.2.2.
Independent Joint Evaluator
To prevent potential unblinding because of observed efficacy changes, a “dual assessor” 
approach will be used with different assessors evaluating joints.
One or more independent assessors, who have documented experience in performing 
joint assessments, will be designated at each trial site to perform joint assessments.  
Preferably the same independent assessor will perform all joint assessment for the same 
subject throughout the trial.  The principal investigator must ensure that the independent 
joint assessor has documented experience and he/she is adhering to locally accepted and 
implemented standards.  This also applies if the independent joint assessor is replaced 
during the trial.
The independent joint assessor should have no other contact with the subject during the 
trial, must not be the treating physician (investigator), should not discuss the subject's 
clinical status with the subject during the joint assessment nor with other site personnel, 
and will not be permitted to review the subject's medical records, the eCRF, nor any of 
the previous joint assessments.
It is essential that assessments completed by the subject and joint assessor are made 
before those by the treating physician.
7.3.3.
Physician’s Global Assessment of Arthritis (PhGA)
Physicians will complete a global assessment of disease activity using the physician 
global assessment item (PhGA), a VAS with anchors “0” (none) to “10” (extremely 
active), respectively. This forms part of the ACR response assessment.
Further details of this assessment are provided in the SRM. 
7.3.4.
Measurement of Serum CRP
Blood samples will be collected in order to measure serum CRP concentrations. This
forms part of the ACR response and DAS28-CRP assessments.
 
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7.4.
Derived measurements
7.4.1.
DAS28 measurements
The DAS28 is a derived measurement with differential weighting given to each 
component.  The DAS28-CRP will be calculated at each assessment timepoint.
The components of the DAS28 arthritis assessment include:

Tender/Painful Joint Count (28).

Swollen Joint Count (28).

CRP.

Patient’s Global Assessment of Arthritis.
Sites/investigators will not have access to ongoing DAS28 scores, apart from the 
screening visit results (needed to confirm eligibility).  
7.4.2.
ACR measurements
The American College of Rheumatology’s definition for calculating improvement in RA 
(ACR20) is calculated as a 20% improvement in tender and swollen joint counts and 20% 
improvement in 3 of the 5 remaining ACR-core set measures: patient and physician 
global assessments, pain, disability, and an acute-phase reactant.  Similarly, ACR50 and 
70 are calculated with the respective percent improvement.  This efficacy measurement 
will be made at every study assessment timepoint.
The specific components of the ACR measurements that will be used in this study are:

Health Assessment Questionnaire – Disability Index (HAQ-DI) which includes an 
item on pain severity during the past week.

Patient’s Assessment of Arthritis Pain.

Patient’s Global Assessment of Arthritis.

Tender/Painful Joint count (assessment of 68 joints).

Swollen Joint Count (assessment of 66 joints).

Physician’s Global Assessment of Arthritis.

CRP
7.5.
Safety
Planned time points for all safety assessments are listed in the Time and Events Tables 
(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.
 
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All subjects will return for a follow-up visit 7 to 14 days after last dose of study 
medication
7.5.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.5.1.1.
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 Day 1 until the follow-up contact (see Section 7.5.1.3), 
at the timepoints specified in the Time and Events Tables (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 4

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4.
7.5.1.2.
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 enquire 
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 
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7.5.1.3.
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 
stabilises, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 4.
7.5.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 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. 
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.
7.5.1.5.
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, IRB/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.
7.5.2.
Pregnancy

Details of all pregnancies in female subjects, and female partners of male subjects 
if available, will be collected after the start of dosing and until 91 days post study.
 
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
If a pregnancy is reported then the investigator should inform GSK within 2 
weeks of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4.
7.5.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height 
and weight will also be measured and recorded. 

A brief physical examination will include, at a minimum assessments of the lungs, 
cardiovascular system, skin and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
7.5.4.
Vital Signs

Vital signs will be measured in semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure and pulse rate.
Three readings of blood pressure and pulse rate will be taken. The first reading should be 
rejected, while the second and third readings should be averaged to give the measurement 
to be recorded in the CRF 
7.5.5.
Electrocardiogram (ECG)
12-lead ECGs will be obtained in triplicate at each timepoint during the study using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. Additional repeat ECG measurements may be taken if required. Refer 
to Section 5.4.3 for QTc withdrawal criteria and additional QTc readings that may be 
necessary.
7.5.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 4, must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
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 that are performed at the 
institution’s local laboratory result in a change in subject management or are considered 
clinically significant by the investigator (e.g., SAE or AE or dose modification) their 
results must be recorded in the CRF. Investigators should note that due to the anticipated 
effect of GSK3117391 on monocyte count, any local WBC panel assessments may 
unblind a subject’s treatment allocation to any reviewer. Therefore, every effort should be 
made to ensure that local monocyte count data is not available to the site during the 
study. Investigators will however be able to view total WBC counts and differential WBC 
counts that do not include monocyte counts.  
 
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Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 4. 
 
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Table 4
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
Reticulocytes
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
MCHC
Monocytes
INR/APTT
Eosinophils
MetHb
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatise
Albumin
CRP
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests

G6PD

HIV

Hepatitis B (HBsAg)

HBcAb

Hepatitis C (Hep C antibody)

QuantiFERON-TB

Rheumatoid Factor (RF), ACPA

FSH and estradiol (as needed in females of non-child bearing potential only)

hCG Pregnancy test (as needed for women of child bearing potential) 2
NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after 
liver stopping or monitoring event are given in Section 5.4.2 and Appendix 3.
2.
Central laboratory serum pregnancy test for the first visit during screening. Local urine testing for all 
other subsequent visits will be standard for the protocol unless serum testing is required by local 
regulation or ethics committee.
3.
The following parameters will only be performed at selected time points as per Time and Events Table: 
INR, MetHb, CRP.
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.
7.6.
Pharmacokinetics
7.6.1.
Blood Sample Collection
Blood samples for pharmacokinetic (PK) analysis of GSK3117391 and its acid 
metabolite GSK3339189 will be collected at the time points indicated in Section 7.1, 
 
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Time and Events Tables.  Additional samples will be collected for investigation of other 
compound-related metabolites (MET ID) as indicated in Section 7.1, Time and Events 
Tables. 
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.  
Processing, storage and shipping procedures are provided in the investigators manual. 
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.
Processing, storage and shipping procedures are provided in the laboratory investigators 
manual. 
7.6.2.
Urine Sample Collection
Urine samples (pre-dose and 0-24h) will be collected for investigation of GSK3117391, 
GSK3339189 and other compound-related metabolites.
Details of urine collection, sample processing, storage and shipping procedures are 
provided in the laboratory investigators manual.
7.6.3.
Monocyte isolation
Where possible, monocytes will be isolated from blood samples for pharmacokinetic 
(PK) analysis of GSK3339189 at the time points indicated in Section 7.1, Time and 
Events Tables. 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. Processing, storage and 
shipping procedures will be provided in the laboratory investigator manual.
7.6.4.
Sample Analysis
Plasma analysis will be performed via Platform Technology and Supply (PTS) - Third 
Party Resourcing (TPR), GlaxoSmithKline, the details of which will be included in the 
investigators manual. Concentrations of GSK3117391 and GSK3339189 will be 
determined in plasma samples using the currently approved bioanalytical methodology.
Raw data will be archived at the bioanalytical site.
Plasma and urine samples collected for metabolite identification will be analysed for 
GSK3117391, GSK3339189 and other compound-related metabolites and the results 
reported under a separate PTS, GlaxoSmithKline protocol.
Concentration analysis in blood monocytes may be performed where samples allow.  
Analysis will be performed at a bioanalytical site under the control of PTS, IVIVT, 
GlaxoSmithKline, the details of which will be included in the Laboratory Investigator 
Manual. Concentrations of GSK3339189 will be determined using an approved 
 
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bioanalytical method. The raw data will be archived by the bioanalytical site, 
GlaxoSmithKline.
7.7.
Pharmacodynamic Biomarkers
7.7.1.
PD Biomarkers
Pharmacodynamic biomarkers may include, but not limited to, the following:

Levels of acetylation in monocyte and non monocyte cells in the blood.

Blood samples will be analysed by flow cytometry for cell markers to determine any 
changes after treatment with GSK3117391.
7.7.2.
RA disease biomarkers
7.7.2.1.
Blood Biomarkers
Blood sample(s) will be collected during this study which may be used for the purposes 
of measuring biomarkers that are thought to influence RA. These may include but are not 
limited to:

Serum C reactive protein

Serum MRP8/14

MMP1

VCAM1

Serum amyloid A
7.7.3.
Novel biomarkers
Blood samples may be used for the purposes of measuring novel biomarkers that may 
influence disease/condition for study treatment, and/or medically related conditions, as 
well as the biological and clinical responses to GSK3117391.  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.
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with RA or medically related conditions and/or the action of 
GSK3117391 may be identified by application of:

RNA transcriptomic analysis of blood samples.

Measurement of the levels of a subset of RNA species in blood samples.

Soluble cytokine and inflammatory mediators including, but not limited to, pro-
inflammatory and anti-inflammatory cytokines, chemokines and acute phase 
proteins. 
 
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These may be reported separately after the clinical study report has been published.  All 
samples may be retained for a maximum of 15 years after the last subject completes the 
trial.
7.8.
Genetics
Subjects who do not wish to participate in the genetic research may still participate in the 
main clinical study. Information regarding genetic research is included in Appendix 5.
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 
will not be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA
9.1.
Hypotheses
The study will evaluate the effect of GSK3117391 relative to placebo on the change from 
baseline in DAS28-CRP after 4 weeks of treatment.  The primary analysis will test the 
null hypothesis of no treatment effect against the alternative hypothesis that there is a 
difference in DAS28-CRP change from baseline between the active and placebo groups.. 
This analysis will be fully documented in the Reporting and Analysis Plan (RAP).
9.2.
Sample Size Considerations
Approximately 40 subjects will be randomised.  Subjects will be randomised to either 
GSK3117391 or placebo with a 1:1 ratio.
9.2.1.
Sample Size Assumptions
The study is not powered to detect pre-defined differences.  For supportive information, 
with 20 subjects randomised to GSK3117391 and placebo groups respectively, the 
smallest difference in DAS28-CRP reduction between the two treatment groups at week 4 
that would be statistically significant using a two sided test would be 0.6, assuming a 
standard deviation of 1.
 
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9.2.2.
Sample Size Sensitivity
The minimum detectable difference in DAS28-CRP reduction will be affected by 
changes from the assumed estimated standard deviation (SD) of 1. Table 5 below shows 
the effect of different estimates of the SD for the change from baseline in DAS28-CRP at 
week 4 on the minimum detectable difference.
Table 5
The effect of different assumptions for SD on the minimum 
detectable difference
Assumed standard deviation 
Minimum detectable difference for change from baseline 
in DAS28-CRP at week 4 
0.7
0.4
0.8
0.5
0.9
0.6
1
0.6
1.1
0.7
1.2
0.8
1.3
0.8
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be conducted.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations and Datasets
Safety Population: The ‘Safety Population’ is defined as subjects who receive at least one 
dose of study medication. This population will be used for the summary of all safety data.
Per-protocol population: The ‘Per-protocol population’ is defined as subjects in the 
‘Safety’ population who are compliant with the dosing regimen (see Section 6.7) and that 
complete all protocol assessments and requirements.  Analyses using the per-protocol 
population will include data from subjects who are compliant with the protocol up to the 
point that they are not compliant (for example if a subject withdraws on day 21 but is 
compliant until then, their data up to day 21 will be used).  This population will be used 
for summary of efficacy, PD and biomarker data.
Pharmacokinetic population: The ‘PK population' is defined as subjects in the ‘Safety’ 
population who received an active dose and for whom a pharmacokinetic sample was 
obtained and analysed. This population is used for the summary of PK data only. In the 
 
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case of PK/PD, the Safety Population is used so that subjects receiving placebo can be 
included.
9.3.2.
Interim Analysis
In line with routine pharmacovigilance, an internal GSK SRT which will include 
members of the 204957 study team, will review blinded safety data.  In addition the DRC 
will review unblinded safety data (see Section 10.8 for further details) if necessary.
An unblinded interim analysis of the effect of GSK3117391 on monocyte counts will be 
conducted and reviewed by the DRC after approximately 10 subjects have completed the 
day 30 visit.  This analysis may alter the timing of assessments in this or future studies.  
In addition to monocyte counts, other safety data may be reviewed and supporting data 
including pharmacokinetic and PD biomarkers may also be reviewed.
Unblinded interim analyses of efficacy will be conducted and reviewed by the DRC once 
appropriate numbers of subjects have completed the week 4 efficacy assessment, which 
may lead to a decision to stop the study for futility.  In addition to efficacy data, safety 
data may be reviewed and supporting data including pharmacokinetic, PD biomarkers 
and RA disease biomarkers may also be reviewed.
A DRC charter will provide details of these reviews including timing, decision making 
and how the integrity of the study will be maintained (see Section 10.8 for further details 
of the DRC and Section 6.4 Blinding).  Full details of the interim analyses will be pre-
specified in the RAP.
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
The primary endpoint will be analysed using a Mixed effect Model for Repeated 
Measures (MMRM) adjusted for baseline DAS28-CRP score, treatment group, visit and 
the visit by treatment group interaction as fixed effects, patient as a random effect and 
visit within subject as a repeated effect, using an unstructured covariance matrix. The 
point estimates and corresponding 95% confidence intervals for the treatment differences 
will be constructed, using the residual error from the repeated measures model. Least 
squares means and 95% confidence intervals over time for each treatment group will be 
plotted.  The per-protocol population will be used for the primary analysis. Further 
sensitivity analyses may be conducted to assess the impact of missing data and 
nonparametric analyses may be conducted if the normality assumption does not hold.
9.4.2.
Secondary Analyses
9.4.2.1.
Safety Analyses
No formal statistical testing will be performed on safety data. All safety evaluations will 
be performed on the safety population. The safety data will be summarised descriptively 
and presented graphically. In addition, 95% credible intervals and probability statements 
 
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around the true event rate for specific AEs may be derived as appropriate to facilitate the 
interpretation of the safety data.
9.4.2.2.
Secondary Efficacy Analyses
The primary endpoint (change in DAS28-CRP) will be analysed within a Bayesian 
framework using a repeated MMRM, adjusting for baseline DAS28-CRP score, treatment 
group, visit and the visit by treatment group interaction as fixed effects, patient as a 
random effect and visit within subject as a repeated effect. 
Specific posterior probability statements around the true treatment difference in change 
from baseline in DAS28-CRP at week 4 and other timepoints as appropriate will be 
presented. For example, the probability that the true treatment difference in change from 
baseline in DAS28-CRP at week 4 is greater than 0.6 may be presented.  Further details 
of the analysis including the definition of the prior distribution, will be specified in the 
RAP.
The proportion of subjects meeting ACR thresholds will be summarised using counts and 
proportions and analysed, if data allow, using a Generalised Estimating Equations (GEE) 
model adjusted for treatment group and baseline DAS28-CRP score. An estimate of the 
odds ratio of achieving the ACR threshold comparing GSK3117391 and placebo and 
associated p-values and 95% confidence intervals will be provided for week 4 and other 
timepoints as appropriate. All data will be summarised, graphically represented and 
listed appropriately.
9.4.2.3.
Pharmacokinetic Analysis
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modelling and Simulation Department, GlaxoSmithKline. Blood samples will be 
collected to determine plasma concentrations of GSK3117391 and its acid GSK3339189. 
Plasma concentration-time data will be analysed by non-compartmental methods with 
Phoenix WinNonlin v.6.2.1 or greater. Calculations will be based on the actual sampling 
times recorded during the study. From the blood concentration-time data, the following 
pharmacokineticparameters will be determined, as data permit: maximum observed blood 
concentration(Cmax), time to Cmax (tmax), area under the blood concentration-time 
curve (AUC(0-t), AUC (0- τ), AUC(0-∞)), and apparent terminal phase half-life (t1/2). 
Trough concentration (C) samples collected on the specified days may be used to assess 
attainment of steady state. To estimate the extent of accumulation after repeat dosing, the 
observed accumulation ratio (Ro) may be determined.
The full pharmacokinetic profile for each subject will be reconstructed using Bayesian 
prediction from a population pharmacokinetic model using NONMEM version VII or 
higher and CL/F and V/F will be determined.
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarised descriptively. All pharmacokinetic data will be stored in the Archives, 
GlaxoSmithKline Pharmaceuticals, R&D. No statistical analysis of PK data will be 
carried out.
 
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9.4.2.4.
Pharmacokinetic/Pharmacodynamic Analyses
Exploratory plots will be presented for individual plasma GSK3117391 (drug) and 
plasma and intracellular GSK3339189 (acid) concentrations versus selected markers of 
clinical efficacy (including DAS28-CRP) and exploratory endpoints (including but not 
limited to selected blood cell quantification, acetylation of selected blood cells, soluble 
cytokine and inflammatory mediators, CRP and MRP8/14 expression). Additional 
exploratory plots will be presented of selected derived PK parameters from plasma levels 
of GSK3117391 and plasma / intracellular levels of GSK3339189 versus selected 
markers of clinical efficacy (e.g DAS28-CRP at week 4) and exploratory endpoints.
If data permit, further PK/PD modelling will be performed based on the results of the 
exploratory graphical analysis showing obvious relationships or trends between plasma 
concentration and the pharmacodynamic parameters. The choice of the structural 
pharmacokinetic/pharmacodynamic model will be dependent on the emerging data. More 
details of any exploratory pharmacokinetic/pharmacodynamic analysis will be provided 
in the RAP.
9.4.3.
Other Analyses
All exploratory endpoints will be summarised descriptively, graphically presented and 
statistically analysed if deemed appropriate. Further details will be specified in the RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable.
 
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
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.

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) agree 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. 
 
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
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.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  
 
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
The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archiving at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with 
the site.
 
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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 randomisation codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
10.8.
Review Committees
10.8.1.
Safety Review Team
Instream review of blinded individual level safety data including AE, SAEs, vital signs 
and laboratory data (with the exception of monocyte counts which will be summarised 
only, see Section 6.4) will be conducted by a Safety Review Team (SRT) during study 
conduct. The membership of the SRT (including members of the central GSK study 
team) and the proposed frequency of review is documented in the SRT charter. 
10.8.2.
Data Review Committee
Interim analyses of unblinded data will be conducted to assess the effect of GSK3117391 
on monocyte count, and for futility. The DRC may also perform an interim analysis on 
safety data if the SRT feels that this is warranted. These results will be reviewed by the 
internal DRC (see Section 9.3.2). No members of the study team involved in the direct 
day to day conduct of the study or in the acquisition of data will take part in the DRC In 
addition, in order to protect the interests of subjects and ensure their safety, the DRC will 
include one or more members of GSK’s Global Safety Board who are not members of the 
study team. The membership and timing of the planned interim analyses and the decision 
making framework for DRC reviews are described in the DRC charter.  The analysis plan 
for DRC reviews are described in the RAP. All available data may be reviewed by the 
DRC.
 
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11.
REFERENCES
Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcomes in arthritis. 
Arthritis Rheum 1980;23:137-45
Furlan A, Monzani V, Reznikov LL, Leoni F,Fossati G, Modena D, et al. 
Pharmacokinetics, Safety and Inducible Cytokine Responses during a Phase 1 Trial of the 
Oral Histone Deacetylase Inhibitor ITF2357 (Givinostat). Mol Med. 2011 May-Jun; 
17(5-6): 353–362.
Glauben R, Batra A, Stroh T, Erben U, Fedke I, Lehr HA, et al. Histone deacetylases: 
novel targets for prevention of colitis-associated cancer in mice. Gut. 2008;57:613–622.
GlaxoSmithKline Document Number 2014N201956_00 GSK3117391 Investigator’s 
Brochure. 22-APR-2016
GlaxoSmithKline Document Number 2014N193968_00 Study ID 201302. A Phase I 
Double-Blind, Randomised, Placebo-controlled, Dose Escalating Study to Assess the 
Safety and Tolerability of Single and Multiple Oral Doses of CHR-5154 and the Effect of 
the Fasted and Fed State on Pharmacokinetics of CHR-5154 and CHR-5426 in Healthy 
Male Volunteers. Report Date 26-May-2015
Joosten LA, Leoni F, Meghji S, Mascagni P. Inhibition of HDAC activity by ITF2357 
ameliorates joint inflammation and prevents cartilage and bone destruction in 
experimental arthritis. Mol Med. 2011 May-Jun;17(5-6):391-6.
Li J, Hsu H-C, and Mountz, JD The Dynamic Duo–Inflammatory M1 macrophages and 
Th17 cells in Rheumatic Diseases. J Orthop Rheumatol. 2013 Nov 1; 1(1): 4. 
Lin HS, Hu CY, Chan HY, Liew YY, Huang HP, Lepescheux L, et al. Anti-rheumatic 
activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis 
in rodents. Br J Pharmacol. 2007 Apr;150(7):862-72.
Nishida K, Komiyama T, Miyazawa S, Shen ZN, Furumatsu T, Doi H, et al. Histone 
deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via 
regulation of p16INK4a and p21(WAF1/Cip1) expression. Arthritis Rheum. 
2004;50:3365–3376.
O'Dell JR., Mikuls TR, Taylor TH, Ahluwalia V, Brophy M, Warren SR, et al, for the 
CSP 551 RACAT Investigators Therapies for Active Rheumatoid Arthritis after 
Methotrexate Failure. N Engl J Med 2013; 369:307-318.
Rubbert-Roth A and Finckh A. Treatment options in patients with rheumatoid arthritis 
failing initial TNF inhibitor therapy: a critical review Arthritis Res Ther. 2009; 11(Suppl 
1): S1.
Vojinovic J, Damjanov N, D'Urzo C, Furlan A, Susic G, Pasic S, et al. Safety and 
efficacy of an oral histone deacetylase inhibitor in systemic-onset juvenile idiopathic 
arthritis. Arthritis Rheum. 2011 May;63(5):1452-8.
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
C
Degree Celsius
g
Microgram
ACPA
Anti-citrullinated protein antibodies
ACR
American College of Rheumatology
ACR20/50/70
20%/50%/70% improvement in tender and swollen joint 
counts and 20%/50%/70% improvement in 3 of the 5 ACR-
core set measures
AE
Adverse event
ALT
Alanine transaminase
AMD
Age-related macular degeneration
AST
Aspartate transaminase
AUC
Area under the curve
AUC0-
Area under plasma (serum) concentration-versus-time curve 
(time zero to infinity)
AUC0-t
Area under the plasma (serum) concentration-versus-time 
curve (time zero to time of last quantifiable concentration)
BUN
Blood Urea Nitrogen
hCG
Human chorionic gonadotropin
CPK
Creatine phosphokinase
CRP
C-reactive protein
CYP
Cytochrome P
DAS28-CRP
Disease activity score for 28 different joints with CRP value
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic acid
DMARD
Disease modifying anti rheumatic drug
DRC
Data Review Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
ESM
Esterase Sensitive Motif
EULAR
European League Against Rheumatism
FRP
Females of reproductive potential
FSH
Follicle-stimulating hormone
FTIH
First time in human
g
Gram
GSK
GlaxoSmithKline
h
Hour 
hCE-1
Human carboxy-esterase-1 
HAQ-DI
Health Assessment Questionnaire Disability Index
HDAC
Histone deacetylase 
HIV
Human Immunodeficiency Virus
 
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HRT
Hormone replacement therapy
IA
Intra-articular
IB
Investigator brochure
IC50
The half maximal inhibitory concentration
ICH
International Conference on Harmonization
IM
Intramuscular
INR
International normalised ratio
IP
Investigational product
IRB/IEC
Institutional Review Board/Independent Ethics Committee 
IRTS
Interactive response technology system
IU
International units
IV
Intravenous
kg
Kilogram
L
Liter
LDH
Lactate dehydrogenase
MCV
Mean corpuscular volume
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MedDRA
Medical dictionary for regulatory activities
MET ID
Metabolite Identification
mg
Milligram
mL
Milliliter
MMRM
Mixed effect Model for Repeated Measures 
MRP
Myeloid-related protein
MSDS
Material safety data sheet
MTX
Methotrexate
ng
Nanogram
NSAID
Non-steroidal anti-inflammatory drug
PD
Pharmacodynamic
PtGA
Patient’s Global Assessment of Arthritis
PtAAP
Patient’s Assessment of Arthritis Pain
PhGA
Physician’s Global Assessment of Arthritis
PK
Pharmacokinetics
PTS
Platform Technology and Supply 
RA
Rheumatoid arthritis
RAP
Reporting and analysis plan
RF
Rheumatoid Factor
SAE
Serious adverse event
SD
Standard Deviation
SJC
Swollen Joint Count
SOP
Standard operating procedure
SRM
Study Reference Manual
SRT
Safety Review Team
t½
Elimination half-life
TB
Mycobacterium tuberculosis
 
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TJC
Tender Joint Count 
TNFα
Tumor necrosis factor alpha
TPR
Third Party Resourcing
VAS
Visual Analogue Scale
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Eanercept
Humira
Prosorba
QuantiFERON-TB
Remicade
Simponi
WinNonlin
 
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12.2.
Appendix 2: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.2.1.
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 sterilisation 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 91 days after the last dose of study medication.
1.
Male condom plus recommendation for partner use of one of the contraceptive 
options below that meets the Standard operating procedure (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.

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]. 
 
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
Injectable progestogen [Hatcher, 2011].

Contraceptive vaginal ring [Hatcher, 2011].

Percutaneous contraceptive patches [Hatcher, 2011].
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.
In addition, male subjects are prohibited from donating sperm until 91 days after the last 
dose of study medication.
12.2.2.
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 foetal 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. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous 
reporting.
Any female subject who becomes pregnant while participating

Will discontinue study medication and be withdrawn from the study.

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomised 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.
 
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
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 foetal 
status (presence or absence of anomalies) or indication for procedure.
 
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12.2.3.
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EMEA/CHMP/GTWP/125459/2006: Guideline on the Nonclinical Studies Required 
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FDA CBER Guidance for industry, “Considerations for Developmental Toxicity Studies 
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FDA Medical Devices Safety Alerts and Notices, “Blood human chorionic gonadotropin 
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Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 
2011: 50. Table 3-2.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Detection of 
Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility. Parent 
Guideline dated 24 June 1993 (Addendum dated 9 November 2000 incorporated in 
November 2005. ICH S5 (R2).
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of Pharmaceuticals For Human Use.  ICH Harmonized Tripartite Guideline. Nonclinical 
Evaluation for Anticancer Pharmaceuticals. ICH S9. 2009.
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Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals. ICH M3 (R2). 2009.
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of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Preclinical 
Safety Evaluation of Biotechnology-Derived Pharmaceuticals. ICH S6 and Addendum 
ICH S6 (R1). 2011.
 
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Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, editors. Williams Textbook of 
Endocrinology, 11th edition. Philadelphia: Saunders, 2008.
Strauss JF, Barbieri RL, editors. Yen and Jaffe’s Reproductive Endocrinology. 5th 
edition, Philadelphia, Elsevier/Saunders, 2004.
U.S. Dept of Health and Human Services, FDA, Center For Biologics Evaluation and 
Research: Guidance for Human Somatic Cell Therapy and Gene Therapy [1998].
WHO, 2013 - WHO - Guidelines on the Nonclinical Evaluation of Vaccine Adjuvants 
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World Health Organization. WHO/CONRAD Technical Consultation on Nonoxynol-9.
World Health Organization; Department of Reproductive Health and Research; Geneva; 
9-10 October 2001. Summary Report. 2001. WHO/RHR/03.8.
 
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12.3.
Appendix 3: 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.
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, stabilise, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with study 
treatment 
MONITORING:

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 24 hours after 
last dose, per protocol where possible5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
 
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Liver Chemistry Stopping Criteria – Liver Stopping Event
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, stabilise 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, stabilise or return to within baseline
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]). 

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  
 
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Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK Medical Monitor within 24 hours of 
learning of the abnormality to discuss subject safety. 

Subject can continue study treatment  

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalise or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, et al.Pharmacokinetics of acetaminophen-protein 
adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab 
Dispos 2009;37:1779-84
 
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12.4.
Appendix 4: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

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 
 
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Events NOT meeting definition of an AE include:
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.4.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalisation 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 hospitalisation or prolongation of existing hospitalisation
NOTE:

In general, hospitalisation 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 hospitalisation are 
AEs.  If a complication prolongs hospitalisation or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalisation” occurred or was 
necessary, the AE should be considered serious.

Hospitalisation 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 
 
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normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
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 hospitalisation but may jeopardise 
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 hospitalisation, 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.
12.4.3.
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
 
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
Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation
12.4.4.
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 Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
12.4.5.
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.
 
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
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 utilised 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.
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.
 
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
If a subject dies during participation in the study or during a recognised 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.
12.4.6.
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 SAE coordinator.

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 SAE 
coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
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12.5.
Appendix 5: 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 GSK3117391 or any concomitant medicines.

RA 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 utilise 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 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.
 
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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 
randomised 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 utilise 
the original sample.  
The genetic sample is labelled (or coded) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
 
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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 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. However, if patient is re-screened successfully then the original 
genetic sample will be kept to avoid re-sampling.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarise 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.  Furthermore, data generated in a research 
laboratory may not meet regulatory requirements for inclusion in clinical care.
References
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular 
Degeneration (AMD) Susceptibility Gene CFH and Treatment Response of AMD: A 
Meta-Analysis. PloS ONE 2012; 7: e42464
Gorin MB. Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.
 
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12.6.
Appendix 6: Country Specific Requirements
No country-specific requirements exist.
 
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12.7.
Appendix 7: Protocol Changes
This is the third Amendment to Protocol 204957 (2016-DEC-08). This amendment is 
applicable to all countries and sites participating in study 204957.
The changes in this amendment are to provide clarity regarding extension to the 
screening window and other study requirements throughout the protocol.
Changes in this amendment:
Section of 
protocol
Original text
Text in amendment
4.1 Overall 
Design
No footnote for Figure 1
The screening window can be 
extended for up to 56 days to allow 
only for the washout of background 
DMARD therapy if necessary 
(footnote added)
4.1.1 Screening
Subjects will be screened up to 28 
days prior to the Day 1 visit 
(randomisation and start of the 
treatment period).
All subjects must provide written 
informed consent for the study prior 
to the start of screening period. 
Subjects will be screened up to 28 
days prior to the Day 1 visit 
(randomisation and start of the 
treatment period). The screening 
window can be extended for up to 
56 days to allow only for the 
washout of background DMARD 
therapy if necessary (see Section 
6.11.2 for washout periods for 
DMARD therapies and other 
medications). Subjects on 
medications requiring longer 
washout than 56 days prior to Day 1 
must have discontinued medication 
for the stated washout time in 
Section 6.11.2 before being 
considered for eligibility in this 
study.
All other screening assessments 
must be performed within 28 days 
prior to Day 1(dosing Day 1).
 
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Section of 
protocol
Original text
Text in amendment
4.3. Type and 
Number of 
Subjects
Approximately 80 subjects with 
RA will be screened, from these 
approximately 40 will proceed to 
randomisation. This assumes a 
screen fail rate of up to 50% and a 
dropout rate of approximately 
15%.
Approximately 40 subjects will be 
randomised. This assumes a dropout 
rate of approximately 15%.  
4.4. Design 
Justification
If a subject experiences an 
unacceptable level of disease 
activity during the study, the 
investigator may withdraw the 
subject at any point.
If a subject experiences an 
unacceptable level of disease 
activity during the study, the 
investigator may withdraw the 
subject from further study treatment 
at any point. The subject is then to 
enter the follow up period, where 
subject will be able to receive 
standard of care treatment at the 
discretion of the investigator as 
early as 7 days after the last dose of 
study medication. 
5.1. Inclusion 
Criteria
Type Of Subject 
And Diagnosis 
Including Disease 
Severity
The subject must have a diagnosis 
of RA according to the 2010 
ACR/EULAR classification 
criteria for RA.
The subject must have a diagnosis 
of RA as an adult (≥18 years) 
according to the 2010 ACR/EULAR 
classification criteria for RA.
5.1. Inclusion 
Criteria
Sex, female
A negative hCG pregnancy test, 
(serum at screening visit and urine 
for subsequent visits, with a 
sensitivity of at least 25 IU/L) is 
required at the screening visit, 
between Day-7 to -4 and on Day 1 
prior to dose administration. 
Further pregnancy tests are 
required at the weekly study visits 
and the follow-up visit.
A negative serum hCG pregnancy 
test at the first screening visit and 
urine hCG pregnancy test (with a 
sensitivity of at least 25 IU/L) at the 
following visits: between Day-7 to -
4, on Day 1 prior to first study 
medication dose administration, at 
the weekly study visits, and the 
follow up visit. 
5.1. Inclusion 
Criteria
The investigator is responsible for 
ensuring that subjects understand 
how to properly use these 
methods of contraception.
The investigator is responsible for 
ensuring that subjects understand 
how to properly use these methods 
of contraception and receive 
continued guidance with respect to 
the avoidance of pregnancy and 
sperm donation as part of the study 
procedures.
 
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Section of 
protocol
Original text
Text in amendment
5.2. Exclusion 
Criteria
Concurrent 
Conditions/Medica
l History (Includes 
Liver Function 
And QTc Interval)
#3
Subjects who have previously 
been treated with more than 1 
biologic agent (such as TNF 
inhibitors eg. adalimumab, 
etanercept, infliximab, 
certolizumab, golimumab or non-
TNF inhibitors eg.abatacept, 
rituximab, tociluzimab) or any 
investigational biologic.
Subjects who have previously been 
treated with more than 1 biologic 
agent (such as TNF inhibitors and 
their biosimilars eg. adalimumab, 
etanercept, infliximab, 
certolizumab, golimumab or non-
TNF inhibitors and their biosimilars 
eg.abatacept, rituximab, 
tociluzimab) or any investigational 
biologic.
5.2. Exclusion 
Criteria
Concurrent 
Conditions/Medica
l History (Includes 
Liver Function 
And QTc Interval)
#7
Inclusion 7 as in original text
Each parameter unit power is 
superscripted for ease of the reader
5.3.1. 
Rescreening
If a subject has not met all of the 
Eligibility Criteria within the 
screening period, rescreening is 
permitted. Subjects are only 
allowed to be re-screened once; 
the entire screening process must 
be repeated. 
Re-screening is permitted with the 
approval of the medical monitor if a 
subject has not met the Eligibility 
Criteria within the screening period 
with the following exception: 

If a subject fails screening due to 
Exclusion Criteria 6 and/or 7 in 
Section 5.2, rescreening is not 
permitted. 
Subjects are only allowed to be re-
screened once; the entire screening 
process must be repeated.
Chest X-ray does not need to be 
repeated during re-screening, if one 
was conducted within 12 weeks of 
re-screening Day 1 and showed no 
evidence of current or previous 
pulmonary tuberculosis, locally read 
by a radiologist.
Repeat testing of glucose-6-
phosphate dehydrogenase (G6PD) 
deficiency during rescreening is not 
needed, if test result during original 
screening was negative. 
 
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5.3.2.1. 
Laboratory tests
If a subject fails any of the 
laboratory exclusion criteria, the 
test may be repeated twice within 
the screening period. If the subject 
fails the laboratory criteria for a 
third time they
will be considered a screen 
failure; these subjects may be re-
screened as described in
Section 5.3.1.
If a blood sample has to be 
redrawn due to sample handling 
problems, breakage or sample 
integrity, this is not considered a 
re-test.
If the investigator is not able to 
assess subject’s eligibility for any of 
the laboratory exclusion criteria in 
cases of (a) technical malfunction 
(e.g. loss of laboratory specimen); 
(b) an indeterminate result or (c) if 
there is reason to believe the result 
may be false (i.e. contradicts recent 
result for the same parameter) the 
test may be repeated once within the 
screening period after consultation 
with the medical monitor. If the 
original result was exclusionary and 
is confirmed by repeat testing then 
the subject is to be considered a 
screen failure; these subjects may be 
re-screened as described in Section 
5.3.1.
6.1. 
Investigational 
Product and 
Other Study 
Treatment
No original text
Store refrigerated (2 – 8oC) (row 
added for study treatment)
6.4. Blinding
The anticipated effect of 
GSK3117391 on monocyte count 
may unblind a subject’s treatment 
allocation to any reviewer. As a 
consequence, monocyte count 
data (which will be analysed in a 
central laboratory) will not be 
available to the site during the 
study. Investigators will be able to 
view blinded WBC counts. 
Summary monocyte counts for
all subjects will be reviewed by 
the SRT; however, individual 
level monocyte count data will 
only be reviewed by the DRC.
The anticipated effect of 
GSK3117391 on monocyte count 
and CRP may unblind a subject’s 
treatment allocation to any reviewer.  
As a consequence, monocyte count 
data and CRP (both of which will be 
analysed in a central laboratory) will 
not be available to the site during 
the study after screening. 
Investigators will, therefore, be 
blinded to the monoctye count but 
will be able to view other WBC 
counts. Summary monocyte counts 
for all subjects will be reviewed by 
the SRT once sufficient subjects 
have been recruited to avoid 
unblinding. Individual level 
monocyte count and CRP data will 
only be reviewed by the DRC. 
 
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Section of 
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Text in amendment
6.6. 
Preparation/Hand
ling/Storage/Acc
ountability
No special preparation of study 
treatment is required.
No special preparation of study 
treatment is required. The study 
treatment must be stored 
refrigerated (2-8oC) at site, and at 
subject’s home.
6.7. Compliance 
with Study 
Treatment 
Administration
Only subjects with appropriate 
compliance will be included in the 
per-protocol dataset for the 
primary analysis.  
Only subjects with appropriate 
compliance will be included in the 
per-protocol population for the 
primary analysis.  
6.8. Treatment of 
Study Treatment 
Overdose
For this study, any dose of 
GSK3117391 > 80mg (ie >4 
capsules) within a 26 hour time
period will be considered an 
overdose.
For this study, more than 4 capsules
of the study medication within a 26 
hour time period will be considered 
an overdose.
6.11.1. Permitted 
Medications and 
Non-Drug 
Therapies
First paragraph removed 
Inserted in Section 6.11. 
Concomitant Medications and Non-
Drug Therapies
6.11.1.2. NSAIDs
Continued use of NSAIDs is 
permitted (i.e. diclofenac, 
ibuprofen, ketoprofen, naproxen
etc) in daily doses up to the 
maximum recommended 
according to locally accepted 
clinical practices if the dosage 
was stable for at least 2 weeks 
before screening.
Continued use of NSAIDs is 
permitted (i.e. diclofenac, ibuprofen, 
ketoprofen, naproxen, celecoxib and 
etoricoxib etc) in daily doses up to 
the maximum recommended 
according to locally accepted 
clinical practices if the dosage was 
stable for at least 2 weeks before 
screening. 
The concomitant use of proton 
pump inhibitors, e.g. omeprazole or 
pantoprazole, is strongly 
recommended in order to lower the 
risk of complications affecting the 
gastrointestinal tract caused by 
NSAIDs.
6.11.2. Prohibited 
Medications and 
Non-Drug 
Therapies
Table 1: Prohibited throughout the 
study, from the time periods 
stated until the follow up clinic 
visit:
For subjects on medications 
requiring washout of >28 days 
(see below), written informed 
consent for the study must be 
Table 1: Prohibited throughout the 
study, from the time periods stated 
until after 7 days from the last dose 
of the study medication:
(paragraph deleted)
 
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obtained prior to beginning the 
screening period. However, other 
screening assessments, other than 
consent, must occur within 28 
days prior to randomisation
Any conventional DMARDs 
No original text
Tofacitinib
Any conventional DMARDs (if not 
listed here please contact medical 
monitor)
26 weeks prior to Day 1 washout for 
Gold salts (row added)
Tofacitinib
Baricitinib
7. Study 
Assessments And 
Procedures
If assessments are scheduled for 
the same nominal time, then the 
assessments should occur in the 
following order:
If assessments are scheduled for the 
same nominal time, then the 
assessments should, where possible, 
occur in the following order:
7.1. Time and 
Events Tables
Table 2: 
Screening and 
Follow-up 
Assessments
Notes: No original text
EW = Early Withdrawal
Informed consent must be 
obtained prior to any study 
procedures being conducted.
Screening is serum pregnancy 
test, all subsequent testing urine. 
An additional pregnancy test is 
required 4-7 days prior to Day 1. 
FRP only.
No original text
1.
Screening period can be 
extended to 56 days to allow ONLY 
the washout of background 
DMARD therapy where necessary. 
All other assessments must be 
completed within 28 days prior to 
Day 1. Some assessment can occur 
on separate visit
2.
For EW = (Early 
Withdrawal) visit, assessments are 
to be conducted as deemed 
necessary based on PI’s judgment 
and to be recorded as a unscheduled 
visit in the subject’s CRF
Informed consent must be obtained 
prior to any study procedures being 
conducted including DMARD 
therapy washout period.
First test in screening is serum 
pregnancy test, all subsequent 
testing urine. An additional 
pregnancy test during screening 
visit (urine) is required 4-7 days 
prior to Day 1. FRP only.
Contraception use compliance (row 
added)
 
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Text in amendment
aCCP
CRP
ACPA
hs-CRP
(reordering of few assessments)
7.1. Time and 
Events Tables
Table 3: Day 1 to 
Day 30 On-Study 
Assessments
No original text
aCCP
CRP
Time in relation to dose (no 
footnote)
D2, 28 & D30 (no footnote)
RA disease biomarker sampling
Isolated monocyte PK (no 
footnote)
Contraception use compliance (row 
added)
ACPA
hs-CRP
Sample collection and assessments 
to be conducted in accordance with 
the time and events table (footnote 
added)
Blood samples to be collected 
within a ± 1 h window of the 
schedule time(footnote added)
Sample will be collected and stored 
for future analysis. (footnote added)
Applicable to selected sites only 
(footnote added)
Abbreviations added, reordering of 
few assessment
7.2. Screening 
and Critical 
Baseline 
Assessments
ACR response
HAQ-DI
No original text
Patient Reported Outcomes 
questionnaires should be 
completed by subjects before any 
other assessment at a clinic visit, 
in the order specified.
No original text
ACR criteria
HAQ-DI which includes an item on 
pain severity during the past week
Patient reported outcome 
(subheading added)
Patient Reported Outcomes 
questionnaires should be completed 
by subjects before any other 
assessment at a clinic visit, in the 
order specified above.
The investigator is responsible for 
ensuring that subjects understand 
how to properly use contraception 
methods detailed in Appendix 2 and 
receive continued guidance during 
screening and study conduct with 
respect to the avoidance of 
pregnancy and sperm donation as 
part of the study procedures. Such 
guidance should include a reminder 
of the followings:

Contraceptive requirements of 
the study
 
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Section of 
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Original text
Text in amendment

Assessment of subject 
compliance through questions 
such as

Have you forgotten to use 
contraception since the last visit? 

Is there a chance you could be 
pregnant?
(section rearranged for consistency)
7.3. Efficacy
Efficacy assessments will include 
evaluation of all 68 joints for 
tenderness and 66 joints for 
swelling to be performed by an 
independent joint evaluator, 
Visual Analogue Scale (VAS) for 
global disease for the subject and 
treating physician, health 
assessment questionnaire –
disability index (HAQ-DI –
physical function, which includes 
an item on pain severity in the 
past week), and laboratory 
assessments (CRP).  Based on 
these assessments ACR (20, 50 
and 70), DAS28-CRP and the 
EULAR response will be 
calculated.
Efficacy assessments will include 
Health Assessment Questionnaire –
Disability Index (HAQ-DI –
physical function,), Patient’s 
assessment of Arthritis Pain, 
Patient’s Global Assessment of 
Arthritis, evaluation of all 68 joints 
for tenderness and 66 joints for 
swelling (to be performed by an 
independent joint evaluator), 
Physician’s Global Assessment of 
Arthritis and laboratory assessments 
(including CRP).  Based on these 
assessments ACR (20, 50 and 70), 
DAS28-CRP and the EULAR 
response will be calculated by the 
central GSK team.
7.4.1.
DAS measurements
Sites/investigators will not have 
access to ongoing DAS scores
DAS28 measurements
Sites/investigators will not have 
access to ongoing DAS28 scores
7.4.2. ACR 
measurements
Health Assessment Questionnaire 
– Disability Index (HAQ-DI) 
Health Assessment Questionnaire –
Disability Index (HAQ-DI) which 
includes an item on pain severity 
during the past week. 
(section rearranged for consistency)
7.5.6. Clinical 
Safety 
Laboratory 
Assessments
No original text
Investigators should note that due to 
the anticipated effect of 
GSK3117391 on monocyte count, 
any local WBC panel assessments 
may unblind a subject’s treatment 
allocation to any reviewer. 
Therefore, every effort should be 
made to ensure that local monocyte 
count data is not available to the site 
 
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Section of 
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Original text
Text in amendment
during the study. Investigators will 
however be able to view total WBC 
counts and differential WBC counts 
that do not include monocyte 
counts.  (paragraph added)
Table 4: Protocol 
Required Safety 
Laboratory 
Assessments
aCCP
ACPA
Central laboratory serum pregnancy 
test for the first visit during 
screening.(sentence added to Note 
#2)
7.6.3. Monocyte 
isolation
Processing, storage and shipping 
procedures are provided in the 
laboratory investigator manual.
Processing, storage and shipping 
procedures will be provided in the 
laboratory investigator manual.
7.7.1. PD 
Biomarkers
Soluble biomarkers in the blood 
which may be predictive of 
response to GSK3117391 such as 
IL-6.
Sentence deleted
9.2. Sample Size 
Considerations
Approximately 80 subjects will be 
screened and approximately 40 
randomised. Subjects will be 
randomised to either 
GSK3117391 or placebo with a 
1:1 ratio.
Approximately 40 subjects will be 
randomised.  Subjects will be 
randomised to either GSK3117391 
or placebo with a 1:1 ratio.
9.3.1. Analysis 
Populations and 
Datasets
Per-protocol dataset
Per-protocol population (replaced 
throughout)
12.5. Appendix 5: 
Genetic Research
“Screen failures” section
However, if patient is re-screened 
successfully then the original 
genetic sample will be kept to avoid 
re-sampling.(sentence added)
 
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Changes in amendment 2:
Section of 
protocol
Original text
Text in amendment
4.4 Design 
justification
The study is sponsor open to 
enable members of the Data 
Review Committee (DRC) to be 
unblinded for the planned interim 
analyses of monocyte counts
The study is sponsor open to 
enable members of the Data 
Review Committee (DRC) to be 
unblinded for the planned interim 
analyses of safety data (including 
clinical laboratory parameters and 
AEs), monocyte counts
5.4.2 Group 
safety stopping 
criteria
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) and/or the 
iSRC in order to ensure 
appropriate subject safety.  
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) and/or the 
DRC in order to ensure 
appropriate subject safety.  
6.4 Blinding
  However, monocyte data will be 
reviewed with other data by the 
iSRC an maybe reviewed by the 
DRC
  Summary monocyte counts for 
all subjects will be reviewed by
the SRT however, individual 
level monocyte count data will 
only be reviewed by the DRC.
7.1 Time and 
events tables
HIV, Hep B and Hep C screen, 
TB, 
HIV, Hep B and Hep C screen, 
TB, G6PD
7.1 Time and 
events tables
PK blood sample 
PK blood sample and MetID
 
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9.3.2 Interim 
analysis
In addition an iSRC will review 
unblinded safety data (see Section 
10.8 for further details) .
In addition the DRC will review 
unblinded safety data (see Section 
10.8 for further details) if 
necessary.
9.3.2 Interim 
analysis
other safety data will be reviewed
other safety data may be reviewed
9.3.2 Interim 
analysis
An unblinded interim analysis of 
efficacy will be conducted and 
reviewed by the DRC once 
appropriate numbers of subjects 
have completed the week 4 
efficacy assessment, which may 
lead to a decision to stop the study 
for lack of efficacy.  In addition to 
efficacy data, safety data will be 
reviewed
Unblinded interim analyses of 
efficacy will be conducted and 
reviewed by the DRC once 
appropriate numbers of subjects 
have completed the week 4 
efficacy assessment, which may 
lead to a decision to stop the 
study for futility.  In addition to 
efficacy data, safety data may be 
reviewed
10.8.1 Safety 
review team
Instream review of blinded safety 
data including AE, SAEs, vital 
signs and laboratory data (with the 
exception of monocyte counts, see 
Section 6.4)
Instream review of blinded 
individual level safety data 
including AE, SAEs, vital signs 
and laboratory data (with the 
exception of monocyte counts 
which will be summarised only, 
see Section 6.4)
10.8.2 Internal 
safety review 
committee
An Internal Safety Review 
Committee (iSRC) will be utilised 
in this study and comprise 
individuals who are not members 
of the clinical study team.  The 
iSRC is positioned to offer an 
internal, independent review of 
safety data (and other data types 
when required) to protect the 
interests of subjects and ensure 
their safety.  All efforts will be 
made to maintain the study 
integrity and validity of study 
data.  The schedule of planned 
reviews of safety data and the 
analysis plan for iSRC review is 
described in the iSRC Charter.
Whole section removed
 
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Section of 
protocol
Original text
Text in amendment
10.8.3 Data 
review 
committee
The DRC may also perform an 
interim analysis on safety data if 
the SRT feel that this is 
warranted.
(sentence added)
10.8.3 Data 
review 
committee
In addition, members of the 
global safety board who are not 
members of the study team will 
perform an independent review of 
safety data when reviewed to 
protect the interests of subjects 
and ensure their safety.  
(sentence added)
Changes in amendment 1:
Section of 
protocol
Original text
Text in amendment
Section 4.1, 
Figures 1
study schematic: outpatient 
visit on day 15
outpatient visit on day 14
Section 5.1, 
Inclusion 
criteria 10
A female subject is eligible to 
participate if she is not 
pregnant (as confirmed by a 
negative urine human 
chorionic gonadotrophin 
(hCG) test),
A female subject is eligible to 
participate if she is not pregnant (as 
confirmed by a negative human 
chorionic gonadotrophin (hCG) test),
Section 5.1, 
Inclusion 
criteria 10b
A negative pregnancy test 
(serum or urine hCG 
pregnancy test with a 
sensitivity of at least 25 IU/L) 
is required on Days -28, Day-
7 to -4 and Day 1
A negative hCG pregnancy test, 
(serum at screening visit and urine for 
subsequent visits, with a sensitivity of 
at least 25 IU/L) is required at the 
screening visit, between Day-7 to -4 
and on Day 1
Section 5.2 
Exclusion 
criteria 28
‘No evidence of active or 
latent infection’
Evidence of active or latent infection’
 
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Section 6.11.2
‘For subjects on medications 
requiring washout of >28 
days (see above’
‘For subjects on medications requiring 
washout of >28 days (see below)’
Section 6.11.2 
Table 1
‘atazanvir’
‘volconazole’
‘atazanavir’
‘voriconazole’
Section 7.1, 
Table 2
On table 2, no foot note next 
to ‘outpatient visit’
Footnote added ‘Additional screening 
visit needed for FRP pregnancy test 4 
to 7 days pre day 1’
Section 7.1, 
Table 2
‘Haem/Chem/Urinalysis 
tests’ 
Footnote added to 
‘Haem/Chem/Urinalysis tests’ 
‘Including INR/APTT (coagulation) 
and MetHb (MetHb, performed 
locally)’
Section 7.1, 
Table 2
‘PD biomarker sample’ 
Footnote added to: ‘PD biomarker 
sample’ 
‘This includes biomarkers for RA
disease and exploratory PD, 
acetylation’
Section 7.1, 
Table 2
‘Chest xray’
Footnote added to ‘Chest xray’
’Only required at screening if no CXR 
performed within 12 weeks of Day 1 
visit’
Section 7.1, 
Table 2
‘gene expression blood’ 
missing from table
Row added ‘Gene expression blood’ 
with ‘x’ in follow up visit column
Section 7.1, 
Table 3
clinical chemistry/urinalysis
‘x’ to indicate additional assessments 
at day 7, 14 and 21  visit
Section 7.1, 
Table 3
Coagulation
Coagulation (INR/IPTT)’
Section 7.1,
Table 3
Joint counts: TJC (68), SJC 
(66)
‘x’ to indicate assessment required at 
day 28
 
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Section of 
protocol
Original text
Text in amendment
Section 7.1, 
Table 3
(MetHb missing from table)
Row added ‘MetHb’ with ‘x’ in 
columns day 14 and day 28
Section 7.1, 
Table 3
‘Monocyte PK blood’
‘Isolated monocyte PK’
Section 7.1, 
table 3
‘gene expression blood’
‘x’ to indicate assessment at day 28 
removed
Section 7.6.6, 
Table 4
Table 4 missing Note 3
Note added
‘ 3 The following parameters will 
only be performed at selected 
time points as per Time and 
Events Table: INR, MetHb, CRP’
Section 7.8.3
GS3117391
GSK3117391
 
2017N353897_00

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
204957
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for a randomised, multi-center, 
double blind (sponsor open), placebo-controlled study to 
assess the efficacy, safety, tolerability, pharmacokinetics and 
pharmacodynamics of GSK3117391 in subjects with severe, 
active rheumatoid arthritis
Compound Number
:
GSK3117391
Effective Date 
:
12-JAN-2018
Description :

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 204957.

A final approved version of the full RAP for each interim reporting and final effort 
including the list of data displays will be made available prior to the respective 
Database Release (DBR).

This study has been terminated early due to business prioritisation.
Author’s Name and Functional Area: 
05-JAN-2018
Principal Statistician
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited
 
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CONFIDENTIAL
The GlaxoSmithKline group of companies
204957
2
Reviewed by: 
10-JAN-2018
eSignature
Operations Study Lead
12-JAN-2018
email
Early Development Lead
10-JAN-2018
eSignature
Biology Lead
12-JAN-2018
eSignature
Global Clinical Safety Pharmacovigilance
11-JAN-2018
eSignature
Data Quality Lead
12-JAN-2018
eSignature
Principal Programmer
 in place of 
11-JAN-2018
eSignature
         Clinical Investigation Lead
Approved by: 
12-JAN-2018
eSignature
Director (Clinical Statistics)
 
12-JAN-2018
eSignature
Programming Manager
 
2017N353897_00
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PPD
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CONFIDENTIAL
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TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNPOSIS.........................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................7
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................7
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ................................................................................................9
2.4.
Statistical Hypotheses...................................................................................9
3.
PLANNED ANALYSES ............................................................................................9
3.1.
Instream Analyses ........................................................................................9
3.2.
Interim Analyses ...........................................................................................9
3.3.
Final Analyses ............................................................................................10
4.
ANALYSIS POPULATIONS ...................................................................................10
4.1.
Protocol Deviations.....................................................................................10
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................12
6.
STUDY POPULATION ANALYSES .......................................................................13
6.1.
Overview of Planned Analyses ...................................................................13
7.
PRIMARY STATISTICAL ANALYSES....................................................................14
7.1.
Primary Efficacy Analyses ..........................................................................14
7.1.1.
Overview of Planned Primary Efficacy Analyses..........................14
8.
SECONDARY STATISTICAL ANALYSES .............................................................15
8.1.
Secondary Efficacy Analyses......................................................................15
8.1.1.
Overview of Planned Secondary Efficacy Analyses .....................15
8.2.
Pharmacodynamic/Biomarker Analyses......................................................15
8.2.1.
Overview of Planned Pharmacodynamic/Biomarker 
Analyses......................................................................................15
8.3.
Safety Analyses..........................................................................................15
8.3.1.
Overview of Planned Adverse Event Analyses ............................15
8.3.2.
Overview of Planned Clinical Laboratory Analyses ......................16
8.3.3.
Overview of Planned Other Safety Analyses................................16
8.4.
Pharmacokinetic Analyses..........................................................................17
9.
OTHER STATISTICAL ANALYSES .......................................................................17
9.1.
Exploratory Analyses ..................................................................................17
10. REFERENCES.......................................................................................................18
11. APPENDICES........................................................................................................19
11.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................20
11.1.1.
Exclusions from the Per Protocol Population ...............................20
11.1.1.1.
Exclusions from Per Protocol Efficacy Dataset ...........20
11.2.
Appendix 2: Time & Events.........................................................................21
 
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11.2.1.
Protocol Defined Time & Events ..................................................21
11.3.
Appendix 3: Assessment Windows .............................................................25
11.3.1.
Definitions of Assessment Windows for Analyses........................25
11.4.
Appendix 4: Treatment States and Phases.................................................26
11.4.1.
Treatment Phases .......................................................................26
11.4.2.
Treatment States .........................................................................26
11.4.2.1.
Treatment States for Safety Data ...............................26
11.4.2.2.
Treatment States for AE Data.....................................26
11.5.
Appendix 5: Data Display Standards & Handling Conventions....................27
11.5.1.
Study Treatment & Sub-group Display Descriptors......................27
11.5.2.
Baseline Definition & Derivations .................................................27
11.5.2.1.
Baseline Definitions....................................................27
11.5.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................27
11.5.3.
Reporting Process & Standards...................................................27
11.6.
Appendix 6: Derived and Transformed Data ...............................................29
11.6.1.
General........................................................................................29
11.6.2.
Study Population..........................................................................29
11.6.3.
Safety ..........................................................................................30
11.6.4.
Efficacy derivations......................................................................30
11.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............32
11.7.1.
Premature Withdrawals................................................................32
11.7.2.
Handling of Missing Data.............................................................32
11.7.2.1.
Handling of Missing Dates..........................................32
11.7.2.2.
Handling of Partial Dates............................................33
11.7.2.3.
Handling of Missing Data for Statistical 
Analysis......................................................................33
11.8.
Appendix 8: Values of Potential Clinical Importance ...................................34
11.8.1.
Laboratory Values........................................................................34
11.8.2.
ECG.............................................................................................35
11.8.3.
Vital Signs....................................................................................35
11.9.
Appendix 9: Multicentre Studies..................................................................36
11.10. Appendix 10: Examination of Covariates, Subgroups & Other Strata..........37
11.10.1. Handling of Covariates, Subgroups & Other Strata......................37
11.11. Appendix 11: Multiple Comparisons & Multiplicity .......................................38
11.12. Appendix 12: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................39
11.12.1. Statistical Analysis Assumptions..................................................39
11.13. Appendix 13: Population Pharmacokinetic and Pharmacokinetic / 
Pharmacodynamic (Or Biomarker) Analyses ..............................................40
11.14. Appendix 14 – Abbreviations & Trade Marks ..............................................41
11.14.1. Abbreviations...............................................................................41
11.14.2. Trademarks .................................................................................42
11.15. Appendix 15: List of Data Displays..............................................................43
11.15.1. Data Display Numbering..............................................................43
11.15.2. Mock Example Shell Referencing ................................................43
11.15.3. Deliverable [Priority].....................................................................43
11.15.4. Efficacy Figures ...........................................................................44
11.15.5. Pharmacodynamic Figures ..........................................................44
11.15.6. ICH Listings .................................................................................44
11.15.7. Non-ICH Listings..........................................................................48
11.16. Appendix 16: Example Mock Shells for Data Displays ................................49
 
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1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 204957.

This study has been terminated early due to business prioritisation.
Protocol

This RAP is based on the version 3 of the protocol (Dated: 01/Jun/2017) of 
study 204957 (GSK Document No. : 2016N270377_03)
Primary 
Objective

To assess the efficacy of GSK3117391 in subjects with severe RA following 
every other day dosing
Primary 
Endpoint

Change from baseline in DAS 28-CRP at Day 28
Secondary 
Objectives

To assess the safety and tolerability of GSK3117391 following every other day 
dosing.

To assess the efficacy of GSK3117391 on other clinical endpoints following 
every other day dosing.

To assess the pharmacokinetics following every other day dosing of 
GSK3117391.

To investigate the monocyte numbers after every other day dosing with 
GSK3117391.

To assess the effects of GSK3117391 on biomarkers of inflammation in the 
blood.
Secondary 
Endpoints

Adverse events, Vital signs (HR, BP & Temperature), ECGs, Clinical laboratory 
tests (haematology, biochemistry and urinalysis).

ACR responders (ACR20, ACR50, ACR70)

Number of swollen joints assessed using 28-joint counts

Number of tender/painful joints assessed using 28-joint counts

Change from baseline in DAS28-CRP over time 

Plasma concentrations and derived pharmacokinetics (PK) parameters of
GSK3117391 and GSK3339189.

Changes in monocyte numbers over time

Changes from baseline in blood biomarkers, including but not limited to:
C-reactive protein (CRP), soluble cytokine and inflammatory mediators
and Myeloid-related protein 8/14 (MRP8/14).
Exploratory 
Objectives

To assess the intracellular pharmacokinetics following every other day dosing 
of GSK3117391.

To evaluate the PD of GSK3117391 following every other day dosing.

To explore the effects of GSK3117391 on the leukocyte population.

To investigate the effect of GSK3117391 on inflammatory gene expression in 
blood.
Exploratory 
Endpoints

Where possible, intracellular concentrations and derived PK parameters of 
GSK3339189 following every other day repeat doses.

Acetylation levels in monocytes, lymphocytes and granulocytes in peripheral 
blood.
 
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Overview
Key Elements of the RAP

Cell marker quantification using flow cytometry.

Change from baseline in inflammatory gene expression in blood.
Study 
Design

This is a randomised, double-blind (sponsor open), multicentre, placebo-
controlled, parallel group study to evaluate the efficacy, safety and tolerability, 
PK and PD of GSK3117391 in subjects with RA resistant to DMARD therapy. 

Approximately 40 subjects with severe RA despite treatment with DMARDs will 
be randomised into the study. 

The total maximum study duration is approximately 10 weeks (not including any
rescreen). Following a screening period of up to 28 days, subjects will be 
randomised (1:1) to placebo or 40 mg GSK3117391 orally-administered every 
other day for a period of 28 days. Subjects will be followed up for 7-14 days 
post final dose.

Study schematic is included below.

Due to early termination of the study, the study had 3 randomised patients, with 
2 completing the study.
Termination 
This study has been terminated early due to business prioritisation.

There were 3 randomised subjects.

A synoptic CSR will be generated with disclosure of safety and key 
primary/secondary endpoints. The final outputs will include listings of 
all safety/tolerability endpoints, the primary endpoint and the key 
secondary endpoint.
Analysis 
Populations

All Screened: The “All Screened” population is defined as all subjects who 
screened.

Enrolled Population: The “Enrolled Population” is defined as subjects (who 
ultimately passed screening, even if rescreened). Randomised Subjects and 
Subjects where no treatment was assigned (e.g. never randomised) even 
though they passed screening.

Safety Population: The ‘Safety Population’ is defined as subjects who receive at 
least one dose of study medication
Hypothesis

No hypothesis is to be tested because of early termination of the study.
Primary 
Analyses

Due to early termination of the study and with 2 completers, listings of the raw 
and change from baseline DAS28 score over time will be produced for each 
subject.
Secondary 
Analyses

The safety and tolerability data will be listed. 

Componenetsof the DAS28 score – Tender Joint count using 28-joint counts 
and swollen joint counts using 28-joint counts, CRP and patient’s global 
assessment of disease activitywill be listed. 

Absolute and change from baseline monocyte numbers and MRP8/14 levels
will be listed and ploted over time.
 
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Overview
Key Elements of the RAP

PK ouptuts will not be generated as the sample were not assayed. 

ACR20, 50 and 70 response will not be calulcated due to the small sample size.
Exploratory 
Analyses

No exploratory analysis will be conducted. 
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Due to the termination of the study, only listings will be produced for the safety events 
and the DAS28 score. This differs to the planned analyses outlined in the protocol.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To assess the efficacy of 
GSK3117391 in subjects with 
severe RA following every other 
day dosing

Change from baseline in DAS 28-CRP at Day 28.
Secondary Objectives
Secondary Endpoints

To assess the safety and 
tolerability of GSK3117391 
following every other day dosing

Adverse events

Vital signs (HR, BP & Temperature)

ECGs

Clinical laboratory tests (haematology,
biochemistry and urinalysis)

To assess the efficacy of 
GSK3117391 on other clinical 
endpoints following every other 
day dosing

ACR responders (ACR20, ACR50, ACR70)

Number of swollen joints assessed using 28-
joint counts

Number of tender/painful joints assessed using
28-joint counts

Change from baseline in DAS28-CRP over time

Components of composite endpoints (ACR 
response, DAS28-CRP) at all assessment 
timepoints will also be reported separately

To assess the pharmacokinetics 
following every other day dosing 
of GSK3117391

Plasma concentrations and derived 
pharmacokinetics (PK) parameters of GSK3117391 
and GSK3339189

To investigate the monocyte 
numbers after every other day 
dosing with GSK3117391

Changes in monocyte numbers over time

To assess the effects of 
GSK3117391 on biomarkers of 
inflammation in the blood

Changes from baseline in blood biomarkers, 
including but not limited to:

C-reactive protein (CRP),

Soluble cytokine and inflammatory mediators
 
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Objectives
Endpoints
     Myeloid-related protein 8/14 (MRP8/14)
Exploratory Objectives
Exploratory Endpoints

To assess the intracellular 
pharmacokinetics following every 
other day dosing of GSK3117391

Where possible, intracellular concentrations and 
derived PK parameters of GSK3339189 following 
every other day repeat doses

To evaluate the PD of 
GSK3117391 following every 
other day dosing

Acetylation levels in monocytes, lymphocytes and 
granulocytes in peripheral blood

To explore the effects of 
GSK3117391 on the leukocyte 
population

Cell marker quantification using flow cytometry

To investigate the effect of 
GSK3117391 on inflammatory 
gene expression in blood

Change from baseline in inflammatory gene 
expression in blood
 
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2.3.
Study Design
Overview of Study Design and Key Features
Design
Features
This is a randomised, double-blind (sponsor open), multicentre, placebo-controlled, 
parallel group study to evaluate the efficacy, safety and tolerability, PK and PD of 
GSK3117391 in subjects with severe RA resistant to DMARD therapy. 40 subjects 
will be randomised to either GSK3117391 or placebo to be taken every other day 
for 28 days of treatment. The maximum total duration of the study is approximately 
10 weeks from screening to the last study visit
Dosing
Subjects in this study will be treated with 40 mg of GSK3117391 every other day 
for a 28-day period.
Interim 
Analysis
No formal interim analysis will be conducted due to the termination of the study. 
An administrative interim analysis was conducted for internal decision making, 
based on unblinded DAS28 (absolute and change from baseline) and its 
components in November 2017. 
2.4.
Statistical Hypotheses
As a result of the termination, no statistical hypothesis will be tested.
3.
PLANNED ANALYSES
3.1.
Instream Analyses
In line with routine pharmacovigilance, an internal GSK Safety Review Team (SRT)
which will include members of the 204957 study team, will review blinded safety data, 
including clinical laboratory parameters and adverse events, at appropriate intervals 
during the period of study conduct. Further details are outlined in the SRT charter.
3.2.
Interim Analyses
No formal interim analysis will be conducted as the study has been terminated after 3 
randomised patients. 
 
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An administrative interim was conducted based on listing of the unblinded DAS28 score 
and its components.
3.3.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All required database cleaning activities have been completed
2.
Final database release and database freeze has been declared by Data Management.
3.
Unblinding of the randomisation codes and distribution according to RandAll NG 
procedures prior to performing the final planned analysis. 
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Screened
This population is defined as all subjects 
who were screened.

Screen Failure
Enrolled
The following subjects (who ultimately 
passed screening, even if rescreened) are 
included in the Enrolled population: 
Randomised Subjects and Subjects where no 
treatment was assigned (e.g. never 
randomised) even though they passed 
screening

Study Population
(sub-set, see TOC
in Appendix 15)
Safety 
Population
Subjects who receive at least one dose of 
study medication.

Safety

Study Population 
(main outputs)

Efficacy

Disease and PD 
Biomarkers
NOTES : 

Please refer to Section 11.15: List of Data Displays which details the population to be used for each displays being 
generated.
4.1.
Protocol Deviations

Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed.

Important deviations which result in exclusion from the analysis population will also 
be summarised and listed. (Please refer to Section 11.1: Protocol Deviation 
Management and Definitions for Per Protocol Population).
 
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
Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to DBR to ensure all important deviations and 
deviations which may lead to exclusion from the analysis are captured and 
categorised on the protocol deviations dataset. 
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.

A separate 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.
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 1
Overview of Appendices
Section
Component
11.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
11.2
Appendix 2: Time & Events
11.3
Appendix 3: Assessment Windows
11.4
Appendix 4: Treatment States and Phases
11.5
Appendix 5: Data Display Standards & Handling Conventions
11.6
Appendix 6: Derived and Transformed Data
11.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
11.8
Appendix 8: Values of Potential Clinical Importance
11.9
Appendix 9: Multicenter Studies
11.10
Appendix 10: Examination of Covariates, Subgroups & Other Strata
11.11
Appendix 11: Multiple Comparisons & Multiplicity
11.12
Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
11.13
Appendix 13: Pharmacokinetic/Pharmacodynamic (Or Biomarker) Analysis
 
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the Safety population, unless otherwise 
specified.
Table 2 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 15: List of Data Displays
Table 2
Overview of Planned Study Population Analyses
Endpoint / Parameter / Display Type
Data Displays Generated
Listing
Randomisation
Randomisation
Y
Subject Disposition
Reasons for Subject Withdrawal
Y
Reasons for Screen Failure
Y
Subjects for Whom the Treatment Blind was Broken
Y
Planned and Actual Treatments
Y
Protocol Deviations
Important Protocol Deviations
Y
Subjects with Inclusion/Exclusion Criteria Deviations
Y
Populations Analysed
Subjects Excluded from Any Population
Y
Demographic and Baseline Characteristics
Demographic Characteristics
Y
Race and Racial Combinations
Y [1]
Prior and Concomitant Medications
Concomitant Medications
Y
Exposure and Treatment Compliance
Exposure to Study Treatment
Y
NOTES :

Y = Yes display generated.
1.
[1] Listing of race.
 
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7.
PRIMARY STATISTICAL ANALYSES
7.1.
Primary Efficacy Analyses
7.1.1.
Overview of Planned Primary Efficacy Analyses
The efficacy analyses will be based on the Safety population.
Table 3 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 15: List of Data Displays
Due to the early termination of study, listings and individual subjects profile plots of 
DAS28-CRP absolute, and change from baseline score will be produced. No summary 
tables or statistical analysis will be generated or conducted. 
Table 3
Overview of Planned Primary Efficacy Analyses
Endpoint
Individual
Figure
Listing
DAS-28 CRP
Absolute and Change from 
Baseline
Y
Y
NOTES :

Y = Yes display generated.

Individual = Represents FL related to any displays of individual subject observed raw data.
 
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8.
SECONDARY STATISTICAL ANALYSES
8.1.
Secondary Efficacy Analyses
8.1.1.
Overview of Planned Secondary Efficacy Analyses
The efficacy analyses will be based on the Safety population.
Table 4 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 15: List of Data Displays
Table 4
Overview of Planned Efficacy Analyses
Endpoint / Parameter/ Display Type
Absolute
Individual
Figure
Listing
Efficacy
TJC68, SJC66, PtGA, CRP
Y
NOTES :

Y = Yes display generated.

Individual = Represents FL related to any displays of individual subject observed raw data.
8.2.
Pharmacodynamic/Biomarker Analyses
8.2.1.
Overview of Planned Pharmacodynamic/Biomarker Analyses
The pharmacodynamic/biomarker analyses will be based on the Safety population, unless 
otherwise specified.
Table 5 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 15: List of Data Displays
Table 5
Overview of Planned Pharmacodynamic/Biomarker Analyses
Endpoint / Parameter/ Display Type
Absolute and change from baseline
Individual 
Listing
Figure
Blood Biomarkers
MRP8/14
Y
Monocyte count
Y
Y
NOTES :

Y = Yes display generated.

Individual = Represents FL related to any displays of individual subject observed raw data.     
8.3.
Safety Analyses
8.3.1.
Overview of Planned Adverse Event Analyses
The safety analyses will be based on the Safety population, unless otherwise specified.
 
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Table 6 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 15: List of Data Displays.
Table 6
Overview of Planned Adverse Event Analyses
Endpoint / Parameter/ Display Type
Absolute
Individual
Listing
Adverse Events (AEs)
All AEs 
Y
Subject Numbers for Individual AEs
Y
Relationship Between AE SOCs, PT and Verbatim Text
Y
Serious and Other Significant AEs
Serious Fatal AEs
Y
Serious Non-Fatal AEs
Y
Drug-Related Serious AEs
Y
Reasons for Considering as a Serious AE
Y
AEs Leading to Withdrawal from Study / Permanent Discontinuation of Study 
Treatment by SOC and PT/by Overall Frequency
Y
NOTES :

Y = Yes display generated.

Individual = Represents FL related to any displays of individual subject observed raw data.     
8.3.2.
Overview of Planned Clinical Laboratory Analyses
The safety analyses will be based on the Safety population.
Table 7 provides an overview of the planned analyses, with further details of data 
displays being presented Appendix 15: List of Data Displays.
Table 7
Overview of Planned Clinical Laboratory Analyses
Endpoint / Parameter/ Display Type
Absolute
Individual
Listing
All Laboratory
Y
All Laboratory Data for Subjects with any Value of Potential Clinical Concern/PCI
Laboratory Values of PCI
Y
NOTES :

Y = Yes display generated.

Individual = Represents FL related to any displays of individual subject observed raw data.     
8.3.3.
Overview of Planned Other Safety Analyses
The safety analyses will be based on the Safety population.
 
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Table 8 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 15: List of Data Displays.
Table 8
Overview of Planned Other Safety Analyses
Endpoint / Parameter/ Display Type
Absolute
Individual
Listing
ECG
All ECG Values for Subjects with any Value of PCI
Y
ECG Values of PCI
Y
Abnormal ECG Findings
Y
Vital Signs
All Vital Signs for Subjects with any Value of PCI
Y
NOTES:

Y = Yes display generated, PCI = Potential Clinical Importance

Individual = Represents FL related to any displays of individual subject observed raw data.
8.4.
Pharmacokinetic Analyses
Due to the sample analysis issues, PK samples will not be analysed and hence the data 
will not be available. 
9.
OTHER STATISTICAL ANALYSES
9.1.
Exploratory Analyses 
No exploratory outputs will be generated.
 
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10.
REFERENCES
GlaxoSmithKline Document Number 2016N270377_03 Study ID 204957. A randomised, 
multi-center, double blind (sponsor open), placebo-controlled study to assess the efficacy, 
safety, tolerability, pharmacokinetics and pharmacodynamics of GSK3117391 in subjects 
with severe, active rheumatoid arthritis. Effective Date: 01-Jul-2017
 
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11.
APPENDICES
Section
Appendix
RAP Section 4 : Analysis Populations
Section 11.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 11.2
Appendix 2: Time and Events
Section 11.3
Appendix 3: Assessment Windows
Section 11.4
Appendix 4: Treatment States & Phases
Section 11.5
Appendix 5: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 11.6
Appendix 6: Derived and Transformed Data

General, Study Population & Safety

Efficacy

Pharmacokinetic

Pharmacodynamic and or Biomarkers
Section 11.7
Appendix 7: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Section 11.8
Appendix 8: Values of Potential Clinical Importance
Section 11.9
Appendix 9: Multicentre Studies

Laboratory Values

ECG

Vital Signs
Section 11.10
Appendix 10: Examination of Covariates and Subgroups
Section 11.11
Appendix 11: Multiple Comparisons and Multiplicity
Section 11.12
Appendix 12: Model Checking and Diagnostics for Statistical Analyses
Section 11.13
Appendix 13: Pharmacokinetic / Pharmacodynamic (or Biomarker) Analyses
Other RAP Appendices
Section 11.14
Appendix 14: Abbreviations & Trade Marks
Section 11.15
Appendix 15: List of Data Displays
Section 11.16
Appendix 16 Example Mock Shells for Data Displays
 
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11.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
11.1.1.
Exclusions from the Per Protocol Population
Not applicable
11.1.1.1.
Exclusions from Per Protocol Efficacy Dataset
Not applicable.
 
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11.2.
Appendix 2: Time & Events
11.2.1.
Protocol Defined Time & Events
Table 9
Screening and Follow-up Assessments
Procedure
Screening
(up to 28 days prior 
to Day 11)
Follow-up Visit (7-14 
days post last dose or 
EW2)
Notes
1.
Screening period can be extended to 56 days to allow ONLY the washout of 
background DMARD therapy where necessary. All other assessments must 
be completed within 28 days prior to Day 1. Some assessment can occur on 
separate visit
2.
For EW (Early Withdrawal) visit, assessments are to be conducted as 
deemed necessary based on PI’s judgment and to be recorded as an
unscheduled visit in the subject’s CRF 
Outpatient Visit
X
X
Additional screening visit needed for FRP pregnancy test 4 to 7 days before day 1
Informed Consent
X
Informed consent must be obtained prior to any study procedures being 
conducted including DMARD therapy washout period.
Medical/medication/drug/alcohol history
X
Demographics
X
Height and weight
X
Full Physical Examination
X
Additional examinations may be performed, or brief examinations made full 
examinations, by the Investigator, as deemed necessary (e.g. where safety or 
laboratory findings indicate).
Brief Physical Examination
X
Eligibility criteria
X
12-lead ECG and vital signs
X
X
Vital signs include HR, BP and temp. 
Pregnancy test
X
X
First test in screening is serum pregnancy test, all subsequent testing urine. An 
additional pregnancy test during screening visit (urine) is required 4-7 days prior to 
Day 1. This test may be performed at home. FRP only.
Contraception use compliance 
X
X
HIV, Hep B and Hep C screen, TB, G6PD
X
RF, ACPA (i.e. aCCP)
X
Haem/Chem/Urinalysis tests
X
X
Including INR/APTT (coagulation) and MetHb (MetHb, performed locally)
PK blood sample and Met ID
X
Sample to be collected only if the 24h-post last dose sample (at D28) has not 
been collected
 
 
 
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Procedure
Screening
(up to 28 days prior 
to Day 11)
Follow-up Visit (7-14 
days post last dose or 
EW2)
Notes
1.
Screening period can be extended to 56 days to allow ONLY the washout of 
background DMARD therapy where necessary. All other assessments must 
be completed within 28 days prior to Day 1. Some assessment can occur on 
separate visit
2.
For EW (Early Withdrawal) visit, assessments are to be conducted as 
deemed necessary based on PI’s judgment and to be recorded as an
unscheduled visit in the subject’s CRF 
PD biomarker sample
X
This includes biomarkers for RA disease and exploratory PD, acetylation
HAQ-DI, PtGA, PtAAP
X
X
Complete before any other assessment at a clinic visit
Joint counts: TJC(68), SJC(66)
X
X
Independent joint assessor
Physician Global Assessment of Arthritis 
(PhGA)
X
X
Where possible, the same physician should perform all disease assessments for 
an individual subject. 
hsCRP
X
X
Chest x-ray
X
Only required at screening if no CXR performed within 12 weeks of Day 1 visit
Adverse Event Review
X
Concomitant Medication Review
X
Gene expression blood
X
 
 
 
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Table 10
Day 1 to Day 30 On-Study Assessments
D1
D2
D3
D73 D144
D213
D27
D28
D30
Study treatment every 
other day including clinic 
visit days as shown
X
X
X
X
X
Time in relation to dose1
pre
0.25h 0.5h 1h
2h 4h 6h 10h 24h5
pre
0.25h 0.5h 1h 4h 8h pre
pre
pre 0.25h
0.5h 1h 2h 4h 6h 10h 24h5
72h5
12 lead ECG and vital 
signs
X
X
X
X
X
X
X
X
X
Brief physical examination
X
X
X
X
X
X
X
X
Pregnancy test (FRP)
X
X
X
X
X
Contraception use 
compliance
X
X
X
X
X
X
X
X
X
Haematology test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chem/Urinalysis test
X
X
X
X
X
X
X
X
Coagulation (INR/APTT)
X
X
X
X
X
X
X
X
X
X
Joint counts: TJC(68), 
SJC(66)
X
X
X
X
X
Patient reported outcomes 
PtGA, PtAAP, HAQ-DI
X
X
X
X
X
PhGA
X
X
X
X
X
hsCRP
X
X
X
X
X
RF, ACPA
X
Met Hb7
X
X
RA disease biomarker 
blood
X
X8
X
8
X8
X8
X8
X
8
X
X
X
X
8
X
Exploratory PD and 
acetylation blood
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK blood
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MET ID blood
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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D1
D2
D3
D73 D144
D213
D27
D28
D30
Study treatment every 
other day including clinic 
visit days as shown
X
X
X
X
X
Time in relation to dose1
pre
0.25h 0.5h 1h
2h 4h 6h 10h 24h5
pre
0.25h 0.5h 1h 4h 8h pre
pre
pre 0.25h
0.5h 1h 2h 4h 6h 10h 24h5
72h5
Isolated monocyte PK9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Gene expression blood
X
PK unrine sample
X
Collect urine for 24h after dose
PGx
X
Drug compliance 
assessment10
X
X
X
X
AE and concurrent med 
review
Collect AE's from D1 to end of follow up visit
FRP, Females of reproductive potential; HAQ-DI, Health Assessment Questionnaire Disability Index; hsCRP, high sensitivity C-reactive protein; ESR: erythrocyte sedimentation rate; 
INR/APTT, International normalised ratio/partial thromboplastin time; PhGA, Physician Global Assessment of Arthritis;  PtGA, Patient Global Assessment of Arthritis; TJC, Tender Joint 
Count; SJC, Swollen Joint Count; PtAAP, Patient Assessment of Arthritis Pain; ACPA, Anti-citrullinated protein antibodies; RF, rheumatoid factor; PK, pharmacokinetics ; MET ID: 
metabolite identification; PGx, pharmacogenomics.
1.
Sample collection and assessments to be conducted in accordance with the time and events table.
2.
Visits may be conducted on previous or next DOSING day.
3.
The D14 visit has a 2 day window and may be on a DOSING or NON DOSING day. If on a dosing day, assessments should be per formed pre-dose.
4.
Blood samples to be collected within a ±1h window of the scheduled time.
5.
Patient Reported Outcomes questionnaires should be completed by subjects before any other assessment at a clinic visit.
6.
Sample will be collected and stored for future analysis.
7.
Applicable to selected sites only.
8.
Record number of capsules in bottle and check patient diary. On non-visit days, phone subject to remind them to take dose.
9.
Applicable to selected sites only.
10. Record number of capsules in bottle and check patient diary. On non-visit days, phone subject to remind them to take dose.
 
 
 
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11.3.
Appendix 3: Assessment Windows
11.3.1.
Definitions of Assessment Windows for Analyses
No Assessment Windows will be defined, and listings will be based on nominal visits.
 
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11.4.
Appendix 4: Treatment States and Phases
11.4.1.
Treatment 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.
Treatment Phase
Definition
Pre-Treatment 
Date ≤ Study Treatment Start Date
On-Treatment
Study Treatment Start Date < Date ≤ Study Treatment Stop Date
Post-Treatment
Date > Study Treatment Stop Date 
11.4.2.
Treatment States
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date of the study treatment.
11.4.2.1.
Treatment States for Safety Data
Treatment State
Definition
Pre-Treatment
Date ≤ Study Treatment Start Date
On-Treatment
Study Treatment Start Date < Date ≤ Study Treatment Stop Date
Post-Treatment
Date > Study Treatment Stop Date +1
NOTES: 

If the study treatment stop date is missing, then the assessment will be considered to be On-Treatment
11.4.2.2.
Treatment States for AE Data
Treatment State
Definition
AE = Pre-Treatment
AE Onset 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.
Study Treatment Start Date  ≤ AE Start Date ≤ Study Treatment Stop Date 
AE = Post-Treatment
If AE onset date is after the treatment stop date.
AE Start Date > Study Treatment Stop Date 
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.
 
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11.5.
Appendix 5: Data Display Standards & Handling 
Conventions
11.5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
A
GSK3117391 40 mg
GSK3117391 40 mg
2
P
Placebo
Placebo
1
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
11.5.2.
Baseline Definition & Derivations
11.5.2.1.
Baseline Definitions
For efficacy, PD biomarker and RA disease biomarker endpoints, the value from the Day 
1 (pre-dose) time point will be used as baseline.  
For all other endpoints the baseline value will be the latest non-missing pre-dose 
assessment before the first dose (including unscheduled visits).
11.5.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
Maximum Change from Baseline
= Calculate the change from baseline at each given time point 
   and determine the maximum change
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 11.5.2.1 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.
11.5.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: UK1SALX00175
HARP Area
: arenv \ arprod \ gsk3117391 \ mid204957 \ final
QC Spreadsheet
: arenv \ arprod \ gsk3117391 \ mid204957 \ final \ documents
 
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Reporting Process
Analysis Datasets 

Analysis datasets will be created according to Integrated Data Standards Library (IDSL) GSK 
A&R dataset standards.
Generation of RTF Files

No RTF files are being generated.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

All data will be reported according to the actual treatment the subject received unless 
otherwise stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses :

Planned time relative to first dosing will be used in figures, listings and calculation of any 
derived parameters, unless otherwise stated..

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 

Visits outside the protocol-defined time windows (i.e. recorded as protocol deviations) will 
be included in listings but omitted from figures.
Unscheduled Visits

Unscheduled visits will not be included in figures, unless otherwise stated.

All unscheduled visits will be included in listings.
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.
 
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11.6.
Appendix 6: Derived and Transformed Data
11.6.1.
General
Multiple Measurements at One Time Point

All data will be listed.
Study Day

Calculated as the number of days from randomisation date :

Ref Date = Missing                       → Study Day = Missing 

Ref Date < Randomisation Date   → Study Day = Ref Date – Randomisation Date    

Ref Data ≥ Randomisation Date   → Study Day = Ref Date – (Randomisation Date) + 1    
11.6.2.
Study Population
Demographics
Age

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 = 30th June YYYY

Calculated as the integer part of (date of baseline – date of birth)
              Age = integer part (date of baseline – 30th June 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’)
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 randomised but did not report a treatment start date will be categorised as 
having zero days of exposure. 

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Number of Days x Total Daily Dose)

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.
 
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11.6.3.
Safety
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 :
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    
11.6.4.
Efficacy derivations
DAS28-CRP
The DAS assessment is a derived measurement with differential weighting given to each 
component. 
The DAS28(CRP) will be calculated at each assessment time point. The components of the DAS28 
arthritis assessment include: 

Tender Joint Count 28 (TJC28) 

Swollen Joint Count 28 (SJC28) 
 
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
C-reactive protein (CRP) (in mg/L) 

Patient’s Global Assessment of Arthritis Disease Activity (PtGA) (visual analogue scale with 
values from 0=best to 100=worst) 
DAS28(CRP) 
The DAS28(CRP) score will be calculated using the following formula: 
If one of the components is missing at an individual assessment point, the DAS28(CRP) value for 
that assessment will be set to missing. See Section 11.7.2.3 for further details of missing data 
approaches.
Swollen and Tender Joint Counts
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 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. 
For example, for a patient with 2 missing tender or swollen joint counts at a given post-baseline 
time, the final score will be based on the 26 that are non-missing. Suppose if 12 of the 26 are 
tender/swollen then final score will be (12/26)x28=12.92.
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.
Patient’s Global Assessment of Arthritis Disease Activity (PtGA)
Subjects will assess the severity of their current arthritis pain using a continuous visual analog scale 
(VAS) with anchors “0” (no pain) and “100” (most severe pain).
No imputations for missing data will be done.
 
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11.7.
Appendix 7: Premature Withdrawals & Handling of Missing 
Data
11.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as one 
who has completed all phases of the study including the follow-up visit.

Withdrawn subjects will not be replaced in the study.

All available data from subjects who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, 
unless otherwise specified.
11.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occur when any requested data are 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 are
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 recorded.
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.
11.7.2.1.
Handling of Missing Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.
Imputed dates should be stored in variables IMPSTDT (Imputed Start Date) and 
IMPENDT (Imputed End Date)
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: Treatment States and Phases.
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 
 
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Element
Reporting Detail
missing.

Start or end dates which are completely missing (i.e. no year specified) will 
remain missing, with no imputation applied.
11.7.2.2.
Handling of Partial Dates
Element
Reporting Detail
Concomitant 
Medications

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.
Adverse 
Events

Any partial dates for adverse events will be raised to data management. If the 
full date cannot be ascertained, the following assumptions will be made:
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
However, if these results in a date prior to Week 1 Day 1 and the event 
could possibly have occurred during treatment from the partial 
information, then the Week 1 Day 1 date will be assumed to be the start 
date. 
o
The AE will then be considered to start on-treatment (worst case).
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.
11.7.2.3.
Handling of Missing Data for Statistical Analysis
Element
Reporting Detail
Efficacy: 
DAS28-CRP

If one of the components is missing at an individual assessment point, the 
DAS28(CRP) value for that assessment will be set to missing.
Tender and 
swollen joint 
counts

If there are missing observations for tender or swollen joints then the relevant 
joint count will be set to missing.

If a joint is “not applicable” or “‘non-evaluable, other’” at Baseline, then that joint 
is set to that value throughout the study for the subject.
Patient’s 
Global 
Assessment 
of Arthritis 
Disease 
Activity 
(PtGA)

No imputations for missing data will be conducted
 
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11.8.
Appendix 8: Values of Potential Clinical Importance
11.8.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Haematocrit 
Ratio of 1
Male
0.3
0.54
Female
0.3
0.54
∆from BL
↓0.075
Haemoglobin 
g/L
Male
90
180
Female
90
180
∆from BL
↓20
Lymphocytes 
x109/ L
0.5
Neutrophil Count 
x109/ L
1.0
Platelet Count 
x109/ L
50
550
While Blood Cell Count (WBC)
x109/ L
3
14
Monocyte
x109/ L
0.2
1.5
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
 
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11.8.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450 
> 450 
≤ 479 
≥ 480
≤ 499 
≥ 500 
Absolute PR Interval
msec
< 110
> 220 
Absolute QRS Interval
msec
< 75 
> 110
11.8.3.
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
 
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11.9.
Appendix 9: Multicentre Studies
No specific outputs will be produced by centre or highlighting the recruitment by site. 
 
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11.10.
Appendix 10: Examination of Covariates, Subgroups & 
Other Strata
11.10.1.
Handling of Covariates, Subgroups & Other Strata
No subgroup analyses are to be conducted in this study.
 
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11.11.
Appendix 11: Multiple Comparisons & Multiplicity
No formal statistical analyses are planned for the study. 
 
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11.12.
Appendix 12: Model Checking and Diagnostics for 
Statistical Analyses
11.12.1.
Statistical Analysis Assumptions
No formal statistical analyses are planned for the study. 
 
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11.13.
Appendix 13: Population Pharmacokinetic and 
Pharmacokinetic / Pharmacodynamic (Or Biomarker)
Analyses
No population PK and PK/PD analyses are planned for the study.
 
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11.14.
Appendix 14 – Abbreviations & Trade Marks
11.14.1.
Abbreviations
Abbreviation
Description
ACR
American College of Rheumatology
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CL/F
Apparent Clearance
CPMS
Clinical Pharmacology Modelling & Simulation
CRP
C-reactive protein
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DAS28
Disease Activity Score for 28 different joints
DRC
Data Review Committee
DOB
Date of Birth
DP
Decimal Places
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
ESR
Erythrocyte sedimentation rate
EULAR
European League against Rheumatism
GEE
Generalized Estimating Equation
IA
Interim Analysis
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
GUI
Guidance
HARP
Harmonised Analysis and Reporting Platform
LLN
Lower Limit of Normal
LOC
Last Observation Carries Forward
MMRM
Mixed Model Repeated Measures
NRS
Numeric rating scale
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PhGA
Physician's Global Assessment of Arthritis
 
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Abbreviation
Description
PK
Pharmacokinetic
PK/PD
Pharmacokinetics/Pharmacodynamics
PP
Per Protocol
PT
Preferred Term
PtGA
Patient's Global Assessment of Arthritis Disease Activity
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RA
Rheumatoid arthritis
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SAE
Serious Adverse Events 
SDTM
Study Data Tabulation Model
SJC
Swollen joint count
SJC28
Swollen joint count for 28 different joints
SOC
System Organ Class
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
TJC
Tender joint count
TJC28
Tender joint count for 28 different joints
ULN
Upper Limit of Normal
VAS
Visual Analogue Scale
V/F
Apparent Volume of Distribution
GSK
GlaxoSmithKline
11.14.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
SAS
 
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11.15.
Appendix 15: List of Data Displays
11.15.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
N/A
N/A
Efficacy
N/A
2.1 to 2.2
Safety
N/A
3.1 to 3.2
Pharmacodynamic and / or Biomarker
N/A
N/A
Section
Listings
ICH Listings
1 to 28
Other Listings
29 to 31
11.15.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required an example 
mock-up displays provided in Appendix 16: 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
Pharmacodynamic and / or Biomarker
PD_Fn
PD_Tn
PD_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’
11.15.3.
Deliverable [Priority]
Delivery [Priority] [1]
Description
SAC
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort.
 
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11.15.4.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
DAS28
2.1.
Safety
EFF_F1
Individual patient profiles of DAS28-CRP score over time
SAC
2.2.
Safety
EFF_F1
Individual patient profiles of change from baseline in DAS28-
CRP score over time
SAC
11.15.5.
Pharmacodynamic Figures
Efficacy: Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Biomarkers
2.3.
Safety
EFF_F1
Individual patient profiles of monocyte count over time
SAC
11.15.6.
ICH Listings
ICH : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Randomisation
1.
Safety
CP_TA1
Listings of Randomised and Actual Treatments 
SAC
 
 
 
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ICH : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
2.
All subjects
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC
3.
Safety
ES2 
Listing of Reasons for Study Withdrawal
ICH E3
SAC
4.
Safety
BL1
Listing of Subjects for Whom the Treatment Blind was Broken
ICH E3
SAC
5.
Safety
TA1 
Listing of Planned and Actual Treatments
IDSL
SAC
Protocol Deviations
6.
Safety
DV2
Listing of Important Protocol Deviations 
ICH E3
SAC
7.
Safety
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
ICH E3
SAC
Demographic and Baseline Characteristics 
8.
Safety
DM2 
Listing of Demographic Characteristics
ICH E3
SAC
9.
Safety
DM9
Listing of Race
ICH E3
SAC
Prior and Concomitant Medications
10.
Safety
CP_CM3
Listing of Concomitant Medications
IDSL
SAC
Exposure and Treatment Compliance
11.
Safety
EX3 
Listing of Exposure Data
ICH E3
SAC
Adverse Events 
12.
Safety
CP_AE8 
Listing of All Adverse Events
ICH E3
SAC
13.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC
14.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
SAC
 
 
 
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ICH : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Serious and Other Significant Adverse Events
15.
Safety
CP_AE8a 
Listing of Fatal Serious Adverse events
ICH E3
SAC
16.
Safety
CP_AE8a 
Listing of Non-Fatal Serious Adverse Events
ICH E3
SAC
17.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICHE3
SAC
18.
Safety
CP_AE8 
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
ICH E3
SAC
All Laboratory
19.
Safety
LB5 
Listing of Laboratory Data for Subjects with Abnormalities of 
Potential Clinical Concern
ICH E3
SAC
20.
Safety
LB5 / LB6
Listing of Laboratory Data Abnormalities of Potential Clinical 
Importance
SAC
ECG
21.
Safety
CP_EG3
Listing of All ECG Values for Subjects with a Value of Potential 
Clinical Importance
IDSL
Include absolute PCI subjects. 
Footnote:
H=High absolute, L= Low absolute."
SAC
22.
Safety
CP_EG3
Listing of All ECG Changes for Subjects with a Value of 
Potential Clinical Importance
IDSL
Include change from baseline PCI
subjects. 
Footnote:
H=High change from baseline value, L= 
Low change from baseline value
SAC
 
 
 
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ICH : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
23.
Safety
CP_EG3 
Listing of ECG Values of Potential Clinical Importance
"Include absolute PCIs. 
Footnote:
H=High absolute, L= Low absolute."
SAC
24.
Safety
CP_EG3
Listing of ECG Changes of Potential Clinical Importance
"Include change from baseline PCIs. 
Footnote:
H=High change, L= Low change."
SAC
25.
Safety
CP_EG5 
Listing of Abnormal ECG Findings
IDSL
SAC
Vital Signs
26.
Safety
CP_VS4 
Listing of All Vital Signs for Subjects with Values of Potential 
Clinical Importance
"Include both absolute and change from 
baseline PCI subjects. 
Footnote:
H=High, L=Low
H1=Lower Increase, H2=Upper 
Increase, L1=Lower Decrease, 
L2=Upper Decrease"
SAC
 
 
 
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11.15.7.
Non-ICH Listings
Non-ICH : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Efficacy
27.
Safety
LS2
Listing of DAS28-CRP Score and Components
Footnote: Swollen Joint Count based 
on 28 and 66 joints. Tender Joint Count 
based on 28 and 68 joints. Patient’s 
Global Assessment of Arthritis Disease 
Activity measured on VAS scale. CRP –
C-Reatove protein 
SAC
Pharmacodynamics/Biomarkers 
28.
Safety
LS1
Listing of Absolute and Change from Baseline MRP8/14 level
SAC
29.
Safety
LS1
Listing of Absolute and Change from Baseline in Monocyte
Count
SAC
 
 
 
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11.16.
Appendix 16: Example Mock Shells for Data Displays
Example 
: LS1
                                         Page 1 of n
Protocol
: 204957
Population
: Safety
Listing xx: Listing of Absolute and Change from Baseline in [variable]
Treatment: Placebo
                                             Visit           Study
              Subject    Visit               Date              Day     Absolute           CFB
              -------------------------------------------------------------------------------
                    XX   SCREENING           13SEP2016          XX          XX
                         DAY 1               26SEP2016          XX          XX
                         EARLY WITHDRAWAL    12OCT2016          XX          XX             XX
                    XX   SCREENING           28SEP2016         XX
                         DAY 1               19OCT2016          XX          XX
                         DAY 7              02NOV2016          XX          XX             XX
                         DAY 14              16NOV2016          XX          XX             XX
                         DAY 21              30NOV2016          XX          XX             XX
                         DAY 28              14DEC2016          XX         XX             XX
          
                    XX   SCREENING           16NOV2016          XX          XX
                         DAY 1               05DEC2016          XX          XX
                         DAY 7               19DEC2016          XX          XX             XX
                         DAY 14              04JAN2017          XX          XX             XX
                         DAY 21              16JAN2017          XX          XX             XX
                         DAY 28              01FEB2017          XX          XX             XX
                         
 
 
 
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Example 
: LS2
                                         Page 1 of n
Protocol
: 204957
Population
: Safety
Listing X   
Listing of DAS28-CRP Score and Components
Treatment: <Placebo, GSKXXXXXXX XXmg>
Site ID/ 
Subject ID
Visit
DAS28(CRP)/ 
DAS28(CRP) 
CfB/  
PGA
TJC28/ 
TJC68
SJC28/ 
SJC66
CRP
XXXX/ XXXXX
Baseline 
x.xx/ x.xx
XX
xx.x/ xx.xx
xx.x/ xx.xx
xx.x/ xx.xx
Week X
x.xx/ -x.xx
XX
xx.x/ xx.xx
xx.x/ xx.xx
xx.x/ xx.xx
Etc. 
Etc.
Etc.
Etc.
Etc.
Etc.
XXXX/ XXXXX
Baseline 
x.xx/ -x.xx
XX
xx.x/ xx.xx
xx.x/ xx.xx
xx.x/ xx.xx
Week X
x.xx/ x.xx
XX
xx.x/ xx.xx
xx.x/ xx.xx
xx.x/ xx.xx
Etc. 
Etc.
Etc.
Etc.
Etc.
Etc.
 
 
 
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Example 
:EFF_F1
Protocol
: 204957
Population
: Safety
Figure xx: Individual patient profiles of [variable] over time
 
 
 
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