Conditions: Osteoarthritis
Keywords: Pain intensity Hand Osteoarthritis GSK3196165 AUSCAN GM-CSF Numerical Rating Scale
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 44
Healthy volunteers: no

Brief summary:
This is a randomized, Phase IIa, multicentre, double-blind, placebo-controlled parallel group study with the primary objective to assess the efficacy potential of GSK3196165 on pain, in subjects with active inflammatory hand osteoarthritis (HOA).

Approximately 40 subjects will be enrolled into the study, following a screening period of up to 4 weeks. The total treatment period will be 12 weeks, with the follow up period completing at Week 22. At least 40 subjects will be randomized across the two treatment arms, to either placebo or GSK3196165 in a 1:1 ratio.

Detailed description:

Arms:
arm 1: Subjects will receive a total of 8 doses of GSK3196165 over a 12-week treatment period. arm 2: Subjects will receive a total of 8 doses of placebo over a 12-week treatment period.

Interventions: intervention 1: GSK3196165 intervention 2: Placebo
Intervention descriptions: intervention 1: GSK3196165 will be supplied as a liquid and will be administered as a subcutaneous injection. The drug will be administered weekly for 5 injections, then every other week for 3 further injections. intervention 2: Matching placebo will be administered as above.

Protocol document:
Prot_000.pdf: 
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A multi-centre Phase IIa double-blind, placebo-controlled study 
to investigate the efficacy and safety of GSK3196165 in subjects 
with inflammatory hand osteoarthritis.
Compound Number:
GSK3196165
Development Phase:
IIa
Effective Date:
03-JAN-2017
Protocol Amendment Number: 2
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
2015N242468_00
2015-AUG-14
Original
2015N242468_01
2015-NOV-16
Amendment No. 1
Correction of contraceptive requirements in Appendix 5, in response to regulatory review 
comments.  Minor correction of question number in post-treatment interview guidance.
2015N242468_02
2017-JAN-03
Amendment No. 2
Amendment of inclusion criteria, #2, #3 and #5, clarification of exclusion criteria #9 and 
amendment of exclusion criteria #19(d).
Addition of two planned interim analyses to Section 9.3 and associated update to study 
blinding details (Section 6.4).
Addition of two PK sample time points (one on Day 85 and one on Day 155).
Further minor corrections and clarifications to wording throughout the protocol. See 
Appendix 14 for full details.
 
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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 Medicines 
Research Centre,
Gunnels Wood 
Road, Stevenage, 
Herts. SG1 2NY
Secondary 
Medical 
Monitor
GSK,
Ironbridge Road,
Stockley Park 
West, Uxbridge.
UB11 1BT 
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number(s):
EudraCT number – 2015-003089-96
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 204851
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 204851......................................................10
2.
INTRODUCTION....................................................................................................12
2.1.
Study Rationale ..........................................................................................12
2.2.
Brief Background ........................................................................................13
2.2.1.
Hand osteoarthritis.......................................................................13
2.2.2.
GM-CSF and OA .........................................................................13
2.2.3.
GSK3196165...............................................................................14
2.2.4.
Clinical Data ................................................................................14
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................15
4.
STUDY DESIGN ....................................................................................................17
4.1.
Overall Design ............................................................................................17
4.2.
Study Schematic.........................................................................................17
4.2.1.
Pharmacokinetics ........................................................................18
4.2.2.
Biomarkers ..................................................................................18
4.3.
Treatment Arms and Duration.....................................................................18
4.4.
Type and Number of Subjects.....................................................................19
4.5.
Design Justification.....................................................................................19
4.6.
Dose Justification........................................................................................20
4.7.
Benefit:Risk Assessment ............................................................................22
4.7.1.
Risk Assessment .........................................................................23
4.7.2.
Benefit Assessment.....................................................................30
4.7.3.
Overall Benefit:Risk Conclusion...................................................30
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............30
5.1.
Inclusion Criteria.........................................................................................31
5.2.
Exclusion Criteria........................................................................................32
5.3.
Screening/Baseline/Run-in Failures............................................................35
5.3.1.
Re-Screening...............................................................................35
5.3.2.
Re-Testing – Laboratory Exclusion ..............................................35
5.4.
Withdrawal/Stopping Criteria.......................................................................35
5.4.1.
Liver Chemistry Stopping Criteria ................................................36
5.4.1.1.
Study Treatment Restart or Rechallenge....................37
5.4.2.
QTc Stopping Criteria ..................................................................37
5.5.
Treatment withdrawal..................................................................................38
5.5.1.
Respiratory Symptoms.................................................................38
5.5.2.
Hematologic abnormalities...........................................................38
5.6.
Subject and Study Completion....................................................................39
6.
STUDY TREATMENT ............................................................................................39
6.1.
Investigational Product and Other Study Treatment....................................39
6.2.
Treatment Assignment................................................................................40
6.3.
Planned Dose Adjustments.........................................................................41
6.4.
Blinding.......................................................................................................41
6.5.
Packaging and Labelling.............................................................................42
6.6.
Preparation/Handling/Storage/Accountability..............................................42
 
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6.7.
Compliance with Study Treatment Administration.......................................42
6.8.
Treatment of Study Treatment Overdose....................................................42
6.8.1.
Overdose of GSK3196165...........................................................42
6.9.
Treatment after the End of the Study ..........................................................43
6.10.
Concomitant Medications and Non-Drug Therapies....................................43
6.10.1.
Permitted Medications and Non-Drug Therapies..........................44
6.10.2.
Prohibited Medications and Non-Drug Therapies.........................44
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................45
7.1.
Time and Events Tables .............................................................................47
7.1.1.
Screening period Time and Events table .....................................47
7.1.2.
Treatment period Time and Events table .....................................48
7.1.3.
Follow-up visit and early withdrawal* procedures list ...................49
7.2.
Screening and Critical Baseline Assessments ............................................50
7.3.
Efficacy.......................................................................................................50
7.3.1.
Subject’s Assessment of Hand Pain, Function, Stiffness, 
and Subject’s / Clinician’s Assessment of Global Disease 
Activity .........................................................................................51
7.4.
Safety .........................................................................................................52
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........52
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................52
7.4.1.2.
Method of Detecting AEs and SAEs ...........................53
7.4.1.3.
Follow-up of AEs and SAEs........................................53
7.4.1.4.
Cardiovascular and Death Events ..............................53
7.4.1.5.
Regulatory Reporting Requirements for SAEs............53
7.4.2.
AEs of Special Interest (AESIs) ...................................................54
7.4.3.
Pregnancy ...................................................................................54
7.4.4.
Physical Exams ...........................................................................54
7.4.5.
Vital Signs....................................................................................55
7.4.6.
Electrocardiogram (ECG).............................................................55
7.4.7.
Pulmonary Assessments .............................................................55
7.4.8.
Immunogenicity............................................................................56
7.4.9.
Clinical Safety Laboratory Assessments ......................................56
7.5.
Pharmacokinetics .......................................................................................58
7.5.1.
Blood Sample Collection..............................................................58
7.5.2.
Sample Analysis ..........................................................................58
7.6.
Biomarkers and Imaging.............................................................................58
7.6.1.
Magnetic Resonance Imaging......................................................58
7.6.2.
Novel Biomarkers ........................................................................59
7.7.
Genetics .....................................................................................................59
7.8.
Value Evidence and Outcomes...................................................................60
7.8.1.
Post-treatment Interviews ............................................................60
8.
DATA MANAGEMENT ...........................................................................................60
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................60
9.1.
Hypotheses.................................................................................................60
9.2.
Sample Size Considerations.......................................................................61
9.2.1.
Sample Size Assumptions ...........................................................61
9.2.2.
Sample Size Sensitivity................................................................61
9.2.3.
Sample Size Re-estimation or Adjustment...................................61
 
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9.3.
Data Analysis Considerations .....................................................................61
9.3.1.
Analysis Populations....................................................................61
9.3.2.
Interim Analysis ...........................................................................61
9.4.
Key Elements of Analysis Plan ...................................................................62
9.4.1.
Primary Analyses.........................................................................62
9.4.2.
Secondary Analyses ....................................................................62
9.4.3.
Other Analyses ............................................................................63
10. STUDY GOVERNANCE CONSIDERATIONS........................................................63
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............63
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................63
10.3.
Quality Control (Study Monitoring) ..............................................................64
10.4.
Quality Assurance.......................................................................................64
10.5.
Study and Site Closure ...............................................................................64
10.6.
Records Retention......................................................................................65
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................66
11. REFERENCES.......................................................................................................67
12. APPENDICES........................................................................................................72
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................72
12.2.
Appendix 2 – Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................76
12.3.
Appendix 3 – Genetic Research .................................................................79
12.4.
Appendix 4 – Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events ............................82
12.4.1.
Definition of Adverse Events........................................................82
12.4.2.
Definition of Serious Adverse Events...........................................83
12.4.3.
Definition of Cardiovascular Events .............................................84
12.4.4.
Recording of AEs and SAEs ........................................................85
12.4.5.
Evaluating AEs and SAEs............................................................85
12.4.6.
Reporting of SAEs to GSK...........................................................87
12.5.
Appendix 5 – Contraception eligibility criteria for female and male 
subjects ......................................................................................................88
12.5.1.
Males:..........................................................................................88
12.5.2.
Females:......................................................................................88
12.5.3.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............89
12.5.4.
Collection of Pregnancy Information (female subjects).................90
12.5.5.
Collection of Pregnancy Information (female partners of 
male subjects) .............................................................................90
12.6.
Appendix 6 – Recommended Pulmonary Assessment Algorithms ..............91
12.6.1.
Follow-up Algorithms ...................................................................91
12.6.2.
Management of Study Medications During Pulmonary 
Assessment.................................................................................92
12.6.3.
Central Review of Pulmonary Investigations................................92
12.6.4.
Adjudication Process for Suspected Cases of Pulmonary 
Alveolar Proteinosis.....................................................................93
12.7.
Appendix 7 – Common Terminology Criteria for Adverse Events 
(CTCAE): Cough.........................................................................................94
 
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12.8.
Appendix 8 – Average Pain NRS................................................................95
12.9.
Appendix 9 – Worst Pain NRS....................................................................96
12.10. Appendix 10 – Patient Global Assessment of Disease Activity 
(PtGA) ........................................................................................................97
12.11. Appendix 11 – Physician Global Assessment of Disease Activity 
(PhGA) .......................................................................................................98
12.12. Appendix 12 – Patient Post-Treatment Interview ........................................99
12.13. Appendix 13 – Country Specific Requirements .........................................103
12.14. Appendix 14 – Protocol Amendment Changes..........................................104
 
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1.
PROTOCOL SYNOPSIS FOR STUDY 204851
Rationale
This study is designed to investigate whether GSK3196165 may offer a treatment benefit 
for subjects with inflammatory hand osteoarthritis (HOA).
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To assess the efficacy potential of 
GSK3196165 on pain in inflammatory 
HOA.

Change from baseline in 24h average hand pain 
intensity at Week 6, as measured by daily pain 
Numerical Rating Scale (NRS) averaged over the 
7 days prior to assessment visit.
Secondary

To evaluate impact of GSK3196165 
on average and worst HOA pain, over 
time.

Change from baseline in 24h average hand pain 
intensity at each visit, measured by daily pain 
NRS and averaged over the 7 days prior to each 
assessment visit. 

Change from baseline of worst hand pain 
intensity over 24h at each visit, measured by 
daily NRS and averaged over the 7 days prior to 
each assessment visit. 

Proportion of subjects in each treatment group 
achieving a 30% reduction in 24h average hand 
pain intensity at each visit, measured by daily 
NRS averaged over the 7 days prior to 
assessment visit.

Proportion of subjects in each treatment group 
achieving a 50% reduction in 24h average hand 
pain intensity at each visit, measured by daily 
NRS averaged over the 7 days prior to 
assessment visit. 

Proportion of subjects in each treatment group 
achieving a 30% reduction in 24h worst hand 
pain intensity at each visit, measured by daily 
NRS averaged over the 7 days prior to 
assessment visit.

Proportion of subjects in each treatment group 
achieving a 50% reduction in 24h worst hand 
pain intensity at each visit, measured by daily 
NRS averaged over the 7 days prior to 
assessment visit.

To assess the impact of GSK3196165 
on hand pain (on use), stiffness and 
function, over time.

Change from baseline in Australian Canadian 
Hand Osteoarthritis Index (AUSCAN) 3.1 NRS, 
total and domains (pain, morning stiffness, 
function) scores at each visit. 
 
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Objectives
Endpoints

To assess the impact of GSK3196165 
on HOA inflammation 

Change in number of swollen and tender hand 
joints at each visit.

To assess potential impact of 
GSK3196165 on disease activity in 
HOA,

Change from baseline in patient global 
assessment (PtGA) and physician global 
assessment (PhGA) of disease activity at Week 
6,12 and 22.

To assess safety of GSK3196165 in 
HOA patients, over the study duration.

Incidence of adverse events and serious adverse 
events.

Incidence of infections.

Incidence of pulmonary events (cough/dyspnea, 
PAP and DLCO).

Immunogenicity.

To assess population 
pharmacokinetics of GSK3196165 in 
HOA.

Population pharmacokinetics endpoints such as 
CL/F, Vss/F, Ka.
* If only one hand is affected by HOA and meets the inclusion criteria, the affected hand will be documented at 
screening and used for all assessments. In cases where both hands are affected by HOA and both meet the 
inclusion criteria, then the dominant hand will be documented at screening and this hand will be used for all single-
hand assessments throughout the study.
Overall Design
This is a randomized Phase IIa, multicentre, double-blind, placebo-controlled parallel 
group study with the primary objective to assess the efficacy potential of GSK3196165 
on pain, in subjects with active inflammatory HOA.
Study schematic
Primary endpoint 
pain at week 6
Baseline pain, function, 
tender and swollen 
joints, biomarkers, 
safety and laboratory 
evaluations. 
Efficacy (pain, 
function, imaging) and 
safety at week 12
5 loading doses (Day 1, 8, 15, 22, 29) followed 
by 3 doses every other week (Day 43, 57, 71).
Safety evaluation, 
MRI and Pain at 
week 22
Dosing: GSK 3196165 or Placebo 
(1:1 randomised)
D 43 
(Week 6)
D 85 
(Week 12)
D 155 
(Week 22)
D 1
(Week 0)
Treatment period
• Pain, function, imaging, PK
Follow up period
• Pain, imaging, safety
D 8  
D 15
D 22
D 29
D 57
D 71
Screening
Period
• ACR 
classification, 
MRI, Pain, 
tender and 
swollen joints 
and Safety 
evaluations
D -28
 
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Treatment Arms and Duration

A screening period of up to 4 weeks, will be followed by a 12 week treatment period 
(dosing with GSK3196165 or placebo) then a follow up period, completing on week 
22. The total study duration for an individual subject will be approximately 26 
weeks. 

The Study consists of 2 arms: treatment with GSK3196165 or placebo will be given 
as a single subcutaneous injection (shielded to subjects) to the abdomen or thigh, by 
an unblinded administrator weekly for 5 injections, from Week 0 to Week 4 (Days 1, 
8, 15, 22, 29), then every other week for 3 further injections, from Week 6 until 
Week 10 (Days 43, 57 and 71).  

In total, each subject will receive up to 8 doses of study treatment.
Type and Number of Subjects
Approximately 40 subjects with active inflammatory HOA who have passed all screening 
assessments, will be enrolled onto the study. At least 40 subjects will be randomized 
across the two treatment arms, to either placebo or GSK3196165, in a 1:1 ratio (n=20 per 
arm).  
Analysis

The study will test the null hypothesis that there is no difference between 
GSK3196165 and placebo in the change from baseline in the 24h average Pain 
Numerical Rating Scale (NRS) at Week 6 versus the alternative hypothesis that there 
is a difference between GSK3196165 and placebo in the change from baseline in the 
24h average Pain NRS at Week 6 using a two-sided test.

The primary endpoint of the study is change from baseline in 24h average hand pain 
intensity at Week 6, as measured by daily pain Numerical Rating Scale (NRS) 
averaged over the 7 days prior to assessment visit.

The primary endpoint will be analysed using a repeated measures model (MMRM) 
adjusted for baseline pain score, treatment group, visit and the visit by treatment 
group interaction as fixed effects, patient as a random effect and day within patient 
as a repeated effect, using an unstructured covariance matrix.
2.
INTRODUCTION
GSK3196165 is a novel human monoclonal antibody which inhibits granulocyte-
macrophage colony stimulating factor (GM-CSF) and is being developed for the
treatment of rheumatoid arthritis (RA) and other inflammatory diseases.
2.1.
Study Rationale
This study is designed to investigate whether GSK3196165 may offer a treatment benefit 
for subjects with inflammatory hand osteoarthritis.
 
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2.2.
Brief Background
2.2.1.
Hand osteoarthritis
Hand osteoarthritis (HOA) is the second most common form of osteoarthritis (OA) which 
is itself, the most common musculoskeletal disorder.  The factors underlying the 
relationship between inflammatory and erosive HOA are not fully understood, though it 
seems likely that erosions could be a consequence of chronic inflammation. The 
presentation of HOA is typically with symptoms reflecting underlying inflammation in 
the proximal joints of the hand affecting the synovium, cartilage and bone. Severe hand 
pain can significantly impair day to day activities through functional impairment in the 
form of stiffness, reduced grip strength, reduced hand mobility, and difficulty performing 
dexterous tasks. Some patients have demonstrable bony erosions on X-Ray or Magnetic 
Resonance Imaging (MRI) [Kortekaas, 2015 and Kwok, 2011]. Erosive disease has the 
potential to irreversibly destroy joint architecture and result in permanent disability. 
Treatment options for both inflammatory and erosive HOA are limited and are focused 
on alleviating symptoms through pain medication, local steroid injections and surgical 
intervention but provide limited, if any, benefit.[Gelber, 2015; Chevalier, 2014; Bijlsma, 
2011; Altman, 2010 and Towheed, 2005]  Hence there is a clear unmet need to develop 
new therapeutics which not only address symptoms but also result in disease modification 
such as reduction in structural joint damage or prevention of inflammatory changes in the 
joints which can lead to deterioration of long term functional ability. 
2.2.2.
GM-CSF and OA
The pathogenic characteristics of OA are loss of cartilage with associated underlying 
bony changes consisting of sclerosis, sub-chondral bone collapse, bone cysts and 
osteophyte formation [Iannone, 2003]. Pain is one of the most important symptoms of 
OA as it causes a significant impairment in function. The etiology of OA is likely to be 
multifactorial, and recent histological evidence indicates that synovitis is an early feature 
in OA, even in joints where it could not be detected clinically [Spector, 1997; Sowers, 
2002; Haywood, 2003], with a mixed inflammatory infiltrate consisting mainly of 
macrophages and with pro-inflammatory mediator production (e.g. TNF, IL-1b) [Farahat, 
1993; Bondeson, 2010]. It has been argued that OA synovial inflammation is 
qualitatively similar to that in RA, differing only in magnitude [Haraoui, 1991].
Granulocyte-macrophage colony stimulating factor receptor (GM-CSFR) is expressed in 
OA synovium [Berenbaum, 1994] and is spontaneously produced by OA synovial cell 
cultures over a time course of 5 days [Haworth, 1991]. GM-CSF induces the proliferation 
and activation of macrophage lineage cells leading to strongly increased production of 
key proinflammatory cytokines (including TNFα, IL-6, and IL-1), chemokines and matrix 
degrading proteases [Fleetwood, 2007; Gasson, 1991; Hamilton, 2004; Hamilton, 2013; 
Hart, 1991; Mantovani, 2007].  GM-CSF also serves as a differentiation factor for 
dendritic cells and induces upregulation of human lymphocyte antigen (HLA) class II on 
antigen presenting cells, which in turn will activate CD4+ T cells.  In addition, GM-CSF 
is a strong chemo-attractant factor for neutrophils and induces the release of activated 
oxygen species from neutrophils, which can directly damage cartilage structure [Dang, 
1999; Gomez-Cambronero, 2003]. Furthermore, it has been demonstrated  pre-clinically 
 
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that GM-CSF is linked to the development of experimental [Cook, 2012] and 
spontaneous osteoarthritis [Stone, 2015] and it is associated with pain, function, matrix 
degrading proteases and structural disease severity [Cook, 2012]. Importantly, GM-CSF 
neutralization by a therapeutic monoclonal antibody rapidly and completely abolished 
existing arthritic pain and suppressed the degree of arthritis development in the 
collagenase induced model of OA. 
Taken together, pre-clinical and clinical data suggest that blocking GM-CSF should 
interfere with several pathophysiological pathways and significantly reduce inflammation 
by inhibiting activation of inflammatory cells within the OA joint and by blocking the 
chemotaxis recruitment of such non-resident inflammatory cells, thus leading to a benefit 
on inflammatory pain and inhibiting bone and cartilage destruction.
2.2.3.
GSK3196165
GSK3196165 is a high-affinity recombinant human monoclonal antibody (mAb) that 
binds specifically to human GM-CSF and neutralises its biological function by blocking 
the interaction of GM-CSF with its cell surface receptor [Steidl, 2008]. This results in an 
anti-inflammatory and anti-nociceptive effect in addition to affecting bone metabolism 
through the Receptor Activator of Nuclear factor-κB ligand (RANKL) pathway and may 
therefore be a viable treatment option for inflammatory HOA [Cook, 2013].
Detailed information relating to non-clinical pharmacology, safety pharmacology, 
pharmacokinetics and metabolism, toxicology and other pre-clinical and clinical data 
with GSK3196165 can be found in the GSK3196165 Investigator’s Brochure (IB) and 
supplement [GSK Document Number 2014N190256_00 and GSK Document Number 
2015N226819_00].
2.2.4.
Clinical Data
GSK3196165 has been studied in 4 clinical trials to date as summarised in the IB [GSK 
Document Number 2014N190256_00]. In addition, a Phase IIb, double-blind, placebo 
controlled, dose adaptive study in 210 subjects with active moderate-severe rheumatoid 
arthritis despite treatment with methotrexate [GSK Document Number 
2014N210890_04] has been initiated in several countries. 
MSC-1001 was a Phase1b/2a multi-center, randomized, sequential group, double-blind, 
placebo-controlled study which evaluated the safety, preliminary efficacy, and PK of 
multiple doses of GSK3195165 in subjects (N=96) with active, mild-moderate RA 
[Behrens, 2015].  Previous treatment with biological/immunosuppressive therapies other 
than cell-depleting agents was allowed with an adequate washout period.  Eligible 
patients had active moderate RA (1987 American College of Rheumatology [ACR] RA 
classification criteria, ≥3 swollen and ≥3 tender joints), an elevated C-reactive 
protein (CRP) >5 mg/L (in sero-negative subjects) or CRP >2 mg/L (in Rheumatoid 
factor [RF] and/or Anti-cyclic citrullinated protein antibody [ACPA] sero-positive 
subjects) and Disease activity score for 28 different joints (DAS28) score ≤5.1.  Subjects 
received 4 IV weekly doses of GSK3195165 at 0.3 mg/kg, 1.0 mg/kg or 1.5 mg/kg or 
placebo in addition to stable concomitant treatment with Disease modifying 
antirheumatic drugs (DMARDs) or low doses of oral corticosteroids.  Rapid and 
significant reductions in disease activity (as measured by DAS28) were observed with the 
1.0 mg/kg and 1.5 mg/kg doses.  Greater reduction in disease activity to Week 4 was 
 
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observed with 1.0 mg/kg than 1.5 mg/kg in this dose-escalation cohort study.  A 
significant reduction in mean DAS28 was not observed in the 0.3 mg/kg group.  Other 
disease activity measures (e.g., ACR response) and patient-reported outcomes were 
consistent with the results for DAS28.  GSK3196165 was generally safe and well-
tolerated in this study.  Treatment emergent adverse events (AEs) in the GSK3195165 
groups were mild or moderate in intensity and generally reported at frequencies similar to 
those in the placebo group.  Infections were the most commonly reported AEs and 
occurred in 26.1% and 29.6% of GSK3196165 and placebo subjects, respectively.  There 
was a numerical imbalance in cough (0/27 placebo, 3/69 active).  There were no apparent 
trends in Pulmonary function tests (PFTs) or Diffusing capacity of the lung for carbon 
monoxide (DLCO) changes.  In two cases, AEs were classified as serious because of 
hospitalization: paronychia in a placebo subject and pleurisy (which responded to 
antibiotics and therefore may have had an infectious etiology) in a GSK3195165 0.3 
mg/kg subject.  Both patients recovered.
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To assess the efficacy potential of 
GSK3196165 on pain in inflammatory 
HOA.

Change from baseline in 24h average hand pain 
intensity at Week 6, as measured by daily pain 
Numerical Rating Scale (NRS) averaged over the 
7 days prior to assessment visit.
Secondary

To evaluate impact of GSK3196165 
on average and worst HOA pain, over 
time.

Change from baseline in 24h average hand pain 
intensity at each visit, measured by daily pain 
NRS and averaged over the 7 days prior to each 
assessment visit. 

Change from baseline of worst hand pain 
intensity over 24h at each visit, measured by 
daily NRS and averaged over the 7 days prior to 
each assessment visit. 

Proportion of subjects in each treatment group 
achieving a 30% reduction in 24h average hand 
pain intensity at each visit, measured by daily 
NRS averaged over the 7 days prior to 
assessment visit.

Proportion of subjects in each treatment group 
achieving a 50% reduction in 24h average hand 
pain intensity at each visit, measured by daily 
NRS averaged over the 7 days prior to 
assessment visit. 

Proportion of subjects in each treatment group 
achieving a 30% reduction in 24h worst hand 
pain intensity at each visit, measured by daily 
NRS averaged over the 7 days prior to 
assessment visit.
 
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Objectives
Endpoints

Proportion of subjects in each treatment group 
achieving a 50% reduction in 24h worst hand 
pain intensity at each visit, measured by daily 
NRS averaged over the 7 days prior to 
assessment visit.

To assess the impact of GSK3196165 
on hand pain (on use), stiffness and 
function, over time.

Change from baseline in Australian Canadian 
Hand Osteoarthritis Index (AUSCAN) 3.1 NRS, 
total and domains (pain, morning stiffness, 
function) scores at each visit. 

To assess the impact of GSK3196165 
on HOA inflammation 

Change in number of swollen and tender hand 
joints at each visit.

To assess potential impact of 
GSK3196165 on disease activity in 
HOA,

Change from baseline in patient global 
assessment (PtGA) and physician global 
assessment (PhGA) of disease activity at Week 
6,12 and 22.

To assess safety of GSK3196165 in 
HOA patients, over the study duration.

Incidence of adverse events and serious adverse 
events.

Incidence of infections.

Incidence of pulmonary events (cough/dyspnea, 
PAP and DLCO).

Immunogenicity.

To assess population 
pharmacokinetics of GSK3196165 in 
HOA.

Population pharmacokinetics endpoints such as 
CL/F, Vss/F, Ka.
Exploratory

To explore the potential impact of 
GSK3196165 on disease 
progression/modification in HOA, 
using MRI imaging.

Change from baseline in synovitis in the affected 
hand*, as measured by DCE-MRI including the 
exchange rate (Ktrans), interstitial volume (ve), 
plasma volume (vp), volume of synovitis, initial 
rate of enhancement (IRE), and maximum signal 
intensity enhancement (ME).

Change from baseline in structural and 
inflammatory HOA features in the affected hand* 
(including synovitis, erosive damage, cysts, 
osteophytes, cartilage space loss, malalignment, 
and  bone marrow lesions) as assessed by the 
OMERACT HOAMRIS scoring system

Change from baseline in structural and 
inflammatory HOA features in the affected hand* 
(including synovitis, bone erosions, joint space 
width, and bone marrow edema) as assessed by 
the RAMRIQ scoring system.

Change from baseline in bone shape as 
assessed by structural MRI of the affected hand*.

The exploration of the relationship 

Relationship between concentration or PK 
 
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Objectives
Endpoints
between GSK3196165 PK and PD 
effects and/or efficacy.
parameters and PD endpoint(s).

To evaluate the potential of 
GSK3196165 to affect biomarkers of 
HOA.

Change in blood biomarkers from baseline at 
each visit.
* If only one hand is affected by HOA and meets the inclusion criteria, the affected hand 
will be documented at screening and used for all assessments. In cases where both hands 
are affected by HOA and both meet the inclusion criteria, then the dominant hand will be 
documented at screening and this hand will be used for the MRI assessments throughout 
the study.
4.
STUDY DESIGN
4.1.
Overall Design
This is a randomized Phase IIa, multicentre, double-blind, placebo-controlled parallel 
group study with the primary objective to assess the efficacy potential of GSK3196165 
on pain, in subjects with active inflammatory HOA. 
4.2.
Study Schematic
Approximately 40 subjects will be enrolled into the study, following a screening period 
of up to 4 weeks. The total treatment period will be 12 weeks, with the follow up period 
completing at Week 22.  At least 40 subjects will be randomized across the two treatment 
arms, to either placebo or GSK3196165 in a 1:1 ratio (n=20 per arm).  

This study will be double-blind (sponsor unblind).  Refer to Section 6.4 for details of 
blinding.
Primary endpoint 
pain at week 6
Baseline pain, function, 
tender and swollen 
joints, biomarkers, 
safety and laboratory 
evaluations. 
Efficacy (pain, 
function, imaging) and 
safety at week 12
5 loading doses (Day 1, 8, 15, 22, 29) followed 
by 3 doses every other week (Day 43, 57, 71).
Safety evaluation, 
MRI and Pain at 
week 22
Dosing: GSK 3196165 or Placebo 
(1:1 randomised)
D 43 
(Week 6)
D 85 
(Week 12)
D 155 
(Week 22)
D 1
(Week 0)
Treatment period
• Pain, function, imaging, PK
Follow up period
• Pain, imaging, safety
D 8  
D 15
D 22
D 29
D 57
D 71
Screening
Period
• ACR 
classification, 
MRI, Pain, 
tender and 
swollen joints 
and Safety 
evaluations
D -28
 
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
For screening, baseline and efficacy assessments, the average pain intensity over 7 
days prior to assessment date will be used. This is calculated from collected daily 
pain NRS data over 7 days.

Imaging MRI will be carried out at screening, Week 12 and Week 22. (Note: MRI at 
screening will serve as the baseline measurement). 

At baseline subjects will be evaluated by pain NRS (average 7 days prior to visit), 
AUSCAN 3.1 NRS, PtGA, PhGA, number of tender and swollen joints in their hands 
and blood will be collected for safety, biomarker monitoring, and pharmacokinetics. 

Throughout the study treatment period, subjects will be assessed for hand pain using a 
daily pain NRS questionnaire (daily from screening to Week 12). In addition, at the 
specified time points (see Section 7.1, time and events table), function and disease 
state will be assessed using the AUSCAN 3.1 NRS, PtGA and PhGA.  The number of 
tender and swollen joints in affected hands will also be assessed and blood samples 
will be collected for safety, biomarkers monitoring, and pharmacokinetics.

At the Week 22 follow up visit, blood will again be collected for safety monitoring as 
well an assessment of pain NRS (average 7 days prior to visit), PtGA, PhGA and 
MRI imaging of the affected hand.
For MRI endpoints the assessments are based on one hand only.  In cases where both 
hands are affected by HOA and both meet the inclusion criteria, then the dominant hand 
will be documented at screening and this hand will be used for the MRI assessments 
throughout the study.
4.2.1.
Pharmacokinetics
The study will use sparse sampling of GSK3196165 to determine PK parameters and 
associated inter- and intra-subject variability.  The relationship between GSK3196165
concentrations and PD effects and/or efficacy endpoints will be evaluated if appropriate, 
as an exploratory endpoint. 
4.2.2.
Biomarkers
In addition, a range of exploratory novel blood biomarkers will be evaluated.  These 
markers will allow confirmation of target engagement and expected pharmacologic 
effects.  These data may also allow hypotheses to be generated with respect to subgroups 
that are most likely to benefit from GSK3196165 treatment or early on-treatment markers 
that may predict subsequent response/remission (or lack of response/remission), that may 
guide further development and ultimately treatment guidelines for prescribers.
4.3.
Treatment Arms and Duration

A screening period of up to 4 weeks, will be followed by a 12 week treatment period 
(dosing with GSK3196165 or placebo) then a follow up period, completing on week 
22. The total study duration for an individual subject will be approximately 26 weeks. 
 
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
The Study consists of 2 arms: treatment with GSK3196165 or placebo will be given 
as a single subcutaneous injection (shielded to subjects) to the abdomen or thigh, by 
an unblinded administrator weekly for 5 injections, from Week 0 to Week 4 (Days 1, 
8, 15, 22, 29), then every other week for 3 further injections, from Week 6 until Week 
10 (Days 43, 57 and 71).  

In total, each subject will receive up to 8 doses of study treatment.
4.4.
Type and Number of Subjects
Approximately 40 subjects with active inflammatory HOA who have passed all screening 
assessments, will be enrolled onto the study. At least 40 subjects will be randomized
across the two treatment arms, to either placebo or GSK3196165, in a 1:1 ratio (n=20 per 
arm).  
4.5.
Design Justification
This study is designed to investigate whether GSK3196165 may be a treatment option for 
inflammatory HOA.
The primary objective is to demonstrate a reduction in pain at week 6, as indicated by an 
improvement of at least 2 points in 24h average pain score measured by pain NRS (0-10)
for active vs. placebo, which is considered a clinically important difference [Farrar, 2008; 
Salaffi, 2004 and Farrar, 2001]. In order to minimise effect of daily fluctuations in 
patients’ perception of pain, baseline and efficacy assessments will use a 7 day average of 
the 24h average pain NRS. Considering the mechanism of action for anti-GM-CSF and 
results from earlier trials in RA it is likely that an impact on pain would be seen within 
the 6 week timeframe. 
Secondary endpoints include evaluation of 24h average pain NRS, 24h worse pain NRS 
and responder analysis. In addition, hand function, pain on use and stiffness which will 
be assessed by AUSCAN Hand Osteoarthritis Index 3.1 NRS. The AUSCAN Index is a 
self-administered questionnaire that assesses the three dimensions of pain on use, 
function and joint stiffness in hand osteoarthritis using a battery of 15 questions with 11-
point (0-10) NRS response options and a 48-hour recall period. The AUSCAN is a valid, 
reliable and responsive measure of outcome and we have chosen the NRS format of the 
AUSCAN in order to provide consistency and ease of use for the patient [Kloppenburg, 
2015; Poole, 2011 and Bellamy, 2002].
Additionally, exploratory MRI imaging (including Dynamic Contrast Enhanced Magnetic 
Resonance Imaging [DCE-MRI], structural bone shape, the Outcome Measures in 
Rheumatology Hand Osteoarthritis Magnetic Resonance Imaging Scoring System 
(OMERACT HOAMRIS) [Haugen, 2014], and the Rheumatoid Arthritis Magnetic 
Resonance Imaging Quantitative Score (RAMRIQ) system [Bowes, 2014]) will be 
employed to explore a potential effect of GSK3196165 on disease modification, which 
includes a reduction in inflammation in terms of synovitis and bone marrow lesions, and 
structural progression in terms of cartilage space loss (as an analog of joint space 
narrowing) and bone shape.
 
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All study endpoints will be evaluated at week 12, following the completion of dosing, to 
assess the effect of GSK3196165 on hand function and disease modification, given it is 
unclear how soon these effects could be seen due to the minimal amount of historic data 
in HOA.  A follow up (observational) period, will then take place, completing the study 
at Week 22.
The purpose of this study is to provide an initial assessment of the therapeutic potential in 
this indication.  Therefore, it is considered appropriate to study the highest dose possible 
(within safety margins), so as not to miss potential efficacy within this exploratory study. 
Placebo is the most relevant control given the small size of this study and that drugs are 
not considered to be very effective in this disease state (Non-steroidal anti-inflammatory 
drug [NSAIDs] non-responder) [Gelber, 2015; Chevalier, 2014; Bijlsma, 2011; Altman, 
2010 and Towheed, 2005]. Secondly standard of care is variable across different 
countries and hence picking one relevant comparator is very challenging.  Further given 
the subjective nature of measuring pain response it is important to run this study in a 
double blinded fashion.
4.6.
Dose Justification
The recommended dosing regimen for this study includes five loading doses of 180 mg 
SC administered every week, followed by maintenance doses of 180 mg SC administered 
every other week.  The predicted PK plasma profile of GSK3196165 at this dose is 
shown in Figure 1 below. This regimen was selected i) to produce sufficient drug 
exposure in both plasma and synovial fluid to inhibit free GM-CSF and ii) to be 
associated with a appropriate margin to the No Observed Adverse Effect Level (NOAEL) 
and the No Effect Level (NOEL) (the dose at which foamy alveolar macrophages were 
not observed in the 13-week rhesus monkey study).  Further details are provided below.  

The Cmin steady-state plasma levels at this dose are predicted to be equal or greater 
than 2 μg/mL, which is the hypothetical plasma concentration required to bind 
synovial GM-CSF based on in vitro data. Similarly, a mechanistic model, based 
on Pharmacokinetics (PK) characteristics of a typical IgG1 [Choy, 2000; Cao, 
2013 and Pejovic, 1995] and GM-CSF binding [Bell, 1995] predicted at least 90% 
inhibition of free GM-CSF in both plasma and synovial fluid. 

The mean steady-state plasma levels predicted at this dose would allow a 26-fold 
margin to the NOAEL (50 mg/kg), where reversible minimal to mild foamy 
alveolar macrophages (considered non-adverse) were seen in the 26-week 
monkey toxicity study, with a 14-and 3-fold margin to the NOEL dose levels (30 
and 5 mg/kg) identified in the 13 and 26 week monkey toxicity studies (see Table 
1 below).
 
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Table 1
Safety margins with 180 mg SC GSK3196165 relative to exposures in 
nonclinical toxicology studies
Study
Species
Assessment
Dose
(mg/kg/wk)
AUC(0-336)
µg.hr/mLb
Fold 
difference
vs. QW
(end of weekly 
dosing phase)
Fold difference 
vs. every other 
week dosing
(steady state)
Repeat Dose 
Toxicology,
4 weeks IV
Rhesus 
Monkey
Week 4
5
8814
3.5
NA
25
44500
18
100c,d
110201
44
Repeat Dose 
Toxicology,
13 weeks SC
Cynomolgus 
Monkey
Week 13
10
7124
2.8
3.8
30d
25870
10
14
100c
75594
30
40
Repeat Dose 
Toxicology,
26 weeks IV
Rhesus 
Monkey
Week 26
5d
5704
2.3
3.0
15
22528
9.0
12
50c
48734
19
26
MSC-1000 
and 
MOR103C10
4 single dose
(IV & SC)a
Human
End of weekly 
dosing phase
Days 28-42
180 mg 
weekly x5
SC
2515
Every other 
week at steady 
state
Days 140-154
180 mg 
every other 
week
SC
1873
IV intravenous; SC subcutaneous
a.
Simulated mean AUC based on analysis of SC and IV data for doses ≥0.5 mg/kg from study MSC1000 (N=18) 
and study MOR103C104 (N=32) with a 2 compartment model and calculation of F by ratio of ClIV/ClSC with 
bioavailability of 44% (95% CI 37%-53%)
b.
As there were no significant differences on sampling occasions or gender differences within each primate study, 
the end of study mean AUC (0-168) values have been used and multiplied by 2 to obtain mean concentrations 
over a two week period
c.
No observed adverse effect dose level (NOAEL)
d.
No observed effect dose level (NOEL)
Figure 1
Predicted GSK3196165 plasma concentrations at the recommended 
dosing regimen (median and 95% confidence interval)
 
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4.7.
Benefit:Risk Assessment
Since GSK3196165 is still in early development with limited efficacy and safety data 
available, an integrated Benefit/Risk evaluation has not been performed at this point in 
time. Summaries of findings from both clinical and non-clinical studies conducted with 
GSK3196165 can be found in the IB and IB supplement [GSK Document Number 
2014N190256_00 and GSK Document Number 2015N226819_00].  The following 
section outlines the risk assessment and mitigation strategy for this protocol:  
 
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4.7.1.
Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK3196165
Infections
Immune-modulating biologic drugs (such as anti-Tumor necrosis 
factor [TNF] agents) are associated with an increased risk of 
serious and opportunistic infections.  Similarly, because of the role 
of GM-CSF in anti-infective immunity, GSK3196165 also has the 
potential to increase the risk of infection.
Non-clinical Data:
No changes in peripheral blood populations (lymphocytes, 
neutrophils, monocytes, eosinophils or basophils), phagocytic 
activity of peripheral blood polymorphonuclear cells (investigational 
endpoint in the 26 week study), T-cell dependent response, B-cell 
primary or secondary response, or circulating cytokine levels (26 
week study) were observed.
Studies in knock-out mice showed that GM-CSF deficiency (GM-
CSF-/-) affects the ability of mice to control infection when infected 
with M. tuberculosis or pulmonary group B streptococcus [LeVine, 
1999].
Clinical Data:
One healthy volunteer in study MSC-1000 experienced septic 
shock secondary to pneumonia 29 days after receiving a single 
dose of IP at 1.5 mg/kg.  Subject recovered after treatment with 
antibiotics, and the subject completed the study follow-up period as 
per protocol.
One RA subject in study MSC-1001 experienced serious pleurisy 
which responded to antibiotics.
Subject selection :

Subjects with active infections or a history of recent or 
recurrent infections are not permitted to enter the study.

Subjects with significant leukopenia (white blood cell count 
≤3.0 x109/L) and neutropenia (absolute neutrophil count ≤1.5 x 
109/L) are not permitted to enter the study.

Subjects will be screened for TB, HIV and Hepatitis B and C, 
and excluded from study participation if positive. Subjects with 
any past history of TB or Hepatitis B will also be excluded. 

Investigators are expected to assess vaccination status, 
including against influenza and pneumococcus, according to 
local guidelines.
Subject monitoring:

Serious infections are categorised as adverse events of 
special interest (AESIs).

Subjects will be closely monitored for infections and additional 
information to clarify the events will be recorded in the eCRF. 
Appropriate diagnostic tests will be considered during the 
study if clinically indicated to ensure appropriate safety 
monitoring.

Subjects will be instructed as to the signs and symptoms of 
infection, and to contact site personnel should they develop.  
This information will also be contained within the patient 
Informed Consent Form.
Withdrawal criteria:

In the event of a serious infection, study medication should be 
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
discontinued and the subject withdrawn from the study.
Pulmonary alveolar 
proteinosis (PAP)
GM-CSF signalling is required to maintain the normal function of 
alveolar macrophages.  Long-term absence of GM-CSF signalling 
(e.g., via hereditary GM-CSF deficiency or development of anti-
GM-CSF auto-antibodies) is known to cause the extremely rare 
condition of PAP, which is characterized by the accumulation of 
surfactant lipids and protein in the alveolar spaces, with resultant 
impairment in gas exchange.
Non-clinical Data:
Non-adverse minimal to mild foamy alveolar macrophage 
accumulation were noted in lungs of monkeys in the 13-week SC 
and 26-week IV toxicology studies, but reversible following off drug 
period.  Dose levels at which foamy alveolar macrophages were 
not observed were identified in these studies.
Clinical Data:
No cases of PAP have been reported to date in the clinical 
development program.  Furthermore evaluation of pulmonary 
function has not demonstrated any abnormalities in pulmonary 
functions.
Subject selection 

Subjects with history of clinically-significant respiratory 
diseases that required treatment and/or follow up, or chronic 
cough or dyspnea will not be permitted to enter the study.

Pulmonary function testing (spirometry, DLCO) will be performed 
at baseline in order to exclude those subjects with impairment. 
Subjects with abnormal DLCO or Forced expiratory volume in 
one second (FEV1) will be excluded. 
Dose Duration:

The exposure duration to GSK3196165 in this study is 3 
months.  Although the time course of Pulmonary alveolar 
proteinosis (PAP) development in humans is unknown, the 
published literature suggests that it requires full inhibition of 
GM-CSF for years before clinical manifestation of the disease 
can be detected (refer to IB GSK Document Number 
2014N190256_00 for further details).  Therefore, the risk of 
development of PAP in this study is anticipated to be low.
Subject Monitoring:

Specific pulmonary assessments are a requirement of the 
study protocol:
o
Subjects will be assessed every visit for the 
development of cough and dyspnea, and will also 
have regular chest auscultation and pulse oximetry 
measurements.  Persistent cough or dyspnea will be 
reported as an AESI.
o
Pulmonary function testing (spirometry and DLCO
measurements) will be performed at baseline, and 
then at week 12 and at the follow-up visit.  Relative 
change in DLCO >15% from baseline will be reported 
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
as an AESI if confirmed with three consecutive 
weekly tests.

In the event of any new or clinically significant pulmonary 
abnormalities that may develop during the study and 
persist for three consecutive weeks (e.g., increased 
shortness of breath/dyspnea, or unexplained and 
persistent coughing; or >15% relative decrease in DLCO
from baseline), the subject will be withdrawn from study 
drug for the remainder of the study and it is recommended 
that the subject be referred to a pulmonologist for further 
assessment [Section 5.5.1]. The subject should be 
followed until the symptoms or signs that caused referral 
have resolved and/or the diagnosis has been determined.  
Suggested pulmonary assessment and management 
algorithms are provided in Appendix 6.
Hypersensitivity reactions, 
including anaphylaxis
There is a potential risk of hypersensitivity reactions, including 
anaphylaxis, during and following the administration of protein-
based products, such as GSK3196165.
Clinical Data:
No allergic or acute systemic reactions have been observed to date 
in the clinical development program.
Subject selection 

Subjects with a history of sensitivity to any of the study 
treatments, or components thereof, or a history of drug or other 
allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation, will not be 
permitted to enter the study.
Study treatment administration/Subject monitoring:

All SC administrations will be performed at the clinical site.

Subjects will be required to remain monitored at the site for 1 
hour after the injection for the first 3 injections, and then for 30 
minutes for subsequent injections.

Subjects should be informed of the signs and symptoms of an 
acute hypersensitivity reaction, and be instructed to seek 
immediate medical care should they develop.  This information 
will also be contained within the patient Informed Consent 
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Form.

Should hypersensitivity or anaphylaxis occur, subjects should 
be managed appropriately per local guidelines/medical 
judgement.

Severe or serious hypersensitivity or anaphylaxis are 
categorised as AESIs.
Subject monitoring:

Subjects should be monitored for hypersensitivity reactions 
throughout the study, and the information recorded in the 
eCRF.

Any clinically-significant event should be reported as an AE.
Withdrawal criteria:

In the event of severe or serious hypersensitivity or 
anaphylaxis, study medication should be discontinued and the 
subject withdrawn from the study.
Injection site reactions
SC injections may be associated with local reactions (e.g., swelling, 
induration, pain).
Non-clinical & Clinical Data:
No macroscopic or microscopic changes indicative of local injection 
site reactions were observed following IV or SC administration.
Subject monitoring:

Subjects should be monitored for injection site reactions 
throughout the study, and the information recorded in the 
eCRF.

Injection sites will be rotated.

Any clinically-significant event should be reported as an AE.
Immunogenicity
Pre-clinical Data
Anti-drug antibodies (ADAs) to GSK3196165 were detected in 
some monkeys and was associated with reduced serum levels of 
GSK3196165; ADA associated toxicity was not observed. 
Clinical Data
In Study MSC1000, one healthy volunteer who received a single 
dose of 25 µg/kg developed an IgM ADA at Day 15, and in Study 
Investigate Risk

Samples (pre-and post-baseline) will be collected from all 
subjects during the study to assess development of anti 
drug antibodies and will be analyzed at the end of the 
study. 

In addition to scheduled immunogenicity assessments, 
“event-driven” testing will also be employed for those 
subjects that experience anaphylaxis, serious 
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
MSC1001 one RA subject who received 4 weekly doses of 1.0 
mg/kg dose developed an IgG ADA at Week 13, but not at Week 
16 (with no impact on GSK3196165 serum concentration).
hypersensitivity or adverse events that are deemed to be 
clinically significant in the opinion of the investigator, and 
related to study drug administration that lead to withdrawal 
from the study, blood samples will be taken for 
immunogenicity testing at the time of the event and again 
12 weeks after.  
Neutropenia
Although there is a perceived theoretical risk that GM-CSF 
blockade may affect maturation of leukocytes and their precursors, 
mice lacking GM-CSF do not develop neutropenia or show any 
major perturbation of hematopoiesis [Stanley, 1994].
Non-clinical & Clinical Data:
There have been no reports of neutropenia or decreases in 
leukocytes in the non-clinical and clinical GSK3196165 program.
Subject selection 

Subjects with significant leukopenia (WBC ≤3.0 x 109/L); 
thrombocytopenia (platelet count ≤100 x 109/L); neutropenia 
(absolute neutrophil count ≤1.5 x 109/L); lymphocytopenia 
(≤0.8 x 109/L) within 28 days prior to Day 1 are not permitted 
to enter the study.
Subject monitoring:

A full blood count (with differential) will be performed at regular 
intervals throughout the study (ref. Time and Events Table,).

Grade 3 or 4 neutropenia will be reported as an AESI.
Reproductive toxicity
Published studies performed with GM-CSF -/- mice have indicated 
that GM-CSF depletion potentially affects fertility, establishment of 
pregnancy and post partum development of offspring in the mouse.
Non-clinical Data:
No GSK3196165-related effects on female or male fertility were 
noted in the SC 13-week repeat dose monkey study at doses up to 
100 mg/kg/week (highest dose tested).  In addition no maternal, 
embryofoetal or effects on fertility were noted in the reproductive 
toxicology studies using the surrogate rat anti-mouse GM-CSF 
monoclonal antibody, 22E9.
The effect on human pregnancy is unknown.
Subject selection 

Male and female subjects will only be permitted to enter the 
study if they meet the contraception requirements detailed in 
inclusion criterion 

In addition, females of child bearing potential will undergo 
pregnancy testing at screening and at regular intervals during 
the study (ref. Time and Events Table, Section 7.1).
Withdrawal criteria:

In the event of a pregnancy in a female subject in the study, 
study medication should be discontinued and the subject 
withdrawn from the study.
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Clinical Data:
No HVs or RA subjects became pregnant during the studies, but 
one MS subject was found to be pregnant during study 
MOR103C10301028 and received four 2.0 mg/kg doses, the 
pregnancy was terminated 2 weeks later by elective abortion.
Other considerations

Female subjects who become pregnant will be followed to 
determine the outcome of the pregnancy. If a female partner of 
a male subject becomes pregnant, they will be followed to 
determine the outcome of the pregnancy.

Any pregnancy complication or elective termination of a 
pregnancy will be reported as an AE or SAE.
Malignancy
Immunomodulatory therapies may increase the risk of malignancy.
Non-clinical & Clinical Data:
There have been no reports of malignancy in the non-clinical and 
clinical GSK3196165 program.
Subject selection 

Subjects with a history of malignant neoplasm within the last 
10 years or breast cancer within the last 20 years, except for 
non-melanoma skin cancers that have been excised and cured 
or carcinoma in situ of the uterine cervix, will not be permitted 
to enter the study.
Study Procedures
Exposure to a high field 
MRI magnet
Certain prostheses or foreign bodies might be incompatible with the 
MRI scanner.
Subject Selection:
All participants will be screened according to local hospital criteria 
and trial inclusion/exclusion before entering the MRI room to 
ensure they are able to have the MRI conducted. Subjects with 
non-MR compatible metal implants or implantable electronic 
devices (e.g. pacemaker, defibrillator) will not be included in this 
study.
Gadolinium (Gd) 
containing MRI contrast 
agents
Non-clinical data:
Animal studies have shown reproductive toxicity of gadolinium-
containing MRI contrast agents at repeated high doses.
Clinical data:
Use of MRI contrast agents in subjects with severely impaired renal 
Subject Selection:

Pregnant or breast feeding females will be excluded from 
taking part in the study.  

Subjects with impaired renal function (GFR<60ml/minute) are 
excluded by the eligibility criteria.  

Subjects with history of sensitivity to Gd-containing contrast 
agents will be excluded from the study. The MRI procedure will 
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
function (Glomerular filtration rate [GFR]<30ml/minute) has been 
associated with Nephrogenic Systemic Fibrosis (NSF).  In subjects 
with severely impaired renal function, the benefits of the use of 
contrast agents should be carefully weighed against the risks.
Gd contrast agents can be associated with 
anaphylactoid/hypersensitivity or other idiosyncratic reactions, 
characterized by cardiovascular, respiratory or cutaneous 
manifestations, and ranging to severe reactions including shock. In 
general, subjects with cardiovascular disease are more susceptible 
to serious or even fatal outcomes of severe hypersensitivity 
reactions.
The risk of hypersensitivity reactions may be higher in case of:

previous reaction to contrast media

history of bronchial asthma

history of allergic disorders
Most of these reactions occur within half an hour of administration. 
Delayed reactions (after hours or several days) have been rarely 
observed.
be conducted under the supervision of a trained and qualified 
clinical staff who are trained to appropriately manage an 
allergic reaction.

Sites will be responsible for following any additional safety 
information for the specific gadolinium contrast agent used at 
their site and not enrol subjects if contraindicated.
Subject monitoring and management:

MRI contrast at a dose less than or equal to 0.1 mmol/kg will 
be used in the MRI protocol.
Effective contraception is required during the study, and pregnancy 
tests will be performed regularly throughout the study prior to 
dosing in females of child bearing potential.
 
 
 
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4.7.2.
Benefit Assessment
Pain associated with HOA does not respond well to current analgesic treatments [Gelber, 
2015; Chevalier, 2014; Bijlsma, 2011; Altman, 2010 and Towheed, 2005]. Thus subjects 
entering the study, who receive active drug, have the potential to receive benefit over 12 
weeks of treatment.
Participation in this study will contribute to the evaluation of a potential new therapy in 
an area of high unmet need.
4.7.3.
Overall Benefit:Risk Conclusion
GSK3196165 is a high-affinity recombinant monoclonal antibody (mAb), IgG1 lambda, 
that binds specifically to human GM-CSF and neutralises its biological function resulting 
in an anti-inflammatory and anti-nociceptive effect in addition to affecting bone 
metabolism through the RANKL pathway and may therefore be a viable treatment option 
in osteoarthritis
Key potential risks are those described above that may be associated with inhibition of 
GM-CSF (e.g., pulmonary toxicity, infection) and those associated with administration of 
a therapeutic monoclonal antibody (e.g. allergic reactions).  Robust and systematic safety 
monitoring will be undertaken in studies of GSK3196165 to proactively address and 
mitigate the potential risks.  
Given the safety monitoring that has been put in place to minimize risk to subjects 
participating in clinical studies of GSK3196165, the potential risks identified are justified 
by the potential benefits that may be afforded to patients with HOA.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB [GSK Document 
Number 2014N190256_00] and IB supplement [GSK Document Number 
2015N226819_00].
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential. 
In addition, investigators are expected to assess vaccination status, including against 
influenza and pneumococcus according to local guidelines.
 
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5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria
apply:
AGE
1. Age ≥ 18 years at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
2. Meets ACR classification of OA and is intolerant to, or has not responded to 
analgesics (level 1 and 2) or to NSAIDs for at least 10 days in the past 3 months.
3. Must have active disease with at least two swollen and tender PIP and/or DIP 
joints in the affected hand*.
4. Signs of inflammation such as synovitis in the MRI scan of the affected hand*.
5. Must have a patient’s self assessment of 24h average hand pain intensity of at least 
‘5’ on an 11-point NRS (0-10), calculated as an average using data from the 7 days 
prior to assessment date.
*If only one hand is affected by HOA and meets the inclusion criteria, the affected hand
will be documented at screening and used for all assessments. In cases where both hands 
are affected by HOA and both meet the inclusion criteria, then the dominant hand will be 
documented at screening and this hand will be used for the MRI assessments throughout 
the study.
WEIGHT
6. Body weight 45 kg.
SEX
7. Male or female subjects are eligible to participate so long as they meet and agree to 
abide by the contraceptive criteria detailed in Appendix 5.
INFORMED CONSENT
8. Written informed consent prior to any of the screening procedures including 
discontinuation of prohibited medications.
OTHER SAFETY-RELATED
9. Diffusing capacity of the lung for carbon monoxide (DLCO) ≥ 70 % predicted and 
forced expiratory volume in 1 second (FEV1) ≥ 80 % predicted.
10. No evidence of active or latent infection with Mycobacterium tuberculosis (TB), as 
defined by all of the following:
a. No history of active or latent TB infection irrespective of treatment status.
 
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b. A negative diagnostic TB test within 28 days of baseline (Day 1) defined as: a 
negative QuantiFERON Gold test or T-spot test (may be performed locally) (NB: 2 
successive indeterminate QuantiFERON tests will be considered as a positive 
result).
Note: If there has been recent close contact with persons who have active TB prior to 
study enrolment the subject will be referred to a TB physician to undergo additional 
evaluation.
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 females.
2. Significant unstable or uncontrolled acute or chronic disease (e.g., cardiovascular 
including uncompensated congestive cardiac failure NYHA III or IV, myocardial 
infarction within 12 months, unstable angina pectoris, uncontrolled hypertension, 
hypercholesterolemia) pulmonary, hematologic, gastrointestinal (including Crohn’s
Disease or ulcerative colitis), hepatic, renal, neurological, psychiatric, malignancy, 
endocrinological, immunologic or infectious diseases, which, in the opinion of the 
investigator, could confound the results of the study or put the subject at undue risk.
3. History of any clinically significant inflammatory disease other than inflammatory 
HOA, especially, but not limited to, rheumatoid arthritis or spondylarthropathies.
4. Diagnosis of rheumatoid arthritis, fibromyalgia, gout, calcium pyrophosphate 
deposition disease CPPD, pseudogout, hemochromatosis or other inflammatory 
rheumatological or autoimmune disorders.
5. Clinical suspicion of, or previous investigation for CPPD or pseudogout, or history of 
chondrocalcinosis.
6. Any injury, medical or surgical procedure to the affected joint(s) that may interfere 
with evaluation of the target HOA joint(s).
7. History of any clinically-significant respiratory disease that required treatment and/or
follow up under the direction of a physician or any respiratory disease which in the 
opinion of the Investigator would compromise the ability of the subject to complete 
the study (e.g. interstitial lung disease, such as pulmonary fibrosis, chronic
obstructive pulmonary disease [COPD], moderate-severe asthma, bronchiectasis,
pneumonitis, pulmonary alveolar proteinosis (PAP), significant exposure to
pneumotoxins (e.g. inhaled silica).
8. Clinically-significant or unstable (in the opinion of the Investigator) persistent cough
or dyspnea that is unexplained.
9. QTc > 450 msec or QTc > 480 msec in subjects with Bundle Branch Block based on 
averaged values of triplicate electrocardiograms obtained over a brief (e.g. 5-10 
minute) recording period

The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method, machine-read or 
 
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manually over-read.
10. ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%). 
11. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
12. A history of malignant neoplasm within the last 10 years or breast cancer within the 
last 20 years, except for non-melanoma skin cancers that have been excised and cured 
or carcinoma in situ of the uterine cervix. 
13. Kidney disease: Current or history of renal disease, or estimated creatinine clearance 
<60 mL/min/1.73m2 or serum creatinine >1.5xULN within 28 days of Day 1.
14. Hereditary or acquired immunodeficiency disorder, including immunoglobulin 
deficiency. 
15. History of infected joint prosthesis at any time, with the prosthesis still in situ.  
History of leg ulcers, catheters, chronic sinusitis or recurrent chest or urinary tract 
infections.
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: 
a. Currently on any suppressive therapy for a chronic infection (such as tuberculosis, 
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical 
mycobacteria).
OR
b. Hospitalization for treatment of infection within 26 weeks of Day 1.
OR
c. Use of parenteral (IV or IM) antimicrobials (antibacterials, antivirals, antifungals, 
or antiparasitic agents) within 26 weeks of Day 1 or oral antimicrobials within 14 
days of Day 1.
17. 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.
18. 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.
19. Contraindication to MRI scanning (as assessed by local MRI safety questionnaire) 
which includes but not limited to:
a.
Intracranial aneurysm clips (except Sugita) or other metallic objects,
b. History of intra-orbital metal fragments that have not been removed by an 
medical professional,
c.
Pacemakers or other implanted cardiac rhythm management devices and non-
MR compatible heart valves,
d. Inner ear implants, except MR-conditional implants scanned within 
manufacturer guidelines,
e.
History of claustrophobia which may impact participation
 
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CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES
20. Use any of prohibited medications, as listed in Section 6.10.2, throughout the study 
until after completion of the week 22 follow-up visit. Prohibited medications must be 
discontinued for the stated time in Section 6.10.2 prior to Day 1.
Note: For patients who need to discontinue prohibited medication > 28 days prior to 
Day 1, written informed consent for the study must be obtained prior to this 
discontinuation, however screening assessments other than consent must still occur 
within the 28 days prior to Day 1.
RELEVANT HABITS
21. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol 
abuse or dependence within a year prior to Day 1.
CONTRAINDICATIONS 
22. History of sensitivity to any of the study treatments, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or GSK 
Medical Monitor, contraindicates their participation.
23. Contraindication to gadolinium contrast agent as assessed by the site.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
24. Must have negative titer rheumatoid factor (RF) and anti-CCP antibody.
25. Any Grade 3 or 4 hematology or clinical chemistry laboratory abnormality [CTCAE, 
2009 v4.0] within 28 days of Day 1.
26. Hemoglobin ≤9 g/dL; white blood cell count ≤3.0 x109/L; platelet count ≤100 X 
109/L; absolute neutrophil count ≤1.5 x 109/L; lymphocyte count ≤0.8 x 109/L within 
28 days of Day 1.
27. Presence of hepatitis B surface antigen (HBsAg) and/or presence of hepatitis B core 
antibody (HBcAb) at screening.
28. Positive hepatitis C antibody test result at screening. Subjects with positive Hepatitis 
C antibody due to prior resolved disease can be enrolled only if a confirmatory 
negative Hepatitis C RNA PCR test is obtained.
29. Positive serology for human immunodeficiency virus (HIV) 1 or 2 (within 28 days of 
Day 1).
30. A positive pre-study drug/alcohol screen.
31. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
32. Exposure to more than 4 investigational medicinal products within 12 months prior to 
the first dosing day.
 
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5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Section 7.4.1.5).
5.3.1.
Re-Screening
If a subject has not met all the eligibility criteria within the 28 day screening period, re-
screening is required.  Subjects are only allowed to be re-screened once; the entire 
screening process must be repeated.
If a blood sample has to be withdrawn due to sample handling problems, breakage or 
sample integrity, this is not considered a re-screening.
Further details regarding the procedure for re-screening may be found in the Study 
Reference Manual (SRM).
5.3.2.
Re-Testing – Laboratory Exclusion
If a subject fails any of the laboratory exclusion criteria, the test may be repeated twice 
within the screening period.  If the subject fails the laboratory criteria for a third time 
they will be considered a screen failure; these subjects may be re-screened as described in 
Section 5.3.1.
If a blood sample has to be withdrawn due to sample handling problems, breakage or 
sample integrity, this is not considered a re-testing.
Further details regarding the procedure for re-testing may be found in the SRM.
5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 
 
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
Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or
administrative reasons. 
In addition, study medications will be discontinued and the subject withdrawn from 
the study in the event of any of the following:

All serious infections. 

Pregnancy.

Confirmed PAP

Severe or serious hypersensitivity reactions, including anaphylaxis.

If the liver chemistry stopping criteria (Section 5.4.1) or QTc stopping criteria 
(Section 5.4.2) are met.

Other serious or severe adverse events, at the discretion of the Investigator, after 
consultation with the GSK Medical Monitor.

Persistent or recurrent hematologic laboratory abnormalities (see Section 5.5.2).
If a subject withdraws from the study, he/she may request destruction of any samples 
taken, and the investigator must document this in the site study records. In each case the 
reason for withdrawal will be recorded in the eCRF.
A subject that is withdrawn early from the study after being randomized to treatment 
cannot be re-screened, but should be encouraged to return for the Early Withdrawal visit.
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
 
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Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2.
5.4.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.4.2.
QTc Stopping Criteria

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  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 Electrocardiogram (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.  
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*
 
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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
5.5.
Treatment withdrawal
Subjects will be permanently withdrawn from study treatment if any of the following 
respiratory symptoms or hematologic abnormalities are seen, investigation will be carried 
out as described below. After withdrawal of treatment under these conditions, where 
possible subjects should remain in the study (off treatment) in order to complete all 
remaining visits/assessments.
5.5.1.
Respiratory Symptoms
Any of the following persistent respiratory symptoms must be reported as an AE and 
require withdrawal of study medications for the remainder of the study and further 
investigation as below:

Persistent reduction in DLCO >15% relative decrease from baseline for three 
consecutive weeks 

Persistent cough (Common terminology criteria [CTC] grade 2 or 3, see Appendix 7) 
for three consecutive weeks

Persistent dyspnea (Borg CR10 scale grade 3 or above, see SRM) for three 
consecutive weeks.
Upon any of these persistent symptoms, it is recommended that the subject be referred to 
a pulmonologist for further assessment.  The subject should be followed until the 
symptoms or signs that caused referral have resolved and/or the diagnosis has been 
determined. Suggested pulmonary assessment and management algorithms are provided 
in Appendix 6.
5.5.2.
Hematologic abnormalities
The following hematological laboratory abnormalities require withdrawal of study 
medications for the remainder of the study and prompt retesting, ideally within 3-5 days:
 
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
White blood cell count <2.0 x 109/L

Absolute neutrophil count <1.0 x 109/L

Lymphocyte count <0.5 x 109/L
Subjects should be followed as appropriate until resolution of the event. Absolute 
neutrophil count <1.0 x 109/L (Grade 3 or greater) should be reported as an AE. 
5.6.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
Treatment with GSK3196165 will be given as a single subcutaneous injection to the 
abdomen or thigh, by an unblinded administrator (shielded to subjects).
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:
GSK3196165
Placebo
Function
Test (investigational product)
Control
Formulation description:
See IB [GSK Document 
Number 2014N190256_00] for 
details.
The placebo in this study will 
be sterile 0.9% (w/v) sodium 
chloride solution.
Dosage form:
Liquid
Liquid
Dosage levels (volumes):
180 mg (1.2mL)
1.2 mL
Route of Administration:
Investigational product should be administered SC into thigh or 
abdomen, sites should be rotated.  Safety should be monitored 
for 1 hour after the injection, for the first 3 injections, then for 30 
minutes thereafter.  Such monitoring will include general safety 
monitoring including monitoring for systemic hypersensitivity 
infusion reactions and local injection site reactions.  Trained 
rescue personnel and rescue medications/equipment must be 
available for use at all times.
 
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Study Treatment
Dosing instructions:
GSK3196165/placebo should be administered on the same day 
each week ± 1 day for the first 5 weekly doses (with a minimum 
of 5 days between doses, for no more than 2 consecutive doses).  
Following this GSK3196165/placebo should be administered on 
the same day every other week ± 3 days (with a minimum of 8 
days between doses).
GSK3196165/placebo will be discontinued as described in 
Section 5.4 and Section 5.5.
Subjects will be randomized as shown in Time and Events Table, 
Section 7.1, and the dosing schedule should be followed as 
closely as possible.
The unblinded administrator (study co-ordinator or nurse) 
assigned to the study will be required to prepare and administer 
the appropriate medication according to the study subject’s 
treatment assignment.  Subjects eligible to enter the study will be 
assigned to treatment randomly through an Interactive Response 
Technology System (IRTS).  Procedures must be in place to 
ensure the blind is maintained by any site staff involved in clinical 
care or assessment of the subject, and by the subject 
themselves. Further details are provided in the SRM.
Every attempt should be made to ensure all doses are 
administered.
If at any time the subject misses a dose, the Medical Monitor 
must be contacted for permission to continue study medication.
Physical description:
Sterile, aqueous solution of 
purified monoclonal antibody 
150 mg/mL
Sterile 0.9% (w/v) sodium 
chloride solution.
Method for individualizing 
dosage:
180 mg (1.2 mL) dose will be 
drawn into a small (e.g. 2 or 3 
mL) syringe and should be 
dosed immediately.
A volume of 1.2 mL will be 
drawn into a small (e.g. 2 or 3 
mL) syringe and should be 
dosed immediately.
6.2.
Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomization 
schedule.
The study will use central randomization and the randomization schedule will be 
generated by Clinical Statistics, prior to the start of the study, using validated internal 
software.  Once a randomization number has been assigned to a subject, it cannot be 
assigned to another subject in the study, even if the original subject withdraws before 
taking study medication.
Randomization numbers will be assigned to subjects using an Interactive Response 
Technology System (IRTS). Information and telephone numbers for the IRTS will be 
provided in the SRM.
 
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Subjects should be randomized and receive their first dose of study medications on the 
same day (Day 1).
6.3.
Planned Dose Adjustments
This protocol uses a fixed dose and no alteration to this dose level is allowed.
6.4.
Blinding
The study will be double-blind (sponsor unblind), which means that the subject, 
investigator and trial staff at site (apart from unblinded administrator(s) and pharmacy 
staff), will be blinded to the trial treatment allocated to each individual subject. In 
addition, the sponsor central and local study teams will be blinded to treatment 
allocations, except for roles required to be ‘unblind’ in order to manage study conduct 
and oversight (including unblinded monitor(s)) and roles specified in the Reporting and 
Analysis Plan (RAP) as involved with the preparation and review of the planned interim 
analyses.
The RAP, which will be approved prior to the first unblinding, will identify the specific 
GSK individuals involved; outline in detail the activities of the interim analyses, and how 
the integrity of the study will be maintained.
At sites, there will be at least one unblinded administrator (study co-ordinator or nurse)
who will prepare and administer the study treatment.
In the case of emergency unblinding (eg. through RAMOS NG or GSK Clinical support 
help desk), the following will apply:

The investigator or treating physician may unblind a subject’s treatment 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject as judged by the 
investigator. 

Investigators have direct access to the subject’s individual study treatment. 

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the subject’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the 
treatment assignment of the unblinded subject, unless that information is 
important for the safety of subjects currently in the study. 

The date and reason for the unblinding must be fully documented in the eCRF 
A subject will be withdrawn if the subject’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the eCRF.
 
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
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind 
the treatment assignment for any subject with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of 
the report, identifying the subject’s treatment assignment, may be sent to 
investigators in accordance with local regulations and/or GSK policy.
6.5.
Packaging and Labelling
The contents of the label for GSK3196165 and placebo will be in accordance with all 
applicable regulatory requirements for clinical supplies.
6.6.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment 
are provided in the SRM. 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case 
of unintentional occupational exposure notify the monitor, Medical Monitor 
and/or GSK study contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.
6.7.
Compliance with Study Treatment Administration
GSK3196165 or placebo will be administered by subcutaneous injection to subjects at the 
site by the unblinded administrator (study co-ordinator or nurse).  The date and time of 
each dose and volume administered in the clinic will be recorded in the eCRF.
6.8.
Treatment of Study Treatment Overdose
6.8.1.
Overdose of GSK3196165
There is very limited clinical safety data at this stage of development.  However there 
have been no reports of overdose with GSK3196165 to date.  The risk of overdose 
 
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occurring is considered low because GSK3196165 will be administered by an 
independent administrator, and the maximum volume that can be withdrawn from the vial 
is equivalent dose to be evaluated (1.2 mL).  No specific treatment is recommended for 
an overdose of GSK3196165, and the investigator should treat as clinically indicated.  
Details (amount of investigational product given and any resulting AEs/SAEs) should be 
recorded in the eCRF.
In the event of an overdose the investigator should:
1. contact the Medical Monitor immediately
2. closely monitor the subject for AEs/SAEs and laboratory abnormalities
3. obtain a serum sample for pharmacokinetic (PK) analysis at the time of the event, 
and three days after the event (unless otherwise requested by the Medical 
Monitor)
4. document the quantity of the excess dose as well as the duration of the overdosing 
in the eCRF.
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 the efficacy of GSK3196165 has not yet been defined. Treatment after the 
end of the study will continue as per the standard of care for HOA at the site.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
6.10.
Concomitant Medications and Non-Drug Therapies
During inflammation, enzymes such as Cytochrome P450 (CYP450) can be down-
regulated leading to instances of reduced clearance and increased plasma concentrations 
of administered drugs.  The administration of GSK3196165 can potentially alter 
circulating cytokine levels in a patient whose cytokine levels have been elevated.  This 
may partially or completely reverse the impact of cytokines on CYP450 enzymes leading 
to changes in the exposure of co-administered drugs whose metabolism is dependent on 
CYP450 enzymes.  The reports so far suggest the magnitude of drug interaction by 
therapeutic proteins (clinically) is generally small (less than two-fold) and therefore only 
likely to be clinically relevant for CYP450 substrates with a narrow therapeutic index, 
where the dose is individually adjusted. 
Upon initiation or discontinuation of GSK3196165, therapeutic drug monitoring should 
be performed in subjects being treated with drugs that are CYP450 substrates and have a 
narrow therapeutic  index  e.g., warfarin or theophylline 
 
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Prescribers should exercise caution when GSK3196165 is co-administered with CYP3A4 
substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, 
lovastatin, atorvastatin, etc.  
The effect of GSK3196165 on CYP450 enzyme activity may persist for several weeks 
after stopping therapy.
6.10.1.
Permitted Medications and Non-Drug Therapies
The only permitted concomitant medication for the duration of this study is Paracetamol 
(acetaminophen) which may be taken on an as needed basis up to 4g/day or to the 
maximum permitted under local label. 
Any use of Paracetamol (acetaminophen) will be recorded as concomitant medication. 
Subjects will record use of Paracetamol (acetaminophen) for hand pain on a daily basis. 
Use of any other concomitant medications by subjects will be assessed during study 
visits.
6.10.2.
Prohibited Medications and Non-Drug Therapies
Use of the medications listed below is prohibited from Day 1 (randomization) until after 
completion of the Week 22 follow-up visit. 
In addition, these prohibited medications must also be discontinued for the stated time 
prior to Day 1 (randomization) as follows:

Hydroxychloroquine must be discontinued at least 3 weeks prior to Day 1.

NSAIDs (both systemic and topical) must be discontinued at least 22 days prior to 
Day 1.

Opioid based analgesics as well as co-formulated medicines of paracetamol and 
opioids must be discontinued at least 22 days prior to Day 1.

Intra-articular corticosteroids for the targeted joints in hand, hip and knee must be 
discontinued at least 12 weeks prior to Day 1.

Intra-articular injection of hyaluronate for the targeted joints in hand, hip and knee 
must be discontinued at least 26 weeks prior to Day 1.

Any investigational medication must be discontinued at least 30 days, 5 half-lives or 
twice the duration of the biological effect of the investigational product, prior to Day 
1 (whichever is longer).

Any physical therapy (including hand splints) must be discontinued at least 28 days 
prior to Day 1

"Nutraceuticals" (e.g. glucosamine and chondroitin) and alternative medicine 
products, unless taken at a stable dose, must be discontinued for a minimum of 12 
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7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1. 
The following points must be noted: 
PROs must be administered prior to any other assessments being performed (at the main 
study site) to avoid influencing subjects. The appropriate order for the PROs and 
approximate time required for completion of each, should be:
Borg CR10 Scale (1 question, approx. 1-2 minutes, see SRM for details)
PtGA (1 question, approx. 1-2 minutes, see Appendix 10)
AUSCAN 3.1 NRS (15 questions, approx. 5-10 minutes, see SRM for details)

Daily pain NRS questionnaire (2 questions, approx. 1-2 minutes, see Appendix 8
and Appendix 9) will be completed by subjects at home, starting on Day 1 of 
screening (although training, including an example pain NRS questionnaire, 
may be given during the Day 1 screening visit at the site). Patients will be 
instructed to complete the pain NRS questionnaire at approximately the same 
time each day (e.g. between 6pm-10pm).

If assessments are scheduled for the same nominal time, THEN the assessments 
should 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, including safety, pharmacokinetic, 
pharmacodynamic/biomarker or others assessments may be altered during the course of 
the study based on newly available data (e.g., to obtain data closer to the time of peak 
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 (IRB)/Independent Ethics Committee (IEC) will 
be informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the Informed Consent Form. 
 
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
No more than 500 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
7.1.1.
Screening period Time and Events table
Subject Screening
(must be carried out 28 days prior to Day 1)
Screening T&E table notes
Screening Day 1
Screening Days 1-7, at home
Screening Day ≥8


Informed Consent
Daily Pain NRS questionnaire2
Pain NRS eligibility assessment3
1) Where possible, the same individual should 
perform all disease assessments for an 
individual subject (with separate joint assessor).
2) Pain NRS questions should be completed at 
approximately the same time each day 
(recommended between 6pm and 10pm).
3) Eligibility assessment will be based on a 7 
day average of the ‘24h average Pain NRS’ 
question.
4) Subjects must have passed all screening 
assessments, including laboratory tests and 7-
day pain NRS assessment, prior to undertaking 
MRI scanning.
Inclusion/exclusion criteria
MRI4
Demographics
Medical/medication/alcohol history
Con. Med. Review
Vital signs
12-lead ECG
Full Physical Exam
Swollen and tender joints1
Haem/Chem/Urinalysis
HIV, TB, Hepatitis B & Hepatitis C screen
RF, ACPA (anti-CCP)
Pregnancy test (serum)
Urine drug / alcohol screen
Spirometry (FEV1, FVC) & DLCO
Pain NRS training
SAE assessment
 
 
 
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7.1.2.
Treatment period Time and Events table
Study events
Screening (≤28 days 
prior to Day 1)
Treatment period
Week 20 phone call 
(Day 141 5d)
Follow up (Week 22
(Day 155 7d)
Treatment period T&E table notes
Week 0
Wk 1
Wk 2
Wk 3
Wk 4
Wk 6
Wk 8
Wk 10
Wk 12
Baseline & Day 
1 treatment visit
Day 3 (1d) PK 
biomarker visit
Day 8 (1d) 
treatment visit
Day 15 (1d) 
treatment visit
Day 22 (1d) 
treatment visit
Day 29 (1d) 
treatment visit
Day 43 (3d) 
treatment visit
Day 57 (3d) 
treatment visit
Day 71 (3d) 
treatment visit
Day 85 (3d) 
treatment visit
Borg CR10 Scale1
See separate T&E table for screening procedures
X
X
X
X
X
X
X
X
X
Site to contact subject by phone and remind them to begin completing the daily 
Pain NRS questionnaire starting 7 days before their Follow-up visit at Week 22
See separate table for follow-up visit procedures
1) Perform PROs before any other 
assessments, or procedures, to 
avoid influencing subject.
2) Where possible, the same 
individual should perform all disease 
assessments for an individual 
subject (with separate joint 
assessor).
3) MRI scanning at week 12 may 
take place on a separate day from 
other assessments and may occur 
on Day 85 (5d).
4) Before dosing (on dosing days).
5) Day 1 immunogenicity sample 
includes anti-GM-CSF auto-antibody 
analysis
6) Consenting subjects only. 
7) Pain NRS questions should be 
completed at approximately the 
same time each day (recommended 
between 6pm and 10pm).
Patient1 and physician global 
assessment2
X
X
X
X
X
AUSCAN 3.1 NRS1
X
X
X
X
X
X
X
X
Brief Physical Exam
X
X
X
X
X
Vital signs
X
X
X
X
X
12-lead ECG
X4
X
Swollen and tender joints2
X
X
X
X
X
X
X
X
MRI3
X3
Haem/Chem/Urinalysis
X
X
X
X
X
X
X
X
PK sampling4
X
X
X
X
X
X
Blood Biomarkers4
X
X
X
X
X
X
X
Urine drug/alcohol
X
X
Study treatment dosing
X
X
X
X
X
X
X
X
Cough, Auscultation, Pulse Oximetry 
X
X
X
X
X
X
X
X
X
Spirometry (FEV1, FVC) & DLCO
X
X
Immunogenicity blood sampling
X5
X
X
X
Pharmacogenetics6
X
Pregnancy test (urine)
X
X
X
X
Post-treatment Interview
X
Daily Pain NRS questions7
<------------------------------------------- X ------------------------------------------->
SAE/AE assessment
<------------------------------------------- X ------------------------------------------->
Con. medication review
<------------------------------------------- X ------------------------------------------->
 
 
 
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7.1.3.
Follow-up visit and early withdrawal* procedures list
Subject Follow-up Visit
Task List
Follow-up T&E table notes
Week 22
(Day 155 7d)

Borg CR10 Scale1
1) Perform PROs before any other assessments, or 
procedures, to avoid influencing subject.
2) Assessment will be based on a 7 day average of 
the Pain NRS questions.
3) Where possible, the same individual should 
perform all disease assessments for an individual 
subject (with separate joint assessor).
4) If scheduling MRI on the same day as the follow 
up visit is not possible, the MRI visit may take place 
on a separate day before the Follow-up visit  but it 
must occur within the same Day 155 7day 
window.
Patient1 and physician global assessment3
Pain NRSassessment2
Vital signs
Full Physical Exam
Swollen and tender joints3
SAE/AE assessment
Con. Med. Review
Pregnancy test (urine)
Haem/Chem/Urinalysis
Immunogenicity
MRI4
PK Sampling
Blood Biomarkers
Cough, Auscultation, Pulse Oximetry
Spirometry (FEV1, FVC) & DLCO
*for early withdrawal, follow Day 85 procedures, then schedule a follow up visit.
 
 
 
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7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the eCRF) will be assessed at 
screening.
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.  
Starting at Screening Day 1, subjects will complete the daily pain NRS questionnaire (2 
questions, approx. 1-2 minutes, see Appendix 8 and Appendix 9), for at least 7 days to 
determine their eligibility to participate in the study.  Subjects will complete their first 
and all subsequent pain NRS questionnaires at home, at approximately the same time 
each day (recommended between 6pm-10pm). Once lab screening results are available 
and after completion of at least 7 consecutive days of pain NRS questionnaires, the 
subject’s eligibility to continue to participate in screening (and progress to MRI scan) 
will be determined. 
Eligibility is based on the ‘24h Average Pain NRS’ question (see Appendix 8), taken over 
7 consecutive days prior to the assessment. The average of the pain intensity scores over 
these 7 days is assessed, and an average of ‘5’ or higher (on the 0-10 NRS), is required in 
order for the subject to be eligible to continue in screening.
If only one hand is affected by HOA and meets the inclusion criteria, the affected hand 
will be documented at screening and used for all assessments. In cases where both hands 
are affected by HOA and both meet the inclusion criteria, then the dominant hand will 
be documented at screening and this hand will be used for all MRI assessments 
throughout the study.
MRI of the affected hand will take place only if the subject has passed all other screening 
assessments, including all lab assessments and the Pain NRS 7-day assessment. MRI will 
be the final screening assessment.
All subjects should continue to complete the daily pain NRS questionnaire until all their 
screening assessments (including MRI) are completed and the final outcome on whether 
they can participate in the study has been determined. If the subject passes screening and 
is able to participate in the study, they should continue to complete their daily pain NRS 
questionnaires until the Week 12 visit has been completed.  A final 7 day period of pain 
NRS questionnaires will then take place in the week prior to the follow-up visit at 
Week 22.
7.3.
Efficacy
Patient Reported Outcomes questionnaires should be completed by subjects before any 
other assessment at a clinic visit, in the order specified at the start of Section 7.
 
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Efficacy assessments will be performed at the time points presented in the Time and 
Events Table (Section 7.1).
Efficacy assessments will include evaluation of hand pain (Pain NRS questionnaire), 
hand function, pain on use and stiffness (AUSCAN 3.1 NRS), disease activity (patient 
and physician global assessment of disease activity, PtGA/PhGA), and number of tender, 
and swollen joints in their hands. For pain efficacy assessments the average pain intensity 
over 7 days prior to the assessment date will be used. This is calculated from collected 
daily pain NRS data over the 7 day period prior to the study visit.
7.3.1.
Subject’s Assessment of Hand Pain, Function, Stiffness, and 
Subject’s / Clinician’s Assessment of Global Disease Activity
The patient reported outcome (PRO) questionnaires (Pain NRS, AUSCAN 3.1 NRS, 
Patient Global Assessment of Disease Activity [PtGA]) will be completed at relevant 
study visits or at home as described in the Time and Events Table (Section 7.1), and the 
data entered into the eCRF.
Pain intensity will be assessed by subjects, at home, using a daily Pain NRS (0-10) 
questionnaire. Subjects will record their ‘average hand pain’ and ‘worst hand pain’ 
intensity over the past 24 hours (see Appendix 8 and Appendix 9), they will also record 
any use of any rescue paracetamol (acetaminophen) for hand pain over the past 24 hours. 
This should take place at approximately the same time each day (recommended between 
6pm-10pm) for the 12-week treatment period of the study. 
Hand function, pain on use and stiffness will be assessed using the AUSCAN Index.  
Patients will complete the AUSCAN 3.1 NRS at study visits. 
A global assessment of disease activity will be completed by subjects and clinicians using 
a Patient Global / Physician Global Assessment of Disease Activity (PtGA/PhGA) item, 
which asks subjects / clinicians to rate the level of disease activity today on an 11-point 
Numeric Rating Scale (NRS, 0-10) with anchors ‘Very well’ and ‘Very Poor’ for the 
PtGA, and anchors ‘None’ and ‘Extremely Active’ for the PhGA.
Joint Assessments
To prevent potential bias because of observed efficacy changes, the Joint Assessor must 
not be the treating physician (PI or sub-investigator) or the unblinded drug administrator. 
The Joint Assessor (or designee) should be a rheumatologist or other skilled arthritis 
assessor and will be responsible only for completing the joint counts.  To ensure 
consistent joint evaluation throughout the trial, individual subjects should preferably be 
evaluated by the same joint assessor for all study visits.
Treating Physician
The Treating Physician (or designee) should be a rheumatologist (or other medically 
qualified physician) and will have access to both safety and efficacy data.  The Treating 
 
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Physician will have access to source documents, laboratory results and eCRFs and will be 
responsible for completing Physician’s Global Assessment of Disease Activity, and 
safety assessments (adverse events, vital signs, concomitant medications, and review of 
laboratory data).
It is essential that assessments completed by the subject and Joint Assessor are made 
before those by the Treating Physician.
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests such as vital signs, physical exams 
and laboratory safety tests may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.4.1.
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. 
7.4.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

AEs will be collected from the start of Study Treatment until the follow-up 
contact (see Section 7.4.1.3), at the time points specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF.

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.
 
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7.4.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”
7.4.1.3.
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 7.4.2) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 4.
7.4.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Section 12.4.3 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 Medical 
dictionary for regulatory activities (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.
7.4.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
 
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Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.4.2.
AEs of Special Interest (AESIs)
Please see Section 4.7.1 for a discussion of potential risks with GSK3196165.  Adverse 
events of special interest include:

Serious infections, including serious respiratory infections and tuberculosis.

Opportunistic infections.

Neutropenia

Respiratory events including
o
Pulmonary alveolar proteinosis (PAP).
o
Persistent (for 3 consecutive weeks) reduction in DLCO >15% 
o
Persistent (for 3 consecutive weeks) cough and/or dyspnea 
o
Non life-threatening pulmonary changes related to surfactant 
accumulation

Hypersensitivity reactions including anaphylaxis.

Injection site reactions
7.4.3.
Pregnancy

Details of all pregnancies in female subjects and female partners of male subjects 
will be collected after the start of dosing and until completion of the follow up 
visit at Week 22. 

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 5.
7.4.4.
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, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
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7.4.5.
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:

First reading should be rejected

Second and third readings should be recorded in the eCRF.
7.4.6.
Electrocardiogram (ECG)

Triplicate 12-lead ECGs will be obtained at each time point during the study using 
an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals (based on averaged QTc values of triplicate 
electrocardiograms obtained over a brief, e.g. 5-10 minute, recording period). 
Refer to Section 5.4.2 for QTc withdrawal criteria and additional QTc readings 
that may be necessary.
7.4.7.
Pulmonary Assessments
Pulmonary assessments are a key aspect of the safety monitoring in this study (refer to 
Section 5.5.1).
The following pulmonary assessments will be performed at the time points presented in 
the Time and Events Table (Section 7.1)

Cough (See Appendix 7).

Borg CR10 Scale (See SRM for details).

Lung auscultation.

Pulse oximetry.

Pulmonary function tests (PFTs - spirometry, gas transfer [DLCO]).
PFTs will be performed by individual sites.  As a general guidance, sites are asked to 
follow the ATS/ERS recommendations for lung function testing [Miller, 2005a; Miller, 
2005b; Macintyre, 2005].  Spirometry should be performed prior to DLCO.  Subjects 
should avoid the following activities prior to undergoing the PFTs:

Smoking within at least 1 hour of testing

Consuming alcohol within 4 hours of testing

Use of bronchodilators within 4 hours of testing

Performing vigorous exercise within 30 minutes of testing

Wearing clothing that substantially restricts full chest and abdominal expansion

Eating a large meal within 2 hours of testing
 
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7.4.8.
Immunogenicity
GSK3196165 is a humanized monoclonal antibody that will be delivered by the 
subcutaneous route and is targeted to bind and neutralize a soluble target, and for these 
reasons, is considered to be a relatively low risk of inducing adverse immune responses 
[FDA, 2014].
Serum samples will be collected and tested for presence of antibodies that bind to 
GSK3196165.  Serum samples for testing anti-GSK3196165 antibodies will be collected 
as described in the Time and Events schedule (Section 7.1).  The actual date and time of 
each blood sample collection will be recorded.  Details of blood sample collection 
(including volume to be collected), processing, storage and shipping procedures are 
provided in the Central Laboratory Manual.
The timing and number of planned immunogenicity samples may be altered during the 
course of the study, based on newly-available data to ensure appropriate safety 
monitoring.  In the event of a hypersensitivity reaction that is either 1) clinically-
significant in the opinion of the investigator, or 2) leads to the subject withdrawing from 
the study, blood samples should be taken from the subject for immunogenicity testing, at 
the time of the event and again 12 weeks after.  For subjects who prematurely withdraw 
from the study, immunogenicity testing will occur at withdrawal and at follow-up 12 
weeks after last dose.
Serum will be tested for the presence of anti-GSK3196165 antibodies using the currently 
approved analytical methodology using a tiered testing schema: screening, confirmation 
and titration steps.  The presence of treatment emergent anti-drug antibodies (ADA) will 
be determined using a GSK3196165 bridging style ADA assay with a bio-analytically 
determined cut point determined during assay validation.  Samples taken after dosing 
with GSK3196165 that have a value at or above the cut-point will be considered 
treatment-emergent ADA-positive.  These ADA positive samples will be further 
evaluated in a confirmatory assay, and confirmed positive samples will be further 
characterized by assessment of titer.  Results of anti-GSK3196165 antibody testing will 
be reported at the end of the study and will include incidence and titer.  The presence or 
absence of antibodies to GSK3196165 in dosed subjects will be analyzed, then 
summarized descriptively and/or graphically presented.
7.4.9.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 2, must be conducted in 
accordance with the Central Laboratory Manual, and Protocol Time and Events Schedule 
(Section 7.1). Laboratory requisition forms must be completed and samples must be 
clearly labelled with the subject number, protocol number, site/centre number, and visit 
date. Details for the preparation and shipment of samples will be provided by the 
laboratory and are detailed in the central laboratory manual. Reference ranges for all 
safety parameters will be provided to the site by the laboratory responsible for the 
assessments.
All study-required laboratory assessments will be performed by a central laboratory.
 
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If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF.
Refer to the Central Laboratory Manual for appropriate processing and handling of 
samples to avoid duplicate and/or additional blood draws.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 2. 
Table 2
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatise
Albumin
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)

Urine pregnancy
Other 
Screening 
Tests

HIV

Hepatitis B surface antigen (HBsAg)

Hepatitis B core antibody (HBcAb)

Hepatitis C (Hep C antibody)

Diagnostic TB test: either QuantiFERON Gold test or T-spot test

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

Serum 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 
5.4.1 and Appendix 2.
2. Local urine testing will be standard for the protocol unless serum testing is 
required by local regulation or ethics committee.
 
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All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 12 weeks after the last dose of study treatment 
should be repeated until the values return to normal or baseline.  If such values do not 
return to normal within a period judged reasonable by the investigator, the etiology 
should be identified and the sponsor notified.
7.5.
Pharmacokinetics
7.5.1.
Blood Sample Collection
Blood samples for pharmacokinetic (PK) analysis of GSK3196165 will be collected at 
the time points indicated in Section 7.1, Time and Events Table.  The actual date and 
time of each blood sample collection will be recorded.  The timing of PK samples may be 
altered and/or PK samples may be obtained at additional time points to ensure thorough 
PK monitoring.  
Collection, processing, storage and shipping procedures are provided in the Central 
Laboratory Manual. 
7.5.2.
Sample Analysis
Serum analysis will be performed under the control of PTS-DMPK/Scinovo, 
GlaxoSmithKline, the details of which will be included in the Central Laboratory 
Manual. Concentrations of GSK3196165 will be determined in serum samples using the 
currently approved bioanalytical methodology. Raw data will be archived at the 
bioanalytical site (detailed in the Central Laboratory Manual).
7.6.
Biomarkers and Imaging
7.6.1.
Magnetic Resonance Imaging
Each subject’s affected hand (corresponding to the affected hand which is determined and 
documented at screening) will be imaged by MRI at screening, week 12 and week 22 (see 
Section 7.1). If a scanning failure occurs at any visit, if feasible a rescan is allowed within 
10 days of the failed scan after consultation and agreement with the GSK medical 
monitor. There will be a minimum of 24 hours between scans where gadolinium contrast 
is used and any rescan will follow local imaging site regulations for repeat gadolinium
administration. The MRI will be used in order to non-invasively quantify the degree of 
inflammation and structural changes within the target joint. 
Each MRI total scan time should not exceed 1 hour. For each subject, MRIs must be 
performed on the same scanner and using the same type of chelated gadolinium contrast 
agent as was used at screening. If scanning cannot occur on the same scanner within the 
visit time window due to hardware failure, an alternate scanner may be used or the time 
window may be extended by 3 days only after consultation and agreement with the GSK 
medical monitor. 
On attendance at the MRI department, subjects will be placed in the scanner and will be 
prepared for intravenous contrast agent administration. The scanning protocol will 
 
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include routine localisers, T1 measurement sequences, dynamic DCE-MRI acquisition, 
structural scans for bone shape analysis, and acquisitions required for OMERACT 
HOAMRIS and RAMRIQ scoring. Additional exploratory MRI endpoints, as detailed in 
the Acquisition Manual, may also be acquired for exploratory purposes.
Details of scanning site training procedures, acceptable gadolinium contrast agents, and 
scanning protocols will be provided in a dedicated Imaging Manual.
All MRI scans will be reported at the site by a radiologist (non-anonymised) for clinical 
abnormalities.
7.6.2.
Novel Biomarkers
With the subject’s consent, blood samples will be collected during this study and may be 
used for the purposes of measuring novel biomarkers to identify factors that may 
influence osteoarthritis disease severity and progression, and/or medically related 
conditions, as well as the biological and clinical responses to GSK3196165. If relevant, 
this approach will be extended to include the identification of biomarkers associated with 
adverse events. 
Blood samples for novel biomarkers will be collected at the time points indicated in 
Section 7.1 and processed to plasma (as summarised below).  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.  
Collection, processing, storage and shipping procedures are provided in the Central 
Laboratory Manual. 
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with osteoarthritis or medically related conditions and/or the action 
of GSK3196165 may be identified by application of techniques including, but not limited 
to: 

Biochemical analysis.

Proteome analysis.

Metabolomic analysis.
All samples will be retained for a maximum of 15 years after the last subject completes 
the trial. 
The results of these biomarker investigations and other exploratory endpoints, may be 
reported separately from the main study report. This will detailed in the reporting and 
analysis plan (RAP).
7.7.
Genetics
Information regarding genetic research is included in Appendix 3.
 
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7.8.
Value Evidence and Outcomes
7.8.1.
Post-treatment Interviews
Post-treatment interviews will be conducted as shown in the Time and Events Table 
(Section 7.1) to explore subjects’ experience with study treatment. Post-treatment 
interviews are qualitative interviews conducted with study subjects to capture subject 
experiences in drug development on completion of participation in a clinical study. 
Interview questions designed to fully assess a subject’s experience with a study 
medication are administered in a semi-structured format by a trained interviewer. Subject 
feedback will be captured in a data collection sheet as well as being audio-taped for 
subsequent transcription and qualitative analysis. The interview technique and questions 
are described in Appendix 12 and training as well as training material references will be 
provided to site personnel who will administer the interviews.
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system. 

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated 
medication dictionary, GSKDrug.  

eCRFs (including queries and audit trails) will be retained by GSK, and copies 
will be sent to the investigator to maintain as the investigator copy.  Subject 
initials will not be collected or transmitted to GSK according to GSK policy.

For this study subject data will be collected in electronic GSK defined case report 
forms (eCRF). For the PRO component, the data will be collected and managed 
on the modality as determined prior to the start of the study.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The primary endpoint of the study is to evaluate the change from baseline in 24h average 
hand pain intensity at Week 6, as measured by daily pain Numerical Rating Scale (NRS) 
(see Appendix 8) averaged over the 7 days prior to assessment visit with GSK3196165 or 
placebo in adult subjects with HOA.
The study will test the null hypothesis that there is no difference between GSK3196165 
and placebo in the change from baseline in the 24h average Pain NRS at Week 6.  The 
alternative hypothesis is there is a difference between GSK3196165 and placebo in the 
change from baseline in the 24h average Pain NRS at Week 6 using a two-sided test.
 
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9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
Using a t-test, a sample size of 20 subjects per arm will detect a minimal significant 
difference over placebo of approximately 2 points in the change from baseline in the 24h 
average Pain NRS at Week 6 of the 12 week treatment period and has approximately 
80% power to detect a difference of 2.7 points assuming an SD = 3 and a 5% significance 
level.  The estimate of variability is based on sample size assumptions from a literature 
review of two studies in knee OA using a pain NRS [Steigerwald; 2012, Afilalo; 2010].
9.2.2.
Sample Size Sensitivity
The power of the study will be affected by changes from the assumed estimate of the SD 
and Table 3 shows the effect on power and the minimally significant difference under 
varying estimates of the SD, and the number of subjects needed for 80% power.
Table 3
Power to Detect a Difference -2.7 points for Change from baseline in 
24h average Pain NRS at 6 Weeks under Varying Estimates of the SD
SD Estimate
Power with 20 
Subjects / arm
Minimal Significant Difference 
with 20 subjects / arm
N / arm for 80% power
2.5
91%
-1.6
15
3
80%
-2
20
3.5
66%
-2.2
28
9.2.3.
Sample Size Re-estimation or Adjustment
No Sample size re-estimation is planned.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Intent to Treat (ITT) population: The ITT population is defined as all subjects who 
were randomised to treatment and who received at least one dose of study treatment. This 
population will be based on the randomised treatment group.
Safety population: The safety population is defined as all subjects who receive at least 
one dose of study treatment. This population will be based on the actual treatment 
received.
Pharmacokinetic (PK) population: The PK population is defined as all subjects who 
are in the ‘Safety’ population and who have at least one valid PK assessment.
9.3.2.
Interim Analysis
An interim analysis will be performed during the study to review the available PK data 
and target engagement biomarkers. The timing of this analysis will coincide with other 
 
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internal decision making across the GSK3196165 project. Unblinded data will be shared 
with members of Clinical Pharmacology Modelling and Simulation (CPMS), Clinical 
Statistics and GSK study team members who have no involvement in the acquisition of 
the data or direct contact with sites. No other members of the GSK study team will be 
unblinded to this data. 
Another formal interim analysis may be conducted on the key safety, primary efficacy 
and key secondary endpoints in this study. The purpose of this interim will be to help 
with decision-making regarding the subsequent clinical development of GSK3196165 for 
OA. The timing of this analysis will be once a minimum of 30 subjects have completed 
day 43 (Week 6). Full details will be provided in the RAP which will be available prior 
to the data being unblinded. Unblinded data will only be shared with selected members 
of the GSK study team. No members of the GSK study team who have involvement in 
the acquisition of the data or who have direct contact with the sites will be unblinded to 
this data.
Recruitment will continue while the interim analyses are being conducted.
For both interim analyses, unblinded summary level data will be available and if required 
anonymised individual data will be available on request. Only the study 
pharmacokineticist or study statistician generating the interim analysis results will be 
unblinded to individual subject treatment allocations.
9.4.
Key Elements of Analysis Plan
Full details of all analyses will be provided in the RAP.
9.4.1.
Primary Analyses
The primary endpoint will be analysed using a repeated measures model (MMRM) 
adjusted for baseline pain score, treatment group, visit and the visit by treatment group 
interaction as fixed effects, patient as a random effect and day within patient 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.  Further 
sensitivity analyses will be conducted to assess the impact of missing data and non-
parametric analyses may be conducted if the normality assumption does not hold.
9.4.2.
Secondary Analyses
Continuous endpoints will be analysed using the same methods as the primary endpoint.
Binary endpoints, e.g. the proportion of subjects that achieve a 30% reduction in the Pain 
NRS score from baseline, will be summarised using counts and proportions in remission 
and analysed using a Generalised Estimating Equation (GEE) model comparing 
GSK3196165 with placebo at each time point.  Subjects with missing Pain NRS scores 
will be considered as non-responders.
 
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9.4.3.
Other Analyses
All safety evaluations will be based on the Safety population.  Clinical interpretation will 
be based upon review and displays of each safety parameter, including adverse events 
(AE), serious adverse events (SAE) and AEs of special interest.  Analyses of AEs by the 
investigator reported relationship to investigational produce will also be performed.
Full details of all summaries and analyses will be included in the RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment 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

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 (and prior to any wash out time needed to discontinue prohibited 
medication).

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.  
 
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
Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK (or designee) monitors will contact the site prior to the start of the study to 
review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK (or designee) will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK (or 
designee) monitor will conduct site closure activities with the investigator or site 
staff, as appropriate, in accordance with applicable regulations including GCP, 
and GSK Standard Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  
 
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
If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with 
the site.
 
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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 randomization codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
 
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11.
REFERENCES
Afilalo M, Etropolski M, Kuperwasswe B, et al.  Efficacy and Safety of Tapentadol 
Extended Release Compared with Oxycodone Controlled Release for the Management of 
Moderate to Severe Chronic Pain related to Osteoarthritis of the Knee. Clin. Drug.
Investig. 2010; 30 (8): 489-505.
Altman RD. Pharmacological therapies for osteoarthritis of the hand. Drug Aging 2010;
27:729-745.
Behrens F, Tak PP, Ostergaard M, et al. MOR103, a human monoclonal antibody to 
granulocyte-macrophage colony-stimulating factor, in the treatment of patients with 
moderate rheumatoid arthritis: results of a Phase Ib/IIa randomised, double-blind, 
placebo-controlled, dose-escalation trial. Ann. Rheum. Dis. 2015 Jun; 74(6):1058-64.
Bell AL, Magill MK, McKane WR. Measurement of colony-stimulating factors in 
synovial fluid: potential clinical value. Rheumatol. Int. 1995; 14:177-82.
Bellamy N, Campell J, Haraoui B et al. Clinimetric properties of the AUSCAN 
Osteoarthritis Hand Index: an evaluation of reliability, validity and responsiveness. 
Osteoarthritis and Cartilage 2002; 10:863-869.
Berenbaum F, Rajzbaum G, Amor B et al. Evidence for GM-CSF receptor expression in 
synovial tissue. An analysis by semi-quantitative polymerase chain reaction on 
rheumatoid arthritis and osteoarthritis synovial biopsies. European Cytokine Network 
1994; 5(1):43-46.
Bijlsma JWJ, Berenbaum F, Lafeber FPJG. Osteoarthritis: an update with relevance of 
clinical practice. The Lancet 2011; 377:2115-2125.
Bondeson J, Blom AB, Wainwright S, Hughes C, Caterson B, van den Berg WB. 
Arthritis Rheum. 2010; 62:647–657.
Bowes MA, Guillard G, Gill E, et al.  Novel quantification of MRI provides a more 
sensitive outcome measure than RAMRIS. [abstract]. Arthritis Rheum. 2014; 66 Issue 
S10 :pages S1-S1402.
Cao Y. Second generation minimal physiologically-based pharmacokinetic model for 
monoclonal antibodies. Journal of Pharmacokinetics & Pharmacodynamics 2013; 40:597-
607.
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.
Chevalier X, Ravaud P, Matheu E, et al. Adalimumab in patients with hand osteoarthritis 
refractory to analgesics and NSAIDs: a randomised, multicentre, double-blind, placebo-
controlled trial. Annals of Rheumatic Disease 2014; 0:1–9. doi:10.1136/annrheumdis-
2014-205348.
 
2017N347456_00


2015N242468_02
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68
Choy EH, Connolly DJ, Rapson N, et al. Pharmacokinetic, pharmacodynamic and 
clinical effects of a humanized IgG1 anti-CD4 monoclonal antibody in the peripheral 
blood and synovial fluid of rheumatoid arthritis patients. Rheumatology (Oxford) 2000;
39:1139-46.
Common Terminology Criteria for Adverse Events (CTCAE), v 4.0, Published: May 28, 
2009.  (v4.03: June 14, 2010) http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf.
Cook AD, Pobjoy J, Sarros S, et al. Granulocyte-macrophage colony-stimulating factor is 
a key mediator in inflammatory and arthritic pain. Ann. Rheum. Dis. 2013 Feb;
72(2):265-70. 
Cook AD, Pobjoy J, Steidl S, et al. Granulocyte-macrophage colony-stimulating factor is 
a key mediator in experimental osteoarthritis pain and disease development. Arthritis 
Res. & Ther. 2012; 14, R199 
Dang PM, Dewas C, Gaudry M, et al. Priming of human neutrophil respiratory burst by 
granulocyte/macrophage colony-stimulating factor (GM-CSF) involves partial 
phosphorylation of p47(phox). J. Biol. Chem. 1999; 274:20704-8.
Farahat MN, Yanni G, Poston R, Panayi GS. Ann. Rheum. Dis. 1993; 52:870–875.
Farrar JT, Troxel AB, Stott C, et al. Validity, reliability, and clinical importance of 
change in a 0-10 numeric rating scale measure of spasticity: A post hoc analysis of a 
randomoized, double-blind placebo-controlled trial. Clinical Therapeutics 2008; 30:974-
985.
Farrar JT, Young JP, Moreaux L, et al. Clinical importance of changes in chronic pain 
intensity measured on an 11-point numerical pain rating scale. Pain 2001; 94:149-158
Fleetwood AJ, Lawrence T, Hamilton JA, Cook AD. Granulocyte-macrophage colony-
stimulating factor (CSF) and macrophage CSF-dependent macrophage phenotypes 
display differences in cytokine profiles and transcription factor activities: implications for 
CSF blockade in inflammation. J. Immunol. 2007; 178,5245-52.
Food and Drug Administration (FDA), Center for Drug Evaluation and Research 
(CDER), Center for Biologics Evaluation and Research (CBER) (2014). Guidance for 
industry: Immunogenicity Assessment for Therapeutic Protein Products. (FDA 
Maryland).
Gasson JC. Molecular physiology of granulocyte-macrophage colony-stimulating factor. 
Blood 1991; 77:1131-45.
Gelber AC. Conventional medical therapy for osteoarthritis: current state of the evidence. 
Current Opinion in Rheumatology, 2015; 27:313-317.
Gomez-Cambronero J, Horn J, Paul CC, Baumann MA. Granulocyte-macrophage 
colony-stimulating factor is a chemoattractant cytokine for human neutrophils: 
 
2017N347456_00


2015N242468_02
CONFIDENTIAL
204851
69
involvement of the ribosomal p70 S6 kinase signaling pathway. J. Immunol. 2003;
171:6846-55.
Gorin MB. Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.
GSK Document Number 2014N190256_00, “GSK3196165 Investigator's Brochure.” 
Investigator's Brochure version 7, 24th November 2014.
GSK Document Number 2014N210890_04, “A Phase IIb, Double-Blind, Placebo-
Controlled, Dose-Adaptive, Study of the Efficacy and Safety of GSK3196165 in 
Combination with Methotrexate Therapy, in Subjects with Active Moderate-Severe 
Rheumatoid Arthritis Despite Treatment with Methotrexate.” Protocol 201755 
amendment 04, 1st May 2015.
GSK Document Number 2015N226819_00,“Supplement to GSK3196165 Investigator's 
Brochure.” Investigator's Brochure version 7, Supplement no. 1, 21st January 2015.
Hamilton JA, Achuthan A. Colony stimulating factors and myeloid cell biology in health 
and disease. Trends Immunol. 2013; 34:81-9.
Hamilton JA, Anderson GP. GM-CSF biology. Growth Factors 2004; 22:225-31.
Haraoui B, Pelletier JP, Cloutier JM, Faure MP, Martel-Pelletier J. Arthritis Rheum. 
1991; 34:153–163.
Hart PH, Vitti GF, Burgess DR, et al. Activation of human monocytes by granulocyte-
macrophage colony-stimulating factor: increased urokinase-type plasminogen activator 
activity. Blood 1991; 77:841-8.
Hatcher RA, Trussell J, Nelson AL, et al, editors. Contraceptive Technology. 20th edition. 
Atlanta, Georgia: Ardent Media, Inc., 2011: 50. Table 3-2.
Haugen, I. K., Østergaard, M., Eshed, I., et al. Iterative development and reliability of the 
OMERACT Hand Osteoarthritis MRI Scoring System. Journal of Rheumatology 2014;
41(2), 386–391.
Haworth C, Brennan FM, Chantry D et al. Expression of granulocyte-macrophage 
colony-stimulating factor in rheumatoid arthritis: regulation by tumor necrosis factor-
alpha. Eur. J. Immunol. 1991; 21(10):2575-9.
Haywood L, McWilliams DF, Pearson CI, et al. Inflammation and angiogenesis in 
osteoarthritis. Arthritis Rheum. 2003; 48:2173–2177.
Iannone F, Lapadula G. The pathophysiology of osteoarthritis. Aging Clin. Exp. Res. 
2003; 15:364–372.
Kloppenburg M, Maheu E, Kraus VB, et al. OARSI clinical trial recommendations: 
design and conduct of clinical trials for hand osteoarthritis. Osteoarthritis and Cartilage 
2015; 23:772-786.
 
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Kortekaas MC, Kwok WY, Reijnierse M, et al. Magnetic Resonance Imaging in Hand 
Osteoarthritis: Intraobserver Reliability and Criterion Validity for Clinical and Structural 
Characteristics. Journal of Rheumatology 2015; 42; 1224-1230.
Kwok WY, Kloppenburg M, Rosendaal FR, et al. Erosive hand osteoarthritis: its 
prevalence and clinical impact in the general population and symptomatic hand 
osteoarthritis. Annals of Rheumatic Disease 2011; 70: 1238-1242.
LeVine AM, Reed JA, Kurak KE, et al. GM-CSF-deficient mice are susceptible 
topulmonary group B streptococcal infection. J. Clin. Invest. 1999; 103:563-9.
Macintyre N, Crapo RO, Viegi G, et al. Standardisation of the single-breath 
determination of carbon monoxide uptake in the lung. Eur. Respir. J. 2005; 26:720-35.
Mantovani A, Sica A, Locati M. New vistas on macrophage differentiation and 
activation. Eur. J. Immunol. 2007; 37:14-6.
Miller MR, Crapo R, Hankinson J, et al. General considerations for lung function testing. 
Eur. Respir. J. 2005a; 26:153-61.
Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur. Respir. J.
2005b; 26:319-38.
Pejovic, M. Determination of the apparent synovial permeability in the knee joint of 
patients suffering from osteoarthritis and rheumatoid arthritis. British Journal of 
Rheumatology 1995; 34:520-524.
Poole JL. Measurement of hand function. Arthritis Care & Research 2011; 63:S189-
S199.
Salaffi F, Stancati A, Silvestri CA, et al. Minimal clinical important changes in chronic 
musculoskeletal pain intensity measured on a numerical rating scale. European Journal of 
Pain 2004; 8:283-291.
Sowers M, Jannausch M, Stein E, Jamadar D, Hochberg M, Lachance L. Osteoarthritis 
Cartilage 2002; 10:595–601.
Spector TD, Hart DJ, Nandra D, Doyle DV, Mackillop N, Gallimore JR, Pepys MB. 
Arthritis Rheum. 1997; 40:723–727.
Stanley E, Lieschke GJ, Grail D, et al. Granulocyte/macrophage colony-stimulating 
factor-deficient mice show no major perturbation of hematopoiesis but develop a 
characteristic pulmonary pathology. Proc. Natl. Acad. Sci. USA 1994; 91:5592-6.
Steidl S, Ratsch O, Brocks B, Durr M, Thomassen-Wolf E.  In vitro affinity maturation of 
human GM-CSF antibodies by targeted CDR-diversification. Molecular Immunology 
2008; 46(1):135-144.   
Steigerwald I, Müller M, Kujawa J, Balblanc J, Calvo-Alén J. Effectiveness and safety of 
tapentadol prolonged release with tapentadol immediate release on-demand for the 
 
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management of severe, chronic osteoarthritis-related knee pain: results of an open label, 
phase 3b study.  Journal of Pain Research 2012; 5:121-138.
Stone AV, Vanderman KS, Willey JS, et al. Osteoarthritis Cartilage 2015; 23(10):1780-9.
Towheed TE. Systematice review of therapies for osteoarthritis of the hand. 
Osteoarthritis and Cartilage 2005; 13:455-462.
 
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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
ACPA
Anti-cyclic citrullinated protein antibody
ACR
American College of Rheumatology
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine transaminase
AMD
Age-related macular degeneration
AST
Aspartate transaminase
ATS
American Thoracic Society
AUC
Area under the curve
AUSCAN
Australian Canadian Hand Osteoarthritis Index
BAL
Bronchoalveolar lavage
βhCG
Beta-subunit human chorionic gonadotropin
BCG
Bacillus Calmette-Guérin
CCP
Cyclic citrullinated peptide
CD4
Cluster of differentiation antigen 4
Cl
Clearance
CL/F
total body clearance from plasma after SC administration
COPD
Chronic obstructive pulmonary disease
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CPMS
Clinical Pharmacology, Modelling and Simulation
CPPD
Calcium pyrophosphate deposition disease
CRF
Case Report Form
CRP
C-reactive protein
CTC
Common terminology criteria
CV
Cardiovascular
CYP450
Cytochrome P450
DAS28
Disease activity score for 28 different joints
DCE-MRI
Dynamic Contrast Enhanced Magnetic Resonance Imaging
DIP
Distal interphalangeal
DLCO
Diffusing capacity of the lung for carbon monoxide
DNA
Deoxyribonucleic acid
DMARD
Disease modifying antirheumatic drugs
ECG
Electrocardiogram
eCRF
Electronic case report form
EDTA
Ethylenediaminetetraacetic acid
ERS
European respiratory society
EULAR
European League against Rheumatism
FEV1
Forced expiratory volume in one second
 
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FRP
Females of reproductive potential
FSH
Follicle-stimulating hormone
FVC
Forced vital capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
Gd
Gadolinium
GFR
Glomerular filtration rate
GM-CSF
Granulocyte-macrophage colony stimulating factor
GM-CSFR
Granulocyte-macrophage colony stimulating factor receptor
GSK
GlaxoSmithKline
h
Hour
HBsAg
Hepatitis B Surface Antigen
HBcAb
Hepatitis B core antibody
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen
HOA
Hand Osteoarthritis
HOAMRIS
Hand Osteoarthritis Magnetic Resonance Imaging Scoring 
System
HRCT
High-resolution computed tomography
HRT
Hormone replacement therapy
HV
Healthy volunteer
IB
Investigator’s brochure
IC50
The half maximal inhibitory concentration
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IL-6
Interleukin 6
IM
Intramuscular
IMP
Investigational medicinal product
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board
IRE
initial rate of enhancement
IRTS
Interactive response technology system
ITT
Intent to Treat
IV
Intravenous
Ka
absoption rate constant
kg
Kilogram
Ktrans
exchange rate
L
Litre
LDH
Lactate dehydrogenase
LFT
Lung function test
mAb
Monoclonal antibody
MCV
Mean cell volume
MCH
Mean corpuscular hemoglobin
ME
maximum signal intensity enhancement
 
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MedDRA
Medical dictionary for regulatory activities
mg
Milligram
mL
Milliliter
MMRM
Mixed model repeated measures
MRI
Magnetic Resonance Imaging
MSDS
Material safety data sheet
NOEL
No observed effect level
NOAEL
No observed adverse effect level
NRS
Numerical Rating Scale
NSAID
Non-steroidal anti-inflammatory drug
NSF
Nephrogenic Systemic Fibrosis
NYHA
New York Heart Association
OA
Osteoarthritis
OMERACT
Outcome Measures in Rheumatology
PAP
Pulmonary alveolar proteinosis
PCR
Polymerase Chain Reaction
PD
Pharmacodynamic
PFT
Pulmonary function test
PIP
Proximal interphalangeal
PtGA
Patient’s Global Assessment
PhGA
Physician’s Global Assessment
PK
Pharmacokinetics
PRO
Patient Reported Outcome
PTS-DMPK
Platform Technologies and Science - Drug Metabolism and 
Pharmacokinetics
QTc
corrected QT interval
QTcB
QT duration corrected for heart rate by Bazett’s formula
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RA
Rheumatoid arthritis
RAMRIQ
Rheumatoid Arthritis Magnetic Resonance Imaging 
Quantitative Score
RAP
Reporting and analysis plan
RANKL
Receptor Activator of Nuclear factor-κB ligand
RF
Rheumatoid factor
RNA
Ribonucleic acid
SC
Subcutaneous
SAE
Serious adverse event
SRM
Study Reference Manual
t½
Elimination half-life
TB
Mycobacterium tuberculosis
TNF
Tumor necrosis factor
TNFα
Tumor necrosis factor alpha
ULN
Upper limit of normal
ve
interstitial volume
vp
plasma volume
Vss/F
total volume of distribution after SC administration
 
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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
AUSCAN
 
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12.2.
Appendix 2 – Liver Safety Required Actions and Follow up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted (refer 
to Section 5.4.1.1.)

If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained within a week after 
last dose5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
 
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treatment and may continue subject in the study 
for any protocol specified follow up assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-72 
hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]). NOTE: not 
required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the 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 normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
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12.3.
Appendix 3 – 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 any treatment regimens under investigation in 
this study or any concomitant medicines;

HOA susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
 
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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 
randomized and provided informed consent for genetic research. Instructions for 
collection and shipping of the genetic sample are described in the laboratory 
manual. The DNA from the blood sample may undergo quality control analyses to 
confirm the integrity of the sample. If there are concerns regarding the quality of 
the sample, then the sample may be destroyed. The blood sample is taken on a 
single occasion unless a duplicate sample is required due to an inability to utilize 
the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
 
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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 analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
 
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12.4.
Appendix 4 – Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

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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condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.4.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfils any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
 
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and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
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

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
 
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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.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
 
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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.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
 
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12.4.6.
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 GSK Medical Monitor.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the GSK 
Medical Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
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12.5.
Appendix 5 – Contraception eligibility criteria for female and 
male subjects
12.5.1.
Males:
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until 12 weeks after the last dose of study medication.
a.
Vasectomy with documentation of azoospermia. The documentation on male 
sterility can come from the site personnel’s: review of subject’s medical records, 
medical examination and/or semen analysis, or medical history interview. 
b. Male condom plus partner use of one of the contraceptive options below that 
meets the SOP effectiveness criteria including a <1% rate of failure per year, as 
stated in the product label:

Contraceptive subdermal implant

Intrauterine device or intrauterine system

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
Male subjects should not donate sperm during the course of the study and should follow 
local guidelines thereafter.
12.5.2.
Females: 
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative serum human chorionic gonadotrophin [βhCG] test), not lactating and at least 
one of the following conditions applies:
a.
Non-reproductive potential defined as:
Pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
 
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
Hysterectomy

Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels).  Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of post-menopausal status prior to study enrolment.
b.
Reproductive potential and agrees to follow one of the options listed in the 
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Section 12.5.3) from 30 days prior to the first 
dose of study medication and until 12 weeks after the last dose of study medication 
and completion of the follow-up visit.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
12.5.3.
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.

Contraceptive subdermal implant

Intrauterine device or intrauterine system

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011])

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]

Male partner sterilization with documentation of azoospermia prior to the 
female subject's entry into the study, and this male is the sole partner for 
that subject [Hatcher, 2011].  The documentation on male sterility can 
come from the site personnel’s: review of subject’s medical records, 
medical examination and/or semen analysis, or medical history interview 
provided by her or her partner.
If using hormonal contraceptives, including oral, injections, implants, and patches, a 
secondary method of contraception must be used.
 
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These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.5.4.
Collection of Pregnancy Information (female subjects)

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating will discontinue 
study medication and be withdrawn from the study.
12.5.5.
Collection of Pregnancy Information (female partners of male 
subjects)

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
and submit it to GSK within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.
 
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12.6.
Appendix 6 – Recommended Pulmonary Assessment 
Algorithms
12.6.1.
Follow-up Algorithms
The following assessment algorithms are recommendations for follow-up  triggered by 
persistent changes in symptoms, spirometry/DLCO, compared with baseline (as detailed in 
Section 5.5.1).  Note: These procedures are recommendations for the treating 
pulmonologist, and are not mandatory study procedures.
Definition
Recommended Follow-up
Symptomatic 
(Moderate to 
Severe)
Present for 3 consecutive 
weeks:

Cough (CTC grade 2 or 3)
OR

Dyspnea (Borg CR10 
Scale grade 3 or above)

History, physical examination, and chest 
X-ray

DLCO measurement
If no clear alternative diagnosis can be made, 
e.g. infection or cardiac failure, then further 
assessment by a local pulmonologist 
(including chest HRCT) is recommended:

If HRCT shows ground glass opacity, and 
no alternative diagnosis, BAL to confirm 
diagnosis e.g. PAP

Repeat chest HRCT 3-6 months later to 
monitor resolution.
Asymptomatic
Present for 3 consecutive 
weeks:

Reduction in DLCO >15% 
relative to baseline value
(NB: A subject’s baseline 
DLCO value will be taken as the 
lowest value obtained from 
the Screening or Day 1 
assessment.)

Repeat spirometry and two further DLCO
(weekly intervals)

If the second or third DLCO returns to a 
normal range (i.e., change from baseline 
≤15%), DLCO should be repeated one 
week later to ensure stability

If DLCO decrease is persistent:
History & physical examination & chest 
X-ray
If no alternative diagnosis e.g. infection 
or cardiac failure, then assessment by 
a pulmonologist and chest HRCT is 
recommended

If HRCT shows ground glass opacity, and 
no alternative diagnosis, BAL to confirm 
diagnosis e.g. PAP

Repeat chest HRCT 3-6 months later to 
monitor resolution.
 
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12.6.2.
Management of Study Medications During Pulmonary 
Assessment
As described above, study medication should be withdrawn for the remainder of the 
study whilst the subject undergoes these additional pulmonary investigations.
12.6.3.
Central Review of Pulmonary Investigations
If a chest HRCT is performed, the HRCT report should be forwarded to GSK and a copy 
of the images may be requested by GSK and centrally reviewed by a third party.
If the subject undergoes a broncho-alveolar lavage (BAL) assessment, the report should 
be forwarded to GSK.  If biopsies are taken during the BAL procedure, the prepared 
histologic slides may be requested by GSK for central review by a third party.
On a case-by-case basis, the reports/images/samples from other pulmonary investigations 
may also be requested by GSK for central review by a third party, and particularly in 
cases where there is a suspicion of PAP.
‘Reactive’ algorithms
• History & physical examination
• GSK3196165 stopped
• Assessment by pulmonologist
• CXR / chest HRCT
• BAL + repeat chest HRCT if indicated
or
Pulmonary safety strategy
Symptomatic 
Cough:  CTC grade 2 or 3, for 3 
consecutive weeks
or 
Dyspnea: Borg scale grade 3  or
greater, for 3 consecutive weeks
Asymptomatic
>15% from
baseline DLCO for 
3 weeks
 
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12.6.4.
Adjudication Process for Suspected Cases of Pulmonary 
Alveolar Proteinosis
There will be an adjudication process for: 1) all events of PAP, 2) all cases suspicious of 
PAP, 3) all events that trigger the pulmonary assessment algorithms where an alternative 
diagnosis cannot be made.  GSK may request additional case information (e.g. medical 
history, imaging data, clinical investigation reports) to assist the adjudication.  
The adjudication process will be performed by external experts who are independent of 
GSK, and will also include independent review of radiological investigations.
 
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12.7.
Appendix 7 – Common Terminology Criteria for Adverse 
Events (CTCAE): Cough
Taken from CTCAE version 4.03 (June 14, 2010): Respiratory, thoracic and mediastinal 
disorders.
Respiratory, thoracic and mediastinal disorders
Grade
Adverse 
Event
1
2
3
Cough
Mild symptoms; non-
prescription 
intervention indicated
Moderate 
symptoms; medical 
intervention indicated; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Definition: A disorder characterized by sudden, often repetitive, spasmodic contraction 
of the thoracic cavity, resulting in violent release of air from the lungs and usually 
accompanied by a distinctive sound.
ADL: activities of daily living
 
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12.8.
Appendix 8 – Average Pain NRS
 
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12.9.
Appendix 9 – Worst Pain NRS
 
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12.10.
Appendix 10 – Patient Global Assessment of Disease 
Activity (PtGA)
 
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12.11.
Appendix 11 – Physician Global Assessment of Disease 
Activity (PhGA)
 
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12.12.
Appendix 12 – Patient Post-Treatment Interview
Title: A multi-centre Phase IIa double-blind, placebo-controlled study to investigate the 
efficacy and safety of GSK3196165 in subjects with inflammatory hand osteoarthritis
Patient Post-Treatment Interview
Instructions for Interviewer:  
1. At the beginning of the interview, please confirm the patient’s study number.
2. Text written in bold is to be read verbatim to each subject. 
3. Text written in [italics] is an instruction to the interviewer.  
4. Probes are to be used as needed to encourage the subject to provide full
responses to each of the questions.  They should be used if the subject gives an 
incomplete or unclear response or explanation with the initial question.
5. Actively listen during the interview and take notes as necessary. 
INTRODUCTION:
Hello, my name is [state first name] and I will be asking you some questions about 
your experience with medications in this study. The interview will be recorded and 
a transcript will be developed. In order to protect your confidentiality, only your 
study number will be included in the transcript. You are free to stop the interview 
at any time if you decide you no longer wish to participate.
The following questions have been developed to provide information on patient 
experiences with medications.  It is important that you give your best answers, so 
please listen carefully to each question before you respond.  
Are you ready to begin? 
[Pause and assess subject readiness to continue] 
I will now turn on the recorder.  Can you confirm that you agree to have this 
interview audio-recorded? [Wait for interviewee to consent; if consent is not provided, 
end the interview.]
This is study number 204851, the date is [state date], and I am interviewing 
participant number [state participant number].
 
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1. Thinking back to when you first entered this study, can you describe the 
symptoms you were experiencing at that time?
[For each symptom mentioned ask:]
1a. [Probe]: When did you first experience [restate symptom]?
Was [restate symptom] constant or did it vary/come and go?
How long did [restate symptom] last?
Please describe the severity of [restate symptom]?
2. Since the beginning of the study, what changes have you experienced?
2a. [Probe]: For example, have you experienced any:
Changes in your symptoms?
New symptoms?
Changes in how you have been feeling?
Changes in your ability to do daily activities (wash, dress, eat, 
household chores)
[For each symptom/change mentioned:]
2b. [Probe]: How did [restate symptom] change? OR You mentioned a new 
symptom –can you please describe [restate symptom] (e.g. 
onset, frequency, severity, duration), OR You mentioned that 
the way you were feeling changed. What was this change like? 
OR You mentioned your ability to do daily activities changed. 
What was this change like?
2c. [Probe]: On a scale of 0 to 10, where 0 is not at all important and 10 is 
extremely important, how important was this change to 
you?What are the reasons you selected X?
2d. [Probe]: [if important] What are the reasons this change was important?
2e. [Probe]: Did you experience any other symptoms or changes since 
starting the study? [Ask follow-up probes 2b through 2d above for 
each symptom / change]
2f. [Probe]: Of the changes you experienced, [read back list of changes], 
which was most important to you?  
2g. [Probe]: What were the reasons it was most important to you?  
2h. [Probe]: Which change was the next most important?  [Have participant 
rank order all remaining symptoms/changes]
[If patient DOES NOT spontaneously mention each of the following symptoms and 
changes- pain in their affected hand(s),stiffness in their affected hand(s), swelling in their 
affected hand(s), ability to do daily activities - ask the relevant questions from questions 
3 - 6.]  
 
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[If patient DOES spontaneously mention pain in their affected hand(s), stiffness in their 
affected hand(s), swelling in their affected hand(s), ability to do daily activities move on 
to question 7.]
3. Since the beginning of the study, did you have any changes in the pain of 
your hand(s)?
3a. [Probe]: What were these changes like?
3b. [Probe]: How important were the changes to you?
3c. [Probe]: [If important] What were the reasons these changes were 
important to you?  
4. Since the beginning of the study, did you have any changes in the stiffness 
of your hand(s)?
4a. [Probe]: What were these changes like?
4b. [Probe]: How important were the changes to you?
4c. [Probe]: [If important] What were the reasons these changes were 
important to you?
5. Since the beginning of the study, did you have any changes in the swelling 
of your hand(s)?
5a. [Probe]: What were these changes like?
5b. [Probe]: How important were the changes to you?
5c. [Probe]: [If important] What were the reasons these changes were 
important to you?
6. Since the beginning of the study, did you have any changes in your ability 
to perform daily activities (for example: washing, dressing, eating, doing 
household chores)
6a. [Probe]: What were these changes like?
6b. [Probe]: How important were the changes to you?
6c. [Probe]: [If important] What were the reasons these changes were 
important to you?
7. Overall, how satisfied or dissatisfied were you with changes in your 
symptoms you may have experienced during treatment in this study?
      [Show the subject the response scale on response scale sheet]
Very 
dissatisfied
Dissatisfied
Not satisfied or 
dissatisfied
Satisfied
Very satisfied
1
2
3
4
5
7a. [Probe]: What were the reasons you selected [restate response]?
 
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8. How does the medication you received in this study compare to medicines 
you have taken in the past for your hand arthritis (hand osteoarthritis)?
8a. [Probe]: Do you prefer the study medication or medications you have 
taken in the past for your hand arthritis (hand osteoarthritis)?
What are the reasons you prefer [insert preferred medication]?
8b. [Probe]: What do you like more about the study medication?  
8c. [Probe]: What do you like more about your past medications?
9. Would you be interested in taking the study medication in the future if it 
were available?
[Show the subject the response scale on response scale sheet]
Not at all 
interested
A little 
interested
Moderately 
interested
Very 
interested
Extremely 
interested
1
2
3
4
5
9a. [Probe]: What about the study medication makes you interested in
continuing to take it?
9b. [Probe]: What about the study medication makes you not interested in 
continuing to take it?  
9c. [Probe]: If there was one thing you could change about the study 
medication, what would it be?  What is the reason you would 
want to make that change?
10. Considering how this study was organized in terms of office visits, lab 
visits, the patient questionnaires, and in-person and phone conversations 
with nurses/doctors, what did you like the best about being in the study?   
10a. [Probe]:What is the reason you liked that best?
10b. [Probe]:What did you like least about being in the study? What is the 
reason you liked that least?
10c. [Probe]:Are there any changes you would suggest for future studies to 
make the experience better for you?
Thank you for your participation in this interview.
[Interviewer:  Turn off recorder]
 
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12.13.
Appendix 13 – Country Specific Requirements
None
 
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12.14.
Appendix 14 – Protocol Amendment Changes
AMENDMENT 01
Where the Amendment Applies
Applicable to all countries and all sites.
Summary of Amendment Changes with Rationale
Correction to contraceptive requirements in Appendix 5, in response to regulatory review 
comments.  Minor correction of question number in post-treatment interview guidance.
List of Specific Changes
Section 12.5.1 Males:
Correction to contraceptive requirements:
ADDED TEXT
Male subjects should not donate sperm during the course of the study and should 
follow local guidelines thereafter.
Section 12.5.3 Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP)
Correction to contraceptive requirements:
ADDED TEXT
If using hormonal contraceptives, including oral, injections, implants, and patches, a 
secondary method of contraception must be used.
Section 12.12 Appendix 12 – Patient Post-Treatment Interview
Minor correction of question number in post-treatment interview guidance Question 2:
PREVIOUS TEXT
[If patient DOES spontaneously mention pain in their affected hand(s), stiffness in their 
affected hand(s), swelling in their affected hand(s), ability to do daily activities move on 
to question 8.]
REVISED TEXT
[If patient DOES spontaneously mention pain in their affected hand(s), stiffness in their 
affected hand(s), swelling in their affected hand(s), ability to do daily activities move on 
to question 7.]
 
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AMENDMENT 02
Where the Amendment Applies
Applicable to all countries and all sites.
Summary of Amendment Changes with Rationale

Amendment of inclusion criteria, #2, #3 and #5, to allow enrolment of subjects who 
are intolerant to analgesics or NSAIDs, and to remove the requirement that the same 
joints must be affected at screening and randomization.

Clarification of exclusion #9 (and Section 7.4.6) to ensure averaged QTc values are 
used throughout study. 

Amendment of exclusion #19(d) to allow enrolment of subjects with MR-conditional 
inner ear implants.

Addition of two planned interim analyses to Section 9.3 and update to planned 
analysis methods in Section 9.4.

Update to Time and Events table in Section 7.1.2 and Section 7.1.3, to increase visit 
Window for Day 3 and to add PK sampling on Day 85 (Week 12 visit) and Day 155 
(Week 22 visit).

Correction to Section 6.10.2 to state that opiate based analgesics must be 
discontinued at least 22 days prior to Day 1.

Update to Section 6.4 (Blinding) to allow unblind sponsor staff during interim 
analyses.

Correction of Section 4.6, Figure 1, to indicate that follow-up takes place at Week 
22.

Clarification in Section 7, that the requirement to complete PROs before any other 
assessments applies to assessments at the main study site.

Update to Section 7.3.1 to clarify which site staff must not be the Joint Assessor.

Clarification of MRI rescan requirements and increase in the allowed MRI rescan 
window from 7 to 10 days, in Section 7.6.1.

Correction of table in Section 12.6.1 to state that the lowest DLCO measurement at 
screening or baseline is used as the reference for any pulmonary safety monitoring.

Correction of “Pulmonary Safety Strategy” diagram in Section 12.6.1, removing 
mention of “MTX”, because this is not used in this study.

Update of primary and secondary medical monitor details.
List of Specific Changes
Amendment of inclusion criteria, #2, #3 and #5, to allow enrolment of 
subjects who are intolerant to analgesics or NSAIDs, and to remove 
 
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the requirement that the same joints must be affected at screening 
and randomisation.
PREVIOUS TEXT
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
2. Meets ACR classification of OA and have not responded to analgesics (level 1 and 2) 
or to NSAIDs for at least 10 days in the past 3 months.
3. Must have active disease at screening and randomization with at least two swollen 
and tender PIP and/or DIP joints in the affected hand*; with the same two joints 
affected at both screening and randomization.
4. Signs of inflammation such as synovitis in the MRI scan of the affected hand*.
5. Must have a patient’s self assessment of 24h average hand pain intensity at baseline
of at least ‘5’ on an 11-point NRS (0-10), calculated as an average using data from 
the 7 days prior to assessment date.
REVISED TEXT
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
2. Meets ACR classification of OA and is intolerant to, or has not responded to 
analgesics (level 1 and 2) or to NSAIDs for at least 10 days in the past 3 months.
3. Must have active disease with at least two swollen and tender PIP and/or DIP joints in 
the affected hand*.
4. Signs of inflammation such as synovitis in the MRI scan of the affected hand*.
5. Must have a patient’s self assessment of 24h average hand pain intensity of at least 
‘5’ on an 11-point NRS (0-10), calculated as an average using data from the 7 days 
prior to assessment date.
Clarification of exclusion #9 (and Section 7.4.6) to ensure averaged 
QTc values are used throughout study.
PREVIOUS TEXT
9. QTc > 450 msec or QTc > 480 msec in subjects with Bundle Branch Block
REVISED TEXT
9. QTc > 450 msec or QTc > 480 msec in subjects with Bundle Branch Block based on 
averaged values of triplicate electrocardiograms obtained over a brief (e.g. 5-10 
minute) recording period
 
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Amendment of exclusion #19(d) to allow enrolment of subjects with 
MR-conditional inner ear implants.
PREVIOUS TEXT
19. Contraindication to MRI scanning (as assessed by local MRI safety questionnaire) 
which includes but not limited to:
d. Inner ear implants
REVISED TEXT
19. Contraindication to MRI scanning (as assessed by local MRI safety questionnaire) 
which includes but not limited to:
d. Inner ear implants, except MR-conditional implants scanned within 
manufacturer guidelines
Addition of two planned interim analyses to Section 9.3 and update to 
planned analysis methods in Section 9.4.
PREVIOUS TEXT
9.3
Data Analysis Considerations
9.3.1 Analysis Populations
Intent to Treat (ITT) population: The ITT population is defined as all subjects who were 
randomised to treatment and who received at least one dose of study treatment.
Pharmacokinetic (PK) population: The PK population is defined as all subjects who were 
randomised to treatment, who received at least one dose of study treatment and who have
at least one valid PK assessment.
9.3.2 Interim Analysis
No interim analyses are planned for this study.
9.4
Key Elements of Analysis Plan
Full details of all analyses will be provided in the RAP.
9.4.1 Primary Analyses
The primary endpoint will be analysed using a repeated measures model (MMRM) 
adjusted for baseline pain score, treatment group, visit and the visit by treatment group 
interaction as fixed effects, patient as a random effect and day within patient 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.  Further 
 
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sensitivity analyses will be conducted to assess the impact of missing data and non-
parametric analyses may be conducted if the normality assumption does not hold.
9.4.2 Secondary Analyses
Continuous endpoints will be analysed using the same methods as the primary endpoint.
Binary endpoints, e.g. the proportion of subjects that achieve a 30% reduction in the Pain 
NRS score from baseline, will be summarised using counts and proportions in remission 
and analysed using a logistic regression analysis adjusted for treatment group and 
baseline Pain NRS score and will be used to test the treatment comparison of 
GSK3196165 versus placebo.  An estimate of the odds ratio, the corresponding p-value 
and 95% confidence interval will be summarised. Subjects with missing Pain NRS 
scores will be considered as non-responders.
REVISED TEXT
9.3
Data Analysis Considerations
9.3.1 Analysis Populations
Intent to Treat (ITT) population: The ITT population is defined as all subjects who were 
randomised to treatment and who received at least one dose of study treatment. This 
population will be based on the randomised treatment group.
Safety population: The safety population is defined as all subjects who receive at 
least one dose of study treatment. This population will be based on the actual 
treatment received.
Pharmacokinetic (PK) population: The PK population is defined as all subjects who are 
in the ‘Safety’ population and who have at least one valid PK assessment.
9.3.2 Interim Analysis
An interim analysis will be performed during the study to review the available PK 
data and target engagement biomarkers.  The timing of this analysis will coincide 
with other internal decision making across the GSK3196165 project.  Unblinded 
data will be shared with members of Clinical Pharmacology Modelling and 
Simulation (CPMS), Clinical Statistics and GSK study team members who have no 
involvement in the acquisition of the data or direct contact with sites.  No other 
members of the GSK study team will be unblinded to this data. 
Another formal interim analysis may be conducted on the key safety, primary 
efficacy and key secondary endpoints in this study.  The purpose of this interim will 
be to help with decision-making regarding the subsequent clinical development of 
GSK3196165 for OA.  The timing of this analysis will be once a minimum of 30 
subjects have completed day 43 (Week 6).  Full details will be provided in the RAP 
which will be available prior to the data being unblinded.  Unblinded data will only 
be shared with selected members of the GSK study team.  No members of the GSK 
 
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study team who have involvement in the acquisition of the data or who have direct 
contact with the sites will be unblinded to this data.
Recruitment will continue while the interim analyses are being conducted.
For both interim analyses, unblinded summary level data will be available and if 
required anonymised individual data will be available on request.  Only the study 
pharmacokineticist or study statistician generating the interim analysis results will 
be unblinded to individual subject treatment allocations.
9.4
Key Elements of Analysis Plan
Full details of all analyses will be provided in the RAP.
9.4.1 Primary Analyses
The primary endpoint will be analysed using a repeated measures model (MMRM) 
adjusted for baseline pain score, treatment group, visit and the visit by treatment group 
interaction as fixed effects, patient as a random effect and day within patient 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.  Further 
sensitivity analyses will be conducted to assess the impact of missing data and non-
parametric analyses may be conducted if the normality assumption does not hold.
9.4.2 Secondary Analyses
Continuous endpoints will be analysed using the same methods as the primary endpoint.
Binary endpoints, e.g. the proportion of subjects that achieve a 30% reduction in the Pain 
NRS score from baseline, will be summarised using counts and proportions in remission 
and analysed using a Generalised Estimating Equation (GEE) model comparing 
GSK3196165 with placebo at each time point.  Subjects with missing Pain NRS scores 
will be considered as non-responders.
Update to Time and Events table in Section 7.1.2 and Section 7.1.3, to 
increase visit Window for Day 3 and to add PK sampling on Day 85 
(Week 12 visit) and Day 155 (Week 22 visit).
ADDED TEXT
Section 7.1.2 Treatment period Time and Events table
Addition of “(1d)” window to Day 3 PK biomarker visit.
Addition of a “X” to “PK sampling” row, on Day 85 treatment visit.
 
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Section 7.1.3 Follow-up visit and early withdrawal* procedures list
Addition of “PK sampling” to Subject Follow-up Visit Task List.
Correction to Section 6.10.2. to state that opiate based analgesics 
must be discontinued at least 22 days prior to Day 1.
PREVIOUS TEXT
6.10.2 Prohibited Medications and Non-Drug Therapies
Use of the medications listed below is prohibited from the start of screening (Screening 
Day 1, see Time and Events table, Section 7.1) until after completion of the Week 22 
follow-up visit. 
In addition, these prohibited medications must also be discontinued for the stated time 
prior to Day 1 as follows:

Hydroxychloroquine must be discontinued at least 3 weeks prior to Day 1.

NSAIDs (both systemic and topical) must be discontinued at least 22 days prior to 
Day 1.

Opioid based analgesics as well as co-formulated medicines of paracetamol and 
opioids must be discontinued at least 12 days prior to Day 1.
REVISED TEXT
6.10.2 Prohibited Medications and Non-Drug Therapies
Use of the medications listed below is prohibited from Day 1 (randomization) until after 
completion of the Week 22 follow-up visit. 
In addition, these prohibited medications must also be discontinued for the stated time 
prior to Day 1 (randomization) as follows:

Hydroxychloroquine must be discontinued at least 3 weeks prior to Day 1.

NSAIDs (both systemic and topical) must be discontinued at least 22 days prior to 
Day 1.

Opioid based analgesics as well as co-formulated medicines of paracetamol and 
opioids must be discontinued at least 22 days prior to Day 1.
Update to Section 6.4 (Blinding) to allow unblind sponsor staff during 
interim analyses.
PREVIOUS TEXT
6.4 Blinding
The study will be double-blind, which means that the investigator and trial staff at site 
(apart from the unblinded administrator [study co-ordinator or nurse]), subject, and 
 
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sponsor personnel (apart from unblinded study monitor) will be blinded to the trial 
treatment allocated to each individual subject. 
There will be an unblinded administrator (study co-ordinator or nurse) who will prepare 
and administer the study treatment.
The following will apply.
REVISED TEXT
6.4 Blinding
The study will be double-blind (sponsor unblind), which means that the subject, 
investigator and trial staff at site (apart from unblinded administrator(s) and 
pharmacy staff), will be blinded to the trial treatment allocated to each individual 
subject. In addition, the sponsor central and local study teams will be blinded to 
treatment allocations, except for roles required to be ‘unblind’ in order to manage 
study conduct and oversight (including unblinded monitor(s)) and roles specified in 
the Reporting and Analysis Plan (RAP) as involved with the preparation and review 
of the planned interim analyses. 
The RAP, which will be approved prior to the first unblinding, will identify the 
specific GSK individuals involved; outline in detail the activities of the interim 
analyses, and how the integrity of the study will be maintained.
At sites, there will be at least one unblinded administrator (study co-ordinator or nurse)
who will prepare and administer the study treatment.
In the case of emergency unblinding (eg. through RAMOS NG or GSK Clinical 
support help desk), the following will apply:
Correction of Section 4.6, Figure 1, to indicate that follow-up takes 
place at Week 22.
PREVIOUS FIGURE
 
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REVISED FIGURE
Clarification in Section 7, that the requirement to complete PROs 
before any other assessments, applies to assessments at the main 
study site.
PREVIOUS TEXT

PROs must be administered prior to any other assessments being performed to 
avoid influencing subjects.
REVISED TEXT

PROs must be administered prior to any other assessments being performed (at 
the main study site) to avoid influencing subjects.
Update to Section 7.3.1. to clarify which site staff must not be the 
Joint Assessor.
PREVIOUS TEXT
Joint Assessments
To prevent potential unblinding because of observed efficacy changes, a “dual assessor”
approach will be used to evaluate efficacy and safety.
REVISED TEXT
Joint Assessments
To prevent potential bias because of observed efficacy changes, the Joint Assessor must 
not be the treating physician (PI or sub-investigator) or the unblinded drug 
administrator.
 
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Clarification of MRI rescan requirements and increase in the allowed 
MRI rescan window from 7 to 10 days, in Section 7.6.1.
PREVIOUS TEXT
Each subject’s affected wrist (corresponding to the affected hand which is determined 
and documented at screening) will be imaged by MRI at screening, week 12 and week 22 
(see Section 7.1). If a scanning failure occurs at any visit, if feasible a rescan is allowed 
within 7 days of the failed scan after consultation and agreement with the GSK medical 
monitor. There will be a minimum of 24 hours between scans where gadolinium contrast 
is used. The MRI will be used in order to non-invasively quantify the degree of 
inflammation and structural changes within the target joint.
REVISED TEXT
Each subject’s affected hand (corresponding to the affected hand which is determined 
and documented at screening) will be imaged by MRI at screening, week 12 and week 22 
(see Section 7.1). If a scanning failure occurs at any visit, if feasible a rescan is allowed 
within 10 days of the failed scan after consultation and agreement with the GSK medical 
monitor. There will be a minimum of 24 hours between scans where gadolinium contrast 
is used and any rescan will follow local imaging site regulations for repeat 
gadolinium administration. The MRI will be used in order to non-invasively quantify 
the degree of inflammation and structural changes within the target joint.
Correction of table in Section 12.6.1. to state that the lowest DLCO
measurement at screening or baseline is used as the reference for 
any pulmonary safety monitoring.
PREVIOUS TEXT
(NB: A subject’s baseline DLCO value will be taken as the highest value obtained 
from the Screening or Day 1 assessment.)
REVISED TEXT
(NB: A subject’s baseline DLCO value will be taken as the lowest value obtained 
from the Screening or Day 1 assessment.)
 
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Correction of “Pulmonary Safety Strategy” diagram in Section 12.6.1, 
removing mention of “MTX”, because this is not used in this study.
PREVIOUS FIGURE
‘Reactive’ algorithms
• History & physical examination
• GSK3196165 (+/- MTX) stopped
• Assessment by pulmonologist
• CXR / chest HRCT
• BAL + repeat chest HRCT if indicated
or
Pulmonary safety strategy
Symptomatic 
Cough:  CTC grade 2 or 3, for 3 
consecutive weeks
or 
Dyspnea: Borg scale grade 3  or
greater, for 3 consecutive weeks
Asymptomatic
>15% from
baseline DLCO for 
3 weeks
 
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REVISED FIGURE
Update of primary and secondary medical monitor details.
PREVIOUS TABLE
Role
Name
Day Time 
Phone Number 
and email 
address
After-hours 
Phone/Cell/
Pager Number
Fax Number
Site Address
Primary 
Medical 
Monitor 
GSK,
Ironbridge Road,
Stockley Park West, 
Uxbridge.
UB11 1BT 
Secondary 
Medical 
Monitor
GSK Medicines 
Research Centre,
Gunnels Wood 
Road, Stevenage, 
Herts. SG1 2NY
‘Reactive’ algorithms
• History & physical examination
• GSK3196165 stopped
• Assessment by pulmonologist
• CXR / chest HRCT
• BAL + repeat chest HRCT if indicated
or
Pulmonary safety strategy
Symptomatic 
Cough:  CTC grade 2 or 3, for 3 
consecutive weeks
or 
Dyspnea: Borg scale grade 3  or
greater, for 3 consecutive weeks
Asymptomatic
>15% from
baseline DLCO for 
3 weeks
 
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REVISED TABLE
Role
Name
Day Time Phone 
Number and 
email address
After-hours 
Phone/Cell/
Pager 
Number
Fax Number
Site Address
Primary 
Medical 
Monitor 
GSK Medicines 
Research Centre,
Gunnels Wood 
Road, Stevenage, 
Herts. SG1 2NY
Secondary 
Medical 
Monitor
GSK,
Ironbridge Road,
Stockley Park 
West, Uxbridge.
UB11 1BT 
 
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PPD

SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
204851 
 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for a multi-centre Phase IIa 
double-blind, placebo-controlled study to investigate the 
efficacy and safety of GSK3196165 in subjects with 
inflammatory hand osteoarthritis. 
Compound Number  
: GSK3196165 
Effective Date  
: 09-FEB-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 204851. 
• 
This RAP is intended to describe the planned efficacy, safety, pharmacokinetic (PK), 
PK/PD and Biomarker analyses required for the study.  
• 
This RAP will be provided to the study team members to convey the content of the 
Interim Analyses and Statistical Analysis Complete (SAC) deliverables. 
 
Author’s Name and Functional Area:  
Approver 
Date 
Approval 
Method 
  
Statistician (Immuno-Inflammation, Clinical 
Statistics) 
NA 
NA 
 
Director Clinical Pharmacology (Immuno-
Inflammation, Clinical Pharmacology 
Modelling and Simulation) 
07-Feb-2018 
eSignature 
 
 
 
 
 
 
 
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CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
204851 
 
 
2 
 
Clinical Statistics and Clinical Programming Line Approvals:  
Approver 
Date 
Approval 
Method 
 
Director, Statistics (Immuno-Inflammation, 
Clinical Statistics) 
09-Feb-2018 
eSignature 
 
Manager, Programming (Immuno-
Inflammation, Clinical Programming) 
08-Feb-2018 
eSignature 
 
RAP Team Approvals:  
Approver 
Date 
Approval 
Method 
Manager, Programming (Immuno-
Inflammation, Clinical Programming) 
08-Feb-2018 
eSignature 
 
Clinical Development Director (Immuno-
Inflammation, Clinical Development) 
08-Feb-2018 
eSignature 
Clinical Development Manager (Immuno-
Inflammation, Clinical Pharmacology Sciences 
and Study Operations) 
08-Feb-2018 
eSignature 
 
Safety Development Lead (Global Clinical 
Safety and Pharmacovigilance) 
07-Feb-2018 
Email 
 
Data Quality Lead (Immuno-inflammation 
Global Clinical Sciences and Operations) 
07-Feb-2018 
eSignature 
 
Copyright 2016 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
 
PPD
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PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL 
 
 
 
204851 
 
3 
 
TABLE OF CONTENTS 
PAGE 
1. 
REPORTING & ANALYSIS PLAN SYNPOSIS ......................................................... 6 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 8 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 8 
2.2. 
Study Objectives and Endpoints ................................................................... 9 
2.3. 
Study Design .............................................................................................. 12 
2.4. 
Statistical Hypotheses................................................................................. 13 
3. 
PLANNED ANALYSES .......................................................................................... 13 
3.1. 
Interim Analyses ......................................................................................... 13 
3.2. 
Final Analyses ............................................................................................ 13 
4. 
ANALYSIS POPULATIONS ................................................................................... 14 
4.1. 
Protocol Deviations ..................................................................................... 15 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 16 
5.1. 
General Considerations .............................................................................. 16 
6. 
STUDY POPULATION ANALYSES ....................................................................... 18 
6.1. 
Overview of Planned Analyses ................................................................... 18 
6.1.1. 
Prior/Concomitant OA Medication ................................................ 18 
7. 
PRIMARY STATISTICAL ANALYSES .................................................................... 19 
7.1. 
Efficacy Analyses ........................................................................................ 19 
7.1.1. 
Overview of Planned Primary Efficacy Analyses .......................... 19 
7.1.2. 
Planned Primary Efficacy Statistical Analyses ............................. 20 
8. 
SECONDARY STATISTICAL ANALYSES ............................................................. 21 
8.1. 
Efficacy Analyses ........................................................................................ 21 
8.1.1. 
Overview of Planned Secondary Efficacy Analyses ..................... 21 
8.1.2. 
Planned Secondary Efficacy Statistical Analyses ......................... 22 
8.1.2.1. 
Continuous Endpoints ................................................ 22 
8.1.2.2. 
Binary Endpoints ........................................................ 23 
8.2. 
Safety Analyses .......................................................................................... 25 
8.2.1. 
Overview of Planned Adverse Event Analyses ............................ 25 
8.2.1.1. 
Adverse Events .......................................................... 25 
8.2.2. 
Overview of Planned Clinical Laboratory Analyses ...................... 27 
8.2.2.1. 
Laboratory Values ...................................................... 27 
8.2.3. 
Overview of Planned Other Safety Analyses ................................ 27 
8.2.3.1. 
ECGs.......................................................................... 28 
8.2.3.2. 
Vital Signs .................................................................. 29 
8.2.3.3. 
Immunogenicity .......................................................... 29 
8.2.3.4. 
Pulmonary Assessments ............................................ 29 
8.2.3.5. 
Cardiovascular Events ................................................ 30 
8.3. 
Pharmacokinetic Analyses .......................................................................... 31 
8.3.1. 
Overview of Planned Pharmacokinetic Analyses ......................... 31 
8.3.2. 
Drug Concentration Measures ..................................................... 31 
8.3.3. 
Population Pharmacokinetic (PopPK) Analyses ........................... 31 


 
CONFIDENTIAL 
 
 
 
204851 
 
4 
 
9. 
OTHER EXPLORATORY STATISTICAL ANALYSES ............................................ 32 
9.1. 
Imaging analyses ........................................................................................ 32 
9.1.1. 
Overview of planned Imaging analyses ........................................ 32 
9.1.2. 
Planned Imaging Statistical Analyses .......................................... 32 
9.2. 
Pharmacokinetic / Pharmacodynamic Analyses .......................................... 33 
9.3. 
Biomarker Analyses .................................................................................... 34 
9.3.1. 
Pharmacodynamic Biomarker Analyses ....................................... 34 
9.3.1.1. 
Overview of Planned Pharmacodynamic 
Biomarker Analyses .................................................... 34 
9.3.2. 
Safety Biomarker Analyses .......................................................... 35 
9.3.2.1. 
Overview of Planned Safety Biomarker 
Analyses ..................................................................... 35 
9.4. 
Analyses on Paracetamol Data ................................................................... 36 
9.4.1. 
Overview of Planned Analyses on Paracetamol Data .................. 36 
10. INTERIM ANALYSES ............................................................................................. 37 
10.1. Overview of planned Week 6 Interim Analysis ............................................ 37 
10.1.1. 
Overview of Study Population Analysis at Week 6 Interim ........... 37 
10.1.2. 
Overview of Safety Analysis at Week 6 Interim ............................ 38 
10.1.3. 
Overview of Planned Efficacy Analysis at Week 6 Interim ............ 38 
10.2. Overview of planned Pharmacokinetic Interim Analysis .............................. 39 
10.3. Overview of Administrative Interim Data Review ......................................... 40 
11. REFERENCES ....................................................................................................... 42 
12. APPENDICES ........................................................................................................ 43 
12.1. Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 44 
12.2. Appendix 2: Time & Events ......................................................................... 45 
12.2.1. 
Protocol Defined Time & Events .................................................. 45 
12.2.1.1. Screening period Time and Events table .................... 45 
12.2.1.2. Treatment period Time and Events table .................... 46 
12.2.1.3. Follow up visit and early withdrawal* 
procedures list ............................................................ 47 
12.3. Appendix 3: Assessment Windows ............................................................. 48 
12.3.1. 
Definitions of Assessment Windows for Analyses ........................ 48 
12.4. Appendix 4: Treatment States and Phases ................................................. 49 
12.4.1. 
Study Phases .............................................................................. 49 
12.4.2. 
Treatment States ......................................................................... 49 
12.4.2.1. Treatment States for AE Data ..................................... 49 
12.5. Appendix 5: Data Display Standards & Handling Conventions .................... 50 
12.5.1. 
Study Treatment & Sub-group Display Descriptors ...................... 50 
12.5.2. 
Baseline Definition & Derivations ................................................. 50 
12.5.2.1. Baseline Definitions .................................................... 50 
12.5.2.2. Derivations and Handling of Missing Baseline 
Data ........................................................................... 51 
12.5.3. 
Reporting Process & Standards ................................................... 51 
12.6. Appendix 6: Derived and Transformed Data ............................................... 54 
12.6.1. 
General ........................................................................................ 54 
12.6.2. 
Study Population .......................................................................... 54 
12.6.3. 
Safety .......................................................................................... 55 
12.6.4. 
Efficacy ........................................................................................ 56 


 
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12.6.5. 
Imaging ........................................................................................ 59 
12.6.6. 
Biomarker .................................................................................... 65 
12.6.6.1. Pharmacodynamic Biomarkers ................................... 65 
12.6.6.2. Safety Biomarkers ...................................................... 66 
12.6.6.3. Biomarker Derivations ................................................ 66 
12.7. Appendix 7: Premature Withdrawals & Handling of Missing Data ............... 67 
12.7.1. 
Premature Withdrawals ................................................................ 67 
12.7.2. 
Handling of Missing Data ............................................................. 67 
12.7.2.1. Handling of Missing and Partial Dates ........................ 68 
12.7.2.2. Handling of Missing Data for Statistical 
Analysis ...................................................................... 68 
12.7.2.3. Handling of Endpoint Specific Missing Data ............... 69 
12.8. Appendix 8: Values of Potential Clinical Importance ................................... 71 
12.8.1. 
Laboratory Values ........................................................................ 71 
12.8.2. 
ECG ............................................................................................. 71 
12.8.3. 
Vital Signs .................................................................................... 72 
12.9. Appendix 9: Multicenter Studies .................................................................. 73 
12.10. Appendix 10: Multiple Comparisons & Multiplicity ....................................... 74 
12.10.1. Handling of Multiple Comparisons & Multiplicity ........................... 74 
12.11. Appendix 11: Model Checking and Diagnostics for Statistical 
Analyses ..................................................................................................... 75 
12.11.1. Statistical Analysis Assumptions .................................................. 75 
12.11.1.1. Continuous Endpoints ................................................ 75 
12.11.1.2. Binary Endpoints ........................................................ 75 
12.12. Appendix 12: Definitions of some Parameters of Interest ............................ 76 
12.12.1. Laboratory Parameters of Interest ............................................... 76 
12.13. Appendix 13: Opportunistic Infections: MedDRA Preferred Terms .............. 78 
12.13.1. Opportunistic Infections: MedDRA Preferred Terms .................... 78 
12.14. Appendix 14 – Abbreviations & Trade Marks .............................................. 86 
12.14.1. Abbreviations ............................................................................... 86 
12.14.2. Trademarks ................................................................................. 88 
12.15. Appendix 15: List of Data Displays.............................................................. 89 
12.15.1. Data Display Numbering .............................................................. 89 
12.15.2. Mock Example Shell Referencing ................................................ 89 
12.15.3. Deliverable [Priority] ..................................................................... 89 
12.15.4. Study Population Tables .............................................................. 90 
12.15.5. Efficacy Tables ............................................................................ 92 
12.15.6. Efficacy Figures ........................................................................... 98 
12.15.7. Safety Tables ............................................................................. 110 
12.15.8. Safety Figures ........................................................................... 115 
12.15.9. Pharmacokinetic Tables ............................................................. 116 
12.15.10. Pharmacokinetic Figures ........................................................... 117 
12.15.11. Pharmacodynamic and / or Biomarker Tables ........................... 118 
12.15.12. Pharmacodynamic and / or Biomarker Figures .......................... 121 
12.15.13. Pharmacokinetic / Pharmacodynamic Figures ........................... 124 
12.15.14. ICH Listings ............................................................................... 125 
12.15.15. Non-ICH Listings ........................................................................ 130 
12.16. Appendix 17: Example Mock Shells for Data Displays .............................. 135 
 


 
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1. 
REPORTING & ANALYSIS PLAN SYNPOSIS 
Overview 
Key Elements of the RAP 
Purpose 
• 
This RAP details all planned analyses and outputs required for the final 
Clinical Study Report (CSR) of study 204851. 
Protocol 
• 
This RAP is based on the protocol amendment 2(Dated:03Jan2017) of study 
204851 (GSK Document No. : 2015N242468_02) 
Primary 
Objective  
• 
To assess the efficacy potential of GSK3196165 on pain in inflammatory 
Hand Osteoarthritis (HOA). 
Primary 
Endpoint 
• 
Change from baseline in 24h average hand pain intensity at Week 6, as 
measured by daily pain Numerical Rating Scale (NRS) averaged over the 7 
days prior to assessment visit. 
Study 
Design 
• 
Randomised Phase IIa, multicentre, double-blind (sponsor unblind), placebo-
controlled parallel group study in patients with active inflammatory HOA. 
• 
At least 40 subjects will be randomised to either placebo or GSK3196165 in 
a 1:1 ratio (n=20 per arm). 
• 
4 week screening period will be followed by a 12 week treatment period 
(dosing with GSK3196165 or placebo), then a follow up period completing on 
week 22. 
• 
Treatment with GSK3196165 or placebo will be given as a single 
subcutaneous injection (shielded to subjects) to the abdomen or thigh, by an 
unblinded administrator weekly for 5 injections, from Week 0 to Week 4 
(Days 1, 8, 15, 22, 29), then every other week for 3 further injections, from 
Week 6 until Week 10 (Days 43, 57 and 71). 
Planned 
Analyses 
• 
Efficacy (Primary Analysis) 
• 
Safety, PK, PK/PD, Biomarkers, Imaging (Secondary/Exploratory analyses) 
Analysis 
Populations 
• Screened population: all subjects who were screened including those who are 
classified as screen failures. 
• Enrolled population: all subjects who passed screening and entered the study. 
• Intent to Treat (ITT) population: all subjects who were randomised to 
treatment and who received at least one dose of study treatment. This 
population will be based on randomised treatment group. 
• Safety population: all subjects who received at least one dose of study 
treatment (GSK3196165 or placebo).This population will be based on the 
treatment actually received. 
• Pharmacokinetic (PK) population: all subjects in the ‘Safety’ population who 
have at least one valid PK assessment. 


 
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Overview 
Key Elements of the RAP 
Hypothesis 
• 
H0: there is no difference between GSK3196165 and placebo in the change 
from baseline in the average Pain NRS Scale at Week 6. 
• 
HA: there is a difference between GSK3196165 and placebo in the change 
from baseline in the average Pain NRS Scale at Week 6. 
Primary 
Analyses 
• 
The primary endpoint will be analysed using a repeated measures model 
(MMRM). 
Secondary 
Analyses 
• 
Continuous endpoints will be analysed using the same methods as the 
primary endpoint. For some endpoints this may be after transformation, if 
applicable. 
• 
Binary endpoints will be summarised using counts and proportions and 
analysed using a Generalised Estimating Equations (GEE) model. 
 


 
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2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
Any changes from the originally planned statistical analysis specified in the protocol 
(GSK Document No. 2015N242468_02, Dated:03JAN2017) are outlined in Table 1. 
Table 1 
Changes to Protocol Defined Analysis Plan 
Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
• Endpoint is defined as 
‘Change from Baseline in 
patient global assessment 
(PtGA) and physician global 
assessment (PhGA) of 
disease activity at Week 6, 12 
and 22’. 
• Endpoint is defined as 
‘Change from Baseline in 
patient global assessment 
(PtGA) and physician global 
assessment (PhGA) of 
disease activity at Weeks 2, 
4, 8 12 and 22’. 
• PtGA and PhGA 
timepoints were 
incorrectly specified in 
the endpoints list on 
pages 11 and 16 of 
protocol, but correct in 
the time and events 
table and elsewhere 
• 
Endpoint is defined as 
‘Change from baseline in 
structural and inflammatory 
HOA features in the affected 
hand (including synovitis, 
bone erosions, joint space 
width, and bone marrow 
edema) as assesses by the 
RAMRIQ scoring system. 
• Endpoint is defined as 
‘Change from baseline in 
structural and inflammatory 
HOA features in the affected 
hand (including synovitis, 
bone erosions, joint space 
width, and bone marrow 
edema) as assesses by the 
HOAMRIQ scoring system. 
• Incorrect scoring 
system is specified in 
the protocol. 
• Administrative Interim Review 
not specified 
• Addition of Administrative 
Interim Review 
• Administrative Interim 
Review was 
requested by II TA 
Head. This was 
requested after the 
protocol amendment 
was created and 
therefore is being 
documented in the 
RAP. The 
administrative interim 
review was approved 
by the MDL on 
18May2017. The 
timing of this interim 
was after unblinding of 
the study at the 
protocol defined PK 
interim. 


 
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Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
• Protocol specifies ‘The 
primary endpoint will be 
analysed using a repeated 
measures model (MMRM) 
adjusted for baseline pain 
score, treatment group, visit 
and the visit by treatment 
group interaction as fixed 
effects, patient as a random 
effect and day within patient 
as a repeated effect, using an 
unstructured covariance 
matrix.’ 
• The MMRM model will also 
be investigated with the 
addition of the baseline*visit 
interaction term and the 
most appropriate model 
selected. 
• Error from protocol 
specified analyses 
 
2.2. 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• To assess the efficacy potential of 
GSK3196165 on pain in 
inflammatory HOA. 
• Change from baseline in 24h average hand pain 
intensity at week 6, as measured by daily pain 
Numerical Rating Scale (NRS) averaged over the 
7 days prior to assessment visit. 
Secondary Objectives 
Secondary Endpoints 
• To evaluate impact of 
GSK3196165 on average and 
worst HOA pain, over time. 
• Change from baseline in 24h average hand pain 
intensity at each visit, measured by daily pain NRS 
and averaged over the 7 days prior to each 
assessment visit.  
• Change from baseline of worst hand pain intensity 
over 24h at each visit, measured by daily NRS and 
averaged over the 7 days prior to each 
assessment visit.  
• Proportion of subjects in each treatment group 
achieving a 30% reduction in 24h average hand 
pain intensity at each visit, measured by daily NRS 
averaged over the 7 days prior to assessment visit. 
• Proportion of subjects in each treatment group 
achieving a 50% reduction in 24h average hand 
pain intensity at each visit, measured by daily NRS 
averaged over the 7 days prior to assessment visit.  
• Proportion of subjects in each treatment group 
achieving a 30% reduction in 24h worst hand pain 
intensity at each visit, measured by daily NRS 
averaged over the 7 days prior to assessment visit. 


 
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Objectives 
Endpoints 
• Proportion of subjects in each treatment group 
achieving a 50% reduction in 24h worst hand pain 
intensity at each visit, measured by daily NRS 
averaged over the 7 days prior to assessment visit. 
• To assess the impact of 
GSK3196165 on hand pain (on 
use), stiffness and function, over 
time. 
• Change from baseline in Australian Canadian 
Hand Osteoarthritis Index (AUSCAN) 3.1 NRS, 
total and domains (pain, morning stiffness, 
function) scores at each visit. 
• To assess the impact of 
GSK3196165 on HOA 
inflammation. 
• Change in number of swollen and tender hand 
joints at each visit. 
• To assess potential impact of 
GSK3196165 on disease activity 
in HOA. 
• Change from baseline in patient global 
assessment (PtGA) and physician global 
assessment (PhGA) of disease activity at Weeks 
2, 4, 8 12 and 22. 
• To assess safety of GSK3196165 
in HOA patients, over the study 
duration. 
• Incidence of adverse events and serious adverse 
events. 
• Incidence of infections. 
• Incidence of pulmonary events (cough/dyspnea, 
PAP and DLCO). 
• Immunogenicty. 
• To assess population 
pharmacokinetics of GSK3196165 
in HOA. 
• Population pharmacokinetics endpoints such as 
CL/F, Vss/F, Ka. 
Exploratory Objectives 
Exploratory Endpoints 
• 
To explore the potential impact of 
GSK3196165 on disease 
progression/modification in HOA, 
using MRI imaging. 
• Change from baseline in synovitis in the affected 
hand*, as measured by DCE-MRI including the 
exchange rate (Ktrans), interstitial volume (ve), 
plasma volume (vp), volume of synovitis, initial rate 
of enhancement (IRE), and maximum signal 
intensity enhancement (ME). 
• Change from baseline in structural and 
inflammatory HOA features in the affected hand* 
(including synovitis, erosive damage, cysts, 
osteophytes, cartilage space loss, malalignment, 
and  bone marrow lesions) as assessed by the 
OMERACT HOAMRIS scoring system 
• Change from baseline in structural and 
inflammatory HOA features in the affected hand* 
(including synovitis, bone erosions, joint space 
width, and bone marrow edema) as assesses by 
the HOAMRIQ scoring system. 
• 
Change from baseline in bone shape as assessed 
by structural MRI of the affected hand*. 


 
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Objectives 
Endpoints 
• 
The exploration of the relationship 
between GSK3196165 PK and PD 
effects and/or efficacy. 
• 
Relationship between concentration or PK 
parameters and PD endpoint(s). 
• 
To evaluate the potential of 
GSK3196165 to affect biomarkers 
of HOA. 
• 
Change in blood biomarkers from baseline at each 
visit. 
* If only one hand is affected by HOA and meets the inclusion criteria, the affected hand 
will be documented at screening and used for all assessments. In cases where both hands 
are affected by HOA and both meet the inclusion criteria, then the dominant hand will be 
documented at screening and this hand will be used for the MRI assessments throughout 
the study. 
 


 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
 
 
Design 
Features 
• Randomised phase IIa, multicentre, double-blind (sponsor unblind), placebo-
controlled, parallel group study in patients with active inflammatory HOA.  
Dosing 
• A screening period of up to 4 weeks. 
• Treatment with GSK3196165 or placebo will be given as a single 
subcutaneous injection (shielded to subjects) to the abdomen or thigh, by an 
unblinded administrator weekly for 5 injections, from Week 0 to Week 4 
(Days 1, 8, 15, 22, 29), then every other week for 3 further injections, from 
Week 6 until Week 10 (Days 43, 57 and 71).   
• In total, each subject will receive up to 8 doses of study treatment. 
Treatment 
Assignment 
• At least 40 subjects will be randomized across the two treatment arms, to 
receive either placebo or GSK3196165 in a 1:1 ratio (n=20 per arm). 
Interim 
Analysis 
• An interim analysis will be performed on available PK and target 
engagement biomarker data to coincide with other internal decision making 
across the GSK3196165 project. 
• Another formal interim analysis may be conducted on the key safety, primary 
efficacy and key secondary endpoints once a minimum of 30 subjects have 
completed day 43 (week 6). 
• In addition to the formal planned interim analyses, further data reviews may 
be carried out by senior managers not involved in the study conduct to aid in 
portfolio and budget decisions. These administrative reviews will have no 
impact on the ongoing study. 
 
Primary endpoint 
pain at week 6
Baseline pain, function, 
tender and swollen 
joints, biomarkers, 
safety and laboratory 
evaluations. 
Efficacy (pain, 
function, imaging) and 
safety at week 12
5 loading doses (Day 1, 8, 15, 22, 29) followed 
by 3 doses every other week (Day 43, 57, 71).
Safety evaluation, 
MRI and Pain at 
week 22
Dosing: GSK 3196165 or Placebo 
(1:1 randomised)
D 43 
(Week 6)
D 85 
(Week 12)
D 155 
(Week 22)
D 1
(Week 0)
Treatment period
• Pain, function, imaging, PK
Follow up period
• Pain, imaging, safety
D 8  
D 15
D 22
D 29
D 57
D 71
Screening
Period
• ACR 
classification, 
MRI, Pain, 
tender and 
swollen joints 
and Safety 
evaluations
D -28


 
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2.4. 
Statistical Hypotheses 
The primary endpoint of the study is to evaluate the change from baseline in the average 
Pain NRS following 6 weeks of treatment with GSK3196165 or placebo in adult subjects 
with HOA. 
The study will test the null hypothesis that there is no difference between GSK3196165 
and placebo in the change from baseline in the 24h average Pain NRS Scale at Week 6.  
The alternative hypothesis is that there is a difference between GSK3196165 and placebo 
in the change from baseline in the 24h Pain NRS Scale at Week 6 using a two-sided test 
(α=0.05). 
 
3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
 An interim analysis will be performed during the study to review the available PK data 
and target engagement biomarkers.  The timing of this analysis will coincide with other 
internal decision making across the GSK3196165 project.   
Another formal interim analysis may be conducted on the key safety, primary efficacy 
and key secondary endpoints in this study.  The purpose of this interim will be to help 
with decision-making regarding the subsequent clinical development of GSK3196165 for 
OA.  The timing of this analysis will be once a minimum of 30 subjects have completed 
day 43 (Week 6).  It is likely that by the time 30 subjects have completed week 6 the 
study would have fully recruited and the interim would not lead to early stopping of this 
study for efficacy. 
In addition to the formal planned interim analyses, further data reviews may be carried 
out by senior managers not involved in the study conduct to aid in portfolio and budget 
decisions. These administrative reviews will have no impact on the ongoing study. 
Full details can be found in Section 10. 
3.2. 
Final Analyses 
The final planned end of study analyses on all endpoints will be performed after the 
completion of the following sequential steps: 
1. All subjects have completed the study as defined in the protocol. 
2. All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management. 
3. All criteria for unblinding the randomisation codes have been met.  
4. Randomisation codes have been distributed according to RandAll NG procedures. 
 


 
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4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened 
• Comprise of all subjects who were screened 
including those subjects who were classified 
as Screen Failures 
• Study Population 
Enrolled 
• 
All participants who passed screening and entered 
the study. Included are: Run-in Failures; 
Randomized Participants; in non-randomized study 
and participants who were assigned a treatment in 
a non-randomised study. 
• 
Note screening failures (who never passed 
screening even if rescreened) and participants 
screened but never enrolled into the study 
(Reserve, Not Used) are excluded from the 
Enrolled population as they did not enter the study. 
• 
Study Population 
Intent-To-Treat 
(ITT) 
• Comprise of all randomised subjects who 
receive at least one dose of study treatment 
(GSK3196165 or placebo). 
• This population will be based on the treatment 
to which the subject was randomised. 
• Any subject who receives a treatment 
randomisation number will be considered to 
have been randomised. 
• Study Population 
• Efficacy 
 
Safety 
• Comprise of all subjects who receive at least 
one dose of study treatment (GSK3196165 or 
placebo). 
• This population will be based on the treatment 
the subject actually received. 
• If a subject consistently received the same 
wrong treatment arm, then this will be 
considered as the actual treatment arm. The 
handling of subjects receiving a wrong 
treatment only for some applications will be 
decided on a case by case basis. 
• Safety 
• PD/Biomarker 
 
Pharmacokinetic 
(PK) 
• Subjects in the ‘Safety’ population for whom a 
pharmacokinetic sample was obtained and 
analysed. 
• PK 
• PK/PD 
NOTES :  
• 
Please refer to Appendix 15: List of Data Displays which details the population to be used for each displays being 
generated. 
 


 
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4.1. 
Protocol Deviations 
Please refer to the Protocol Deviation Management Plan (PDMP): Dated: 30Nov2017 
(Version 3) for full details.  
• 
Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed. 
• 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan. 
o Data will be reviewed prior to unblinding and freezing the database 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 summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the eCRF. 


 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
Table 2 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions.  
Table 2 
Overview of Appendices 
Section Component 
12.1 
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population 
12.2 
Appendix 2: Time & Events 
12.3 
Appendix 3: Assessment Windows 
12.4 
Appendix 4: Treatment States and Phases 
12.5 
Appendix 5: Data Display Standards & Handling Conventions 
12.6 
Appendix 6: Derived and Transformed Data 
12.7 
Appendix 7: Premature Withdrawals & Handling of Missing Data 
12.8 
Appendix 8: Values of Potential Clinical Importance 
12.9 
Appendix 9: Multicentre Studies 
12.10 
Appendix 10: Multiple Comparisons & Multiplicity 
12.11 
Appendix 11: Model Checking and Diagnostics for Statistical Analyses. 
12.12 
Appendix 12: Definition of some Parameters of Interest 
12.13 
Appendix 13: Opportunistic Infections: MedDRA Preferred Terms  
12.14 
Appendix 14: Abbreviations & Trade Marks 
12.1512
.15 
Appendix 15: List of Data Displays 
12.16 
Appendix 16: Example Mock Shells for Data Displays 
 
5.1. 
General Considerations 
• 
This is a multi-centre study and there are no planned adjustments for multiple centres 
or regions. 
• 
There are no planned adjustments for multiple comparisons or multiplicity.  
Unless otherwise stated, the following rules will apply: 
• 
Summaries and displays will present data by treatment group. 
• 
Listings will be sorted by treatment group. 
• The following statistics will be used to summarise the data, unless otherwise 
specified: 


 
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o Continuous Variables: number of observations (n), mean, standard deviation 
(SD), median, minimum and maximum. 
o Categorical Variables: number of observations (n), frequency counts and 
percentages.  
• Summaries by Visit: Only scheduled visits will be presented, unless otherwise stated. 
Scheduled visits will be slotted as shown in section 12.3.1. 
• Unscheduled visits will be listed but will not contribute towards any summary 
statistics/analyses, unless otherwise stated. 
•  For continuous endpoints, no imputation for missing values across visits will be 
done, individual missing item scores contributing to PRO domain scores may be 
imputed as per the rules given within each PRO (see section 12.7.2.3 for full details).. 
• For binary endpoints, subjects with missing values will be considered as non-
responders. 


 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Analyses 
The Study Population analyses will be based on the Screened, Enrolled or Intent-to-Treat 
(ITT) population, as appropriate unless otherwise specified. 
Table 3 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 17: List of Data Displays. 
Table 3 
Overview of Planned Study Population Analyses 
Display Type 
Data Displays Generated 
Table 
Listing 
Randomisation 
Randomised and Actual Treatments 
 
Y 
Subject Disposition 
Subject Disposition 
Y 
 
Screening Status and Reasons for Screening Failures 
Y 
Y 
Subjects by Country and Site ID 
Y 
 
Reasons for Subject Withdrawals 
 
Y 
Subjects for Whom the Treatment Blind was Broken 
 
Y 
Protocol Deviations 
Important protocol deviations 
Y 
Y 
Subjects with Inclusion/Exclusion Criteria Deviations 
 
Y[1] 
Populations Analysed 
Study Populations 
Y 
 
Subjects Excluded from Any Population 
 
Y 
Demographic and Baseline Characteristics 
Demographics Characteristics 
Y 
Y 
Baseline Efficacy Parameters 
Y 
 
Race and Racial Combinations 
Y 
Y[2] 
OA Disease History 
Y 
Y 
Medical Condition & Concomitant Medications 
Current Medical Conditions  
Y 
Y 
Concomitant medication 
Y 
Y 
Concomitant OA medication 
Y 
 
Prior Medication 
Y 
Y 
Prior OA medication 
Y 
 
Exposure &Treatment Compliance 
Exposure to Study Treatment 
Y 
Y 
NOTES : 
• 
Y = Yes display generated. 
• 
[1] Listing also includes analysis population exclusions. 
• 
[2] Listing of race. 
 
6.1.1. 
Prior/Concomitant OA Medication 
OA medications will be identified by the Medical Monitor through review of unique 
terms and indications prior to unblinding. 


 
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7. 
PRIMARY STATISTICAL ANALYSES 
7.1. 
Efficacy Analyses 
7.1.1. 
Overview of Planned Primary Efficacy Analyses 
The Primary Endpoint is defined as the change from baseline in 24h average hand pain 
intensity at week 6, as measured by the daily pain Numerical Rating Scale (NRS) 
averaged over the 7 days prior to assessment visit. 
The primary efficacy analyses will be based on the “Intent-To-Treat” population, unless 
otherwise specified. 
 Table 4 provides an overview of the planned efficacy analyses, with full details of data 
displays being presented in Section 12.15: List of Data Displays. 
Table 4 
Overview of Planned Primary Efficacy Analyses 
 
Endpoint  
Absolute 
Change from Baseline 
Stats Analysis 
Summary 
Individual 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Pain 
24h average hand 
pain NRS score 
averaged over 7 days 
prior to assessment 
Y[2] 
 
Y 
[1,2] 
Y[2] 
Y[2] 
Y 
Y 
Y 
Y 
Y 
[1] 
Y 
Y 
 
Y 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
• 
[1] Raw SAS log output from analysis 
• 
[2] Absolute values will be displayed in the same outputs as the change from baseline. 
 


 
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7.1.2. 
Planned Primary Efficacy Statistical Analyses 
Primary Statistical Analyses 
Endpoint(s) 
• Change from baseline in 24h average hand pain intensity at week 6, as measured by daily pain 
Numerical Rating Scale (NRS) averaged over the 7 days prior to assessment visit. 
Model Specification 
• Endpoints will be statistically analysed using a mixed model repeated measures (MMRM) 
model.  
• The model will be fitted using an unstructured covariance matrix. 
• Terms fitted in the MMRM model will include: 
 
Fixed Categorical 
: Treatment group, Visit, Treatment group * Visit Interaction 
 
Fixed Continuous Covariates 
Random Covariates 
: Baseline pain score # 
: Subject 
 
Repeated 
: Visit 
 
# A model will also be explored fitting Baseline*Visit & the most appropriate model selected. 
 
Model Checking & Diagnostics 
• Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• Point estimates and corresponding 95% confidence intervals will be constructed for the 
treatment differences (GSK3196165-Placebo) at each visit, using the least squared (LS) 
means obtained from the repeated measures mixed-effects model. 
• Plots of LS means and 95% confidence intervals from the model will be generated for each 
treatment group by time. 
 
Sensitivity and Supportive Statistical Analyses 
• Following review of the data, additional analyses maybe conducted to further support the 
primary statistical analyses, if deemed appropriate. 
• Non-parametric analyses may be conducted if the normality assumption does not hold. 
• Analyses using different covariance structures may be explored if the unstructured covariance 
matrix does not converge. The first covariance structures to be tested will be compound 
symmetry (CS) and then first order autoregressive (AR(1)). 
• Sensitivity analyses maybe conducted to assess the impact of missing data. 
• Further sensitivity analyses may be conducted to assess the impact of rescue medication use: 
• E.g. The impact of imputing all 24h average pain scores to be the 24h worst pain score on 
days in which paracetamol was used (any dose) may be assessed. 
• Further sensitivity analyses may be conducted excluding any subjects taking prohibited 
medications throughout the study. 
•  
 
 


 
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8. 
SECONDARY STATISTICAL ANALYSES 
8.1. 
Efficacy Analyses 
8.1.1. 
Overview of Planned Secondary Efficacy Analyses 
The secondary efficacy analyses will be based on the “Intent-To-Treat” population, 
unless otherwise specified. 
Table 5 provides an overview of the planned efficacy analyses, with further details of 
data displays being presented in Appendix 17: List of Data Displays. 
Table 5 
Overview of Planned Efficacy Analyses 
Endpoint  
Absolute 
Change from Baseline 
Stats Analysis 
Summary Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
24h average hand pain NRS score  
Proportion of 
subjects achieving a  
30% reduction in 24h 
average hand pain 
NRS score averaged 
over 7 days prior to 
assessment  
Y 
[2] 
 
Y 
[1] 
Y 
[2] 
Y 
 
Y 
 
 
 
 
 
 
 
Proportion of 
subjects achieving a  
50% reduction in 24h 
average hand pain 
NRS score averaged 
over 7 days prior to 
assessment  
Y 
[2] 
 
Y 
[1] 
Y 
[2] 
Y 
 
Y 
 
 
 
 
 
 
 
Daily 24h average 
hand pain NRS 
 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
24h worst hand pain NRS score 
24h worst pain NRS 
score averaged over 
7 days prior to 
assessment 
Y[
3] 
 
Y 
[1,3] 
Y 
[3] 
Y 
[3] 
Y 
Y 
Y 
Y 
Y[1] 
 
Y 
 
Y 
 
Y 
Daily 24h worst hand 
pain NRS 
 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
Proportion of 
subjects achieving a  
30% reduction in 24h 
worst pain NRS 
score averaged over 
7 days prior to 
assessment 
Y 
[2] 
 
Y 
[1] 
Y 
[2] 
Y 
 
Y 
 
 
 
 
 
 
 
Proportion of 
subjects achieving a  
50% reduction in 24h 
worst pain NRS 
Y 
[2] 
 
Y 
[1] 
Y 
[2] 
Y 
 
Y 
 
 
 
 
 
 
 


 
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Endpoint  
Absolute 
Change from Baseline 
Stats Analysis 
Summary Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
score averaged over 
7 days prior to 
assessment 
AUSCAN 
AUSCAN 3.1 NRS 
Components 
Y 
[3] 
 
Y 
[1,3] 
Y 
[3] 
Y 
[3] 
Y  
Y  
Y  
Y 
Y 
[1] 
Y 
 
Y 
 
 
Y  
Joint Assessments 
Swollen hand joints 
Y 
[3] 
 
Y[1,3] Y 
[3] 
Y 
[3] 
 
Y  
Y  
Y  
Y[1] 
  
Y 
 
Y 
 
 
Y 
 
Tender hand joints 
Y[
3] 
 
Y[1,3] Y 
[3] 
Y 
[3] 
 
Y  
Y  
Y  
Y[1] 
Y 
 
Y 
 
 
Y 
 
Pain/Tenderness 
Hand Joint 
Assessment 
 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
Disease Global Assessment 
PhGA 
Y 
[3] 
 
Y[1,3] Y 
[3] 
Y 
[3] 
 
Y  
Y  
Y  
Y[1] 
Y 
Y 
 
Y 
PtGA 
Y[
3] 
 
Y[1,3] Y 
[3] 
Y 
[3] 
 
Y  
Y  
Y  
Y[1]  Y 
Y 
 
Y 
NOTES : 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
Individual = Represents FL related to any displays of individual subject observed raw data. 
[1] Raw SAS log output from analysis. 
[2] Summaries and analysis will be presented together in one output. 
[3] Absolute values will be displayed in the same outputs as the change from baseline. 
 
8.1.2. 
Planned Secondary Efficacy Statistical Analyses 
8.1.2.1. 
Continuous Endpoints 
Secondary Statistical Analyses 
Endpoint(s) 
• Change from baseline in 24h average hand pain intensity at each visit, measured by daily pain 
NRS and averaged over the 7 days prior to each assessment visit.  
• Change from baseline of worst hand pain intensity over 24h at each visit, measured by daily 
NRS and averaged over the 7 days prior to each assessment visit.  
• Change from baseline in Australian Canadian Hand Osteoarthritis Index (AUSCAN) 3.1 NRS, 
total and domains (pain, morning stiffness, function) scores at each visit. 
• Change from baseline in number of swollen and tender hand joints at each visit. 
• Change from baseline in patient global assessment (PtGA) and physician global assessment 
(PhGA) of disease activity at Weeks 2, 4, 8, 12 and 22. 
Model Specification 


 
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Secondary Statistical Analyses 
• Continuous endpoints will be statistically analysed using the same methods as the primary 
endpoint (MMRM). See Section 7.1.2 for full details. 
Model Checking & Diagnostics 
• Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• Continuous endpoints will be presented using the same methods as the primary endpoint. 
 
Sensitivity and Supportive Statistical Analyses 
• Non-parametric analyses may be conducted if the normality assumption does not hold. 
• Analyses using different covariance structures may be explored if the unstructured covariance 
matrix does not converge. The first covariance structures to be tested will be compound 
symmetry and then first order autoregressive (AR(1)).  
• Further sensitivity analyses may be conducted to assess the impact of missing data. 
• Further sensitivity analyses may be conducted to assess the impact of rescue medication use: 
o E.g. The impact of imputing all 24h average pain scores to be the 24h worst pain score 
on days in which paracetamol was used (any dose) may be assessed. 
• Further sensitivity analyses may be conducted excluding any subjects taking prohibited 
medications throughout the study. 
 
 
8.1.2.2. 
Binary Endpoints 
Secondary Statistical Analyses 
Endpoint(s) 
• Proportion of subjects in each treatment group achieving a 30% reduction in 24h average hand 
pain intensity at each visit, measured by daily NRS averaged over the 7 days prior to 
assessment visit. 
• Proportion of subjects in each treatment group achieving a 50% reduction in 24h average hand 
pain intensity at each visit, measured by daily NRS averaged over the 7 days prior to 
assessment visit.  
• Proportion of subjects in each treatment group achieving a 30% reduction in 24h worst hand 
pain intensity at each visit, measured by daily NRS averaged over the 7 days prior to 
assessment visit. 
• Proportion of subjects in each treatment group achieving a 50% reduction in 24h worst hand 
pain intensity at each visit, measured by daily NRS averaged over the 7 days prior to 
assessment visit. 
Model Specification 
• Binary efficacy endpoints will be statistically analysed using a Generalised Estimating 
Equations (GEE) model, which will be used to test the treatment comparison of GSK3196165 
versus placebo, accounting for the within-subject correlation of outcomes across the multiple 
visits.  


 
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Secondary Statistical Analyses 
• The model will be fitted using an unstructured covariance structure of the correlated 
responses. 
• Terms fitted in the GEE model will include: 
 
Fixed Categorical 
: Treatment group, Visit, Treatment group * Visit Interaction, 
Respective Baseline NRS score 
 
Repeated 
: Visit 
Model Checking & Diagnostics 
• Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• The Binary endpoints will be summarised using counts and proportions of subjects achieving a 
response by treatment group. 
• Differences in the proportions of subjects achieving response between active and placebo will 
be summarised at each visit. 95% CI for the differences will be constructed using their asymptotic 
standard errors (asymptotic Wald confidence limits) without continuity correction. 
• Point estimates and corresponding 95% confidence intervals will be constructed using 
contrasts for the treatment by day interactions. 
• Plots of the point estimates and 95% confidence intervals from the model will be generated for 
each treatment group by time. 
 
Sensitivity and Supportive Statistical Analyses 
• 
Analyses using different covariance structures may be explored if considered appropriate. 
• 
Further sensitivity analyses may be conducted excluding any subjects taking prohibited 
medications throughout the study. 
 
 


 
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8.2. 
Safety Analyses 
8.2.1. 
Overview of Planned Adverse Event Analyses 
The Adverse Event analyses will be based on the “Safety” population, unless otherwise 
specified. 
Table 6 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 16: List of Data Displays. 
Table 6 
Overview of Planned Safety Analyses 
Endpoint  
Absolute 
Summary 
Individual 
T 
F 
F 
L 
Adverse Events (AEs) 
AE’s (Overview)  
Y 
 
 
 
All AE’s  
Y 
 
 
Y 
Common (>=5%) AE’s  
Y 
Y[1] 
 
 
All Drug-Related AE’s 
Y 
 
 
 
Subjects & No. Of Occurrences of Common (>=5%) 
Non-Serious AE’s 
Y 
 
 
 
Subject Numbers for Individual AE’s 
 
 
 
Y 
Relationship between AE SOC, PT and Verbatim 
Text 
 
 
 
Y 
Serious and Other Significant AE’s 
 
Serious AE’s  
Y 
 
 
 
Fatal Serious AE’s 
 
 
 
Y 
Non-Fatal Serious AE’s 
 
 
 
Y 
Reasons for Considering as a Serious AE 
 
 
 
Y 
AE’s leading to permanent discontinuation of study 
treatment/ withdrawal 
Y 
 
 
Y 
AESI’s 
Y 
 
 
Y 
AESI’s – Injection site reactions 
Y 
 
 
 
AESI’s – Systemic Hypersensitivity Reactions 
Y 
 
 
 
NOTES: 
• 
T=Table, F=Figure, L=Listing, Y=Yes display generated. 
• 
Summary= Represents TFL related to any summaries (i.e. descriptive statistics) of the 
observed raw data. 
• 
Individual= Represents FL related to any displays of individual subject observed raw data. 
[1] Plot of common AEs and Relative Risk will be generated. 
 
8.2.1.1. 
Adverse Events 
• Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) in the latest available version.   
• Adverse events of special interest (AESI) will be derived using Common 
Terminology Criteria for Adverse Events, 2009 v4.0 (CTCAE) and will include: 


 
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AESI 
Programmatical Derivation 
Serious infections, including serious 
respiratory infections. 
 
SAEs, Filter on infections SOC. Also 
include HLT Respiratory Infections which 
will be derived from the Respiratory SOC.  
 
Opportunistic infections including 
TB reactivation 
Opportunistic infections will be adjudicated 
by the SRT, using the  preferred terms list 
given in Section 12.13.  Final adjudication 
conducted by SRT. 
Neutropenia 
Based on Grade 3 or 4 absolute neutrophil 
count 
  
PAP (Pulmonary alveolar 
proteinosis) 
Derived using PAP PT. 
Hypersensitivity reactions, including 
anaphylaxis 
Hypersensitivity reactions will be 
adjudicated by the SRT, using AE data and 
data from hypersensitivity reactions eCRF 
page.  Final adjudication conducted by SRT. 
Injection site reactions 
Derived from PT. 
 
• 
AEs with missing intensity will be considered severe.  
• 
Common AEs will be defined as those reported by ≥ 5% of the subjects in either 
treatment group, with the threshold applied before any rounding. 
• 
AEs with partial or missing start and/or stop dates will be assumed to be treatment-
emergent unless there is evidence through comparison of partial dates to suggest 
otherwise. 
• 
AEs will be summarised and sorted by system organ class (SOC) and preferred term 
(PT), unless otherwise specified. Tables will be sorted by overall decreasing 
frequency of the SOC and then decreasing frequency of PT within the AE. 
• 
Summaries will provide the number and percentage of subjects reporting at least one 
AE and the total number of events reported.   
 
 


 
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8.2.2. 
Overview of Planned Clinical Laboratory Analyses 
The Clinical Laboratory analyses will be based on the “Safety” population, unless 
otherwise specified. 
Table 7 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 16: List of Data Displays. 
Table 7 
Overview of Planned Clinical Laboratory Analyses 
Endpoint / Parameter/ Display Type 
Absolute 
Change from BL 
Summary 
Individual 
Summary 
Individual 
T 
F 
L 
T 
F 
L 
Labs 
Clinical Chemistry 
 
  
 
Y 
 
 
Haematology 
 
 
 
Y 
 
 
Urinalysis 
 
 
 
Y 
 
 
Proportion of Subjects with Urinalysis findings 
 
 
 
Y 
 
 
Lab Parameters of Interest by CTCAE Grade 
 
 
 
Y 
Y 
 
Shift of Lab Parameters of Interest from Baseline to 
Worst CTCAE Grade 
Y 
 
 
 
 
 
All Lab Data for Subjects with any value of PCI 
 
 
Y 
 
 
 
Lab Values of PCI 
 
 
Y 
 
 
 
Lab Data with Character Results 
 
 
Y 
 
 
 
Urinalysis Data for Subjects with any value if PCI 
 
 
Y 
 
 
 
NOTES: 
• 
T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.  
 
8.2.2.1. 
Laboratory Values 
• 
Refer to Appendix 6 for handling of laboratory values that are above or below the 
lower limit of quantification.   
 
8.2.3. 
Overview of Planned Other Safety Analyses 
The safety analyses will be based on the “Safety” population, unless otherwise specified. 
Table 8 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 17: List of Data Displays. 


 
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Table 8 
Overview of Planned Other Safety Analyses 
Endpoint / Parameter/ Display Type 
Absolute 
Change from BL 
Summary 
Individual Summary 
Individual 
T 
F 
L 
F 
T 
F 
L 
ECG 
ECG Findings  
Y 
 
 
 
 
 
 
ECG Values  
 
 
 
 
Y 
Y 
 
Maximum QTc Values Post-Baseline 
Y 
 
 
 
 
 
 
All ECG Values for Subjects with a Value of PCI 
 
 
Y 
 
 
 
 
ECG Values of PCI 
 
 
Y 
 
 
 
 
Abnormal ECG Findings 
 
 
Y 
 
 
 
 
Subjects meeting QTc discontinuation criteria 
 
 
Y 
 
 
 
 
Vital Signs 
Vital Signs 
 
 
Y 
 
Y 
 
 
Vital Signs of PCI 
 
 
Y 
 
 
 
 
All Vital Signs for Subjects with Values of PCI 
 
 
Y 
 
 
 
 
Immunogenicity 
Immunogenicity Results 
Y 
 
Y 
 
 
 
 
Pulmonary Assessments 
Subjects with Pulmonary Findings 
Y 
 
 
 
 
 
 
Persistent Cough, Dyspnea and DLCO Decrease 
Y 
 
 
 
 
 
 
Pulse Oximetry 
Y 
 
Y 
 
Y 
 
 
DLCO 
 
 
Y 
Y 
Y 
 
 
Proportion of Subjects with 15% Relative Decrease in 
DLCO 
Y 
 
 
 
 
 
 
Spirometry (FEV1 and FVC) 
 
 
Y 
 
Y 
 
 
Cough 
Y 
 
Y 
 
 
 
 
Borg CR10 
Y 
 
Y 
 
Y 
 
 
Lung Auscultation 
 
 
Y 
 
 
 
 
NOTES: 
• 
T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.  
 
8.2.3.1. 
ECGs 
• 
Triplicate 12-lead ECGs will be collected at the various time points throughout the 
study shown in Appendix 2.  All ECG parameters will be calculated by taking the 
mean of the non-missing values obtained in the up to three 12-lead ECG evaluations 
at each visit. 


 
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8.2.3.2. 
Vital Signs 
• 
The following vital signs will be assessed at the various time points in the study 
shown in Appendix 2: 
o Temperature (in °C) 
o Systolic and diastolic blood pressure (mmHg) 
o  Heart rate (beats/min) 
o Height (cm) 
o Weight(kg)  
o Calculated BMI (kg/m²)  
o Blood oxygen (%).  
 
8.2.3.3. 
Immunogenicity  
• 
Serum samples for anti-drug antibody (ADA) measurements will be obtained from all 
randomized subjects after administration of study drug at the scheduled visits.  
• 
Samples taken after dosing with GSK3196165 that have a value at or above the cut-
point will be considered potentially treatment-emergent ADA-positive. A Shift table 
from baseline to every assessment will be produced for the Immunogenicity population 
to assess the number of subjects going from: 
1) negative → negative,  
2) negative → positive,  
3) positive → negative, and  
4) positive → positive.  
• 
Serum analysis will be performed under the management of Immunogenicity and 
Clinical Immunology (ICI), GlaxoSmithKline.  Serum will be tested for the presence 
of anti- GSK3196165 antibodies using the currently approved analytical methodology 
incorporating screening, confirmation and titration steps.   
Anti-GSK3196165 Binding AB Detection (positive/negative) will be listed together 
with titre value (mL) 
 
8.2.3.4. 
Pulmonary Assessments 
• 
The following pulmonary assessments will be performed at the various time points in 
the study shown in Appendix 2: 
o Cough (as defined by CTCAE) 
o Borg CR10 
o Lung Auscultation 
o Pulse Oximetry 
o Pulmonary Function Tests (PFTs – spirometry, gas transfer [DLCO]) 
Pulmonary findings are defined as follows: 
o At least one 15% relative decrease from baseline in DLCO. 


 
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o At least one 15% relative decrease from baseline in DLCO to <70%. 
o Cough of any grade. 
o Any abnormal lung auscultation. 
 Respiratory Events are defined as follows: 
Event 
Definition 
Persistent cough  
Cough CTCAE grade 2 or greater recorded 
for 3 consecutive weeks (15 or more days). 
 
Identified through Cough ‘Yes’ entered in 
the eCRF with Grade determined from AE 
reporting with the following definition: 
AESEV=Mild = Grade 1 
AESEV=Moderate= Grade 2 
AESEV=Severe= Grade 3 
Persistent dyspnea 
Borg Scale grade 3 or greater recorded for 3 
consecutive weeks (15 or more days) on the 
eCRF page. 
Persistent decrease of DLCO by 
>15% 
Relative decrease of DLCO of >15% 
compared to Baseline for 3 consecutive 
weeks (15 or more days) 
 
These definitions are provided for guidance to identify potential cases.  Final adjudication 
will be conducted by the SRT. 
8.2.3.5. 
Cardiovascular Events 
In the occurrence of a Cardiovascular Event, patient profiles will be produced using IDSL 
standard templates. 


 
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8.3. 
Pharmacokinetic Analyses  
The pharmacokinetic (PK) analyses will be based on the “Pharmacokinetic” population, 
unless otherwise specified. There are no planned statistical analyses. 
GSK3196165 serum concentration data will be analysed using population approach as 
described in section 8.3.3. 
8.3.1. 
Overview of Planned Pharmacokinetic Analyses 
8.3.2. 
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 12.5.3 
Reporting Process & Standards) for details on how the concentration data will be derived. 
8.3.3. 
Population Pharmacokinetic (PopPK) Analyses 
The primary goal of this analysis is to characterise the PK of GSK3196165 administered 
subcutaneously in subjects with HOA and compare it with other populations. 
o The influence of subject demographics, baseline characteristics, and 
immunogenicity on the pharmacokinetics of GSK3196165 in this population will 
be investigated.  
o The individual subject PK parameters will be estimated and documented for the 
purposes of any subsequent model based exposure-response (PK/PD) analyses. 
PK analysis will be performed based on population PK approach. GSK3196165 serum 
concentration-time data will be subjected to nonlinear mixed effects modelling using the 
program NONMEM. To support this analysis a NONMEM file will be generated, which 
will be combined with already existing NONMEM file from pooled population PK 
analysis (Population Pharmacokinetic Analysis of GSK3196165 Following Intravenous 
and Subcutaneous Administration to Healthy Volunteers, Subjects with Rheumatoid 
Arthritis and Multiple Sclerosis (Date: 08-Jan-2016)). PK model from previous pooled 
analysis will be starting point this analysis. If the current PK model described the PK data 
from HOA subjects well (as per criteria set in TP-EP.BS-WW-001-01) no further base 
model development will be done. Effect of following covariates will be tested:  
• Population type (HOA, healthy volunteers, rheumatoid arthritis and multiple 
sclerosis)  
• Subject demographics (age, sex, and race) 
• Baseline characteristics (body weight, free GM-CSF levels) 
• Immunogenicity 
Results of population PK analysis and PK/PD described in section 9.2 will be reported in 
detail in a standalone report which will go as an appendix/attachment to the CSR. 


 
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9. 
OTHER EXPLORATORY STATISTICAL ANALYSES 
9.1. 
Imaging analyses  
9.1.1. 
Overview of planned Imaging analyses  
The Imaging analyses will be based on the “Intent-To-Treat” population, unless 
otherwise specified. 
Table 10 provides an overview of the planned Imaging analyses, with further details of 
data displays being presented in Section 12.15: List of Data Displays. 
Table 9 
Overview of Planned Imaging Analyses 
 
Endpoint  
Absolute 
Change from Baseline 
Stats Analysis 
Summa
ry 
Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Inflammatory Structural Joint Damage 
HOAMRIS Individual 
Components 
Y[2] 
 
Y 
[1,2] 
Y 
[2] 
Y 
[2] 
 
Y 
Y 
 
Y 
 
Y 
[1] 
Y 
 
Y 
 
Y 
Y 
HOAMRIQ Individual 
Components 
Y[2] 
 
Y 
[1,2] 
Y 
[2] 
Y 
[2] 
 
Y 
Y 
 
Y 
 
Y 
[1] 
Y 
 
Y 
 
Y 
Y 
Joint Inflammation 
DCE-MRI quantitative 
parameters 
Y[2] 
 
Y 
[1,2] 
Y 
[2] 
Y 
[2] 
 
Y 
Y 
 
Y 
 
Y 
[1] 
Y 
 
Y 
 
Y 
Y 
Bone Shape Parameters 
Bone Shape Parameters 
 
 
 
Y 
[2] 
Y 
[2] 
 
Y 
 
 
 
Y 
 
Y 
 
 
Y 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
• 
[1] Raw SAS log output from analysis. 
• 
[2] Absolute values will be displayed in the same outputs as the change from baseline.  
 
9.1.2. 
Planned Imaging Statistical Analyses  
Planned Statistical Analyses  
Endpoint(s) 
• Change from baseline in structural and inflammatory HOA features in the affected hand* 
(including synovitis, erosive damage, cysts, osteophytes, cartilage space loss, malalignment, 
and bone marrow lesions) as assessed by the OMERACT HOAMRIS scoring system 
• Change from baseline in structural and inflammatory HOA features in the affected hand* 
(including synovitis, bone erosions, joint space width, and bone marrow edema) as assessed 
by the HOAMRIQ scoring system. 


 
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Planned Statistical Analyses  
• Change from baseline in synovitis in the affected hand*, as measured by DCE-MRI including 
the exchange rate (Ktrans), interstitial volume (ve), plasma volume (vp), volume of synovitis, 
initial rate of enhancement (IRE), and maximum signal intensity enhancement (ME). 
• Change from baseline in bone shape as assessed by structural MRI of the affected hand. 
Planned Analyses and Model Specification 
• Descriptive Statistics will be calculated for the change from baseline in each individual 
component of the HOAMRIS (i.e. synovitis, erosive damage, cysts, osteophytes, cartilage 
space loss, malalignment and bone marrow lesions), as a total for the affected/dominant 
(whichever is scanned) hand.  
• Individual Components of Interest in the HOAMRIS will be statistically analysed using the same 
methods as the primary endpoint (MMRM). 
• Descriptive statistics will be calculated for each individual component of the HOAMRIQ (i.e. 
synovitis, erosive damage, cysts, osteophytes, cartilage space loss, malalignment and bone 
marrow lesions), a total for the affected/dominant (whichever is scanned) hand. 
• Individual Components of Interest in the HOAMRIQ will be statistically analysed using the 
same methods as the primary endpoint (MMRM). 
• Individual components of the HOAMRIQ may be presented as measured, standardized or both 
(see section 12.6.5 for full details). 
• Descriptive Statistics will be calculated for the change from baseline in DCE-MRI quantitative 
derived parameters (i.e. Ktrans, ve, vp, IRE, ME and volume of synovitis), as a total for the 
affected/dominant (whichever is scanned) hand.  
• DCE-MRI Parameters of interest will be statistically analysed using the same methods as the 
primary endpoint (MMRM). 
• Individual components of the DCE-MRI may be presented as measured and standardized (see 
section 12.6.5 for full details). 
• Descriptive Statistics will be calculated for the change from baseline in bone shape parameters 
(i.e. Surface area of bone) as a total for the affected/dominant (whichever is scanned) hand.  
• All parameters will be listed by subject and joint/bone. 
Model Checking & Diagnostics 
• Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• Results will be presented using the same methods as the primary endpoint. 
 
9.2. 
Pharmacokinetic / Pharmacodynamic Analyses  
The pharmacokinetic / pharmacodynamic (PK/PD) analyses will be based on the 
“Pharmacokinetic” population, unless otherwise specified.  
The primary goal of this analysis is to characterize the PK/PD relationship of 
GSK3196165 administered subcutaneously in subjects with HOA. 
Sensitivity and Supportive Statistical Analyses 
• Non-parametric analyses may be conducted if the normality assumption does not hold. 
• Analyses using different covariance structures may be explored if the unstructured covariance 
matrix does not converge. 


 
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The analysis will be a graphical analysis and if data permits model based analysis might 
be conducted on adhoc basis. Overall plots will be generated for response/biomarker data 
against GSK3196165 exposure parameter. 
Examples of the PK/PD plots include: 
• Scatter plot of change from baseline in 24h average hand pain intensity at week 4 
versus pre-dose concentration values (Ctrough) at week 4. 
• Scatter plot of change from baseline in 24h average hand pain intensity at week 6 
versus Ctrough at week 6. 
9.3. 
Biomarker Analyses  
9.3.1. 
Pharmacodynamic Biomarker Analyses 
9.3.1.1. 
Overview of Planned Pharmacodynamic Biomarker Analyses 
The pharmacodynamic biomarker analyses will be based on the “Safety” population, 
unless otherwise specified. 
See section 12.6.6.1 for a full list of Pharmacodynamic Biomarkers. 
Table 10 provides an overview of the planned pharmacodynamic biomarker analyses, 
with full details of data displays being presented in Appendix 16: List of Data Displays. 
All Biomarkers may require transformations; see Section 12.5.3 regarding the process of 
presenting log transformed data. 
Prior to any data being analysed, the distributions and proportion of data falling within 
the quantification limits will be assessed to determine if analysis is appropriate. 
Additional analysis assessing the relationship between biomarkers and clinical efficacy 
endpoints may be conducted if considered appropriate. 
Table 10 
Overview of Planned Pharmacodynamic Biomarker Analyses 
Endpoint  
Transformed/Untransformed 
Absolute 
Change from Baseline 
Stats Analysis 
Summary Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Target Engagement Biomarkers 
Distribution 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
By Treatment & Time 
 
 
 
Y[1] 
Y 
 
Y 
 
 
 
Y 
Y 
 
Y 


 
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Endpoint  
Transformed/Untransformed 
Absolute 
Change from Baseline 
Stats Analysis 
Summary Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Predictive Biomarkers 
Distribution 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
By Treatment & Time  
Y 
Y 
Y 
[1,2] 
Y[1] 
Y 
 
Y 
Y 
Y 
Y[2] 
Y 
Y 
 
Y 
Cartilage Biomarkers 
Distribution 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
By Treatment & Time 
 
 
 
Y[1] 
Y 
 
Y 
 
 
 
Y 
Y 
 
Y 
Mechanistic Biomarkers 
Distribution 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
By Treatment & Time 
 
 
 
Y[1] 
Y 
 
Y 
 
 
 
Y 
Y 
 
Y 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
• 
 [1] Absolute values will be displayed in the same outputs as the change from baseline.  
• 
[2] [1] Raw SAS log output from analysis. 
 
9.3.2. 
Safety Biomarker Analyses 
9.3.2.1. 
Overview of Planned Safety Biomarker Analyses 
The safety biomarker analyses will be based on the “Safety” population, unless otherwise 
specified. See section 12.6.6.2 for a full list of Safety Biomarkers. 
Table 11 provides an overview of the planned safety biomarker analyses, with full details 
of data displays being presented in Appendix 16: List of Data Displays. 
 
Table 11 
Overview of Planned Safety Biomarker Analyses 
Endpoint  
Transformed/Untransformed 
Absolute 
Change from Baseline 
Stats Analysis 
Summary Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Safety Biomarkers 
Distribution 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
By Treatment & Time 
 
 
 
Y[1] 
Y 
 
Y 
 
 
 
Y 
Y 
 
Y 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
• 
[1] Absolute values will be displayed in the same outputs as the change from baseline.  
 
 


 
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9.4. 
Analyses on Paracetamol Data  
9.4.1. 
Overview of Planned Analyses on Paracetamol Data 
The analyses on the paracetamol data will be based on the “Intent-to-Treat” population, 
unless otherwise specified. 
Table 12 provides an overview of the planned efficacy analyses, with full details of data 
displays being presented in Section 12.15: List of Data Displays. 
Table 12 
Overview of Planned Analyses on Paracetamol Data 
 
Endpoint  
Absolute 
Change from Baseline 
Stats Analysis 
Summary 
Individual 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Paracetamol 
24h Dose of 
Paracetamol Averaged 
over 7 Days Prior to 
Assessment 
 
 
 
Y[1] 
Y[1] 
 
Y 
 
 
 
Y[1] 
Y[1] 
 
 
Proportion of Subjects 
Using Paracetamol 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
• 
[1] Absolute values will be displayed in the same outputs as the change from baseline. 
 
 


 
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10. 
INTERIM ANALYSES  
Two formal interim analyses are planned during the course of this study. In addition to 
the formal planned interim analyses, further data reviews may be carried out by senior 
managers not involved in the study conduct to aid in portfolio and budget decisions. 
These administrative reviews will have no impact on the ongoing study. 
The timing and content of each Interim deliverable is summarised in Table 13. 
Table 13 Interim Deliveries 
Analysis 
Timing 
Unblinded Team 
Main Objective 
PK Interim 
To coincide with 
other internal 
decision making 
across the 
GSK3196165 
project 
Study 
Pharmacokineticist, 
Statistics and 
Programming, 
Project Statistician, 
GSK3196165 MDT  
To compare PK of 
GSK3196165 in 
subjects with HOA 
with other populations 
Week 6 
Interim  
Once a minimum 
of 30 subjects have 
completed day 43 
(week 6) 
Study Statistician and 
Programmer, Project 
Statistician and 
Programmer, TA 
Head, Clinical 
Statistics TA Head, 
MDL  
To assist with decision 
making regarding the 
subsequent clinical 
development of 
GSK3196165 for OA 
Administrative 
Interim Data 
Review 
At the discretion of 
Senior Managers 
not involved in the 
study conduct 
Study Statistician and 
Programmer, Project 
Statistician and 
Programmer, TA 
Head, Clinical 
Statistics TA Head, 
MDL 
To aid with dynamic 
portfolio and budget 
decisions 
 
10.1. 
Overview of planned Week 6 Interim Analysis 
10.1.1. 
Overview of Study Population Analysis at Week 6 Interim 
The Study Population analyses will be based on the Intent-to-Treat (ITT) population, 
unless otherwise specified. 
Table 14 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 16: List of Data Displays. 


 
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Table 14 
Overview of Planned Study Population Analyses at Week 6 Interim 
Display Type 
Data Displays Generated 
Table 
Listing 
Demographic and Baseline Characteristics 
Demographics Characteristics 
Y 
 
NOTES : 
• 
Y = Yes display generated. 
10.1.2. 
Overview of Safety Analysis at Week 6 Interim 
The Adverse Event analyses will be based on the “Safety” population, unless otherwise 
specified. 
Table 15 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 16: List of Data Displays. 
Table 15 
Overview of Planned Safety Analyses at Week 6 Interim 
Endpoint / Parameter/ Display Type 
Absolute 
Change from BL 
Summary 
Individual Summary 
Individual 
T 
F 
F 
L 
T 
F 
L 
Adverse Events (AE’s) 
All AE’s 
Y 
 
 
 
 
 
 
Serious and Other Significant AE’s 
Serious AE’s 
Y 
 
 
 
 
 
 
Withdrawal AE’s 
Y 
 
 
 
 
 
 
Drug Related AE’s 
Y 
 
 
 
 
 
 
AE’s leading to death 
 
 
 
 
 
 
Y 
NOTES: 
• 
T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.  
10.1.3. 
Overview of Planned Efficacy Analysis at Week 6 Interim 
Table 17 provides an overview of the planned interim analyses, with full details of data 
displays being presented in Appendix 16: List of Data Displays 
Table 16 Overview of Planned Efficacy Analysis at Week 6 Interim 
Endpoint  
Absolute 
Change from Baseline 
Stats Analysis 
Summary Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Pain 
24h average hand 
pain NRS score 
averaged over 7 
 
 
 
Y 
[2] 
Y[2] 
 
 
Y 
Y 
Y[1] 
Y[2] 
Y[2] 
 
 


 
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Endpoint  
Absolute 
Change from Baseline 
Stats Analysis 
Summary Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
days prior to 
assessment  
24h worst hand pain 
NRS score averaged 
over 7 days prior to 
assessment  
 
 
 
Y 
[2] 
Y[2] 
 
 
Y 
Y 
Y[1] 
Y[2] 
Y[2] 
 
 
AUSCAN 
AUSCAN 3.1 NRS 
Components 
 
 
 
 
 
Y  
  
Y  
Y 
Y[1]  
Y  
Y  
 
  
C-Reactive Protein 
C-Reactive Protein 
 
 
 
Y 
[2] 
Y[2] 
 
 
Y 
Y 
Y[1] 
Y[2] 
Y[2] 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
[1] Raw SAS log output from Analysis. 
[2] Absolute value and change from baseline will be displayed on the same output 
 
 
Week 6 Interim Analysis 
Model Specification 
• Continuous endpoints will be statistically analysed using the same methods as described in 
Sections 7.1.2 and 8.1.2.1 
Model Checking & Diagnostics 
• Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• Continuous endpoints will be presented using the same methods as described in Sections 
7.1.2 and 8.1.2.1 
 
Sensitivity and Supportive Statistical Analyses 
• Following review of the data, additional analyses maybe conducted to further support the 
primary statistical analyses, if deemed appropriate. 
• Analyses using different covariance structures may be explored if considered appropriate. 
 
10.2. 
Overview of planned Pharmacokinetic Interim Analysis 
The pharmacokinetic (PK) analysis will be based on the “Pharmacokinetic” population, 
unless otherwise specified. 


 
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The primary objective of the interim PK analysis is to compare PK of GSK3196165 in 
subjects with HOA with other populations. Plot of GSK3196165 concentration with 
median value by visit will be produced and compared with similar plot from BAROQUE 
study including data only till week 12 and 180 mg dose group.  
To derive PK parameters, GSK3196165 serum concentration-time data from HOA will 
be pooled with dataset generated for population PK meta analysis (Population 
Pharmacokinetic Analysis of GSK3196165 Following Intravenous and Subcutaneous 
Administration to Healthy Volunteers, Subjects with Rheumatoid Arthritis and Multiple 
Sclerosis (Date: 08-Jan-2016)) and subjected to nonlinear mixed effects modelling using 
the program NONMEM.  Effect of following covariates will be tested:  
• Population type (HOA, healthy volunteers, rheumatoid arthritis and multiple 
sclerosis) 
• Subject demographics (age, sex, and race) 
• Baseline characteristics (body weight, free GM-CSF levels) 
• Immunogenicity 
Individual PK parameters will be summarized by population type and distribution of the 
derived PK parameters will be plotted by population type. 
10.3. 
Overview of Administrative Interim Data Review 
The purpose of the Administrative Interim Data Review is to aid with dynamic portfolio 
and budget decisions. The outcome of the Administrative Interim Data Review will have 
no direct impact on the ongoing study. 
Table 17 provides an overview of the planned analyses, with full details of data displays 
being presented in Section 12.15: List of Data Displays. 
 
Table 17 
Overview of Analyses for Administrative Interim Data Review 
Endpoint  
Absolute 
Change from Baseline 
Stats Analysis 
Summary 
Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Pain 
24h average hand 
pain NRS score 
averaged over 7 days 
prior to assessment 
 
 
 
 
 
 
 
Y 
 
Y 
 
Y 
Y 
 
 
24h worst hand pain 
NRS score averaged 
over 7 days prior to 
assessment 
 
 
 
 
 
 
 
Y 
 
Y 
 
Y 
Y 
 
 
Paracetamol 
24h Dose of 
Paracetamol 
Averaged over 7 
 
 
 
 
 
 
 
 
 
 
 
Y 
 
 


 
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Endpoint  
Absolute 
Change from Baseline 
Stats Analysis 
Summary 
Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Days Prior to 
Assessment  
Proportion of 
Subjects Using 
Paracetamol 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
 
 


 
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11. 
REFERENCES 
 
[1] Population Pharmacokinetic Analysis of GSK3196165 Following Intravenous and 
Subcutaneous Administration to Healthy Volunteers, Subjects with Rheumatoid Arthritis 
and Multiple Sclerosis (Date: 08-Jan-2016) 


 
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12. 
APPENDICES 
Section 
Appendix 
RAP Section 4 : Analysis Populations 
Section 12.1 
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population 
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions 
Section 12.2 
Appendix 2: Time and Events 
Section 12.3 
Appendix 3: Assessment Windows 
Section 12.4 
Appendix 4: Treatment States & Phases 
Section 12.5 
Appendix 5: Data Display Standards & Handling Conventions 
• Study Treatment & Sub-group Display Descriptors 
• Baseline Definitions & Derivations 
• Reporting Process & Standards 
Section 12.6 
Appendix 6: Derived and Transformed Data 
• General, Study Population & Safety 
• Efficacy 
• Pharmacokinetic 
• Pharmacodynamic and or Biomarkers 
Section 12.7 
Appendix 7: Premature Withdrawals & Handling of Missing Data 
• Premature Withdrawals 
• Handling of Missing Data 
Section 12.8 
Appendix 8: Values of Potential Clinical Importance 
Section 12.9 
Appendix 9: Multicentre Studies 
Section 12.10 
Appendix 10: Multiple Comparisons and Multiplicity 
Section 12.11 
Appendix 11: Model Checking and Diagnostics for Statistical Analyses 
Section 12.12 
Appendix 12: Definition of some Parameters of Interest 
Section 12.13 
Appendix 13: Opportunistic Infections: MedDRA Preferred Terms  
Other RAP Appendices 
Section 12.14 
Appendix 14: Abbreviations & Trade Marks 
Section 12.15 
Appendix 15: List of Data Displays 
Section 12.16 
Appendix 16: Example Mock Shells for Data Displays 
 


 
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12.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
 
There is no planned Per Protocol population in this phase IIa study. 


 
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12.2. 
Appendix 2: Time & Events 
12.2.1. 
Protocol Defined Time & Events 
12.2.1.1. 
Screening period Time and Events table 
Subject Screening 
(must be carried out  28 days prior to Day 1) 
Screening Day 1 
Screening Days 1-7, at home 
Screening Day ≥8 
 
 
 
Informed Consent 
Daily Pain NRS questionnaire[2] 
Pain NRS eligibility 
assessment[3] 
Inclusion/exclusion criteria 
 
MRI[4] 
Demographics 
 
 
Medical/medication/alcohol history 
 
 
Con. Med. Review 
 
 
Vital signs 
 
 
12-lead ECG 
 
 
Full Physical Exam 
 
 
Swollen and tender joints[1] 
 
 
Haem/Chem/Urinalysis 
 
 
HIV, TB, Hepatitis B & Hepatitis C screen 
 
 
RF, ACPA (anti-CCP) 
 
 
Pregnancy test (serum) 
 
 
Urine drug / alcohol screen 
 
 
Spirometry (FEV1, FVC) & DLCO 
 
 
Pain NRS training 
 
 
SAE assessment 
 
 
NOTES: 
• 
[1] Where possible, the same individual should perform all disease assessments for an individual subject (with 
separate joint assessor). 
• 
[2] Pain NRS questions should be completed at approximately the same time each day (recommended between 
6pm and 10pm). 
• 
[3] Eligibility assessment will be based on a 7 day average of the ‘24h average hand pain NRS’ question. 
• 
[4] Subjects must have passed all screening assessments, including laboratory tests and 7-day pain NRS 
assessment, prior to undertaking MRI scanning. 
 
 
 
 
 
 


 
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12.2.1.2. 
Treatment period Time and Events table 
Study events 
Screening (≤28 days 
prior to Day 1)
Treatment period 
Week 20 phone call 
(Day 141  5d) 
Follow up (Week 22 
(Day 155  7d) 
 
Treatment period T&E table notes 
Week 0 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 6 
Wk 8 
Wk 10 
Wk 12 
 
Baseline & Day 
1 treatment visit 
Day 3 ( 1d)PK 
biomarker visit
Day 8 ( 1d) 
treatment visit 
Day 15 ( 1d) 
treatment visit 
Day 22 ( 1d) 
treatment visit 
Day 29 ( 1d) 
treatment visit 
Day 43 ( 3d) 
treatment visit 
Day 57 ( 3d) 
treatment visit 
Day 71 ( 3d) 
treatment visit 
Day 85 ( 3d) 
treatment visit 
 
 
Borg CR10 Scale[1] 
See separate T&E table for screening procedures 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Site to contact subject by phone and remind them to begin completing the daily 
Pain NRS questionnaire starting 7 days before their Follow-up visit at Week 22 
See separate table for follow-up visit procedures 
 
[1] PROs are performed before any 
other assessments, or procedures, 
to avoid influencing subject. 
[2] Where possible, the same 
individual should perform all disease 
assessments for an individual 
subject (with separate joint 
assessor). 
[3] MRI scanning at week 12 may 
take place on a separate day from 
other assessments and may occur 
on Day 85 ( 5d).  
[4] Before dosing. 
[5] Day 1 immunogenicity sample 
includes anti-GM-CSF auto-antibody 
analysis 
[6] Consenting subjects only.  
[7] Pain NRS questions should be 
completed at approximately the 
same time each day (recommended 
between 6pm and 10pm). 
 
Patient[1] and physician global 
assessment[2] 
X 
  
  
X  
  
X 
  
X 
  
X 
 
AUSCAN 3.1 NRS[1] 
X 
  
X 
X 
  
X 
X 
X 
X 
X 
 
Brief Physical Exam 
X 
  
  
X 
  
X 
  
X 
  
X 
 
Vital signs 
X 
  
  
X 
  
X 
  
X 
  
X 
 
12-lead ECG 
X4 
  
  
 
  
 
  
 
  
X 
 
Swollen and tender joints[2] 
X 
  
X 
X 
  
X 
X 
X 
X 
X 
 
MRI[3] 
  
  
  
  
  
  
 
  
  
X[3] 
 
Haem/Chem/Urinalysis 
X 
  
X 
X 
  
X 
X 
X 
X 
X 
 
PK sampling[4] 
X 
X 
X 
 
  
X 
X  
 
  
X 
 
Blood Biomarkers[4] 
X 
X 
X 
X 
  
X 
  
X 
  
X 
 
Urine drug/alcohol 
X 
  
  
 
  
 
  
 
  
X 
 
Study treatment dosing 
X 
  
X 
X 
X 
X 
X 
X 
X 
  
 
Cough, Auscultation, Pulse Oximetry  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
 
Spirometry (FEV1, FVC) & DLCO 
X 
  
  
  
  
  
  
  
  
X 
 
Immunogenicity blood sampling 
X[5] 
  
  
X 
  
X 
  
  
  
X 
 
Pharmacogenetics[6] 
X 
  
  
  
  
  
  
  
  
  
 
Pregnancy test (urine) 
X 
  
  
  
  
X 
  
X 
  
X 
 
Post-treatment Interview 
 
 
 
 
 
 
 
 
 
X 
 
Daily Pain NRS questions[7] 
<------------------------------------------- X -------------------------------------------> 
 
SAE/AE assessment 
<------------------------------------------- X -------------------------------------------> 
 
Con. medication review 
<------------------------------------------- X -------------------------------------------> 
 


 
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12.2.1.3. 
Follow up visit and early withdrawal* procedures list 
Subject Follow-up Visit 
Task List 
Week 22 
(Day 155  7d) 
 
 
Borg CR10 Scale[1] 
Patient1 and physician global assessment[3] 
Pain NRS assessment[2] 
Vital signs 
Full Physical Exam 
Swollen and tender joints[3] 
SAE/AE assessment 
Con. Med. Review 
Pregnancy test (urine) 
Haem/Chem/Urinalysis 
Immunogenicity 
MRI[4] 
Blood Biomarkers 
PK Sampling 
Cough, Auscultation, Pulse Oximetry 
Spirometry (FEV1, FVC) & DLCO 
NOTES: 
• 
[1] PROs are performed before any other assessments, or procedures, to avoid influencing subject. 
• 
[2] Assessment is based on a 7 day average of the Pain NRS questions. 
• 
[3] Where possible, the same individual should perform all disease assessments for an individual subject (with 
separate joint assessor). 
• 
[4] If scheduling MRI on the same day as the follow up visit is not possible, the MRI visit may take place on a 
separate day before the Follow-up visit  but it must occur within the same Day 155 7day window. 
 
*for early withdrawal, Day 85 procedures are followed and a follow up visit scheduled. 
 
 
 
 
 
 


 
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12.3. 
Appendix 3: Assessment Windows 
12.3.1. 
Definitions of Assessment Windows for Analyses  
Analysis Set 
/ Domain 
Parameter      
(if applicable) 
Target  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
All 
All 
Day -1 
Day -28 
Day -1 
Screening 
MRI 
MRI 
Day -1 
Day -28 
Day 1 
Baseline 
All 
All 
Day 1 
Day 1 
Day 1 
Baseline 
PK/Biomarker 
PK/Biomarker 
Day 3 
Day 2 
Day 4 
Day 3 
All 
All 
Day 8 
Day 6 
Day 10 
Week 1 
All 
All 
Day 15 
Day 13 
Day 17 
Week 2 
All 
All 
Day 22 
Day 20 
Day 24 
Week 3 
All 
All 
Day 29 
Day 27 
Day 31 
Week 4 
All 
All 
Day 43 
Day 38 
Day 48 
Week 6 
All 
All 
Day 57 
Day 52 
Day 62 
Week 8 
All 
All 
Day 71 
Day 66 
Day 76 
Week 10 
All 
All 
Day 85 
Day 80 
Day 90 
Week 12 
MRI 
MRI 
Day 85 
Day 76 
Day 94 
Week 12 
All 
All 
Day 155 
Day 148 
Day 162 
12 Week 
Follow Up 
All (subjects 
withdrawn early 
from treatment) 
All (subjects 
withdrawn early 
from treatment) 
84 days after last 
treatment 
77 days after 
last treatment 
91 days after 
last treatment 
12 Week 
Follow Up 
 
Note: All data will be listed, but ‘out of window’ data would not contribute towards any 
summary statistics or analyses. 
 
Note: MRI rescan visits will be slotted to the nearest analysis time window and will contribute 
towards summary statistics and analyses. 
 


 
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12.4. 
Appendix 4: Treatment States and Phases  
12.4.1. 
Study Phases 
Assessments and events will be classified according to the time of occurrence relative to 
study treatment start date, unless otherwise specified. 
Study Phase 
Definition 
Pre-Treatment  
Date < Study Treatment Start Date 
On-Treatment 
Study Treatment Start Date ≤ Date ≤ Study Treatment Stop Date + 14 Days 
Safety Follow-Up 
Date > Study Treatment Stop Date + 14 Days 
 
12.4.1.1. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
If medication end date is not missing and is before first dose of study treatment. 
Concomitant 
Any medication that is not a prior 
NOTES:  
Please refer to Appendix 7 for handling of missing and partial dates for concomitant medication. Use the rules in this 
table if concomitant medication date is completely missing. 
 
12.4.2. 
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. 
12.4.2.1. 
Treatment States for AE Data 
Treatment State 
Definition 
Pre-Treatment 
AE Start Date < Study Treatment Start Date 
On-Treatment 
Study Treatment Start Date  ≤ AE Start Date ≤ Study Treatment Stop Date + 14 
Days  
Safety Follow-Up 
AE Start Date > Study Treatment Stop Date + 14 Days 
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. 
Duration (Days)  
AE Resolution Date – AE Onset Date + 1 
Drug-related 
If relationship is marked ‘YES’ on Inform/CRF OR value is missing. 
NOTES:  
• 
AE’s with partial start and/stop dates will be assumed to have occurred on treatment unless there is 
evidence through comparison of partial dates to suggest otherwise. 
 
 


 
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12.5. 
Appendix 5: Data Display Standards & Handling 
Conventions  
12.5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
RandAll NG  
Data Displays for Reporting  
Code 
Description 
Description 
Order [1] 
A 
GSK3196165 180mg 
GSK3196165 180mg 
2 
P 
Placebo 
Placebo 
1 
NOTES: 
1. 
Order represents treatments being presented in TFL, as appropriate. 
 
12.5.2. 
Baseline Definition & Derivations 
12.5.2.1. 
Baseline Definitions 
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment.  
Parameter 
Study Assessments Considered As 
Baseline 
Baseline Used in 
Data Display 
Screening 
Day 1 (Pre-Dose) 
Primary 
24h average hand pain NRS 
score averaged over 7 days 
prior to assessment[1]  
X 
X 
Day 1 (Pre-Dose) 
Secondary 
24h worst pain NRS score 
averaged over 7 days prior to 
assessment[1] 
X 
X 
Day 1 (Pre-Dose) 
AUSCAN 3.1 NRS 
 
X 
Day 1 (Pre-Dose) 
Swollen/Tender hand joints 
 
X 
Day 1 (Pre-Dose) 
PtGA/PhGA 
 
X 
Day 1 (Pre-Dose) 
PK parameters 
 
X 
Day 1 (Pre-Dose) 
Safety 
Vital signs (HR, BP & temp)[2] 
X 
X 
Day 1 (Pre-Dose) 
ECG  (12-lead)[2] 
X 
X 
Day 1 (Pre-Dose) 
Laboratory (Haematology, 
clinical chemistry and 
urinalysis)[2] 
X 
X 
Day 1 (Pre-Dose) 


 
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Parameter 
Study Assessments Considered As 
Baseline 
Baseline Used in 
Data Display 
Screening 
Day 1 (Pre-Dose) 
Pulmonary Assessments[2] 
X 
X 
Day 1 (Pre-Dose) 
Exploratory 
MRI 
X 
 
Screening  
PK/PD 
 
X 
Day 1 (Pre-Dose) 
NOTES : 
• 
Unless otherwise stated, the mean of replicate assessments at any given time point will be used as the value for 
that time point. 
• 
Where both screening and pre-dose are available, the value closest to first dose will be used. 
• 
[1] For all Pain NRS scores averaged over 7 days prior to assessment, the baseline values will be calculated as 
the average of the 7 days preceding the first dose of study treatment  
• 
[2] For all vital signs, ECG, labs and pulmonary assessments except DLCO, the baseline values will be the latest 
pre-dose assessment. For DLCO, a subject’s baseline will be taken as the lowest value obtained from the Screening 
or Day 1(Pre-dose) assessment, or any unscheduled visit in between. 
 
12.5.2.2. 
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. 
Note that for the ECG outputs this is the maximum increase 
from baseline 
Ratio to Baseline 
= Post-Dose Visit Value / Baseline 
NOTES : 
• 
Unless otherwise specified, the baseline definitions specified in Section 12.5.2.1 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. 
• 
The baseline definition will be footnoted on all change from baseline displays. 
 
12.5.3. 
Reporting Process & Standards 
Reporting Process 
Software 
• The currently supported versions of SAS software will be used to perform all data analyses, 
generate tables, figures and listings. 
Reporting Area 
HARP Server 
uk1salx00175 
HARP Area 
arenv \ arprod \ gsk3196165 \ mid204851 \ final 
arenv \ arprod \ gsk3196165 \ mid204851 \ primary 
arenv \ arprod \ gsk3196165 \ mid204851 \ internal_01 


 
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Reporting Process 
arenv \ arprod \ gsk3196165 \ mid204851 \ internal_02 
arenv \ arprod \ gsk3196165 \ mid204851 \ internal_03 
arenv \ arprod \ gsk3196165 \ mid204851 \ internal_04 
arenv \ arprod \ gsk3196165 \ mid204851 \ internal_05 
arenv \ arprod \ gsk3196165 \ mid204851 \ spotfire 
QC Spreadsheet 
arenv \ arwork \ gsk3196165 \ mid204851 \ final \ documents 
arenv \ arwork \ gsk3196165 \ mid204851 \ primary \ documents 
arenv \ arwork \ gsk3196165 \ mid204851 \ internal_01 \ documents 
arenv \ arwork \ gsk3196165 \ mid204851 \ internal_02 \ documents 
arenv \ arwork \ gsk3196165 \ mid204851 \ internal_03 \ documents 
arenv \ arwork \ gsk3196165 \ mid204851 \ internal_04 \ documents 
arenv \ arwork \ gsk3196165 \ mid204851 \ internal_05 \ documents 
arenv \ arwork \ gsk3196165 \ mid204851 \ spotfire \ documents 
Analysis Datasets  
• For the final reporting effort, analysis datasets will be created according to CDISC standards 
(SDTM IG Version 3.1.3 & AdaM IG Version 1.0 
• For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will 
be implemented for conversion from SI to SDTM. 
• For the purpose of the Administrative Interim Review and Interim analyses, analysis 
datasets will be generated from SI Datasets. 
Generation of RTF Files 
• RTF files will be generated for final reporting effort. 
 
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  
* website IDSL → supporting documentation → component → stats displays → principles 
Formats 
• GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected. 
• Numeric data will be reported at the precision collected on the eCRF. 
• The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time 
• Reporting for tables, figures and formal statistical analyses : 
• Planned time relative to dosing will be used in figures, summaries, statistical analyses 
and calculation of any derived parameters, unless otherwise stated. 


 
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Reporting Standards 
• The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as 
appropriate. 
• Reporting for Data Listings:  
• Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1). 
• Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) 
will be included in listings but omitted from figures, summaries and statistical analyses. 
Unscheduled Visits 
• Unscheduled visits will not be included in summary tables or contribute to any analyses, 
unless otherwise stated. 
• 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, % 
Reporting of Pharmacokinetic Concentration Data 
Descriptive 
Summary Statistics 
Refer to IDSL Statistical Principle 6.06.1 
Assign zero to NQ values (Refer to GUI_51487 for further details) 
Reporting of Log-Transformed Parameters 
Descriptive 
Summary Statistics  
N, n, geometric mean, 95% CI of geometric mean, standard deviation 
(SD) of logged data and geometric coefficient of variation (CVb (%)) will be 
reported. 
[1] CVb (%) = √ (exp(SD2) - 1) * 100 
(SD = SD of log transformed data)  
Figures 
Axes will be presented with actual values with an appropriate log-scale 
(either base 2 or base 10) depending on range of values 
Graphical Displays 
• Refer to IDSL Statistical Principals 7.01 to 7.13. 
 


 
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12.6. 
Appendix 6: Derived and Transformed Data 
12.6.1. 
General 
Multiple Measurements at One Time Point 
• Mean of the measurements will be calculated and used in any derivation of summary 
statistics but if listed, all data will be presented. 
• If there are two values within a time window the value closest to the target day for that 
window will be used except for ECGs, Blood Pressure and Pulse Rate Measures. If values 
are the same distance from the target, then the latest assessment value will be taken. 
• Triplicate ECG measures will be averaged for each subject and visit prior to generating 
summary tables. 
• Duplicate Blood Pressure and Pulse Rate measures will be averaged for each subject and 
visit prior to generating summary tables. 
• Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables. 
Study Day 
• Calculated as the number of days from  date of first dose of study treatment: 
• Ref Date = Missing                       → Study Day = Missing  
• Ref Date < Date of First Dose of Study Treatment   → Study Day = Ref Date –Date of 
First Dose of Study Treatment    
• Ref Data ≥ Randomisation Date   → Study Day = Ref Date – (First Dose of Study 
Treatment) + 1     
 
12.6.2. 
Study Population 
Demographics 
Age 
• GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows: 
o Any subject with a missing day will have this imputed as day ‘15’.  
o Any subject with a missing date and month will have this imputed as ‘30th June’. 
• Calculated as the integer part of (latest of (randomisation date, screening date)– date of birth). 
• Birth date will be presented in listings as ‘YYYY’. 
• Age will be categorised into subgroups <18 years, 18-<65 years and >=65 years 
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 


 
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Demographics 
• 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) + 14 
• Subjects who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure.  
• The cumulative dose will be based on the formula: 
Cumulative Dose = Sum of (Number of Visits x Total Dose at Each Visit) 
• If there are any treatment breaks during the study, exposure data will be adjusted accordingly. 
Medical History 
Disease Duration 
• OA duration since diagnosis in months will be calculated based on the formula: 
OA Duration Since Diagnosis in Months =  (Date of First Dose of Study Treatment - Start 
date of formal OA diagnosis + 1)/30.25 
• OA duration since first symptoms in months will be calculated based on the formula: 
OA Duration Since First Symptoms in Months =  (Date of First Dose of Study Treatment - 
Start date of first symptoms + 1)/30.25 
 
12.6.3. 
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 : 
𝑅𝑅= [( 𝑄𝑇
𝑄𝑇𝑐𝐵)
2
] ∗1000 
[2] If QTcF is machine read and QTcB is not provided, then:  
𝑅𝑅= [( 𝑄𝑇
𝑄𝑇𝑐𝐹)
3
] ∗1000 
• 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 :  


 
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ECG Parameters 
𝑄𝑇𝑐𝐵= 
𝑄𝑇
√𝑅𝑅
1000
 
𝑄𝑇𝑐𝐹= 
𝑄𝑇
3√𝑅𝑅
1000
 
 
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 Decimal Places=  ‘< x ‘ becomes x – 0.01 
o Example 2: 1 Decimal Place=  ‘> x’ becomes x + 0.1 
o Example 3: 0 Decimal Places= ‘< x’ becomes x – 1     
 
Pulmonary Assessments 
Borg CR10 
• The Borg CR10 Scale is being used to assess patient-reported shortness of breath (difficulty in 
breathing) 
• The Borg CR10 Scale®    is graded from: 
o 0,  “Nothing at all”, = none, to 10, “Extremely Strong”, “Maximal”, = the most intense 
perception or feeling the subject has ever experienced. 
o There is allowance for  gradings > 10, which are designated as “Absolute Maximum” or 
“Highest Possible” and is marked with a “●” in the scale 
o A 3 is designated as being “Moderate” on the scale. 
• 
No imputations will be done for missing data. 
Pulse Oximetry 
• Pulse Oximetry will be categorised into subgroups <80%, 80% to 90% and ≥90%. 
• Lower values represent a worse result. 
 
12.6.4. 
Efficacy 
Efficacy 
24h average hand pain NRS score 
• Measured by a daily pain Numerical Rating Scale (NRS) based on 24h average hand pain 
intensity with anchors “0” (no pain) and “10” (worst imaginable pain), which is averaged over 
the 7 days prior to assessment visit with GSK3196165 or placebo. 
• The 7 day average score is calculated by 
∑(𝐷𝑎𝑖𝑙𝑦 24ℎ 𝑎𝑣𝑒𝑟𝑎𝑔𝑒 ℎ𝑎𝑛𝑑 𝑝𝑎𝑖𝑛 𝑁𝑅𝑆 𝑠𝑐𝑜𝑟𝑒𝑠 𝑖𝑛 𝑡ℎ𝑒 7 𝑑𝑎𝑦𝑠 𝑝𝑟𝑖𝑜𝑟 𝑡𝑜 𝑎𝑠𝑠𝑒𝑠𝑠
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑒𝑟 𝑜𝑓 𝑑𝑎𝑦𝑠  24ℎ 𝑎𝑣𝑒𝑟𝑎𝑔𝑒 ℎ𝑎𝑛𝑑 𝑝𝑎𝑖𝑛 𝑁𝑅𝑆 𝑖𝑠 𝑟𝑒𝑐𝑜𝑟𝑑𝑒𝑑 𝑖𝑛 7 𝑑𝑎𝑦𝑠 𝑝𝑟𝑖𝑜𝑟 𝑡𝑜
• * If a subject records their daily pain NRS scores for  less than 4 days out of the 7 days prior 
to assessment visit, then the average NRS score for the week prior to the assessment visit 
will be recorded as missing.  


 
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• The 7 day average score will be calculated using the 7 days prior to assessment visit, 
excluding any values that have been used to calculate previous averages, e.g. if a patient 
attends a visit on Day 9 (hence 7 day average will be calculated using Days 2 to 8) and 
attends their next visit on Day 14 (hence 7 day average should be calculated using Days 7 to 
13), any overlapping days will be excluded from the calculation of the Day 14 average (i.e. 
Days 7 and 8). 
24h worst hand pain NRS score 
• Measured by patients using a daily pain Numerical Rating Scale (NRS) based on 24h worst 
hand pain intensity with anchors “0” (no pain) and “10” (worst imaginable pain, which is 
averaged over the 7 days prior to assessment visit with GSK3196165 or placebo. 
• The score is calculated by 
 
∑(𝐷𝑎𝑖𝑙𝑦 24ℎ 𝑤𝑜𝑟𝑠𝑡 ℎ𝑎𝑛𝑑 𝑝𝑎𝑖𝑛 𝑁𝑅𝑆 𝑠𝑐𝑜𝑟𝑒𝑠 𝑖𝑛 𝑡ℎ𝑒 7 𝑑𝑎𝑦𝑠 𝑝𝑟𝑖𝑜𝑟 𝑡𝑜 𝑎𝑠𝑠𝑒𝑠𝑠𝑚𝑒𝑛𝑡 𝑣𝑖𝑠𝑖𝑡)
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑒𝑟 𝑜𝑓 𝑑𝑎𝑦𝑠  24ℎ 𝑤𝑜𝑟𝑠𝑡 ℎ𝑎𝑛𝑑 𝑝𝑎𝑖𝑛 𝑁𝑅𝑆 𝑖𝑠 𝑟𝑒𝑐𝑜𝑟𝑑𝑒𝑑 𝑖𝑛 7 𝑑𝑎𝑦𝑠 𝑝𝑟𝑖𝑜𝑟 𝑡𝑜 𝑎𝑠𝑠𝑒𝑠𝑠𝑚𝑒𝑛𝑡 𝑣𝑖𝑠𝑖𝑡∗ 
• * If a subject records their daily pain NRS scores for  less than 4 days out of the 7 days prior 
to assessment visit, then the average NRS score for the week prior to the assessment visit 
will be recorded as missing. 
• The 7 day average score will be calculated using the 7 days prior to assessment visit, 
excluding any values that have been used to calculate previous averages, e.g. if a patient 
attends a visit on Day 9 (hence 7 day average will be calculated using Days 2 to 8) and 
attends their next visit on Day 14 (hence 7 day average should be calculated using Days 7 to 
13), any overlapping days will be excluded from the calculation of the Day 14 average (i.e. 
Days 7 and 8). 
AUSCANTM 
• The AUSCANTM Index is a self-administered questionnaire consisting of a 15-item scale 
which measures pain (5 items), stiffness (1 item) and degree of disability/physical function (9 
items) during the preceding 48h. All items are rated on an NRS scale with anchors “0” (none) 
to “10” (extreme). 
• The scores for each individual domain (Pain/Stiffness/Physical Function) are calculated 
using a simple summation of the component item scores relating to that domain, therefore 
the Pain component ranges from 0-50, Stiffness component 0-10 and Physical Function 
component (0-90). 
• The total AUSCANTM score is calculated using simple summation of the 15 component item 
scores and therefore ranges from 0-150. 
• If ≥2 pain, the stiffness, >2 physical function items are missing, the patient’s response on the 
affected subscale will be regarded as invalid and the deficient subscale(s) will not be used in 
any analysis. 
• Where 1 pain or 1-2 physical function items are missing, the average value for the subscale 
will be substituted in lieu of the missing item value(s). 
Swollen Hand Joint Count 
• Measured by the total number of swollen joints out of a possible 30 (8 DIP, 8 PIP, 2 IP, 10 
MCP, 2 CMC) across both hands. 
• 
If there are missing observations for swollen joints then the remaining observations will be 
assessed and weighted by dividing the number presented by the number of non-missing, 
and by multiplying by 30 for the joint count.  


 
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• 
No imputations for individual joints will be done.  
• 
If a joint is not evaluable at Baseline, then that joint is set to missing throughout the study. 
• 
If data for more than 50% of the joints are missing at the time of a given assessment, then 
the total count will be set to missing for that visit. 
Painful/Tender Hand Joint Count 
• Measured by the total number of tender joints out of a possible 30 (8 DIP, 8 PIP, 2 IP, 10 
MCP, 2 CMC) across both hands. 
• Joints can be rated 0=no pain/tenderness, 1=mild pain, 2=moderate pain and 3=severe pain. 
• A joint is considered tender if it is scored >0 on the tender joint severity scale. 
• 
If there are missing observations for tender joints then the remaining observations will be 
assessed and weighted by dividing the number presented by the number of non-missing, 
and by multiplying by 30 for the joint count.  
• 
No imputations for individual joints will be done.  
• 
If a joint is not evaluable at Baseline, then that joint is set to missing throughout the study. 
• 
If data for more than 50% of the joints are missing at the time of a given assessment, then 
the total count will be set to missing for that visit. 
Patient Global Assessment (PtGA) 
• 
Measured by patients who will complete a global assessment of disease activity using the 
patient global assessment (PtGA) item, an NRS with anchors “0” (very well) to “10” (very 
poor). 
• 
No imputations for missing data will be done. 
Physician Global Assessment (PhGA) 
• 
Measured by Physicians who will complete a global assessment of disease activity using the 
physician global assessment item (PhGA), an NRS with anchors “0” (none) to “10” 
(extremely active). 
• 
No imputations for missing data will be done. 
24h Paracetamol Dose 
• Measured by total dose of paracetamol taken in 24 hours, which is averaged over the 7 days 
prior to assessment visit with GSK3196165 or placebo. 
• If paracetamol dose is missing on a particular day but a pain NRS score has been recorded 
on that day, then paracetamol dose is set to 0mg for that day. 
• If paracetamol dose is missing on a particular day and a pain NRS score is also missing on 
that day, then paracetamol dose is set to missing for that day. 
• The 7 day average dose is calculated by  
∑(𝐷𝑎𝑖𝑙𝑦 24ℎ 𝑝𝑎𝑟𝑎𝑐𝑒𝑡𝑎𝑚𝑜𝑙 𝑑𝑜𝑠𝑒𝑎𝑔𝑒 𝑖𝑛 𝑡ℎ𝑒 7 𝑑𝑎𝑦𝑠 𝑝𝑟𝑖𝑜𝑟 𝑡𝑜 𝑎𝑠𝑠𝑒𝑠𝑠𝑚𝑒𝑛𝑡 𝑣𝑖𝑠𝑖𝑡)
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑒𝑟 𝑜𝑓 𝑑𝑎𝑦𝑠  24ℎ 𝑝𝑎𝑟𝑎𝑐𝑒𝑡𝑎𝑚𝑜𝑙 𝑑𝑜𝑠𝑒 𝑖𝑠 𝑟𝑒𝑐𝑜𝑟𝑑𝑒𝑑 𝑖𝑛 7 𝑑𝑎𝑦𝑠 𝑝𝑟𝑖𝑜𝑟 𝑡𝑜 𝑎𝑠𝑠𝑒𝑠𝑠𝑚𝑒𝑛𝑡 𝑣𝑖𝑠𝑖𝑡∗ 
• * If a subject is missing more than 3 daily paracetamol doses out of the 7 days prior to 
assessment visit, then the average paracetamol dose for the week prior to the assessment 
visit will be recorded as missing.  
• The 7 day average dose will be calculated using the 7 days prior to assessment visit, 
excluding any values that have been used to calculate previous averages, e.g. if a patient 
attends a visit on Day 9 (hence 7 day average will be calculated using Days 2 to 8) and 


 
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attends their next visit on Day 14 (hence 7 day average should be calculated using Days 7 to 
13), any overlapping days will be excluded from the calculation of the Day 14 average (i.e. 
Days 7 and 8). 
 
12.6.5. 
Imaging 
Imaging 
HOAMRIS 
• 
HOAMRIS measures consist of 7 different parameters (Synovitis, Erosive Damage, Cyst, 
Osteophytes, Cartilage Space Loss, Mal-alignment and Bone Marrow Lesions) that are semi-
quantitatively assessed by an independent reviewer on a scale of 0-3/3.5, or can be scored as 
“Not Visible” or “Surgically Modified”.  
• 
Each parameter is evaluated on a total of 8 hand joints (DIP Joints 2-5 and PIP Joints 2-5). For 
erosive damage, cysts, and bone marrow lesions, the distal and proximal ends of the joint are 
assessed as sub-regions (i.e. D1, D2, P1, and P2). 
• 
There is one score for each parameter per location, per time point. 
• 
Each parameter is scored as follows: 
o Synovitis Scoring: 
Score 
Description 
0 
Normal, no synovitis 
0.5 
Minimal: >0 but decreased from a timepoint scored 1. 
1 
Mild: 1-33% volume enhancement 
1.5 
Mild-Moderate: >0 and <2, but increased from a timepoint scored 1 or decreased 
from a timepoint scored 2. 
2 
Moderate: 34-67% volume enhancement 
2.5 
Moderate-Severe: >1 and <3, but increased from a timepoint scored 2 or decreased 
from a timepoint scored 3. 
3 
Severe: 68-100% volume enhanced 
3.5 
Very Severe: Increased from a timepoint scored 3. 
N 
Not Visible 
S 
Surgically Modified 
 
o Erosive Damage Scoring: 
Score 
Description 
0 
Normal, no erosive damage 
0.5 
Minimal: >0 but decreased from a timepoint scored 1. 
1 
Mild: ≤10% of bone volume or ≤25% joint surface affected 
1.5 
Mild-Moderate: >0 and <2, but increased from a timepoint scored 1 or decreased 
from a timepoint scored 2. 
2 
Moderate: 11-20% of bone volume and/or 26-50% of joint surface affected 
2.5 
Moderate-Severe: >1 and <3, but increased from a timepoint scored 2 or decreased 
from a timepoint scored 3. 
3 
Severe: >20% of bone volume and/or >50% of joint surface affected 
3.5 
Very Severe: Increased from a timepoint scored 3. 


 
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Imaging 
N 
Not Visible 
S 
Surgically Modified 
 
o Cyst Scoring: 
Score 
Description 
0 
Normal, no cyst development 
1 
Mild: cysts are ≤10% of bone volume 
2 
Moderate: cysts are 11-20% of bone volume  
3 
Severe: cysts are >20% of bone volume  
N 
Not Visible 
S 
Surgically Modified 
 
o Osteophyte Scoring: 
Score 
Description 
0 
Normal, no osteophytes 
1 
Mild: 1-3 small osteophytes 
2 
Moderate: ≥4 small osteophytes and/or ≥1 moderate osteophyte(s) 
3 
Severe: at least 1 large osteophyte 
N 
Not Visible 
S 
Surgically Modified 
 
o Cartilage Space Loss Scoring: 
Score 
Description 
0 
Normal, no loss of cartilage Space 
1 
Mild: loss of cartilage space without bone-to-bone contact 
2 
Moderate: focal complete loss of cartilage space 
3 
Severe: complete cartilage space loss affecting >50% of articulating joint area 
N 
Not Visible 
S 
Surgically Modified 
 
o Mal-alignment Scoring: 
Score 
Description 
0 
Normal, no apparent mal-alignment 
1 
Mild: ≤10 degree angulation and/or not congruent joint surfaces 
2 
Moderate: 11-20 degrees angulation and/or moderate subluxation without crossing 
the midline 
3 
Severe: >20 degrees angulation and/or subluxation without crossing the midline 
N 
Not Visible 
S 
Surgically Modified 
 
o Bone Marrow Lesions: 
Score 
Description 
0 
Normal, no bone marrow lesions 
0.5 
Minimal: >0 but decreased from a timepoint scored 1. 
1 
Mild: Lesions are 1-33% of bone volume 


 
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1.5 
Mild-Moderate: >0 and <2, but increased from a timepoint scored 1 or decreased 
from a timepoint scored 2. 
2 
Moderate: lesions are 34-66% of bone volume 
2.5 
Moderate-Severe: >1 and <3, but increased from a timepoint scored 2 or decreased 
from a timepoint scored 3. 
3 
Severe: lesions are 67-100% of bone volume 
3.5 
Very Severe: Increased from a timepoint scored 3. 
N 
Not Visible 
S 
Surgically Modified 
 
• 
If an individual location is scored either “Not Visible” or “Surgically Modified” then the score for 
that location will be set to missing. 
• 
Each individual Parameter will be presented as a total score for the affected/dominant hand which 
will be calculated by summing scores of all joints at each time point. 
 
HOAMRIQ  
• 
HOAMRIQ measures consist of the quantitative measurements from the bones and synovial 
capsules of the following joints: 
o DIP Joints 2-5 
o PIP Joints 2-5 
o MCP Joints 1-5 
o CMC-1 
• 7 different parameters are quantitatively assessed as follows: 
o Synovitis (Volume of Enhancing Pannus): 
- 
The total volume (in mm3) of contrast-enhanced voxels within the synovial 
capsule. 
- 
The following joints will be considered: 
▪ CMC-1 
▪ DIP 2-5 
▪ PIP 2-5 
▪ MCP 1-5 
- 
Synovitis will be presented as a total measure which is calculated by 
summing the individual measure for each joint at each time point. 
o Synovitis (Normalised) 
- 
Normalised Synovitis will be calculated using the Volume of Enhancing 
Pannus (VEP): 
∑
𝑉𝐸𝑃
𝑎𝑙𝑙 𝑗𝑜𝑖𝑛𝑡𝑠
∑
𝐽𝑜𝑖𝑛𝑡 𝑉𝑜𝑙𝑢𝑚𝑒
𝑎𝑙𝑙 𝑗𝑜𝑖𝑛𝑡𝑠
 
- 
The following joints will be considered: 
▪ CMC-1 
▪ DIP 2-5 


 
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▪ PIP 2-5 
▪ MCP 1-5 
o Erosive Damage (Volume of Bone Erosions):  
- 
The volume (in mm3) difference between the segmented bones and 
modelled healthy bones within the 3D MR Image. The measure is taken at 
the extremities of the bones (15mm length from the joint) or the whole bone.  
- 
The following bones will be considered: 
▪ D2-5 
▪ I2-5 
▪ M2-5 
▪ P2-5 
▪ Trapezium 
- 
Erosive Damage will be presented as a total measure which is calculated by 
summing the individual measure for each bone at each time point. 
o Erosive Damage (Normalised) 
- 
Normalised Erosive Damage will be calculated using the Volume of Bone: 
∑
𝑉𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝐵𝑜𝑛𝑒 𝐸𝑟𝑜𝑠𝑖𝑜𝑛
𝑎𝑙𝑙 𝑏𝑜𝑛𝑒𝑠
∑
𝑉𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝐵𝑜𝑛𝑒
𝑎𝑙𝑙 𝑏𝑜𝑛𝑒𝑠
 
o Cyst: 
- 
Measured as part of the erosions measurement and is therefore quantified 
but not differentiated from the quantification of erosions, hence no measure 
is presented separately for this parameter. 
o Osteophyte: 
- 
Captured by Bone Shape Parameters, hence no measure is presented 
separately for this parameter. 
o Cartilage Space Loss (Joint Space Width):  
- 
The mean difference (in mm) between corresponded patches on the ends of 
the phalanges of each joint. 
- 
The following joints will be considered: 
▪ CMC-1 
▪ DIP 2-5 
▪ PIP 2-5 
▪ MCP 1-5 
- 
Cartilage Space Loss will be presented as a total measure which is 
calculated by summing the individual measure for each joint at each time 
point. 
o Mal-alignment (Alignment of Bone):  
- 
The 2D angle (in degrees) between phalanges at the DIP, PIP, MCP and 
CMC joints in the plane of the wrist bones. 
- 
The following joints will be considered: 


 
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Imaging 
▪ CMC-1 
▪ DIP 2-5 
▪ PIP 2-5 
▪ MCP 1-5 
- 
Mal-alignment will be presented as a total measure which is calculated by 
summing the absolute value of the individual measure for each joint at each 
time point. 
o Bone Marrow Lesions (Volume of Bone Edema) (Normalised):  
- 
The total volume (in mm3) of enhanced voxels within the segmented bone 
volumes at each joint. The measure is taken at the extremities of the bones 
(15mm length from the joint), or the whole bone. 
- 
The following bones will be considered: 
▪ D2-5 
▪ I2-5 
▪ M2-5 
▪ P2-5 
▪ Trapezium 
- 
Normalised Bone Marrow Lesions will be calculated using the volume of 
bone: 
∑
𝑉𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝐵𝑜𝑛𝑒 𝐸𝑑𝑒𝑚𝑎
𝑎𝑙𝑙 𝑏𝑜𝑛𝑒𝑠
∑
𝑉𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝐵𝑜𝑛𝑒
𝑎𝑙𝑙 𝑏𝑜𝑛𝑒𝑠
 
 
• All parameters will be presented as a total measure for the affected/dominant hand at each time 
point. 
DCE-MRI 
• 
Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) parameters are 
measured at each individual joint (DIP Joints 2-5, PIP Joints 2-5, MCP Joints 1-5 and CMC-1) 
and consist of: 
o Exchange Rate (Ktrans) 
o Interstitial Volume (ve) 
o Plasma Volume (vp) 
o Initial Rate of Enhancement (IRE) 
o Maximum signal intensity enhancement (ME). 
• All DCE-MRI parameters will be presented as a total measure over all joints at each time point. 
• DCE-MRI Parameters will be calculated as: 
∑
𝑃𝑎𝑟𝑎𝑚𝑒𝑡𝑒𝑟
𝑎𝑙𝑙 𝑗𝑜𝑖𝑛𝑡𝑠
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝐽𝑜𝑖𝑛𝑡𝑠 
• 
All DCE-MRI Parameters will also be presented normalised by the Volume of Enhancing Pannus 
(VEP). 
• 
Normalised DCE-MRI parameters will be calculated as: 


 
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Imaging 
∑
(𝑉𝐸𝑃∗𝑃𝑎𝑟𝑎𝑚𝑒𝑡𝑒𝑟)
𝑎𝑙𝑙 𝑗𝑜𝑖𝑛𝑡𝑠
∑
𝑉𝐸𝑃
𝑎𝑙𝑙 𝑗𝑜𝑖𝑛𝑡𝑠
 
• 
All parameters will be presented as a total measure for the affected/dominant hand at each time 
point. 
Bone Shape Parameters 
• 
Surface Area of the Bone: 
o Measured as the whole bone area (in mm2). At the metacarpals, the joint of interest is 
the MCP and therefore the distal part (15mm length from the joint) shall be measured. 
o The following bones will be considered: 
- 
D2-5 
- 
I2-5 
- 
M2-5 
- 
P2-5 
- 
Trapezium 
• 
All bone shape parameters will be presented as a total measure for the affected/dominant hand 
which is calculated by summing the individual measure for each bone at each time point. 
 


 
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12.6.6. 
Biomarker 
12.6.6.1. 
Pharmacodynamic Biomarkers  
Test Analyte  
LBCAT 
LBTESTCD 
Units 
Derived 
Details 
Target Engagement 
Free  Soluble GM-CSF 
 
BIOMARKER 
GMCSFFS 
ng/L 
 
 
GM-CSF: drug complex 
BIOMARKER 
GMCSFC 
ng/L 
 
 
Predictive Biomarkers  
HSCRP 
CHEMISTRY 
CRP 
mg/L 
 
 
MRP8/14 COMPLEX 
BIOMARKER 
S100A8A9 
mg/L 
 
 
CCL17 (TARC) 
BIOMARKER 
CCL17 
ng/L 
 
 
14-3-3ƞ 
BIOMARKER 
ETA1433 
mg/L 
 
 
MMP-3 
BIOMARKER 
MMP3 
μg/L 
 
 
CXCL13 (BLC) 
BIOMARKER 
CXCL13 
ng/L 
 
 
SAA 
BIOMARKER 
AMYLOIDA 
ng/L 
 
 
YKL-40 
BIOMARKER 
CHI3L1 
μg/L 
 
 
IL6 
BIOMARKER 
INTLK6 
ng/L 
 
 
CCL22 
BIOMARKER 
MDC 
ng/L 
 
 
Cartilage Biomarkers  
ARGS Neoepitope 
BIOMARKER 
ARGSNEOE 
 
 
 
C1M 
BIOMARKER 
C1M 
 
 
 
C2M 
BIOMARKER 
C2M 
 
 
 
C3M 
BIOMARKER 
C3M 
 
 
 
CRPM 
BIOMARKER 
CRPM 
 
 
 
VICM 
BIOMARKER 
VICM 
 
 
 
Mechanistic Biomarkers 
VEGF 
BIOMARKER 
VEGF 
ng/L 
 
 
TNFa 
BIOMARKER 
TNF 
ng/L 
 
 
IL-1β 
BIOMARKER 
INTLK1B 
ng/L 
 
 
IL-8 
BIOMARKER 
INTLK8 
ng/L 
 
 
IL-10 
BIOMARKER 
INTLK10 
ng/L 
 
 
IL-13 
BIOMARKER 
INTLK13 
ng/L 
 
 
IL-4 
BIOMARKER 
INTLK4 
ng/L 
 
 


 
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IFN-γ 
BIOMARKER 
IFNG 
ng/L 
 
 
 
 
12.6.6.2. 
Safety Biomarkers  
Test Analyte  
LBCAT 
LBTESTCD 
Units 
Derived 
Details 
Lung Damage 
Anti-GM-CSF auto AB 
BIOMARKER 
GMCSFAA 
 
 
 
 
12.6.6.3. 
Biomarker Derivations 
All Parameters 
Below Limit of Quantification 
• If a biomarker 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 indicated as less than x in the comment field) is present, the 
corresponding numeric value will be imputed using one half the lower limit of quantification.   
• This value will be used in Summary Tables and Figures, but the original recorded result will be listed. 


 
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12.7. 
Appendix 7: Premature Withdrawals & Handling of Missing 
Data 
12.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• Subject study completion (i.e. as specified in the protocol) was defined as 
completion of 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. 
• Early withdrawal (EW) visits will be assigned to the respective visit according 
to the Time and Events table in Section 12.2, using the day of the EW visit 
relative to Day 1. 
• For the first 4 weeks an EW visit more than ±3 days in comparison to the 
target visit will be assigned to the closest target visit. Starting at Week 4, an 
EW visit more than 7 days after target visit day will be assigned to the next 
visit. 
• If a scheduled visit and an EW visit occur within the same visit window and 
are both available, the later visit will be used for any summaries/analyses. 
The earlier visit will appear in listing only. 
• For efficacy analyses, if an EW visit is assigned to a non-standard efficacy 
visit, i.e., a visit at which efficacy assessments are not scheduled per the 
Time and Events Table, then these EW data will be ignored in the statistical 
analysis but all data will be listed. 
 
12.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• Missing data occurs when any requested data is not provided, leading to 
blank fields on the collection instrument : 
o These data will be indicated by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered 
to be missing data and should be displayed as such. 
Outliers 
• Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 


 
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12.7.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
Partial dates will be displayed as captured in subject listing displays. 
Adverse 
Events 
• The eCRF allows for the possibility of partial dates (i.e., only month and year) to 
be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event: 
o Missing Start Day: First of the month will be used unless this is before the 
start date of study treatment; in this case the study treatment start date will 
be used and hence the event is considered On-treatment as per Appendix 
4: 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 
missing. 
• Start or end dates which are completely missing (i.e. no year specified) will 
remain missing, with no imputation applied. 
Concomitant 
Medications/ 
Medical 
History 
• Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention: 
o If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month 
o If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month. 
• The recorded partial date will be displayed in listings. 
 
 
12.7.2.2. 
Handling of Missing Data for Statistical Analysis 
Element 
Reporting Detail 
NRI 
• Subjects with missing pain NRS scores will be considered as non-responders 
for the purpose of analyses on the binary endpoints. 
Change 
from 
Baseline 
• 
For any analysis on change from baseline values, if the baseline value is 
missing then all following assessment values are excluded from the analysis. 


 
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12.7.2.3. 
Handling of Endpoint Specific Missing Data  
Element 
Reporting Detail 
NRS score  
• If a subject records their daily pain NRS scores for less than 4 days out of the 
7 days prior to assessment visit, then the average NRS score for the week 
prior to the assessment visit will be recorded as missing. 
• For the purpose of the analyses on the continuous endpoints, no imputations 
for the missing data will be done. 
• For the purpose of the analyses on the binary endpoints, subjects with 
missing NRS scores will be considered as non-responders. 
AUSCANTM 
• If ≥2 pain, the stiffness item or >2 physical function items are missing, the 
subject’s response on the affected subscale will be regarded as invalid and 
the deficient subscale(s) will not be used in any analysis. 
• Where 1 pain or 1-2 physical function items are missing, the average value 
for the subscale will be substituted in lieu of the missing item value(s). 
• Where any individual component score is missing, total score will be set to 
missing. 
• No imputation for missing total individual component scores will be done. 
Swollen Hand 
Joint Count 
• 
If there are missing observations for swollen joints then the remaining 
observations will be assessed and weighted by dividing the number 
presented by the number of non-missing, and by multiplying by 30 for the 
joint count.  
• 
No imputations for individual joints will be done.  
• 
If a joint is not evaluable at Baseline, then that joint is set to missing 
throughout the study. 
• If data for more than 50% of the joints are missing at the time of a given 
assessment, then the total count will be set to missing for that visit. 
Tender Hand 
Joint Count 
• 
If there are missing observations for tender joints then the remaining 
observations will be assessed and weighted by dividing the number 
presented by the number of non-missing, and by multiplying by 30 for the 
joint count.  
• 
No imputations for individual joints will be done.  
• 
If a joint is not evaluable at Baseline, then that joint is set to missing 
throughout the study. 
• 
If data for more than 50% of the joints are missing at the time of a given 
assessment, then the total count will be set to missing for that visit. 
PtGA 
• No imputations for missing data will be done. 
PhGA 
• No imputations for missing data will be done. 


 
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Element 
Reporting Detail 
HOAMRIS 
• If an individual joint has a missing score, then the score will be imputed using 
the average score across all available evaluable joints for each individual 
component. 
• If data for more than 50% of locations are missing at the time of a given 
assessment, then the total individual component score will be set to missing 
for that visit. This threshold may be altered after review of the actual raw 
data. 
• No imputation for missing total individual component scores will be done.  
HOAMRIQ 
• If an individual joint has a missing value, then the value will be imputed using 
the average score across all available evaluable joints for each individual 
component. 
• If data for more than 50% of locations are missing at the time of a given 
assessment, then the total individual component score will be set to missing 
for that visit. This threshold may be altered after review of the actual raw 
data. 
• No imputation for missing total individual component values will be done. 
DCE-MRI 
• If an individual joint has a missing value, then the value will be imputed using 
the average score across all available evaluable joints for each individual 
component. 
• If data for more than 50% of locations are missing at the time of a given 
assessment, then the total individual component score will be set to missing 
for that visit. This threshold may be altered after review of the actual raw 
data. 
• No imputation for missing total individual component values will be done. 
 


 
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12.8. 
Appendix 8: Values of Potential Clinical Importance 
12.8.1. 
Laboratory Values 
Haematology 
Laboratory Parameter 
 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Hematocrit  
Ratio of 1 
Male 
 
0.54 
Female 
 
0.54 
∆ from BL 
↓0.075 
 
Hemoglobin  
g/L 
 
Male 
 
180 
Female 
 
180 
∆ from BL 
↓25 
 
Lymphocytes  
x109/ L 
 
0.8 
 
Neutrophil Count  
x109/ L 
 
1.5 
 
Platelet Count  
x109/ L 
 
100 
550 
While Blood Cell Count (WBC) 
x109/ L 
 
3 
20 
 
Clinical Chemistry 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Albumin  
mmol/L 
 
30 
 
Calcium 
mmol/L 
 
2 
2.75 
Creatinine 
mmol/L 
∆ from BL 
 
↑ 44.2 
Glucose 
mmol/L 
 
3 
9 
Magnesium 
mmol/L 
 
0.5 
1.23 
Phosphorus 
mmol/L 
 
0.8 
1.6 
Potassium 
mmol/L 
 
3 
5.5 
Sodium 
mmol/L 
 
130 
150 
Total CO2 
mmol/L 
 
18 
32 
 
 
 
12.8.2. 
ECG  
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Absolute QTc Interval 
msec 
 
>450 
Absolute PR Interval 
msec 
< 110 
> 220  
Absolute QRS Interval 
msec 
< 75  
> 110  
Change from Baseline 


 
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ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Increase from Baseline QTc 
msec 
 
>60 
 
12.8.3. 
Vital Signs  
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
< 85 
> 160 
Diastolic Blood Pressure 
mmHg 
< 45 
> 100 
Heart Rate 
bpm 
< 40 
> 110 
 
Vital Sign Parameter 
(Change from Baseline) 
Units 
Clinical Concern Range 
Decrease 
Increase 
Lower 
Upper 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
≥ 20 
≥ 40 
≥ 20 
≥ 40 
Diastolic Blood Pressure 
mmHg 
≥ 10 
≥ 20 
≥ 10 
≥ 20 
Heart Rate 
bpm 
≥ 15 
≥ 30 
≥ 15 
≥ 30 
 


 
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12.9. 
Appendix 9: Multicenter Studies  
 
There are no planned adjustments for multiple centres or regions. For all analyses, all 
sites, countries and regions will be pooled. 
 
 
 


 
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12.10. 
Appendix 10: Multiple Comparisons & Multiplicity 
12.10.1. 
Handling of Multiple Comparisons & Multiplicity 
In this phase IIa study, no adjustments will be made for multiple comparisons or 
multiplicity. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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12.11. 
Appendix 11: Model Checking and Diagnostics for 
Statistical Analyses  
12.11.1. 
Statistical Analysis Assumptions 
12.11.1.1. Continuous Endpoints 
Endpoint(s) • Continuous Endpoints as described in Section 8.1.2.1 . 
Analysis 
• MMRM 
• For the MMRM, model assumptions will be applied, but appropriate adjustments may be made 
based on the data. 
• The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used. 
• An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on 
the REPEATED line. 
o In the event that this model fails to converge, alternative correlation structures may be 
considered such as spatial power, CS or AR(1).  
o Akaike's Information Criteria (AIC) will be used to assist with the selection of covariance 
structure. 
• Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable. 
• If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data. 
12.11.1.2. Binary Endpoints 
Endpoint(s) • Binary Endpoints as described in Section 8.1.2.2 
Analysis 
• Generalised Estimating Equations (GEE) 
• For the GEE analyses, model assumptions will be applied, but appropriate adjustments may be 
made based on the data. 
• An unstructured working correlation structure will be assumed and standard errors will be 
calculated based on the empirical sandwich covariance estimate (default setting for PROC 
GENMOD in SAS) 
• An unstructured correlation structure will be used by specifying ‘type=UN’ on the REPEATED 
line. 
o In the event that this model fails to converge, alternative correlation structures may be 
considered such as Independent, CS or AR(1).  
o Quasilikelihood under the Independence Model Criteria (QIC) will be used to assist with 
the selection of covariance structure. 
 


 
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12.12. 
Appendix 12: Definitions of some Parameters of Interest 
 
12.12.1. 
Laboratory Parameters of Interest 
Lab parameters 
of interest 
Grade 
1 
2 
3 
4 
HEMOGLOBIN 
decrease 
 Hemoglobin (Hgb) <LLN - 10.0   g/dL; 
<LLN - 6.2 mmol/L; <LLN -  100 g/L   
 Hgb <10.0 - 8.0 g/dL; <6.2 - 4.9   
mmol/L; <100 - 80g/L   
 Hgb <8.0 g/dL; <4.9 mmol/L;   <80 
g/L; transfusion indicated 
 Life-threatening 
consequences;   
urgent intervention 
indicated   
WHITE CELL 
COUNT decrease 
 <LLN - 3000/mm3; <LLN - 3.0 x   
10e9 /L   
 <3000 - 2000/mm3; <3.0 - 2.0 x   
10e9 /L   
 <2000 - 1000/mm3; <2.0 - 1.0 x   
10e9 /L   
 <1000/mm3; <1.0 x 
10e9 /L   
TOTAL 
NEUTROPHILS 
ABSOLUTE 
COUNT 
 <LLN - 1500/mm3; <LLN - 1.5 x   
10e9 /L   
 <1500 - 1000/mm3; <1.5 - 1.0 x   
10e9 /L   
 <1000 - 500/mm3; <1.0 - 0.5 x   
10e9 /L   
 <500/mm3; <0.5 x 
10e9 /L   
LYMPHOCYTES 
ABSOLUTE 
COUNT 
decreased 
  <LLN - 800/mm3; <LLN - 0.8 x   10e9 
/L   
 <800 - 500/mm3; <0.8 - 0.5 x   
10e9 /L   
 <500 - 200/mm3; <0.5 - 0.2 x   
10e9 /L   
 <200/mm3; <0.2 x 
10e9 /L   
LYMPHOCYTES 
ABSOLUTE 
increased 
  
 >4000/mm3 - 20,000/mm3 ; >4-20 
x  10e9 /L  
 >20,000/mm3;  >20 x  10e9 /L   
  
PLATELET 
COUNT 
 <LLN - 75,000/mm3; <LLN -  75.0 x 
10e9 /L   
 <75,000 - 50,000/mm3; <75.0 -  
50.0 x 10e9 /L   
 <50,000 - 25,000/mm3; <50.0 -  
25.0 x 10e9 /L   
<25,000/mm3; <25.0 x 
10e9 /L 
CREATININE 
 >1 - 1.5 x baseline; >ULN - 1.5   x 
ULN   
 >1.5 - 3.0 x baseline; >1.5 - 3.0   x 
ULN   
 >3.0 baseline; >3.0 - 6.0 x ULN  
 >6.0 x ULN   


 
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SODIUM 
decrease 
<LLN - 130 mmol/L  
  
<130 - 120 mmol/L 
<120 mmol/L; 
SODIUM increase >ULN - 150 mmol/L   
>150 - 155 mmol/L   
>155 - 160 mmol/L 
>160 mmol/L 
POTASSIUM 
decrease 
<LLN - 3.0 mmol/L   
<LLN - 3.0 mmol/L 
<3.0 - 2.5 mmol/L 
<2.5 mmol/L 
POTASSIUM 
increase 
>ULN - 5.5 mmol/L   
>5.5 - 6.0 mmol/L   
>6.0 - 7.0 mmol/L   
 >7.0 mmol/L 
CALCIUM 
increase 
>ULN - 11.5 mg/dL; >ULN - 2.9 
mmol/L 
>11.5 - 12.5 mg/dL; >2.9 - 3.1 
mmol/L 
>12.5 - 13.5 mg/dL; >3.1 - 3.4 
mmol/L; 
>13.5 mg/dL; >3.4 
mmol/L 
CALCIUM 
decrease 
<LLN -  1.0 mmol/L   
<1.0 -  0.9 mmol/L 
<0.9 -  0.8 mmol/L 
<0.8 mmol/L   
ASAT (SGOT) 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
ALAT (SGPT) 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
ALKALINE 
PHOSPHATASE 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
BILIRUBIN, 
TOTAL 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 10.0 x ULN 
>10.0 x ULN 
ALBUMIN 
<LLN - 3 g/dL; <LLN - 30 g/L 
<3 - 2 g/dL; <30 - 20 g/L 
<2 g/dL; <20 g/L 
  
GLUCOSE 
>ULN -160 mg/dL;  >ULN - 8.9 mmol/L  
>160 -250 mg/dL; >8.9 - 13.9 
mmol/L  
>250 - 500 mg/dL; >13.9 - 27.8  
>500 mg/dL; >27.8 
mmol/L 
EST.CREATININ
E CLEARANCE 
 <LLN - 60   ml/s/1.73 m2 
59 - 30  ml/s/1.73 m2   
29 - 15   ml/s/1.73 m2   
<15 ml/s/1.73 m2 


 
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12.13. 
Appendix 13: Opportunistic Infections: MedDRA Preferred 
Terms 
 
12.13.1. 
Opportunistic Infections: MedDRA Preferred Terms 
Opportunistic Infections: MedDRA Preferred Terms 
AIDS retinopathy 
Herpes pharyngitis 
Acid fast bacilli infection 
Herpes sepsis 
Acinetobacter bacteraemia 
Herpes simplex 
Acinetobacter infection 
Herpes simplex cervicitis 
Acquired immunodeficiency syndrome 
Herpes simplex hepatitis 
Actinomycosis 
Herpes simplex meningoencephalitis 
Actinomycotic abdominal infection 
Herpes simplex otitis externa 
Actinomycotic pulmonary infection 
Herpes simplex test positive 
Acute HIV infection 
Herpes simplex virus conjunctivitis 
neonatal 
Acute hepatitis B 
Herpes simplex visceral 
Acute hepatitis C 
Herpes virus infection 
Adrenal gland tuberculosis 
Herpes zoster 
Arthritis fungal 
Herpes zoster cutaneous disseminated 
Arthritis salmonella 
Herpes zoster disseminated 
Aspergilloma 
Herpes zoster infection neurological 
Aspergillosis oral 
Herpes zoster meningitis 
Aspergillus infection 
Herpes zoster meningoencephalitis 
Asymptomatic HIV infection 
Herpes zoster meningomyelitis 


 
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Opportunistic Infections: MedDRA Preferred Terms 
Asymptomatic viral hepatitis 
Herpes zoster necrotising retinopathy 
Atypical mycobacterial infection 
Herpes zoster oticus 
Atypical mycobacterial lower respiratory 
tract infection 
Herpes zoster pharyngitis 
Atypical mycobacterial lymphadenitis 
Histoplasmosis 
Atypical mycobacterial pneumonia 
Histoplasmosis cutaneous 
Atypical mycobacterium pericarditis 
Histoplasmosis disseminated 
Bacterial parotitis 
Human T-cell lymphocytic virus type II 
infection 
BK virus infection 
Human T-cell lymphotropic virus 
infection 
Biliary tract infection cryptosporidial 
Human T-cell lymphotropic virus type I 
infection 
Biliary tract infection fungal 
Human polyomavirus infection 
Blastomycosis 
Immune reconstitution inflammatory 
syndrome associated tuberculosis 
Bone tuberculosis 
Intestinal tuberculosis 
Brachyspira infection 
JC virus granule cell neuronopathy 
Brain empyema 
JC virus infection 
Bronchitis fungal 
Joint tuberculosis 
Bronchopulmonary aspergillosis 
Kaposi's sarcoma 
Bronchopulmonary aspergillosis allergic 
Kaposi's sarcoma AIDS related 
Brucella sepsis 
Kaposi's varicelliform eruption 
Brucellosis 
Leptotrichia infection 
Candida endophthalmitis 
Listeria encephalitis 
Candida infection 
Listeria sepsis 


 
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Opportunistic Infections: MedDRA Preferred Terms 
Candida osteomyelitis 
Listeriosis 
Candida pneumonia 
Lower respiratory tract herpes infection 
Candida retinitis 
Lower respiratory tract infection fungal 
Candida sepsis 
Lymph node tuberculosis 
Cerebral aspergillosis 
Lymphadenitis fungal 
Cerebral fungal infection 
Lymphoma AIDS related 
Cerebral toxoplasmosis 
Male genital tract tuberculosis 
Choroid tubercles 
Meningitis aspergillus 
Chronic hepatitis 
Meningitis candida 
Chronic hepatitis C 
Meningitis coccidioides 
Coccidioides encephalitis 
Meningitis cryptococcal 
Coccidioidomycosis 
Meningitis fungal 
Colitis herpes 
Meningitis herpes 
Congenital HIV infection 
Meningitis histoplasma 
Congenital cytomegalovirus infection 
Meningitis listeria 
Congenital hepatitis B infection 
Meningitis salmonella 
Congenital herpes simplex infection 
Meningitis toxoplasmal 
Congenital toxoplasmosis 
Meningitis tuberculous 
Congenital tuberculosis 
Meningoencephalitis herpes simplex 
neonatal 
Congenital varicella infection 
Meningoencephalitis herpetic 
Conjunctivitis tuberculous 
Minor cognitive motor disorder 
Corynebacterium infection 
Mucocutaneous candidiasis 
Corynebacterium sepsis 
Mycobacterial infection 


 
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Opportunistic Infections: MedDRA Preferred Terms 
Cryptococcal cutaneous infection 
Mycobacterium abscessus infection 
Cryptococcal fungaemia 
Mycobacterium avium complex immune 
restoration disease 
Cryptococcosis 
Mycobacterium avium complex infection 
Cryptosporidiosis infection 
Mycobacterium chelonae infection 
Cutaneous coccidioidomycosis 
Mycobacterium fortuitum infection 
Cutaneous tuberculosis 
Mycobacterium kansasii infection 
Cytomegalovirus chorioretinitis 
Mycobacterium marinum infection 
Cytomegalovirus colitis 
Mycobacterium ulcerans infection 
Cytomegalovirus duodenitis 
Mycotic endophthalmitis 
Cytomegalovirus enteritis 
Mycotoxicosis 
Cytomegalovirus enterocolitis 
Myocarditis mycotic 
Cytomegalovirus gastritis 
Myocarditis toxoplasmal 
Cytomegalovirus gastroenteritis 
Nasal herpes 
Cytomegalovirus gastrointestinal infection 
Necrotising fasciitis fungal 
Cytomegalovirus gastrointestinal ulcer 
Necrotising herpetic retinopathy 
Cytomegalovirus infection 
Neonatal candida infection 
Cytomegalovirus mononucleosis 
Neonatal mucocutaneous herpes simplex 
Cytomegalovirus mucocutaneous ulcer 
Neurocryptococcosis 
Cytomegalovirus myelomeningoradiculitis 
Neutropenic sepsis 
Cytomegalovirus myocarditis 
Nocardia sepsis 
Cytomegalovirus oesophagitis 
Nocardiosis 
Cytomegalovirus pancreatitis 
Oesophageal candidiasis 
Cytomegalovirus pericarditis 
Oesophageal tuberculosis 


 
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Opportunistic Infections: MedDRA Preferred Terms 
Cytomegalovirus syndrome 
Ophthalmic herpes simplex 
Cytomegalovirus urinary tract infection 
Ophthalmic herpes zoster 
Cytomegalovirus viraemia 
Oro-pharyngeal aspergillosis 
Disseminated cryptococcosis 
Oropharyngeal candidiasis 
Disseminated cytomegaloviral infection 
Osteomyelitis blastomyces 
Disseminated tuberculosis 
Osteomyelitis fungal 
Ear tuberculosis 
Osteomyelitis salmonella 
Eczema herpeticum 
Overgrowth fungal 
Encephalitis cytomegalovirus 
Pancreatitis fungal 
Encephalitis fungal 
Paratyphoid fever 
Encephalitis post immunisation 
Pericarditis fungal 
Encephalitis post varicella 
Pericarditis histoplasma 
End stage AIDS 
Pericarditis tuberculous 
Endocarditis candida 
Perinatal HIV infection 
Endocarditis histoplasma 
Peritoneal candidiasis 
Enterocolitis AIDS 
Peritoneal tuberculosis 
Enterocolitis fungal 
Persistent generalised lymphadenopathy 
Epididymitis blastomyces 
Pneumocystis jirovecii infection 
Epididymitis tuberculous 
Pneumocystis jirovecii pneumonia 
Epstein-Barr virus associated lymphoma 
Pneumonia blastomyces 
Erythema induratum 
Pneumonia cytomegaloviral 
Erythrasma 
Pneumonia fungal 
Exanthema subitum 
Pneumonia herpes viral 
Extrapulmonary tuberculosis 
Pneumonia salmonella 


 
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Opportunistic Infections: MedDRA Preferred Terms 
Eye infection toxoplasmal 
Pneumonia toxoplasmal 
Female genital tract tuberculosis 
Polyomavirus-associated nephropathy 
Fungaemia 
Presumed ocular histoplasmosis syndrome 
Fungal abscess central nervous system 
Proctitis herpes 
Fungal endocarditis 
Proctitis monilial 
Fungal infection 
Progressive multifocal 
leukoencephalopathy 
Fungal oesophagitis 
Prostatitis tuberculous 
Fungal peritonitis 
Pulmonary mycosis 
Fungal sepsis 
Pulmonary trichosporonosis 
Fungal tracheitis 
Pulmonary tuberculoma 
Funguria 
Pulmonary tuberculosis 
Gastritis fungal 
Pyelonephritis fungal 
Gastritis herpes 
Renal tuberculosis 
Gastroenteritis cryptococcal 
Respiratory moniliasis 
Gastroenteritis cryptosporidial 
Respiratory tract infection fungal 
Gastrointestinal candidiasis 
Retinitis histoplasma 
Gastrointestinal fungal infection 
Retroviral infection 
Genital blister 
Retroviral rebound syndrome 
Genital herpes 
Salmonella bacteraemia 
Genital herpes zoster 
Salmonella sepsis 
Haemorrhagic pneumonia 
Salmonellosis 
Hepatosplenic abscess 
Salpingitis tuberculous 
HIV associated nephropathy 
Silicotuberculosis 


 
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Opportunistic Infections: MedDRA Preferred Terms 
HIV cardiomyopathy 
Sinusitis aspergillus 
HIV enteropathy 
Skin candida 
HIV infection 
Spleen tuberculosis 
HIV infection CDC Group I 
Splenic candidiasis 
HIV infection CDC Group II 
Splenic infection fungal 
HIV infection CDC Group III 
Stoma site candida 
HIV infection CDC Group IV subgroup A 
Stoma site infection 
HIV infection CDC Group IV subgroup B 
Superinfection fungal 
HIV infection CDC Group IV subgroup C1 Superinfection mycobacterial 
HIV infection CDC Group IV subgroup C2 Systemic candida 
HIV infection CDC Group IV subgroup D 
Systemic mycosis 
HIV infection CDC Group IV subgroup E 
T-cell lymphoma 
HIV infection CDC category A 
T-cell type acute leukaemia 
HIV infection CDC category B 
Thyroid tuberculosis 
HIV infection CDC category C 
Tongue fungal infection 
HIV infection CDC group IV 
Toxoplasmosis 
HIV infection WHO clinical stage I 
Tropical spastic paresis 
HIV infection WHO clinical stage II 
Tuberculoma of central nervous system 
HIV infection WHO clinical stage III 
Tuberculosis 
HIV infection WHO clinical stage IV 
Tuberculosis bladder 
HIV peripheral neuropathy 
Tuberculosis gastrointestinal 
HIV wasting syndrome 
Tuberculosis liver 
Hepatic candidiasis 
Tuberculosis of central nervous system 
Hepatic infection fungal 
Tuberculosis of eye 


 
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Opportunistic Infections: MedDRA Preferred Terms 
Hepatitis B 
Tuberculosis of genitourinary system 
Hepatitis C 
Tuberculosis of intrathoracic lymph nodes 
Hepatitis chronic persistent 
Tuberculosis of peripheral lymph nodes 
Hepatitis fulminant 
Tuberculosis ureter 
Hepatitis toxoplasmal 
Tuberculous abscess central nervous 
system 
Hepatitis viral 
Tuberculous endometritis 
Hepatitis virus-associated nephropathy 
Tuberculous laryngitis 
Hepatosplenic candidiasis 
Tuberculous pleurisy 
Herpes dermatitis 
Tuberculous tenosynovitis 
Herpes oesophagitis 
Typhoid fever 
Herpes ophthalmic 
Varicella keratitis 
 
 


 
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12.14. 
Appendix 14 – Abbreviations & Trade Marks 
12.14.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AIC 
Akaike's Information Criteria 
A&R 
Analysis and Reporting  
AUC 
Area under the curve 
AUSCAN 
Australian Canadian Hand Osteoarthritis Index  
Cave 
Average  steady state concentration during dosing interval 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CL 
Clearance 
CL/F 
Total body clearance from plasma after SC administration 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CRF 
Case Report Form 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
CTR 
Clinical Trial Register 
CVb / CVw 
Coefficient of Variation (Between) / Coefficient of Variation (Within) 
DLCO 
Diffusing capacity of the lung for carbon monoxide 
DCE-MRI 
Dynamic Contrast Enhanced Magnetic Resonance Imaging 
DOB 
Date of Birth 
DP 
Decimal Places 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
FEV1 
Forced Expiratory Volume in one Second 
FVC 
Forced Vital Capacity 
GM-CSF 
Granulocyte-macrophage colony stimulating factor 
GUI 
Guidance 
GSK 
GlaxoSmithKline 
H 
Hour 
HIV 
Human Immunodeficiency Virus 
HOA 
Hand Osteoarthritis 
HOAMRIS 
Hand Osteoarthritis Magnetic Resonance Imaging Scoring System 
HOAMRIQ 
Hand Osteoarthritis Magnetic Resonance Imaging Quantitative score 
IA 
Interim Analysis 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
Ig 
Immunoglobulin 
IMMS 
International Modules Management System 


 
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Abbreviation 
Description 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
Ka 
Absorption rate constant 
Kg 
Kilogram 
Ktrans 
Exchange rate 
L 
Litre 
MDL 
Medicines Development Lead 
MDT 
Medicines Development Team 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
mL 
Milliliter 
MMRM 
Mixed Model Repeated Measures 
MRI 
Magnetic Resonance Imaging 
NRI 
Non-responder Imputation 
NRS 
Numerical Rating Scale 
OA 
Osteoarthritis 
OMERACT 
Outcome measures in Rheumatology 
PAP 
Pulmonary alveolar proteinosis 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PhGA  
Physician’s Global Assessment 
PtGA 
Patient’s Global Assessment 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PRO 
Patient reported outcome 
QC 
Quality Control 
QTc 
Corrected QT interval 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAMOS 
Randomization & Medication Ordering System  
RAMRIS 
Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System 
RAP 
Reporting & Analysis Plan 
SAC 
Statistical Analysis Complete 
SAE 
Serious adverse event 
SC 
Subcutaneous  
SDTM 
Study Data Tabulation Model 
SOP 
Standard Operation Procedure 
t ½  
Elimination half life 
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  
ve 
Interstitial volume 
vp 
Plasma volume 
Vss/F 
Total volume of distribution after SC administration 
 


 
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12.14.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
NONE 
 
WinNonlin 
 
 
SAS 
 
 
AUSCAN 
 


 
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12.15. 
Appendix 15: List of Data Displays  
12.15.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.n 
1.1 to 1.n 
Efficacy 
2.1 to 2.n 
2.1 to 2.n 
Safety 
3.1 to 3.n 
3.1 to 3.n 
Pharmacokinetic 
4.1 to 4.n 
4.1 to 4.n 
Pharmacodynamic and / or Biomarker 
5.1 to 5.n 
5.1 to 5.n 
Pharmacokinetic / Pharmacodynamic 
6.1 to 6.n 
6.1 to 6.n 
Section 
Listings 
ICH Listings 
1 to x 
Other Listings 
y to z 
 
12.15.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required an example 
mock-up displays provided in Appendix : Example Mock Shells for Data Displays. 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Efficacy 
EFF_Fn 
EFF_Tn 
EFF_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
Pharmacodynamic and / or Biomarker 
PD_Fn 
PD_Tn 
PD_Ln 
Pharmacokinetic / Pharmacodynamic 
PKPD_Fn 
PKPD_Tn 
PK/PD_Ln 
NOTES:  
• 
Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’ 
 
12.15.3. 
Deliverable [Priority] 
Delivery [Priority] [1] 
Description 
PK IA [X] 
PK Interim Statistical Analysis Complete 
Wk6 IA [X] 
Week 6 Interim Statistical Analysis Complete 
AIR [X] 
Administrative Interim Review Complete 
SAC [X] 
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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12.15.4. 
Study Population Tables 
Study Population Tables 
No. 
Populatio
n 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1. 
 
ITT 
ES1 
Summary of Subject Disposition for the Subject Conclusion 
Record 
ICH E3, FDAAA, EudraCT 
SAC 
1.3. Screened 
ES6 
Summary of Screening Status and Reasons for Screen 
Failures 
Journal Requirements 
Add footnote: For rescreened subjects, 
the earlier screening is not included. 
Subjects who got rescreened 
successfully are not 
seen as subjects with screening 
failures. 
SAC 
1.4. 
 
Enrolled 
NS1 
Summary of Number of Subjects by Country and Site ID 
EudraCT/Clinical Operations 
SAC 
Protocol Deviation 
1.5. 
 
ITT 
DV1 
Summary of Important Protocol Deviations 
ICH E3 
SAC 
Population Analysed 
1.6. 
 Screened 
SP1 
Summary of Study Populations  
IDSL 
SAC 
Demographic and Baseline Characteristics 
1.7. 
 
ITT 
DM1 
Summary of Demographic Characteristics 
ICH E3, GSK CTR, FDAAA, EudraCT 
Programming note: Include smoking 
history 
Wk6 IA, SAC 
1.8. 
 
ITT 
Non Standard 
POP_T1 
Summary of Baseline Efficacy Parameters 
Include all Efficacy Parameters  
SAC 
1.9. 
 
ITT 
DM5 
Summary of Race and Racial Combinations 
ICH E3, FDA, , GSK CTR, FDAAA, 
EudraCT 
SAC 


 
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Study Population Tables 
No. 
Populatio
n 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.10. 
 
ITT 
Non Standard 
POP_T2 
Summary of Hand OA Disease History 
 
SAC 
Medical condition & Concomitant Medications 
1.11. 
 
ITT 
Non Standard 
POP_T3 
Summary of Current Medical Conditions 
ICH E3 
SAC 
1.12. 
 
ITT 
CM1 
Summary of Concomitant Medication 
ICH E3 
SAC 
1.13. 
 
ITT 
CM1 
Summary of Concomitant OA Medication 
 
SAC 
1.14. 
ITT 
CM1 
Summary of Prior Medication 
 
SAC 
1.15. 
 
ITT 
CM1 
Summary of Prior OA Medication 
 
SAC 
Exposure and Treatment Compliance 
1.16. 
 
Safety 
EX1 
Summary of Exposure to Study Treatment 
ICH E3 
Rows include: 
- Duration of Drug Exposure (Days) 
- Number of Injections 
- Volume of Doses Received (ml) 
Footnote ‘Note: Exposure includes 13 
days after the last injection.’ 
SAC 


 
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12.15.5. 
Efficacy Tables 


 
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Efficacy: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
24h average hand pain NRS score  
2.1.  
ITT 
Non Standard 
EFF_T1 
Summary of Observed Result and Change from Baseline in 
24h average hand pain NRS Averaged over 7 days Prior to 
Each Visit 
 
AIR, Wk6 IA, 
SAC 
2.2.  
ITT 
Non Standard 
EFF_T2 
Mixed Model Repeated Measures Analysis (MMRM) of Change 
from Baseline in 24h average hand pain NRS Averaged over 7 
days Prior to Each Visit 
 
AIR, Wk6 IA, 
SAC 
24h worst hand pain NRS score  
2.3.  
ITT 
Non Standard 
EFF_T1 
Summary of Observed Result and Change from Baseline in 
24h worst hand pain NRS Averaged over 7 days Prior to Each 
Visit 
 
AIR, Wk6 IA, 
SAC 
2.4.  
ITT 
Non Standard 
EFF_T2 
Mixed Model Repeated Measures Analysis (MMRM) of Change 
from Baseline in 24h worst hand pain NRS Averaged over 7 
days Prior to Each Visit 
 
AIR, Wk6 IA, 
SAC 
Proportion of subjects with percentage reduction in 24h average hand pain NRS 
2.5.  
ITT 
Non Standard 
EFF_T3 
Summary and Analysis of the Proportion of Subjects Achieving 
a 30% or More Reduction in 24h average hand pain NRS 
Averaged over 7 days Prior to Each Visit 
 
SAC 
2.6.  
ITT 
Non Standard 
EFF_T3 
Summary and Analysis of the Proportion of Subjects Achieving 
a 50% or More Reduction in 24h average hand pain NRS 
Averaged over 7 days Prior to Each Visit, at Each Visit 
 
SAC 
Proportion of subjects with percentage reduction in 24h worst hand pain NRS 
2.7.  
ITT 
Non Standard 
EFF_T3 
Summary and Analysis of the Proportion of Subjects Achieving 
a 30% or More Reduction in 24h worst hand pain NRS 
Averaged over 7 days Prior to Each Visit, at Each Visit 
 
SAC 


 
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Efficacy: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.8.  
ITT 
Non Standard 
EFF_T3 
Summary and Analysis of the Proportion of Subjects Achieving 
a 50% or More Reduction in 24h worst hand pain NRS 
Averaged over 7 days Prior to Each Visit, at Each Visit 
 
SAC 
AUSCAN 3.1 NRS 
2.9.  
ITT 
Non Standard 
EFF_T1 
Summary of Observed Result and Change from Baseline in 
AUSCAN 3.1 NRS Individual Components Scores, at Each 
Visit 
Include: AUSCAN Pain, AUSCAN 
Physical Function, AUSCAN Stiffness, 
AUSCAN Total 
Note: Page by Component. 
Wk6 IA, SAC 
2.10. 
 
ITT 
Non Standard 
EFF_T2 
Mixed Model Repeated Measures Analysis (MMRM) of Change 
from Baseline in AUSCAN 3.1 NRS Individual Components 
Scores 
Include: AUSCAN Pain, AUSCAN 
Physical Function, AUSCAN Stiffness, 
AUSCAN Total 
Note: Page by Component. 
Wk6 IA, SAC 
Joint Assessments 
2.11. 
 
ITT 
Non Standard 
EFF_T1 
Summary of Observed Result and Change from Baseline in the 
Number of Soft Tissue Swollen Hand Joints, at Each Visit 
 
SAC 
2.12. 
 
ITT 
Non Standard 
EFF_T2 
Mixed Model Repeated Measures Analysis (MMRM) of Change 
from Baseline in the Number of Soft Tissue Swollen Hand 
Joints 
 
SAC 
2.13. 
 
ITT 
Non Standard 
EFF_T1 
Summary of Observed Result and Change from Baseline in the 
Number of Tender Hand Joints, at Each Visit 
 
SAC 
2.14. 
 
ITT 
Non Standard 
EFF_T2 
Mixed Model Repeated Measures Analysis (MMRM) of Change 
from Baseline in the Number of Tender Hand Joints 
 
SAC 
Disease Global Assessment 
2.16. 
ITT 
Non Standard 
EFF_T1 
Summary of Observed Result and Change from Baseline in the 
Physician’s Global Assessment (NRS 0-10), at Each Visit 
 
SAC 


 
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Efficacy: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.17. 
 
ITT 
Non Standard 
EFF_T2 
Mixed Model Repeated Measures Analysis (MMRM) of Change 
from Baseline in the Physician’s Global Assessment (NRS 0-
10) 
 
SAC 
2.18. 
 
ITT 
Non Standard 
EFF_T1 
Summary of Observed Result and Change from Baseline in the 
Patients’ Global Assessment (NRS 0-10), at Each Visit 
 
SAC 
2.19. 
 
ITT 
Non Standard 
EFF_T2 
Mixed Model Repeated Measures Analysis (MMRM) of Change 
from Baseline in the Patients’ Global Assessment (NRS 0-10) 
 
SAC 
Imaging 
2.20. 
 
ITT 
Non Standard 
EFF_T4 
Summary of Observed Result and Change from Baseline in 
Inflammatory Structural Joint Damage: HOAMRIS 
• 
Individual Components Include: 
Synovitis, Erosive damage, Cyst, 
Osteophyte Cartilage Space Loss, 
Mal-alignment and Bone Marrow 
Lesions 
SAC 
2.21. 
 
ITT 
Non Standard 
EFF_T5 
Mixed Model Repeated Measures Analysis (MMRM) of Change 
from Baseline in Inflammatory Structural Joint Damage: 
HOAMRIS 
• 
Individual Components Include: 
Synovitis, Erosive damage, Cyst, 
Osteophyte Cartilage Space Loss, 
Mal-alignment and Bone Marrow 
Lesions 
SAC 


 
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Efficacy: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.22. 
 
ITT 
Non Standard 
EFF_T4 
Summary of Observed Result and Change from Baseline in 
Inflammatory Structural Joint Damage: HOAMRIQ 
• 
Individual Components Include 
synovitis, normalised synovitis, 
normalised erosive damage, 
cartilage space loss, mal-
alignment and normalised bone 
marrow lesions. 
• 
Add footnote ‘Note: Synovitis is 
normalised by the total joint 
volume, erosive damage and 
bone marrow lesions are 
normalised by volume of bone.’ 
 
SAC 
2.23. 
 
ITT 
Non Standard 
EFF_T5 
Mixed Model Repeated Measures Analysis (MMRM) of Change 
from Baseline in Inflammatory Structural Joint Damage: 
HOAMRIQ 
• 
Individual Components Include 
synovitis, normalised synovitis, 
normalised erosive damage, 
cartilage space loss, mal-
alignment and normalised bone 
marrow lesions. 
• 
Add footnote ‘Note: Synovitis is 
normalised by the total joint 
volume, erosive damage and 
bone marrow lesions are 
normalised by volume of bone.’ 
 
SAC 


 
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Efficacy: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.24. 
 
ITT 
Non Standard 
EFF_T4 
Summary of Observed Result and Change from Baseline in 
Joint Inflammation: DCE-MRI 
• 
Includes ktrans, normalised 
Ktrans, VE, normalised VE, VP, 
normalised VP, IRE, normalised 
IRE, ME, normalised ME. 
• 
Add Footnote: ‘Note: All 
normalised parameters have been 
normalised using the Volume of 
Enhancing Pannus (VEP).’ 
• 
Add units to parameter line. 
SAC 
2.25. 
 
ITT 
Non Standard 
EFF_T5 
Mixed Model Repeated Measures Analysis (MMRM) of Change 
from Baseline in Joint Inflammation: DCE-MRI 
• 
Includes ktrans, normalised 
Ktrans, VE, normalised VE, VP, 
normalised VP, IRE, normalised 
IRE, ME, normalised ME. 
• 
Add Footnote: ‘Note: All 
normalised parameters have been 
normalised using the Volume of 
Enhancing Pannus (VEP).’ 
• 
Add units to parameter line. 
SAC 
2.26. 
 
ITT 
Non Standard 
EFF_T4 
Summary of Observed Result and Change from Baseline in 
Bone Shape Parameters 
• 
Includes Surface Area of Bone 
SAC 
Paracetamol 
2.27. 
 
ITT 
Non Standard 
EFF_T1 
Summary of Observed Result and Change from Baseline in 
24h Total Dosage of Paracetamol Averaged over 7 days Prior 
to Each Visit  
 
SAC 
2.28. 
 
ITT 
Non Standard 
EFF_T6 
Summary of the Proportion of Subjects Reporting Paracetamol 
Use in the 7 days Prior to Each Visit 
 
AIR, SAC 
 


 
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12.15.6. 
Efficacy Figures 


 
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Efficacy: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
24h average hand pain NRS score 
2.1.  
ITT 
Non Standard 
EFF_F1 
Individual Subject Profile Plots of 24h Average Hand Pain NRS 
Averaged Over 7 Days Prior to Each Visit, by Treatment Group 
X-Axis : Visit : Continuous Scale 
Y-Axis : Parameter (Unit) scaled 
accordingly 
Legend: no legend to be displayed 
SAC 
2.3.
ITT 
Non Standard 
EFF_F2 
Plot of Mean and 95% CI of Change from Baseline in 24h 
Average Hand Pain NRS Averaged over 7 days Prior to Each 
Visit 
X-Axis :  Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
AIR, Wk6 IA, 
SAC 
2.4.  
ITT 
Non Standard 
EFF_F2 
Plot of Least Squares Means and 95% CI of Change from 
Baseline in 24h Average Hand Pain NRS Averaged over 7 
days Prior to Each Visit (from Repeated Measures Analysis) 
X-Axis : Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
Add footnote: ‘Note: Repeated 
Measures Analysis adjusted for 
Baseline Value, Treatment Group, 
Visit, Treatment Group by Visit 
Interaction [and Baseline Value by Visit 
Interaction]’ 
AIR, Wk6 IA, 
SAC 
24h worst hand pain NRS score 
2.5.  
ITT 
Non Standard 
EFF_F1 
Individual Subject Profile Plots of 24h Worst Hand Pain NRS 
Averaged over 7 days Prior to Each Visit, by Treatment Group 
X-Axis : Visit : Continuous Scale 
Y-Axis : Parameter (Unit) scaled 
accordingly 
Legend: no legend to be displayed 
SAC 
2.6.  
ITT 
Non Standard 
EFF_F1 
Individual Subject Profile Plots of Daily 24h Worst Hand Pain 
NRS, by Treatment Group 
X-Axis : Day : Continuous Scale 
Y-Axis : Parameter (Unit) scaled 
accordingly 
Legend: no legend to be displayed 
SAC 


 
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Efficacy: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.7.  
ITT 
Non Standard 
EFF_F2 
Plot of Mean and 95% CI of Change from Baseline in 24h 
Worst Hand Pain NRS Averaged over 7 days Prior to Each 
Visit, at Each Visit 
X-Axis : Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
AIR, Wk6 IA, 
SAC 
2.8.  
ITT 
Non Standard 
EFF_F2 
Plot of Least Squares Means and 95% CI of Change from 
Baseline in 24h worst hand pain NRS Averaged over 7 days 
Prior to Each Visit (from Repeated Measures Analysis), at Each 
Visit 
X-Axis : Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
Add footnote: ‘Note: Repeated 
Measures Analysis adjusted for 
Baseline Value, Treatment Group, 
Visit, Treatment Group by Visit 
Interaction [and Baseline Value by Visit 
Interaction]’ 
AIR, Wk6 IA, 
SAC 
Proportion of subjects with percentage reduction in 24h average hand pain NRS 
2.9.  
ITT 
Non Standard 
EFF_F2 
Proportion of Subjects in Each Treatment Group Achieving a 
30% Reduction in 24h Average Hand Pain NRS Averaged over 
7 days Prior to Each Visit 
X-Axis: Visit 
Y-Axis: Proportion of Subjects (%) 
 
Note: Do not incude CI’s 
SAC 
2.10. 
ITT 
Non Standard 
EFF_F3 
Proportion of Subjects in Each Treatment Group Achieving a 
50% Reduction in 24h Average Hand Pain NRS Averaged over 
7 days Prior to Each Visit, at Each Visit 
X-Axis: Visit 
Y-Axis: Proportion of Subjects (%) 
 
Note: Do not incude CI’s 
SAC 
Proportion of subjects with percentage reduction in 24h worst hand pain NRS 
2.11. 
ITT 
Non Standard 
EFF_F3 
Proportion of Subjects in Each Treatment Group Achieving a 
30% Reduction in 24h Worst Hand Pain NRS Averaged over 7 
days Prior to Each Visit, at Each Visit 
X-Axis: Visit 
Y-Axis: Proportion of Subjects (%) 
 
Note: Do not incude CI’s 
SAC 


 
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Efficacy: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.12. 
ITT 
Non Standard 
EFF_F3 
Proportion of Subjects in Each Treatment Group Achieving a 
50% Reduction in 24h Worst Hand Pain NRS Averaged over 7 
days Prior to Each Visit, at Each Visit 
X-Axis: Visit 
Y-Axis: Proportion of Subjects (%) 
 
Note: Do not incude CI’s 
SAC 
AUSCAN 3.1 NRS 
2.13. 
ITT 
Non Standard 
EFF_F1 
Individual Subject Profile Plots of AUSCAN 3.1 NRS Individual 
Component Scores, by Treatment Group 
X-Axis : Visit 
Y-Axis : Parameter (Unit) scaled 
accordingly 
 
Individual Components include: 
AUSCAN Pain, AUSCAN Physical 
Function, AUSCAN Stiffness, 
AUSCAN Total 
SAC 
2.14. 
ITT 
Non Standard 
EFF_F2 
Plot of Mean and 95% CI of Change from Baseline in AUSCAN 
3.1 NRS Individual Component Scores, at Each Visit 
X-Axis : Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
Individual Components include: 
AUSCAN Pain, AUSCAN Physical 
Function, AUSCAN Stiffness, 
AUSCAN Total 
Wk6 IA, SAC 


 
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Efficacy: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.15. 
ITT 
Non Standard 
EFF_F2 
Plot of Least Squares Means and 95% CI of Change from 
Baseline in AUSCAN 3.1 NRS Individual Component Scores 
(from Repeated Measures Analysis) 
X-Axis : Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
Add footnote: ‘Note: Repeated 
Measures Analysis adjusted for 
Baseline Value, Treatment Group, 
Visit, Treatment Group by Visit 
Interaction [and Baseline Value by Visit 
Interaction]’ 
 
Individual Components include: 
AUSCAN Pain, AUSCAN Physical 
Function, AUSCAN Stiffness, 
AUSCAN Total  
Wk6 IA, SAC 
Joint Assessments 
2.16. 
ITT 
Non Standard 
EFF_F2 
Plot of Mean and 95% CI of Change from Baseline in Number 
of Soft Tissue Swollen Hand Joints, at Each Visit 
X-Axis : Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
SAC 
2.17. 
ITT 
Non Standard 
EFF_F2 
Plot of Least Squares Means and 95% CI of Change from 
Baseline in the Number of Soft Tissue Swollen Hand Joints 
(from Repeated Measures Analysis) 
X-Axis : Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
Add footnote: ‘Note: Repeated 
Measures Analysis adjusted for 
Baseline Value, Treatment Group, 
Visit, Treatment Group by Visit 
Interaction [and Baseline Value by Visit 
Interaction]’ 
SAC 


 
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Efficacy: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.18. 
ITT 
Non Standard 
EFF_F2 
Plot of Mean and 95% CI of Change from Baseline in Number 
of Tender Hand Joints, at Each Visit 
X-Axis : Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
SAC 
2.19. 
ITT 
Non Standard 
EFF_F2 
Plot of Least Squares Means and 95% CI of Change from 
Baseline in the Number of Tender Hand Joints (from Repeated 
Measures Analysis) 
X-Axis : Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
Add footnote: ‘Note: Repeated 
Measures Analysis adjusted for 
Baseline Value, Treatment Group, 
Visit, Treatment Group by Visit 
Interaction [and Baseline Value by Visit 
Interaction]’ 
SAC 
Disease Global Assessment 
2.20. 
ITT 
Non Standard 
EFF_F2 
Plot of Mean and 95% CI of Change from Baseline in 
Physician’s Global Assessment (NRS 0-10), at Each Visit 
X-Axis : Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
SAC 
2.21. 
ITT 
Non Standard 
EFF_F2 
Plot of Least Squares Means and 95% CI of Change from 
Baseline in Physician’s Global Assessment (NRS 0-10) (from 
Repeated Measures Analysis) 
X-Axis : Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
Add footnote: ‘Note: Repeated 
Measures Analysis adjusted for 
Baseline Value, Treatment Group, 
Visit, Treatment Group by Visit 
Interaction [and Baseline Value by Visit 
Interaction]’ 
SAC 
2.22. 
ITT 
Non Standard 
EFF_F2 
Plot of Mean and 95% CI of Change from Baseline in Patients’ 
Global Assessment, at Each Visit 
X-Axis : Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
SAC 


 
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Efficacy: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.23. 
ITT 
Non Standard 
EFF_F2 
Plot of Least Squares Means and 95% CI of Change from 
Baseline in Patients’ Global Assessment (from Repeated 
Measures Analysis) 
X-Axis : Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
Add footnote: ‘Note: Repeated 
Measures Analysis adjusted for 
Baseline Value, Treatment Group, 
Visit, Treatment Group by Visit 
Interaction [and Baseline Value by Visit 
Interaction]’ 
SAC 
Imaging 
2.24. 
ITT 
 
Non Standard 
EFF_F2 
Plot of Mean and 95% CI of Change from Baseline in 
Inflammatory Structural Joint Damage: HOAMRIS 
X-Axis : Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
Individual Components Include: 
Synovitis, Erosive damage, Cyst, 
Osteophyte Cartilage Space Loss, 
Mal-alignment and Bone Marrow 
Lesions 
SAC 


 
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Efficacy: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.25. 
ITT 
Non Standard 
EFF_F2 
Plot of Least Squares Means and 95% CI of Change from 
Baseline in Inflammatory Structural Joint Damage: HOAMRIS 
(from Repeated Measures Analysis) 
X-Axis : Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
Individual Components Include: 
Synovitis, Erosive damage, Cyst, 
Osteophyte Cartilage Space Loss, 
Mal-alignment and Bone Marrow 
Lesions 
Add footnote: ‘Note: Repeated 
Measures Analysis adjusted for 
Baseline Value, Treatment Group, 
Visit, Treatment Group by Visit 
Interaction [and Baseline Value by Visit 
Interaction]’ 
 
2.26. 
ITT 
 
Non Standard 
EFF_F2 
Plot of Mean and 95% CI of Change from Baseline in 
Inflammatory Structural Joint Damage: HOAMRIQ 
X-Axis : Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
Individual Components Include: 
synovitis, normalised synovitis, 
normalised erosive damage, cartilage 
space loss, mal-alignment and 
normalised bone marrow lesions. 
 
Add footnote ‘Note: Synovitis is 
normalised by the total joint volume, 
erosive damage and bone marrow 
lesions are normalised by volume of 
bone.’ 
 
SAC 


 
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Efficacy: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.27. 
ITT 
Non Standard 
EFF_F2 
Plot of Least Squares Means and 95% CI of Change from 
Baseline in Inflammatory Structural Joint Damage: HOAMRIQ 
(from Repeated Measures Analysis) 
X-Axis : Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
Individual Components Include: 
synovitis, normalised synovitis, 
normalised erosive damage, cartilage 
space loss, mal-alignment and 
normalised bone marrow lesions. 
 
Add footnote ‘Note: Synovitis is 
normalised by the total joint volume, 
erosive damage and bone marrow 
lesions are normalised by volume of 
bone.’ 
 
Add footnote: ‘Note: Repeated 
Measures Analysis adjusted for 
Baseline Value, Treatment Group, 
Visit, Treatment Group by Visit 
Interaction [and Baseline Value by Visit 
Interaction]’ 
SAC 


 
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Efficacy: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.28. 
ITT 
Non Standard 
EFF_F2 
Plot of Mean and 95% CI of Change from Baseline in Joint 
Inflammation: DCE-MRI 
X-Axis : Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
Includes ktrans, normalised Ktrans, 
VE, normalised VE, VP, normalised 
VP, IRE, normalised IRE, ME, 
normalised ME. 
 
Add Footnote: ‘Note: All normalised 
parameters have been normalised 
using the Volume of Enhancing 
Pannus (VEP).’ 
 
Add units to parameter line. 
SAC 


 
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Efficacy: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.29. 
ITT 
Non Standard 
EFF_F2 
Plot of Least Squares Means and 95% CI of Change from 
Baseline in Joint Inflammation: DCE-MRI (from Repeated 
Measures Analysis) 
X-Axis : Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
Includes ktrans, normalised Ktrans, 
VE, normalised VE, VP, normalised 
VP, IRE, normalised IRE, ME, 
normalised ME. 
 
Add Footnote: ‘Note: All normalised 
parameters have been normalised 
using the Volume of Enhancing 
Pannus (VEP).’ 
 
Add units to parameter line. 
 
Add footnote: ‘Note: Repeated 
Measures Analysis adjusted for 
Baseline Value, Treatment Group, 
Visit, Treatment Group by Visit 
Interaction [and Baseline Value by Visit 
Interaction]’ 
SAC 
2.30. 
ITT 
Non Standard 
EFF_F2 
Plot of Mean and 95% CI of Change from Baseline in Bone 
Shape Parameters 
X-Axis : Visit 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
Includes Surface Area of Bone 
 
Add units to parameter line. 
SAC 
Paracetamol  


 
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Efficacy: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.31. 
ITT 
Non Standard 
EFF_F2 
Plot of Mean and 95% CI of Change from Baseline in 24h Total 
Dosage of Paracetamol Averaged over 7 days Prior to Each 
Visit 
 
AIR, SAC 
Additional MRI 
2.32. 
ITT 
Non Standard  
Ordered Scatter Plot of Change from Baseline in Inflammatory 
Structural Joint Damage: HOAMRIS 
X-Axis : Percentile 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
SAC 
2.33. 
ITT 
Non Standard  
Ordered Scatter Plot of Change from Baseline in Inflammatory 
Structural Joint Damage: HOAMRIQ 
X-Axis : Percentile 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
SAC 
2.34. 
ITT 
Non Standard  
Ordered Scatter Plot of Change from Baseline in Joint 
Inflammation: DEC-MRI 
X-Axis : Percentile 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
SAC 
2.35. 
ITT 
Non Standard  
Ordered Scatter Plot of Change from Baseline in Bone Shape 
Parameters 
X-Axis : Percentile 
Y-Axis : Change from Baseline in 
Parameter (Unit) scaled accordingly 
 
SAC 
 


 
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12.15.7. 
Safety Tables 


 
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111 
 
Safety : Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events 
3.1.  
Safety 
Non Standard 
SAFE_T1 
Overall Summary of Adverse Events 
 
SAC 
3.2.  
Safety 
AE1 
Summary of All Adverse Events by System Organ Class and 
Preferred Term 
ICH E3 
Wk6 IA, SAC 
3.3.  
Safety 
AE3 
Summary of Common (>=5%) Adverse Events by Overall 
Frequency 
ICH E3 
 
SAC 
3.4.  
Safety 
AE1 
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term 
GSK CTR 
Wk6 IA, SAC 
3.5.  
Safety 
AE15 
 
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of 
Participant and Occurrences)  
FDAAA, EudraCT 
SAC 
Serious and Other Significant Adverse Events 
3.6.  
Safety 
AE16  
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences) 
 FDAAA, EudraCT 
 
Wk 6 IA, SAC 
3.7.  
Safety 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study 
by System Organ Class and Preferred Term  
IDSL 
Wk6 IA, SAC 
3.8.  
Safety 
Non Standard 
SAFE_T2 
Summary of Adverse Events of Special Interest 
Include any AESI, Serious Infections 
with subgroup of serious respiratory 
infections, Opportunistic Infections, 
PAP, Neutropenia, Hypersensitivity 
Reactions 
SAC 
3.9.  
Safety 
Non Standard 
SAFE_T3 
Summary of Adverse Events of Special Interest – Injection Site 
Reactions 
 
SAC 


 
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Safety : Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.10. 
Safety 
Non Standard 
SAFE_T4 
Summary of Adverse Events of Special Interest – Systemic 
Hypersensitivity Reactions related to GSK3196165 
 
SAC 
Laboratory  
3.11. 
Safety 
LB1 
Summary of Clinical Chemistry Changes from Baseline  
ICH E3 
SAC 
3.12. 
Safety 
LB1 
Summary of Hematology Changes from Baseline 
ICH E3 
SAC 
3.13. 
Safety 
LB1 
Summary of Urinalysis Changes from Baseline 
ICH E3 
SAC 
3.14. 
Safety 
Non Standard 
SAFE_T6 
Summary of the Proportion of Subjects with Urinalysis Findings 
 
SAC 
3.15. 
Safety 
Non Standard 
SAFE_T7 
Summary of Laboratory Parameters of Interest by CTCAE 
Grade 
Note: Definitions of Grades can be 
found in and Laboratory Parameters of 
Interest can be found in Section 
12.12.1. 
If multiple values are mapped to one 
visit: the value with the worst CTCAE 
grade will be considered. If there are 
more than one value of this grade, the 
later value will be considered. 
SAC 


 
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Safety : Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.16. 
Safety 
LB18 
Shift Table of Laboratory Parameters of Interest from Baseline 
to Worst CTCAE Grade  
Note: Definitions of Grades can be 
found in and Laboratory Parameters of 
Interest can be found in Section 
12.12.1. 
Add footnotes:  
Note: Just parameters which can be 
classified in CTCAE grades are 
displayed. 
Note: Laboratory parameters of 
interest that have no results with a 
CTCAE grade were not included. 
SAC 
ECG 
3.17. 
 
Safety 
EG1 
Summary of ECG Findings  
IDSL 
SAC 
3.18. 
Safety 
EG2 
Summary of Change from Baseline in ECG Values by Visit 
IDSL 
SAC 
3.19. 
Safety 
EG10 
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category 
IDSL 
SAC 
Vital Signs 
3.20. 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs  
 
SAC 
Immunogenicity 
3.21. 
Safety 
Non Standard  
SAFE_T8 
Summary of Immunogenicity Results  
 
SAC 
Pulmonary Assessments 
3.22. 
Safety 
Non Standard  
SAFE_T9 
Summary of Subjects with Pulmonary Findings 
 
SAC 


 
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Safety : Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.23. 
Safety 
Non Standard 
SAFE_T5 
Summary of Persistent Cough, Dyspnea and DLCO Decrease 
 
SAC 
3.24. 
Safety 
Non Standard  
SAFE_T10 
Summary of Pulse Oximetry 
 
SAC 
3.25. 
Safety 
Non Standard  
SAFE_T11 
Summary of Change from Baseline in Pulse Oximetry (%) 
 
SAC 
3.26. 
Safety 
Non Standard 
SAFE_T11 
Summary of Change from Baseline in DLCO 
Note: Baseline is defined as the lowest 
value during the screening period prior 
to the first study drug administration. 
SAC 
3.27. 
Safety 
Non Standard 
SAFE_T12 
Proportion of Subjects with a 15% Relative Decrease from 
Baseline in DLCO 
 
SAC 
3.28. 
Safety 
Non Standard 
SAFE_T11 
Summary of Change from Baseline in Spirometry Data 
Please add a parameter information 
above the table for the two separate 
parameters FEV1 and FVC 
SAC 
3.29. 
Safety 
Non Standard 
SAFE_T13 
Summary of Cough Data 
 
SAC 
3.30. 
Safety 
Non Standard  
SAFE_T11 
Summary of Change from Baseline in Borg Dyspnea Score 
 
SAC 
3.31. 
Safety 
Non Standard 
SAFE_T14 
Summary of Borg Dyspnea Questionnaire Data 
 
SAC 
 


 
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12.15.8. 
Safety Figures 
Safety : Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events 
3.1.  
Safety 
AE10 
Plot of Common (>=5%) Adverse Events and Relative Risks 
Sorted by decreasing relative risk 
SAC  
Laboratory Values 
3.2.  
Safety 
LB9 
Distribution of Laboratory Parameters of Interest by Visit 
and Treatment with Maximum over Time 
Generate plots for the following 
parameters Hemoglobin, Total WBCs, 
Neutrophil Counts, Platelet Counts, 
ALT, AST and Total Bilirubin. 
SAC 
ECGs 
3.3.  
Safety 
EG8 
Distribution of QTc Change by Time and Treatment 
 
SAC 
Pulmonary Assessments 
3.4.  
Safety 
Non Standard  
SAFE_F1 
DLCO Patient Profiles Over Time by Treatment 
 
SAC 
 


 
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12.15.9. 
Pharmacokinetic Tables  
Pharmacokinetic : Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK Concentration 
4.1.  
PK 
Non Standard 
EFF_T1 
Summary of GSK3196165 serum concentrations by visit 
 
PK IA, Wk6 
IA, SAC 
4.2.  
PK 
Non Standard 
Summary of derived steady state exposure parameters 
 
PK IA, Wk6 IA  
PK parameters 
4.3.  
PK 
Non Standard 
Summary of derived PK parameters 
 
PK IA, Wk6 IA  
 


 
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12.15.10. Pharmacokinetic Figures  
Pharmacokinetic : Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK concentration 
4.1.  
PK 
Non Standard 
Plot of GSK3196165 concentration by visit 
 
PK IA, Wk6 IA 
4.2.  
PK 
Non Standard 
Comparison of GSK3196165 concentration by visit in 
HOA and RA population 
 
PK IA, Wk6 IA 
4.3.  
PK 
Non Standard 
Comparison of derived GSK3196165 steady state 
exposure in HOA, RA, healthy volunteers and multiple 
sclerosis population 
 
PK IA, Wk6 IA 
PK parameters 
4.4.  
PK 
Non Standard 
Plot of distribution of the derived PK parameters in HOA, 
RA, healthy volunteers and multiple sclerosis population 
 
PK IA, Wk6 IA 
 


 
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12.15.11. Pharmacodynamic and / or Biomarker Tables  


 
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Pharmacodynamic and/or Biomarker : Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Target Engagement Biomarkers 
5.1.  
Safety 
Non Standard 
PD_T1a or 
PD_T1b 
Summary of Observed Result and Change from Baseline in 
Target Engagement Biomarkers  
Use appropriate table shell depending 
on whether or not log transformation 
has been performed.  
If there are both log transformed and 
not log transformed biomarkers, then 
display in two separate outputs. 
SAC 
Predictive Biomarkers 
5.2.  
Safety 
Non Standard 
PD_T1a or 
PD_T1b 
Summary of Observed Result and Change from Baseline in 
Predictive Biomarkers  
Use appropriate table shell depending 
on whether or not log transformation 
has been performed.  
If there are both log transformed and 
not log transformed biomarkers, then 
display in two separate outputs. 
SAC 
5.3.  
Safety 
Non Standard 
PD_T2a or 
PD_T2b 
Mixed Model Repeated Measures Analysis (MMRM) of Change 
from Baseline in Predictive Biomarkers 
Use appropriate table shell depending 
on whether or not log transformation 
has been performed.  
If there are both log transformed and 
not log transformed biomarkers, then 
display in two separate outputs. 
SAC 
Cartilage Biomarkers 
5.4.  
Safety 
Non Standard 
PD_T1a or 
PD_T1b 
Summary of Observed Result and Change from Baseline in 
Cartilage Biomarkers  
Use appropriate table shell depending 
on whether or not log transformation 
has been performed.  
If there are both log transformed and 
not log transformed biomarkers, then 
display in two separate outputs. 
SAC 
Mechanistic Biomarkers 


 
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Pharmacodynamic and/or Biomarker : Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
5.5.  
Safety 
Non Standard 
PD_T1a or 
PD_T1b 
Summary of Observed Result and Change from Baseline in 
Mechanistic Biomarkers  
Use appropriate table shell depending 
on whether or not log transformation 
has been performed.  
If there are both log transformed and 
not log transformed biomarkers, then 
display in two separate outputs. 
SAC 
Safety Biomarkers 
5.6.  
Safety 
Non Standard 
PD_T1a or 
PD_T1b 
Summary of Observed Result and Change from Baseline in 
Safety Biomarkers  
Use appropriate table shell depending 
on whether or not log transformation 
has been performed.  
If there are both log transformed and 
not log transformed biomarkers, then 
display in two separate outputs. 
SAC 
 


 
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12.15.12. Pharmacodynamic and / or Biomarker Figures 


 
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Pharmacodynamic and or Biomarker : Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Target Engagement Biomarkers 
5.1.  
Safety 
Non Standard 
PD_F2 
Plot of Distribution of Target Engagement Biomarkers 
 
SAC 
5.2.  
Safety 
Non Standard 
PD_F1 
Plot of Mean/Geometric Mean and 95% CI of Change from 
Baseline in Target Engagement Biomarkers, at Each Visit 
X-Axis: Visit 
Y-axis: “Change from Baseline in 
<Biomarker>” or “Ratio to Baseline in 
<Biomarker>” if log-transformation is 
required 
SAC 
Predictive Biomarkers 
5.3.  
Safety 
Non Standard 
PD_F2 
Plot of Distribution of Predictive Biomarkers 
 
SAC 
5.4.  
Safety 
Non Standard 
PD_F1 
Plot of Mean/Geometric Mean and 95% CI of Change from 
Baseline in Predictive Biomarkers, at Each Visit 
X-Axis: Visit 
Y-axis: “Change from Baseline in 
<Biomarker>” or “Ratio to Baseline in 
<Biomarker>” if log-transformation is 
required 
SAC 
5.5.  
Safety 
Non Standard 
PD_F1 
Plot of Least Squares Means and 95% CI of Change from 
Baseline in Predictive Biomarkers (from Repeated Measures 
Analysis) 
X-Axis: Visit 
Y-axis: “Change from Baseline in 
<Biomarker>” or “Ratio to Baseline in 
<Biomarker>” if log-transformation is 
required 
SAC 
Cartilage Biomarkers 
5.6.  
Safety 
Non Standard 
PD_F2 
Plot of Distribution of Cartilage Biomarkers 
 
SAC 


 
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Pharmacodynamic and or Biomarker : Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
5.7.  
Safety 
Non Standard 
PD_F1 
Plot of Mean/Geometric Mean and 95% CI of Change from 
Baseline in Cartilage Biomarkers, at Each Visit 
X-Axis: Visit 
Y-axis: “Change from Baseline in 
<Biomarker>” or “Ratio to Baseline in 
<Biomarker>” if log-transformation is 
required 
SAC 
Mechanistic Biomarkers 
5.8.  
Safety 
Non Standard 
PD_F2 
Plot of Distribution of Mechanistic Biomarkers 
 
SAC 
5.9.  
Safety 
Non Standard 
PD_F1 
Plot of Mean/Geometric Mean and 95% CI of Change from 
Baseline in Mechanistic Biomarkers, at Each Visit 
X-Axis: Visit 
Y-axis: “Change from Baseline in 
<Biomarker>” or “Ratio to Baseline in 
<Biomarker>” if log-transformation is 
required 
SAC 
Safety Biomarkers 
5.10. 
Safety 
Non Standard 
PD_F2 
Plot of Distribution of Safety Biomarkers 
 
SAC 
5.11. 
Safety 
Non Standard 
PD_F1 
Plot of Mean/Geometric Mean and 95% CI of Change from 
Baseline in Safety Biomarkers, at Each Visit 
X-Axis: Visit 
Y-axis: “Change from Baseline in 
<Biomarker>” or “Ratio to Baseline in 
<Biomarker>” if log-transformation is 
required 
SAC 
 
 


 
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12.15.13. Pharmacokinetic / Pharmacodynamic Figures  
Pharmacokinetic / Pharmacodynamic : Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
6.1.  
PK 
Non Standard 
Plot of change from baseline in 24h average hand pain 
intensity at week 4 versus pre-dose concentration at week 
4 
 
SAC  
6.2.  
PK 
Non Standard 
Plot of change from baseline in 24h average hand pain 
intensity at week 6versus pre-dose concentration at week 
6  
 
SAC 
 


 
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12.15.14. ICH Listings 


 
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ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.  
Screened 
ES7 
Listing of Reasons for Screening Failure 
Journal guidelines 
SAC 
2.  
Enrolled 
 
ES2 
Listing of Reasons for Study Withdrawal 
ICH E3 
 
SAC 
4. 
Enrolled 
BL1 
Listing of Subjects for Whom the Treatment Blind was Broken 
ICH E3 
SAC 
5.  
Enrolled 
TA1 
Listing of Planned and Actual Treatments 
IDSL 
SAC 
Protocol Deviations 
6.  
Enrolled 
DV2 
Listing of Important Protocol Deviations 
ICH E3 
 
SAC 
7.  
Enrolled 
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
ICH E3 
SAC 
Populations Analysed 
8.  
Enrolled 
SA3 
Listing of Subjects Excluded from Any Population 
 
ICH E3 
 
SAC 
Demography 
9.  
ITT 
DM2 
Listing of Demographic Characteristics 
ICH E3 
SAC 
10.  
ITT 
DM9 
Listing of Race 
ICH E3 
SAC 
Medical condition & concomitant medications 
11.  
ITT 
MH2 
Listing of Current/Past Medical Conditions 
 
SAC 
12.  
ITT 
CM3 
Listing of Prior and Concomitant Medications (Non-OA) 
IDSL 
SAC 
13.  
ITT 
CM3 
Listing of Prior and Concomitant OA Medications 
 
SAC 
16. 
ITT 
Non Standard 
POP_L1 
Listing of OA Disease History 
 
SAC 


 
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ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Exposure 
17.  
Safety 
EX1 
Listing of Exposure to Study Treatment Data 
ICH E3 
SAC 
Adverse Events 
18.  
Safety 
AE8 
Listing of All Adverse Events 
ICH E3 
SAC 
19.  
Safety 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
ICH E3 
SAC 
20.  
Safety 
AE2 
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text 
IDSL 
SAC 
Serious and Other Significant Adverse Events 
21.  
Safety 
AE8 
Listing of Fatal Serious Adverse Events 
ICH E3 
Wk6 IA, SAC 
22.  
Safety 
AE8 
Listing of Non-Fatal Serious Adverse Events 
ICH E3 
SAC 
23.  
Safety 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event 
ICH E3 
SAC 
24.  
Safety 
AE8 
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment 
ICH E3 
SAC 
25.  
Safety 
AE7 
Listing of Subject Numbers for Adverse Events of Special 
Interest (AESIs) 
ICH E3 
SAC 
Labs 
26.  
Safety 
LB5 
Listing of All Laboratory Data for Subjects with Any Value of 
Potential Clinical Importance 
ICH E3 
SAC 
27.  
Safety 
LB5 
Listing of Laboratory Values of Potential Clinical Importance 
 
SAC 
28.  
Safety 
LB14 
Listing of Laboratory Data with Character Results 
ICH E3 
SAC 
29.  
Safety 
UR2a 
Listing of Urinalysis Data for Subjects with Abnormalities of 
Potential Clinical Importance 
ICH E3 
SAC 
Vital signs 


 
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ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
30.  
Safety 
VS4 
Listing of Vital Signs Data 
 
SAC 
ECG 
31. 
Safety 
EG3 
Listing of ECG Values for Subjects with Any Value of Potential 
Clinical Importance 
IDSL 
SAC 
32.  
Safety 
EG3 
Listing of ECG Values of Potential Clinical Importance 
IDSL 
SAC 
33.  
Safety 
EG5 
Listing of All ECG Findings for Subjects with an Abnormal ECG 
Finding 
IDSL 
SAC 
34.  
Safety 
EG5 
Listing of Abnormal ECG Findings 
IDSL 
SAC 
Vital signs 
35.  
Safety 
VS4 
Listing of Vital Signs of Potential Clinical Importance 
IDSL 
Include Systolic BP, Diastolic BP, 
Pulse and Oxygen Saturation. 
SAC 
36.  
Safety 
VS4 
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance 
IDSL 
SAC 
Immunogenicity 
37.  
Safety 
IMM2 
Listing of Immunogenicity Results  
 
SAC 
Pulmonary Assessments 
38.  
Safety 
Non Standard 
POP_L2 
Listing of Subjects with Persistent Cough, Dyspnea or DLCO 
Decrease 
 
SAC 
39.  
Safety 
Non Standard 
POP_L3 
Listing of Pulmonary Assessments 
 
SAC 
40.  
Safety 
Non Standard 
POP_L4 
Listing of Pulmonary Function Tests 
 
SAC 


 
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12.15.15. Non-ICH Listings  


 
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Non-ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Efficacy 
41.  
ITT 
Non Standard 
EFF_L1 
Listing of Individual Subject Hand Pain NRS Averaged over 7 
Days Prior to Each Visit 
 
SAC 
42.  
ITT 
Non-Standard 
EFF_L2 
Statistical Listing of Repeated Measures Analysis of Change 
from Baseline in Average Hand Pain NRS Averaged over 7 
Days Prior to Each Visit 
 
SAC 
43.  
ITT 
Non-Standard 
EFF_L2 
Statistical Listing of GEE Analysis on Proportion of Subjects 
Achieving 30% Reduction in Average Hand Pain NRS 
Averaged over 7 Days Prior to Each Visit 
 
SAC 
44.  
ITT 
Non-Standard 
EFF_L2 
Statistical Listing of GEE Analysis on Proportion of Subjects 
Achieving 50% Reduction in Average Hand Pain NRS 
Averaged over 7 Days Prior to Each Visit 
 
SAC 
45.  
ITT 
Non-Standard 
EFF_L2 
Statistical Listing of Repeated Measures Analysis of Change 
from Baseline in Worst Hand Pain NRS Averaged over 7 Days 
Prior to Each Visit, by Visit 
 
SAC 
46.  
ITT 
Non-Standard 
EFF_L2 
Statistical Listing of GEE Analysis on Proportion of Subjects 
Achieving 30% Reduction in Worst Hand Pain NRS Averaged 
over 7 Days Prior to Each Visit 
 
SAC 
47.  
ITT 
Non-Standard 
EFF_L2 
Statistical Listing of GEE Analysis on Proportion of Subjects 
Achieving 50% Reduction in Worst Hand Pain NRS Averaged 
over 7 Days Prior to Each Visit 
 
SAC 
48.  
ITT 
Non-Standard 
EFF_L3 
Listing of Individual Subject AUSCAN 3.1 NRS Individual 
Component Scores 
 
SAC 
49.  
ITT 
Non-Standard 
EFF_L2 
Statistical Listing of Repeated Measures Analysis of Change 
from Baseline in AUSCAN 3.1 NRS Individual Component 
Scores, by Visit 
 
SAC 


 
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Non-ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
50.  
ITT 
Non-Standard 
EFF_L4 
Listing of Individual Subject Number of Soft Tissue Swollen or 
Tender Hand Joints, by Visit 
 
SAC 
51.  
ITT 
Non-Standard 
EFF_L2 
Statistical Listing of Repeated Measures Analysis of Change 
from Baseline in Number of Soft Tissue Swollen Hand Joints, 
by Visit 
 
SAC 
52.  
ITT 
Non-Standard 
EFF_L2 
Statistical Listing of Repeated Measures Analysis of Change 
from Baseline in Number of Tender Hand Joints, by Visit 
 
SAC 
53.  
ITT 
Non Standard 
EFF_L5 
Listing of Individual Subject Pain/Tenderness Hand Joint 
Assessment, by Visit 
 
SAC 
54.  
ITT 
GA4 
Listing of Individual Subject Patient’s and Physician’s Global 
Assessments, by Visit 
List both the Patients and Physicians 
Global Assessments in the same 
output with separate columns for each 
SAC 
55.  
ITT 
Non-Standard 
EFF_L2 
Statistical Listing of Repeated Measures Analysis of Change 
from Baseline in Physician’s Global Assessment, by Visit 
 
SAC 
56.  
ITT 
Non-Standard 
EFF_L2 
Statistical Listing of Repeated Measures Analysis of Change 
from Baseline in Patient’s Global Assessment, by Visit 
 
SAC 
Imaging 
57.  
ITT 
 
Non Standard 
EFF_L6 
Listing of Individual Subject Inflammatory Structural Joint 
Damage: HOAMRIS 
Individual Components Include: 
Synovitis, Erosive damage, Cyst, 
Osteophyte Cartilage Space Loss, 
Mal-alignment and Bone Marrow 
Lesions 
SAC 
58.  
ITT 
 
Non Standard 
EFF_L6 
Listing of Individual Subject Inflammatory Structural Joint 
Damage: HOAMRIQ 
Individual Components Include: 
synovitis, normalised synovitis, 
normalised erosive damage, cartilage 
space loss, mal-alignment and 
normalised bone marrow lesions 
SAC 


 
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Non-ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
59.  
ITT 
Non Standard 
EFF_L6 
Listing of Individual Subject Joint Inflammation: DCE-MRI 
Includes ktrans, normalised Ktrans, 
VE, normalised VE, VP, normalised 
VP, IRE, normalised IRE, ME, 
normalised ME. 
SAC 
60.  
ITT 
Non Standard 
EFF_L6 
Listing of Individual Subject Bone Shape Parameter 
Includes Surface Area of Bone 
SAC 
PK 
61.  
PK 
Non Standard 
PK_L1 
Listing of Individual Subject Pharmacokinetic Data 
 
SAC 
Biomarker 
62.  
Safety 
Non Standard 
PD_L1 
Listing of Individual Subject Target Engagement 
 
SAC 
63.  
Safety 
Non Standard 
PD_L1 
Listing of Individual Subject Predictive Biomarkers 
 
SAC 
64.  
Safety 
Non Standard 
PD_L1 
Listing of Individual Subject Cartilage Biomarkers 
 
SAC 
65.  
Safety 
Non Standard 
PD_L1 
Listing of Individual Subject Mechanistic Biomarkers 
 
SAC 
66.  
Safety 
Non Standard 
PD_L1 
Listing of Individual Subject Safety Biomarkers 
 
SAC 
67.  
Safety 
Non Standard 
EFF_ L2 
Statistical Listing of Repeated Measures Analysis of Change 
from Baseline in Predictive Biomarkers 
 
SAC 
Additional 


 
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Non-ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
68.  
ITT 
GA4 
Listing of Individual Subject Daily Hand Pain NRS Scores 
List both the 24h Average and 24h 
Worst Hand Pain Score in the same 
output with separate columns for each. 
Only display absolute values 
SAC 
69.  
ITT 
Non Standard 
EFF_L6 
Listing of Individual Subject Change from Baseline in 
Inflammatory Structural Joint Damage: HOAMRIS 
Individual Components Include: 
Synovitis, Erosive damage, Cyst, 
Osteophyte Cartilage Space Loss, 
Mal-alignment and Bone Marrow 
Lesions 
SAC 
70.  
ITT 
 
Non Standard 
EFF_L6 
Listing of Individual Subject Change from Baseline in 
Inflammatory Structural Joint Damage: HOAMRIQ 
Individual Components Include: 
synovitis, normalised synovitis, 
normalised erosive damage, cartilage 
space loss, mal-alignment and 
normalised bone marrow lesions 
SAC 
71.  
ITT 
Non Standard 
EFF_L6 
Listing of Individual Subject Change from Baseline in Joint 
Inflammation: DCE-MRI 
Includes ktrans, normalised Ktrans, 
VE, normalised VE, VP, normalised 
VP, IRE, normalised IRE, ME, 
normalised ME. 
SAC 
72.  
ITT 
Non Standard 
EFF_L6 
Listing of Individual Subject Change from Baseline in Bone 
Shape Parameter 
Includes Surface Area of Bone 
SAC 
 


 
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12.16. 
Appendix 17: Example Mock Shells for Data Displays  
Example: POP_T1 
Protocol: 204851 Confidential                                                                    Page 1 of x 
Population: Intent-to-Treat                                                              
 
Table 1.x 
Summary of Baseline Efficacy Parameters 
 
 
 
Statistic 
Placebo 
N=xx 
GSK3196165 180mg 
N=xx 
Total 
N=xx 
 
 
 
 
 
24h average hand pain 
NRS score averaged over 
7 days prior to BL 
n 
xx 
xx 
xx 
 
Mean 
xx.xx 
xx.xx 
xx.xx 
 
SD 
xx.xxx 
xx.xxx 
xx.xxx 
 
Median 
xx.xx 
xx.xx 
xx.xx 
 
Min 
xx.x 
xx.x 
xx.x 
 
Max 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
 
 
 
n 
xx 
xx 
xx 
 
… 
… 
… 
… 
24h worst hand pain NRS 
score averaged over 7 
days prior to BL 
n 
xx 
xx 
xx 
 
 
 
 
 
AUSCAN 3.1 NRS Total 
Score 
n 
xx 
xx 
xx 
 
 
 
 
 
AUSCAN 3.1 NRS Pain 
Score 
n 
xx 
xx 
xx 
 
… 
… 
… 
… 
AUSCAN 3.1 NRS Physical 
Function Score 
n 
xx 
xx 
xx 
 
… 
… 
… 
… 


 
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Statistic 
Placebo 
N=xx 
GSK3196165 180mg 
N=xx 
Total 
N=xx 
 
 
 
 
 
AUSCAN 3.1 NRS 
Stiffness Score 
n 
xx 
xx 
xx 
 
… 
… 
… 
… 
 
 
 
 
 
Number of Soft Tissue 
Swollen Hand Joints 
n 
xx 
xx 
xx 
 
… 
… 
… 
… 
Number of Tender Hand 
Joints  
n 
xx 
xx 
xx 
 
… 
… 
… 
… 
PhGA 
n 
xx 
xx 
xx 
 
… 
… 
… 
… 
PtGA 
n 
xx 
xx 
xx 
 
… 
… 
… 
… 
CRP (mg/L) 
n 
xx 
xx 
xx 
 
… 
… 
… 
… 
Note: PtGA= Patient's Global Assessment of Disease Activity, PhGA= Physician's Global Assessment of Disease Activity, 
CRP= C-Reactive Protein 
 
Programming Note: Make sure to use the correct number of decimal places for each of the variables. 
Programming Note: show for all variables all descriptive statistics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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137 
 
Example: POP_T2 
Protocol: 204851 Confidential                                                                    Page 1 of x 
Population: Intent-to-Treat                                                              
 
Table 1.x 
Summary of OA Disease History 
 
 
Statistic 
Placebo 
N=xx 
GSK3196165 180mg 
N=xx 
Total 
N=xx 
 
 
 
 
 
Time since OA diagnosis (months) 
n 
xx 
xx 
xx 
 
Mean 
xxx.x 
xxx.x 
xxx.x 
 
SD 
xx.xx 
xx.xx 
xx.xx 
 
Min 
xxx 
xxx 
xxx 
 
Median 
xxx 
xxx 
xxx 
 
Max 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
Time since start of OA symptoms (months) 
n 
xx 
xx 
xx 
 
Mean 
xxx.x 
xxx.x 
xxx.x 
 
SD 
xx.xx 
xx.xx 
xx.xx 
 
Min 
xxx 
xxx 
xxx 
 
Median 
xxx 
xxx 
xxx 
 
Max 
xxx 
xxx 
xxx 
 
 
 
 
 
 
Note: Time since OA diagnosis and start of 0A symptoms is calculated up to date of first study drug administration. 
 
 
 
 
 
 
 
 
 
 
 


 
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Example: POP_T3 
Protocol: 204851 Confidential                                                                    Page 1 of x 
Population: Intent-to-Treat                                                              
 
Table 1.x 
Summary of Current Medical Conditions 
 
 
MedDRA vX.X 
System Organ Class 
  Preferred Term 
Placebo 
N=xx 
n (%) 
GSK3196165 180mg 
N=xx 
n (%) 
Total 
 
 
 
 
Number of subjects with at least 
one medical history condition 
xx (xx) 
xx (xx) 
xx (xx) 
 
 
 
 
Cardiovascular Risk Factors 
xx (xx) 
xx (xx) 
xx (xx) 
  Coronary Artery Disease 
xx (xx) 
xx (xx) 
xx (xx) 
  Myocardial Infarction 
xx (xx) 
xx (xx) 
xx (xx) 
  ... 
xx (xx) 
xx (xx) 
xx (xx) 
 
 
 
 
System Organ Class 1 
xx (xx) 
xx (xx) 
xx (xx) 
  Preferred Term 1 
xx (xx) 
xx (xx) 
xx (xx) 
  Preferred Term 2 
xx (xx) 
xx (xx) 
xx (xx) 
  ... 
xx (xx) 
xx (xx) 
xx (xx) 
… 
 
 
 
 
 
 
 
 
Notes to Programming Team: 
• 
Cardiac Disorders to be taken from CRF. 
 
 
 
 
 
 
 
 
 
 


 
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Example: EFF_T1 
Protocol: 204851 Confidential                                                                    Page 1 of x 
Population: Intent-to-Treat                                                              
                                                 Table 2.x 
Summary of Observed Result and Change from Baseline in [Parameter] 
 
[Component: AUSCAN Pain/AUSCAN Physical Function/AUSCAN Stiffness/AUSCAN Total] 
Treatment 
Group 
Visit 
Observed Results 
 
Change from Baseline Results 
n 
Mean 
(95% CI) 
SD 
Median 
(Min,Max) 
 
n 
BL 
Mean 
 
Mean 
(95% CI) 
SD 
Median 
(Min,Max) 
 
 
 
 
 
 
  
 
 
 
 
Placebo 
(N=XX) 
Baselin
e 
x
x 
x.xx 
(x.xx, x.xx) 
x.xxx 
x.xx 
(x.x, x.x) 
 
 
 
 
 
 
 
Week 1 
x
x 
x.xx 
(x.xx, x.xx) 
x.xxx 
x.xx 
(x.xx, x.xx) 
 
xx 
x.xx 
x.x 
(x.x,x.x) 
x.xx 
x.x 
(x.x, x.x) 
 
Week 2 
x
x 
x.xx 
(x.xx, x.xx) 
x.xxx 
x.xx 
(x.xx, x.xx) 
 
xx 
x.xx 
x.x 
(x.x,x.x) 
x.xx 
x.x 
(x.x, x.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
… 
… 
… 
… 
 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
 
GSK319616
5 180mg  
(N=XX) 
Baselin
e 
x
x 
x.xxx 
(x.xx, x.xx) 
x.xxx 
x.xx 
(x.xx, x.xx) 
 
 
 
 
 
 
 
Week 1 
x
x 
x.xxx 
(x.xx, x.xx) 
x.xxx 
x.xx 
(x.xx, x.xx) 
 
xx 
x.xx 
x.x 
(x.x,x.x) 
x.xx 
x.x 
(x.x, x.x) 
 
… 
… 
… 
… 
… 
 
… 
… 
… 
… 
… 
 
 
 
 
 
 
  
 
 
 
 
 
Note: BL Mean for Week X is the mean of the Baseline values of all subjects with a non-missing value at Week X. 
 
 
 
 
 
 
 


 
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Example: EFF_T2 
Protocol: 204851 Confidential                                                                    Page 1 of x 
Population: Intent-to-Treat                                                              
                                                 Table 2.x 
Mixed Model Repeated Measures Analysis (MMRM)of the Change from Baseline in [Parameter] 
 
 
[Component: AUSCAN Pain/AUSCAN Physical Function/AUSCAN Stiffness/AUSCAN Total] 
Visit 
Statistic 
Placebo 
N=xx 
GSK3196165  
180mg 
N=xx 
 
 
 
 
Week 1 
n 
xx 
xx 
 
LS Mean 
x.xx 
x.xx 
 
LS Mean Change 
x.xx 
x.xx 
 
Standard Error 
x.xxx 
x.xxx 
 
Difference from Placebo 
 
x.xx 
 
  95% Confidence Interval  
 
(x.xx, x.xx) 
 
  p-value 
 
0.xxx 
 
 
 
 
Week 2 
n 
 
 
 
LS Mean 
x.xx 
x.xx 
 
LS Mean Change 
x.xx 
x.xx 
 
Standard Error 
x.xxx 
x.xxx 
 
Difference from Placebo 
 
x.xx 
 
  95% CI for Difference 
 
(x.xx, x.xx) 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Repeated Measures Analysis adjusted for Baseline Value, Treatment Group, Visit and Treatment Group by Visit 
Interaction [and Baseline Value by Visit Interaction] 
Note: n is the number of subjects with non-missing data at that visit. 


 
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Example: EFF_T3 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Intent-to-Treat                                     
Table 2.x  
Summary and Analysis of the Proportion of Subjects Achieving a [30/50]% or More Reduction in [Parameter] at 
Each Visit 
 
Visit 
Statistic 
Placebo 
N=xx 
GSK3196165 180mg 
N=xx 
 
 
 
 
Week 1 
 n (%) 
xx (xx) 
xx (xx) 
 
Difference to 
Placebo (%) 
 
xx 
 
    95% CI (%) 
 
(xx.x, xx.x) 
 
  Odds Ratio 
 
xx.x 
 
    95% CI (%) 
 
(xx.xx, xx.xx) 
 
 
 
 
Week 2 
 n (%) 
xx (xx) 
xx (xx) 
 
Difference to 
Placebo (%) 
 
xx 
 
    95% CI (%) 
 
(xx.x, xx.x) 
 
  Odds Ratio 
 
xx.x 
 
    95% CI (%) 
 
(xx.xx, xx.xx) 
 
 
 
 
… 
 
 
 
 
 
 
 
Note: Missing subjects have been assumed to be non-responders.  
Note: Positive differences and Odds Ratios >1 indicate an improvement of treatment over placebo. 
Note: 95% confidence intervals for the difference to placebo are constructed using asymptotic Wald confidence limits 
without correction. 
Note: 95% confidence intervals for odds ratios are constructed using exact confidence limits. 
Note: Generalised Estimating Equations Analysis adjusted for Baseline Score, Treatment Group, Visit and 
Treatment Group by Visit Interaction 
 
 
  
 


 
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142 
 
Example: EFF_T4 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Intent-to-Treat                                    
 
 
Table 2.x 
Summary of Observed Result and Change from Baseline in [Inflammatory Structural Joint Damage/Joint Inflammation/Bone Shape 
Parameters]: [HOAMRIS/HOAMRIQ/DCE-MRI] 
  
Parameter (Unit): <Synovitis/ Erosive Damage/ Cysts/ Osteophyte/ Cartilage Space Loss/ Mal-alignment/ Bone Marrow Lesions> 
< Synovitis/ Synovitis (Normalised)/ Erosive Damage/ Erosive Damage (Normalised)/ Cartilage Space Loss/ Mal-alignment/ Bone 
Marrow Lesions (Normalised)> 
< Exchange rate, Interstitial volume, Plasma volume, Initial rate of enhancement, Maximal signal intensity enhancement> 
<Surface Area of Bone> 
 
Treatment 
Group 
Visit 
Observed Results 
 
Change from Baseline Results 
n 
Mean 
(95% CI) 
SD 
Median 
(Min,Max) 
 
n 
BL Mean 
 
Mean 
(95% CI) 
SD 
Median 
(Min,Max) 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
(N=XX) 
Baseline 
xx 
x.xx 
(x.xx,x.xx) 
x.xxx 
x.xx 
(x.x, x.x) 
 
 
 
 
 
 
 
Week 1 
xx 
x.xx 
(x.xx,x.xx) 
x.xxx 
x.xx 
(x.xx, x.xx) 
 
xx 
x.xx 
x.x 
(x.x,x.x) 
x.xx 
x.x 
(x.x, x.x) 
 
Week 2 
xx 
x.xx 
(x.xx,x.xx) 
x.xxx 
x.xx 
(x.xx, x.xx) 
 
xx 
x.xx 
x.x 
(x.x,x.x) 
x.xx 
x.x 
(x.x, x.x) 
 
Week 4 
xx 
x.xx 
(x.xx,x.xx) 
x.xxx 
x.xx 
(x.xx, x.xx) 
 
xx 
x.xx 
x.x 
(x.x,x.x) 
x.xx 
x.x 
(x.x, x.x) 
 
… 
… 
… 
… 
… 
 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
 
GSK3196165 
180mg  
(N=XX) 
Baseline 
xx 
x.xxx 
(x.xx,x.xx) 
x.xxx 
x.xx 
(x.xx, x.xx) 
 
 
 
 
 
 
 
Week 1 
xx 
x.xxx 
(x.xx,x.xx) 
x.xxx 
x.xx 
(x.xx, x.xx) 
 
xx 
x.xx 
x.x 
(x.x,x.x) 
x.xx 
x.x 
(x.x, x.x) 
 
… 
… 
… 
… 
… 
 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
<Note: Synovitis is normalized by the total joint volume, erosive damage and bone marrow lesions are normalized by volume of 
bone.>  
< Note: All parameters have been normalized by the Volume of Enhancing Pannus (VEP).> 
 


 
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143 
 
Example: EFF_T5 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Intent-to-Treat                                    
 
 
Table 2.x 
Repeated Measures Analysis of Observed Result and Change from Baseline in [Inflammatory Structural Joint Damage/Joint 
Inflammation]: [HOAMRIS/HOAMRIQ/DCE-MRI] 
 
Parameter (Unit): <Synovitis/ Erosive Damage/ Cyst/ Osteophyte Cartilage Space Loss/ Mal-alignment/ Bone Marrow Lesions> 
< Synovitis/ Synovitis (Normalised)/ Erosive Damage (Normalised)/ Cartilage Space Loss/ Mal-alignment/ Bone Marrow 
Lesions (Normalised)> 
< Exchange Rate, Interstitial Volume, Plasma Volume, Initial Rate of Enhancement, Maximal Signal Intensity Enhancement> 
Visit 
Statistic 
Placebo 
N=xx 
GSK3196165  
180mg 
N=xx 
 
 
 
 
Week 1 
n 
xx 
xx 
 
LS Mean 
x.xx 
x.xx 
 
LS Mean Change 
x.xx 
x.xx 
 
Standard Error 
x.xxx 
x.xxx 
 
Difference from Placebo 
 
x.xx 
 
  95% Confidence Interval  
 
x.xx - x.xx 
 
  p-value 
 
0.xxx 
 
 
 
 
Week 2 
n 
 
 
 
LS Mean 
x.xx 
x.xx 
 
LS Mean Change 
x.xx 
x.xx 
 
Standard Error 
x.xxx 
x.xxx 
 
Difference from Placebo 
 
x.xx 
 
  95% CI for Difference 
 
x.xx - x.xx 
 
  p-value 
 
0.xxx 
… 
 
 
 
 
 
 
 
 
 
 
 
Note: Repeated measures analysis adjusted for <Parameter> baseline value, treatment group, visit, treatment group by visit 
interaction and baseline value by visit interaction. 
Note: n is the number of subjects with non-missing data at that visit. 
<Note: Synovitis is normalized by the total joint volume, erosive damage and bone marrow lesions are normalized by volume 
of bone.>  
< Note: All parameters have been normalized by the Volume of Enhancing Pannus (VEP).> 


 
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144 
 
Example: EFF_T6 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Intent-to-Treat                                    
 
2.x 
Summary of the Proportion of Subjects Reporting Paracetamol Use in the 7 Days Prior to Each Visit 
 
 
 
Visit 
Statistic 
Placebo 
N=xx 
GSK3196165 180mg 
N=xx 
 
 
 
 
Baseline 
 n  
xx 
xx 
 
 No Paracetamol (%) 
xx (xx) 
xx (xx) 
 
 Paracetamol for >=1 day (%) 
xx (xx) 
xx (xx) 
 
 
 
 
 
 
 
 
 
 
 
 
Week 1 
 n  
xx 
xx 
 
 No Paracetamol (%) 
xx (xx) 
xx (xx) 
 
 Paracetamol for >=1 day (%) 
xx (xx) 
xx (xx) 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


 
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145 
 
Example: EFF_F1 
 
 
 
 
 
 
 
 
 
 
 
     Page 1 of x 
Protocol: 204851 Confidential 
Population: Intent-to-Treat 
Figure 2.x 
Individual Subject Profile Plots of [Parameter], by Treatment Group 
Component: <AUSCAN Pain/AUSCAN Physical Function/AUSCAN Stiffness/ AUSCAN Total>  
 
Note: Each of the lines represents one subject. 
Note: B=Baseline 


 
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146 
 
Example: EFF_F2 
Protocol: 204851 Confidential                                                                    Page 1 of x 
Population: Intent-to-Treat                                                              
                                                 Figure 2.x 
Plot of Mean and 95% CI of Change from Baseline in [Parameter], at Each Visit 
              
[Component/Parameter(Unit)]: <AUSCAN Pain/AUSCAN Physical Function/AUSCAN Stiffness/ AUSCAN Total>  
<Synovitis/ Erosive Damage/ Cyst/ Osteophyte Cartilage Space Loss/ Mal-alignment/ Bone Marrow Lesions> 
< Synovitis/ Synovitis (Normalised)/ Erosive Damage (Normalised)/ Cartilage Space Loss/ Mal-alignment/ Bone Marrow Lesions 
(Normalised)> 
< Exchange Rate, Interstitial Volume, Plasma Volume, Initial Rate of Enhancement, Maximal Signal Intensity Enhancement> 
 
Programming Note: Legend to be centered. 


 
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147 
 
 
Example: SAFE_T1 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Safety                                                              
 
Table 3.x 
Overall Summary of Adverse Events  
 
 
Category 
Placebo 
N=xx 
n (%) [#] 
GSK3196165 180mg 
N=xx 
n (%) [#] 
 
 
 
Any AEs 
xx (xx) [x] 
xx (xx) [x] 
 
 
 
  Serious AEs 
xx (xx) [x] 
xx (xx) [x] 
  AEs leading to permanent discontinuation of study treatment 
xx (xx) [x] 
xx (xx) [x] 
  Drug-related AEs 
xx (xx) [x] 
xx (xx) [x] 
  AEs leading to Death 
xx (xx) [x] 
xx (xx) [x] 
 
 
 
 
Note: n=number of subjects with at least one event. #=number of individual occurrences 
 
Programming note: Include Withdrawals due to AE to “permanent discontinuation of study drug”. 
 
 
 
 
 
 
 
 


 
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148 
 
Example: SAFE_T2 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Safety                                                              
Table 3.x 
Summary of Adverse Events of Special Interest 
 
Category 
Placebo 
(N=xx) 
n   (%)   [#] 
GSK3196165 180mg 
(N=xx) 
n   (%)   [#] 
 
Any AESI 
Serious Infections  
   Serious Respiratory Infections 
Opportunistic Infections 
Neutropenia 
Pulmonary Alveolar Proteinosis 
Hypersensitivity Reactions 
Injection Site Reactions 
 
xx   (xx%)   [xx] 
xx   (xx%)   [xx] 
xx   (xx%)   [xx] 
xx   (xx%)   [xx] 
xx   (xx%)   [xx] 
xx   (xx%)   [xx] 
xx   (xx%)   [xx] 
xx   (xx%)   [xx] 
 
 
xx   (xx%)   [xx] 
xx   (xx%)   [xx] 
xx   (xx%)   [xx] 
xx   (xx%)   [xx] 
xx   (xx%)   [xx] 
xx   (xx%)   [xx] 
xx   (xx%)   [xx] 
xx   (xx%)   [xx] 
 
 
 
 
 
 
AESI = Adverse Event of Special Interest.  
Note: n=number of subjects reporting at least one event. [#] is the number of individual occurrences. 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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149 
 
Example: SAFE_T3 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Safety                                         
                      
Table 3.x 
Summary of Adverse Events of Special Interest - Injection Site Reactions 
 
 
Number of Subjects with an 
Placebo 
N=xx 
n (%) [#] 
GSK3196165 180mg 
N=xx 
n (%) [#] 
 
 
 
Injection Site Reaction 
xx (xx) [xx] 
xx (xx) [xx] 
  <= 1 Day Post Injection 
xx (xx) [xx] 
xx (xx) [xx] 
  > 1 Day Post Injection ($) 
xx (xx) [xx] 
xx (xx) [xx] 
  Reported as AE 
xx (xx) [xx] 
xx (xx) [xx] 
  Reported as SAE 
xx (xx) [xx] 
xx (xx) [xx] 
  Itching/pruritis occurrence 
xx (xx) [xx] 
xx (xx) [xx] 
  Redness/erythema occurrence 
xx (xx) [xx] 
xx (xx) [xx] 
  Pain occurrence 
xx (xx) [xx] 
xx (xx) [xx] 
  Bruising occurrence 
xx (xx) [xx] 
xx (xx) [xx] 
  Swelling/edema 
xx (xx) [xx] 
xx (xx) [xx] 
  Warm to touch 
xx (xx) [xx] 
xx (xx) [xx] 
 
 
 
 
 
Note: n=number of subjects with at least one event. #=number of individual occurrences 
Note: ($) until 1 day before next injection. 
 
 
 
 
 
 
 
 
 
 
 
 


 
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150 
 
Example: SAFE_T4 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Safety                                         
 
Table 3.x  
Summary of Adverse Events of Special Interest - Systemic Hypersensitivity Reactions Related to GSK3196165 
 
 
Type of Systemic Reaction 
Placebo 
N=xx 
n (%) [#] 
GSK3196165 180mg 
N=xx 
n (%) [#] 
 
 
 
Systemic Hypersensitivity Reaction 
xx (xx) [xx] 
xx (xx) [xx] 
  <= 1 Day Post Injection 
xx (xx) [xx] 
xx (xx) [xx] 
  > 1 Day Post Injection ($) 
xx (xx) [xx] 
xx (xx) [xx] 
  Reported as an AE 
xx (xx) [xx] 
xx (xx) [xx] 
  Reported as an SAE 
xx (xx) [xx] 
xx (xx) [xx] 
  Headache 
xx (xx) [xx] 
xx (xx) [xx] 
  Pruritis 
xx (xx) [xx] 
xx (xx) [xx] 
  Urticaria 
xx (xx) [xx] 
xx (xx) [xx] 
  Rash 
xx (xx) [xx] 
xx (xx) [xx] 
  Angioedema 
xx (xx) [xx] 
xx (xx) [xx] 
  … 
 
 
 
 
 
  Met an Anaphylaxis Criterion 
xx (xx) [xx] 
xx (xx) [xx] 
    Anaphylactic Criterion 1 
xx (xx) [xx] 
xx (xx) [xx] 
    Anaphylactic Criterion 2 
xx (xx) [xx] 
xx (xx) [xx] 
    Anaphylactic Criterion 3 
 
 
 
 
 
 
Note: n=number of subjects with at least one event. #=number of individual occurrences 
Note: ($) until 1 day before next injection. 
 
 
 
 
 
 
 
 
 


 
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151 
 
 
Example: SAFE_T5 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Safety                                         
Table 3.x 
Summary of Persistent Cough, Dyspnea and DLCO Decrease 
 
 
 
Placebo 
N=xx 
n (%) 
GSK3196165 180mg 
N=xx 
n (%) 
 
 
 
Persistent Cough 
xx (xx) 
xx (xx) 
Persistent Dyspnea 
xx (xx) 
xx (xx) 
Persistent DLCO decrease >15% from baseline 
xx (xx) 
xx (xx) 
 
 
 
 
Note: n=number of subjects reporting at least one event in that category. 
Note: Persistent is defined as any event with duration >=15 days. Cough must be grade 2 or 3. Dyspnea is 
determined from Borg scores >=3. Events were confirmed by the Safety Review Team. 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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152 
 
Example: SAFE_T6 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Safety                                         
Table 3.x 
Laboratory Evaluation: Summary of Proportion of Subjects with Urinalysis Findings 
(Intent-to-Treat Population) 
 
Laboratory Parameter: Protein 
 
Placebo 
N=xx 
n (%) 
GSK3196165 180mg 
N=xx 
n (%) 
 
 
 
Baseline 
 
 
  n 
xx 
xx 
  1+ 
xx (xx) 
xx (xx) 
  2+ 
xx (xx) 
xx (xx) 
  3+ 
xx (xx) 
xx (xx) 
  Negative 
xx (xx) 
xx (xx) 
  Trace 
xx (xx) 
xx (xx) 
 
 
 
Week xx 
 
 
  n 
xx 
xx 
  1+ 
xx (xx) 
xx (xx) 
  2+ 
xx (xx) 
xx (xx) 
  3+ 
xx (xx) 
xx (xx) 
  Negative 
xx (xx) 
xx (xx) 
  Trace 
xx (xx) 
xx (xx) 
 
 
 
Week xx 
 
 
  … 
xx 
xx 
… 
 
 
 
 
 
Note: Percentages calculated based on the number of subjects with a valid assessment at the respective visit (n/M*100%). 
 
Programming Note: If multiple values are mapped to one visit: the value with the worst CTCAE grade will be considered. 
If there are more than one value of this grade, the later value will be considered. 
Programming Note: Use this shell for all categorical parameters of Urinalysis, in case there are more than only Protein. 
 
 
 


 
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Example: SAFE_T7 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Safety                                         
 
Table 3.x 
Summary of Laboratory Parameters of Interest by CTCAE Grade  
 
Parameter 
Visit 
CTCAE Version 4.0 
Placebo 
N=xx 
n(%) 
GSK3196165 180mg 
N=xx 
n(%) 
 
 
 
 
 
Parameter 1 
Baseline  
n 
xx 
xx 
 
 
Grade 1 
xx(xx) 
xx(xx) 
 
 
Grade 2  
xx(xx) 
xx(xx) 
 
 
Grade 3 
xx(xx) 
xx(xx) 
 
 
Grade 4 
xx(xx) 
xx(xx) 
 
 
 
 
 
 
Week x 
n 
xx 
xx 
 
 
Grade 1 
xx(xx) 
xx(xx) 
 
 
Grade 2  
xx(xx) 
xx(xx) 
 
 
Grade 3 
xx(xx) 
xx(xx) 
 
 
Grade 4 
xx(xx) 
xx(xx) 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
Parameter 2 
… 
 
 
 
 
 
 
 
 
 
Note: Just parameters which can be classified in CTCAE grades are displayed. 
Note: Laboratory parameters of interest that have no results with a CTCAE grade were not included. 
Note: Percentages calculated based on the number of subjects with a valid assessment at the respective visit. 
 
Programming Note: Laboratory Parameters of Interest and according CTCAE Grades can be found in the RAP Appendix 12. 
Programming Note: If multiple values are mapped to one visit: the value with the worst CTCAE grade will be considered. 
If there are more than one value of this grade, the later value will be considered. 
 
 
 
 
 


 
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Example: SAFE_T8 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Safety                                         
 
Table 3.x 
Summary of Immunogenicity Results 
 
 
Assay: [Anti-GSK3196165 Binding AB Detection] 
Visit 
 
Placebo 
N=xx 
n (%) 
GSK3196165 180mg 
N=xx  
n (%) 
 
 
 
 
Baseline  
n 
xx 
xx 
 
Positive 
xx (xx%) 
xx (xx%) 
 
Negative 
xx (xx%) 
xx (xx%) 
 
 
 
 
Anytime Post-Baseline 
n 
xx 
xx 
 
Positive 
xx (xx%) 
xx (xx%) 
 
  - to + 
xx (xx%) 
xx (xx%) 
 
  + to + 
xx (xx%) 
xx (xx%) 
 
Negative 
xx (xx%) 
xx (xx%) 
 
  + to - 
xx (xx%) 
xx (xx%) 
 
  - to - 
xx (xx%) 
xx (xx%) 
 
 
 
 
Week 1 
n 
xx 
xx 
 
Positive 
xx (xx%) 
xx (xx%) 
 
Negative 
xx (xx%) 
xx (xx%) 
 
 
 
 
Week X 
n 
xx 
xx 
 
… 
… 
… 
 
 
 
 
Note: Change refers to change from Baseline. Percentages for change are based on the number at risk at baseline,  
e.g. “- to +” and “- to -” are based on “Negative” at baseline. 
Note: Percentages for Positive/Negative are based on the number of subjects at each visit. 
Programming Note: Positive here refers to confirmed positive results, this should be evident from the dataset. 
Programming Note: “Anti-GSK3196165 Binding AB Detection” might have a slightly different naming convention in the 
dataset. Use the term from the dataset. 
Programming Note: Include all relevant assessments. 
 
 


 
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155 
 
 
Example: SAFE_T9 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Safety                                         
 
Table 3.x 
Summary of Subjects with Pulmonary Findings  
 
 
 
Subjects with at least one event of 
Placebo 
N=xx 
n (%) 
GSK3196165 180mg 
N=xx 
n (%) 
 
 
 
15% relative decrease from Baseline in DLCO 
xx (xx) 
xx (xx) 
 
 
 
15% relative decrease from Baseline in DLCO to <70% 
xx (xx) 
xx (xx) 
 
 
 
Cough 
xx (xx) 
xx (xx) 
 
 
 
Abnormal Lung Auscultation 
xx (xx) 
xx (xx) 
 
 
 
Note: Subjects with at least one event of 15% relative decrease from baseline in DLCO includes any subject with at least 
one decrease >15%.  Cough includes subjects who reported cough of any grade. Abnormal lung auscultation includes subjects 
with any abnormality reported. 
 
 
 
 


 
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156 
 
Example: SAFE_T10 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Safety                                         
Table 3.x 
Summary of Pulse Oximetry  
 
Visit 
  Blood Oxygen 
Placebo 
N=xx 
n (%) 
GSK3196165 180mg 
N=xx 
n (%) 
 
 
 
Baseline 
 
 
  n 
xx  
xx 
  < 80% 
xx (xx) 
xx (xx) 
  80% to 90% 
xx (xx) 
xx (xx) 
  >=90% 
xx (xx) 
xx (xx) 
 
 
 
Worst Post-Baseline Result 
 
 
  n 
xx  
xx 
  < 80% 
xx (xx) 
xx (xx) 
  80% to 90% 
xx (xx) 
xx (xx) 
  >=90% 
xx (xx) 
xx (xx) 
 
 
 
 
 
 
 
 
Note: Post-baseline percentages calculated based on the number of subjects in the relevant subgroup (n/M*100%). 
 
 
 
 
 
 
 
 
 
 
 


 
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157 
 
Example: SAFE_T11 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Safety                                         
 
Table 3.x 
Summary of Change from Baseline in DLCO 
 
 
Treatment Group 
Visit 
Observed Results 
 
Change from Baseline Results 
n   Mean  SD   
Median  Min  Max  n   BL Mean 
Mean  SD   
Median  Min  Max  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Placebo 
(N=XX) 
Baseline 
xx x.xx x.xxx 
x.xx 
x.x x.x  
 
 
 
 
 
 
 
 
Week 1 
xx x.xx x.xxx 
x.xx 
x.x x.x  xx 
x.xx 
x.xx 
x.xxx 
x.xx 
x.x 
x.x 
 
Week 2 
xx x.xx x.xxx 
x.xx 
x.x x.x  xx 
x.xx 
x.xx 
x.xxx 
x.xx 
x.x 
x.x 
 
Week 3 
xx x.xx x.xxx 
x.xx 
x.x x.x  xx 
x.xx 
x.xx 
x.xxx 
x.xx 
x.x 
x.x 
 
Week 4 
xx x.xx x.xxx 
x.xx 
x.x x.x  xx 
x.xx 
x.xx 
x.xxx 
x.xx 
x.x 
x.x 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GSK3196165 180mg 
(N=XX) 
Baseline 
xx x.xx x.xxx 
x.xx 
x.x x.x  
 
 
 
 
 
 
 
 
... 
xx x.xx x.xxx 
x.xx 
x.x x.x  xx 
 
x.xx 
x.xxx 
x.xx 
x.x 
x.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Baseline is defined as the lowest value during the screening period prior to the first study drug administration. 
Note: BL Mean for Week X is the mean of the Baseline values of all subjects with a non-missing value at Week X. 
 
Programming note: First footnote only applies to DLCO outputs. 
 
 
 
 
 
 
 
 
 
 
 


 
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Example: SAFE_T12 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Safety                                         
 
 
Table 3.x 
Summary of Proportion of Subjects with a 15% Relative Decrease from Baseline in DLCO  
 
Visit   
  Decrease 
Placebo 
N=xx 
n (%) 
GSK3196165 180mg 
N=xx 
n (%) 
 
 
 
Week 12 
 
 
  n 
xx 
xx 
  ≥15% 
xx (xx) 
xx (xx) 
  <15% 
xx (xx) 
xx (xx) 
  Missing 
xx (xx) 
xx (xx) 
 
 
 
Note: Percentages calculated based on the number of subjects attending the respective visit. 
Notes to Programming Team:  
• 
Compare Baseline value with value from Visit X. Count all subjects with a decrease of at least 15%. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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159 
 
Example: SAFE_T13 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Safety                                         
 
Table 3.x 
Summary of Cough Data 
 
 
Visit   
Category 
Placebo 
N=xx 
n(%) 
GSK3196165 180mg 
N=xx 
n(%) 
 
 
 
 
Baseline 
n 
xx 
xx 
 
Had a Cough 
xx (xx) 
xx (xx) 
 
  New  
xx (xx) 
xx (xx) 
 
  Stable 
xx (xx) 
xx (xx) 
 
  Worsening 
xx (xx) 
xx (xx) 
 
No Cough 
xx (xx) 
xx (xx) 
 
Missing 
xx (xx) 
xx (xx) 
 
 
 
 
Week <1, …, X> 
n 
xx 
xx 
 
Had a Cough Since last Visit 
xx (xx) 
xx (xx) 
 
  New  
xx (xx) 
xx (xx) 
 
  Stable 
xx (xx) 
xx (xx) 
 
  Worsening 
xx (xx) 
xx (xx) 
 
No Cough 
xx (xx) 
xx (xx) 
 
Missing 
xx (xx) 
xx (xx) 
 
 
 
 
 
Note: Percentages calculated based on the number of subjects attending the respective visit. 
 
 
 
 
 
 
 
 
 


 
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160 
 
Example: SAFE_T14 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Safety                                         
 
Table 3.x 
Summary of Borg Dyspnea Questionnaire Data 
 
 
Visit   
Result 
Placebo 
N=xx 
n (%) 
GSK3196165 180mg 
N=xx 
n (%) 
 
 
 
 
Baseline 
n 
xx 
xx 
 
0 Nothing at all 
xx (xx) 
xx (xx) 
 
0.3 
xx (xx) 
xx (xx) 
 
0.5 Extremely weak  
(Just noticeable) 
xx (xx) 
xx (xx) 
 
0.7 
xx (xx) 
xx (xx) 
 
1 Very weak 
xx (xx) 
xx (xx) 
 
1.5 
xx (xx) 
xx (xx) 
 
2 Weak (Light) 
xx (xx) 
xx (xx) 
 
2.5 
xx (xx) 
xx (xx) 
 
3 Moderate 
xx (xx) 
xx (xx) 
 
4 
xx (xx) 
xx (xx) 
 
5 Strong (Heavy) 
xx (xx) 
xx (xx) 
 
… 
xx (xx) 
xx (xx) 
 
Missing 
xx (xx) 
xx (xx) 
 
 
 
 
Week <1, …, X> 
n 
xx 
xx 
 
0 Nothing at all 
xx (xx) 
xx (xx) 
 
0.3 
xx (xx) 
xx (xx) 
 
0.5 Extremely weak  
(Just noticeable) 
xx (xx) 
xx (xx) 
 
… 
 
 
 
Note: Percentages calculated based on the number of subjects with a valid assessment at the respective visit. 
 
 
 


 
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161 
 
 
Example: SAFE_F1 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Safety                                         
Figure 3.x 
DLCO Patient Profiles over Time by Treatment 
 
 
 
 
 
 
 
 


 
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162 
 
Example: PD_T1a 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Safety                                         
 
Table 5.x 
Summary of Observed Result and Change from Baseline in Target Engagement Biomarkers  
##For Not Log Transformed Biomarkers## 
 
Biomarker (Unit): <Name of Biomarker> 
Treatment 
Group 
Visit 
Observed Results 
 
Change from Baseline Results 
n 
Mean 
(95% CI) 
SD 
Median 
(Min,Max) 
 
n 
BL Mean 
 
Mean 
(95% CI) 
SD 
Median 
(Min,Max) 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
(N=XX) 
Baseline 
xx 
x.xx 
(x.xx,x.xx) 
x.xxx 
x.xx 
(x.x, x.x) 
 
 
 
 
 
 
 
Week 1 
xx 
x.xx 
(x.xx,x.xx) 
x.xxx 
x.xx 
(x.xx, x.xx) 
 
xx 
x.xx 
x.x 
(x.x,x.x) 
x.xx 
x.x 
(x.x, x.x) 
 
Week 2 
xx 
x.xx 
(x.xx,x.xx) 
x.xxx 
x.xx 
(x.xx, x.xx) 
 
xx 
x.xx 
x.x 
(x.x,x.x) 
x.xx 
x.x 
(x.x, x.x) 
 
Week 4 
xx 
x.xx 
(x.xx,x.xx) 
x.xxx 
x.xx 
(x.xx, x.xx) 
 
xx 
x.xx 
x.x 
(x.x,x.x) 
x.xx 
x.x 
(x.x, x.x) 
 
… 
… 
… 
… 
… 
 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
 
GSK3196165 
180mg  
(N=XX) 
Baseline 
xx 
x.xxx 
(x.xx,x.xx) 
x.xxx 
x.xx 
(x.xx, x.xx) 
 
 
 
 
 
 
 
Week 1 
xx 
x.xxx 
(x.xx,x.xx) 
x.xxx 
x.xx 
(x.xx, x.xx) 
 
xx 
x.xx 
x.x 
(x.x,x.x) 
x.xx 
x.x 
(x.x, x.x) 
 
… 
… 
… 
… 
… 
 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Note: The baseline value is the latest pre-dose assessment. 
Note: BL Mean for Week X is the mean of the Baseline values of all subjects with a non-missing value at Week X. 
Note: Values below LLQ are imputed to 0.5*LLQ 
 
Programming Note: The number of displayed decimal digits in the table can be different for each Biomarker.  
 
 
 
 
 


 
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Example: PD_T1b 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Safety                                         
 
Table 5.x 
Summary of Observed Result and Change from Baseline in Target Engagement Biomarkers  
## for log transformed biomarkers ## 
 
Biomarker (Unit): <Name of Biomarker> 
Treatment 
Group 
Visit 
Observed Results 
 
Ratio to Baseline Results 
n 
Geometric Mean 
(95% CI) 
CVb (%) 
Median 
(Min,Max) 
 
n 
BL 
Geometric 
Mean 
 
Geometric 
Mean Ratio 
(95% CI) 
CVb (%) 
Median 
(Min,Max) 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
(N=XX) 
Baseline 
xx 
x.xx 
(x.xx,x.xx) 
x.xxx 
x.xx 
(x.x, x.x) 
 
 
 
 
 
 
 
Week 1 
xx 
x.xx 
(x.xx,x.xx) 
x.xxx 
x.xx 
(x.xx, x.xx) 
 
xx 
x.xx 
x.x 
(x.x,x.x) 
x.xx 
x.x 
(x.x, x.x) 
 
Week 2 
xx 
x.xx 
(x.xx,x.xx) 
x.xxx 
x.xx 
(x.xx, x.xx) 
 
xx 
x.xx 
x.x 
(x.x,x.x) 
x.xx 
x.x 
(x.x, x.x) 
 
Week 4 
xx 
x.xx 
(x.xx,x.xx) 
x.xxx 
x.xx 
(x.xx, x.xx) 
 
xx 
x.xx 
x.x 
(x.x,x.x) 
x.xx 
x.x 
(x.x, x.x) 
 
… 
… 
… 
… 
… 
 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
 
GSK3196165 
180mg  
(N=XX) 
Baseline 
xx 
x.xxx 
(x.xx,x.xx) 
x.xxx 
x.xx 
(x.xx, x.xx) 
 
 
 
 
 
 
 
Week 1 
xx 
x.xxx 
(x.xx,x.xx) 
x.xxx 
x.xx 
(x.xx, x.xx) 
 
xx 
x.xx 
x.x 
(x.x,x.x) 
x.xx 
x.x 
(x.x, x.x) 
 
… 
… 
… 
… 
… 
 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: CVb = geometric coefficient of variation. 
Note: The baseline value is the latest pre-dose assessment. BL Geometric Mean for Week X is the geometric mean of the 
Baseline values of all subjects with a non-missing value at Week X. 
Note: Values below LLQ are imputed to 0.5*LLQ 
 
Programming Note: The number of displayed decimal digits in the table can be different for each Biomarker.  
 


 
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Example: PD_T2a 
Protocol: 204851 Confidential                                                                   Page 1 of x 
Population: Safety                                         
 
Table 5.x 
Mixed Model Repeated Measures Analysis (MMRM) of Change from Baseline in Target Engagement Biomarkers  
## for not-log transformed biomarkers ## 
Biomarker (Unit): <Biomarker> 
Visit 
Statistic 
Placebo 
N=xx 
GSK3196165  
180mg 
N=xx 
 
 
 
 
Week 1 
n 
xx 
xx 
 
LS Mean 
x.xx 
x.xx 
 
LS Mean Change 
x.xx 
x.xx 
 
Standard Error 
x.xxx 
x.xxx 
 
Difference from Placebo 
 
x.xx 
 
  95% Confidence Interval  
 
x.xx - x.xx 
 
  p-value 
 
0.xxx 
 
 
 
 
Week 2 
n 
 
 
 
LS Mean 
x.xx 
x.xx 
 
LS Mean Change 
x.xx 
x.xx 
 
Standard Error 
x.xxx 
x.xxx 
 
Difference from Placebo 
 
x.xx 
 
  95% CI for Difference 
 
x.xx - x.xx 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Repeated measures analysis adjusted for <Biomarker> baseline value, treatment group, visit, treatment group by 
visit and baseline by visit interactions. 
Note: n is the number of subjects with non-missing data at that visit. 
 
 


 
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Example: PD_T2b 
Protocol: 204851 Confidential                                                                   Page 1 of x 
 
Table 5.x 
Mixed Model Repeated Measures Analysis (MMRM) of Change from Baseline in Target Engagement Biomarkers 
 ## for log transformed biomarkers ## 
Biomarker (Unit): <Biomarker> 
Visit 
Statistic 
Placebo 
N=xx 
GSK3196165  
180mg 
N=xx 
 
 
 
 
Week 1 
n 
xx 
xx 
 
LS Geometric Mean 
x.xx 
x.xx 
 
LS Geometric Mean Ratio to Baseline 
x.xx 
x.xx 
 
Standard Error 
x.xxx 
x.xxx 
 
Ratio to Placebo 
 
x.xx 
 
  95% Confidence Interval  
 
x.xx - x.xx 
 
  p-value 
 
0.xxx 
 
 
 
 
Week 2 
n 
 
 
 
LS Geometric Mean 
x.xx 
x.xx 
 
LS Geometric Mean Ratio 
x.xx 
x.xx 
 
Standard Error 
x.xxx 
x.xxx 
 
Ratio to Placebo 
 
x.xx 
 
  95% Confidence Interval  
 
x.xx - x.xx 
 
  p-value 
 
0.xxx 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Repeated measures analysis adjusted for <Biomarker> baseline value, treatment group, visit, treatment group by 
visit and baseline by visit interactions. 
Note: n is the number of subjects with non-missing data at that visit. 
 
 
 
 
 


 
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Example: PD_F1 
Protocol: 204851 Confidential                                                                    Page 1 of x 
Population: Intent-to-Treat                                                              
                                                 Figure 5.x 
Plot of Mean/Geometric Mean and 95% CI of Change from Baseline in Target Engagement Biomarkers, at Each Visit 
              
Biomarker(Unit): <Biomarker>  
 
 
Note: Values below LLQ are imputed to 0.5*LLQ. 
Note: The baseline value is the latest pre-dose assessment. 
<Note: Repeated measures analysis adjusted for <Biomarker> baseline value, treatment group, visit and treatment group by 
visit and baseline by visit interactions.> 
Programming Note: Legend to be centered. 
Programming Note:  Y-axis label is “Change from Baseline in <Biomarker>” or “Ratio to Baseline in <Biomarker>” if log-
transformation is required  
 


 
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Example: PD_F2 
Protocol: 204851 Confidential                                                                    Page 1 of x 
Population: Intent-to-Treat                                                              
Figure 5.x 
Plot of Distribution of <Biomarkers> 
Biomarker(Unit): <Biomarker>  
Treatment: <Overall/Placebo/GSK3196165 180mg> 
 
 
 
Note: Values below LLQ are imputed to 0.5*LLQ. 
Note: The baseline value is the latest pre-dose assessment. 
 
 


 
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Example: POP_L1 
Protocol: 204851 Confidential                                                                    Page 1 of x 
Population: Intent-to-Treat                                                              
 
Listing x 
Listing of OA Disease History  
 
Treatment Group: <Placebo, GSK3196165 180mg> 
Site ID/ 
Subject ID 
Date of OA Diagnosis 
Time since OA Diagnosis 
(months) [a] 
Start Date of OA 
Symptoms  
Time since Start of OA 
Symptoms (months) [a] 
 
 
 
 
 
XX/XXXXX 
DD-MMM-YYYY 
XX.X 
DD-MMM-YYYY 
XX.X 
 
 
 
 
 
XX/XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XX/XXXXX 
 
 
 
 
 
 
 
 
 
[a] Up to date of first study medication administration. 
 
 
 
 
 
 
 
 
 
 


 
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Example: POP_L2 
Protocol: 204851 Confidential                                                                    Page 1 of x 
Population: Intent-to-Treat                                                              
Listing x 
Subjects with Persistent Cough, Dyspnea or DLCO Decrease 
 
 
 
Site ID/ Subject ID 
Gender/Age(years)/Race/Weight(kg): 
Treatment 
at Event 
Onset 
Type of 
Event 
Start of Event (Relative Day) 
 
 
 
 
 
XXXX/XXXXXX 
F/XX/XXXX/XX 
Placebo 
DLCO 
DD-MMM-YYYY (XX) 
 
 
 
Cough 
 
 
 
 
 
 
 
 
 
 
 
Programming Note: Just show subjects who experienced at least one of the events during the study. 
 
 
 
 
 
 
 
 
 
 


 
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Example: POP_L3 
Protocol: 204851 Confidential                                                                    Page 1 of x 
Population: Intent-to-Treat                                                              
Listing x 
Listing of Pulmonary Assessments  
 
 
Treatment Group: <Placebo, GSK3196165 180mg> 
Site ID/ Subject ID: XXXX/XXXXXX Gender/Age(years)/Race/Weight(kg): F/XX/XXXX/XX 
Visit 
Date of 
Assessment 
DD-MMM-YYYY 
(Relative Day) 
Chest X-Ray 
Blood 
Oxygen 
(%) 
Cough/ 
Grade 
Borg 
Dyspnea 
Result 
Chest Auscultation 
abnormal/ 
Classification of 
Chest Auscultation 
abnormal 
 
 
 
 
 
 
 
Screening 
DD-MMM-YYYY (XX) <normal, Abnormal - 
Not Clinically 
Significant, Abnormal 
– Clinically 
Significant > 
xx 
Yes/ x 
XXXX 
Yes/ Stable 
Baseline 
DD-MMM-YYYY (XX)  
xx 
No 
XXXX 
No 
 
Week 1 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Example: POP_L4 
Protocol: 204851 Confidential                                                                    Page 1 of x 
Population: Intent-to-Treat                                                              
Listing x 
Listing of Pulmonary Function Tests  
 
Treatment Group: <Placebo, GSK3196165 180 mg> 
Site ID/ Subject ID: XXXX/XXXXXX Gender/Age(years)/Race/Weight(kg): F/XX/XXXX/XX 
Visit 
Date of 
Assessment 
DD-MMM-YYYY 
(Relative Day) 
Spirometry 
Reason of Missed 
Spirometry 
Gas 
Transfer 
(DLCO) (%) 
Reason of Missed 
DLCO 
DLCO Lower than 85% 
of Baseline Value 
FEV1 
(L) 
FVC 
(L) 
 
 
 
 
 
 
 
 
Screening 
DD-MMM-YYYY 
(XX) 
xx.x 
xx.x 
XXXXXXXX 
xx.x 
XXXXXXXX 
Yes 
Baseline 
DD-MMM-YYYY 
(XX) 
xx.x 
xx.x 
XXXXXXXX 
xx.x 
XXXXXXXX 
No 
 
Week 1 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Baseline is the visit recording the lowest DLCO value obtained from the Screening or Day 1 assessment, or any 
unscheduled visit in between. 
 
 
 
 
 
 
 
 


 
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Example: EFF_L1 
Protocol: 204851 Confidential                                                                    Page 1 of x 
Population: Intent-to-Treat                                                              
 
Listing x 
Listing of Individual Subject Hand Pain NRS Averaged over 7 Days Prior to Each Visit 
 
 
Treatment Group: <Placebo, GSK3196165 180mg> 
 
 
24h Average Hand Pain NRS Averaged over 7 
Days Prior to Visit  
 
24h Worst Hand Pain NRS Averaged over 7 Days 
Prior to Visit 
Site ID/ 
Subject ID 
Visit 
Observed/CfB 
30% 
Reduction 
from 
Baseline  
50% 
Reduction 
from 
Baseline 
 
Observed/ CfB   
30% 
Reduction 
from 
Baseline  
50% 
Reduction 
from 
Baseline 
XXXX/ XXXXX Baseline  x.xx 
 
 
 
x.xx 
 
 
Week X 
x.xx/ -x.xx 
Yes 
No 
 
x.xx/ x.xx 
No 
No 
Etc.  
Etc. 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
XXXX/ XXXXX Baseline  x.xx 
 
 
 
x.xx 
 
 
Week X 
x.xx/ x.xx 
No 
No 
 
x.xx/ -x.xx 
Yes  
Yes 
Etc.  
Etc. 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
Note: CfB= Change from Baseline. 
Notes to Programming Team:  
• 
This listing will be sorted by Site ID, Subject ID, Visit Date 
 
 
 
 
 


 
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Example: EFF_L2 
Protocol: 204851 Confidential                                                                    Page 1 of x 
Population: Intent-to-Treat                                                              
Listing x 
Statistical Listing of […] 
 
 
 
 
 
 
 
Display all SAS Output from Analysis 
 
 
 
 
 
 
 
 


 
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174 
 
Example: EFF_L3 
Protocol: 204851 Confidential                                                                    Page 1 of x 
Population: Intent-to-Treat                                                              
Listing x 
Listing of Individual Subject AUSCAN 3.1 NRS Individual Component Scores 
 
Treatment Group: <Placebo, GSK3196165 180mg>  
Site ID/ 
Subject ID 
 
Visit 
Pain Subscale 
Score 
Physical Function 
Subscale Score 
Stiffness Subscale 
Score 
Total Score 
XXXX/ XXXX 
Baseline 
Week X 
Etc. 
 
Xx 
Xx 
… 
Xx 
Xx 
… 
Xx 
Xx 
… 
Xxx 
Xxx 
… 
XXXX/ XXXX 
Baseline 
Week X 
Etc. 
 
Xx 
Xx 
… 
Xx 
Xx 
… 
Xx 
Xx 
… 
Xxx 
Xxx 
… 
Notes to Programming Team:  
• 
This listing will be sorted by Site ID, Subject ID, Visit Date  
 
 
 
 
 
 
 
 
 
 
 


 
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Example: EFF_L4 
Protocol: 204851 Confidential                                                                    Page 1 of x 
Population: Intent-to-Treat                                                              
Listing x 
Listing of Individual Subject Number of Tender or Swollen Hand Joints, by Visit 
 
Treatment Group: <Placebo, GSK3196165 180mg> 
Site ID/Subject ID: XXXXX/ XXXXXXX 
Visit 
 
Right Hand Joints 
Left Hand Joints 
Total Number of Joints 
Baseline 
Tender 
PIP 2, PIP3, PIP4, 
MCP1 
PIP2, PIP3 
6 
 
Swollen 
PIP2, PIP4 
 
2 
 
 
 
 
 
Week 1 
Tender 
PIP 2, PIP3, PIP4, 
MCP1 
PIP2, PIP3 
6 
 
Swollen 
PIP2, PIP4 
 
2 
Notes to Programming Team:  
• This listing will be sorted by Site ID, Subject ID, Visit Date 
 
 
 
 
 
 
 
 
 
 


 
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Example: EFF_L5 
Protocol: 204851 Confidential                                                                    Page 1 of x 
Population: Intent-to-Treat                                                              
Listing x 
Listing of Individual Subject Pain/Tenderness Hand Joint Assessment, by Visit 
 
Treatment Group: <Placebo, GSK3196165 180mg> 
Site ID/Subject ID: XXXXX/ XXXXXXX 
Visit 
Pain/Tenderness 
Severity 
Right Hand Joints 
Left Hand Joints 
Total Number of Joints 
Baseline 
Mild 
PIP 2, PIP3, PIP4, 
MCP1 
PIP2, PIP3 
6 
 
Moderate 
 
Severe 
PIP2, PIP4 
 
PIP5 
 
2 
 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 1 
Mild 
PIP 2, PIP3, PIP4, 
MCP1 
PIP2, PIP3 
6 
 
Moderate 
 
Severe 
PIP2, PIP4 
 
PIP5 
 
2 
 
1 
 
 
 
 
 
Notes to Programming Team:  
• This listing will be sorted by Site ID, Subject ID, Visit 
 
 
 
 
 
 


 
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Example: EFF_L6 
Protocol: 204851 Confidential                                                                    Page 1 of x 
Population: Intent-to-Treat                                                              
Listing x 
Listing of Individual Subject Inflammatory Structural Joint Damage: HOAMRIS 
 
Treatment Group: <Placebo, GSK3196165 180mg> 
Site ID/ 
Subject ID 
Visit 
Number of 
Available 
Joints 
Synovitis 
Erosive 
Damage 
Cyst 
Osteophyte 
Cartilage 
Space Loss 
Mal-
alignment 
Bone 
Marrow 
Lesions 
XXXX/ XXXXX 
Baseline 
Week X 
… 
 
Xx 
Xx 
… 
Xxx 
Xxx 
… 
Xxx 
Xxx 
… 
Xxx 
Xxx 
… 
Xxx 
Xxx 
… 
Xxx 
Xxx 
… 
Xxx 
Xxx 
… 
Xxx 
Xxx 
… 
XXXX/ XXXXX 
Baseline 
Week X 
… 
 
Xx 
Xx 
… 
Xxx 
Xxx 
… 
Xxx 
Xxx 
… 
Xxx 
Xxx 
… 
Xxx 
Xxx 
… 
Xxx 
Xxx 
… 
Xxx 
Xxx 
… 
Xxx 
Xxx 
… 
Notes to Programming Team:  
• 
This listing will be sorted by Site ID, Subject ID, Visit  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Example: PK_L1 
Protocol: 204851 Confidential                                                                    Page 1 of x 
Population: Intent-to-Treat                                                              
Listing x 
Listing of Individual Subject Pharmacokinetic Data 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Group: <Placebo, GSK3196165 180mg> 
Site ID/ Subject ID: XXXX/XXXXXX Gender/Age(years)/Race/Weight(kg): F/XX/XXXX/XX 
Visit 
Date and Time Sample 
Taken (Relative Day) 
Dose Volume administered (mL) 
PLASMA GSK3196165 ng/mL 
Reason Test not Done 
 
 
 
 
 
Screening 
DDMMMYYY/ HH:MM (XX) 
x.x 
xxx 
 
Baseline 
DDMMMYYY/ HH:MM (XX) 
x.x 
 
XXXXX 
Week X 
 
x.x 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Example: PD_L1 
Protocol: 204851 Confidential                                                                    Page 1 of x 
Population: Intent-to-Treat  
Listing x 
Listing of Individual Subject <Target Engagement/Predictive/…> Biomarkers 
 
Treatment Group: <Placebo, GSK3196165 180mg > 
Site ID/ Subject ID: XXXX/XXXXXX Gender/Age(years)/Race/Weight(kg): F/XX/XXXX/XX 
Biomarker (Unit) 
Visit 
Date and Time Sample Taken 
(Relative Day) 
Result 
Change from 
Baseline 
Ratio from 
Baseline (%) 
 
 
 
 
 
 
XXXXX (XX) 
Screening 
DD-MMM-YYYY / HH:MM (xx) 
xx.x 
xx.x 
xx.x 
 
Baseline  
DD-MMM-YYYY / HH:MM (xx) 
xx.x 
xx.x 
xx.x 
 
Week X 
 
 
 
 
 
Etc.  
 
 
 
 
 
 
 
 
 
 
XXXXX (XX) 
Baseline  
DD-MMM-YYYY / HH:MM (xx) 
xx.x 
xx.x 
xx.x 
 
Week X 
 
 
 
 
 
Etc.  
 
 
 
 
 
 
 
 
 
 
Note: Values below LLQ are imputed to 0.5*LLQ.