A Multi-centre Long-term Extension Study to Assess the Safety and Efficacy of GSK3196165 in the Treatment of Rheumatoid Arthritis
Phase: PHASE3
Conditions: Arthritis, Rheumatoid
Sponsor: GlaxoSmithKline

 Protocol 
Study ID:  209564 
Official Title of Study: A multi-centre long-term extension study to assess the safety and 
efficacy of GSK3196165 in the treatment of rheumatoid arthritis 
NCT ID: NCT04333147 
Date of Document: 14 Oct 2019 

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GlaxoSmithKline group of companies
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TITLE PAGE
Protocol Title: A multi-centre long-term extension study to assess the safety and efficacy 
of GSK3196165 in the treatment of rheumatoid arthritis.
Protocol Number: 209564
Compound Number:
GSK3196165
Compound Name: 
Otilimab 
Study Phase: Phase 3
Short Title: Long-term safety and efficacy of GSK3196165 in the treatment of 
rheumatoid arthritis.
Study Name: contRAst-X
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual
Regulatory Agency Identifying Number(s):
IND: 121958
EudraCT: 2019-000878-30
Approval Date: 14-OCT-2019
Copyright 2019 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.

PPD
PPD

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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SUMMARY..........................................................................................7
1.1.
Synopsis.......................................................................................................7
1.2.
Schema ......................................................................................................10
1.3.
Schedule of Activities (SoA)........................................................................10
1.3.1.
SoA – Treatment Period ..............................................................11
1.3.2.
SoA – Safety follow-up (8 weeks after last dose of study 
intervention).................................................................................12
1.3.3.
Assessments for Early Withdrawal from Study.............................12
2.
INTRODUCTION....................................................................................................14
2.1.
Study Rationale ..........................................................................................14
2.2.
Background ................................................................................................14
2.3.
Benefit/Risk Assessment ............................................................................14
2.3.1.
Risk Assessment .........................................................................15
2.3.2.
Benefit Assessment.....................................................................23
2.3.3.
Overall Benefit: Risk Conclusion..................................................23
3.
OBJECTIVES AND ENDPOINTS...........................................................................24
4.
STUDY DESIGN ....................................................................................................25
4.1.
Overall Design ............................................................................................25
4.2.
Scientific Rationale for Study Design ..........................................................27
4.3.
Justification for Dose ..................................................................................27
4.4.
End of Study Definition ...............................................................................27
5.
STUDY POPULATION...........................................................................................27
5.1.
Inclusion Criteria.........................................................................................28
5.2.
Exclusion Criteria........................................................................................28
5.3.
Lifestyle Restrictions...................................................................................30
5.4.
Screen Failures...........................................................................................30
6.
STUDY INTERVENTION........................................................................................30
6.1.
Study Intervention(s) Administered .............................................................30
6.1.2.
Medical Devices...........................................................................33
6.2.
Preparation/Handling/Storage/Accountability..............................................33
6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................34
6.4.
Study Intervention Compliance ...................................................................35
6.5.
Concomitant Therapy..................................................................................35
6.5.1.
Permitted Therapies ....................................................................35
6.5.2.
Prohibited Therapies....................................................................36
6.6.
Dose Modification .......................................................................................37
6.6.1.
Dose Modification of Study Intervention.......................................37
6.6.2.
Dose Modification of Background csDMARD treatment ...............37
6.7.
Intervention after the End of the Study........................................................38
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7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................39
7.1.
Discontinuation of Study Intervention..........................................................39
7.1.1.
Liver Chemistry Stopping Criteria ................................................39
7.1.1.1.
Study Intervention Restart or Rechallenge after
liver stopping criteria met............................................40
7.1.2.
Other Stopping Criteria ................................................................40
7.1.3.
Temporary Discontinuation ..........................................................41
7.1.3.1.
Respiratory Symptoms ...............................................41
7.1.3.2.
Serious and Opportunistic Infections ..........................41
7.1.3.3.
Haematologic Abnormalities.......................................41
7.1.3.4.
TB Reactivation..........................................................42
7.2.
Participant Discontinuation/Withdrawal from the Study ...............................42
7.3.
Lost to Follow Up........................................................................................42
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................44
8.1.
Efficacy Assessments.................................................................................44
8.1.1.
Joint Assessments.......................................................................44
8.1.2.
Physician’s Global Assessment of Arthritis ..................................45
8.1.3.
Patient Reported Outcomes.........................................................45
8.1.3.1.
Health Assessment Questionnaire – Disability 
Index (HAQ-DI)...........................................................45
8.1.3.2.
Patient’s Assessment of Arthritis Pain ........................45
8.1.3.3.
Patient’s Global Assessment of Arthritis .....................45
8.1.3.4.
SF-36 Short Form Health Survey................................45
8.1.3.5.
Functional Assessment of Chronic Illness 
Therapy (FACIT)-Fatigue............................................45
8.2.
Safety Assessments ...................................................................................46
8.2.1.
Dyspnoea Assessments ..............................................................46
8.2.2.
Physical Examinations.................................................................46
8.2.3.
Electrocardiograms......................................................................46
8.2.4.
Vital Signs....................................................................................46
8.2.5.
Clinical Safety Laboratory Assessments ......................................47
8.2.6.
Pulmonary Assessments .............................................................47
8.2.7.
Tuberculosis Monitoring...............................................................48
8.2.7.1.
Tuberculosis Status Definitions ..................................48
8.2.7.2.
Tuberculosis Testing ..................................................49
8.2.7.3.
Treatment of Latent TB During the Study ...................49
8.2.7.4.
Monitoring for TB Infection and Re-activation 
During the Study.........................................................50
8.2.8.
Hepatitis B Monitoring..................................................................50
8.2.8.1.
Risk of Reactivation in Participants Positive for 
Hepatitis B Core Antibody (HBcAb) ............................52
8.2.8.2.
Treatment of Participants Who Are HBcAb 
Positive and Who Develop Detectable HBV 
DNA Requiring Initiation of Antiviral Therapy..............52
8.2.8.3.
Follow Up of Participants Treated With Anti-
viral Therapy...............................................................52
8.3.
Adverse Events and Serious Adverse Events.............................................52
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................53
8.3.2.
Method of Detecting AEs and SAEs.............................................53

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8.3.3.
Follow-up of AEs and SAEs.........................................................53
8.3.4.
Regulatory Reporting Requirements for SAEs .............................53
8.3.5.
Pregnancy ...................................................................................54
8.3.6.
Cardiovascular and Death Events................................................54
8.3.7.
AEs of Special Interest.................................................................55
8.3.8.
Medical Device Deficiencies ........................................................55
8.3.8.1.
Time Period for Detecting Medical Device 
Deficiencies................................................................55
8.3.8.2.
Follow-up of Medical Device Deficiencies...................56
8.3.8.3.
Prompt Reporting of Medical Device 
Deficiencies to Sponsor..............................................56
8.3.8.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................56
8.4.
Treatment of Overdose...............................................................................56
8.7.
Genetics .....................................................................................................58
8.8.
Biomarkers .................................................................................................58
8.9.
Immunogenicity Assessments.....................................................................58
8.10.
Medical Resource Utilisation and Health Economics ..................................58
9.
STATISTICAL CONSIDERATIONS........................................................................59
9.1.
Statistical Hypotheses.................................................................................59
9.2.
Sample Size Determination ........................................................................59
9.3.
Populations for Analyses ............................................................................59
9.4.
Statistical Analyses.....................................................................................59
9.4.1.
Safety Analyses...........................................................................60
9.4.2.
Efficacy & Patient-Reported Outcome Analyses ..........................60
9.4.3.
Other Analyses ............................................................................60
9.5.
Interim Analyses .........................................................................................60
9.5.1.
Independent Data Monitoring Committee (IDMC) ........................60
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................61
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................61
10.1.1.
Regulatory and Ethical Considerations ........................................61
10.1.2.
Financial Disclosure.....................................................................61
10.1.3.
Informed Consent Process ..........................................................62
10.1.4.
Data Protection............................................................................62
10.1.5.
Committees Structure ..................................................................62
10.1.6.
Publication Policy.........................................................................63
10.1.7.
Dissemination of Clinical Study Data ...........................................63
10.1.8.
Data Quality Assurance ...............................................................64
10.1.9.
Source Documents ......................................................................65
10.1.10. Study and Site Closure ................................................................65
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................66
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................68
10.3.1.
Definition of AE............................................................................68
10.3.2.
Definition of SAE..........................................................................69
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10.3.3.
Definition of Cardiovascular Events .............................................70
10.3.4.
Recording and Follow-Up of AE and SAE....................................71
10.3.5.
Reporting of SAE to GSK.............................................................72
10.4.
Appendix 4:Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................74
10.4.1.
Definitions:...................................................................................74
10.4.1.1.
Woman of Childbearing Potential (WOCBP)...............74
10.4.1.2.
Women in the following categories are not 
considered WOCBP ...................................................74
10.4.2.
Contraception Guidance: .............................................................75
10.4.3.
Collection of Pregnancy Information: ...........................................76
10.4.4.
Contraception Eligibility Criteria for Female and Male 
Participants..................................................................................77
10.5.
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................79
10.6.
Appendix 6:Summary of composite endpoints ............................................82
10.6.1.
Disease Activity Score (DAS).......................................................82
10.6.2.
Clinical Disease Activity Index (CDAI)..........................................82
10.6.3.
ACR and EULAR Remission (Boolean and SDAI) .......................82
10.7.
Appendix 7: Medical Device Adverse Events (AEs), Adverse Device 
Effects (ADEs), Serious Adverse Events (SAEs) and Device 
Deficiencies: Definition and Procedures for Recording, Evaluating, 
Follow-up, and Reporting............................................................................84
10.7.1.
Definition of Medical Device AE and ADE....................................84
10.7.2.
Definition of Medical Device SAE, SADE and USADE .................84
10.7.3.
Definition of Device Deficiency.....................................................85
10.7.4.
Recording and Follow-Up of Medical Device AE and/or 
SAE and Device Deficiencies.......................................................85
10.7.5.
Reporting of Medical Device SAEs ..............................................87
10.7.6.
Reporting of SADEs.....................................................................88
10.8.
Appendix 8: Country-specific requirements.................................................89
10.9.
Appendix 9: Abbreviations and Trademarks................................................90
11. REFERENCES.......................................................................................................93

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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A multi-centre long-term extension study to assess the safety and efficacy 
of GSK3196165 in the treatment of rheumatoid arthritis.
Short Title: Long-term safety and efficacy of GSK3196165 in the treatment of 
rheumatoid arthritis.
Rationale: This is a long-term safety and efficacy study. The participants in this study 
will be adults with rheumatoid arthritis (RA) who have completed the treatment phase of 
a qualifying GSK3196165 clinical study (including phase 3 studies contRAst 1 (201790), 
contRAst 2 (201791) and contRAst 3 (202018)) and who, in the investigator’s judgement 
will benefit from extended treatment with GSK3196165.  The primary aim of this study 
is to provide long-term safety data for GSK3196165, dosed at 90 mg or 150 mg every 
week.
Objectives and Endpoints:
Objectives
Endpoints
Primary
To determine the long-term safety of 
GSK3196165 at weekly doses of 90 mg or 150 
mg for the treatment of participants with 
moderately to severely active rheumatoid 
arthritis (RA).

Incidence of adverse events (AEs) and 
serious adverse events (SAEs) and adverse 
events of special interests (AESI).

Change from baseline* in key laboratory 
parameters.

Proportion of participants with NCI-CTCAE 
≥Grade 3 haematological/clinical chemistry 
abnormalities.  
Secondary
To determine the long-term efficacy of 
GSK3196165.
Proportion of participants at Weeks 24, 48 and 
every 48 weeks thereafter, achieving:

CDAI total score ≤10 (CDAI LDA)

CDAI total score ≤2.8 (CDAI Remission)

DAS28-CRP <2.6 and DAS28-ESR <2.6 
(DAS28 remission).

ACR and EULAR Remission (Boolean and 
SDAI).
Absolute values at Weeks 24, 48 and every 48 
weeks thereafter for: 

CDAI total score.

DAS28-CRP & DAS28-ESR.

van der Heijde mTSS score (participants 
from 201790 and 201791 only)

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Objectives
Endpoints
To determine effects of GSK3196165 on 
Patient Reported Outcomes (PROs).
Patient Reported Endpoints
Absolute values at Weeks 24, 48 and every 48 
weeks thereafter for: 

HAQ-DI.

Arthritis pain VAS.

The physical and mental component scores 
and the domain scores of SF-36.

FACIT-Fatigue.
To determine the immunogenic potential of 
GSK3196165.
Immunogenicity Endpoints

Anti-GSK3196165 antibodies
CDAI = clinical disease activity index; HAQ-DI = health assessment questionnaire disability index; VAS = visual 
analogue scale; LDA = low disease activity; DAS28 = disease activity score including 28 different joints; CRP = C-
reactive protein; EULAR = European League Against Rheumatism; SDAI = simplified disease activity index; mTSS = 
modified total Sharp score; ESR = erythrocyte sedimentation rate; AEs = adverse events; SAEs = serious adverse 
events; FACIT = functional assessment of chronic illness therapy; AESI = adverse event of special interest; NCI-
CTCAE = National Cancer Institute common terminology criteria for adverse events; RA = rheumatoid arthritis; SF-36 
= short form-36.
*See Statistical Analyses section.
Overall Design: This is a long-term safety and efficacy study in participants with RA 
who have completed treatment in one of the qualifying GSK3196165 clinical studies.  
Participants who have not developed any discontinuation criteria in their qualifying study 
and who consent to take part in this study will be assessed for eligibility upon completion 
of their final assessment visit within their qualifying study.  Eligible participants will be 
enrolled and receive weekly GSK3196165 90 mg or 150 mg by subcutaneous (SC) 
injection.
The anticipated study duration is approximately 4 years which will enable participants to 
receive treatment with GSK3196165 until it is expected to become commercially 
available.  The study duration may be increased if necessary to align with revised 
commercial availability, or reduced, if an alternative early access (or equivalent) 
programme is started, or if development of GSK3196165 in RA is stopped.  An 
individual participant’s treatment duration in this study is expected to be between 1-4 
years depending on a number of factors, including: continued efficacy response of the 
participant, safety and tolerance of the study drug, consent of the participant to continue 
with study assessments, the opinion of the investigator and the development status of the 
drug.  All participants will have a safety follow-up visit 8 weeks after their last dose of 
study intervention.
Participants will continue to receive the same background conventional synthetic disease 
modifying antirheumatic drug(s) (csDMARD) treatment as they received in their 
qualifying study.  However, if clinically indicated, a participant's background 
csDMARD(s) dose may be changed, including dose reduction/discontinuation per the 
guidance within protocol, starting from Week 12 (or from Week 24, for participants who 
joined from 202018).

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During the course of this extension study, it is expected that an autoinjector (AI) device 
will become available to supplement/replace the pre-filled syringes (PFS).  When the AI 
device becomes available, a sub-study of approximately 200 new participants who join 
the extension study at this time, will examine AI device usability and steady state PK.
Disclosure Statement: This is a parallel group treatment study with two arms that are 
initially participant and investigator blinded.  A participant’s treatment allocation will 
remain blinded at least until their qualifying study has been reported.
Number of Participants: It is anticipated that approximately 3000 participants from the 
qualifying studies already planned (201790, 201791 and 202018) may be eligible to 
participate in this long-term extension study. This number may increase if the number of 
qualifying studies increases. All subjects will be considered evaluable.  
Intervention Groups and Duration: Upon successful enrolment to this study, 
participants will be assigned by interactive response technology (IRT) to receive 
GSK3196165 90 mg or 150 mg weekly SC injection as follows:

Participants who were receiving GSK3196165 in their qualifying study will 
continue to receive GSK3196165 at the same dose level (90 mg or 150 mg weekly), 
in this study.

Participants who were receiving a comparator (e.g. tofacitinib or sarilumab) in their 
qualifying study will be re-randomised, in a ratio of 1:1, to receive either 
GSK3196165 90 mg or 150 mg weekly.  
Note: If it is determined at any time (for example, at the time of the primary analysis of 
the qualifying studies) that one of the doses does not have a positive benefit:risk profile, 
then this arm may be discontinued and all patients transferred to the remaining dose arm. 
Independent Data Monitoring Committee: Yes.
Major Adverse Cardiac Event and Gastrointestinal Perforation Adjudication 
Committee: Yes.
Pulmonary Adjudication Committee: Yes.

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1.2.
Schema
W 0
GSK3196165 90mg weekly
GSK3196165 150mg weekly
GSK3196165 90mg
GSK3196165 150mg
Comparator
Previous qualifying study
Re-Randomise
W24
W72
W12
W36
Transition to long-term 
efficacy and safety study on 
final visit of previous study
Long-term safety and efficacy study
Assessment visits every 12 weeks, for duration of study
Safety
Visits*
W48
W60
W84
*Safety visits: All participants must be monitored for safety for 1 hour post-dose for their first two 
doses in this study (Week 0 and Week 1).  In addition, participants joining from study 202018, will 
attend for a safety visit at Week 4.
1.3.
Schedule of Activities (SoA)
See Section 8 for further details of study procedures listed in the SoA.
Order of Assessments:

PROs should be completed first, before any other assessments, procedures or 
consultations, to avoid influencing participants’ perception.

Where possible, joint counts should follow PRO completion.  The physician global 
assessment (PhGA) should then take place, followed by other assessments 
(including safety), ECGs, vital signs and blood draws, before dosing.

and blood draws must always take place before dosing.
Study SC Dosing and Visit Schedule:

Study SC injection should be administered weekly, on the same day each week. 

A window of ±2 days is acceptable for the SC injection (minimum gap of 5 days 
between each dose, for no more than 2 consecutive doses).  Participants should 
return to their 7 day dosing schedule as soon as possible thereafter.  See Section 6.1
for further information.

Where possible, assessment visits should be scheduled to coincide with the 
weekly administration of study SC injection, so that the participant may 
receive their dose at site on visit days. The injection will then be performed at the 
site, after completion of study assessments, 
and other blood draws.

All participants must be monitored for safety, for 1 hour post-dose for their first two 
doses in this study (Week 0 and Week 1).
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1.3.1. SoA – Treatment Period
Visit
(Visit windows: W1-4 ±2 days; W12-W48 ±1 week; W60 onwards ±2 weeks)
Notes
Assessment visit Week
      Study activities
Day 11,3
Week 0
Week 13
Week 44
Week 12
Week 24
Week 36
Week 48
Repeat every 48 weeks until EoS
1. Participants wishing to enrol in contRAst-X should 
complete Day 1 study activities on the day of their 
qualifying study final assessment visit or if not possible, 
within 7 days. Exceptions to this must be agreed with 
the medical monitor.
2. Pre-dose Day 1 assessments will not be collected as 
part of this study if enrolment is on the same day as the 
qualifying study final assessment visit, or within 7 days.
3. All participants must be monitored for 1 hour post-dose 
on Weeks 0 and 1 (because some participants will be 
receiving GSK3196165 for the first time).
4. Safety visit for participants from 202018 only (to monitor 
safety when switching from biologic comparator).
5. PROs should be completed before any other 
assessments, procedures or consultations, to avoid 
influencing participants’ perception.
6. ECGs should be performed before vital signs and blood 
draws, with triplicate ECGs at pre-dose Day 1.2
7. Where possible the same assessor should perform all 
joint assessments for an individual participant.
8. Where possible, the same individual should perform all 
physician global assessments for an individual 
participant.
9. Participants from 201790 and 201791 only.
10.For women of child-bearing potential.
11.ESR measured locally using kit provided by the central 
laboratory.
15.Window for AE/conmed call is +/-1 week.
Week 60
(then W108, W156…)
Week 72
(then W120, W168…)
Week 84
(then W132, W180…)
Week 96
(then W144, W192…)
Informed consent
X
Eligibility (Inclusion/Exclusion)
X
Randomisation
X
PROs
HAQ-DI, Arthritis pain VAS, PtGA5
X2
X
X
X
X
X
X
X
X
SF-36, FACIT-Fatigue5
X2
X
X
X
X
X
X
AI sub-study usability questionnaire5,13
X
Assessments
12-lead ECG6
X2
X
X
Vital signs
X2
X
X
X
X
X
X
X
X
X
X
Physical Exam (B - brief, F - full)
F2
B
B
B
B
B
F
B
B
B
F
Dyspnoea & Cough assessment, Lung
Auscultation, Pulse Oximetry
X2
X
X
X
X
X
X
X
X
X
X
Swollen (66) & Tender (68) joint count7
X2
X
X
X
X
X
X
X
X
Physician Global Assessment8
X2
X
X
X
X
X
X
X
X
Hands and Feet x-ray9
X
X
X
Chest X-ray (posteroanterior)
X
X
Labs and blood draws
Hematology, Chemistry, Urinalysis
X2
X
X
X
X
X
X
X
X
X
X
Lipid profile
X
X
X
Urine pregnancy test10
X2
<-------------------------------- Every 8 weeks -------------------------------->
hsCRP, ESR11
X2
X
X
X
X
X
X
X
X
TB testing
X
X
Immunogenicity blood sampling
X2
X
X
X
X
 
Dose
Dispense treatment
X
X
<--------------------------- Every 4 weeks --------------------------->
Weekly study treatment SC injection
X3,
X3
<------------------------------------ X ------------------------------------>
SAE/AE and AESI review
<-------------------------------------------- X -------------------------------------------->
Concomitant medication review
<-------------------------------------------- X -------------------------------------------->
AE/conmed phone call if no site visit15
<------ Every 4 weeks to Week 48, then every 6 weeks to Week 96 ------>
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1.3.2.
SoA – Safety follow-up (8 weeks after last dose of study intervention)
Safety follow-up visit procedures
Last dose + 8 weeks

Assessments
Vital signs
Full Physical Exam
Dyspnoea & Cough assessment, Lung Auscultation, 
Pulse Oximetry
Concomitant Medication Review
SAE/AE review
Labs
Haematology, Chemistry, Urinalysis (dipstick), Urine 
pregnancy test (women of child bearing potential only)
Immunogenicity blood sampling
1.3.3.
Assessments for Early Withdrawal from Study
Follow the Week 96 procedures* at the time of withdrawal from the study, or within 1 week of withdrawal, and schedule a safety follow-up visit 8 
weeks post last dose of study intervention.
*Note: A hands/feet x-ray should not be performed at early withdrawal if one has been carried out within 8 weeks of the early withdrawal date, as 
part of study procedures, and a chest x-ray should not be performed if one has been carried out within 12 weeks of the early withdrawal. 

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2.
INTRODUCTION
GSK3196165 is a novel human monoclonal anti-granulocyte-macrophage colony 
stimulating factor (GM-CSF) antibody that is being developed for once-weekly treatment 
of rheumatoid arthritis (RA).
2.1.
Study Rationale
This is a long-term study, primarily to assess safety, with efficacy assessment as a 
secondary objective.  The participants in this study will be adults with rheumatoid 
arthritis (RA) who have completed the treatment phase of a qualifying GSK3196165 
clinical study (including Phase 3 studies 201790, 201791 and 202018) and who, in the 
investigator’s and participant’s judgement will benefit from extended treatment with 
GSK3196165.  The aim of this study is to provide long-term safety and efficacy data for 
GSK3196165, dosed at 90 mg or 150 mg every week.
2.2.
Background
RA is a chronic, systemic inflammatory autoimmune disease, characterised by a 
symmetrical polyarthritis that can be associated with substantial disability and morbidity.
Since RA is a chronic disease, patients will require treatment for a long period of time 
and it is important to study the long-term safety and efficacy of the continuous treatment 
with GSK3196165 over several years. 
More detailed information on RA and the mechanism of action of GSK3196165 may be 
found in the Investigator's Brochure (IB).
2.3.
Benefit/Risk Assessment
The potential risk assessment and mitigation strategy for the administration of 
GSK3196165 in this protocol is outlined below.

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2.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK3196165]
Infections
Immune-modulating biologic drugs used in RA (such 
as anti-TNF agents) are associated with an increased 
risk of serious and opportunistic infections.  Similarly, 
because of the role of GM-CSF in anti-infective 
immunity, GSK3196165 also has the potential to 
increase the risk of infection.
Non-clinical Data:
No changes in peripheral blood populations 
(lymphocytes, neutrophils, monocytes, eosinophils or 
basophils), phagocytic activity of peripheral blood 
polymorphonuclear cells (investigational endpoint in 
the 26 week study), T-cell dependent B-cell primary or 
secondary response, or circulating cytokine levels (26 
week study) were observed.
Studies in knock-out mice showed that GM-CSF 
deficiency (GM-CSF-/-) affects the ability of mice to 
control infection when infected with M. tuberculosis or 
pulmonary group B streptococcus [LeVine, 1999].
Clinical Data:
Based on the mechanism of action of GSK3196165, 
an increased risk of infection including TB, fungal and 
opportunistic infections could be expected for anti-GM-
CSF treatment, because of the role of GM-CSF in anti-
infective immunity.
One healthy volunteer (HV) in study MSC-1000 
experienced septic shock secondary to pneumonia 29 
days after receiving a single dose of 1.5 mg/kg but 
Eligibility Criteria (Section 5):
Exclusion of participants with:

Evidence of untreated latent Mycobacterium 
tuberculosis (TB) (unless willing to undergo 
TB therapy or have successfully undergone 
TB therapy).

Current or previous active TB regardless of 
treatment.
Monitoring:

Serious and opportunistic infections, TB and 
TB reactivation are categorised as adverse 
events of special interest (AESIs).

Monitoring for signs of infection with 
appropriate diagnostic tests as necessary.

Instructions to participants as to the signs and 
symptoms of infection, and to contact site 
personnel should they develop (also 
contained within the ICF).

Monitoring for TB and TB re-activation 
throughout the study (Section 8.2.7.4).

Participants diagnosed with latent TB will 
need to complete a course of at least 6 
months of isoniazid (INH) therapy during the 
study. For the first 4 weeks of INH therapy, 
the participant must be temporarily 
discontinued from study intervention (Section 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
recovered after treatment with antibiotics.
In Phase II completed studies, no significant infections 
or opportunistic infections were reported.
8.2.7.3).
Withdrawal Criteria:
Temporarily discontinue the study intervention for: 

Serious infections until the infection has 
resolved.

Suspected TB reactivation.

New diagnosis of latent TB

WBC count < 2 x 109/L
Permanently discontinue the study intervention for:

New active TB infection

HBV DNA level ≥ 200 IU/mL or HBV DNA 
detected at any level with recent increase in 
hepatic transaminases (see Figure 1 in 
Section 8.2.8).

HBV DNA positive (any level < 200 IU/mL) 
and on repeat testing within 1 week either: 
HBV DNA positive (any level) OR HBV 
surface antigen positive OR increase in 
hepatic transaminases (see Figure 1 in 
Section 8.2.8).
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.  PAP is characterised by the 
accumulation of surfactant lipids and protein in the 
alveolar spaces, which might lead to persistent dry 
cough and is also associated with impairment in gas 
exchange which may lead to an increased risk of 
dyspnoea and pulmonary infection.
Monitoring:

PAP is categorized as an AESI.
Persistent cough (CTCAE Grade 2) or 
persistent dyspnoea (dyspnoea scale Grade 
2) are categorised as AESIs.

Regular chest auscultation and pulse oximetry 
measurements.

Specific pulmonary assessments throughout 
the study with referral to a pulmonologist for 
clinically-significant pulmonary events.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
The duration of exposure to GSK3196165 in this study 
may be approximately 4 years.  Although the time 
course of PAP development in humans is unknown, 
the published literature suggests that the clinical onset 
of PAP requires prolonged and complete inhibition of 
GM-CSF [Martinez-Moczygemba, 2008; Suzuki, 
2008]. Risk of PAP is anticipated to be low.
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 were reversible following an 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.  Pulmonary function 
tests have not identified any safety signals.

Pulmonary Safety Guidance Document 
containing pulmonary assessment and 
management algorithms will be provided to 
the investigator. 
Withdrawal Criteria:
Temporarily discontinue study intervention for:

persistent cough (CTCAE Grade 2) or 
persistent dyspnoea (dyspnoea scale 
Grade 2) for 3 consecutive weeks (21 
days).
Permanently discontinue study intervention for:

Confirmed PAP
Hypersensitivity reactions
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 serious allergic or acute systemic reactions have 
been observed to date in the clinical development 
program.
Eligibility Criteria (Section 5):
Exclusion of participants with:

A history of sensitivity to any of the study 
interventions, or components thereof.
Monitoring:

Serious hypersensitivity reactions are 
categorised as AESIs.

Instructions to participants as to the signs and 
symptoms of an acute hypersensitivity 
reaction and to seek immediate medical care 
should they develop (also contained within the 
ICF)

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy

Hypersensitivity to be managed appropriately 
per local guidelines/medical judgement

All participants must be monitored for 1 hour 
post dose on Weeks 0 and 1.
Withdrawal Criteria:

Permanently discontinue study intervention for 
serious hypersensitivity reactions
Injection site reactions
SC injections may be associated with local reactions 
(e.g., swelling, induration, pain).
Non-clinical Data:
No macroscopic or microscopic changes indicative of 
local injection site reactions were observed following 
SC administration in cynomolgus monkeys.
Clinical Data:
Injection site reactions have been reported in 
completed Phase II studies and were non-serious and 
of mild to moderate intensity.
Monitoring:

Injection site reactions are categorised as 
AESIs; injection site reactions to be reported 
as an AE.

Monitor for injection site reactions throughout 
study.

Injection sites will be rotated.
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 haematopoiesis [Stanley, 1994].
Clinical Data:
Neutropenia has been observed in completed studies 
of GSK3196165; however, no clinically significant 
cases have been observed.
Monitoring:

Neutropenia Grade 3 (< 1.0 x 109/L) is 
categorised as an AESI.

Full blood count (with differential) performed 
at regular intervals throughout the study
Withdrawal Criteria:

Temporarily discontinue study intervention for 
the following haematological abnormality until 
resolved (Section 7.1.3.3):

Absolute neutrophil count (ANC) ≤ 1 x 109/L
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
Eligibility Criteria (Section 5 and Appendix 4):

Women of child bearing potential (WOCBP)
and males to meet contraceptive 
requirements.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
[Robertson, 1999; Robertson, 2007].
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.
Clinical Data:
Two pregnancies have been reported during clinical 
studies with GSK3196165, 1 in a female partner of a 
healthy volunteer (HV) participant and 1 in an multiple 
sclerosis (MS) participant. Both pregnancies were 
electively terminated. The effect of GSK3196165 on 
human pregnancy is unknown.
Exclusion of female participants who are:

Pregnant, lactating, planning to become 
pregnant or initiating breastfeeding.
Monitoring:

Females of reproductive potential using 
hormonal contraceptives, including oral, 
injections, implants, and patches, are required 
to use a secondary method of contraception.

Routine urine pregnancy testing of WOCBP 
throughout the study.

Collection of pregnancy information in females 
and in female partners of male participants.

Pregnancy to be followed to determine 
outcome.

Report as AE/SAE any pregnancy 
complication or elective termination.
Withdrawal criteria:

Permanently discontinue study intervention in 
event of pregnancy (Section 7.1.2).
Malignancy
Risk of malignancy is increased in RA and the 
immunomodulatory therapies may also increase the 
risk.
Non-clinical & Clinical Data:
There are no reports of malignancy in the non-clinical 
or completed studies in the GSK3196165 program.
Eligibility Criteria (Section 5):
Exclusion of participants who:

Develop a new cancer or malignancy except 
for basal and squamous cell carcinoma of the 
skin or in situ carcinoma of the cervix treated 
and considered cured by the investigator

Have developed any lymphoproliferative 
disorder, such as Epstein Barr Virus (EBV) 
related lymphoproliferative disorder, or signs 
and symptoms suggestive of current 
lymphatic disease

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Immunogenicity
GSK3196165 is a humanised monoclonal antibody 
that will be delivered by the subcutaneous route and is 
targeted to bind and neutralise a soluble target, and 
for these reasons, is considered to be a relatively low 
risk of inducing adverse immune responses [FDA, 
2014]. Participants who discontinue from background 
csDMARD/MTX will have extra immunogenicity 
samples collected following discontinuation.
Non-clinical Data:
Anti-drug antibodies (ADAs) to GSK3196165 were 
detected in some monkeys and this was associated 
with reduced serum levels of GSK3196165; ADA 
associated toxicity was not observed.
Clinical Data:
In clinical trials to date, there is no evidence that anti-
GSK3196165 antibodies affect GSK3196165 serum 
concentrations.

Blood samples will be tested for ADAs to 
GSK3196165 on week 0 (Day 1) and at select 
time points throughout the study (including 
Follow-up). If present, ADA titres and 
presence of neutralising antibodies will be 
assessed. 

In addition to scheduled immunogenicity 
assessments, “event-driven” testing will be 
performed in the context of serious 
hypersensitivity reactions or AEs deemed to 
be clinically significant in the opinion of the 
investigator resulting in discontinuation from 
study intervention.
Potential drug interaction with CYP450 substrates
Cytokines can produce concentration-dependent 
inhibition on various CYP isoforms at the transcription 
level or by alteration of CYP enzyme stability in 
patients with infection or inflammation and increase 
the plasma concentrations of specific CYP substrate 
drugs.
Cytokine modulators may reverse the apparent 
“inhibition” effect of the cytokines on CYP substrates, 
resulting in a “normalisation” of CYP activities. 
GSK3196165 is a cytokine modulator, so it has the 
potential to ‘normalise’ CYP expression from a 
suppressed state in patients with a pro-inflammatory 
disease (RA).

Information will be collected on concomitant 
warfarin use (e.g. International normalized 
ratio (INR) results and any information related 
to warfarin dose).

Participants of reproductive potential using 
hormonal contraceptives, including oral, 
injections, implants, and patches are required 
to use a secondary method of contraception.

Participants receiving a concomitant CYP450 
substrate with narrow therapeutic index (e.g. 
theophylline) should be monitored for signs in 
changes in drug exposure.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Clinical Data:
In a phase II study for GSK3196165, the ratio of 4β-
hydroxycholesterol to cholesterol was monitored as a 
biomarker predictive of change in CYP3A4 activity.
Based on the data, GSK3196165 showed no risk of 
alteration of CYP450 3A4 enzyme.
Study Procedures
Blood draws
Venous access in some participants may be 
problematic and the needles used may cause bruising 
(ecchymosis) around the access site.

A maximum of approximately 400 mL of whole 
blood will be collected from each participant 
over the course of the study (assuming a 4-
year treatment period, including extra 
assessments for csDMARD tapering and AI 
sub-study). 

At visits to collect whole blood samples, one 
or more samples of sufficient volume will be 
collected and divided into suitable portions for 
the various analyses. 

Whole blood samples will be collected by site 
personnel experienced in phlebotomy.
Chest X-ray
Generally, the amount of radiation during an X-ray is 
equivalent to between a few days and a few years of 
exposure to natural radiation from the environment. 
The risk of cancer from exposure to X-rays is very 
small.

Minimal procedures during study (annual 
Chest X-ray)

Exposure to radiation from X-rays is far less 
than the exposure to natural radiation.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
X-rays of the hands/feet
Structural joint damage evaluation by X–rays (van der 
Heijde modified total Sharp scores mTSS) is an 
established endpoint that is accepted in the US and 
EMA regulatory guidelines to demonstrate prevention 
of joint damage.  This study aims to establish if 
structural bone damage does or does not deteriorate 
after treatment with GSK3196165.

Minimal procedures performed to assess
structural joint damage in patients from 
qualifying studies 201790 and 201791 (annual 
X-ray)

Exposure to radiation from X-rays is far less 
than the exposure to natural radiation.

Positioning devices will be used to minimise 
the risk of repeat X-ray
Study Medical Devices
Handling and usage risks associated with the 
prefilled syringe and autoinjector devices.
A life-threatening serious risk has been identified that 
is caused by the participant removing the rigid needle 
shield with their teeth and choking on the small part. 
This risk is considered improbable and non-intuitive, it 
has not been observed in human factors studies for 
this patient group and is not precedented with other 
GSK products using the same devices.
All other anticipated device effects are non-serious 
and primarily unlikely, improbable, occasional or 
remote and are due to user error.
Instructions For Use (IFU) on how to correctly handle 
and use the device is provided.

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2.3.2.
Benefit Assessment
GM-CSF plays a key role in initiation and progression of inflammation in RA and 
indirectly increases the destruction of the bone and cartilage.  GSK3196165 binds human 
GM-CSF and inhibits GM-CSF mediated responses in vitro.  Clinical studies in RA have 
shown that GSK3196165 [Behrens, 2015] and mavrilimumab (an anti-GM-CSF alpha-
subunit receptor antibody) [Burmester, 2017, Burmester, 2018; Cook 2018b] and 
namilumab [Taylor, 2019] were able to reduce RA disease activity and pain.  In addition, 
results from BAROQUE (GSK Study 201755) showed that all doses of GSK3196165 
above 22.5 mg in combination with methotrexate (MTX) resulted in a significant 
reduction in DAS28(CRP), significantly higher ACR20 response rates, substantial 
improvements in tender and swollen joint counts, a large effect in CDAI and rapid 
improvements in pain with an acceptable safety profile when compared with placebo. 
These data support further evaluation of GSK3196165 as a treatment option in RA, 
including the long term evaluation of clinical benefit and safety that will be achieved 
within this study.
All participants enrolled will have been deemed by the investigator as likely to benefit 
from receiving continuous treatment with GSK3196165 upon completion of the 
qualifying study and all will receive GSK3196165. Furthermore, each participant will 
continue to benefit from extensive monitoring of their disease activity with numerous 
assessments throughout the study such as physical examinations, X-rays, ECGs, vital 
signs, pulse oximetry, respiratory function tests, laboratory tests, and swollen/tender joint 
assessments among others.
If it is determined at any time (for example, at the time of the primary analysis of the 
qualifying studies) that one of the doses does not have a positive benefit:risk profile, then 
this dose arm may be discontinued and all patients transferred to the remaining dose arm.
2.3.3.
Overall Benefit: Risk Conclusion
Current preclinical and clinical data with GSK3196165 indicates that it binds and inhibits 
the function of GM-CSF and that this inhibition may have clinical utility in the treatment 
of inflammatory and autoimmune diseases, such as RA. 
The main potential risks are those that may be associated with inhibition of GM-CSF, 
including infection, PAP, neutropenia, malignancy and reproductive toxicity, plus those 
associated with the administration of a therapeutic monoclonal antibody, including 
hypersensitivity reactions, injection site reactions and immunogenicity.
In addition to routine pharmacovigilance, the safety review team (SRT) will review 
blinded safety data approximately every 4 weeks during the period of study conduct and 
unblinded safety data will be reviewed by the Independent Data Monitoring Committee 
(IDMC) at scheduled intervals (see Section 9.5.1).  Key safety data will be reviewed by 
the IDMC allowing ongoing assessment of the overall benefit:risk throughout the study.  
Full details will be provided in the IDMC charter.
Taking into account the measures taken to minimise risk to participants randomised in 
this study, the potential risks identified in association with GSK3196165 are justified by 

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after completion of the final assessment visit of their qualifying study, preferably on 
the same day.  There is no formal screening period in this extension study.

If the participant is enrolled on the same day as the final assessment visit, or within 
7 days following this, no collection of pre-dose assessments under this extension 
study is required and the participant may proceed to dosing (the data from their final 
assessment of the qualifying study will be used as pre-dose values for this study).  
With approval of the medical monitor, participants may be enrolled after 7 days 
following the completion of their qualifying study final assessment visit, in these 
cases pre-dose assessments per the SoA will be collected prior to dosing.
o
Note: Participants should be advised of this extension study in the weeks and 
months prior to the end of their qualifying study, to ensure they have enough 
time to consider this study prior to their final assessment visit on the 
qualifying study.

Participants who consent and are eligible, will be enrolled and assigned to receive 
GSK3196165 90 mg or 150 mg weekly SC injection, by interactive response 
technology (IRT) as follows:  
o
Participants who were receiving GSK3196165 in their qualifying study will 
be assigned by IRT to continue to receive GSK3196165 at the same dose 
level in this study.
o
Participants who were receiving a comparator (e.g. tofacitinib or sarilumab) 
in their qualifying study will be re-randomised by IRT, in a ratio of 1:1, to 
receive either GSK3196165 90 mg or 150 mg weekly, in this study.  

A participant’s treatment allocation will remain blinded at least until their qualifying 
study has been reported.

Participants will continue to receive the same background csDMARD treatment as 
they received in their qualifying study.  However, if clinically indicated, a 
participant’s background csDMARD(s) dose may be changed, 
 
 
  See Section 6.6.2 for details about background 
csDMARD (including MTX) 

Participants who join from Study 201790 or Study 201791, or any other qualifying 
study/ies in which radiographic assessment of joints has been performed will 
continue to have radiographs of the hands and feet (see SoA, Section 1.3) to assess 
long-term radiographic progression of structural joint damage. 
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4.2.
Scientific Rationale for Study Design
Participation in this study will allow participants who have completed one of the 
qualifying GSK3196165 clinical studies to receive long-term treatment with 
GSK3196165 at doses of 90 mg or 150 mg weekly. 
The data from this study will provide an evaluation of the long-term safety and efficacy 
outcomes of GSK3196165 in adults with RA. 
4.3.
Justification for Dose
The GSK3196165 doses of 90 mg and 150 mg weekly (SC) proposed for this study are 
the doses that were used in qualifying Phase 3 studies 201790, 201791 and 202018.  
These were selected based on the pharmacokinetic (PK) data, efficacy and safety data, 
and the exposure-response relationship for efficacy endpoints in the Phase 2b dose 
finding study (BAROQUE, 201755). 
4.4.
End of Study Definition
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last visit including the safety follow up visit, 8 weeks 
after the last dose. 
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
There is no formal screening period in this extension study.  Clinical laboratory 
assessments will be collected in the qualifying study, approximately two to four weeks 
prior to the final assessment visit and assessed and managed as per the qualifying study 
protocol.  Any temporary or permanent discontinuation of study medication resulting 
from these assessments must be considered against the eligibility criteria detailed in 
Section 5.1 and Section 5.2 below.
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5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
TYPE OF PARTICIPANT
1. Participants with rheumatoid arthritis who are aged ≥18 years at the time of signing 
informed consent, who have completed one of the qualifying GSK3196165 clinical 
studies and who, in the opinion of the investigator, may benefit from treatment with 
GSK3196165.
WEIGHT
2. Body weight 40 kg
SEX
3. Male or female participants are eligible to participate as long as they meet the 
contraceptive eligibility criteria in Section 10.4.4 and agree to abide by the 
contraceptive requirements detailed in Appendix 4. 
INFORMED CONSENT
4. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol.
OTHER SAFETY-RELATED
5. For participants on MTX: must be willing to continue treatment with oral folic acid 
(at least 5 mg/week) or equivalent while receiving MTX (mandatory co-medication 
for MTX treatment).
5.2.
Exclusion Criteria
A participant will not be eligible for inclusion in this study if any of the following criteria 
apply:
MEDICAL CONDITIONS
1. Had study intervention permanently discontinued at any time during a qualifying 
study except any participant with a new diagnosis of latent TB at the end of study 
assessment in a qualifying study and currently undertaking or willing to complete 
at least 4 weeks of anti-TB treatment off study treatment, per WHO or national 
guidelines prior to re-commencing therapy and complete the remainder of anti-TB 

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treatment while on study.
2. Evidence of latent TB (as documented by a positive QuantiFERON-TB Gold plus 
test or T-SPOT.TB test, no findings on medical history or clinical examination 
consistent with active TB, and a normal chest radiograph) except for participants 
that 
o
Are currently undertaking or willing to complete at least 4 weeks of anti-TB 
therapy off study treatment, as per WHO or national guidelines prior to re-
commencing study treatment and agree to complete the remainder of anti-
TB treatment while in the study OR
o
Had documented evidence of satisfactory anti-TB treatment as per WHO or 
national guidelines following review by a physician specialising in TB on 
entry to a qualifying study.
3. Current or previous active Mycobacterium tuberculosis (TB) regardless of 
treatment. 
4. Were temporarily discontinued from study intervention at the time of the final 
study visit of a qualifying study and, in the opinion of the investigator, participation 
in the extension study poses an unacceptable risk for the patient’s participation.
5. A new cancer or malignancy except for basal and squamous cell carcinoma of the 
skin or in situ carcinoma of the cervix treated and considered cured by the 
investigator.
6. Have developed any lymphoproliferative disorder during a qualifying study, such 
as Epstein Barr Virus (EBV) related lymphoproliferative disorder, or signs and 
symptoms suggestive of current lymphatic disease.
7. Have significant uncontrolled cardiovascular, cerebrovascular, respiratory, hepatic, 
renal, gastrointestinal, endocrine, hematologic, or neuropsychiatric disorders, or 
abnormal laboratory values that developed during a qualifying study that, in the 
opinion of the investigator, poses an unacceptable risk for the patient’s 
participation.
PRIOR/CONCOMITANT THERAPY
8.
Participants who are expected to be non-compliant with restrictions on medications 
and vaccinations prior to the study, during the study or during the 8-week safety 
follow-up of the study.  See Section 6.5.2 for details of prohibited 
medications/treatments and Section 6.5.1 for details of permitted
medications/treatments.
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
9. Participants who are currently participating in any interventional clinical study other 
than a qualifying GSK3196165 clinical study.

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DIAGNOSTIC ASSESSMENTS
10. Abnormal chest radiograph within the last 12 weeks judged by the investigator as 
clinically-significant.
OTHER EXCLUSIONS
11. Pregnant or lactating, or women planning to become pregnant or initiating 
breastfeeding 
12. 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.
5.3.
Lifestyle Restrictions
No restrictions are required.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered into the study.  There is no formal screening period in 
this extension study, however a minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse events (SAEs).
Individuals who do not meet the criteria for participation in this study at the time of 
eligibility assessment (screen failure) cannot be reconsidered at a later point in time,
“rescreening” is not permitted.
6.
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
6.1.
Study Intervention(s) Administered
An overview of the study interventions is provided in Table 1.  Investigators should note 
the following:

Study SC injection should be administered weekly, on the same day each week.  The 
SC injection should be administered to the abdomen, thigh or upper arm, and should 
preferably be rotated left and right, or to a different site, each week.

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
A window of 2 days is acceptable for the SC injection (minimum gap of 5 days 
between each dose, for no more than 2 consecutive doses).  Participants should 
return to their 7 day dosing schedule as soon as possible thereafter.

All participants must receive their Week 0 and Week 1 SC injections at site, with 
general safety monitoring for 1 hour post-dose. Safety monitoring will include 
monitoring for systemic hypersensitivity and local injection site reactions. 

Where possible, assessment visits should be scheduled to coincide with the 
weekly administration of study SC injection, so that the participant may 
receive their dose at site on visit days. The injection will then be performed at the 
site, after completion of study assessments, 
and other blood draws (see 
Section 1.3).

Any participant who doses at home must be instructed to contact the site 
immediately if they experience any symptoms of a drug reaction following dosing.

When available the active treatment will be supplied in an autoinjector format. Until 
this time treatment will be supplied in PFS (or from vials, if PFS are not available).

Study intervention for each arm is expected to be supplied in volume-matched PFS
or AI for the duration of this study. However, if at any time while the study is
blinded to site or participant, the study intervention is supplied from vials (for 
example, if supply of PFS or AI is interrupted), an unblinded administrator must 
prepare and administer the injection, keeping the syringe and vial shielded from the 
participant at all times.  If this situation occurs, additional guidance will be provided 
in an updated pharmacy manual or addendum.
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Table 1
Overview of Study Intervention
ARM Name
GSK3196165 
90 mg
GSK3196165
150 mg
Intervention Name
GSK3196165
GSK3196165
Type 
Biologic
Biologic
Dose Formulation
Solution in vial (1.2 mL), solution in 
PFS (1.0mL) and solution in AI 
(1.0 mL)
Solution in vial (1.2 mL), solution
in PFS (1.0mL) and solution in AI 
(1.0 mL)
Unit Dose Strength(s)
Vial: 150mg/mL
PFS and AI: 90 mg/mL
Vial: 150mg/mL
PFS and AI: 150 mg/mL
Dosage Level(s)
90 mg once weekly
150 mg once weekly
Route of 
Administration
SC injection
SC injection
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the Sponsor
Provided centrally by the Sponsor
Dosing instructions
PFS and AI: Inject all per 
instructions for use (IFU).
Vial: withdraw 0.6 mL into a small 
syringe and dose immediately; 
discard remaining material.
PFS and AI: Inject all per 
instructions for use (IFU).
Vial: withdraw 1.0 mL into a small 
syringe and dose immediately; 
discard remaining material.
Special instructions
Avoid excessive shaking of vials, 
PFS and AI, as this could lead to 
product precipitation.
Avoid excessive shaking of vials, 
PFS and AI, as this could lead to 
product precipitation.
Packaging and 
Labelling
Study Intervention will be provided 
in a single use vial, PFS or AI in an 
individual carton and labelled as 
required per country requirement.
Study Intervention will be provided 
in a single use vial, PFS or AI in 
an individual carton and labelled 
as required per country 
requirement.
Current/Former 
Name(s) or Alias(es)
otilimab
Anti human GM-CSF monoclonal 
Ab
MOR103
MOR04357
otilimab
Anti human GM-CSF monoclonal 
Ab
MOR103
MOR04357
PFS = prefilled syringe; AI = Autoinjector; GM-CSF = granulocyte macrophage colony stimulating factor; Ab = antibody, 
IFU= Instructions for use.
GSK3196165 in vials will be administered SC, using syringes and needles commonly used for SC administration; 
compatibility with commonly used syringes and needles has been demonstrated.

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6.1.2.
Medical Devices

The medical devices provided for use in this study are injection devices: a prefilled 
syringe (PFS) assembled into a safety syringe device (SSD) and a prefilled syringe 
contained within an autoinjector (AI).  The devices used in the study are 
representative of the devices and regionally appropriate device instructions planned 
to be marketed for the product.

The components that comprise the PFS and SSD, including glass barrel with 
prestaked needle and plunger are sourced for GSK by a third party provider.  The 
prefilled syringe is filled and assembled with the safety syringe components by GSK 
(or its affiliates).

The AI components are manufactured for GSK by a third party.  The autoinjector 
components are assembled with the prefilled syringe by GSK (or its affiliates).

The instructions for use (IFU) for these injection devices are provided in the study 
reference manual (SRM).  The instructions were developed and optimised as a result 
of formative human factors (HF) studies and are representative of those that are 
planned for the product.  The summary HF information will be provided in the 
regulatory submission.

All device deficiencies (including malfunction, use error and inadequate labelling) 
shall be documented and reported by the investigator throughout the clinical 
investigation (see Section 8.3.8) and appropriately managed by the sponsor.
6.2.
Preparation/Handling/Storage/Accountability

The site pharmacist administrator must confirm appropriate temperature conditions 
have been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.

Only participants enrolled in the study may receive study intervention and only 
authorised site staff or patients with sufficient training may administer study 
intervention. All study interventions must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorised site 
staff.

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study intervention accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study 
intervention are provided in the SRM.

Under normal conditions of handling and administration, study intervention 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.

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
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.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Participants who received GSK3196165 in their qualifying study will continue in this 
study on the same dose. Participants who received a comparator in their qualifying study 
will be centrally randomised using IRT in a ratio of 1:1 to either GSK3196165 90 mg or 
150 mg.  Before the study is initiated, the log in information and directions for the IRT 
will be provided to each site.  Study intervention will be dispensed at the study visits 
summarised in the SoA for the treatment period (Section 1.3.1).  Returned study 
intervention should not be re-dispensed to the participants.
The IRT will be programmed with blind-breaking instructions.  In case of an emergency, 
the investigator has the sole responsibility for determining if unblinding of a participant’s 
intervention assignment is warranted.  Participant safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding 
is warranted, the investigator should make every effort to contact GSK or designee prior 
to unblinding a participant’s intervention assignment unless this could delay emergency 
intervention of the participant.  If a participant’s intervention assignment is unblinded, 
GSK must be notified within 24 hours after breaking the blind.  The date and reason that 
the blind was broken must be recorded in the source documentation and case report form
CRF, as applicable.
Participants who were not receiving weekly GSK3196165 90 mg or 150 mg in their 
qualifying study, will be randomised by the IRT in a ratio of 1:1, to one of these two 
treatment arms on Day 1.  Participants who were receiving GSK3196165 90 mg or 150 
mg in their qualifying study will be allocated by IRT to the same dose level in this study.
Study intervention will be dispensed at the study visits summarized in the SoA for the 
treatment period (Section 1.3).  Returned study intervention should not be re-dispensed to 
the participants.
A participant’s treatment allocation will remain blinded at least until their qualifying 
study has been reported.  A participant may continue in the study if that participant’s 
intervention assignment is unblinded. 
Although it is expected that study intervention for each arm will be supplied in volume-
matched PFS or AI for the duration of this study, an interruption to supply of PFS or AI 
could require supply of intervention in fixed concentration vials. If such a situation 
occurs, at a time while the study is blinded to site or participant, sites will need to ensure 
the blind is maintained. An unblinded pharmacist (or unblinded designee) would then be 
responsible for the dispensation of the study intervention from vial, and an unblinded 
administrator would be responsible for administration of the SC injection, keeping the 
syringe and vial shielded from the participant at all times. If this situation occurs, 
additional guidance will be provided in an updated pharmacy manual or addendum.

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GSK’s Pharma Safety staff may unblind the intervention assignment for any participant 
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 participant’s intervention 
assignment, may be sent to investigators in accordance with local regulations and/or GSK 
policy.
6.4.
Study Intervention Compliance
GSK3196165 will be administered by site staff to participants at the site or participants 
will have the option to self-administer using pre-filled syringes or auto-injector for 
weekly SC administration at home.  A record of the number of syringes or auto-injectors 
dispensed to and taken by each participant must be maintained by the site staff and 
reconciled with study intervention and compliance records.  Intervention start and stop 
dates, including dates for intervention delays will also be recorded in the CRF.
6.5.
Concomitant Therapy
Due to effect of cytokines on the CYP450 enzymes (Section 2.3.1), initiation or 
discontinuation of study intervention may have clinically relevant effect for CYP 
substrates with a narrow therapeutic index (e.g. warfarin and theophylline).  Where a 
CYP3A4 substrate drug is co-administered during the study, in addition to recording the 
initial dose and any dosage changes over time in the CRF, the results of any therapeutic 
monitoring (e.g. INR results, theophylline levels), if available, should also be recorded.
Investigators should exercise caution when study intervention is co-administered with 
CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral 
contraceptives, lovastatin, atorvastatin, etc. unless such time that this risk is negated by 
results from the preceding phase 3 studies.
6.5.1.
Permitted Therapies
Medications or treatments deemed necessary by the investigator to provide adequate 
supportive care will be permitted during the study unless specifically excluded in Section 
6.5.2.  These medications, if permitted and taken during the study, must be recorded in 
the CRF, along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.  The requirements for use of specific permitted 
medications/treatments are listed below.

Investigators should follow routine clinical practice to manage RA pain.  Any new 
analgesic or oral corticosteroid use or change in dose should not take place within 
24 hours before a study assessment visit and must be recorded in the concomitant 
medication CRF.

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
Other medications (including vitamins, herbal and dietary supplements) will be 
permitted if in the opinion of the investigator, the medication will not interfere 
with the study procedures or compromise participant safety.  These must be 
recorded in the concomitant medication CRF.

Background MTX/csDMARD change, dose reduction or discontinuation is 
permitted as per guidance in Section 6.6.2.

At most two concomitant background csDMARDs are permitted as follows:
a.
Methotrexate (MTX): up to 25mg per week whether oral or injected.
b. Hydroxychloroquine up to 400 mg/day or chloroquine up to 250 mg/day.
c.
Sulfasalazine up to 3000 mg/day.
d. Leflunomide up to 20 mg/day.  Note: concomitant use of leflunomide and 
methotrexate is not allowed, for safety reasons.
e.
Tacrolimus up to 3 mg/day.
f.
Bucillamine up to 100 mg/day (or up to 300 mg/day if permitted per local 
requirements).
g. Iguratimod up to 50 mg/day.

All participants may receive inactivated flu vaccines during the study at the 
discretion of the investigator.
6.5.2.
Prohibited Therapies
Medications prohibited or restricted are as follows:

Treatment with any targeted synthetic DMARD (tsDMARD) or biologic DMARD 
(bDMARD) is prohibited between the last administration of study dose in the 
qualifying study and Day 1 of this study, during the study treatment period and 
during safety follow-up (8 weeks after the last study dose).

Treatment with more than two csDMARDs or combination of leflunomide and 
MTX is prohibited between the last administration of study dose in the qualifying 
study and Day 1 of this study, during the study treatment period and during safety 
follow-up (8 weeks after the last study dose).

Live or attenuated vaccinations are prohibited between the last administration of 
study dose in the qualifying study and Day 1 of this study, during the study 
treatment period and during safety follow-up (8 weeks after the last study dose).

Plasmapheresis or intravenous immunoglobulin (IVIG) or use of Staph protein A 
column (Prosorba) are prohibited within 26 weeks of Day 1, during the study 
treatment period and during safety follow-up (8 weeks after the last study dose).

Any treatment antagonizing GM-CSF or its receptor (other than study treatment) is 
prohibited prior to and during the study and during safety follow-up (8 weeks after 
the last study dose).

csDMARDs which are not listed in Section 6.5.1 are prohibited.

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6.6.
Dose Modification
6.6.1.
Dose Modification of Study Intervention
Dose modification of the SC study interventions is not permitted in this study.
6.6.2.
Dose Modification of Background csDMARD treatment
Dose reduction or temporary interruption of the background csDMARD(s) may be 
performed at any time for safety reasons (e.g. intolerance or toxicity) and must be clearly 
documented.  If clinically indicated, csDMARD(s) may be re-started following an 
interruption and increased back to the dose taken prior to the change.
Dose modification of background csDMARD(s) (including MTX) for reasons other 
than safety are permitted with the following guidance:

From week 12 onwards (for participants from 201790 and 201791) or from week 24 
onward (for participants from 202018), if clinically indicated (i.e. when a participant 
achieves CDAI low disease activity (CDAI ≤ 10) for 2 consecutive assessment 
visits), csDMARD dose reduction can be implemented. Instructions on dose 
reduction can be found below, with an example of MTX tapering.  The dose 
reduction can continue while still clinically indicated.

Any change in csDMARD treatment should be performed according to the 
investigator’s practice and as tolerated by the participant, including restarting 
csDMARD and documented in the patient's records.

In this study, MTX dose should not be reduced by more than 5 mg every 8 weeks 
[Fleischmann, 2005], except for safety reasons.  The recommended minimum time 
between each 5 mg reduction is 12 weeks, to align with study visits.  Longer periods 
between dose reductions and/or smaller dose reductions are permitted per 
investigators judgement and local guidance.  See Table 2 below.


If a participant flares during, or after, the csDMARD tapering/withdrawal, the 
participant may return to their previous dose of csDMARD(s) treatment, as 
clinically indicated.
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Table 2
Example MTX Tapering table
Visit
(time since tapering started)
        Week
MTX
dose
+0 weeks
+12 weeks
+24 weeks
+36 weeks
+48 weeks
25 mg
20 mg
15 mg
10 mg
5 mg
0 mg
20 mg
15 mg
10 mg
5 mg
0 mg
0 mg
15 mg
10 mg
5 mg
0 mg
0 mg
0 mg
10 mg
7.5 mg
(or 5 mg)
0 mg
0 mg
0 mg
0 mg
7.5 mg
5 mg
(or 2.5 mg)
0 mg
0 mg
0 mg
0 mg
This table shows for participants tapering off MTX, the recommended minimum 12 
weeks between each 5 mg reduction, to align with study visits.  Longer periods between 
dose reductions and/or smaller dose reductions are permitted, per investigator’s 
judgement and local guidance.
6.7.
Intervention after the End of the Study
Participants will be treated according to local standard of care for RA disease after the 
end of the study.

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7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention.  A participant will permanently discontinue study intervention if there is no 
longer a positive risk:benefit ratio at any time point in the study as determined by the 
investigator.  If study intervention is permanently discontinued, refer to Section 1.3.3
(Assessments for Early Withdrawal from Study) for assessments to be collected at the 
time of discontinuation of study intervention and for scheduling of safety follow-up.
7.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Discontinuation of study intervention for abnormal liver tests is required when a 
participant meets one of the conditions outlined in the algorithms. 
Algorithm A: Phase III-IV Liver Chemistry Stopping and Increased Monitoring 
Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
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*
Abbreviations: ALT = alanine transaminase;  INR = international normalized ratio; SAE = serious adverse 
event; ULN = upper limit of normal.
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 5.

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Algorithm B: Phase III-IV Liver Chemistry Increased Monitoring Algorithm with 
Continued Therapy for ALT 3xULN but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
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*
Abbreviations: ALT = alanine transaminase; bili = bilirubin; INR = international normalized ratio; SAE = 
serious adverse event; ULN = upper limit of normal.
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 5.
7.1.1.1.
Study Intervention Restart or Rechallenge after liver stopping criteria 
met
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
7.1.2.
Other Stopping Criteria
A participant will be withdrawn from study intervention if any of the following criteria 
are met:

Pregnancy (see Section 8.3.5 and Appendix 4).

Confirmed pulmonary alveolar proteinosis (see Section 8.2.6).

Serious hypersensitivity reactions, including anaphylaxis (see Section 8.3.7).

Other serious or severe adverse events, at the discretion of the investigator, after 
consultation with the Medical Monitor (see Section 8.3.7).

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
HBV DNA level ≥ 200 IU/mL or HBV DNA detected at any level with recent 
increase in hepatic transaminases (see Figure 1 in Section 8.2.8)

HBV DNA positive (any level < 200 IU/mL) and on repeat testing within 1 week 
(see Figure 1 in Section 8.2.8) either:
o
HBV DNA positive (any level) OR
o
HBV surface antigen positive OR
o
increase in hepatic transaminases.

New active TB infection (see Section 8.2.7.4).

Introduction of prohibited therapies or dosages where continuation of the study 
intervention would place the participant at risk in the opinion of the investigator and 
medical monitor (see Section 6.5.2).
7.1.3.
Temporary Discontinuation
7.1.3.1.
Respiratory Symptoms
Study intervention will be temporarily discontinued if a participant develops a persistent 
cough (CTCAE Grade 2) [NCI, 2017] or persistent dyspnoea (dyspnoea scale 
Grade 2) for 3 consecutive weeks (21 days).  The participant should be referred to a 
pulmonologist for further assessment.  Study intervention should remain suspended until 
the symptoms or signs that caused referral have resolved and/or the diagnosis has been 
determined and clinically significant events have been excluded by the pulmonologist.  
Participants with a confirmed diagnosis of pulmonary alveolar proteinosis must 
permanently discontinue study intervention (Section 8.2.6).  Pulmonary assessment and 
management algorithms are provided in a separate Pulmonary Safety Guidance 
Document in the SRM.
7.1.3.2.
Serious and Opportunistic Infections
If a serious or opportunistic infection or sepsis develops, temporarily discontinue study 
intervention until the infection is controlled and discuss further management with the 
medical monitor.
7.1.3.3.
Haematologic Abnormalities
Study intervention will be temporarily discontinued for the following haematological 
abnormalities that must be reported as an AE.  These should be promptly re-tested, 
ideally within 3-5 days:

White blood cell (WBC) count <2.0 x 109/L.

ANC ≤ 1.0 x 109/L.

Lymphocyte count <0.5 x 109/L.

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Do not restart study intervention until the haematological parameters rise above these 
values and monitor the participant until the event has resolved.  Note that for the above 
haematological abnormalities, a repeat test must be performed locally and assessed within 
7 days with additional samples sent for central testing.  The medical monitor should be 
consulted if the repeat test is still abnormal and a further repeat test performed again 
within 7 days.
7.1.3.4.
TB Reactivation
Study intervention must be temporarily discontinued for the following after consultation 
with the medical monitor:

Suspected TB reactivation (see Section 8.2.7.4).
7.2.
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance or administrative reasons.

At the time of discontinuing from the study, if possible, an early withdrawal 
visit should be conducted and safety follow-up visit scheduled. Refer to Section 
1.3.3 (Assessments for Early Withdrawal from Study) for assessments to be 
collected at the time of discontinuation of study intervention and for scheduling 
of safety follow-up.

The participant will be permanently discontinued both from the study 
intervention and from the study at that time.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.
If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.
7.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled assessment or dispensing visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

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
Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1.

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8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarised in the SoA (Section 1.3). 

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the medical monitor 
immediately upon occurrence or awareness to determine if the participant should 
continue or discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct.

A thorough eligibility review must be completed to confirm that potential 
participants meet all required study entry criteria. The investigator will maintain a 
log to record details of all participants assessed and to confirm eligibility or 
record reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s prior qualifying study and 
obtained before signing of ICF for this long-term extension study, may be utilised 
for eligibility assessments and/or baseline purposes provided the procedure met 
the protocol-specified criteria and was performed within the time frame defined in 
the SoA (Section 1.3).

The amount of blood collected from each participant over the duration of the 
study (assuming a 4-year treatment period), including extra assessments for 
csDMARD tapering and AI sub-study, will not exceed 400 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
8.1.
Efficacy Assessments
8.1.1.
Joint Assessments
An evaluation of all 68 joints for tenderness and 66 joints for swelling will be performed 
by a joint evaluator.  Replaced or fused joints are considered non-evaluable and will not 
be included in joint evaluations.  The reason for absence of the evaluations of those joints 
must be recorded.  If a joint has undergone intra-articular injection of corticosteroid 
during the course of the study, the injected joint must be recorded in the eCRF at that 
time.
One or more assessors, who have documented experience in performing joint 
assessments, will be designated at each trial site to perform joint assessments.  Preferably 
the same assessor will perform all joint assessment for the same participant throughout 
the trial.  The principal investigator must ensure that the joint assessor has documented 
experience and he/she is adhering to locally accepted and implemented standards.  This 
also applies if the joint assessor is replaced during the trial.
The procedure for joint assessments is provided in the SRM.

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8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
In the event that pulmonary follow-up criteria are triggered, all sites must have access to 
a pulmonologist (Section 7.1.3.1 and Section 8.2.6).
8.2.1.
Dyspnoea Assessments
The dyspnoea scale grades the effect of breathlessness on daily activities and measures 
perceived respiratory disability.  The scale will be completed by the investigator in 
consultation with the participant.  Dyspnoea will be reported on a rating scale from 0 (not 
breathless at rest or on exertion) through 4 (breathless at rest).
8.2.2.
Physical Examinations

A full physical examination will include, at a minimum, assessments of the skin, 
cardiovascular, respiratory, gastrointestinal and neurological systems.  Smoking
status will be recorded, height and weight will be measured and recorded. 

A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). 

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.

All physical examinations will include monitoring for signs and symptoms of TB 
(see Section 8.2.7).
8.2.3.
Electrocardiograms

12-lead ECG measurements should be recorded pre-dose and where possible 
before vital sign measurements and blood draws.

Participants should be in a quiet setting without distractions and rest in a supine 
position for at least 5 or 10 minutes before ECG collection.

Triplicate 12-lead ECG measurements will be obtained at baseline (pre-dose Day 
1), with single ECG measurements obtained at all other time points, as outlined in 
the SoA (see Section 1.3) using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and QTc intervals.

ECG traces will be read locally.
8.2.4.
Vital Signs

Vital signs should be measured pre-dose, and where possible before blood draws.

Temperature, pulse rate, respiratory rate and blood pressure will be assessed.

Blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is 
not available. The participant should use the same position throughout all visits.

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
All blood pressure readings will be recorded using an appropriate cuff size with 
the same arm being used throughout the study.

Blood pressure and pulse measurements should be preceded by at least 5 minutes 
of rest for the participant in a quiet setting without distractions (e.g., television, 
cell phones).

When the timing of these measurements coincides with blood collection, the 
blood pressure and heart rate should be obtained first.
8.2.5.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to 
the SoA in Section 1.3 for the timing and frequency. 

All study-required laboratory assessments will be performed by a central 
laboratory except erythrocyte sedimentation rate (ESR), T.SPOT TB, dipstick 
urinalysis, and urine pregnancy tests which will be analysed locally.

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant’s condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 8 weeks after the last dose of study 
intervention should be repeated until the values return to normal or baseline (pre-
dose Day 1) or are no longer considered significantly abnormal by the investigator 
or medical monitor. 

If such values do not return to normal/baseline (pre-dose Day 1) within a period 
of time judged reasonable by the investigator, the etiology should be identified 
and the sponsor notified.

In this study, the key laboratory parameters are WBCs, lipids, haemoglobin, 
platelets, lymphocytes, neutrophils and liver function tests.

Participants who develop hyperlipidemia should be managed according to clinical 
guidelines [e.g., National Cholesterol Educational Program (NCEP)].

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3).
8.2.6.
Pulmonary Assessments
Pulmonary assessments are a key aspect of the safety monitoring in this study. The 
following pulmonary assessments will be performed as specified in the SoA (Section 
1.3).

Chest X-ray (posteroanterior).

Cough assessment.

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
Dyspnoea assessment (see Section 8.2.1).

Lung auscultation.

Pulse oximetry.
In the event of any new or clinically significant pulmonary abnormalities that may
develop during the study (e.g., increased shortness of breath/dyspnoea, or unexplained 
and persistent coughing), it is recommended that the participant be referred to a 
pulmonologist for further assessment.  
If, at any time during the study, a participant reports new onset or increase (if present at 
baseline [pre-dose Day 1]) in cough (CTCAE Grade ≥2) or dyspnoea (dyspnoea scale 
Grade ≥2), they must be asked again (either by phone or during the site visit) on a weekly 
basis for 3 further consecutive weeks or until symptoms resolve, if earlier.  Any new 
onset or worsening cough and/or dyspnoea must be reported as an AE.
If a participant experiences persistent cough Grade ≥2 for three consecutive weeks (≥21 
days) or persistent dyspnoea Grade ≥2 for three consecutive weeks (≥21 days), study 
intervention must be temporarily discontinued immediately, and the participant undergo a 
local pulmonologist review within 1-2 days. Chest X-ray and repeat spirometry must be 
performed within 1 week in addition to any other assessments deemed appropriate by the 
consulting pulmonologist. The study intervention must be temporarily discontinued as 
per the pulmonary guidance document until the symptoms or signs that caused referral 
have resolved and/or the underlying diagnosis has been determined and clinically 
significant events have been excluded by the pulmonologist. Pulmonary 
assessment/management algorithms are provided in a separate Pulmonary Safety 
Guidance Document in the SRM.
The participant may undergo additional pulmonary imaging (high-resolution computed 
tomography [HRCT]) or other tests during the study to investigate pulmonary 
abnormalities; the Pulmonary Adjudication Committee (PAC), IDMC or SRT may 
request copies of any reports or images for central review.
Any participant with a diagnosis of PAP must permanently discontinue study intervention 
(Section 7.1.2).
8.2.7.
Tuberculosis Monitoring
8.2.7.1.
Tuberculosis Status Definitions
In this study the following definitions for active TB, latent TB and adequate treatment of 
latent TB will be utilised. 
Active TB is defined as:

Microbiological evidence of TB (including, but not limited to, microscopy for 
acid-fast bacilli, mycobacterial culture, GeneXpert, or other validated polymerase 
chain reaction (PCR) in any clinical sample (including, but not limited to, sputum, 
pus, or biopsied tissue),

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OR

Findings on medical history or clinical examination and/or chest radiograph 
consistent with active TB as assessed by a physician specialising in TB, sufficient 
to warrant empirical treatment for active TB even in the absence of 
microbiological evidence of TB.
Latent TB is defined as:

A positive QuantiFERON-TB Gold plus test or T-SPOT.TB test, no findings on 
medical history or clinical examination consistent with active TB and a normal 
chest radiograph.
Adequate TB treatment status
For participants that have received treatment for latent TB within 5 years prior to the 
qualifying study entry, a participant is considered to have received adequate treatment if a 
physician specialising in TB agrees that:

sufficient evidence exists demonstrating that completion of treatment has 
occurred AND

the participant has no findings on medical history or clinical examination 
consistent with active TB, and a normal chest radiograph.
Appropriate treatment for latent TB is considered to be:

Completion of at least 6 months of INH or an alternative regimen consistent with 
WHO or national guidelines.
8.2.7.2.
Tuberculosis Testing
In this study the following testing for TB must be followed:

The QuantiFERON-TB Gold plus test will be used in countries where it is 
available.  Where QuantiFERON-TB Gold plus test is not available T-SPOT.TB 
will be used.
8.2.7.3.
Treatment of Latent TB During the Study
If a participant had a positive QuantiFERON-TB Gold Plus test result (or a positive 
T.SPOT.TB test result) at the end of their qualifying study, who previously had a 
negative result at study start, then the participant must have been referred to a physician 
specialising in TB to determine if the participant has active or latent TB as per TB 
exclusion criteria (see Section 5.2).  If active TB infection is diagnosed, then the 
participant will not be eligible for this study (see Section 7.1.2). 
Participants diagnosed with latent TB will need to complete a course of at least 6 months
of INH therapy during the study:

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
If diagnosed prior to study commencement, then at least 4 weeks of therapy 
should occur prior to commencement of study intervention.

If diagnosed during the study, then the participant must temporarily discontinue 
study intervention and complete 4 weeks of INH therapy.  Participants may only 
start or re-commence study treatment once ALT elevation resolves to ALT < 3 x 
ULN during ongoing INH therapy.  Participants with persisting ALT ≥ 3 x ULN 
must be discussed with the GSK medical monitor.
Participants will require safety monitoring of blood haematology and liver biochemistry 
every 4 weeks during INH therapy.  Should elevated levels rise above the liver stopping 
criteria for participants receiving INH within the study then participants should be 
withdrawn from the study.
8.2.7.4.
Monitoring for TB Infection and Re-activation During the Study
Routine monitoring for the signs and symptoms of TB will be performed during this 
study as part of every physical exam (see SoA in Section 1.3).  In addition, annual TB 
test must be performed.
If at any point during the study, the investigator suspects that a participant may have TB 
reactivation or new TB infection, an immediate and thorough investigation should be 
undertaken including consultation with a physician specializing in TB. The investigator 
should discuss with the medical monitor and interruption of study intervention should be 
considered. 
If active TB infection is diagnosed, study intervention must be permanently discontinued.
8.2.8.
Hepatitis B Monitoring
All participants with positive HBcAb results from qualifying study, will have HBV DNA 
levels monitored throughout the study as summarized in Figure 1.

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Figure 1
Monitoring of HBV DNA Levels in HBcAb Positive Participants
HBV DNA level ≥ 200 IU/mL
or
HBV DNA detected at any level with 
recent increase in hepatic 
transaminases
HBV DNA level <200 IU/mL 
(with no increase in hepatic 
transaminases)
Discontinue study intervention and 
refer to expert for initiation of 
appropriate antiviral therapy
Repeat HBV DNA with HBV surface 
antigen and hepatic transaminases 
within 1 week
Result:  HBV DNA 
positive (any level) 
or HBV surface 
antigen positive or 
increase in hepatic 
transaminases
Discontinue study 
intervention and refer 
to expert for initiation of
appropriate antiviral 
therapy
Result: HBV DNA 
negative, HBV surface 
antigen negative and no 
increase in hepatic 
transaminases
Repeat HBV DNA at 
4 weeks then return 
to routine 
monitoring
HBV DNA detected
HBV DNA levels will be assessed every 4 weeks up to Week 12 in these participants, 
then every 8 weeks to Week 36 and then every 12 weeks for the duration of the study.  
This increased monitoring at the start of this study is important because some participants 
will have changed their treatment from comparator in qualifying study, to GSK3196165 
in this study.

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8.2.8.1.
Risk of Reactivation in Participants Positive for Hepatitis B Core 
Antibody (HBcAb)
Participants who are HBcAb positive, will be informed of the risk of reactivation and that 
if this occurs treatment with antiviral therapy, such as with nucleo(s)tide analogues like 
entecavir or tenofovir, will be needed.
8.2.8.2.
Treatment of Participants Who Are HBcAb Positive and Who Develop 
Detectable HBV DNA Requiring Initiation of Antiviral Therapy
HBcAb positive participants who become positive for HBV DNA and require antiviral 
therapy must have study intervention discontinued. The participant must also be referred 
to a hepatologist or infectious diseases expert so that treatment advice regarding whether 
to commence anti-viral therapy is received within 7 days of HBV DNA elevation being 
identified. The participant should then be reviewed by the expert within 14 days of HBV 
DNA elevation being identified and managed as per local guidelines or under EASL or 
AASLD guidelines if none are available.
8.2.8.3.
Follow Up of Participants Treated With Anti-viral Therapy
All participants will be followed up within the study by the investigator in addition to 
local expert follow up. After completion of the study, participants should be followed up 
as per local expert opinion based on guideline recommendations.
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
The definitions of device-related safety events, (adverse device effects (ADEs) and 
serious adverse device effects (SADEs)), can be found in Appendix 7.  Device 
deficiencies are covered in Section 8.3.8.
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study intervention (see Section 7). 
Participants will be assessed for cough or dyspnoea at selected visits as specified in the 
SoA (Section 1.3).  The investigator will determine the severity of the cough based on 
CTCAE grading scale and will record the grade of dyspnoea.  Lung auscultation and 
pulse oximetry will also be performed at the visits specified in the SoA (Section 1.3).
If a participant, at times other than scheduled visits, reports new onset or an increase (if 
present at baseline [pre-dose Day 1]) in cough (CTCAE Grade ≥2) or dyspnoea 
(dyspnoea scale Grade ≥2), the participant will be questioned (in clinic or by phone) on a 
weekly basis for 3 further consecutive weeks or until symptoms resolve, if earlier.  Any 
new onset or worsening cough and/or dyspnoea must be reported as an AE.

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8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All AEs and SAEs will be collected from the time of signing the informed 
consent form until the follow-up visit at the time points specified in the SoA 
(Section 1.3).  

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs after the conclusion 
of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the 
sponsor.
8.3.2.
Method of Detecting AEs and SAEs

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3.

Care will be taken not to introduce bias when detecting AE and/or SAE. Open-
ended and non-leading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence. 
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special 
interest (as defined in Section 8.3.7), will be followed until the event is resolved, 
stabilised, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is given in Appendix 3.
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study intervention under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under 
clinical investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

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
An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
8.3.5.
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners 
of male participants which commence after the start of study intervention and 
until 8 weeks after the last dose will be collected and followed through the end of 
pregnancy.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 
4.

Female participants who become pregnant after the start of study intervention 
must be permanently discontinue study intervention and be withdrawn from the 
study following guidance in Section 7.2.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.3.6.
Cardiovascular and Death Events
For any cardiovascular (CV) events detailed in Appendix 3 and all deaths, whether or not 
they are considered SAEs, specific CV and Death sections of the CRF will be required to 
be completed. These sections include questions regarding CV (including sudden cardiac 
death) and non-CV death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
(Medical dictionary for regulatory activities) terms. The CV information should be 
recorded in the specific CV 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.
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:

Myocardial infarction/unstable angina.

Congestive heart failure.

Arrhythmias.

Valvulopathy.

Pulmonary hypertension.

Cerebrovascular events/stroke and transient ischemic attack.

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
Peripheral arterial thromboembolism.

Deep venous thrombosis/pulmonary embolism.

Revascularisation.
This information should be recorded in the specific CV eCRF within one week of when 
the AE/SAE(s) are first reported.
8.3.7.
AEs of Special Interest
The potential risks with GSK3196165 are discussed in Section 2.3.1. 
Adverse events of special interest (AESIs) for GSK3196165 include:

Serious infections

Opportunistic infections.

TB and TB reactivation.

Neutropenia Grade 3 (<1.0 x 109/L).

Pulmonary alveolar proteinosis

Hypersensitivity reactions.

Injection site reactions.

Persistent cough (CTCAE Grade 2)

Persistent dyspnoea (dyspnoea scale Grade 2).
8.3.8.
Medical Device Deficiencies
Medical devices are being provided for use in this in the form of pre-filled syringes 
assembled into either a safety syringe or autoinjector device. In order to fulfil regulatory 
reporting obligations worldwide, the investigator is responsible for the detection and 
documentation of events meeting the definitions of device deficiency that occur during 
the study with such devices.
The definition of a Medical Device Deficiency can be found in Appendix 7.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 8.3.3 and Appendix 3 of the protocol.
8.3.8.1.
Time Period for Detecting Medical Device Deficiencies

Medical device deficiencies will be detected, documented, and reported during 
all periods of the study in which the medical device is used. 

If the investigator learns of any device deficiency at any time after a participant 
has been discharged from the study, and such device deficiency is considered 

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reasonably related to a medical device provided for the study, the investigator 
will promptly notify the sponsor.

The method of documenting Medical Device Incidents is provided in Appendix 
7.
8.3.8.2.
Follow-up of Medical Device Deficiencies

Follow-up applies to all participants, including those who discontinue study 
intervention or the study.

The investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality 
of the deficiency.

New or updated information will be recorded on the originally completed form 
with all changes signed and dated by the investigator.
8.3.8.3.
Prompt Reporting of Medical Device Deficiencies to Sponsor

Device deficiencies will be reported to the sponsor using the Medical Device 
Deficiency Report Form (provided in the Pharmacy Manual), within 24 hours 
after the investigator determines that the event meets the protocol definition of a 
device deficiency.

The Medical Device Deficiency Report Form will be sent to the sponsor device 
complaints email address, as provided in the Pharmacy Manual.

The sponsor will be the contact for the receipt of device deficiency reports.

Refer to the Pharmacy Manual for further guidance.
8.3.8.4.
Regulatory Reporting Requirements for Medical Device Incidents

The investigator will promptly report all deficiencies occurring with any medical 
device provided for use in the study in order for the sponsor to fulfill the legal 
responsibility to notify appropriate regulatory authorities and other entities about 
certain safety information relating to medical devices being used in clinical 
studies.

The investigator, or responsible person according to local requirements (e.g., the 
head of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of device deficiencies to the IRB/IEC.
8.4.
Treatment of Overdose
For this study, any dose of GSK3196165 greater than the highest dose used in this study 
(150 mg once-weekly) will be considered an overdose.  It should be noted that the 
minimum time between dosing with GSK3916165 is 5 days but it is strongly 
recommended that dosing should revert back to 7 days as soon as possible.
No specific treatment is recommended for an overdose of GSK3196165 and the 
investigator should treat as clinically indicated.

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In the event of an overdose, the investigator should:

Contact the Medical Monitor immediately.

Closely monitor the participant for AE/SAE and laboratory abnormalities.

Obtain a plasma sample for PK analysis within 3-5 days from the date of the last 
dose of study intervention if requested by the Medical Monitor (determined on a 
case-by-case basis).

Contact the unblinded CRA with the quantity and duration of the overdose to be 
documented.
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 
participant.
CCI

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8.7.
Genetics
Genetics are not evaluated in this study.
8.8.
Biomarkers
Biomarkers are not evaluated in this study.
8.9.
Immunogenicity Assessments
Whole blood samples of approximately 6 mL will be collected from all participants and 
divided into suitable portions for immunogenicity assessments of anti-drug antibody 
(ADA) development.  Antibodies to GSK3196165 will be evaluated in serum samples 
collected from all participants according to the SoA (Section 1.3).  Serum samples should 
also be collected at the final visit from participants who discontinued study intervention 
or are withdrawn from the study.  In addition to scheduled immunogenicity assessments, 
“event-driven” testing will be performed in the context of serious hypersensitivity 
reactions or AEs deemed to be clinically significant in the opinion of the investigator 
resulting in discontinuation from study intervention.
Serum samples will be screened for antibodies binding to GSK3196165 and the titer of 
confirmed positive samples will be reported.  Other analyses may be performed to verify 
the stability of antibodies to GSK3196165 and/or further characterise the immunogenicity 
of GSK3196165.
The detection and characterisation of antibodies to GSK3196165 will be performed using 
validated assay methods by or under the supervision of the sponsor.  Antibodies may be 
further characterised and/or evaluated for their ability to neutralise the activity of the 
study intervention(s).  Samples may be stored for a maximum of 15 years (or according 
to local regulations) following the last participant’s last visit for the study at a facility 
selected by the sponsor to enable further analysis.
8.10.
Medical Resource Utilisation and Health Economics
Medical Resource Utilisation and Health Economics parameters are not evaluated in this 
study.

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9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
There are no formal statistical hypotheses to be tested: this study is designed to describe 
the long-term safety and efficacy of GSK3196165.
9.2.
Sample Size Determination
There are no formal statistical sample size calculations.  Sample size will be determined 
by the number of participants who choose to continue after completion of their qualifying 
GSK3196165 study.  All subjects will be considered evaluable.  
9.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign the ICF
Safety
All randomised participants who take at least 1 dose of study 
intervention. Participants will be analyzed according to the 
intervention they actually received.
The primary analysis population will be the Safety Population.
9.4.
Statistical Analyses
The primary objective of this study is to assess long-term safety. Data will be 
summarised descriptively.  
For assessment of change from baseline in safety assessments, baseline will be the pre-
dose assessment(s) on the day of the participant’s scheduled first dose of GSK3196165 in 
their qualifying study, or at the start of this study (if the participant did not receive 
GSK3196165 in their qualifying study).  For descriptive efficacy assessments (except x-
ray data), baseline from the pre-dose assessment on entry to this study will be used.  For 
x-ray data, baseline will be defined in the Charter for Independent Imaging Assessment.
Results will be presented split by GSK3196165 dose in this study and treatment arm from 
the qualifying study.
Where important for interpretation, safety data from the qualifying study will be included 
in the results tables.
Full details of all data analyses will be provided in the reporting and analysis plan (RAP).  
Any changes to the original planned analysis provided in this section of the protocol will 
be described in the RAP and/or the Clinical Study Report.

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9.4.1.
Safety Analyses
All safety analyses will be performed on the Safety Population.
Endpoint
Statistical Analysis Methods
All
All analyses will be descriptive in nature.  Data will be summarised using 
frequency counts, proportions, summary statistics, graphs and listings.  In 
particular, incidence rates will be calculated for AEs, SAEs and AESIs, and 
the proportions of participants with laboratory abnormalities (NCI-CTCAE ≥ 
Grade 3) will be calculated. 
9.4.2.
Efficacy & Patient-Reported Outcome Analyses
Endpoint
Statistical Analysis Methods
All
All analyses will be descriptive in nature. Data will be summarised using 
summary statistics, frequency counts, proportions, graphs and listings.  
9.4.3.
Other Analyses
Details for exploratory endpoints will be provided in the RAP.
Exploratory endpoints may be presented separately from the main clinical study report 
(CSR).
9.5.
Interim Analyses
Several unblinded analyses for regulatory purposes are planned.  The first unblinded 
interim analysis of the data in this continuation study is planned to coincide with the 
primary analysis of the Phase 3 qualifying studies 201790, 201791 and 202018 in order 
to analyse and submit this long-term data to regulatory authorities.  Additional unblinded 
interim analyses may be required to support, for example, subsequent safety updates to 
regulatory authorities, and the final analysis will be conducted after all patients have 
completed the study.
The Reporting and Analysis Plan will describe the planned interim analyses in greater 
detail.
9.5.1.
Independent Data Monitoring Committee (IDMC)
An IDMC will be utilised in this study to ensure ongoing objective medical and/or 
statistical review of safety data in order to protect the ethical and safety interests of 
participants and to protect the scientific validity of the study. See Section 10.1.5 for 
further details.
Full details of the data to be reviewed and membership of the committee will be available 
in the charter.

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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
10.1.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study

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10.1.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
10.1.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
10.1.5.
Committees Structure
An Independent Data Monitoring Committee (IDMC), a Major Adverse Cardiac 
Event/Gastrointestinal Perforation (MACE/GI Perforation) Adjudication Committee and 
a Pulmonary Adjudication Committee (PAC) will be utilized in this study, in addition to 
the routine sponsor review of blinded safety data that will occur approximately every 4 
weeks during the period of study conduct.
The overall responsibility of the IDMC is to protect the ethical and safety interests of 
participants recruited into this study while protecting as far as possible the scientific 
validity of the data.  The IDMC and Adjudication Committees will include physicians 
with relevant clinical expertise and a statistician, none of whom is affiliated with the 

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sponsor.  The IDMC will adopt a staggered approach to reviewing unblinded data.  The 
initial early review, frequency of further reviews and the safety data included will be 
detailed in the IDMC charter.
The MACE/GI Perforation Adjudication Committee, PAC and IDMC will function as 
detailed in their respective charters.
10.1.6.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments. 

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
10.1.7.
Dissemination of Clinical Study Data

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 all 
participants who joined from the same qualifying study, after that qualifying 
study has reported.

The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy.

GSK intends to make anonymized patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that 
can help advance medical science or improve patient care. This helps ensure the 
data provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding.

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10.1.8.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 

This study uses a number of assessments and questionnaires to evaluate the 
participant’s symptoms and impacts at a particular moment in time (see efficacy 
assessments listed in Section 8.1).  These patient-reported outcomes and impact 
instruments completed directly by participants, investigators and joint assessors 
as source records (e.g. site tablet or eCOA portal) contribute to the secondary 
and exploratory endpoints and must not be changed or overwritten (with the 
exception of administrative/operational data items), in order to minimize bias.

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote,
or on-site monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals
(e.g., Contract Research Organisations).

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorised site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period.  No records may be 
destroyed during the retention period without the written approval of the 
sponsor.  No records may be transferred to another location or party without 
written notification to the sponsor. 

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10.1.9.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected.  Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained.  The investigator may need to request previous 
medical records or transfer records, depending on the study.  Also, current 
medical records must be available.

Definition of what constitutes source data can be found in Source Document 
Acknowledgement.
10.1.10.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development

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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 3 will be performed by the central laboratory except 
for ESR, dipstick urinalysis and urine pregnancy tests, which will be analysed 
locally.

Except for ESR, dipstick urinalysis, and urine pregnancy tests, local laboratory 
results are only required in the event that the central laboratory results are not 
available in time for either study intervention administration and/or safety 
evaluation.  If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Pregnancy Testing 
o
Refer to Section 5.1 Inclusion Criteria for eligibilty pregnancy criteria.
o
Pregnancy testing (urine or serum as required by local regulations) for 
WOCBP will be conducted once every 8 weeks during study treatment 
period.
o
Pregnancy testing (urine or serum as required by local regulations) will 
also be conducted at the safety follow up visit.
o
Additional serum or urine pregnancy tests may be performed, as 
determined necessary by the investigator or required by local regulation, 
to establish the absence of pregnancy at any time during the participation 
of a WOCBP in the study.
Table 3
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase 
(ALT)
Total Protein
Glucose (non-
fasting)
Calcium
Alkaline 
phosphatase (AP)
Albumin

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Laboratory 
Assessments
Parameters
Albumin/globulin 
ratio
Phosphate
Creatine 
Phosphokinase 
(CPK)
High sensitivity 
C-reactive 
protein (hsCRP)
γ-Glutamyl 
transpeptidase 
(GGT)
Lactate 
dehydrogenase
(LDH)
Lipid profile

Total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density 
lipoprotein-cholesterol, triglycerides and other lipoprotein tests as needed.
Urinalysis

Performed locally by dipstick
Urine 
pregnancy test

Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential)2
Other Tests

Estradiol (as needed in women of non-childbearing potential only)

Highly sensitive serum hCG pregnancy test (as needed for women of 
childbearing potential)2

Serology [Hepatitis B surface antigen (HBsAg), HBV DNA], hsCRP, ESR, 
QuantiFERON-TB Gold plus test (or, if unavailable, T-Spot TB)

eGFR calculated by the CKD-EPI calculation.
All study-required laboratory assessments will be performed by a central 
laboratory, except ESR, dipstick urinalysis and urine pregnancy tests which 
will be performed locally. Only the results of tests performed locally will be 
recorded in the eCRF. 
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 7.1 and Appendix 5. All events of ALT 3 × upper limit of normal 
(ULN) and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalised ratio (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).
2.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC.
The following results will not be reported to investigative sites or the study team involved 
in the conduct of the study:

Note: ESR/CRP/hsCRP are not blinded in this study and additional local testing (outside 
of the study) may be performed when necessary.  
CCI

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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting

This Appendix contains definitions and procedures required for AEs and SAEs 
which do not involve GSK Medical Devices used in this study (see Section 6.1.2
for the list of GSK medical devices).

Refer to Appendix 7 for definitions and reporting requirements of Medical Device 
AEs, SAEs, incidents and deficiencies.
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not considered 
related to the study intervention.

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 study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

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 intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses 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. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 

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Events NOT Meeting the AE Definition 

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 participant’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 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which 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.
10.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalisation for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
Results in death
Is life-threatening
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
Requires inpatient hospitalisation or prolongation of existing hospitalisation
In general, hospitalisation signifies that the participant 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 
outpatient setting. Complications that occur during hospitalisation are AE. If a 
complication prolongs hospitalisation or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalisation” occurred or was necessary, the 
AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.

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Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect

Possible Hy’s Law Case: ALT ≥3xULN and Bilirubin ≥2 xULN (>35% direct) or 
INR > 1.5*
*INR value not applicable to participants on anticoagulants
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalisation but 
may jeopardise the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation, or development of drug dependency or 
drug abuse.
10.3.3.
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

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
Revascularisation
10.3.4.
Recording and Follow-Up of AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’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 case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilised for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/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.

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
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in 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 in which 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 before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognised follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
10.3.5.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

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
The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of 
SAE entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool 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 participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the SRM.
SAE Reporting to GSK via Paper CRF

Secure email transmission of the scanned SAE paper CRF is the preferred method to 
transmit this information to the medical monitor or the SAE coordinator.

In rare circumstances and in the absence of secure email facilities, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in SRM.

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10.4.
Appendix 4:Contraceptive Guidance and Collection of 
Pregnancy Information
10.4.1.
Definitions:
10.4.1.1.
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered.
10.4.1.2.
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the 
participant’s medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 

A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement is required.

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment.

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10.4.2.
Contraception Guidance:

CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:

Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year 
when used consistently and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of ovulationc

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Vasectomised partner
Note: Vasectomised partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the absence 
of sperm has been confirmed. If not, an additional highly effective method of contraception 
should be used. Spermatogenesis cycle is approximately 90 days.

Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when 
used consistently and correctly.

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc
oral
intravaginal
transdermal

injectable

Progestogen-only hormone contraception associated with inhibition of ovulationc
oral

injectable

Sexual abstinence
Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the 
study intervention. The reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the study and the preferred and usual lifestyle of the participant.
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b.
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when 
used consistently and correctly.
c.
Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with Clinical 
Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those which inhibit 
ovulation as the primary mode of action.
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure with friction)

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10.4.3.
Collection of Pregnancy Information:
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study.  This applies only to male participants who receive study intervention.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy.

The female 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.
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study.

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant’s pregnancy.

Participant will be followed to determine the outcome of the pregnancy.  The 
investigator will collect follow up information on participant and neonate, 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 intervention by the investigator, will be reported to 
GSK as described in Appendix 3.  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 participant who becomes pregnant while participating will discontinue study 
intervention but can continue in the study and attend all clinic visits if she wishes.

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10.4.4.
Contraception Eligibility Criteria for Female and Male Participants
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
a.
Male Participants:
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 8 weeks after last dose of study SC intervention:

Refrain from donating sperm
PLUS, either:

Be abstinent from heterosexual or homosexual intercourse as their preferred and 
usual lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent
OR

Must agree to use contraception/barrier as detailed below
o
Agree to use a male condom AND female partner to use an additional highly 
effective contraceptive method with a failure rate of <1% per year (as 
described in Section 10.4.2) when having sexual intercourse with a woman 
of childbearing potential who is not currently pregnant.
b. Female Participants: 

A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and at least one of the following conditions applies:
o
Is NOT a woman of childbearing potential (WOCBP) as defined in Section 
10.4.1.
OR
o
Is a WOCBP and using a contraceptive method that is highly effective with a 
failure rate of <1% per year(see Section 10.4.2), for 30 days before the first 
dose of study intervention, during the intervention period and at least 8 
weeks after the last dose of study SC intervention and agrees not to donate 
eggs (ova, oocytes) for the purpose of reproduction during this period.  
Additionally, WOCBP using hormonal contraceptives, including oral, 
injections, implants, and patches, are required to use a secondary method of 
contraception. The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention.

In addition to contraception requirements for blinded study medication as 
outlined above, participants should follow csDMARD local labelling.

A WOCBP must have both: 

A confirmed menstrual period prior to the first dose of study intervention
AND

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
A negative highly sensitive pregnancy test (urine or serum as required by 
local regulations) within 24 hours before the first dose of study intervention.
If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a 
serum pregnancy test is required.  In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive.

The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy.
Pregnancy tests for WOCBP are specified in the SoA (Section 1.3).

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10.5.
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase 3-4 liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology 
Phase 3-4 liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN persists for 2 weeks
ALT 3xULN but <5xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN 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 
Actions
Follow Up Assessments

Immediately discontinue study intervention

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 participant until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Permanently discontinue study intervention 
and continue participant in the study for any 
protocol specified follow up assessments

Viral hepatitis serology4

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained less than 8 weeks
after last dose6

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 

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MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and INR) and 
perform liver event follow up assessments 
within 24 hrs

Monitor participants 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 INR) and 
perform liver event follow up assessments 
within 24-72 hrs 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
formincluding acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form (CRF) 
page
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants 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 intervention for that participant 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 which may 
indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the threshold value stated will not apply to participants 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 immunoglobulin M (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; cytomegalovirus 
IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot 
testing); and hepatitis E IgM antibody. 
5.
If hepatitis delta antibody assay cannot be performed, it can be replaced with a polymerase chain reaction (PCR) 
of hepatitis D RNA virus (where needed) [Le Gal, 2005].
6.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention prior to 
the PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best 

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approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.
Phase 3-4 liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
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 
participant safety. 

Participant can continue study intervention

Participant 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 participant meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and <8xULN 
to ≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants 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.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369

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10.6.
Appendix 6:Summary of composite endpoints
These composite endpoints are calculated using the data collected from assessments 
described in Section 8.1.
10.6.1.
Disease Activity Score (DAS)
The Disease Activity Score (DAS) assessment is a derived measurement with differential 
weighting given to each component.  The DAS 28(CRP) or DAS 28(ESR) will be 
calculated at each assessment timepoint.
The components of the DAS 28 arthritis assessment include:

Tender/Painful Joint Count (28).

Swollen Joint Count (28).

hsCRP or ESR.

PtGA.
10.6.2.
Clinical Disease Activity Index (CDAI)
The CDAI for rheumatoid arthritis is a clinical composite score to determine disease 
severity using only clinical data.  The CDAI score will be calculated at each assessment 
timepoint.
The components of the CDAI include:

Tender/Painful Joint Count (28).

Swollen Joint Count (28).

PtGA.

PhGA.
10.6.3.
ACR and EULAR Remission (Boolean and SDAI)
ACR/EULAR remission in rheumatoid arthritis clinical trials [Felson, 2011] will be 
assessed using both Boolean and SDAI definitions, at each assessment timepoint.  
For the Boolean definition, this includes:

Tender/Painful Joint Count (28).

Swollen Joint Count (28).

hsCRP.

PtGA.

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For the SDAI definition, this includes:

Tender/Painful Joint Count (28).

Swollen Joint Count (28).

hsCRP.

PtGA.

PhGA.

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10.7.
Appendix 7: Medical Device Adverse Events (AEs), Adverse 
Device Effects (ADEs), Serious Adverse Events (SAEs) and 
Device Deficiencies: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting

The detection and documentation procedures described in this Appendix apply to 
all GSK medical devices provided for use in the study (see Section 6.1.2 for the 
list of GSK medical devices).  Refer to Appendix 3 for all other AE/SAE
reporting not involving a GSK medical device.

The definitions and procedures detailed in this appendix are in accordance with 
ISO 14155.

Both the investigator and the sponsor will comply with all local medical device 
reporting requirements.
10.7.1.
Definition of Medical Device AE and ADE
Medical Device AE and ADE Definition 

An AE is defined as any untoward medical occurrence, unintended disease or injury, 
or untoward clinical signs (including abnormal laboratory finding) in study 
participants, users, or other persons, whether or not related to the investigational 
medical device. This definition includes events related to the investigational medical 
device or comparator and events related to the procedures involved except for events 
in users or other persons, which only include events related to investigational 
devices.

An adverse device effect (ADE) is defined as an adverse event related to the use of 
an investigational medical device. This definition includes any adverse events 
resulting from insufficient or inadequate instructions for use, deployment, 
implantation, installation, or operation, or any malfunction of the investigational 
medical device as well as any event resulting from use error or from intentional 
misuse of the investigational medical device.
10.7.2.
Definition of Medical Device SAE, SADE and USADE
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).
A Medical Device SAE is a Medical Device AE that:
a.
Led to death 
b.
Led to serious deterioration in the health of the participant, that either resulted in:
1. A life-threatening illness or injury. The term ‘life-threatening' in the definition of 
serious' refers to an event in which the participant was at risk of death at the time 
of the event. It does not refer to an event, which hypothetically might have caused

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death, if it were more severe
2. A permanent impairment of a body structure or a body function,
3. Inpatient or prolonged hospitalization, Planned hospitalization for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration in 
health, is not considered an SAE
4. Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function
c.
Led to fetal distress, fetal death or a congenital abnormality or birth defect
Serious Adverse Device Effect (SADE) definition

A SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event.
Unanticipated Serious Adverse Device Effect (USADE) definition

A USADE is a serious adverse device effect which by its nature, incidence, severity 
or outcome has not been identified in the current version of the risk analysis report 
(see Section 2.3).
10.7.3.
Definition of Device Deficiency
Device Deficiency definition

A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety, or performance. Device deficiencies include 
malfunctions, use errors, and inadequate labelling.
10.7.4.
Recording and Follow-Up of Medical Device AE and/or SAE and 
Device Deficiencies
Medical Device AE, SAE and Device Deficiency Recording

When an AE/SAE/device deficiency occurs, it is the responsibility of the investigator 
to review all documentation (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event.

The investigator will then record all relevant AE/SAE/device deficiency information 
in the participant’s medical records, in accordance with the investigator’s normal 
clinical practice, and on the appropriate form of the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the AE/SAE/device deficiency CRF 
page.

There may be instances when copies of medical records for certain cases are 

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requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.

For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of a device 
deficiency. This includes any amendment to the device design to prevent recurrence.
Assessment of Intensity

The investigator will make an assessment of intensity for each AE/SAE/device 
deficiency reported during the study and assign it to one of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe 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 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.

Other measures to evaluate AEs and SAEs may be utilized (e.g., National Cancer 
Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE]).
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE/device deficiency

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/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 underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 

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Information, for marketed products, in his/her assessment.

For each AE/SAE/device deficiency, the investigator must document in the medical 
notes that he/she has reviewed the AE/SAE/device deficiency and has provided an 
assessment of causality.

There may be situations in which 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 before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of Medical Device AE/SAE/device deficiency

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE/SAE/device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.

If a participant 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 24 hours of 
receipt of the information.
10.7.5.
Reporting of Medical Device SAEs
Medical Device SAE Reporting to GSK via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool 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 participant or receives 

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updated data on a previously reported SAE after the electronic data collection tool 
has been taken off-line, then the site can report this information on a paper SAE 
form (see next section) or to the medical monitor or the SAE coordinator by 
telephone.

Contacts for SAE reporting can be found in SRM.
Medical Device SAE Reporting to GSK via Paper CRF

Secure email transmission of the scanned SAE paper CRF is the preferred method 
to transmit this information to the medical monitor or the SAE coordinator.

In rare circumstances and in the absence of secure email facilities, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time 
frames.

Contacts for SAE reporting can be found in the SRM.
10.7.6.
Reporting of SADEs
SADE Reporting to GSK 
NOTE: There are additional reporting obligations for medical device incidents that are 
potentially related to SAEs that must fulfil the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies. 

Any device deficiency that is associated with an SAE must be reported to GSK 
within 24 hours after the investigator determines that the event meets the definition 
of a device deficiency.

GSK shall review all device deficiencies and determine and document in writing 
whether they could have led to an SAE. These shall be reported to the regulatory 
authorities and IRBs/IECs as required by national regulations.

Contacts for SAE reporting can be found in the SRM.

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10.8.
Appendix 8: Country-specific requirements

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10.9.
Appendix 9: Abbreviations and Trademarks
Abbreviations
AASLD
American Association for the Study of Liver Diseases
ACR
American College of Rheumatology
ADA
Anti-Drug Antibody
ADE
Adverse Device Effect
AE
Adverse event
AESI
Adverse event of special interest
AI
Auto Injector
ALT
Alanine transaminase
ANC
Absolute Neutrophil Count
AP
Alkaline phosphatase
AST
Aspartate transaminase
bDMARD
Biologic disease modifying antirheumatic drug
CDAI
Clinical disease activity index
CIOMS
Council for International Organisations of Medical Sciences
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CPK
Creatine phosphokinase
CRF
Case report form
CRP
C-reactive protein
csDMARD
Conventional synthetic disease modifying antirheumatic drug
CSR
Clinical Study Report
CTFG
Clinical Trial Facilitation Group
CV
Coefficient Variance
CYP
Cytochrome
DAS28
Disease activity score including 28 different joints
DAS28(CRP)
Disease activity score including 28 different joints with CRP value
DAS28(ESR)
Disease activity score including 28 different joints with ESR value
DNA
Deoxyribonucleic acid
DMARD
Disease modifying antirheumatic drug
EASL
European Association for the Study of the Liver
EBV
Epstein Barr Virus
ECG
Electrocardiogram
eCRF
Electronic case report form
ESR
Erythrocyte sedimentation rate
EULAR
European League against Rheumatism
FACIT
Functional assessment of chronic illness therapy
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GI
Gastrointestinal
GM-CSF
Granulocyte-macrophage colony stimulating factor
GSK
GlaxoSmithKline
HAQ-DI
Health Assessment Questionnaire Disability Index
HBcAb
Hepatitis B core Antibody

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HBV
Hepatitis B Virus
hCG
Human chorionic gonadotropin
HF
Human factors
HRCT
High-resolution computed tomography
HRQL
Health Related Quality of Life
HRT
Hormone replacement therapy
HV
Healthy volunteer
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IgM
Immunoglobulin M
IEC
Institutional Ethics Committee
IFU
Instructions for use
IMP
Investigational medicinal product
INH
Isoniazid
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board
IRT
Interactive response technology
IU
International units
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IVIG
Intravenous immunoglobulin
IRT
Interactive Response Technology
kg
Kilogram
L
Litre
LAM
Lactational amenorrhoea method
LDH
Lactate dehydrogenase
MACE
Major Adverse Cardiac Event
MCV
Mean cell volume
MCH
Mean corpuscular haemoglobin
MedDRA
Medical dictionary for regulatory activities
mg
Milligram
mL
Milliliter
MOS
Medical Outcomes Study
MS
Multiple sclerosis
MSDS
Material safety data sheet
mTSS
Modified Total Sharp Score
MTX
Methotrexate
NCEP
National Cholesterol Educational Program
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NIMP
Non-investigational medicinal product
PAC
Pulmonary Adjudication Committee

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11.
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