Conditions: Arthritis, Rheumatoid
Keywords: bDMARD GSK3196165 Rheumatoid Arthritis Sarilumab Otilimab
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 550
Healthy volunteers: no

Brief summary:
This study (contRAst 3 \[202018: NCT04134728\]) is a Phase 3, randomized, multicenter, double-blind study to assess the safety and efficacy of GSK3196165 in combination with conventional (cs) DMARD\[s\]) or the treatment of adult participants with moderate to severe active rheumatoid arthritis (RA) who have had an inadequate response to biologic (b) DMARD\[s\]) and/or JAK inhibitors. The study will consist of a screening phase of up to 6 weeks followed by 24 week treatment phase in which participants will be randomized in ratio of 6:6:6:1:1:1 to GSK3196165 150 milligrams (mg) subcutaneously (SC) weekly,GSK3196165 90 mg SC weekly, sarilumab 200 mg SC every other week or placebo (three arms) respectively, all in combination with background csDMARD(s). At Week 12, participants in the three placebo arms will switch from placebo to active intervention (either GSK3196165 150 mg SC weekly, GSK3196165 90 mg SC weekly, or sarilumab 200 mg SC every other week). Participants who, in investigator's judgement will benefit from extended treatment with GSK3196165, may be included in the long-term extension study (contRAst X \[209564: NCT04333147\]). Any participant who does not transition into study 209564 will undergo a safety follow-up visit at Week 34 (corresponding to 12 weeks after the last potential dose of sarilumab, at Week 22).

Detailed description:

Arms:
arm 1: Entire treatment period (24 Weeks): GSK3196165 90 mg SC injection once weekly. Participants will also receive a stable dose of csDMARD(s) as standard of care (SoC). arm 2: Entire treatment period (24 Weeks): GSK3196165 150 mg SC injection once weekly. Participants will also receive a stable dose of csDMARD(s) as SoC. arm 3: Entire treatment period (24 Weeks): Sarilumab 200 mg SC injection every other week + placebo SC injection in the intervening weeks. Participants will also receive a stable dose of csDMARD(s) as SoC. arm 4: From Week 0-11: Placebo SC injection once weekly. From Week 12 onwards: GSK3196165 90 mg SC injection once weekly. Participants will also receive a stable dose of csDMARD(s) as SoC. arm 5: From Week 0-11: Placebo SC injection once weekly. From Week 12 onwards: GSK3196165 150 mg SC injection once weekly. Participants will also receive a stable dose of csDMARD(s) as SoC. arm 6: From Week 0-11: Placebo SC injection once weekly. From Week 12 onwards: Sarilumab 200 mg SC injection every other week + placebo SC injection in the intervening weeks. Participants will also receive a stable dose of csDMARD(s) as SoC.

Interventions: intervention 1: GSK3196165 (Otilimab) intervention 2: Sarilumab intervention 3: Placebo to GSK3196165/ Sarilumab intervention 4: csDMARDs
Intervention descriptions: intervention 1: GSK3196165 solution in vial/pre-filled syringe (PFS) to be administered SC. intervention 2: Sarilumab solution in PFS to be administered SC. intervention 3: Placebo sterile 0.9 percentage (%) weight by volume (w/v) sodium chloride solution in vial/PFS to be administered SC. intervention 4: Stable dose of csDMARD(s) as SoC.

Protocol document:
Prot_000.pdf: 
2018N385816_02
CONFIDENTIAL
GlaxoSmithKline group of companies
202018
1
TITLE PAGE
Protocol Title: A 24-week, phase 3, multicentre, randomised, double-blind, efficacy and 
safety study, comparing GSK3196165 with placebo and with sarilumab, in combination 
with conventional synthetic DMARDs, in participants with moderately to severely active 
rheumatoid arthritis who have an inadequate response to biological DMARDs and/or 
Janus Kinase inhibitors.
Protocol Number: 202018 / Amendment 02
Compound Number:
GSK3196165 
Compound Name:
Otilimab
Study Phase: Phase 3 
Short Title: Efficacy and safety of GSK3196165 versus placebo and sarilumab in 
participants with moderately to severely active rheumatoid arthritis who have an 
inadequate response to biological DMARDs and/or Janus Kinase inhibitors.
Study Name: contRAst-3
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:  2019-000868-18
Approval Date: 21-JAN-2020
Copyright 2020 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
DNG Number
Amendment 2
21-JAN-2020
2018N385816_02
Amendment 1
22-MAY-2019
2018N385816_01
Original Protocol
06-MAR-2019
2018N385816_00
Amendment 2: 21-JAN-2020
Overall Rationale for the Amendment:  To introduce new medical device safety 
reporting wording, required in advance of roll out of pre-filled syringes to this study.  
Other minor corrections and clarifications added throughout the protocol.
Section # and Name
Description of Change
Brief Rationale
Section 1.1 Synopsis
Addition of time points to safety and 
tolerability endpoint; update to Number 
of Participants section, to clarify key 
Asian country subgroup.
To reflect the updates in body of 
protocol (detailed below).
Section 1.2 Schema
Addition of “JAKi-IR” to schema
Correction.
Section 1.3 Schedule of 
Activities (SoA)
Updated SoAs: remove fasting 
requirement for lipid test; clarify ECG 
requirement; refer to SAE section for 
reporting times at screening; add urine 
pregnancy test at safety f/u; and remove 
cholesterol sample from early 
withdrawal.
Clarifications and reflect updates 
in body of protocol.
Section 2.3.1 Risk 
Assessment
Injection site reaction mitigation strategy 
- recommendation to rotate sites.
Clarification.
Handling and usage risks associated 
with the prefilled syringe devices
Addition to align with introduction 
of prefilled syringes.
Section 3 Objectives and 
Endpoints
Addition of time points to safety and 
tolerability endpoint.
Clarification.
Section 5 Study 
Population
Addition of reference to EULAR 
recommendations for vaccination.
Provide guidance for countries 
where no local guidelines exist. 
Section 5.2 Exclusion 
Criteria
Exclusion 12: Reduce myocardial 
infarction exclusion to 3 months.
3 months is considered to be 
appropriate to stabilise ischemic 
heart disease.
Section 5.4 Screen 
Failures
Update to clarify implications of a 
positive repeat TB test.
Clarification.
Section 6.1. Study 
Intervention(s) 
Administered
Added timepoints for permitted home 
administration of pre-filled syringe.
Clarification.
Section 6.1.1 Medical 
Devices
Description of pre-filled syringes 
(medical devices) used in the study.
To comply with new regulatory 
requirements.


2018N385816_02
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4
Section # and Name
Description of Change
Brief Rationale
Section 6.5.1 Permitted 
Therapies, Table 2
Permit PRN use of NSAIDs and weak 
opioids except 24hr before assessment 
visits, and permit PRN use of strong 
opioids after week 12 except 24hr before 
assessment visits.
Clarification to make clear how 
PRN use is managed.
Addition of Hyaluronic acid and 
associated restrictions.
To clarify and align with clinical 
practice.
Section 6.5.2 Prohibited 
Therapies, Table 3
Removal of marijuana from prohibited list 
and update to vaccination 
recommendations wording.
To clarify and align with clinical 
practice.
Update exclusion period for tsDMARDs.
Clarification.
Section 7.1.2 Other 
Stopping Criteria
Permit permanent discontinuation due to 
a significant medical event, at discretion 
of investigator.
Clarification.
Section 7.1.3.3
Haematologic 
Abnormalities
Clarification of local confirmatory test 
requirement.
Clarification.
Section 8.2.7.2 
Tuberculosis Testing
Addition of unscheduled TB testing if 
participant has been in contact with 
someone who has untreated active TB.
To mitigate risk further
Section 8.3.1 Time Period 
and Frequency for 
Collecting AE and SAE 
Information
Clarification that SAE collection is from 
beginning of study intervention (except in 
China, or if related to study 
participation).
Clarification of safety reporting 
requirements.
Section 8.3.8 Medical 
Device Deficiencies
Added sections covering the reporting 
and follow-up of medical device 
deficiencies.
To comply with new regulatory 
requirements.
Section 8.4 Treatment of 
Overdose
Clarify definition, require documentation 
to be handled by unblinded CRA.
Clarification.
Section 9.2 Sample Size 
Determination
Update to more clearly explain that key 
Asian country subgroup may continue to 
be recruited after study target reached.
Clarification.
Section 9.5 Interim 
Analyses
Interim analysis wording updated to 
describe how the key Asian country 
subgroup will be analysed.
Clarification.
Section 10.1.8 Data 
Quality Assurance
Addition of eCOA quality wording.
Clarification
Section 10.2: Clinical 
Laboratory Tests
Removal of fasting requirement for lipid 
tests.
Not considered necessary, so 
remove fasting requirement to 
minimise unnecessary 
inconvenience to participants.
Permit final assessment visit values of 
hsCRP & ESR to be provided to site.
These are baseline for LTE and 
are not individually unblinding.


2018N385816_02
CONFIDENTIAL
202018
5
Section # and Name
Description of Change
Brief Rationale
Section 10.3 Appendix 3: 
Adverse Events: 
definitions and 
procedures for Recording, 
Evaluation, Follow-up and 
Reporting
Explain that this section is for AEs and 
SAEs which are not related to medical 
devices, and reference to Appendix 9 for 
medical device incidents. 
To enable addition of medical 
device incidents appendix.
Section 10.9: Appendix 9: 
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
Addition of medical Device Adverse 
Effects reporting appendix.
To comply with new regulatory 
requirements.
All sections
Other minor, grammatical and typographical corrections to improve 
readability.


2018N385816_02
CONFIDENTIAL
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6
TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
PROTOCOL SUMMARY........................................................................................10
1.1.
Synopsis.....................................................................................................10
1.2.
Schema ......................................................................................................13
1.3.
Schedule of Activities (SoA)........................................................................13
2.
INTRODUCTION....................................................................................................17
2.1.
Study Rationale ..........................................................................................17
2.2.
Background ................................................................................................17
2.3.
Benefit/Risk Assessment ............................................................................18
2.3.1.
Risk Assessment .........................................................................19
2.3.2.
Benefit Assessment.....................................................................30
2.3.3.
Overall Benefit: Risk Conclusion..................................................30
3.
OBJECTIVES AND ENDPOINTS...........................................................................31
4.
STUDY DESIGN ....................................................................................................33
4.1.
Overall Design ............................................................................................33
4.2.
Scientific Rationale for Study Design ..........................................................34
4.3.
Justification for Dose ..................................................................................34
4.4.
End of Study Definition ...............................................................................36
5.
STUDY POPULATION...........................................................................................36
5.1.
Inclusion Criteria.........................................................................................37
5.2.
Exclusion Criteria........................................................................................38
5.3.
Lifestyle Considerations..............................................................................41
5.4.
Screen Failures...........................................................................................41
6.
STUDY INTERVENTION........................................................................................42
6.1.
Study Intervention(s) Administered .............................................................42
6.1.1.
Medical Devices...........................................................................46
6.2.
Preparation/Handling/Storage/Accountability..............................................46
6.3.
Measures to Minimise Bias: Randomisation and Blinding ...........................47
6.4.
Study Intervention Compliance ...................................................................48
6.5.
Prior and Concomitant Therapies ...............................................................49
6.5.1.
Permitted Therapies ....................................................................49
6.5.2.
Prohibited Therapies....................................................................52
6.5.3.
Rescue Medicine .........................................................................53
6.6.
Dose Modification .......................................................................................54
6.6.1.
Dose Modification of Study Intervention.......................................54
6.6.2.
Dose Modification of Background Therapy...................................54
6.7.
Intervention after the End of the Study........................................................54
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................54
7.1.
Discontinuation of Study Intervention..........................................................54
7.1.1.
Liver Chemistry Stopping Criteria ................................................55
7.1.1.1.
Study Intervention Restart or Rechallenge after 
liver stopping criteria met............................................55


2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
7
7. 1. 2.  
Ot h er St o p pi n g Crit eri a ................................................................5 6
7. 1. 3.
T e m p or ar y Di s c o nti n u ati o n ..........................................................5 6
7. 1. 3. 1.
R e s pir at or y S y m pt o m s ...............................................5 6
7. 1. 3. 2.
S eri o u s a n d O p p ort u ni sti c I nf e cti o n s ..........................5 7
7. 1. 3. 3.
H e m at ol o gi c A b n or m aliti e s .........................................5 7
7. 1. 3. 4.
T B R e a cti v ati o n ..........................................................5 7
7. 2.
P arti ci p a nt Di s c o nti n u ati o n/ W it h dr a w al fr o m t h e St u d y...............................5 7
7. 3.
L o st t o F oll o w U p ........................................................................................5 8
8.
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S .....................................................5 9
8. 1.
Effi c a c y A s s e s s m e nt s .................................................................................5 9
8. 1. 1.
J oi nt A s s e s s m e nt s .......................................................................5 9
8. 1. 2.
P h y si ci a n’ s Gl o b al A s s e s s m e nt of Art hriti s ..................................6 0
8. 1. 3. 1.
P ati e nt’ s A s s e s s m e nt of Art hr iti s P ai n........................6 0
8. 1. 3. 2.
P ati e nt’ s Gl o b al A s s e s s m e nt of Art hriti s .....................6 0
8. 1. 3. 3.
H e alt h A s s e s s m e nt Q u e sti o n n air e – Di s a bilit y 
I n d e x ( H A Q- DI)...........................................................6 0
8 . 1. 3. 7.
F u n cti o n al A s s e s s m e nt of C hr o ni c Ill n e s s 
T h er a p y ( F A CI T) -F ati g u e ............................................6 1
8. 1. 3. 8.
S F -3 6 S h ort F or m H e alt h S ur v e y ................................6 1
8. 2.
S af et y A s s e s s m e nt s ...................................................................................6 2
8. 2. 1.
D y s p n o e a A s s e s s m e nt s ..............................................................6 2
8. 2. 2.
P h y si c al E x a mi n ati o n s .................................................................6 2
8. 2. 3.
El e ctr o c ar di o gr a m s ......................................................................6 2
8. 2. 4.
Vit al Si g n s ....................................................................................6 3
8. 2. 5.
Cli ni c al S af et y L a b or at or y A s s e s s m e nt s ......................................6 3
8. 2. 6.
P ul m o n ar y A s s e s s m e nt s .............................................................6 4
8. 2. 7.
T u b er c ul o si s M o n it ori n g...............................................................6 5
8. 2. 7. 1.
T u b er c ul o si s St at u s D efi niti o n s ..................................6 5
8. 2. 7. 2.
T u b er c ul o si s T e sti n g ..................................................6 6
8. 2. 7. 3.
Tr e at m e nt of L at e nt T B D uri n g t h e St u d y ...................6 6
8. 2. 7. 4.
M o nit ori n g f or T B I nf e cti o n a n d R e -a cti v ati o n 
D uri n g t h e St u d y .........................................................6 6
8. 2. 8.
H e p atiti s B M o nit ori n g ..................................................................6 7
8. 2. 8. 1.
Ri s k of R e a cti v ati o n i n P arti ci p a nt s P o siti v e f or 
H e p atiti s B C or e A nti b o d y ( H B c A b) ............................6 8
8. 2. 8. 2.
Tr e at m e nt of P arti ci p a nt s W h o Ar e H B c A b 
P o siti v e a n d W h o D e v el o p D et e ct a bl e H B V 
D N A R e q uiri n g I niti ati o n of A nti vir al T h er a p y ..............6 8
8. 2. 8. 3.
F oll o w U p of P arti ci p a nt s Tr e at e d Wi t h A nti-
v ir al T h er a p y...............................................................6 8
8. 2. 9.
M ar k er s of dr u g -dr u g i nt er a cti o n s ................................................6 8
8. 3.
A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s .............................................6 8
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2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
8
8. 3. 1.
Ti m e P eri o d a n d Fr e q u e n c y f or C oll e cti n g A E a n d S A E 
I nf or m ati o n...................................................................................6 9
8. 3. 2.
M et h o d of D et e cti n g A E s a n d S A E s .............................................6 9
8. 3. 3.
F oll o w -u p of A E s a n d S A E s .........................................................7 0
8. 3. 4.
R e g ul at or y R e p orti n g R e q uir e m e nt s f or S A E s .............................7 0
8. 3. 5.
Pr e g n a n c y ...................................................................................7 0
8. 3. 6.
C ar di o v a s c ul ar a n d D e at h E v e nt s ................................................7 1
8. 3. 7.
A E s of S p e ci al I nt er e st .................................................................7 1
8. 3. 8.
M e di c al D e vi c e D efi ci e n ci e s ........................................................7 2
8. 3. 8. 1
Ti m e P eri o d f or D et e cti n g M e di c al D e vi c e 
D efi ci e n ci e s ................................................................7 2
8. 3. 8. 2
F oll o w -u p of M e di c al D e vi c e D efi ci e n ci e s ...................7 2
8. 3. 8. 3
Pr o m pt R e p orti n g of M e di c al D e vi c e 
D efi ci e n ci e s t o S p o n s or ..............................................7 2
8. 3. 8. 4
R e g ul at or y R e p orti n g R e q uir e m e nt s f or 
M e di c al D e vi c e I n ci d e nt s ............................................7 3
8. 4.
Tr e at m e nt of O v er d o s e ...............................................................................7 3
8. 5.
P h ar m a c o ki n eti c s .......................................................................................7 3
8. 6.
P h ar m a c o d y n a mi c s ....................................................................................7 4
8. 6. 1.
T ar g et e n g a g e m e nt .....................................................................7 4
8. 7.
G e n eti c s .....................................................................................................7 4
8. 8. 1.
P h ar m a c o d y n a mi c ( P D) Bi o m ar k er s ............................................7 5
8. 9.
I m m u n o g e ni cit y A s s e s s m e nt s.....................................................................7 6
8. 1 0.
M e di c al R e s o ur c e Utili s ati o n a n d H e alt h E c o n o mi c s ..................................7 6
9.
S T A TI S TI C A L C O N SI D E R A TI O N S ........................................................................7 7
9. 1.
St ati sti c al H y p ot h e s e s .................................................................................7 7
9. 2.
S a m pl e Si z e D et er mi n ati o n ........................................................................7 7
9. 2. 1.
S a m pl e Si z e S e n siti vit y ................................................................7 7
9. 3.
P o p ul ati o n s f or A n al y s e s ............................................................................7 8
9. 4.
St ati sti c al A n al y s e s .....................................................................................7 9
9. 4. 1.
Effi c a c y A n al y s e s .........................................................................8 0
9. 4. 1. 1.
E sti m a n d str at e g y .......................................................8 0
9. 4. 2.
S af et y A n al y s e s ...........................................................................8 1
9. 4. 3.
Ot h er A n al y s e s ............................................................................8 1
9. 5.
I nt eri m A n al y s e s .........................................................................................8 1
9. 5. 1.
D at a M o nit ori n g C o m mitt e e ( D M C) ..............................................8 2
1 0.
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L
C O N SI D E R A TI O N S ...............................................................................................8 3
1 0. 1.
A p p e n di x 1: R e g ul at or y, Et hi c al, a n d St u d y O v er si g ht 
C o n si d er ati o n s ............................................................................................8 3
1 0. 1. 1.
R e g ul at or y a n d Et hi c al C o n si d er ati o n s ........................................8 3
1 0. 1. 2.
Fi n a n ci al Di s cl o s ur e .....................................................................8 3
1 0. 1. 3.
I nf or m e d C o n s e nt Pr o c e s s ..........................................................8 4
1 0. 1. 4.
D at a Pr ot e cti o n ............................................................................8 4
1 0. 1. 5.  
C o m mitt e e s Str u ct ur e ..................................................................8 4
1 0. 1. 6.
P u bli c ati o n P oli c y .........................................................................8 5
1 0. 1. 7.
Di s s e mi n ati o n of Cli ni c al St u d y D at a ...........................................8 5
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10.1.8.
Data Quality Assurance ...............................................................86
10.1.9.
Source Documents ......................................................................87
10.1.10. Study and Site Closure ................................................................87
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................88
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................90
10.3.1.
Definition of AE............................................................................90
10.3.2.
Definition of SAE..........................................................................91
10.3.3.
Definition of Cardiovascular Events .............................................92
10.3.4.
Recording and Follow-Up of AE and SAE....................................93
10.3.5.
Reporting of SAE to GSK.............................................................94
10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................96
10.4.1.
Definitions:...................................................................................96
10.4.1.1.
Woman of Childbearing Potential (WOCBP)...............96
10.4.1.2.
Women in the following categories are not 
considered WOCBP ...................................................96
10.4.2.
Contraception Guidance: .............................................................97
10.4.3.
Collection of Pregnancy Information: ...........................................98
10.4.4.
Contraception Eligibility Criteria for Female and Male 
Participants..................................................................................99
10.5.
Appendix 5: Genetics................................................................................101
10.6.
Appendix 6: Liver chemistry stopping and monitoring criteria and 
required actions and follow up assessments (study specific for 
202018) ....................................................................................................102
10.6.1.
Liver chemistry stopping criteria and required follow up 
assessments..............................................................................102
10.6.2.
Liver chemistry increased monitoring criteria with 
temporary discontinuation of study intervention .........................104
10.7.
Appendix 7: Summary of composite endpoints .........................................105
10.7.1.
ACR...........................................................................................105
10.7.2.
Disease Activity Score ...............................................................105
10.7.3.
Clinical Disease Activity Index (CDAI)........................................105
10.8.
Appendix 8: Hierarchy Options to Demonstrate Superiority of Each 
Dose of GSK3196165 Versus Placebo or Sarilumab ................................107
10.9.
Appendix 9: 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..........................................................................108
10.9.1.
Definition of Medical Device AE and ADE..................................108
10.9.2.
Definition of Medical Device SAE, SADE and USADE ...............108
10.9.3.
Definition of Device Deficiency...................................................109
10.9.4.
Recording and Follow-Up of Medical Device AE and/or 
SAE and Device Deficiencies.....................................................109
10.9.5.
Reporting of Medical Device SAEs ............................................111
10.9.6.
Reporting of SADEs...................................................................112
10.10. Appendix 10: Country-specific requirements.............................................113
10.11. Appendix 11: Abbreviations and Trademarks............................................114
10.12. Appendix 12: Protocol Amendment History...............................................118
11. REFERENCES.....................................................................................................119


2018N385816_02
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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A 24-week, phase 3, multicentre, randomised, double-blind, efficacy and 
safety study, comparing GSK3196165 with placebo and with sarilumab, in combination 
with conventional synthetic DMARDs, in participants with moderately to severely active 
rheumatoid arthritis who have an inadequate response to biological DMARDs and/or 
Janus Kinase inhibitors.
Short Title: Efficacy and safety of GSK3196165 versus placebo and sarilumab in 
participants with moderately to severely active rheumatoid arthritis who have an 
inadequate response to biological DMARDs and/or Janus Kinase inhibitors.
Rationale: The aim of this study is to determine the efficacy and safety of GSK3196165, 
in combination with conventional synthetic disease-modifying antirheumatic drug(s)
(csDMARD)(s), for the treatment of adults with moderately to severely active rheumatoid 
arthritis (RA) who have had an inadequate response to biologic DMARD(s) 
(bDMARD)(s) and/or JAK inhibitors.  Two doses of GSK3196165 (90 mg subcutaneous 
[SC] weekly and 150 mg SC weekly) will be compared with placebo (to Week 12) and 
with sarilumab (200 mg SC every other week), an inhibitor of IL-6 that is approved in 
many countries for the treatment of adults with moderately to severely active RA who 
have an inadequate response to bDMARD(s) and/or JAK inhibitors.
Objectives and Endpoints:
Objectives
Endpoints
Primary

To compare the efficacy of GSK3196165 
at doses of 90 mg and 150 mg weekly 
versus placebo, for the treatment of 
participants with moderately to severely 
active RA who are on a stable background 
of csDMARD(s) and who have had an 
inadequate response to biological 
DMARDs and/or JAK inhibitors.

Proportion of participants achieving ACR20 
at Week 12.
Secondary
To compare:

Efficacy of GSK3196165 at doses of 90 mg 
and 150 mg weekly versus sarilumab, for 
the treatment of participants with 
moderately to severely active RA who are 
on a stable background of csDMARD(s) 
and who have had an inadequate 
response to biological DMARDs and/or 
JAK inhibitors.
Major Secondary Efficacy Endpoints
Change from baseline at Week 12 (versus 
placebo) in:

HAQ-DI.
Change from baseline at Week 12 (versus 
sarilumab) in: 

CDAI total score.

Arthritis pain VAS.


2018N385816_02
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11
Objectives
Endpoints
Other Secondary Efficacy Endpoints
Proportion of participants at Week 12 (vs. 
placebo and vs. sarilumab) and Week 24 (vs. 
sarilumab) achieving:

CDAI total score ≤10 (CDAI LDA).

CDAI total score ≤2.8 (CDAI Remission).

ACR20/50/70.

DAS28-CRP ≤3.2 and DAS28(ESR) ≤3.2
(DAS28 LDA).

DAS28(CRP) <2.6 and DAS28(ESR) <2.6 
(DAS28 Remission).

A good/moderate EULAR response

ACR/EULAR Remission.
Change from baseline at Week 12 (vs. placebo 
and vs. sarilumab) and Week 24 (vs. 
sarilumab) in:

CDAI total score.

DAS28(CRP)/DAS28(ESR).

The effect of GSK3196165 on Patient 
Reported Outcomes (PROs) versus 
placebo and the active comparator 
sarilumab.
Change from baseline at Week 12 (vs. placebo 
and vs. sarilumab) and Week 24 (vs. 
sarilumab) in:

HAQ-DI.

Arthritis pain VAS.

SF-36 physical and mental component 
scores, and domain scores.

FACIT-Fatigue.

Safety and tolerability of GSK3196165 
versus placebo and the active comparator 
sarilumab

Incidence of AEs, SAEs and AESIs.

Change from baseline in key lab 
parameters at Weeks 12 and 24.

Proportion of participants with NCI-CTCAE 
≥Grade 3 haematology/clinical chemistry 
abnormalities.

To determine the immunogenic potential of 
GSK3196165
Safety Biomarker Endpoints

GM-CSF autoantibody concentrations.

Immunogenicity.
csDMARD = conventional synthetic disease modifying antirheumatic drug; ACR20/50/70 = 20%/50%/70% 
improvement in American College of Rheumatology criteria; 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; ESR = erythrocyte sedimentation rate; AEs = adverse events; SAEs = serious adverse events; AESIs = 
adverse events of special interest; NCI-CTCAE = National Cancer Institute-common terminology criteria for adverse 
events; GM-CSF = granulocyte-macrophage colony stimulating factor; SF-36 = short form-36; FACIT = functional 
assessment of chronic illness therapy; RA = rheumatoid arthritis


2018N385816_02
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12
Overall Design: This is a double-blind, parallel group, multicentre, placebo and active 
comparator-controlled study of the efficacy and safety of GSK3196165 in participants 
with moderately to severely active RA, who have had an inadequate response to 
treatment with bDMARDs and/or JAK inhibitors.  The study consists of a screening 
phase of up to 6 weeks, a 24-week treatment phase and a safety follow-up visit at 
Week 34.  Upon successful screening, participants will be randomised to one of six 
intervention arms.  Participants who complete the treatment period of this study may be 
eligible to participate in a long-term extension study to further evaluate the efficacy and 
safety of GSK3196165.
Disclosure Statement: This is a parallel group treatment study with 6 arms that is 
participant, investigator and outcomes assessor blinded.
Number of Participants: Approximately 1050-1200 participants will be screened to 
achieve between 525 and 600 randomly assigned to study intervention.  Approximately 
525 evaluable participants are expected to be included in the primary analysis, of whom 
approximately 473 are expected to complete the Week 12 visit.  When the approximate 
target of 525 participants is reached, recruitment may continue up to a maximum of 600 
participants to ensure sufficient numbers in the key Asian country subgroup. 
The sample size calculation is provided in Section 9.2.
Intervention Groups and Duration:
Participants will be randomised to one of six intervention arms, in a ratio of 6:6:6:1:1:1 to 
GSK3196165 150 mg SC weekly, GSK3196165 90 mg SC weekly, sarilumab 200 mg SC 
every other week or placebo (3 arms) respectively, all in combination with background 
csDMARD(s).  At Week 12, the 3 placebo arms will switch from placebo to active 
intervention (either GSK3196165 150 mg SC weekly, GSK3196165 90 mg SC weekly, 
or sarilumab 200 mg SC every other week).  Randomisation will be stratified by 
previously failed medication (1 bDMARD, >1 bDMARD or ≥1 JAK inhibitor [regardless 
of whether bDMARD received in past]).
A separate randomisation cohort in addition to the main randomisation may be utilised 
for the key Asian country subgroup, in order to allow separate analyses for these 
countries if required.
The total treatment period is 24 weeks, with a safety follow-up visit at Week 34, for those 
participants who do not continue into the long term-extension study.
Independent Data Monitoring Committee: Yes.
Major Adverse Cardiac Event/Gastrointestinal Perforation Adjudication 
Committee: Yes.
Pulmonary Adjudication Committee: Yes.


2018N385816_02
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1.2.
Schema
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. PhGA should then 
take place, followed by other assessments (including safety), ECGs, vital signs 
and blood draws, before dosing.

PK sampling and blood draws must always take place before dosing.
Study 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 intervention, the injection will then be 
performed at the site, after completion of PK sampling.

Dosing must always be performed by an unblinded administrator on weeks 0, 2, 4, 
6, 8, 10, 12, 14, 16, 18, 20, 22, even if PFS are available.  On Weeks 0, 1, 12 and 
13, participants must be dosed at site (after completion of study assessments) and 
monitored for 1 hour post dose.


2018N385816_02
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SoA – Screening Period
Participant Screening
Task List
Screening assessment notes
(after informed consent, all screening assessments 
must be completed within the 42 days prior to 
Randomisation)
Day -42 to Day -1

Informed Consent and optional Genetics consent
1) ECGs should be performed before vital signs 
and blood draws.
2) Joint assessments should be performed by 
an independent assessor. Where possible the 
same assessor should perform all joint 
assessments for an individual participant.
3) Unless performed within previous 12 weeks.
4) For women of child-bearing potential.
5) Fasting is not required, but 6hr fasting status 
at time of blood draw must be noted on 
requisition form.
6) See Section 8.3.1 for the time period of SAE 
collection, which varies between countries. 
See Section 5.4 for screen failures and 
rescreening.
Inclusion/exclusion criteria
Participant Demographics
Medical, disease and therapy history
Review of asthma/COPD/pulmonary disease history
Concomitant Medication Review
Assessments
Triplicate 12-lead ECG1
Vital signs
Full Physical Exam
Dyspnoea & Cough assessment, Lung Auscultation, 
Pulse Oximetry
TB evaluation
SAE assessment6
Swollen (66) & Tender (68) joint count2
Chest X-ray (posteroanterior)3
Labs
Haematology, Chemistry, Urinalysis (dip stick)
HIV, TB, Hepatitis B & Hepatitis C screen
hsCRP
Serum pregnancy test4
Lipid profile5


2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
1 5
S o A  – Tr e at m e nt P eri o d
St u d y i nt er v e nti o n G S K 3 1 9 6 1 6 5 v s 
s aril u m a b v s Pl a c e b o ( W 0 -W 1 1)
St u d y i nt er v e nti o n G S K 3 1 9 6 1 6 5 v s s aril u m a b
( W 1 2-W 2 4)
N ot e s
W e e k
0
1
2
3
4
5
6
7
8
9
1 0 1 1
1 2
1 3 1 4 1 5 1 6 1 7 1 8 1 9 2 0 2 1 2 2 2 3
2 4
1. P R Os s h o ul d b e c o m p l et e d b ef or e a ny 
ot h er ass ess m e nts, pr oc e d ur es or 
c o ns ult ati o ns, t o av oi d i nfl u e nci n g 
p artici p a nts’ p erc e pti o n.
2. E C Gs s h o ul d b e p erf or m e d b ef or e vit al 
si g ns a n d bl o o d dr a ws.
3. J oi nt ass ess m e nts s h o ul d b e p erf or m e d 
by a n i n d e p e n d e nt ass ess or. W h er e 
p ossi bl e t h e s a m e ass ess or s h o ul d 
p erf or m all j oi nt ass ess m e nts f or a n 
i n divi d u al p artici p a nt.
4. W h er e p ossi bl e, t h e s a m e i n divi d u al 
s h o ul d p erf or m all p hysici a n gl o b al 
ass ess m e nts f or a n i n divi d u al p artici p a nt.
5. Sc h e d ul e X -r ay b et w e e n W e eks 2 2-2 3.
6. F asti n g is n ot r e q uir e d, b ut 6 hr f asti n g 
st at us at ti m e of bl o o d dr a w m ust b e n ot e d 
o n r e q uisiti o n f or m.
7. F or w o m e n of c hil d -b e ari n g p ot e nti al.
8. E S R m e as ur e d l oc ally ( usi n g kit pr ovi d e d) 
by u n bli n d sit e st aff.
9. D ay 1 s a m pl e i ncl u d es a nti -G M -C S F a ut o -
a nti b o dy a n d fr e e G M -C S F a n aly sis.
1 0. G e n etics c o ns e nti n g p artici p a nts o nly.
1 1. First a n d s ec o n d S C i nj ecti o n giv e n at sit e
f or all p artici p a nts; m o nit or p artici p a nts f or 
1 h o ur p ost d osi n g at W e eks 0, 1, 1 2, a n d 
1 3.
1 2. D osi n g m ust al w ays b e p erf or m e d b y a n 
u n bli n d e d a d mi ni str at or o n w e e k s 0, 2 , 
4, 6, 8, 1 0, 1 2, 1 4, 1 6, 1 8, 2 0, 2 2, e v e n if 
P F S ar e a v ail a bl e . R ef er t o S ecti o n 6. 1 .
1 3. Dis p e ns e w e ekly f or sit e a d mi nistr ati o n; 
O R if av ail a bl e, dis p e ns e P F S i n b ox es of 
4, ev ery 4 w e eks, f or h o m e S C d osi n g.
1 4. Mi ni m u m w e ekly r evi e w t o W e ek 1 2, t h e n 
ev ery t w o w e eks t o W e ek 2 4. A p h o n e c all 
is acc e pt a bl e if a sit e visit is n ot 
sc h e d ul e d.
1 5. M ay b e p erf or m e d b ef or e D ay 1 if r e q uir e d.
A s s e s s m e nt vi sit D a y   
      St u d y a cti viti e s 1
B a s eli n e
D ay 1
D ay 8 ( 2 d)
D ay 1 5 ( 2 d)
D ay 2 2 ( 2 d)
D ay 2 9 ( 2 d)
D ay 3 6 ( 2 d)
D ay 4 3 ( 2 d)
D ay 5 0 ( 2 d)
D ay 5 7 ( 2 d)
D ay 6 4 ( 2 d)
D ay 7 1 ( 2 d)
D ay 7 8 ( 2 d)
Pri m ar y e n d p oi nt 
D ay 8 5 ( 3 d)
D ay 9 2 ( 3 d)
D ay 9 9 ( 3 d)
D ay 1 0 6 ( 3 d)
D ay 1 1 3 ( 3 d)
D ay 1 2 0 ( 3 d)
D ay 1 2 7 ( 3 d)
D ay 1 3 4 ( 3 d)
D ay 1 4 1 ( 3 d)
D ay 1 4 8 ( 3 d)
D ay 1 5 5 ( 3 d)
D ay 1 6 2 ( 3 d)
E n d of tr e at m e nt
D ay 1 6 9 ( 7 d)
R a n d o mis ati o n
X
P R Os 1
Art hritis p ai n V A S, Pt G A, H A Q -DI
X
X
X
X
X
X
X
X
X
F A CI T -F ati g u e, S F -3 6, P R O MI S Sl e e p
X
X
X
X
X
Ass ess m e nts
1 2 -l e a d E C G2 ( S =si n gl e, T =tri plic at e)
S
T
Vit al si g ns
X
X
X
X
X
X
X
X
Bri ef P hysic al Ex a m
X
X
X
X
X
X
X
X
Dys p n o e a & C o u g h ass ess m e nt, L u n g 
A usc ult ati o n, P uls e Oxi m etry
X 
X
X
X
X
X 
X
X
X
P ul m o n ary f u ncti o n t ests ( F E V 1, F V C)
X 1 5
S w oll e n ( 6 6) & T e n d er ( 6 8) j oi nt c o u nt 3
X
X
X
X
X
X
X
X
X
P hysici a n Gl o b al Ass ess m e nt 4
X
X
X
X
X
X
X
X
X
C h est x -r ay ( p ost er o a nt eri or)
X 5
L a bs a n d bl o o d dr a ws
H a e m at ol o gy, C h e mistry, Uri n alysis
X
X
X
X
X
X
X
X
X
Li pi d pr ofil e 6
X
X
X 6
Uri n e pr e g n a ncy t est 7
X
X
X
X
X
X
hs C R P, E S R 8
X
X
X
X
X
X
X
X
X
R F, A C P A ( a nti -C C P)
X
4 ß -O H c h ol est er ol a n d c h ol est er ol
X
X
X
T B t esti n g
X
Pr e -d os e P K s a m pl e ( & G M C S F c o m pl ex)
X
X
X
X
X
X
I m m u n o g e nicity bl o o d s a m pli n g
X 9
X
X
X
X
X
G e n etic s a m pl e 1 0
X
S a m pli n g f or R N A a n alysis
X
X
X
X
Bl o o d P D & Bi o m ark ers
X
X
X
X
X
X
W e ekly st u dy S C i nj e cti o n 1 1, 1 2, 1 3
X 1 1, 1 2 X 1 1 X 1 2 X X 1 2 X X 1 2 X X 1 2 X X 1 2 X
X 1 1, 1 2 X 1 1 X 1 2 X X 1 2 X X 1 2 X X 1 2 X X 1 2 X
S A E/ A E r evi e w 1 4
< ------------------------------------------------------------ X ------------------------------------------------------------>
C o nc o mit a nt m e dic ati o n r evi e w 1 4
< ------------------------------------------------------------ X ------------------------------------------------------------>
C CI
C CI


2018N385816_02
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16
SoA – Safety follow-up visit
Safety follow-up visit procedures
(Follow-up visit only for participants who do not 
transition into LTE study 209564)
Week 34 (Day 239 7 days)

Assessments
Vital signs
Full Physical Exam
Dyspnoea & Cough assessment, Lung Auscultation, 
Pulse Oximetry
Concomitant Medication Review
SAE/AE review
Labs
Haematology, Chemistry, Urinalysis (dip stick)
Urine pregnancy test (for women of child bearing 
potential only)
Immunogenicity blood sampling
Assessments for Early withdrawal from study
Follow Week 24 procedures (with the exception of the 4ß-OH cholesterol sample) at the 
time of withdrawal, or within 1 week, then schedule a safety follow-up visit 12 weeks 
post last dose of study intervention.


2018N385816_02
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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
The aim of this study is to determine the efficacy and safety of GSK3196165, in 
combination with conventional synthetic disease-modifying antirheumatic drug(s)
(csDMARD)(s), for the treatment of adults with moderately to severely active RA who 
have had an inadequate response to biologic DMARD(s) (bDMARD)(s) and/or JAK 
inhibitors.  Two doses of GSK3196165 (90 mg subcutaneous [SC] weekly and 150 mg 
SC weekly) will be compared with placebo (to Week 12) and with sarilumab 200 mg SC 
every other week, an inhibitor of IL-6 that is approved for the treatment of adults with 
moderately to severely active RA who have had an inadequate response to bDMARD(s) 
and/or JAK inhibitors.
2.2.
Background
RA is a chronic, systemic inflammatory autoimmune disease, characterised by a 
symmetrical polyarthritis that is associated with substantial disability and morbidity.  RA 
affects approximately 0.5-1.0% of the worldwide population, primarily women, with a 
peak incidence of onset between 40 and 60 years of age.
A substantial proportion of patients either fail to respond, or have inadequate response, to 
currently available RA therapies [Gaujoux-Viala, 2014; Nam, 2014].  Therefore, there is 
still a medical need for more effective treatments for RA with alternative mechanisms of 
action.
GM-CSF is a pro-inflammatory cytokine that regulates the functions of myeloid lineage 
cells that are considered to play key roles in the pathology of RA including macrophages 
and neutrophils [Avci, 2016; Hamilton, 2016; Wicks, 2016].  Increased levels of GM-
CSF are found in the synovial fluid from RA patients and its receptor is expressed in 
synovial tissue [Avci, 2016; Wicks, 2016].  Preclinical studies using various 
inflammatory arthritis models have shown that GM-CSF removal or neutralisation 
improved pain, function and joint histologic structure [Cook, 2001; Plater-Zyberk, 2007; 
Cook, 2013; Cook 2018a] and inhibited matrix metalloproteinase (MMP)-mediated 
cartilage degradation in experimental arthritis induced by joint instability [Cook, 2012].
GSK3196165 is a high-affinity recombinant human monoclonal antibody (mAb) that 
binds specifically to human GM-CSF and prevents its interaction with its cell surface 
receptor [Steidl, 2008].  Clinical studies in patients with RA have shown that 
GSK3196165 [Behrens, 2015] and mavrilimumab (an anti-GM-CSF receptor -subunit 
antibody) [Burmester, 2017; Burmester, 2018; Cook, 2018b] are able to reduce RA 
disease activity and pain.  A Phase IIb dose-ranging study of GSK3196165 with 
methotrexate (MTX) treatment, in patients with RA and an inadequate response to MTX, 
has also been completed.


2018N385816_02
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In the BAROQUE Phase IIb study (201755), treatment with GSK3196165 in 
combination with MTX demonstrated efficacy in the treatment of active RA.  At Week 
12 of the study, all doses above 22.5 mg resulted in a significant reduction in 
DAS28(CRP) (Disease Activity Score including 28 different joints) and significantly 
higher ACR20 (20% improvement in American College of Rheumatology criteria)
response rates in comparison to placebo.  Substantial improvements in tender and swollen 
joint counts, a large effect in CDAI (Clinical Disease Activity Index) and rapid 
improvements in pain were also identified. The overall adverse event (AE) and serious 
adverse event (SAE) profile was unremarkable.  The majority of AEs were of mild or 
moderate intensity and there were no deaths, malignancies or venous thromboembolisms 
during the trial.  Additional information is provided in the GSK3196165 Investigator’s 
Brochure (IB) [GSK Document Number 2014N190256_02].  It is therefore hypothesised 
that GSK3196165, in combination with csDMARD(s), may provide clinical benefit to 
patients with RA.
2.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK3196165 may be found in the IB.  The risks 
associated with the active comparator sarilumab can be found in the approved product 
label or local prescribing information.
The potential risk assessment and mitigation strategy for the administration of 
GSK3196165 in this protocol is outlined below.


2018N385816_02
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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 5.2):
Exclusion of participants with:

Active infections (including localised 
infections), or a history of recurrent infections 
or has required interventions to manage 
acute/chronic infections.

Symptomatic herpes zoster.

Hereditary or acquired immunodeficiency 
disorder, including immunoglobulin 
deficiency.

History of infected joint prosthesis, chronic leg 
ulcers, permanent in-dwelling catheters, 
chronic sinusitis, recurrent chest infections or 
recurrent urinary tract infections.

White blood cell (WBC) count ≤3.0 x 109/L

Evidence of untreated latent TB (unless 
willing to undergo TB therapy or have 
successfully undergone TB therapy).

Current or previous active TB regardless of 
treatment.

Previous close contact with a person with 
active TB and did not receive satisfactory 
anti-tuberculosis treatment.

Current acute or chronic Hepatitis B and/or 
Hepatitis C.

Known infection with human 
immunodeficiency virus (HIV) or positive test 


2018N385816_02
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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.
at screening.
Assessment of vaccination status (including against 
influenza and pneumococcus, according to local 
guidelines) prior to enrolment.
Monitoring:

Serious and opportunistic infections, TB and 
TB reactivation are categorised as 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).

TB evaluation at screening and monitoring for 
TB and TB re-activation throughout the study 
(Section 8.2.7.4).

Participants diagnosed with latent TB during 
screening will need to complete a course of at 
least 6 months of isoniazid (INH) therapy 
during the study including at least 4 weeks of 
therapy prior to randomisation (Section 
8.2.7.3).
Withdrawal Criteria:
Temporarily discontinue the study intervention for: 

Serious infections until the infection has 
resolved.

Suspected TB reactivation.

WBC count (<2 x 109/L)
Permanently discontinue the study intervention for:

New latent or active TB infection

HBV DNA level ≥200 IU/mL or HBV DNA 


2018N385816_02
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
detected at any level with recent increase in 
hepatic transaminases (see Figure 2 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 2 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 
pulmonary infection.
The exposure duration to GSK3196165 in this study is 
24 weeks.  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 
Eligibility Criteria (Section 5.2):
Exclusion of participants with:

Any baseline symptomatology that in the 
investigator’s opinion would confound the 
early detection of PAP based upon clinical 
features, such as persistent cough (CTC 
Grade ≥2) or dyspnoea (dyspnoea scale 
Grade ≥2).
Monitoring:

Diagnosis of PAP, 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.

Pulmonary Safety Guidance Document 
containing pulmonary assessment and 
management algorithms will be provided to 
the investigator.


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Potential Risk of Clinical Significance
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Mitigation Strategy
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.

A Pulmonary Adjudication Panel consisting of 
external experts is available for adjudication 
of cases. 
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 5.2):
Exclusion of participants with:

Significant allergies to humanised monoclonal 
antibodies.

Clinically significant multiple or severe drug 
allergies, or severe post-treatment 
hypersensitivity reactions

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)

Hypersensitivity to be managed appropriately 
per local guidelines/medical judgement

All participants will be monitored for 1 hour 


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Potential Risk of Clinical Significance
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Mitigation Strategy
after the first two exposures of GSK3196165 
(i.e. Weeks 0, 1, 12, and 13).
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 and reported as an AE.

Monitor for injection site reactions throughout 
study.

Recommended that injection sites are 
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 hematopoiesis [Stanley, 1994].
Clinical Data:
Neutropenia has been observed in completed studies 
of GSK3196165; however, no clinically significant 
cases have been observed.
Eligibility Criteria (Section 5.2):
Exclusion of participants with 

Significant neutropenia (absolute neutrophil 
count <2 x 109/L) at screening.
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) ≤1.0 x 109/L
Permanently discontinue study intervention for the 
following haematological abnormality (Section 7.1.2):


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Potential Risk of Clinical Significance
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Mitigation Strategy

ANC <0.5 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 
postpartum development of offspring in the mouse.
Non-clinical Data:
No GSK3196165-related effects on female or male 
fertility were noted in the SC 13-week repeat dose 
monkey study at doses up to 100 mg/kg/week (highest 
dose tested).  In addition, no maternal, embryofoetal 
or effects on fertility were noted in the reproductive 
toxicology studies using the surrogate rat anti-mouse 
GM-CSF monoclonal antibody, 22E9.
Clinical Data:
Two pregnancies have been reported during clinical 
studies with GSK3196165, 1 in a female partner of a 
HV participant and 1 in an MS participant. Both 
pregnancies were electively terminated. The effect of 
GSK3196165 on human pregnancy is unknown.
Eligibility Criteria (Section 5.1 and Section 5.2):

WOCBP and males to meet contraceptive 
requirements.

Negative serum pregnancy test at screening.
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 
Eligibility Criteria (Section 5.2):
Exclusion of participants with:

Breast cancer within the past 10 years or 
lymphoma, leukaemia, or any other 


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Potential Risk of Clinical Significance
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or clinical GSK3196165 program.
malignancy within the past 5 years except for 
cervical carcinoma in situ that has been 
resected with no evidence of recurrence or 
metastatic disease, or basal cell or squamous 
epithelial cancers of the skin that have been 
resected with no evidence of recurrence or 
metastatic disease for at least 3 years.

History of any lymphoproliferative disorder, 
such as Epstein Barr Virus (EBV) related 
lymphoproliferative disorder, or signs and 
symptoms suggestive of current lymphatic 
disease.
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].
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 anti-drug antibodies 
(ADAs) to GSK3196165 on 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 

Information will be collected on concomitant 
warfarin use (e.g. INR results and any 
information related to warfarin dose).

4β-hydroxycholesterol to cholesterol ratio 


2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
2 6
P ot e nti al Ri s k of Cli ni c al Si g nifi c a n c e
S u m m ar y of D at a/ R ati o n al e f or Ri s k
Miti g ati o n Str at e g y
t h e pl as m a co nc e ntr ati o ns of s p ecific C Y P s u bstr at e 
dr u gs.
Cyt oki n e m o d ul at ors m ay r ev ers e t h e a p p ar e nt 
“i n hi biti o n” eff ect of t h e cyt oki n es o n C Y P s u bstr at es, 
r es ulti n g i n a “ n or m alis ati o n” of C Y P activiti es. 
G S K 3 1 9 6 1 6 5 is a cyt oki n e m o d ul at or, s o it h as t h e 
p ot e nti al t o ‘ n or m alis e’ C Y P ex pr essi o n fr o m a 
s u p pr ess e d st at e i n p ati e nts wit h a pr o-i nfl a m m at ory 
dis e as e ( R A).
Cli ni c al D at a:
m e as ur e m e nts will b e c oll ect e d.

P artici p a nts of r e pr o d uctiv e p ot e nti al usi n g 
h or m o n al c o ntr ac e ptiv es, i ncl u di n g or al, 
i nj ecti o ns, i mpl a nts, a n d p atc h es ar e r e q uir e d 
t o us e a s ec o n d ary m et h o d of c o ntr ac e pti o n.

P artici p a nts r ec eivi n g a c o nc o mit a nt C Y P 4 5 0 
s u bstr at e wit h n arr o w t h er a p e utic i n d ex ( e. g. 
t h e o p hylli n e) s h o ul d b e m o nit or e d f or si g ns i n 
c h a n g es i n dr u g ex p os ur e.
St u d y Pr o c e d ur e s
Pl ac e b o
D u e t o et hic al c o nsi d er ati o ns, pl ac e b o c o ntr ol will o nly 
b e all o w e d u ntil W e ek 1 2, wit h all pl ac e b o p artici p a nts 
b ei n g s witc h e d t o o n e of t h e 3 activ e i nt erv e nti o n ar ms 
( G S K 3 1 9 6 1 6 5 9 0 m g, 1 5 0 m g or s aril u m a b 2 0 0 m g 
S C ev ery ot h er w e ek) at t h eir W e ek 1 2 visit. T his will 
e n a bl e t h e st u dy t o g e n er at e c o ntr oll e d d at a i n 
p artici p a nts i niti ally r a n d o mis e d t o pl ac e b o.

P artici p a nts r a n d o mis e d t o t h e pl ac e b o ar m 
will s witc h at W e ek 1 2 t o 1 of 3 activ e 
i nt erv e nti o n ar ms ( S ecti o n 4. 1 , S ecti o n 6. 3 ).

R a n d o mis ati o n r ati o of 6: 6: 6: 1: 1: 1 will 
mi ni miz e t h e n u m b er of p artici p a nts i n t h e 
pl ac e b o ar m ( S ecti o n 1. 1 , S ecti o n 4. 1 , 
S ecti o n 6. 1 , S ecti o n 6. 3 ).

B ack gr o u n d t h er a py wit h cs D M A R D(s) is 
r e q uir e d, h o w ev er t h e p artici p a nts ar e lik ely 
t o h av e f ail e d cs D M A R D t h er a py pri or t o t h eir 
pr evi o us b D M A R D or J A K tr e at m e nt.

C h a n g es i n b ack gr o u n d m e dic ati o n ar e n ot 
p er mitt e d u nl ess r e q uir e d f or s af ety a n d a ny 
C CI


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Potential Risk of Clinical Significance
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Mitigation Strategy
dose adjustments must be documented. 

Participants are permitted to receive a stable 
dose of ≤10 mg/day oral prednisolone or 
equivalent and/or a stable dose of NSAID(s).
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 400 mL of whole blood will 
be collected over the course of the 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 such as 
PD biomarkers.

Whole blood samples for genetic research 
will only be collected from those 
consenting to participate in this research.

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 performed at Screening 
and end of treatment phase (Week 24).

No requirement for screening X-ray if one 
was performed within the previous 12 weeks.

Exposure to radiation from X-rays is far less 
than the exposure to natural radiation.
Study Medical Devices
Handling and usage risks associated with the prefilled 
syringe 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 

Instructions For Use (IFU) on how to correctly 
handle and use the device is provided.


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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.
Other
Sarilumab (risks per label)
Label includes a warning for risk of serious infections, 
including opportunistic infections such as TB resulting 
in hospitalisation or death.  GI perforations have been 
reported in clinical studies, primarily as a complication 
of diverticulitis.
Decreases in absolute neutrophil count and platelets 
and increases in liver enzymes and lipid parameters 
(low-density lipoprotein [LDL] cholesterol, and high-
density lipoprotein [HDL] cholesterol and/or 
triglycerides) have been reported.
Malignancies were reported in clinical studies; 
however, the impact of sarilumab on development of 
malignancies is not known.
Hypersensitivity reactions have been reported with 
sarilumab.
See GSK3196165 above for serious infections, 
malignancies, laboratory changes and hypersensitivity.
Eligibility criteria (Section 5.2):
Exclusion of participants with:

Any condition or contraindication as 
addressed in the local product information or 
local clinical practice for sarilumab.

Evidence of untreated latent TB (unless 
willing to undergo TB therapy or have 
successfully undergone TB therapy).

Current or previous active TB regardless of 
treatment.

Previous close contact with a person with 
active TB and did not receive satisfactory 
anti-tuberculosis treatment.

Hepatic exclusion criteria included in protocol 
per sarilumab label.

History of gastrointestinal disease, including 
diverticulitis.
Monitoring:
As above for GSK3196165

Laboratory tests to assess potential changes 


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Potential Risk of Clinical Significance
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Mitigation Strategy
in lymphocytes, neutrophils, haemoglobin, 
liver enzymes and lipids. Participants should 
be managed according to clinical 
guidelines/standard of care for the 
management of hyperlipidaemia.

TB evaluation at screening and monitoring for 
TB and TB re-activation throughout the study 
(Section 8.2.7.4). 

Participants diagnosed with latent TB during 
screening will need to complete a course of at 
least 6 months of INH therapy during the 
study including at least 4 weeks of therapy 
prior to randomisation (Section 8.2.7.3).

Study specific Liver monitoring and 
interruption criteria included in protocol 
(Section 7.1.1).
Withdrawal:
As above for GSK3196165. 

Study specific liver stopping criteria (Section 
7.1.1)

Permanently discontinue for gastrointestinal 
perforation.


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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] were able 
to reduce RA disease activity and pain. In addition, results from BAROQUE showed that 
all doses of GSK3196165 above 22.5 mg in combination with 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.
Participants randomised to the active comparator arm, will receive the marketed drug 
sarilumab, which is approved in many countries for the treatment of adults with 
moderately to severely active RA.  Participants randomised to one of the placebo arms, 
will receive placebo intervention only for 12 weeks, and will switch at Week 12 to 
receiving either GSK3196165 or active comparator for the remainder of the study.
Furthermore, each participant will 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.
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, pulmonary alveolar proteinosis, 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 10.1.5).  Key safety data that meets 
predefined thresholds will be reviewed by the IDMC allowing ongoing assessment of the 
overall benefit:risk throughout the study.  Full details of safety thresholds 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 
the anticipated benefits that may be afforded to participants with RA.


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3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To compare the efficacy of GSK3196165 at 
doses of 90 mg and 150 mg weekly versus 
placebo for the treatment of participants 
with moderately to severely active RA who 
are on a stable background of 
csDMARD(s) and who have had an 
inadequate response to biological 
DMARDs and/or JAK inhibitors.

Proportion of participants achieving ACR20 
at Week 12.
Secondary
To compare:

Efficacy of GSK3196165 at doses of 90 mg 
and 150 mg weekly versus sarilumab, for 
the treatment of participants with 
moderately to severely active RA who are 
on a stable background of csDMARD(s) 
and who have had an inadequate response 
to biological DMARDs and/or JAK 
inhibitors.
Major Secondary Efficacy Endpoints
Change from baseline at Week 12 (versus 
placebo) in:

HAQ-DI.
Change from baseline at Week 12 (versus 
sarilumab) in: 

CDAI total score.

Arthritis pain VAS.
Other Secondary Efficacy Endpoints
Proportion of participants at Week 12 (vs. 
placebo and vs. sarilumab) and Week 24 (vs. 
sarilumab) achieving:

CDAI total score ≤10 (CDAI LDA).

CDAI total score ≤2.8 (CDAI Remission).

ACR20/50/70.

DAS28-CRP ≤3.2 and DAS28(ESR) ≤3.2
(DAS28 LDA).

DAS28(CRP) <2.6 and DAS28(ESR) <2.6 
(DAS28 Remission).

A good/moderate EULAR response.

ACR/EULAR Remission.
Change from baseline at Week 12 (vs. placebo 
and vs. sarilumab) and Week 24 (vs. 
sarilumab) in:

CDAI total score.

DAS28(CRP)/DAS28(ESR).

The effect of GSK3196165 on Patient 
Reported Outcomes (PROs) versus 
placebo and the active comparator 
sarilumab.
Change from baseline at Week 12 (vs. placebo 
and vs. sarilumab) and Week 24 (vs. 
sarilumab) in:

HAQ-DI.


2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
3 2
O bj e cti v e s
E n d p oi nt s

Art hritis p ai n V A S.

S F -3 6 p hysic al a n d m e nt al c o m p o n e nt 
sc or es a n d d o m ai n sc or es.

F A CI T -F ati g u e.

S af ety a n d t ol er a bility of G S K 3 1 9 6 1 6 5 
v ers us pl ac e b o a n d t h e activ e c o m p ar at or 
s aril u m a b

I nci d e nc e of A Es, S A Es a n d A E SIs.

C h a n g e fr o m b as eli n e i n k ey l a b 
p ar a m et ers at W e eks 1 2 a n d 2 4.

Pr o p orti o n of p artici p a nts wit h N CI -C T C A E 
≥Gr a d e 3 [ N CI , 2 0 1 7] h a e m at ol o gy/cli nic al 
c h e mistry a b n or m aliti es.
T o d et er mi n e t h e i m m u n o g e nic p ot e nti al of 
G S K 3 1 9 6 1 6 5.
S af et y Bi o m ar k er E n d p oi nt s

G M -C S F a ut o a nti b o dy c o nc e ntr ati o ns.

I m m u n o g e nicity.
E x pl or at or y
T o d et er mi n e:

P h ar m ac oki n etics ( P K)

Ex p os ur e -r es p o ns e

P h ar m ac o dy n a mic ( P D) bi o m ark ers
P K/ P D E n d p oi nt s

G S K 3 1 9 6 1 6 5 a p p ar e nt cl e ar a nc e ( C L/ F) 
a n d ot h er P K p ar a m et ers as a p pr o pri at e.

Ex p os ur e -r es p o ns e r el ati o ns hi p f or k ey 
effic acy a n d s af ety e n d p oi nts.

Bi o m ark ers of t ar g et e n g a g e m e nt, 
d o w nstr e a m si g n alli n g of G M- C S F a n d 
E C M d e gr a d ati o n.

.
cs D M A R D = c o nv e nti o n al sy nt h etic dis e as e m o difyi n g a ntir h e u m atic dr u g; A C R 2 0/ 5 0/ 7 0 = 2 0%/50 %/ 7 0 % 
i m pr ov e m e nt i n A m eric a n C oll e g e of R h e u m at ol o gy crit eri a; C D AI = cli nic al dis e as e activity i n d ex; H A Q-DI = h e alt h 
ass ess m e nt q u esti o n n air e dis a bility i n d ex; V A S = vis u al a n al o g u e s c al e; L D A = l o w dis e as e activity; D A S 2 8 = 
dis e as e activity sc or e i ncl u di n g 2 8 diff er e nt j oi nts; C R P = C -r e activ e pr ot ei n; E U L A R = E ur o p e a n l e a g u e a g ai nst 
r h e u m atis m
 E S R = eryt hr ocyt e 
C CI
C CI
C CI
C CI


2018N385816_02
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sedimentation rate; AEs = adverse events; SAEs = serious adverse events; AESIs = adverse events of special 
interest; NCI-CTCAE = National Cancer Institute-common terminology criteria for adverse events; GM-CSF = 
granulocyte-macrophage colony stimulating factor; ECM = extracellular matrix; RNA = ribonucleic acid; SF-36 = short 
form-36; FACIT = functional assessment of chronic illness therapy; RA = rheumatoid arthritis
4.
STUDY DESIGN
4.1.
Overall Design

This is a Phase 3, randomised, multicentre, double-blind, parallel group, placebo 
and active comparator (sarilumab) controlled study, with primary objective to 
assess the efficacy and safety of GSK3196165 in combination with csDMARD(s) 
in participants with moderately to severely active RA who have an inadequate 
response to bDMARDs and/or JAK inhibitors.

This is a 24-week study with primary endpoint at Week 12 to coincide with the 
duration of placebo intervention.

Upon successful screening, participants will be randomised to one of six 
intervention arms, in a ratio of 6:6:6:1:1:1 to GSK3196165 150 mg SC weekly, 
GSK3196165 90 mg SC weekly, sarilumab 200 mg SC every other week or 
placebo (three arms) respectively, all in combination with background 
csDMARD(s).  At Week 12, participants in the three placebo arms will switch 
from placebo to active intervention (either GSK3196165 150 mg SC weekly, 
GSK3196165 90 mg SC weekly, or sarilumab 200 mg SC every other week).  
Randomisation will be stratified by previously failed medication (1 bDMARD, >1 
bDMARD or ≥1 JAK inhibitor [regardless of whether bDMARD received in 
past]).

GSK3196165 and placebo will be administered by weekly subcutaneous (SC) 
injection; participants randomised to sarilumab will receive SC injections of 
sarilumab every other week, plus a placebo injection in the intervening weeks to 
maintain the blind.  See Section 6.1.

Due to ethical considerations, placebo control will only be allowed until Week 12.  
At their Week 12 visit, participants in the three placebo arms will switch to 
receiving the active intervention specified for that arm.  This will enable placebo 
participants to receive active intervention from Week 12 onwards and for the 
study to accrue additional randomised safety data. The intervention switch at 
Week 12 will be managed automatically by the Interactive Response Technology 
(IRT) in order to maintain the blind.

Participants who successfully complete the 24-week treatment period may be 
eligible to transition into long term extension study 209564.  Any participant who 
does not transition into study 209564 will undergo a safety follow-up visit at 
Week 34 (corresponding to 12 weeks after the last potential dose of sarilumab, at 
Week 22).


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4.2.
Scientific Rationale for Study Design
This study is a placebo-controlled, sarilumab-controlled, parallel-dose study of SC doses 
of GSK3196165 added on to stable dose(s) of csDMARD(s).  Participants will be 
allowed to receive a stable dose of ≤10 mg/day oral prednisolone or equivalent and/or a 
stable dose of NSAID(s).
The double-blind, placebo-controlled, randomised clinical study is considered the gold 
standard for the safety and efficacy assessment of a new therapy both by clinicians and 
regulatory authorities.  Control with a comparator, sarilumab, will also comply with 
recent guidelines from regulatory authorities and help further establish the safety and 
efficacy in comparison with an established bDMARD.  In the proposed study, 
participants will continue to receive stable dose(s) of csDMARD(s).  All placebo 
participants will switch to active intervention (either GSK3196165 150 mg or 90 mg or 
sarilumab 200 mg) at their Week 12 visit.  Participants are not allowed to receive any 
additional bDMARDs other than GSK3196165 or sarilumab, or any targeted synthetic 
DMARD (tsDMARD) (including JAK inhibitors) during the study, to mitigate the 
potential increased safety risks of administering a combination of bDMARDs or a 
combination of a bDMARD and a tsDMARD.
Efficacy and safety of GSK3196165 will be compared with placebo (until Week 12) and 
an established active comparator (until Week 24), sarilumab which is approved in many 
countries for the treatment of RA in patients inadequately controlled with DMARDs.
ACR20 is considered an established endpoint which continues to be an acceptable 
measure to demonstrate reduction in disease activity as recommended in the US 
regulatory guidelines.
Health assessment Questionnaire Disability Index (HAQ-DI) is considered an established 
endpoint which continues to be an acceptable measure to demonstrate improvement in 
physical function as recommended in the US and EU regulatory guidelines.
4.3.
Justification for Dose
GSK3196165
The GSK3196165 doses for this study have been selected based on pharmacokinetics 
(PK), efficacy, safety data and exposure-response relationship for efficacy endpoints 
from the phase 2b dose finding study, BAROQUE (201755).
The BAROQUE study showed an acceptable safety profile and clinically meaningful 
efficacy at the highest dose of 180 mg SC weekly for 5 injections, then every other week 
until Week 50.  The efficacy however started to plateau after Week 6 with no further 
improvement post Week 12.  This effect is likely due to lower trough concentrations 
achieved in BAROQUE than predicted from PK data from historic studies (MSC-1000, 
MSC1001 and MOR103C104).  The reason for the lower than expected exposure to 
GSK3196165 in RA participants in BAROQUE is not fully understood.  The PK of 
GSK3196165 was linear over the tested dose range (IV; 0.025 – 3 mg/kg and SC; 22.5 –
180 mg), which is consistent with the PK profile of a mAb against soluble cytokine [GSK 


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Document Number 2017N353526_00].  However, GSK3196165 clearance in healthy 
volunteers (HV) was 3 times higher (0.93, confidence interval [CI]: 0.83 – 1.04 L/day) 
than generally reported for a mAb (0.3 L/day) and the half-life (t1/2) of 12 days was 
shorter than a typical mAb.  In addition, the SC bioavailability (0.34, CI: 0.26 – 0.44) was 
lower than expected for a mAb.  In RA participants, the apparent clearance (CL/F) after 
SC administration of GSK3196165 was 2.4 times higher than HV and the estimated t1/2 
was 10 days.
In this study, the dosing frequency will be increased to every week to overcome the 
higher CL/F and lower t1/2 of 10 days.  The GM-CSF-GSK3196165 complex data from 
BAROQUE also supports weekly administration as an optimal dosing regimen for 
GSK3196165.  This dosing frequency with a 90 and 150 mg dose is predicted to result in 
steady-state pre-dose concentrations of 1500 and 2500 ng/mL, respectively.  Based on a 
longitudinal exposure-response model of DAS28(CRP), a dose of 90 mg SC every week 
is predicted to provide clinically meaningful efficacy similar to the 180 mg regimen in 
the BAROQUE study and in line with other RA targeted DMARDs, whilst 150 mg SC 
every week dose is predicted to provide greater efficacy to that achieved in BAROQUE.
Figure 1
Comparison of PK/PD Model Predicted Median Change from 
Baseline in DAS28(CRP) given 3 Dose Regimens of GSK3196165: 
180 mg Weekly for 5 Weeks Followed by Every Other Week 
(BAROQUE Regimen), 90 mg Weekly and 150 mg Weekly
Based on dose-response relationship at Week 4 (matching the weekly dose regimen to be 
used in this study) the 90 mg and 150 mg doses translate into a ED70 and ED80 
respectively.  Logistic regression analysis of ACR20 and ACR50 response at Week 12, 
also indicated higher trough concentrations are associated with response rate.  The 
predicted ACR20 response rate for the 90 mg and 150 mg weekly doses are 63% and 
69%, respectively.


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Furthermore, the safety profile of GSK3196165 in BAROQUE was acceptable at all 
doses with no apparent dose response in the incidence of AEs or SAEs.  More details are 
provided in the GSK3196165 IB.
Given the GSK3196165 half-life of 10 days, steady-state is expected to be reached after 5 
weekly doses (as in BAROQUE), therefore GSK3196165 concentrations with the 150 mg 
every week dosing regimen should not exceed concentrations studied in BAROQUE.  
The highest dose of 150 mg weekly provides a 3 to 5-fold safety margin to the 5 mg/kg 
dose in the 26-week monkey toxicology study where no foamy alveolar macrophages 
were observed (NOEL).
In summary, PK, exposure-response, dose-response and safety data from the BAROQUE
study, supported by modelling strongly support the selection of the 90 mg and 150 mg 
weekly doses, where 90 mg is expected to provide clinically-meaningful efficacy at 
levels similar to BAROQUE and existing targeted DMARDs, and 150 mg is predicted to 
provide greater clinical benefit.  Both doses are also covered by an appropriate safety 
margin.
Sarilumab
The sarilumab dose has been selected based on the recommended approved dose (200 mg 
every other week) in the countries where it is commercially available.
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.  This will be the Week 24 visit for those 
participants who transition into the long-term follow-up study or the safety follow-up 
visit for all other participants.
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.
Investigators should review and update the vaccination status of potential participants as 
per local guidelines for adult vaccination prior to entering them into the study (refer to 
EULAR recommendations where no local guidelines are available [Furer, 2019]).  All 
participants who have not received the herpes zoster vaccine at study entry will be
recommended to complete vaccination >30 days prior to randomisation.  All participants 
may receive inactivated flu vaccines during the study at the discretion of the investigator.
Note that “Inadequate response” to prior treatment in this population, is defined as: In the 
opinion of the investigator, after at least 3 months of treatment the participant 
experienced insufficient efficacy or loss of response (e.g. no EULAR response; failure to 
achieve ACR20; any other clinical criteria recommended per local guidelines that would 


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trigger a change of treatment), or the participant discontinued treatment due to 
intolerability or toxicity irrespective of treatment duration.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
AGE
1. Age ≥18 years at the time of signing informed consent.
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS
2. Meets ACR/EULAR 2010 RA Classification Criteria (see study reference manual 
[SRM]) with a duration of RA disease of ≥6 months at time of screening and 
participant not diagnosed before 16 years of age.
3. Must have active disease at both screening and baseline, as defined by having both:
a.
≥6/68 tender/painful joints (TJC), and
b. ≥6/66 swollen joints (SJC).
If surgical treatment of a joint has been performed, that joint cannot be 
counted in the TJC or SJC for enrolment purposes
4. Must have a high sensitivity C-reactive protein (hsCRP) measurement ≥3 mg/L at 
screening.
5. Must meet Class I, II or III of the ACR 1991 Revised Criteria for Global Functional 
Status in RA (see SRM).
6. Must have inadequate response despite currently taking at least one and at most two 
concomitant csDMARDs for at least 12 weeks prior to Day 1, from the following:
a.
Methotrexate (MTX): weekly 15-25 mg oral or injected, for at least 12 weeks 
at the maximum tolerated dose prior to Day 1, with no change in route of 
administration in this time.  A lower dose of ≥7.5 mg/week is acceptable if 
reduced for reasons of intolerance to MTX, e.g. nausea/vomiting, hepatic or 
hematologic toxicity, or per local requirement (there must be clear 
documentation in the medical record).  Exception: A lower dose of 6 mg/week 
is allowed if the minimum locally approved or recommended dose is lower 
than 7.5 mg/week.
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.
Bucillamine up to 100 mg/day (or up to 300 mg/day if permitted per local 
requirements).


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f.
Iguratimod up to 50 mg/day.
g. Tacrolimus up to 3 mg/day.
NOTE: The dose of csDMARD(s) must be stable and tolerated for at least 8 
weeks prior to Day 1 and should remain stable throughout the study from 
screening to end of treatment period, except adjustment for safety reasons.  See 
Section 6.5.
7. Must have inadequate response to at least one biologic DMARD at an approved dose 
and/or at least one JAK inhibitor (JAKi) at an approved dose.  In both cases this may 
be with or without combination with a csDMARD.  Prior bDMARD or JAKi therapy 
must be discontinued before randomisation per the guidance in Section 6.5.2
Prohibited Therapies.
WEIGHT
8. Body weight 40 kg
SEX
9. Male or female participants are eligible to participate so 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
10. 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
11. For participants on MTX: must be willing to continue or initiate treatment at 
screening, with oral folic acid (at least 5 mg/week) or equivalent and be treated during 
the entire study (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. Active infections (including localised infections), or history of recurrent infections 
(excluding recurrent fungal infections of the nail bed), or has required management of 
acute or chronic infections, as follows:

Currently taking any suppressive anti-infective therapy for a chronic infection 
(such as pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster 


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and atypical mycobacteria) OR

Hospitalisation for treatment of infection within 26 weeks of Day 1 OR

Use of parenteral (IV) or intramuscular (IM) antimicrobials (antibacterials, 
antivirals, antifungals, or antiparasitic agents) within 26 weeks of Day 1 or 
oral antimicrobials (apart from INH use for latent TB treatment) within 
14 days of Day 1.
2. Symptomatic herpes zoster within 3 months prior to screening
3. Hereditary or acquired immunodeficiency disorder, including immunoglobulin 
deficiency.
4. Known infection with human immunodeficiency virus (HIV) or positive test at 
screening.
5. History of infected joint prosthesis at any time, with the prosthesis still in situ.  
History of chronic leg ulcers, permanent in-dwelling catheters, chronic sinusitis, 
recurrent chest infections or recurrent urinary tract infections.
6. Any baseline symptomatology that in the investigator’s opinion would confound the 
early detection of pulmonary alveolar proteinosis based upon clinical features, such as 
persistent cough (CTC grade ≥2) or persistent dyspnoea (dyspnoea scale Grade ≥2).
7. Current unstable liver or biliary disease per investigator assessment defined by the 
presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal 
or gastric varices, persistent jaundice, or cirrhosis.
8. Current acute or chronic Hepatitis B and/or Hepatitis C.
9. Current or history of renal disease or estimated glomerular filtration rate (eGFR) by 
Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) 
calculation <30 mL/min/1.73m2 at screening.
10. Breast cancer within the past 10 years or lymphoma, leukaemia, or any other 
malignancy within the past 5 years except for cervical carcinoma in situ that has been 
resected with no evidence of recurrence or metastatic disease, or basal cell or 
squamous epithelial cancers of the skin that have been resected with no evidence of 
recurrence or metastatic disease for at least 3 years.
11. History of any lymphoproliferative disorder, such as Epstein Barr Virus (EBV) 
related lymphoproliferative disorder, or signs and symptoms suggestive of current 
lymphatic disease.
12. Have a history or presence of significant other concomitant illness according to the 
Investigator judgment such as, but not limited to cardiovascular (including Stage III 
or IV cardiac failure according to New York Heart Association classification, 
myocardial infarction within 3 months, unstable angina pectoris, uncontrolled 
hypertension, uncontrolled hypercholesterolemia), neurological, endocrinological, 
gastrointestinal (including diverticulitis), hepatic disease, metabolic, lymphatic 
disease, or previous renal transplant that would adversely affect the participant’s 
participation in this study.
13. Any condition or contraindication as addressed in the local product information or 


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local clinical practice for sarilumab that would preclude the participant from 
participating in this protocol.
14. History of other inflammatory rheumatologic or systemic autoimmune disorder, other 
than Sjögren’s syndrome secondary to RA, that may confound the evaluation of the 
effect of the investigational product such as mixed connective tissue disease, psoriatic 
arthritis, juvenile chronic arthritis, spondyloarthritis, Felty’s Syndrome, systemic 
lupus erythematosus, scleroderma, Crohn’s disease, ulcerative colitis, or vasculitis. 
15. Presence of fibromyalgia that, in the investigator’s opinion, would make it difficult to 
appropriately assess RA activity for the purposes of this study.
16. Undergone any major surgery within 8 weeks prior to study entry or will require 
major surgery during the study that, in the opinion of the investigator in consultation 
with the medical monitor, would pose an unacceptable risk to the participant.
17. Current or previous active Mycobacterium tuberculosis (TB) regardless of treatment.
18. Evidence of latent TB (as documented by a positive QuantiFERON-TB Gold plus test 
or T-SPOT.TB test at screening, no findings on medical history or clinical 
examination consistent with active TB, and a normal chest radiograph) except for 
participants that either:

Are willing to complete at least 4 weeks of anti-TB therapy as per WHO or 
national guidelines prior to randomisation and agree to complete the 
remainder of treatment while in the study OR

Are documented as having evidence of satisfactory anti-TB treatment as per 
WHO or national guidelines within the last 5 years following review by a 
physician specialising in TB.
19. Previous close contact with a person with active TB and did not receive satisfactory 
anti-tuberculosis treatment as per WHO or national guidelines.
20. Significant allergies to humanised monoclonal antibodies or known hypersensitivity 
to sarilumab or any of its inactive ingredients.
21. Clinically significant multiple or severe drug allergies or severe post-treatment 
hypersensitivity reactions (including, but not limited to, erythema multiforme major, 
linear immunoglobulin A [IgA] dermatosis, toxic epidermal necrolysis, and 
exfoliative dermatitis).
PRIOR/CONCOMITANT THERAPY 
22. Any prior treatment antagonising GM-CSF or its receptor.
23. Any prior treatment with Anti-interleukin 6 (IL-6) or IL-6 receptor (IL-6R) 
antagonists (including but not limited to sarilumab and tocilizumab).
24. Participants who are expected to be non-compliant with restrictions on medications 
and vaccinations prior to the study, during the study or during the 12-week safety 
follow-up of the study.  See Table 3 in Section 6.5.2 for details of prohibited 
medications/treatments and Table 2 in Section 6.5.1 for details of permitted 
medications/treatments.


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PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
25. Current enrolment or past participation within the last 42 days before randomisation 
in any other clinical study involving an investigational study treatment or any other 
type of medical research.
DIAGNOSTIC ASSESSMENTS
26. Alanine transferase (ALT) or aspartate aminotransferase (AST) >1.5 x upper limit of 
normal (ULN).
27. Bilirubin >1.5 x ULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
28. Has a positive test for hepatitis B virus (HBV) defined as either:

positive for hepatitis B surface antigen (HBsAg) or

positive for hepatitis B core antibody (HBcAb) and positive for HBV 
deoxyribonucleic acid (DNA).
29. Positive test for hepatitis C antibody at screening. Participants with positive Hepatitis 
C antibody due to prior resolved disease can be enrolled, only if a confirmatory 
negative hepatitis C RNA test is obtained.
30. Haemoglobin ≤9 g/dL; white blood cell (WBC) count ≤3.0 x 109/L; platelet count 
<150 x 109/L; absolute neutrophil count (ANC) <2 x 109/L; lymphocyte count ≤0.75 x 
109/L at screening.
31. Abnormal chest radiograph within 12 weeks of screening judged by the investigator 
as clinically-significant.
OTHER EXCLUSIONS
32. Pregnant or lactating, or women planning to become pregnant or initiating 
breastfeeding.
33. Current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or 
dependence within a year prior to Day 1.
34. 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 Considerations
There are no lifestyle restrictions in this study.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomised. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 


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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 (screen failure) 
may be rescreened once with the agreement of the Medical Monitor.  The entire 
screening process must be repeated (except for chest X-ray if performed within 12 weeks 
of the re-screening period).
A QuantiFERON-TB Gold plus test may be repeated once during screening if the initial 
result is indeterminate, alternatively a T-SPOT.TB test may be used following an 
indeterminate result.  This is not considered a rescreening.  If the repeat test is positive or 
indeterminate, then the participant will be considered to have active or latent TB.
For those participants requiring Isoniazid (INH) therapy for latent TB, LFTs must be 
assessed following 3 weeks of INH treatment in screening. Participants will fail screening 
if ALT >1.5 x ULN is identified; these participants may be re-screened if ALT elevation 
resolves to ALT <x 1.5 ULN during ongoing INH therapy following discussion with the 
medical monitor.
If a participant fails any of the laboratory exclusion criteria, the test may be repeated once 
within the screening period.  If the participant fails the laboratory criteria for a second 
time, they will be considered a screen failure.
Retesting within screening window of any blood sample withdrawn due to sample 
handling problems, breakage or sample integrity is not considered a rescreening.
Further details regarding the procedure for re-screening can be found in the SRM.
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:

GSK3196165 and placebo will be administered by weekly subcutaneous (SC) 
injection; participants randomised to sarilumab will receive SC injections of 
sarilumab every other week, plus a placebo injection in the intervening weeks to 
maintain the blind.

Study SC injection should be administered weekly, on the same day each week.  
The weekly SC injections of study intervention should rotate between the thighs 
and abdomen.


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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.

Participants must receive their SC injection at the site and be monitored for 
general safety for 1 hour after the injection at Weeks 0, 1, 12, and 13; the safety 
monitoring at Weeks 12 and 13 is due to the switch of the placebo participants to 
active intervention at the Week 12 visit.  Safety monitoring will include 
monitoring for systemic hypersensitivity and local injection site reactions.

Until such time as GSK3196165 becomes available in a pre-filled syringe, every 
SC injection must be delivered by an unblinded administrator and the syringe 
must be shielded from the participant at all times, to avoid unblinding.

If/when GSK3196165 becomes available in a pre-filled syringe, the SC injection 
must still be delivered by an unblinded administrator at weeks corresponding to 
sarilumab dosing (i.e. Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22), to avoid 
unblinding.  Self-administration of pre-filled syringe may be permitted on 
intervening weeks (i.e. Weeks 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23).  Prior to 
permitting home dosing, the investigator must first ensure the participant (or 
caregiver) is able to correctly administer the injection from PFS.  Any participant 
who doses at home must be instructed to contact the site immediately if they 
experience any symptoms following dosing.

Where possible, assessment visits should be scheduled to coincide with the 
weekly administration of study SC injection, the injection will then be 
performed at the site, after completion of PK sampling (see Section 1.3).

Participants who are initially dosed with SC injections of study intervention 
supplied from vials, should continue to be dosed from the vials until at least Week 
12 to coincide with the timing of the primary endpoint unless this is impractical 
due to supply issues; these participants may be switched to SC injections from the 
pre-filled syringes after Week 12, if sufficient supply is available.

Participants who are initially dosed with SC injections of study intervention from 
the pre-filled syringes should continue to be dosed in this manner for the duration 
of the study providing sufficient supplies are available.
In parallel to receiving study intervention, all participants will receive a stable dose of 
background csDMARD(s) (refer to Section 6.5).  Any participant whose background 
DMARD is MTX must also receive ≥5 mg/week folic (or folinic) acid orally (dosing 
regimen at the discretion of the investigator). Dose modifications to background
DMARDs are discussed in Section 6.6.2.
All local standard-of-care practices for the administration of csDMARD(s), including 
laboratory testing, follow-up care, contraindications, and (for MTX) folic acid 
administration, should be performed throughout the study.


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Table 1
Overview of Study Intervention
ARM Name
GSK3196165
90 mg
GSK3196165
150 mg
Placebo*
Sarilumab
Intervention 
Name
GSK3196165 
(Approved Name 
not yet assigned)
GSK3196165 
(Approved Name 
not yet assigned)
Placebo to 
GSK3196165 and 
Sarilumab
Kevzara
Type 
Biologic
Biologic
Placebo to 
Biologic
Biologic
Dose 
Formulation
Solution in vial 
(1.2 mL) or PFS 
(1.0 mL)
Solution in vial 
(1.2 mL) or PFS 
(1.0 mL)
Sterile 0.9% (w/v) 
sodium chloride 
solution or PFS 
(1.0 mL)
Solution in PFS 
(1.14 mL)
Unit Dose 
Strength(s)
180 mg/vial
(180 mg/1.2 mL)
PFS 90 mg/mL
180 mg/vial
(180 mg/1.2 mL)
PFS 150 mg/mL
Not applicable
200 mg/1.14 mL 
solution in a 
single-dose PFS
Dosage 
Level(s)
90 mg once-
weekly
150 mg once 
weekly
Weekly
(every other week 
on Sarilumab 
arm)
200 mg every 
other week
Route of 
Administration
SC injection
SC injection
SC injection
SC injection
IMP and NIMP
IMP
IMP
IMP
IMP
Sourcing
Provided centrally 
by the Sponsor
Provided centrally 
by the Sponsor
Locally approved 
sodium chloride 
solution may be 
sourced at site or 
provided centrally. 
PFS provided 
centrally by the 
Sponsor
Provided 
centrally by the 
Sponsor
Dosing 
instructions
Vials: withdraw 
0.6 mL into a 
small syringe and 
dose immediately; 
discard remaining 
material.
Vials: withdraw 
1.0 mL into a 
small syringe and 
dose immediately; 
discard remaining 
material.
Withdraw 1.0 mL 
into a small 
syringe and dose 
immediately; 
discard remaining 
material.
PFS - inject all


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ARM Name
GSK3196165
90 mg
GSK3196165
150 mg
Placebo*
Sarilumab
PFS: Inject all
PFS: Inject all
PFS: Inject all
Special 
instructions
Avoid excessive 
shaking of 
GSK3196165 
vials as this could 
lead to product 
precipitation. Do 
not administer 
with other drugs 
concomitantly in 
the same syringe
Avoid excessive 
shaking of 
GSK3196165 
vials as this could 
lead to product 
precipitation. Do 
not administer 
with other drugs 
concomitantly in 
the same syringe
None
None
Packaging and 
Labelling
Study Intervention 
will be provided in 
a single use vial 
or PFS in an 
individual carton 
and labelled as 
required per 
country 
requirement
Study Intervention 
will be provided in 
a single use vial 
or PFS in an 
individual carton 
and labelled as 
required per 
country 
requirement
Commercial 
saline may be 
sourced at site or 
provided centrally 
/ PFS will be 
provided for 
single-use in an 
individual carton 
and labelled as 
required per 
country 
requirement
Study 
Intervention will 
be provided in a 
single use PFS 
in an individual 
carton and 
labelled as 
required per 
country 
requirement
Current/Former 
Name(s) or 
Alias(es)
GSK3196165, 
otilimab, anti-
human GM-CSF 
monoclonal Ab, 
MOR103, 
MOR04357
GSK3196165, 
otilimab, anti-
human GM-CSF 
monoclonal Ab, 
MOR103, 
MOR04357
Not applicable
Kevzara, 
sarilumab, 
SAR153191 and 
REGN88
* Placebo consists of 3 arms to Week 12, after which participants will be switched to 1 of the 3 active intervention arms.
PFS = prefilled syringe; GM-CSF = granulocyte macrophage colony stimulating factor; Ab = antibody.
GSK3196165 in vials and placebo will be administered SC, using syringes and needles commonly used for SC 
administration (e.g. 1 mL syringe, with 25 or 27 gauge needle); compatibility with commonly used syringes and needles 
has been demonstrated.


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6.1.1.
Medical Devices

The medical devices provided for use in this study are injection devices: 
o
a prefilled syringe (PFS) containing 150 mg or 90 mg otilimab solution, or 
placebo, assembled into a safety syringe device (SSD)
o
a prefilled syringe containing 200 mg sarilumab solution.  
The otilimab PFS/SSD 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 otilimab and placebo PFS/SSD, including glass 
barrel with prestaked needle, flange, plunger and needle guard are sourced for GSK 
by a third-party provider.  The otilimab and placebo PFS is filled and assembled 
with the safety syringe components by GSK (or its affiliates). 

The sarilumab PFS is marketed, manufactured and assembled by Sanofi and 
Regeneron Pharmaceuticals, Inc. (or its affiliates).

The instructions for use (IFU) for these injection devices are provided in the study 
reference manual (SRM).  

The otilimab and placebo PFS 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 or unblind 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 may supply or 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.


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
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.

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 Minimise Bias: Randomisation and Blinding
All participants will be centrally randomised using Interactive Response Technology 
(IRT). 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). 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, 
as applicable.
Participants will be randomised in a ratio of 6:6:6:1:1:1 to receive study intervention 
(Section 1.2 and Section 6.1).  Investigators will remain blinded to each participant’s 
assigned study intervention throughout the course of the study.  To maintain this blind, all 
participants will receive once-weekly SC injections for the duration of the treatment 
period. Until such time as a matched placebo becomes available for GSK3196165, every 
SC injection must be delivered by an unblinded administrator and the syringe must be 
shielded from the participant to avoid unblinding.
The sarilumab dosing regimen is every other week, therefore participants randomised to 
sarilumab will receive SC injections of sarilumab every other week, plus a placebo 
injection in the intervening weeks to maintain the blind.  This will be managed by the 
IRT.  In addition, regardless of whether PFS are available, on weeks corresponding to 
sarilumab dosing (weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22), all participants must 
receive their study SC injection from an unblinded administrator, with the injection 
syringe shielded from the participant, to avoid unblinding.
An unblinded pharmacist (or unblinded designee) will be responsible for the dispensation 
of the study intervention and will endeavour to ensure that there are no differences in 
time taken to dispense between the different intervention arms.  While the study drug is 


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supplied in vials, care will be taken to ensure that participants are not able to see the 
injection volume, syringe size or colour of liquid. The syringe should be prepared away 
from view of the participant, and appropriate shielding or masking of the syringe applied 
prior to administration.
In addition, in order to maintain the integrity of the blind, investigators and site staff will 
not have access to ongoing post-randomisation hsCRP/ESR analyses and should refrain 
from performing either routine ESR or CRP assessments unless clinically indicated for 
AE assessment.  Furthermore, the results of the PK analyses of GSK3196165 will not be 
provided to the sites.
In order to reduce bias, an independent joint assessor will perform all joint assessments 
(Section 8.1.1).
Unblinded monitors and in the event of a Quality Assurance audit, the auditor(s) will be 
allowed access to unblinded study intervention records at the site(s) to verify that 
randomisation/dispensing has been done accurately.
A participant may continue in the study if that participant’s intervention assignment is 
unblinded.
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 or matching placebo will be administered by SC injection at the times 
indicated in the SoA (Section 1.3).  Participants should receive all doses per schedule, 
however exceptional circumstances may lead to a dose being missed.  If a dose is missed, 
the dose may be rescheduled to a new date/time providing the new date is within the SoA 
window for the missed dose.  If the dose cannot be rescheduled within the visit window, 
the dose must not be given outside the window and must be marked as missed in the IRT.  
After a missed dosed, further dosing may continue per SoA with the following 
requirements:

Except for doses temporarily interrupted for safety reasons, the investigator must 
meet to discuss compliance with the study intervention with any participant who 
appears to be non-compliant.

If the participant continues to be non-compliant and missed further doses, the 
investigator may decide to permanently discontinue the participant from study 
intervention and initiate standard of care.  The participant will be encouraged to 
continue to attend study visits until week 24.
A record of the number of study intervention injections dispensed to and taken by each 
participant must be maintained by the site staff and reconciled with study intervention 


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and compliance records.  Intervention start and stop dates, including dates for 
intervention delays will also be recorded in the CRF. 
6.5.
Prior and Concomitant Therapies
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), 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.
6.5.1.
Permitted Therapies
Medications or treatments deemed necessary by the investigator to provide supportive 
care will be permitted during the study except when administration would occur during a 
time of restricted use, as in Table 2, or if the medication is specifically excluded, as in 
Section 6.5.2.  The permitted dose is the usual marketed dose approved in the country in 
which the study is being conducted. Any use of these medications must be recorded in 
the eCRF, 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 in Table 2.


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Table 2
Requirements for Use of Specific Permitted Medications/Treatments
Medications/Treatments
Restriction
Prior to study treatment 
period
During study treatment 
period
Day 1 to Week 24
During 12-
week follow-
up
Conventional synthetic DMARDs
Participants must currently be taking at least one and at most two of the following concomitant csDMARDs
Methotrexate 15-25mg/week oral or 
injected. 
A lower dose of ≥7.5 mg/week is 
acceptable if reduced for reasons of 
intolerance to MTX. e.g. hepatic or 
hematologic toxicity, or per local 
requirement (this must be clearly 
documented in medical records). 
Exception: A lower dose of 6 mg/week 
is only allowed if the minimum locally 
approved or recommended dose is 
lower than 7.5 mg/week.
At least one and at most two 
required
(must have received at least 
12 weeks treatment prior to 
Day 1, with stable and 
tolerated dose for at least 8 
weeks prior to Day 1)
At least one and at most two 
required
(dose must remain stable 
except adjustment for safety 
reasons)
Permitted
Hydroxychloroquine up to 400 mg/day
Chloroquine up to 250 mg/day
Sulfasalazine up to 3000 mg/day
Leflunomide up to 20 mg/day
Tacrolimus up to 3 mg/day
Bucillamine up to 100 mg/day (or up to 
300 mg/day if permitted per local 
requirements)
Iguratimod up to 50 mg/day
Corticosteroids
Stable dosing regimen of oral 
corticosteroids ≤10 mg/day 
prednisolone or equivalent.
Permitted
(dose must be stable 4 
weeks prior to Day 1 and 
during screening if longer, 
with no changes except for 
safety reasons)
Permitted
(dose must remain stable 
except for safety reasons)
Permitted
Intra-articular corticosteroids
Prohibited within 4 weeks 
prior to Day 1 and during 
screening, if longer.
A single IA injection will be 
permitted between Week 12 
and Week 20 only. The site 
of injection must be 
recorded.
Permitted
Inhaled steroids, topical steroids or 
topical immunosuppressive agents 
(e.g., eye drops, creams)
Permitted
Permitted
Permitted
Analgesics
Acetaminophen (paracetamol) taken as 
rescue for RA pain: up to a maximum 
of 4g/day or locally approved maximum 
(if lower).
Permitted as needed
(but not within 24 hours of 
Day 1 baseline visit)
Permitted as needed
(but not within 24 hours of 
assessment visits)
Permitted


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Medications/Treatments
Restriction
Prior to study treatment 
period
During study treatment 
period
Day 1 to Week 24
During 12-
week follow-
up
NSAIDs including aspirin and selective 
cyclooxygenase inhibitors.

In this study, aspirin is considered 
a NSAID, except for low-doses 
(e.g. 75-150 mg/day) prescribed 
for cardiovascular or 
cerebrovascular disease.
Permitted
Participants on regular 
doses: Dosing regimen 
must be stable 7 days prior 
to Day 1, no changes 
except for safety reasons. 
Do not discontinue in 
advance of visits.
Participants on PRN 
prescription: Record each 
dose during screening, or 
frequency with start/end 
dates, in CRF. Should not 
be taken within 24h of Day 1 
baseline visit.
Permitted
Participants on stable, 
regular doses: From Day 1 
to Week 12, dose regimen 
must not change except for 
safety reasons. Do not 
discontinue in advance of 
visits.
After Week 12, any new 
analgesic or change in 
regimen should not occur 
within 24h of assessment 
visits.
Participants on PRN 
prescription: Record each 
dose, or frequency with 
start/end dates, in CRF.
Should not be taken within 
24h of assessment visits.
Permitted
Weak opioid analgesics (e.g. tramadol 
up to 400 mg/day, codeine)
Strong opioid analgesics (e.g. 
morphine, hydromorphone, oxycodone, 
hydrocodone, fentanyl, meperidine, 
methadone)
Prohibited within 4 weeks 
prior to Day 1 and during 
screening, if longer.
Permitted after Week 12
After week 12, PRN or 
regular doses may be 
considered, but any new 
analgesic or change in 
regimen should not occur 
within 24h of assessment 
visits. 
Participants on PRN 
prescription: Record each 
dose, or frequency with 
start/end dates, in CRF.
Should not be taken within 
24h of assessment visits.
Permitted
Other Medications
Intra-articular Hyaluronic acid and any 
other intra-articular compounds used as 
lubricant in the joints.
Prohibited within 2 weeks 
prior to Day 1 and during 
screening, if longer.
Prohibited within 2 weeks 
prior to Week 12 and Week 
24 assessments.
Permitted
Prior to any dose changes in csDMARD(s) or oral corticosteroids, it is recommended that 
the Investigator contacts the medical monitor to discuss and agree with the dose change. 
Use of analgesics is restricted during the first 12 weeks of study intervention and 
thereafter, investigators should follow routine clinical practice to manage RA pain (see 
Table 2).  Any new analgesic or change in analgesic use must be recorded in the 
concomitant medication eCRF.


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Other medications (including vitamins, herbal and dietary supplements) will be 
considered on a case-by-case basis and will be permitted if in the opinion of the 
Investigator, after consultation with the medical monitor as necessary, the medication 
will not interfere with the study procedures or compromise participant safety.
6.5.2.
Prohibited Therapies
Medications prohibited or restricted prior to the study, during the study and/or during the 
safety follow-up of the study are listed in Table 3, along with any period of exclusion 
which must be applied.
Table 3
Prohibited medications/treatments
Medications/Treatments
Restriction
Prior to study treatment 
period
During study treatment 
period
Day 1 to Week 24
During 12-week 
follow-up
Treatments affecting GM-CSF pathway
Any treatment antagonising GM-CSF or 
its receptor
Prohibited
(Exclusion)
Prohibited
(except study intervention)
Prohibited
Conventional synthetic DMARDs
Combination treatment with MTX and 
Leflunomide
Discontinue at least 12 
weeks prior to Day 1
Prohibited
No restriction
Combination treatment of 3 or more 
csDMARDs
Discontinue at least 4 
weeks prior to Day 1
Prohibited
No restriction
Combination treatment with Azathioprine 
and Methotrexate
Discontinue at least 4 
weeks prior to Day 1
Prohibited
No restriction
Hydroxychloroquine, chloroquine, 
sulfasalazine, minocycline, tacrolimus, 
cyclosporin, bucillamine, iguratimod.
If not being continued as background 
medication during the study.
Discontinue at least 4 
weeks prior to Day 1
Prohibited
No restriction
Leflunomide If 
not being 
continued as 
background 
medication 
during the 
study.
Without washout 
treatment
Discontinue at least 12 
weeks prior to Day 1
Prohibited
No restriction
With washout treatment 
for 11 days with oral 
cholestyramine (8 g 
three times daily) or 
charcoal (50 g four 
times daily)
Washout treatment must 
complete at least 2 weeks 
prior to Day 1
Prohibited
No restriction
Other csDMARDs
If not being continued as background 
medication during the study.
Discontinue at least 4 
weeks prior to Day 1
Prohibited
No restriction
Biologic DMARDs
Anti-interleukin 6 (IL-6), IL-6 receptor (IL-
6R) antagonist (including but not limited 
to sarilumab and tocilizumab)
Prohibited
(Exclusion)
Prohibited
(except study intervention)
Prohibited
Etanercept (including its biosimilars).
Discontinue at least 4 
weeks prior to Day 1
Prohibited
Prohibited


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Medications/Treatments
Restriction
Prior to study treatment 
period
During study treatment 
period
Day 1 to Week 24
During 12-week 
follow-up
Any cell-depleting therapies, e.g., anti-
CD20.
Discontinue at least 52 
weeks prior to Day 1.
Prohibited
Prohibited
Any other biologic DMARDs 
(experimental or approved)
Discontinue at least 8 
weeks prior to Day 1.
Prohibited
Prohibited
Targeted synthetic DMARDs
Janus kinase (JAK) inhibitors (e.g. 
tofacitinib, baricitinib, upadacitinib, 
filgotinib and peficitinib).
Discontinue at least 4 
weeks or 5 half-lives, 
(whichever is longer) prior 
to Day 1.
Prohibited
Prohibited
Any other Targeted Synthetic DMARDs 
(either experimental or approved)
Other RA therapies
Plasmapheresis or intravenous 
immunoglobulin (IVIG) or use of plasma 
filtering devices (eg. Staph protein A 
column (Prosorba))
Discontinue at least 26 
weeks prior to Day 1.
Prohibited
Prohibited
Corticosteroids
Irregular (not stable) doses of oral 
corticosteroids ≤10 mg/day prednisolone 
or equivalent
Prohibited (except for 
safety reasons)
Prohibited (except for 
safety reasons)
No restriction
Oral corticosteroids >10 mg/day 
prednisolone or equivalent
Discontinue or reduce to 
≤10 mg/day, at least 4 
weeks prior to Day 1.
Prohibited (except for 
safety reasons)
No restriction
Intra-muscular or intravenous 
corticosteroids
Discontinue at least 4 
weeks prior to Day 1.
Prohibited (except for 
safety reasons)
No restriction
Vaccine immunisations
Note: Investigators should review and update the vaccination status of potential participants as per local guidelines for 
adult vaccination prior to entering them into the study (refer to EULAR recommendations where no local guidelines are 
available [Furer, 2019]). All participants who have not received the herpes zoster vaccine at study entry will be 
recommended to complete vaccination >30 days prior to randomisation. All participants may receive inactivated flu 
vaccines during the study at the discretion of the investigator.
Live-attenuated vaccinations
Discontinue at least 30 
days prior to Day 1
Prohibited
Prohibited
BCG vaccination
Discontinue at least 365 
days prior to Day 1.
Prohibited
Prohibited
6.5.3.
Rescue Medicine
Acetaminophen (paracetamol) is permitted as needed, both prior to and during the study 
as rescue medicine for RA pain management, up to 4g/day or to the maximum permitted 
under local label (if lower than 4g/day).  However, acetaminophen (paracetamol) must 
not be taken within 24 hours prior to the baseline (Day 1) or any assessment visit.
Any use of rescue medication must be recorded in the appropriate concomitant 
medication form, in the CRF.


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6.6.
Dose Modification
6.6.1.
Dose Modification of Study Intervention
Dose adjustment of the study SC injection is not permitted in this study.
The dose adjustment criteria described in the Sarilumab prescribing information has been 
incorporated in the study stopping criteria (refer to the temporary discontinuation and 
stopping criteria guidance in Section 7).
6.6.2.
Dose Modification of Background Therapy
Dose reduction or temporary interruption of the background csDMARD medication(s) 
may be performed at any time for safety reasons (e.g. intolerance or toxicity) but must be 
clearly documented.  If clinically indicated, csDMARD may be re-started following an
interruption and increased back to the dose taken prior to the change.
Dose modifications for reasons other than safety are not permitted during the study 
treatment period.
6.7.
Intervention after the End of the Study
Participants who complete the 24-week treatment period may have the option to 
transition into long term extension study 209564.  Exceptionally, participants who missed 
their final dose at Week 23 in this study may still be eligible, after consultation with the 
medical monitor.  Participants receiving GSK3196165 in this study will continue to
receive the same dose in the extension study.  Participants receiving sarilumab in this 
study will be re-randomised in a 1:1 ratio to either GSK3196165 90 mg or GSK3196165 
150 mg once-weekly in the extension study, following a blinded washout period (three 
weeks of placebo SC injection).
Participants who do not transition into long term extension study 209564, will not receive 
any further treatment with GSK3196165 but will be treated according to local standard of 
care for RA disease.
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, the participant will, where 
possible, remain in the study and continue with study visits in order to be evaluated for 
efficacy and safety.  These participants will not be eligible for the long term extension 
study 209564.


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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 algorithm below.  Additionally, 
study intervention must be discontinued if there are any clinical signs/symptoms 
suggestive of hepatic decompensation such as ascites and hepatic encephalopathy.
Liver Chemistry Stopping and Increased Monitoring Algorithm for Study 202018
Temporarily Discontinue Intervention and Monitor Weekly
Study intervention may be restarted if ALT < 1.5 x ULN.  Monitor ALT as directed in the Appendix.
OR
If ALT does not resolve to ≤ 1.5 x ULN within 4 weeks or other stopping criteria met, 
permanently discontinue study intervention
*INR value not applicable to participants on anticoagulants
If participant to be monitored weekly, must refer to Liver Safety Required Actions and Follow up 
Assessments section in the Appendix
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT ≥ 3 x ULN and Bilirubin ≥ 2 x ULN (>35% direct) or 
INR > 1.5*
Permanently Discontinue Study Intervention 
Yes
Yes
Yes
No
Plus
Bilirubin ≥ 2 x 
ULN (>35% 
direct) or plus
INR > 1.5*
Possible
Hy’s Law
ALT ≥ 5 x 
ULN
ALT ≥ 3 x ULN
Plus
Symptoms of liver 
injury
or hypersensitivity
ALT ≥ 3 x ULN
but able to 
monitor weekly 
for 
4 weeks
ALT ≥ 3 x ULN
Yes
No
No
No
Yes
No
Continue 
Study 
Intervention 
Abbreviations: ALT = alanine transaminase; bili = bilirubin; INR = international normalised ratio; SAE = 
serious adverse event; ULN = upper limit of normal.
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.
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.


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7.1.2.
Other Stopping Criteria
A participant will be permanently discontinued from study intervention (but may 
continue to be followed in the study) 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 (see Section 8.3.7).

Other serious or severe adverse events or other significant medical event, at the 
discretion of the investigator, after consultation with the Medical Monitor.

HBV DNA level ≥200 IU/mL or HBV DNA detected at any level with recent 
increase in hepatic transaminases (see Figure 2 in Section 8.2.8).

HBV DNA positive (any level ≤200 IU/mL) and on repeat testing within 1 week 
(see Figure 2 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 latent or active TB infection (see Section 8.2.7.4).

Gastrointestinal perforation.

Platelet count <50 x 109/L.

Absolute neutrophil count (ANC) <0.5 x 109/L.

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.
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 7.1). Suggested pulmonary 
assessment and management algorithms are provided in a separate Pulmonary Safety 
Guidance Document in the SRM.


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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.
Hematologic Abnormalities
Study intervention will be temporarily discontinued upon confirmatory (local) repeat test, 
for the following haematological abnormalities:

Platelet count ≤100 x 109/L. (Dosing should be interrupted until Platelets ≥150 x 
109/L.)

Absolute neutrophil count (ANC) ≤1 x 109/L. (Dosing should be interrupted until 
ANC >2 x 109/L.)

White blood cell (WBC) count <2.0 x 109/L

Lymphocyte count <0.5 x 109/L
The local repeat test must be performed and assessed within 7 days (ideally 3-5 days), 
with additional sample(s) sent for central testing.
If study intervention is temporarily discontinued, the abnormality must be reported as an 
AE and a further repeat test should be performed within 7 days of discontinuation.  The 
medical monitor should be consulted if the repeat test is still abnormal.  Study 
intervention can be restarted if the haematological parameters rise above these values.
7.1.3.4.
TB Reactivation
Study intervention may 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, 
behavioural, compliance or administrative reasons. This is expected to be 
uncommon.

At the time of discontinuing from the study, if possible, an early withdrawal visit 
should be conducted following the procedures at the Week 24 visit, as shown in 
the SoA (Section 1.3).  A safety follow-up visit should also be scheduled, per the 
SoA, to take place 12 weeks post last dose of study intervention.

The participant will be permanently discontinued both from the study intervention 
and from the study at that time.


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
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 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.

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.

All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of ICF may be utilised for 
screening 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 maximum amount of blood collected from each participant over the duration 
of the study, including any extra assessments that may be required, 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 an independent 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.
One or more independent assessors, who have documented experience in performing 
joint assessments, will be designated at each trial site to perform joint assessments.  
Preferably the same independent assessor will perform all joint assessment for the same 
participant throughout the trial.  The principal investigator must ensure that the 
independent joint assessor has documented experience and he/she is adhering to locally 
accepted and implemented standards.  This also applies if the independent joint assessor 
is replaced during the trial.
The independent joint assessor should have no other contact with the participant during 
the trial, must not be the treating physician (investigator), should not discuss the clinical 
status of the participant with them during the joint assessment nor with other site 


2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
6 0
pers o n nel, a n d will n ot be per mitte d t o re vie w t he partici pa nt’s me dical rec or ds, t he 
e C R F, n or a n y of t he pre vi o us j oi nt assess me nts.
T he pr oce d ure f or j oi nt assess me nts is pr o vi de d i n t he S R M. 
8. 1. 2.
P h y si ci a n’ s Gl o b al A s s e s s m e nt of A rt hriti s
In vesti gat ors will c o m plete a gl o bal assess me nt of R A disease acti vit y usi n g t he 
p h y sicia n gl o bal assess me nt ite m ( P h G A), a vis ual a nal o g ue scale ( V A S) wit h a nc h ors 
“ 0” ( 
) t o “ 1 0 0” (
), res pecti vel y.
8. 1. 3. 1.
P ati e nt’ s A s s e s s m e nt of A rt hriti s P ai n
Partici pa nts will assess t he se verit y of t heir art hritis pai n o ve r t he past wee k, usi n g a 1 0 0 
u nit V A S, wit h a nc h ors “ 0” ( 
) a n d “ 1 0 0” (
).
T he res ults of t his q uesti o n will be use d f or t he H A Q -DI , w here t he l ocal versi o n of 
H A Q -DI  as ks t he sa me q uesti o n.
8. 1. 3. 2.
P ati e nt’ s Gl o b al A s s e s s m e nt of A rt hriti s
Par tici pa nts will c o m plete a gl o bal assess me nt of disease acti vit y usi n g t he patie nt gl o bal 
assess me nt ( Pt G A) ite m, a V A S wit h a nc h ors “ 0” (
) t o “ 1 0 0” (
).
8. 1. 3. 3.
H e alt h A s s e s s m e nt Q u e sti o n n air e – Di s a bilit y I n d e x ( H A Q- DI)
T he f u ncti o nal stat us of t he partici pa nt will be assesse d b y mea ns of t he Disa bilit y  In de x 
of t he Sta nf or d Healt h Assess me nt Q uesti o n naire ( H A Q- DI ).  T his 2 0-q uesti o n 
i nstr u me nt assesses t he de gree of diffic ulty a pers o n has i n acc o m plis hi n g tas ks i n ei g ht 
f u ncti o nal areas [Fries , 1 9 8 0]: dressi n g a n d gr o o mi n g, arisi n g, eati n g, wal ki n g, h y gie ne, 
reac h, gri p, a n d c o m m o n dail y acti vities.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


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C O N FI D E N TI A L
2 0 2 0 1 8
6 1
8. 1. 3. 7.
F u n cti o n al A s s e s s m e nt of C hr o ni c Ill n e s s T h er a p y  ( F ACI T) - F ati g u e
T he F u ncti o nal Assess me nt of C hr o nic Ill nes s T hera py ( F A CI T) -fati g ue q uesti o n naire is 
a vali date d patie nt -re p orte d meas ure de vel o pe d ori gi nally t o assess fati g ue i n i n di vi d uals 
wit h ca ncer.  T he F A CI T -fati g ue has s u bse q ue ntl y bee n use d a n d vali date d i n n u mer o us 
c hr o nic c o n diti o ns, i ncl u di n g R A.
8. 1. 3. 8.
S F -3 6 S h ort F or m H e alt h S ur v e y
Healt h -relate d q uality of life ( H R Q L) will be assesse d usi n g t he partici pa nt -c o m plete d 
Me dical O utc o mes St u d y ( M O S) S h ort -F or m 3 6 ( S F -3 6) w hic h is a ge neric healt h s ur ve y  
t hat c o ntai ns 3 6 q uesti o ns c o veri n g ei g ht d o mai ns of healt h.  T he S F-3 6 y iel ds a n ei g ht-
scale pr ofile of f u ncti o nal healt h a n d well-bei n g sc ores as well as p h y sical a n d me ntal 
c o m p o ne nt healt h s u m mar y sc ores.  T he versi o n 2, 1 -wee k recall q uesti o n naire will be 
use d.
C CI
C CI


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C O N FI D E N TI A L
2 0 2 0 1 8
6 2
8. 2.
S af et y A s s e s s m e nt s
Pla n ne d ti me p oi nts f or all safet y  assess me nts are pr o vi de d i n t he S o A ( Secti o n 1. 3 ).
I n t he e ve nt t hat p ul m o nar y f oll o w-u p criter ia are tri g gere d, all sites m ust ha ve access t o 
a p ul m o n ol o gist (see Secti o n 7. 1. 3. 1 a n d Secti o n 8. 2. 6 ).
8. 2. 1.
D y s p n o e a A s s e s s m e nt s
T he d y s p n oea scale gra des t he effect of breat hless ness o n dail y  acti vities a n d meas ures 
percei ve d res pirat or y  disa bilit y.  T he scale will be c o m plete d b y t he i n vesti gat or i n 
c o ns ultati o n wit h t he partici pa nt.  D ys p n oea will be re p orte d o n a rati n g scale fr o m 0 ( 
 
) t hr o u g h 4 (
).
8. 2. 2.
P h y si c al E x a mi n ati o n s

A c o m plete p h ys ical e xa mi nati o n (e. g. at t he Scree ni n g visit) will i ncl u de, at a 
mi ni m u m, assess me nts of t he S ki n, Car di o vasc ular, Res pirat or y , Gastr oi ntesti nal 
a n d Ne ur ol o gical s yste ms. Hei g ht a n d wei g ht will als o be meas ure d a n d rec or de d.

A brief p h ys ical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he s ki n, 
l u n gs, car di o vasc ular sys te m, a n d a b d o me n (li ver a n d s plee n).

I n vesti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us 
seri o us ill nesses.

All p h y sical e xa mi nati o ns will i ncl u de m o nit ori n g f or si g ns a n d sy m pt o ms of T B 
(see Secti o n 8. 2. 7 ).
8. 2. 3.
El e ctr o c ar di o gr a m s

1 2-lea d E C G meas ure me nts s h o ul d be rec or de d pre- d ose a n d w here p ossi ble 
bef o re vital si g n meas ure me nts a n d bl o o d dra ws.

Partici pa nts s h o ul d be i n a q uiet setti n g wit h o ut distracti o ns a n d rest i n a s u pi ne 
p ositi o n f or at least 5 or 1 0 mi n utes bef ore E C G c ollecti o n.

Tri plicate 1 2 -lea d E C G meas ure me nts will be o btai ne d at scree ni n g wit h si n gle 
E C G meas ure me nts o btai ne d p ost -baseli ne as o utli ne d i n t he S o A (see Secti o n 
1. 3 ) usi n g a n E C G mac hi ne t hat a ut o matically calc ulates t he heart rate a n d 
meas ures P R, Q R S, Q T, a n d Q Tc i nter vals.

At t he s cree ni n g visit w here tri plicate E C G are re q uire d, t hree i n di vi d ual E C G 
traci n gs s h o ul d be o btai ne d as cl osely as p ossi ble i n s uccessi o n, b ut n o m ore t ha n 
2 mi n utes a part. T he f ull set of tri plicates s h o ul d be c o m plete d i n less t ha n 4 
mi n utes.

E C G traces wi ll be rea d l ocall y.
C CI
C CI
C CI


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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.

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), 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 15 weeks after the last dose of study 
intervention should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal/baseline 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).


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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.

Dyspnoea assessment (see Section 8.2.1).

Lung auscultation.

Pulse oximetry.

Pulmonary function tests (PFTs) – spirometry (FEV1 and FVC) at baseline only 
(or prior to Day 1) or as required by the pulmonologist in the event of participant 
referrals for further assessment.
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) in cough (CTC Grade ≥2) or dyspnoea (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 pulmonary alveolar proteinosis must permanently 
discontinue study intervention (Section 7.1.2).


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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 PCR) in 
any clinical sample (including, but not limited to, sputum, pus, or biopsied tissue),
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 latent TB treatment status
For participants that have received treatment for latent TB within the previous 5 years, 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.

Participants who received treatment more than 5 years ago for latent TB infection 
and who remain QuantiFERON-TB Gold plus or T-SPOT.TB test positive will 
need to complete treatment for latent TB prior to study entry as per Section 
8.2.7.3.


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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.

A QuantiFERON-TB Gold plus test may be repeated once during screening if the 
initial result is indeterminate, alternatively a T-SPOT.TB test may be used 
following an indeterminate result.  This is not considered a rescreening.

Unscheduled TB testing should be performed if a participant is known or 
suspected to have come in close contact with someone who has untreated active
TB.
8.2.7.3.
Treatment of Latent TB During the Study
Participants diagnosed with latent TB during screening will need to complete a course of 
at least 6 months of INH therapy during the study including at least 4 weeks of therapy 
prior to randomisation.
Following 3 weeks of INH treatment in screening, LFTs must be assessed. Participants 
will fail screening if ALT >1.5 x ULN is identified, these participants may be re-screened 
if ALT elevation resolves to ALT <x 1.5 ULN during ongoing INH therapy following 
discussion with the medical monitor. Participants who are randomised will require LFT 
assessment every 4 weeks during 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 full or brief physical exam (see SoA in Section 1.3).
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 specialising in TB.  The investigator 
should discuss with the medical monitor and interruption of study intervention should be 
considered.
A QuantiFERON-TB Gold Plus test or a T.SPOT.TB test must be performed as part of 
the Week 22 assessment (see SoA in Section 1.3).  If a participant has a positive result at 
Week 22 who previously had a negative result at study start, then the participant must be 
referred to a physician specialising in TB to determine if the participant has active or 
latent TB.
If TB infection is diagnosed, study intervention must be discontinued.


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8.2.8.
Hepatitis B Monitoring
All participants with positive HBcAb results will have HBV DNA levels monitored 
throughout the study as summarised in Figure 2.
Figure 2
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
From the start of study intervention, HBV DNA levels will be assessed every 4 weeks to 
Week 24.


2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
6 8
8. 2. 8. 1.
Ri s k of R e a cti v ati o n i n P arti ci p a nt s P o siti v e f or H e p atiti s B C or e 
A n ti b o d y ( H B c Ab)
Partici pa nts w h o are H Bc A b p ositi ve, will be i nf or me d of t he ris k of reacti vati o n a n d t hat 
if t his occ urs treat me nt wit h a nti viral t hera py, s uc h as wit h n ucle o(s)ti de a nal o g ues li ke 
e nteca vir or te n of o vir, will be nee de d.
8. 2. 8. 2.
Tr e at m e nt of P arti ci p a nt s W h o A r e H B c Ab P o siti v e a n d W h o D e v el o p 
D et e ct a bl e H B V D N A  R e q uiri n g I niti ati o n of A nti vir al T h er a p y
H Bc A b p ositi ve partici pa nts w h o bec o me p ositi ve f or H B V D N A a n d re q uire a nti viral 
t hera py m ust ha ve st u d y i nter ve nti o n disc o nti n ue d. T he partici pa nt m ust als o be referre d 
t o a he pat ol o gist or i nfecti o us diseases e x pert s o t hat treat me nt a d vice re gar di n g w het her 
t o c o m me nce a nti-viral t hera p y is recei ve d wit hi n 7 da ys of H B V D N A ele vati o n bei n g 
i de ntifie d. T he partici pa nt s h o ul d t he n be re vie we d b y  t he e x pert wit hi n 1 4 da ys of H B V 
D N A ele vati o n bei n g i de ntifie d a n d ma na ge d as per l ocal g ui deli nes or u n der E A S L or 
A A S L D g ui deli nes if n o ne are a vaila ble.
8. 2. 8. 3.
F oll o w U p of P arti ci p a nt s Tr e at e d Wit h A nti -vir al T h er a p y
All partici pa nts will be f oll o we d u p w it hi n t he st u d y b y t he i n vesti gat or i n a d diti o n t o 
l ocal e x pert f oll o w u p. After c o m pleti o n of t he st u d y, partici pa nts s h o ul d be f oll o we d u p 
as per l ocal e x pert o pi ni o n base d o n g ui deli ne rec o m me n dati o ns.
8. 2. 9.
M ar k er s of dr u g -dr u g i nt er a cti o n s
Plas ma deri ve d fr o m w h ole bl o o d of a p pr o xi matel y  2 m L will be c ollecte d f or 4 β-
h y dr o x yc h olester ol a n d c h olester ol c o nce ntrati o n a nal ys is, at t he visits s pecifie d i n t he 
S o A ( Secti o n 1. 3 ).  T he act ual date a n d ti me ( 2 4-h o ur cl oc k ti me) of eac h s a m ple will be 
rec or de d. 
 
 
.
8. 3.
A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s

T he defi niti o ns of a n A E or S A E ca n be f o u n d i n A p pe n di x 3 .

T he i n vesti gat or a n d a n y q ualifie d desi g nees are res p o nsi ble f or detecti n g, 
d oc u me nti n g, a n d re p orti n g e ve nts t hat meet t he defi niti o n of a n A E or S A E a n d 
re mai n res p o nsi ble f or f oll o wi n g u p A Es t hat are seri o us, c o nsi dere d relate d t o t he 
st u d y i nter ve nti o n or t he st u d y, or t hat ca use d t he partici pa nt t o disc o nti n ue t he 
st u d y i nter ve nti o n (see Secti o n 7 ). 

Partici pa nts will be assesse d f or c o u g h or d ys p n oea at selecte d visits as s pecifie d 
i n t he S o A ( Secti o n 1. 3 .  T he i n vesti gat or will c o m plete t he C T C c o u g h scale if a 
c o u g h is prese nt a n d will rec or d d ys p n oea as per t he d y s p n oea scale.  L u n g 
a usc ultati o n a n d p ulse o xi metr y  will als o be perf or me d at t he visits s pecifie d i n 
t he S o A ( Secti o n 1. 3 ).
C CI


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
If a participant, at times other than scheduled visits, reports new onset or an 
increase (if present at baseline) 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.
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of study intervention until the follow-up 
visit (for participants who do not enter the long-term safety study) or the Week 24 
visit (for participants who enter the long-term safety study) at the time points 
specified in the SoA (Section 1.3). 

In addition, any SAEs assessed as related to study participation (e.g., study 
intervention, protocol-mandated procedures, invasive tests, or change in existing 
therapy) or related to a GSK product will be recorded from the time a participant 
consents to participate in the study. In China (and where this is a local 
requirement) all SAEs will be collected from the time of signing informed 
consent.

All AEs will be collected from the start of study intervention until the follow-up 
visit (for participants who do not enter the long-term safety study) or the Week 24 
visit (for participants who enter the long-term safety study) at the time points 
specified in the SoA (Section 1.3).

Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section.

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.


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
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.

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 will be collected after the start of study intervention and until 
the safety follow-up visit at Week 34 (or until 12 weeks after the last dose, for 
participants who withdraw from the study early).

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 but can continue to be 
followed in the study if they wish (Section 7.1.2).  If the participant does not wish 
to continue in the study, follow guidance in Section 7.2.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.


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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.

Peripheral arterial thromboembolism.

Deep venous thrombosis/pulmonary embolism.

Revascularisation.
This information should be recorded in the specific CV CRF/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


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
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 study, in the form of pre-filled 
syringes.  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 9.
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 
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 
9.
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.


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
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 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.

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 or sarilumab greater than the dose used in this 
study, or used more frequently than permitted (GSK3196165 once-weekly, sarilumab 
every other week) will be considered an overdose.  It should be noted that the minimum 
time between dosing with GSK3196165 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. Investigators should refer to the approved 
product label or local prescribing information for treatment of an overdose of sarilumab.
In the event of a potential 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/Monitor 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.
8.5.
Pharmacokinetics

Whole blood samples of approximately 3.5 mL will be collected prior to dosing, 
for measurement of serum concentrations of GSK3196165 at the visits specified 
in the SoA (Section 1.3); SC study intervention must be withheld until after PK 


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sampling has been performed.  The actual date and time (24-hour clock time) of 
each sample will be recorded.

Samples will be used to evaluate the PK of GSK3196165. Each serum sample will 
be divided into 2 aliquots (1 each for PK and target engagement (TE) [Section 
8.8]). Samples collected for analyses of GSK3196165 serum concentration may 
also be used to evaluate safety or efficacy aspects related to concerns arising 
during or after the study.

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.  Further details on the blood 
sample collection, processing, storage and shipping procedures are provided in the 
Central Laboratory Manual.

Note: Drug concentration information that would unblind the study will not be 
reported to investigative sites or blinded personnel until the study has been 
unblinded.
8.6.
Pharmacodynamics
The pharmacodynamic (PD) biomarkers evaluated in this study are described in Section 
8.8.
8.6.1.
Target engagement
The same blood samples obtained for PK analysis (see Section 8.5) will also be assessed 
for target engagement of GSK3196165, by measurement of serum concentrations of 
soluble GM-CSF-GSK3196165 complex, at the time points specified in the SoA (Section 
1.3).  Excess material from the immunogenicity baseline Day 1 blood sample (see 
Section 8.9) will be assessed for serum concentrations of free GM-CSF.
8.7.
Genetics
A 6 mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Appendix 5 for Information regarding genetic research.  Further details on the blood 
sample collection, processing, storage and shipping procedures are provided in the 
Central Laboratory Manual.


2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
7 5
8. 8. 1.
P h ar m a c o d y n a mi c ( P D) Bi o m ar k er s
A bl o o d sa m ple of a p pr o xi matel y  1 2 m L will be c ollecte d a n d di vi de d i nt o s uita ble 
p orti o ns f or meas ure me nt of t he f oll o wi n g bi o mar kers ass ociate d wit h G M -C S F 
si g nalli n g a n d/ or disease pat h ol o g y:

Meas ure me nt of ser u m P D bi o mar kers of d o w nstrea m si g nalli n g of G M -C S F t o 
assess t he res p o nse t o G S K 3 1 9 6 1 6 5. T he bi o mar kers ma y  i ncl u de b ut are n ot 
li mite d t o C C L1 7.

Meas ure me nt of ser u m P D bi o mar kers t o assess or pre dict t he res p o nse t o 
G S K 3 1 9 6 1 6 5. T he bi o mar kers ma y  i ncl u de b ut are n ot li mite d t o C C L2 2, s ol u ble 
i nterle u ki n (I L) 2 R, a n d I L 6.

Assess me nt of ser u m bi o mar kers of E C M de gra dati o n. T he bi o mar kers ma y  
i ncl u de b ut are n ot li mite d t o C 1 M, C 3 M, a n d P 4 N P 7 S.
C CI
C CI


2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
7 6
8. 9.
I m m u n o g e ni cit y As s e s s m e nt s
W h ole bl o o d sa m ples of a p pr o xi matel y  6 m L will be c ollecte d fr o m all partici pa nts a n d 
di vi de d i nt o s uita ble p orti o ns f or i m m u n o ge nicit y assess me nts of a nti-dr u g a nti b o d y  
( A D A) de vel o p me nt. A nti b o dies t o G S K 3 1 9 6 1 6 5 will be e val uate d i n ser u m sa m ples 
c ollecte d fr o m all partici pa nts acc or di n g t o t he S o A ( Secti o n 1. 3 ). Ser u m sa m ples s h o ul d 
als o be c ol lecte d at t he fi nal visit fr o m partici pa nts w h o disc o nti n ue d st u d y i nter ve nti o n 
or are wit h dra w n fr o m t he st u d y .  I n a d diti o n t o sc he d ule d i m m u n o ge nicit y assess me nts, 
“e ve nt-dri ve n” testi n g will be perf or me d i n t he c o nte xt of seri o us h y perse nsiti vit y  
reacti o ns or A Es dee me d t o be cli nicall y si g nifica nt i n t he o pi ni o n of t he i n vesti gat or 
res ulti n g i n wit h dra wal.
Ser u m sa m ples will be scree ne d f or a nti b o dies bi n di n g t o G S K 3 1 9 6 1 6 5 a n d t he titre of 
c o nfir me d p ositi ve sa m ples will be re p orte d. Ot her a nal ys es ma y be perf or me d t o verif y  
t he sta bilit y of a nti b o dies t o G S K 3 1 9 6 1 6 5 a n d/ or f urt her c haracterise t he i m m u n o ge nicity 
of G S K 3 1 9 6 1 6 5. T he ser u m sa m ple c ollecte d at Da y 1 will als o be a nal ys e d f or a nti-G M -
C S F a ut o -a nti b o dies a n d free G M-C S F le vels.
T he detecti o n a n d c haracterisati o n of a nti b o dies t o G S K 3 1 9 6 1 6 5 will be perf or me d usi n g 
vali date d assa y  met h o ds b y or u n der t he s u per visi o n of t he s p o ns or.  A nti b o dies ma y be 
f urt her c haracterise d a n d/ or e val uate d f or t heir a bilit y t o ne utralise t he acti vit y of t he 
st u d y i nter ve nti o n(s).  Sa m ples ma y be st ore d f or a ma xi m u m of 1 5 years ( or acc or di n g 
t o l ocal re g ulati o ns) f oll o wi n g t he last partici pa nt’s last visit f or t he st u d y at a facilit y 
selecte d by t he s p o ns or t o e na ble f urt her a nal ys is.
8. 1 0.
M e di c al R e s o ur c e Utili s ati o n a n d H e alt h E c o n o mi c s
Me dical Res o urce Utilisati o n a n d Healt h Ec o n o mics para meters are n ot e val uate d i n t his 
st u d y.
C CI


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9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
The primary objective of the study is to determine whether GSK3196165 is superior to 
placebo in the treatment of participants with moderately to severely active RA despite 
treatment with biological DMARDs and/or Janus Kinase inhibitors (i.e. bDMARD-IR 
and/or JAK-IR), as assessed by the proportion of participants achieving ACR20 at Week 
12. 
The study will test the null hypothesis that there is no difference between 150 mg dose of
GSK3196165 and placebo in the proportion of participants achieving ACR20 response at 
Week 12 versus the alternative hypothesis that the 150 mg dose of GSK3196165 differs
from placebo in the proportion of participants with ACR20 response at Week 12.
9.2.
Sample Size Determination
Approximately 1050-1200 participants will be screened to achieve between 525 and 600 
randomly assigned to study intervention. Approximately 525 evaluable participants are 
expected to be included in the primary analysis, of whom approximately 473 are expected 
to complete the week 12 visit. When the approximate target of 525 participants is 
reached, recruitment may continue up to a maximum of 600 participants to ensure 
sufficient numbers in the key Asian country subgroup.
For the purpose of analyses up to week 12, the placebo-sequence groups will be pooled 
into a single pooled placebo arm.
The minimum sample size of 525 will provide:

96% power to detect a 25% difference between GSK3196165 and the pooled 
placebo group in ACR20 response rate (52% vs. 27%) at Week 12 based on a 2-
sided significance level of 0.05, using a pooled Z-test. The Least Significant 
Difference this sample size will detect is 13.3%.

In addition, the above sample size will detect a Least Significant Difference of 3.5 
against sarilumab in the CDAI score change from baseline at Week 12, based on a 
2-sided significance level of 0.05, using a Z-test assuming equal variance of 15.6 
in each group.
The above sample size and power estimates were obtained from PASS version 12.0.2.
9.2.1.
Sample Size Sensitivity
The power of the primary analysis of the study will be affected by changes in the 
assumed response rate. The effect on power under varying response rates on both placebo 
and GSK3196165 assuming a fixed sample size of 150 in the GSK3196165 arm and 75 in 
the placebo arm, based on a 2-sided significance level of 0.05, using a pooled Z-test are 
shown in Table 4:


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Table 4
Power for ACR20 Response at Week 12 under varying response 
rates on GSK3196165 and Placebo
Placebo Response Rate
GSK3196165 Response Rate
49%
52%
55%
27%
90%
96%
99%
30%
79%
89%
95%
33%
63%
78%
89%
9.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign the ICF
Intent-to-treat (ITT)
All randomised participants who receive at least one dose of study 
intervention.
Per-protocol (PP)
All randomised participants who are compliant with intervention, who 
do not have significant protocol violations, and whose investigator site 
does not have any GCP issues that require report to the regulatory 
agencies.
Safety
All randomised participants who take at least 1 dose of study 
intervention. Participants will be analysed according to the 
intervention they actually received.
The primary analysis population will be the ITT population. In addition, the primary and 
major secondary analyses will be repeated using the PP population. Full details of all 
protocol violations that lead to exclusion from the PP population will be listed in the 
Reporting and Analysis plan (RAP).


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9.4.
Statistical Analyses
Full details of all analyses will be described in the RAP.
The primary analysis will be performed when the minimum target sample size of 525 has 
been achieved.  All inferences will be drawn from the primary analysis.
The proposed sequence of primary and key secondary endpoints is:
1. ACR20 at week 12
2. HAQ-DI at week 12
3. CDAI total score at week 12
4. Pain VAS at week 12
In order to preserve the type I error, each endpoint will be assessed sequentially using a 
step-down approach where statistical significance can be claimed for the second endpoint 
only if the first endpoint in the sequence meets the requirements for significance.
Additionally, as there are two doses of GSK3196165 within each endpoint, each to be 
compared with placebo, a step-down procedure, where the high dose will be tested first, 
will be used within each endpoint, i.e. the high dose (150mg) at a given endpoint can 
achieve significance only if the high dose at the prior endpoint is significant; the low dose 
(90mg) at a given endpoint can achieve significance only if both the high dose at the 
same endpoint and the low dose at the prior endpoint are significant. For each endpoint, 
and for each GSK3196165 dose group, the comparison will be conducted using a 2-sided 
significance level of 0.05.
The comparisons for ACR20 and HAQ-DI will be against placebo, after which the 
comparisons for CDAI and Pain VAS will be against sarilumab. The schematic is shown 
in Appendix 8.
This step-down approach strongly protects the Type I error rate at the 0.05 (2-sided) level 
across endpoints within each dose and across doses within each endpoint. However, there 
is weak control of the Type I error rate when the low dose at the first endpoint and the 
high dose at the second endpoint are tested simultaneously. Note this is only a risk in 
situations where the high dose has some effect at the first endpoint but not the second, 
and the low dose is not effective at the first endpoint. This is a situation that is not 
expected since if the high dose is effective for a given endpoint, there is likely to be some 
effect (non-zero) at the low dose.


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9.4.1.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
The proportion of participants with ACR20 response will be summarised 
using counts and proportions of responders, and analysed using a 
Generalised Estimating Equations (GEE) model, comparing intervention 
group with placebo at each time point, with fixed effects of intervention, visit, 
baseline swollen joint count (66), baseline tender joint count (68), previously 
failed medication, intervention-by-visit interaction and a random effect of 
participant.
Secondary
The CDAI total score will be expressed as a change from baseline and will be 
analysed using a mixed effect repeated measures model (MMRM) with fixed 
effects of intervention, visit, baseline value, intervention-by-visit interaction 
and a random effect of participant. An unstructured covariance structure will 
be used to model the between and within-participant errors, however if this 
analysis fails to converge, other structures will be tested. The Kenward-
Roger method will be used to estimate the degrees of freedom. Least 
Squares means will be used for the statistical comparisons; CIs will also be 
reported. Intervention group comparisons versus placebo at week 12 and 
other visits will be tested.
The HAQ-DI total score will be analysed using the same method as 
described above for CDAI total score. 
The Pain VAS will be analysed using the same method as described above 
for CDAI total score.
Additional 
Secondary 
and 
Exploratory
Will be described in the reporting and analysis plan
9.4.1.1.
Estimand strategy
The main intercurrent (post-randomisation) event anticipated to impact on the 
interpretation of the treatment effect for the primary objective is withdrawal from study 
intervention.
The estimand for the primary comparison will be defined using:
1. Population: defined through the inclusion/exclusion criteria
2. Variable: Proportion of participants at week 12 with ACR20 response
3. Intercurrent Event: the participant withdrew from intervention
4. Population Level Summary: Comparisons of proportions between the active 
groups and placebo


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The primary estimand used will be the treatment policy estimand.  This follows the 
principle that participants should be followed up, assessed and analysed irrespective of 
compliance to planned intervention.  This strategy answers the question of what the effect 
is of assigning participants to an intervention.  Therefore, if a participant withdraws from 
study intervention but efficacy data continues to be collected, their data will be analysed 
as if they were still on the original randomised intervention.
Further details will be provided in the RAP on any sensitivity estimators 
and supplementary estimands used to assess the primary objective and any estimands 
used to assess the secondary objectives.
9.4.2.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Endpoint
Statistical Analysis Methods
Secondary
For safety data, no formal hypotheses will be tested. Incidence of AEs, SAEs, and 
AESIs, including laboratory tests, vital signs, pulmonary function tests and 12-Lead 
ECGs will be displayed in the form of listings, frequencies, summary statistics, 
graphs and statistical analyses where appropriate. Interpretation will be aided by 
clinical expertise. Full details, including example outputs, will be documented in the 
RAP.
9.4.3.
Other Analyses
PK, pharmacodynamic, and biomarker exploratory analyses will be described in the 
reporting and analysis plan, as well as PROs (Patient Reported Outcomes). The 
population PK analysis and pharmacodynamic analyses will be presented separately from 
the main clinical study report (CSR). 
9.5.
Interim Analyses
The primary analysis will be conducted when the planned target of 525 randomised 
participants has been reached. No interim analysis with respect to this population is 
planned. However, if at the time of reaching approximately 525 randomised participants a 
sufficient number of participants that are required for the key Asian country subgroups is 
not reached, then recruitment in these countries may continue. Participants who have 
already been enrolled from Asian country subgroups at the time of reaching the 525 
target will be included in the primary analysis. Double-blinding will be maintained for 
any subjects continuing in the study at the time of the primary analysis. The primary 
analysis will be the basis of all inferences. If enrolment continues beyond the planned 
target of 525 randomised participants, secondary analyses will be conducted upon 
completion of enrolment/follow-up for the entire study population, based on all 
randomised subjects.


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9.5.1.
Data Monitoring Committee (DMC)
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 which will be available prior to the first participant’s visit.


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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 
Organisations 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 authorised representative and answer all 
questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorised 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 centre. 

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 authorised 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 authorised 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 authorised 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 utilised 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.


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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 
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 and PAC will function as detailed in 
the IDMC charter.
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 multicentre 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 participants, as appropriate.

GSK will provide the investigator with the randomisation codes for their site 
only after completion of the full statistical analysis.

The procedures and timing for public disclosure of the 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 anonymised participant-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 electronic clinical outcome assessment 
(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 the Source Data 
Agreement.
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 5 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.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.

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 screening pregnancy criteria.
o
Pregnancy testing (urine or serum as required by local regulations) for 
WOCBP should be conducted once every 4 weeks to Week 16 and then 
again at Week 24.
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 5
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
%Reticulocytes
erythrocyte count
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

Follicle-stimulating hormone and 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 [HIV antibody, hepatitis B surface antigen (HBsAg), hepatitis B core 
antibody (HBcAb), HB DNA, HCV RNA and hepatitis C virus antibody], 
rheumatoid factor (RF), ACPA (anti-CCP), 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. Details for recording the post-randomisation ESR 
values will be provided in the SRM
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 6. 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.
Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded. This 
includes results of PK analyses, ESR (performed locally by an unblinded independent 
study team member) and hsCRP.  The only exception is the result of ESR and hsCRP at
the participant’s final assessment visit, if the participant is moving to the extension study.
Note: Monitoring of CRP/hsCRP during the course of this study by local measurements, 
is not permitted, in order to protect the blind.  However individual local measured 
CRP/hsCRP may be performed if required for safety reasons.


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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 Medical Devices used in this study (see Section 6.1.1 for the 
list of medical devices).

Refer to Appendix 9 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 fulfil 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 fulfils 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 (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
Other situations:

Medical or scientific judgment should be exercised in deciding whether 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

Revascularisation


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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.

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 


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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.

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 


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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 enrolment.


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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 may 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 12 weeks post last dose of study 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 12 
weeks after the last dose of study 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 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: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility, severity and progression of disease. Variable response to study 
intervention may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; disease 
etiology; and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis

DNA samples will be used for research related to GSK3196165 or RA and related 
diseases. They may also be used to develop tests/assays (including diagnostic tests) 
related to GSK3196165, and RA. Genetic research may consist of the analysis of one 
or more candidate genes or the analysis of genetic markers throughout the genome or 
analysis of the entire genome (as appropriate)

DNA samples will be analysed if it is hypothesised that this may help further 
understand the clinical data. 

The samples may be analysed as part of a multi-study assessment of genetic factors 
involved in the response to GSK3196165 or study interventions of this class. The 
results of genetic analyses may be reported in the clinical study report or in a 
separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on GSK3196165 (or study interventions 
of this class) or RA continues but no longer than 15 years after the last participant 
last visit or other period as per local requirements.


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10.6.
Appendix 6: Liver chemistry stopping and monitoring 
criteria and required actions and follow up assessments 
(study specific for 202018)
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology 
10.6.1.
Liver chemistry stopping criteria and required follow up 
assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT absolute
ALT 5xULN
ALT Increase
ALT 3xULN and does not resolve to ALT ≤1.5 x ULN after 4 weeks of increased 
monitoring (see below)
Bilirubin1,2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5
Cannot 
Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT 3xULN associated with symptoms (new or worsening) believed to be related to 
liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments
Immediately discontinue study intervention
Report the event to GSK within 24 hours
Complete the liver event CRF and complete 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, stabilise, or return to within baseline (see 
MONITORING below)
Since restart/rechallenge is not allowed per 
protocol permanently discontinue study 
intervention but may 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
Blood sample for pharmacokinetic (PK) 
analysis, obtained 8 weeks after last dose5
Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).
Fractionate bilirubin, if total bilirubin2xULN
Obtain complete blood count with differential to 
assess eosinophilia
Record the appearance or worsening of clinical 
symptoms of liver injury, or hypersensitivity, on 
the AE report form
Record use of concomitant medications on the 
concomitant medications report form including 
acetaminophen, herbal remedies, other over the 


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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 hours
Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to within 
baseline
A specialist or hepatology consultation is 
recommended
For All other criteria:
Repeat liver chemistries(include ALT, AST, alkaline 
phosphatase, bilirubin, and INR) and perform liver 
event follow up assessments within 24-72 hours 
Monitor participants weekly until liver chemistries 
resolve, stabilise or return to within baseline
counter medications.
Record alcohol use on the liver event alcohol 
intake case report form
For bilirubin or INR criteria:
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total 
immunoglobulin G (IgG or gamma globulins).
Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen contribution 
to liver injury in 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 INR 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; Hepatitis B surface antigen (HBsAg) and Hepatitis B Core 
Antibody (HBcAb); Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM 
antibody (or if unavailable, obtain heterophile antibody or monospot testing); Hepatitis E IgM antibody.
5.
PK sample may not be required for participants known to be receiving placebo or non-comparator interventions. 
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 
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 Central Laboratory Manual.


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10.6.2.
Liver chemistry increased monitoring criteria with temporary 
discontinuation of study intervention
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event with temporary 
discontinuation of study intervention
If ALT 3xULN, temporarily discontinue study intervention and monitor weekly for up to 4 weeks.  If 
participant cannot be monitored, then permanently discontinue study intervention.  After temporary 
discontinuation, study intervention may be restarted if ALT <1.5 x ULN with additional monitoring.  If ALT 
does not resolve to ≤1.5 x ULN within 4 weeks or other stopping criteria met, permanently discontinue 
study intervention.
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks
Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss participant 
safety. 
Temporarily discontinue study intervention.
Participant must return weekly for repeat liver
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 
Study intervention may be restarted if ALT <1.5 x 
ULN.  After restarting study intervention, participant 
must return for repeat liver chemistries at 1, 2 and 4 
weeks, then scheduled monitoring can resume. If 
ALT ≥1.5 x ULN during additional monitoring, 
permanently discontinue study intervention.
                                 OR
If ALT does not resolve to ≤1.5 x ULN within 4 
weeks or other stopping criteria met, permanently 
discontinue study intervention.  
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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10.7.
Appendix 7: Summary of composite endpoints
These composite endpoints are derived using the data collected from assessments 
described in Section 8.1.
10.7.1.
ACR
The American College of Rheumatology’s definition for calculating improvement in RA 
(ACR20) is calculated as a 20% improvement from baseline in tender and swollen joint 
counts and 20% improvement in 3 of the 5 remaining ACR-core set measures: patient and 
physician global assessments, pain, disability, and an acute-phase reactant.  Similarly, 
ACR50 and ACR70 are calculated with the respective percent improvement.
The specific components of the ACR Assessments that will be used in this study are:

Tender/Painful Joint count (68).

Swollen Joint Count (66).

Pain VAS.

Patient’s Global Assessment of Arthritis.

Physician’s Global Assessment of Arthritis.

Acute-phase reactant (hsCRP or ESR).

Health Assessment Questionnaire – Disability Index (HAQ-DI).
10.7.2.
Disease Activity Score
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.

Patient’s Global Assessment of Arthritis.
10.7.3.
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).


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
Swollen Joint Count (28).

Patient’s Global Assessment of Arthritis.

Physician’s Global Assessment of Arthritis.


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10.8.
Appendix 8: Hierarchy Options to Demonstrate Superiority 
of Each Dose of GSK3196165 Versus Placebo or Sarilumab


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10.9.
Appendix 9: 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 
the medical devices provided for use in the study as detailed in Section 6.1.1.  
Refer to Appendix 3 for all other AE/SAE reporting not involving a 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.
10.9.1.
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.
10.9.2.
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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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 2.3.1).
10.9.3.
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.
10.9.4.
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 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.


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
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 
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 


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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.
10.9.5.
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 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.


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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.
10.9.6.
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. For medical device deficiencies with no associated 
AE or SAE please refer to Section 8.3.8.4.

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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10.10.
Appendix 10: Country-specific requirements
Not Applicable.


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10.11.
Appendix 11: Abbreviations and Trademarks
Abbreviations
ACPA
Anti-citrullinated protein antibody
ACR
American College of Rheumatology
ACR20/50/70
20%/50%/70% improvement in American College of Rheumatology 
Criteria
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine transaminase
AP
Alkaline phosphatase
AST
Aspartate transaminase
BCG
Bacillus Calmette-Guérin
bDMARD
Biologic disease-modifying antirheumatic drug
BID
Twice daily
CDAI
Clinical disease activity index
CD20
Cluster of differentiation antigen 20
CDC
Complement-dependent cytotoxicity
CI
Confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
COX
Cyclo-oxygenase
CPK
Creatine phosphokinase
CRP
C-reactive protein
csDMARD
Conventional synthetic disease modifying antirheumatic drug
CTC
Common terminology criteria
CTFG
Clinical Trial Facilitation Group
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
DRE
Disease-related event
EBV
Epstein Barr Virus
ECG
Electrocardiogram
ECM
Extracellular matrix
eCRF
Electronic case report form
ED
Effective dose
ESR
Erythrocyte sedimentation rate
EULAR
European League against Rheumatism
FACIT
Functional assessment of chronic illness therapy
FEV1
Forced expiratory volume in one second
FSH
Follicle-stimulating hormone
FVC
Forced vital capacity
GCP
Good Clinical Practice


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GEE
Generalised Estimating Equation
GFR
Glomerular filtration rate
GM-CSF
Granulocyte-macrophage colony stimulating factor
GSK
GlaxoSmithKline
HAQ-DI
Health Assessment Questionnaire Disability Index
hCG
Human chorionic gonadotropin
HF
Human Factors
HOA
Hand osteoarthritis
HRCT
High-resolution computed tomography
HRT
Hormone replacement therapy
HV
Healthy volunteer
IA
Intra-articular
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Institutional ethics committee
IFU
Instructions For Use
IgM
Immunoglobulin M
IL
Interleukin
IM
Intramuscular
IMP
Investigational medicinal product
INR
International normalised ratio
IP
Investigational product
IR
Inadequate response
IRB
Institutional review board
ITT
Intent to Treat
IU
International units
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IVIG
Intravenous immunoglobulin
IRT
Interactive Response Technology
JAK
Janus Kinase
kg
Kilogram
L
Litre
LAM
Lactational amenorrhoea method
LDA
Low disease activity
LDH
Lactate dehydrogenase
LFT
Liver function test
LTE
Long-term extension
mAb
Monoclonal antibody
MCV
Mean cell volume
MCH
Mean corpuscular haemoglobin
MCHC
Mean corpuscular haemoglobin concentration
MedDRA
Medical dictionary for regulatory activities


2 0 1 8 N 3 8 5 8 1 6 _ 0 2
C O N FI D E N TI A L
2 0 2 0 1 8
1 1 6
m g
Milli gra m
m L
Millilitre
M M P
Matri x metall o pr otei nase
M M R M
Mi xe d M o del f or Re peate d Meas ures
M O S
Me dical O utc o mes St u d y
M S
M ulti ple scler osis
M S D S
Material safet y data s heet
m T S S
M o difie d T otal S har p Sc ore
M T X
Met h otre xate
N C E P
Nati o nal C h olester ol E d ucati o nal Pr o gra m
N CI -C T C A E
Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y  Criteria f or A d verse 
E ve nts
N O E L
N o o bser ve d effect le vel
N R S
N u merical Rati n g Scale
N S AI D
N o n -ster oi dal a nti-i nfla m mat or y dr u g
P A C
P ul m o nar y  A dj u dicati o n C o m mittee
P A P
P ul m o nar y  al ve olar pr otei n osis
P C R
P ol y merase c hai n reacti o n
P D
P har mac o d y na mic
P F S
Prefille d s y ri n ge
P F T
P ul m o nar y  f u ncti o n test
P P
Per Pr ot oc ol
P R N
Pr o Re Nata (as nee de d)
Pt G A
Patie nt’s Gl o bal Assess me nt of Art hritis
P h G A
P h y sicia n’s Gl o bal Assess me nt of Art hritis
P K
P har mac o ki netics
R A
R he u mat oi d art hritis
R A P
Re p orti n g a n d a nal ys is pla n
R F
R he u mat oi d fact or
R N A
Ri b o n ucleic aci d
S C
S u bc uta ne o us
S A E
Seri o us a d verse e ve nt
SJ C
S w olle n j oi nt c o u nt
S F - 3 6
S h ort f or m ( 3 6)
S O P
Sta n dar d o pe rati n g pr oce d ure
S R M
St u d y  Refere nce Ma n ual
S R T
Safet y  Re vie w Tea m
S S D
Safet y  Syri n ge De vice
T B
Myc o b acteri u m t u berc ul osis
T E
Tar get e n ga ge me nt
TJ C
Te n der j oi nt c o u nt
T N F α
T u m or necr osis fact or al p ha
ts D M A R D
Tar gete d s y nt hetic disease -m o dif y i n g a ntir he u matic dr u g
T S T
T u berc uli n s ki n test
U L N
U p per li mit of n or mal
C CI


2018N385816_02
CONFIDENTIAL
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117
VAS
Visual Analogue Scale
WOCBP
Woman of Childbearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Kevzara
MedDRA
PROMIS
Prosorba
QuantiFERON
T.SPOT TB


2018N385816_02
CONFIDENTIAL
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118
10.12.
Appendix 12: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Protocol Amendment 01 22-MAY-2019
Overall Rationale for the Amendment:  Correction of contraceptive requirements for 
Women of Child Bearing Potential (WOCBP) and additional clarifications.
Section # and Name
Description of Change
Brief Rationale
Section 10.4.4 
Contraception Eligibility 
Criteria for Female and 
Male Participants
Correction of bullet ‘b’ for WOCBP, to 
remove “with low user dependency” 
wording and remove requirement for 
“two” methods, except if hormonal 
contraceptives are used.
Corrected to align with the 
Investigator Brochure (IB) 
Development Core Safety 
Information and the Study Risk 
Assessment (see Section 2.3).
Section 8.1.3 Patient 
reported outcomes
Clarification that some (exploratory) 
PROs will only be implemented if, and 
when translations are available.
Some PROs may be delayed or 
may not be available in all 
languages for the global study.
Section 5.1 Inclusion 
criteria and Section 6.5.1 
Permitted therapies
Maximum allowed dose of Bucillamine 
increased to 300 mg/day if permitted per 
local requirements.
Enable dosing of permitted 
regimen in countries including 
Republic of Korea/China.
Section 1.3 SoA and
Section 2.3.1 Study risk 
table and Section 5.4 
Screen Failures
Correction, a baseline chest X-ray is 
required during rescreening (if not 
carried out recently).
Correction of requirement.
Section 8.6.1 Target 
engagement and Section 
8.9 Immunogenicity
Clarification that free GM-CSF levels will 
be measured at baseline using excess 
material from immunogenicity sample.
Clarification of procedure.
Section 1.3 SoA
Footnotes updated for above changes.
Guidance.
Section 9 Statistical 
Considerations
Correction of hypothesis to state 150 mg 
dose, and addition of stratification factor 
to the model specification.
Align hypothesis with multiple 
testing hierarchy and adjust for 
stratification factor in the model.
All sections
Minor grammatical and typographical corrections to improve readability.


2018N385816_02
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119
11.
REFERENCES
Avci AB, Feist E, Burmester GR. Targeting GM-CSF in rheumatoid arthritis. Clin Exp 
Rheumatol. 2016, 34(4 Suppl 98):39-44.
Behrens F, Tak PP, Østergaard M, Stoilov R, Wiland P, Huizinga TW, et al. MOR103, a 
human monoclonal antibody to granulocyte-macrophage colony-stimulating factor, in the 
treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa 
randomised, double-blind, placebo-controlled, dose-escalation trial. Ann Rheum Dis 
2015;74:1058-64.
Bjorner JB, Rose M, Gandek B; Stone AA, Junghaenel DU, Ware Jr JE. Method of 
administration of PROMIS scales did not significantly impact score level, reliability, or 
validity. Journal of Clinical Epidemiology 2014;67:108-113.
Burmester G, McInnes IB, Kremer JM, Miranda P, Korkosz M, Vencovsky J, et al. A 
randomised phase IIb study of mavrilimumab, a novel GM-CSF receptor alpha 
monoclonal antibody, in the treatment of rheumatoid arthritis. Ann Rheum Dis 
2017;76:1020-30.
Burmester GR, McInnes IB, Kremer JM, Miranda P, Vencovský J, Godwood A, et al. M. 
Mavrilimumab, a Fully Human Granulocyte-Macrophage Colony-Stimulating Factor 
Receptor α Monoclonal Antibody: Long-Term Safety and Efficacy in Patients With 
Rheumatoid Arthritis. Arthritis Rheumatol. 2018;70(5):679-689.
Cella D, Riley W, Stone A, Rothrock N, Reeve B, Yount S, et al. The Patient-Reported 
Outcomes Measurement Information System (PROMIS) developed and tested its first 
wave of adult self-reported health outcome item banks: 2005–2008. Journal of clinical 
epidemiology 2010;63:1179-1194.
Cook AD, Braine EL, Campbell IK, Rich MJ, Hamilton JA. Blockade of collagen-
induced arthritis post-onset by antibody to granulocyte-macrophage colony-stimulating 
factor (GM-CSF): requirement for GM-CSF in the effector phase of disease. Arthritis Res 
2001;3:293-8.
Cook AD, Hamilton JA. Investigational therapies targeting the granulocyte macrophage 
colony-stimulating factor receptor-α in rheumatoid arthritis: focus on mavrilimumab. 
Ther Adv Musculoskelet Dis. 2018b;10(2):29-38.
Cook AD, Lee MC, Saleh R, Khiew HW, Christensen AD, Achuthan A, et al. TNF and 
granulocyte macrophage-colony stimulating factor interdependence mediates 
inflammation via CCL17. JCI Insight. 2018a, 3(6).
Cook AD, Pobjoy J, Sarros S, Steidl S, Dürr M, Lacey DC, et al. Granulocyte-
macrophage colony-stimulating factor is a key mediator in inflammatory and arthritic 
pain. Ann Rheum Dis. 2013, 72(2):265-70.


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Cook AD, Pobjoy J, Steidl S, Dürr M, Braine EL, Turner AL, et al. Granulocyte-
macrophage colony-stimulating factor is a key mediator in experimental osteoarthritis 
pain and disease development. Arthritis Res Ther 2012;14:R199.
FDA (Food and Drug Administration, 2014). Guidance for Industry: Immunogenicity 
Assessment for Therapeutic Protein Products. 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm338856.pdf
Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcomes in arthritis. 
Arthritis Rheum 1980;23:137-45.
Furer V, Rondaan C, Heijstek MW, Agmon-Levin N, van Assen S, Bijl M,et al. 2019 
update of EULAR recommendations for vaccination in adult patients with autoimmune 
inflammatory rheumatic diseases. Ann Rheum Dis. 2020 Jan;79(1):39-52.
Gaujoux-Viala C, Nam J, Ramiro S, Landewé R, Buch MH, Smolen JS, et al. Efficacy of 
conventional synthetic disease-modifying antirheumatic drugs, glucocorticoids and 
tofacitinib: a systematic literature review informing the 2013 update of the EULAR 
recommendations for management of rheumatoid arthritis. Ann Rheum Dis 2014;73:510-
5.
GSK Document Number 2014N190256_02. GSK3196165 Investigator's Brochure 
Version 9 (2019).
GSK Document Number 2017N353526_00. Pharmacokinetic Study Analysis Report. 
Population Pharmacokinetic Analysis of GSK3196165 Following Intravenous and 
Subcutaneous Administration to Healthy Volunteers, and Subjects with Rheumatoid 
Arthritis and Multiple Sclerosis, Date: 07-Dec-2017
Hamilton JA, Cook AD, Tak PP. Anti-colony-stimulating factor therapies for 
inflammatory and autoimmune diseases. Nat Rev Drug Discov. 2016 29;16(1):53-70.
LeVine AM, Reed JA, Kurak KE, Cianciolo E, Whitsett JA. GM-CSF-deficient mice are 
susceptible to pulmonary group B streptococcal infection. J Clin Invest 1999;103:563-9.
Martinez-Moczygemba M, Doan ML, Elidemir O, Fan LL, Cheung SW, Lei JT, et al. 
Pulmonary alveolar proteinosis caused by deletion of GM-CSFRalpha gene in the X 
chromosome pseudoautosomal region 1. J Exp Med 2008;205:2711-6.
Nam JL, Ramiro S, Gaujoux-Viala C, Takase K, Leon-Garcia M, Emery P, et al. Efficacy 
of biological disease-modifying antirheumatic drugs: a systematic literature review 
informing the 2013 update of the EULAR recommendations for the management of 
rheumatoid arthritis. Ann Rheum Dis 2014;73:516-28.
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NCI, NIH, DHHS. November 27th. 2017. 
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GM-CSF neutralisation suppresses inflammation and protects cartilage in acute 
streptococcal cell wall arthritis of mice. Ann Rheum Dis 2007;66:452-7.
Stanley E, Lieschke GJ, Grail D, Metcalf D, Hodgson G, Gall JA, et al. 
Granulocyte/macrophage colony-stimulating factor-deficient mice show no major 
perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc 
Natl Acad Sci USA 1994;91:5592-6.
Steidl S, Ratsch O, Brocks B, Dürr M, Thomassen-Wolf E. In vitro affinity maturation of 
human GM-CSF antibodies by targeted CDR-diversification. Mol Immunol 2008;46:135-
44.
Suzuki T, Sakagami T, Rubin BK, Nogee LM, Wood RE, Zimmerman SL, et al. Familial 
pulmonary alveolar proteinosis caused by mutations in CSF2RA. J Exp Med 
2008;205:2703-10.
Wicks IP, Roberts AW. Targeting GM-CSF in inflammatory diseases. Nat Rev 
Rheumatol. 2016; 12(1):37-48.

SAP_001.pdf: 
 
 
 
 
Reporting and Analysis Plan 
 
Study ID:  202018 
 
Official Title of Study: Reporting and Analysis Plan for A 24-week, phase 3,multicentre , 
randomised, double-blind, efficacy and safety study, comparing GSK3196165 with placebo 
and with sarilumab, in combination with conventional synthetic DMARDs, in participants 
with moderately to severely active rheumatoid arthritis who have an inadequate response to 
biological DMARDs and/or Janus Kinase inhibitors 
 
IND: 121958 
 
 
EudraCT: 2019-000868-18 
 
 
Approval Date of Document: 04-Feb-2022 
 
 


 
C O N FI D E N TI A L  
 
T h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
2 0 2 0 1 8  
 
1  
 
Di visi o n  
: W orl d wi de De vel o p me nt  
I nf or m ati o n T y pe 
: Re p orti n g a n d A nal ysis Pla n ( R A P)  
 
Title  
: Re p orti n g a n d A nal ysis Pla n f or A 2 4 -wee k, p has e 3, 
m ultice ntre, ra n d o mise d, d o u ble -bli n d, efficac y a n d safet y 
st u d y, c o m pari n g G S K 3 1 9 6 1 6 5 wit h place b o a n d wit h 
saril u ma b, i n c o m bi nati o n wit h c o n ve nti o nal s y nt hetic 
D M A R Ds, i n partici pa nts wit h m o deratel y t o se verel y 
acti ve r he u m at oi d art hritis w h o ha ve a n i n a de q uat e 
res p o nse t o bi ol o gical D M A R Ds a n d/ or J a n us Ki nase 
i n hi bit ors. 
C o m p o u n d N a me  
: Otili ma b  
C o m p o u n d N u m ber   : G S K 3 1 9 6 1 6 5  
Effecti ve D ate  
: Refer t o D oc u m e nt Date  
 
Descri pti o n:  
•  
T he p ur p ose of t his R A P is t o descri be t he pla n ne d a nal ys es a n d o ut p ut t o b e 
i ncl u de d i n t he Cli nical St u d y Re p ort f or Pr ot oc ol 2 0 1 8 N 3 8 5 8 1 6 _ 0 2 . 
•  
T his R A P is i nte n de d t o descri be t he fi nal a nal ys es re q uire d f or t he st u d y.  
•  
T his R A P will be pr o vi de d t o t he st u d y tea m me m bers t o c o n ve y t he c o nte nt of 
t he Statistical A nal ysis C o m plete ( S A C) deli vera ble. 
 
R A P A ut h or(s):  
A p pr o ver  
D ate  
 
Refer t o D oc u m e nt 
Date  
Statistic s Lea der ( Bi ostatistics) 
 
C o p yri g ht 2 0 2 2  t he Gla x o S mit h Kli ne gr o u p of c o m pa nies. All ri g hts r eser ve d.  
U na ut h orise d c o p yi n g or use of t his i nf or mati o n is pr o hi bite d  
 
P P D


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
2  
 
Bi ost atistics Li ne A p pr o v als:  
A p pr o ver  
D ate  
A p pr o v al 
Met h o d  
 
 ( Bi ostatistics) 
Refer t o 
D oc u me nt Date  
e Si g nat ur e  
 
Pr o gra m mi n g Lea der ( Bi ostatistics)  
Refer t o 
D oc u me nt Date  
e Si g nat ur e  
P P D
P P D
P P D


 
CONFIDENTIAL 
 
 
 
202018 
 
3 
 
TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 7 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 7 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 7 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 9 
2.3. 
Study Design .............................................................................................. 11 
2.4. 
Statistical Hypotheses / Statistical Analyses ............................................... 12 
3. 
PLANNED ANALYSES .......................................................................................... 13 
3.1. 
Interim Analyses ......................................................................................... 13 
3.2. 
Final Analyses ............................................................................................ 13 
4. 
ANALYSIS POPULATIONS ................................................................................... 14 
4.1. 
Protocol Deviations ..................................................................................... 15 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 16 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 16 
5.1.1. 
Study Treatment & Sub-group Display Descriptors for 
Study Population Displays ........................................................... 16 
5.1.2. 
Study Treatment & Sub-group Display Descriptors for 
Efficacy Displays .......................................................................... 17 
5.1.3. 
Study Treatment & Sub-group Display Descriptors for 
Safety Displays - Adverse Events (AEs) and Laboratory 
Assessments ............................................................................... 17 
5.1.4. 
Study Treatment descriptors used for Figures ............................. 20 
5.2. 
Baseline Definitions .................................................................................... 20 
5.2.1. 
Baseline definition in Period 1 and Period 1+2 ............................. 20 
5.2.2. 
Baseline definition in Period 2 ...................................................... 21 
5.3. 
Multicentre Studies ..................................................................................... 21 
5.4. 
Examination of Covariates, Other Strata and Subgroups ............................ 22 
5.4.1. 
Covariates and Other Strata ........................................................ 22 
5.4.2. 
Examination of Subgroups ........................................................... 22 
5.5. 
Multiple Comparisons and Multiplicity ......................................................... 23 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 27 
6. 
STUDY POPULATION ANALYSES ....................................................................... 28 
6.1. 
Overview of Planned Study Population Analyses ........................................ 28 
7. 
EFFICACY ANALYSES .......................................................................................... 29 
7.1. 
Primary Efficacy Analyses .......................................................................... 29 
7.1.1. 
Primary Estimand Strategy .......................................................... 29 
7.1.1.1. 
Population .................................................................. 29 
7.1.1.2. 
Treatment ................................................................... 29 
7.1.1.3. 
Outcome Variable ....................................................... 29 
7.1.1.4. 
Summary Measure ..................................................... 29 
7.1.1.5. 
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................ 30 


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
4  
 
7. 1. 1. 6.  
H a n dli n g of mi s si n g d at a  ............................................ 3 0  
7. 1. 1. 7.  
S e n siti vit y A n al y si s f or t h e h a n dli n g of mi s si n g 
d at a  ............................................................................ 3 1  
7. 1. 2.  
S u p pl e m e nt ar y A n al y si s  .............................................................. 3 1  
7. 1. 2. 1.  
S u p pl e m e nt al E sti m a n d 1  ........................................... 3 1  
7. 1. 2. 2.  
S u p pl e m e nt al E sti m a n d 2  ........................................... 3 1  
7. 1. 2. 3.  
P er -pr ot o c ol A n al y si s  .................................................. 3 2  
7. 1. 3.  
St ati sti c al A n al y s e s / M et h o d s  ..................................................... 3 2  
7. 1. 3. 1.  
St ati sti c al M et h o d ol o g y S p e cifi c ati o n  .......................... 3 3  
7. 2.  
S e c o n d ar y Effi c a c y A n al y s e s  ...................................................................... 3 3  
7. 2. 1.  
E sti m a n d str at e g y  ........................................................................ 3 3  
7. 2. 1. 1.  
P o p ul ati o n  .................................................................. 3 4  
7. 2. 1. 2.  
Tr e at m e nt  ................................................................... 3 4  
7. 2. 1. 3.  
O ut c o m e V ari a bl e s  ..................................................... 3 4  
7. 2. 1. 4.  
S u m m ar y M e a s ur e  ..................................................... 3 4  
7. 2. 1. 5.  
Str at e g y f or I nt er c urr e nt ( P o st -R a n d o mi z ati o n) 
E v e nt s  ........................................................................ 3 5  
7. 2. 1. 6.  
H a n dli n g of mi s si n g d at a  ............................................ 3 5  
7. 2. 1. 7.  
S e n siti vit y A n al y si s f or t h e h a n dli n g of mi s si n g 
d at a  ............................................................................ 3 5  
7. 2. 2.  
S u p pl e m e nt ar y A n al y si s  .............................................................. 3 5  
7. 2. 3.  
St ati sti c al A n al y s e s / M et h o d s  ..................................................... 3 6  
7. 2. 3. 1.  
St ati sti c al M et h o d ol o g y S p e cifi c ati o n  .......................... 3 7  
8.  
S A F E T Y A N A L Y S E S  ............................................................................................. 4 3  
8. 1.  
A d v er s e E v e nt s A n al y s e s  ........................................................................... 4 3  
8. 1. 1.  
A d v er s e E v e nt s of S p e ci al I nt er e st a n d Ot h er I m p ort a nt 
A E s A n al y s e s  .............................................................................. 4 4  
8. 2.  
Cli ni c al L a b or at or y A n al y s e s  ....................................................................... 4 4  
8. 3.  
Ot h er S af et y A n al y s e s  ................................................................................ 4 5  
8. 3. 1.  
I m m u n o g e ni cit y A n al y s e s ............................................................ 4 5  
9.  
P H A R M A C O KI N E TI C A N A L Y S E S  ......................................................................... 4 7  
9. 1.  
Pri m ar y P h ar m a c o ki n eti c A n al y s e s  ............................................................. 4 7  
9. 1. 1.  
E n d p oi nt / V ari a bl e s  ..................................................................... 4 7  
9. 1. 1. 1.  
Dr u g C o n c e ntr ati o n M e a s ur e s  .................................... 4 7  
9. 1. 2.  
S u m m ar y M e a s ur e  ...................................................................... 4 7  
9. 1. 3.  
P o p ul ati o n of I nt er e st  ................................................................... 4 7  
9. 1. 5.  
St ati sti c al A n al y s e s / M et h o d s  ..................................................... 4 7  
1 0.  P O P U L A TI O N P H A R M A C O K I N E TI C ( P O P P K) A N A L YS E S  .................................. 4 8  
1 1.  P H A R M A C O D Y N A MI C A N D BI O M A R K E R A N A L Y S E S  ........................................ 4 9  
1 1. 1.  E x pl or at or y P h ar m a c o d y n a mi c a n d Bi o m ar k er A n al y s e s  ............................ 4 9  
1 1. 1. 1.  
E n d p oi nt / V ari a bl e s  ..................................................................... 4 9  
C CI


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
5  
 
1 1. 1. 2.  
S u m m ar y M e a s ur e  ...................................................................... 4 9  
1 1. 1. 3.  
P o p ul ati o n of I nt er e st  ................................................................... 4 9  
1 1. 1. 5.  
St ati sti c al A n al y s e s / M et h o d s  ..................................................... 5 0  
1 2.  P H A R M A C O KI N E TI C / P H A R M A C O D Y N A MI C A N A L Y S E S  ................................. 5 1  
1 3.  R E F E R E N C E S  ....................................................................................................... 5 2  
1 4.  A P P E N DI C E S  ........................................................................................................ 5 3  
1 4. 1.  A p p e n di x 1: Pr ot o c ol D e vi ati o n M a n a g e m e nt a n d D efi niti o n s f or P er 
Pr ot o c ol P o p ul ati o n  ..................................................................................... 5 3  
1 4. 1. 1.  
E x cl u si o n s fr o m P er Pr ot o c ol P o p ul ati o n  ..................................... 5 3  
1 4. 2.  A p p e n di x 2: S c h e d ul e of A cti viti e s  .............................................................. 5 4  
1 4. 2. 1.  
Pr ot o c ol D efi n e d S c h e d ul e of E v e nt s  ........................................... 5 4  
1 4. 3.  A p p e n di x 3: A s s e s s m e nt Wi n d o w s  ............................................................. 5 7  
1 4. 3. 1.  
D efi niti o n s of A s s e s s m e nt Wi n d o w s f or A n al y s e s  ........................ 5 7  
1 4. 4.  A p p e n di x 4: St u d y P h a s e s a n d Tr e at m e nt E m er g e nt A d v er s e 
E v e nt s  ........................................................................................................ 5 8  
1 4. 4. 1.  
St u d y P h a s e s  .............................................................................. 5 8  
1 4. 4. 1. 1.  St u d y P h a s e s f or C o n c o mit a nt M e di c ati o n  ................. 5 9  
1 4. 4. 2.  
Tr e at m e nt E m er g e nt Fl a g f or A d v er s e E v e nt s  ............................. 5 9  
1 4. 5.  A p p e n di x 5: D at a Di s pl a y St a n d ar d s & H a n dli n g C o n v e nti o n s  .................... 6 0  
1 4. 5. 1.  
R e p orti n g Pr o c e s s  ....................................................................... 6 0  
1 4. 5. 2.  
R e p orti n g St a n d ar d s  .................................................................... 6 0  
1 4. 5. 3.  
R e p orti n g St a n d ar d s f or P h ar m a c o ki n eti c C o n c e ntr ati o n 
D at a  ............................................................................................. 6 1  
1 4. 5. 4.  
R e p orti n g St a n d ar d s f or L o g -tr a n sf or m e d P ar a m et er s ................. 6 1  
1 4. 6.  A p p e n di x 6: D eri v e d a n d Tr a n sf or m e d D at a  ............................................... 6 2  
1 4. 6. 1.  
G e n er al  ........................................................................................ 6 2  
1 4. 6. 2.  
St u d y P o p ul ati o n  .......................................................................... 6 3  
1 4. 6. 3.  
Effi c a c y  ........................................................................................ 6 8  
1 4. 6. 3. 1.  A C R 2 0/ 5 0/ 7 0  .............................................................. 6 8  
1 4. 6. 3. 2.  T e n d er/ P ai nf ul a n d S w oll e n J oi nt C o u nt s  ................... 6 9  
1 4. 6. 3. 3.  P ai n V A S  .................................................................... 6 9  
1 4. 6. 3. 4.  P ati e nt’ s/ P h y si ci a n’ s Gl o b al A s s e s s m e nt of 
Art hriti s Di s e a s e A cti vit y  ............................................. 6 9  
1 4. 6. 3. 6.  C D AI  .......................................................................... 7 1  
1 4. 6. 3. 7.  D A S 2 8 -C R P a n d D A S 2 8 -E S R  .................................... 7 1  
1 4. 6. 3. 8.  E U L A R R e s p o n s e  ...................................................... 7 3  
1 4. 6. 3. 9 . A C R/ E U L A R R e mi s si o n  ............................................. 7 3  
1 4. 6. 3. 1 0.  S F -3 6  ......................................................................... 7 4  
1 4. 7.  A p p e n di x 7: R e p orti n g St a n d ar d s f or Mi s si n g D at a  ..................................... 8 3  
1 4. 7. 1.  
Pr e m at ur e Wit h dr a w al s  ................................................................ 8 3  
1 4. 7. 2.  
H a n dli n g of Mi s si n g D at a  ............................................................. 8 3  
1 4. 7. 2. 1.  H a n dli n g of Mi s si n g  a n d P arti al D at e s  ........................ 8 4  
1 4. 7. 2. 2.  H a n dli n g of Mi s si n g Effi c a c y D at a  .............................. 8 4  
C CI
C CI
C CI


 
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14.8. 
Appendix 8: Laboratory Parameters of Interest ........................................... 85 
14.8.1. 
Laboratory Value Gradings .......................................................... 85 
14.8.2. 
Laboratory Values of Potential Clinical Importance ...................... 85 
14.8.3. 
ECG Values of Potential Clinical Importance ............................... 88 
14.8.4. 
Vital Signs Values of Potential Clinical Importance ...................... 88 
14.9. 
Appendix 9: List of Preferred Terms ............................................................ 89 
14.9.1. 
Herpes Zoster .............................................................................. 89 
14.9.2. 
Mycobacterium Tuberculosis ....................................................... 89 
14.10. Appendix 10: Missing Data Imputation Strategies ....................................... 90 
14.10.1. Primary Estimand Strategy .......................................................... 90 
14.10.1.1. Multiple Imputation using off-treatment data 
within treatment arm ................................................... 90 
14.10.1.2. Multiple Imputation using off-treatment data 
across all treatment arms ........................................... 90 
14.10.1.3. Multiple imputation under MAR assumption ................ 90 
14.10.2. Supplemental Estimand 1 Strategy .............................................. 91 
14.10.3. Supplemental Estimand 2 Strategy .............................................. 91 
14.10.4. Intermittent Missing Data Multiple Imputation ............................... 91 
14.11. Appendix 11: Abbreviations and Trademarks .............................................. 92 
14.11.1. Abbreviations ............................................................................... 92 
14.11.2. Trademarks ................................................................................. 94 
14.12. Appendix 12: List of Data Displays.............................................................. 95 
14.12.1. Data Display Numbering .............................................................. 95 
14.12.2. Mock Example Shell Referencing ................................................ 95 
14.12.3. Deliverables ................................................................................. 95 
14.13. Appendix 13: Example Mock Shells for Data Displays .............................. 163 
 


 
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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol: 
Revision Chronology: 
2018N385816_00 
06-MAR-2019 
Original 
2018N385816_01 
22-MAY-2019 
Correction of contraceptive requirements for Women of 
Childbearing Potential (WOCBP) and additional 
clarifications. 
2018N385816_02 
21-JAN-2020 
(1) To introduce new medical device safety reporting 
wording, required in advance of roll out of pre-filled syringes 
to this study. (2) Other minor corrections and clarifications. 
  
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
Changes from the originally planned statistical analysis specified in the protocol 
amendment 2 (Dated: 21/Jan/2020) and protocol addendum Appendix 10_JPN_03 
(Dated:16/JUL/2020) are outlined in Table 1. 
Table 1 
Changes to Protocol Defined Analysis Plan 
Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
• 
In order to preserve type 1 
error, each of the primary and 
key secondary endpoints 
(ACR20, HAQ-DI, CDAI and 
Pain VAS) will be assessed 
sequentially using a step-down 
approach.  
• 
The step-down approach 
detailed in the protocol is 
extended to make use of a 
graphical multiple testing 
procedure and the 
principle of alpha-
propagation.  
• 
Additional comparisons for 
superiority versus placebo 
and versus sarilumab on 
the FACIT-Fatigue score 
are added into the 
multiplicity control. 
• 
To ensure that 
comparisons of interest 
are controlled for 
multiplicity per the 
regulatory agency’s 
feedback 
• 
Major Secondary Efficacy 
Endpoints are HAQ-DI, CDAI 
total score and Arthritis Pain 
VAS 
• 
FACIT Fatigue is added as 
a Major Secondary 
Efficacy Endpoint 
• 
Major Secondary Efficacy 
Endpoints are aligned with 
the updated hierarchy 
(described on row above) 
• 
ACR20 will be analysed using 
GEE 
• 
ACR20 will be analysed 
using Logistic Regression 
• 
Missing data handling 
strategies will implement 
multiple imputation to 
generate full analysis 
datasets. GEE analysis 


 
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Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
provides no additional 
benefit over logistic 
regression when working 
with full datasets 
• 
CDAI total score, HAQ-DI and 
pain VAS will be analysed 
using MMRM 
• 
CDAI total score, HAQ-DI 
and pain VAS will be 
analysed using ANCOVA 
• 
Missing data handling 
strategies will implement 
multiple imputation to 
generate full analysis 
datasets. MMRM analysis 
provides no additional 
benefit over ANCOVA 
when working with full 
datasets  
• 
Intercurrent Event specified as 
discontinuation of study 
intervention  
• 
Additional intercurrent 
events specified: 
o Discontinuation of 
study intervention for 
any reason. 
o  Use of prohibited 
medication 
o  Change in stable 
dose of background 
medication. 
• 
Following regulatory 
feedback. 
• 
For the Japan submission, only 
the analysis of the primary 
endpoint will determine the 
success of the study and this 
will be assessed sequentially 
across doses to control for 
multiplicity, as contained in the 
first two steps of the step-down 
procedure. 
• 
Japan submission will use 
the same multiple testing 
procedure as the global 
submission.  
• 
Following regulatory 
feedback. 
 


 
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2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• 
To compare the efficacy of 
GSK3196165 at doses of 90 mg and 
150 mg weekly versus placebo for the 
treatment of participants with 
moderately to severely active RA who 
are on a stable background of 
csDMARD(s) and who have had an 
inadequate response to biological 
DMARDs and/or JAK inhibitors. 
• 
Proportion of participants achieving ACR20 at Week 12. 
Secondary Objectives 
Secondary Endpoints 
To Compare: 
• 
Efficacy of GSK3196165 at doses of 
90 mg and 150 mg weekly versus 
sarilumab, for the treatment of 
participants with moderately to 
severely active RA who are on a 
stable background of csDMARD(s) 
and who have had an inadequate 
response to biological DMARDs 
and/or JAK inhibitors. 
Major Secondary Efficacy Endpoints 
Change from baseline at Week 12 (versus placebo) in: 
• 
HAQ-DI 
• 
FACIT-Fatigue 
Change from baseline at Week 24 (versus sarilumab) in: 
• 
CDAI total score 
• 
Arthritis pain VAS 
• 
FACIT-Fatigue 
 
Other Secondary Efficacy Endpoints 
Proportion of participants at Week 12 (vs. placebo and vs. 
sarilumab) and Week 24 (vs. sarilumab) achieving: 
• 
CDAI total score ≤ 10 (CDAI LDA) 
• 
CDAI total score ≤ 2.8 (CDAI Remission) 
• 
ACR20/50/70 
• 
DAS28-CRP ≤ 3.2 and DAS28(ESR) ≤ 3.2 (DAS28 
LDA) 
• 
DAS28(CRP)<2.6 and DAS28(ESR) <2.6 (DAS28 
Remission). 
• 
A good/moderate EULAR response 
• 
ACR/EULAR Remission 
 
Change from baseline at Week 12(vs. placebo and vs. 
sarilumab) and Week 24 (vs. sarilumab) in: 
• 
CDAI total score 
• 
DAS28(CRP)/DAS28(ESR) 
• 
The effect of GSK3196165 on Patient 
Reported Outcomes (PROs) versus 
placebo and the active comparator 
sarilumab. 
• 
Change from baseline at Week 12 (vs. placebo and vs. 
sarilumab) and Week 24 (vs. sarilumab) in: 
• 
HAQ-DI 
• 
Arthritis pain VAS 
• 
SF-36 physical and mental component scores, and 
domain scores 
• 
Safety and tolerability of GSK3196165 
versus placebo and the active 
comparator sarilumab 
• 
Incidence of AEs, SAEs, AESIs 
• 
Change from baseline in key lab parameters 
• 
Proportion of participants with NCICTCAE ≥ Grade 3 
haematology/clinical chemistry abnormalities 


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
1 0  
 
O bj e cti ve s  
E n d p oi nt s  
•  
T o d et er mi n e  t he i m m u n og e nic 
p ot e nti al of G S K 3 1 9 6 16 5  
S af et y Bi o m ar k er E n d p oi nt s  
•  
G M -C S F a ut o anti b ody c o nce ntr ati o ns  
•  
I m m u n og e nicity 
E x pl orat ory  
E x pl or at ory  E n d p oi nt s  
•  
P h ar m ac oki n etics ( P K)  
•  
Ex p os ur e -res p ons e 
•  
P h ar m ac ody n a mic ( P D) bi o mark ers  
P K/ P D E n d p oi nt s  
•  
G S K 3 1 9 6 1 65 a p p are nt cl e ar anc e ( CL/ F) a nd ot h er P K 
p ar a m et ers as a p pr opri at e.  
•  
Ex p os ur e -res p ons e r el ati ons hip f or k ey effic acy a n d 
s af ety e n d p oi nts. 
•  
Bi o m ark ers  of  tar g et en g a g e me nt, d o w nstre a m si g nalli n g 
of G M -C S F  a nd E C M d e gra d ati o n.  
•  
. 
C CI
C CI
C CI


 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
• 
Phase 3, randomized, double-blind, parallel group, multicentre, placebo and active 
comparator (sarilumab)-controlled study of the efficacy and safety of GSK3196165 
in participants with moderately to severely active RA, who have had an inadequate 
response to treatment with bDMARDs and/or JAK inhibitors. 
Dosing 
• 
GSK3196165 and placebo will be administered by weekly subcutaneous (SC) 
injection; participants randomized to sarilumab will receive SC injections of 
sarilumab every other week, plus a placebo injection in the intervening weeks to 
maintain the blind. 
• 
In parallel to receiving study intervention, all participants will receive a stable dose 
of background csDMARD(s) (refer to Section 6.5 of the protocol).  Any participant 
whose background DMARD is MTX must also receive ≥5 mg/week folic (or folinic) 
acid orally (dosing regimen at the discretion of the investigator). Dose modifications 
to background DMARDs are discussed in Section 6.6.2 of the protocol. 
Time & 
Events 
• 
Refer to Appendix 2: Schedule of Activities 
Treatment 
Assignment 
• 
Upon successful screening, participants will be randomised to one of six 
intervention arms, in a ratio of 6:6:6:1:1:1 to GSK3196165 150 mg SC weekly, 
GSK3196165 90 mg SC weekly, sarilumab 200 mg SC every other week or placebo 
(three arms) respectively, all in combination with background csDMARD(s).  
• 
At Week 12, participants in the three placebo arms will switch from placebo to 
active intervention (either GSK3196165 150 mg SC weekly, GSK3196165 90 mg 
SC weekly, or sarilumab 200 mg SC every other week).   
• 
Randomisation will be stratified by previously failed medication (1 bDMARD, >1 
bDMARD or ≥1 JAK inhibitor [regardless of whether bDMARD received in past]). 
• 
For the purpose of all analyses up to week 12, the placebo-sequence arms will be 
pooled into a single placebo arm. 
Interim 
Analysis 
• 
The primary analysis will be conducted when the planned target of 525 randomised 
participants has been reached. No interim analysis with respect to this population is 
planned. However, if at the time of the primary analysis a sufficient number of 
participants that are required for the key Asian subgroup is not reached, then 
recruitment in these countries may continue.  


 
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Overview of Study Design and Key Features 
• 
Participants who have already been enrolled from the key Asian country subgroup 
at the time of reaching the 525 target will be included in the primary analysis. 
Double-blinding will be maintained for any subjects continuing in the study at the 
time of the primary analysis. The primary analysis will be the basis of all inferences.  
• 
If enrolment continues beyond the planned target of 525 randomised participants, 
secondary analyses will be conducted upon completion of enrolment/follow-up for 
the entire study population, based on all randomised subjects. 
 
2.4. 
Statistical Hypotheses / Statistical Analyses 
The primary objective of the study is to determine whether GSK3196165 is superior to 
placebo in the treatment of participants with moderately to severely active RA despite 
treatment with biological DMARDs and/or Janus Kinase inhibitors (i.e. bDMARD-IR 
and/or JAK-IR), as assessed by the proportion of participants achieving ACR20 at Week 
12.  
The study will test the null hypothesis that there is no difference between 150 mg dose of 
GSK3196165 and placebo in the proportion of participants achieving ACR20 response at 
Week 12 versus the alternative hypothesis that the 150 mg dose of GSK3196165 differs 
from placebo in the proportion of participants with ACR20 response at Week 12.  


 
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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
The primary analysis will be conducted when the planned target of 525 randomised 
participants has been reached. No interim analysis with respect to this population is 
planned. However, if at the time of reaching approximately 525 randomised participants a 
sufficient number of participants that are required for the Key Asian subgroup is not 
reached, then recruitment in these countries may continue. Participants who have already 
been enrolled from the key Asian country subgroup at the time of reaching the 525 target 
will be included in the primary analysis. Double-blinding will be maintained for any 
subjects continuing in the study at the time of the primary analysis. The primary analysis 
will be the basis of all inferences. If enrolment continues beyond the planned target of 
525 randomised participants, secondary analyses will be conducted upon completion of 
enrolment/follow-up for the entire study population, based on all randomised subjects. 
 
An Independent Data Monitoring Committee (IDMC) will be utilised in this study to 
ensure ongoing objective medical and/or statistical review of safety data in order to 
protect the welfare of participants in the study and the scientific validity of the study. Full 
details of the data to be reviewed, the frequency of review and members of the committee 
are included in the IDMC Charter [Version 1.0 09 May 2019]. Full details of the analyses 
are included in a separate IDMC RAP [Version 1.0 30 Apr 2020] . Monthly Safety 
Review Team (SRT) reviews will be performed using blinded SDTM datasets and will be 
reviewed using Spotfire software.  
3.2. 
Final Analyses 
The final planned analyses on the primary analysis cohort (i.e. the first approximately 
525 participants) will be performed after the completion of the following sequential steps: 
1. All participants to be included in the primary analyses have completed the study as 
defined in the protocol.  
2. All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management. 
3. All criteria for unblinding the randomization codes have been met.  
4. Prior to unblinding, all protocol deviations that will result in an exclusion from the 
per-protocol population have been assigned in the analysis dataset. 
5. Randomization codes have been distributed according to Cenduit Interactive 
Response Technology (C.I.R.T) system procedures. 
If required, the final planned analyses on the overarching set will be performed after the 
completion of the following sequential steps: 
1. All additional participants from the key Asian country cohort who are not included in 
the primary analysis have completed the study as defined in the protocol.  


 
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2. All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management. 
3. All criteria for unblinding the randomization codes have been met.  
4. Prior to unblinding, all protocol deviations that will result in an exclusion from the 
per-protocol population have been assigned in the analysis dataset. 
5. Randomization codes have been distributed according to Cenduit Interactive 
Response Technology (C.I.R.T) system procedures. 
 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened  
• 
All participants who were screened for eligibility 
• 
Study Population 
Randomized  
 
• 
All participants who were randomly assigned to 
treatment in the study. 
• 
This population will be based on the treatment the 
participant was randomized to. 
• 
Any participant who receives a treatment randomization 
number will be considered to have been randomized. 
• 
Study Population 
Enrolled 
• 
All participants who passed screening and entered the 
study.  
• 
Note screening failures (who never passed screening 
even if rescreened) and participants screened but never 
enrolled into the study (Reserve, Not Used) are 
excluded from the Enrolled population as they did not 
enter the study. 
• 
Study Population 
Safety 
• 
All randomized participants who received at least one 
dose of study treatment. 
• 
This population will be based on the treatment the 
subject actually received. 
• 
Note: Participants who were not randomized but 
received at least one dose of study treatment should be 
listed. 
• 
Safety 
• 
Biomarker 
Safety – Subjects 
who Entered 
Period 2 
• 
All participants randomized to a placebo switch 
treatment arm (i.e. Placebo to GSK3196165 90mg, 
Placebo to GSK3196165 150mg or Placebo to 
Sarilumab 200mg) who received at least one dose of 
study treatment in period 2. 
• 
This population will be based on the treatment the 
subject actually received. 
• 
Safety 
Intent-To-Treat 
(ITT) 
• 
All randomized participants who received at least one 
dose of study treatment. 
• 
This population will be based on the treatment the 
subject was randomized to. 
• 
Any participant who receives a treatment randomization 
number will be considered to have been randomized. 
• 
Study Population 
• 
Efficacy 
Per-Protocol  
• 
All participants in the ITT population who comply with 
the protocol. 
• 
Efficacy  


 
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Population 
Definition / Criteria 
Analyses Evaluated 
(PP) 
• 
Protocol deviations that would exclude participants from 
the PP population are defined in Appendix 1: Protocol 
Deviation Management and Definitions for Per Protocol 
Population). 
• 
The PP set will not be analysed if this population 
comprises more than 85% of the ITT population. 
Pharmacokinetic 
(PK) 
• 
All participants in the Safety population who had at least 
1 non-missing PK assessment (Non-quantifiable [NQ] 
values will be considered as non-missing values). 
• 
PK 
Refer to Appendix 12: List of Data Displays which details the population used for each display. 
 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised by IQVIA CTMS category. GSK subcategories will be included in 
individual subject listings. 
Important deviations and other criteria which result in exclusion from the analysis 
population will also be summarised and listed. (Please refer to Appendix 1: Protocol 
Deviation Management and Definitions for Per Protocol Population). 
Protocol deviations will be tracked by IQVIA and overseen by the GSK study team 
throughout the conduct of the study in accordance with the latest version of the Protocol 
Deviation Management Plan maintained by IQVIA in their TMF system. 
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations are captured and categorised in the protocol deviations 
dataset.  
o Deviations leading to exclusion from the Per Protocol Population will be 
identified in the ADDV dataset. 
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
summary will be based on data as recorded on the inclusion/exclusion page of the eCRF. 
Additional protocol deviations may be identified during the study and will be 
documented in protocol deviation adjudication meeting minutes prior to database freeze.   
All violations will be discussed and adjudicated as important or not important. Only 
protocol deviations that have the potential to impact the efficacy evaluation (and are 
important) will lead to exclusion from the per-protocol population. 
 


 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
5.1.1. 
Study Treatment & Sub-group Display Descriptors for Study 
Population Displays 
Unless otherwise specified, all study population outputs will display the pooled placebo 
arm as follows: 
Treatment Group Descriptions  
Cenduit Interactive Response 
Technology (CIRT) 
Data Displays for Reporting 
Code 
Description 
Description 
Order in TLF  
1 
GSK3196165 150mg 
OTI 150mg QW 
3 
2 
GSK3196165 90mg 
OTI 90mg QW 
2 
3 
Sarilumab 200mg 
SARI 200mg Q2W 
4 
4+5+6 Placebo to GSK3196165 150mg 
+ Placebo to GSK3196165 90mg 
+ Placebo to Sarilumab 200mg 
Pooled PBO 
1 
All study population outputs required to be displayed by randomised treatment arm will 
display all randomised treatment arms as follows: 
Treatment Group Descriptions  
Cenduit Interactive Response 
Technology (CIRT) 
Data Displays for Reporting 
Code Description 
Description 
Order in TLF  
1 
GSK3196165 150mg 
OTI 150mg QW 
5 
2 
GSK3196165 90mg 
OTI 90mg QW 
4 
3 
Sarilumab 200mg 
SARI 200mg Q2W 
6 
4 
Placebo to GSK3196165 150mg 
PBO to OTI 150mg QW 
2 
5 
Placebo to GSK3196165 90mg 
PBO to OTI 90mg QW 
1 
6 
Placebo to Sarilumab 200mg 
PBO to SARI 200mg Q2W 
3 
 


 
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5.1.2. 
Study Treatment & Sub-group Display Descriptors for Efficacy 
Displays 
Treatment Group Descriptions  
Cenduit Interactive Response 
Technology (CIRT) 
Data Displays for Reporting 
Code 
Description 
Description 
Order in TLF  
1 
GSK3196165 150mg 
OTI 150mg QW 
3 
2 
GSK3196165 90mg 
OTI 90mg QW 
2 
3 
Sarilumab 200mg 
SARI 200mg Q2W 
4 
4 
Placebo to GSK3196165 150mg 
PBO to OTI 150mg QW 
6 
5 
Placebo to GSK3196165 90mg 
PBO to OTI 90mg QW 
5 
6 
Placebo to Sarilumab 200mg 
PBO to SARI 200mg Q2W 
7 
4+5+6 Placebo to GSK3196165 150mg 
+ Placebo to GSK3196165 90mg 
+ Placebo to Sarilumab 200mg 
Pooled PBO 
1 
For the purpose of analyses up to week 12, the placebo-sequence groups will be pooled 
into a single placebo arm. 
 
Treatment comparisons will be displayed as follows using the descriptors as specified: 
1. Otilimab 90mg vs Pooled Placebo 
2. Otilimab 150mg vs Pooled Placebo 
3. Sarilumab 200mg vs Pooled Placebo 
4. Otilimab 90mg vs Sarilumab 200mg 
5. Otilimab 150mg vs Sarilumab 200mg 
 
5.1.3. 
Study Treatment & Sub-group Display Descriptors for Safety 
Displays - Adverse Events (AEs) and Laboratory Assessments 
Each AE display will be produced for the time periods below (see Figure 1 for graphical 
representation): 
1. Period 1 – up to week 12, to be displayed for all participants. 
• Period 1 is defined as time from randomisation and first dose of treatment up to 
dosing of Period 2 treatment (Week 12) or date of study withdrawal or date of 
treatment withdrawal plus safety follow up, whichever is earlier. AEs that occur 
at week 12 visit i.e. AE start date is at week 12 visit will be assigned to Period 2. 
• The placebo-sequence groups up to week 12 will be pooled into a single placebo 
arm. 
2. Period 2 – post week 12, to be displayed for participants who were originally 
randomised to receive placebo and switched at week 12 only. 
• Period 2 is defined as time from first dose of treatment of period 2 (week 12) 
until date of study completion or date of study withdrawal or date of treatment 
withdrawal plus safety follow up, whichever is earlier. 


 
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3. Period 1+2 – from week 0 to week 24, to be displayed for participants who were 
originally randomised to Otilimab 150mg, Otilimab 90mg or Sarilumab 200mg only. 
• Period 1+2 is defined as time from randomisation until date of study completion 
or date of study withdrawal or date of treatment withdrawal plus safety follow 
up, whichever is earlier. 
Figure 1 
Graphical Representation of Study Design with Periods and 
Treatment Arms within Each Period  
 
For displays for Period 1 (up to week 12), the following treatment group descriptions will 
be used: 
Treatment Group Descriptions  
Cenduit Interactive Response 
Technology (CIRT) 
Data Displays for Reporting 
Code 
Description 
Description 
Order in TLF  
1 
GSK3196165 150mg 
OTI 150mg QW 
3 
2 
GSK3196165 90mg 
OTI 90mg QW 
2 
3 
Sarilumab 200mg 
SARI 200mg Q2W 
4 
4+5+6 Placebo to GSK3196165 150mg 
+ Placebo to GSK3196165 90mg 
+ Placebo to Sarilumab 200mg 
Pooled PBO 
1 
 
Treatment comparisons will be displayed as follows using the descriptors as specified: 
1. Otilimab 150mg vs Pooled Placebo 
2. Otilimab 90mg vs Pooled Placebo 
3. Sarilumab 200mg vs Pooled Placebo 
4. Otilimab 150mg vs Sarilumab 200mg 
5. Otilimab 90mg vs Sarilumab 200mg 


 
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6. Otilimab 150mg vs Otilimab 90mg  
 
For displays for Period 2 (post week 12), the following treatment group descriptions will 
be used: 
Treatment Group Descriptions  
Cenduit Interactive Response 
Technology (CIRT) 
Data Displays for Reporting 
Code Description 
Description 
Order in TLF  
4 
Placebo to GSK3196165 150mg 
PBO to OTI 150mg QW 
2 
5 
Placebo to GSK3196165 90mg 
PBO to OTI 90mg QW 
1 
6 
Placebo to Sarilumab 200mg 
PBO to SARI 200mg Q2W 
3 
 
Treatment comparisons will be displayed as follows using the descriptors as specified: 
1. Placebo to Otilimab 150mg vs Placebo to Sarilumab 200mg 
2. Placebo to Otilimab 90mg vs Placebo to Sarilumab 200mg 
3. Placebo to Otilimab 150mg vs Placebo to Otilimab 90mg 
 
For displays for Period 1+2 (Week 0 to week 24), the following treatment group 
descriptions will be used: 
Treatment Group Descriptions  
Cenduit Interactive Response 
Technology (CIRT) 
Data Displays for Reporting 
Code Description 
Description 
Order in TLF  
1 
GSK3196165 150mg 
OTI 150mg QW 
2 
2 
GSK3196165 90mg 
OTI 90mg QW 
1 
3 
Sarilumab 200mg 
SARI 200mg Q2W 
3 
 
Treatment comparisons will be displayed as follows using the descriptors as specified: 
1. Otilimab 150mg vs Sarilumab 200mg 
2. Otilimab 90mg vs Sarilumab 200mg 
3. Otilimab 150mg vs Otilimab 90mg 
 


 
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5.1.4. 
Study Treatment descriptors used for Figures 
Table 2 describes the format required for the reporting of figures.  
Table 2 
Treatment Descriptors, Colours, Line Style, and Symbols to be used 
for Figures 
Treatment Description 
Colour 
SAS Colour 
Marker 
Symbol 
Line pattern 
Pooled PBO 
Black 
#333333 
X 
2 
PBO to OTI 90mg QW 
Orange 
#F36633 
SquareFilled 
2 
PBO to OTI 150mg QW 
Green 
#167716 
DiamondFilled 
2 
PBO to SARI 200mg Q2W 
Purple 
#BF00BF 
TriangleFilled 
2 
OTI 90mg QW 
Orange 
#F36633 
Square 
1 
OTI 150mg QW 
Green 
#167716 
Diamond 
1 
SARI 200mg Q2W 
Purple 
#BF00BF 
Triangle 
1 
 
5.2. 
Baseline Definitions 
5.2.1. 
Baseline definition in Period 1 and Period 1+2 
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline. 
Parameter 
Study Assessments Considered as 
Baseline 
Baseline Used in 
Data Display 
Screening 
Day 1 (Pre-Dose) 
Efficacy 
Tender Joint Count 28 
 
X 
Day 1 (Pre-Dose) 
Tender Joint Count 68 
 
X 
Day 1 (Pre-Dose) 
Swollen Joint Count 28 
 
X 
Day 1 (Pre-Dose) 
Swollen Joint Count 66 
 
X 
Day 1 (Pre-Dose) 
Pain VAS 
 
X 
Day 1 (Pre-Dose) 
Patient’s Global Assessment of 
Arthritis (PtGA) 
 
X 
Day 1 (Pre-Dose) 
Physician’s Global Assessment of 
Arthritis (PhGA) 
 
X 
Day 1 (Pre-Dose) 
Acute-phase reactant (CRP) 
 
X 
Day 1 (Pre-Dose) 
Acute-phase reactant (ESR) 
 
X 
Day 1 (Pre-Dose) 
HAQ-DI 
 
X 
Day 1 (Pre-Dose) 
DAS28-CRP Total Score 
 
X 
Day 1 (Pre-Dose) 
DAS28-ESR Total Score 
 
X 
Day 1 (Pre-Dose) 


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
2 1  
 
P ar a m et er  
St u d y A s s e s s m e nts C o n si der e d a s 
B a s eli n e  
B a s eli n e U s e d i n 
D at a Di s pl a y  
S cr e e ni n g  
D a y 1 ( Pre -D o s e)  
S F -3 6  
 
X  
D ay 1 ( Pr e -D os e)  
F A CI T -F ati g u e  
 
X  
D ay 1 ( Pr e -D os e)  
S af et y  
Vit al Si g ns  
X  
X  
D ay 1 ( Pr e -D os e) [ 1] 
E C G ( 1 2 -l e a d) 
X  
X  
D ay 1 ( Pr e -D os e) [ 1] 
L a b or at ory  
X  
X  
D ay 1 ( Pr e -D os e) [ 1] 
P ul m o n ary ass ess m ents  
X  
X  
D ay 1 ( Pr e -D os e) [ 1] 
I m m u n og e nicity 
 
X  
D ay 1 ( Pr e -D os e)  
E x pl orat ory  
Bl o o d P D Bi o m ark ers  
 
X  
D ay 1 ( Pr e -D os e)  
[ 1] t he baseli ne val ue will be t he latest pre-d os e assess me nt wit h a n o n -missi n g val ue  
U nless ot her wise state d, if baseli ne dat a is missi n g n o deri vati o n will  be perf or me d a n d 
baseli ne will be set t o missi n g.  
5. 2. 2.  
B a s eli n e d efi niti o n i n P eri o d 2  
F or all safet y assess me nts t he baseli ne val ue will be t he latest pre -d ose ass ess me nt bef ore 
t he first d ose i n peri o d 2 wit h a n o n-missi n g val ue, i ncl u di n g t h ose fr o m u nsc he d ule d 
visits.  
5. 3.  
M ulti c e ntr e St u di e s  
I n t his m ultice ntre gl o bal st u d y, e nr ol me nt will be prese nte d b y i n vesti gati v e site, 
c o u ntr y, a n d t he re gi o ns.  
Re gi o n  
C o u ntri e s  
U S a n d C a n a d a  
U nit e d St at es a n d C an a d a  
E ur o p e a n C o nti n e nt  
B el gi u m, Cz ech R e p u blic, G er m a ny, H u ng ary, It aly,  Lith u a nia, 
P ol a n d, S p ai n, U nite d Ki n gd o m  
L ati n A meric a a n d S o uth Afric a  
Ar g e nti n a, S out h Afric a  
Asi a  
J a p a n, S out h K or e a  
C CI


 
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5.4. 
Examination of Covariates, Other Strata and Subgroups 
5.4.1. 
Covariates and Other Strata 
The list of covariates and other strata may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses. Additional 
covariates and other strata of clinical interest may also be considered. 
Category 
Details 
Strata 
Randomisation Stratification Factors: 
• 
Previously failed medication: 
o 1 bDMARD 
o > 1 bDMARD 
o ≥ 1 JAK inhibitor 
Covariates 
Relevant baseline score 
  
5.4.2. 
Examination of Subgroups 
The list of subgroups may be used in descriptive summaries and statistical analyses for 
the primary and/or key secondary endpoints. Additional subgroups of clinical interest 
may also be considered. 
• 
If the percentage of subjects is small (<1%) within a particular subgroup, then the 
subgroup categories may be refined prior to unblinding the trial. 
• 
If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup. 
Subgroup 
Categories  
Overall Group 
Prior Failed Medication 
1 bDMARD, >1 bDMARD, ≥ 1 JAK inhibitor 
Disease Characteristic 
Region 
US and Canada, European Continent, Latin 
America and South Africa, Asia 
Demographic 
Specific Region 
Europe, other 
Demographic 
Specific Region 
USA, other 
Demographic 
Specific Region 
Japan (Japan Region and Japanese Heritage 
Race), other 
Demographic 
Age 
<50 years, 50 to 64 years, ≥65 years 
Demographic 
Ethnicity 
Hispanic or Latino, Not Hispanic or Latino 
Demographic 
Race 
Black or African American/African Heritage, 
Asian, White, Other (American Indian or 
Alaskan Native, Native Hawaiian or Other 
Pacific Islander, Multiple) 
Demographic 
Gender 
Male, Female 
Demographic 
Baseline Body Weight 
<60kg, 60-100kg, >100kg 
Demographic 
Baseline both RF Negative 
and Anti-CCP Negative 
Both Negative, At Least One Positive 
Disease Characteristic 
Baseline DAS28-CRP 
<5.1, ≥5.1 
Disease Characteristic 
Baseline CDAI 
<22, ≥22 
Disease Characteristic 


 
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Subgroup 
Categories  
Overall Group 
Duration of RA 
≤5 years, >5 to ≤10 years, >10 years 
Disease Characteristic 
BMI 
<25, ≥25 and <30, ≥30 
Demographic 
 
5.5. 
Multiple Comparisons and Multiplicity 
The following graphical multiple testing procedure described in [Bretz, 2009] will be 
used to control the type I error for the primary and key secondary endpoints. 
Each hypothesis will be assessed sequentially using a step-down approach where testing 
of the second hypothesis will commence only if all null hypotheses of the prior steps are 
rejected. Additionally, as there are two doses of GSK3196165 within each test, this will 
also be incorporated into the step-down procedure.  
A graphical presentation of the multiplicity control is provided in Figure 2. 
If any of the hypotheses in the list are not rejected (i.e. the testing sequence fails at this 
step), the subsequent test(s) will still be performed but the results will be uncontrolled for 
multiplicity. 
The proposed testing sequence of primary and key secondary hypotheses is: 
1. ACR20 GSK3196165 vs Placebo for Superiority at week 12  
2. HAQ-DI GSK3196165 vs Placebo for Superiority at week 12  
3. CDAI total score GSK3196165 vs Sarilumab for Superiority at week 24 
4. FACIT-Fatigue GSK3196165 vs. Placebo for Superiority at Week 12 
5. Pain VAS GSK3196165 vs Sarilumab for Superiority at week 24 
6. FACIT-Fatigue GSK3196165 vs. Sarilumab for Superiority at Week 24 


 
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The following steps will be followed to test the aforementioned hypotheses: 
Step Test 
Pre-requisite(s) 
P-value 
(2-sided) 
1 
ACR20 at week 12 for 
GSK3196165 150mg vs. 
placebo 
None 
0.05 
2 
ACR20 at week 12 for 
GSK3196165 90mg vs. 
placebo 
Step 1 passed 
0.025 
3 
HAQ-DI at week 12 for 
GSK3196165 150mg vs. 
placebo 
Both step 1 and 2 passed 
0.05 
Step 1 passed and step 2 failed 
0.025 
4 
HAQ-DI at week 12 for 
GSK3196165 90mg vs. 
placebo 
Step 3 tested at p=0.05 and passed 
0.025 
Step 3 tested at p=0.025 and passed 
0.0125 
5 
CDAI total score at week 
24 for superiority of 
GSK3196165 150mg vs. 
Sarilumab 
Step 3 tested at p=0.05 and step 4 
passed 
0.05 
Step 3 tested at p=0.05 and step 4 
failed  
0.025 
Step 3 tested at p=0.025 and step 4 
passed  
0.025 
Step 3 tested at p=0.025 and step 4 
failed 
0.0125 
6 
CDAI total score at week 
24 for superiority of 
GSK3196165 90mg vs. 
Sarilumab 
Step 5 tested at p=0.05 and passed 
0.05 
Step 5 tested at p=0.025 and passed 
0.025 
Step 5 tested at p=0.0125 and passed 
0.0125 
7 
FACIT-Fatigue at week 
12 for superiority of 
GSK3196165 150mg vs. 
placebo 
Step 6 tested at p=0.05 and passed 
0.05 
Step 6 tested at p=0.025 and passed 
0.025 
Step 6 tested at p=0.0125 and passed 
0.0125 
8 
FACIT-Fatigue at week 
12 for superiority of 
GSK3196165 90mg vs. 
placebo 
Step 7 tested at p=0.05 and passed 
0.05 
Step 7 tested at p=0.025 and passed 
0.025 
Step 7 tested at p=0.0125 and passed 
0.0125 
9 
Pain VAS at week 24 
superiority of 
GSK3196165 150mg vs. 
Sarilumab 
Step 8 tested at p=0.05 and passed 
0.05 
Step 8 tested at p=0.025 and passed 
0.025 
Step 8 tested at p=0.0125 and passed 
0.0125 
10 
Pain VAS at week 24 
superiority of 
GSK3196165 90mg vs. 
Sarilumab 
Step 9 tested at p=0.05 and passed 
0.05 
Step 9 tested at p=0.025 and passed 
0.025 
Step 9 tested at p=0.0125 and passed 
0.0125 
11 
FACIT-Fatigue at week 
24 for superiority of 
Step 10 tested at p=0.05 and passed 
0.05 
Step 10 tested at p=0.025 and passed 
0.025 
Step 10 tested at p=0.0125 and passed 
0.0125 


 
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Step Test 
Pre-requisite(s) 
P-value 
(2-sided) 
GSK3196165 150mg vs. 
Sarilumab 
12 
FACIT-Fatigue at week 
24 for superiority of 
GSK3196165 90mg vs. 
Sarilumab 
Step 11 tested at p=0.05 and passed 
0.05 
Step 11 tested at p=0.025 and passed 
0.025 
Step 11 tested at p=0.0125 and passed 
0.0125 
 
Analyses of other efficacy endpoints will not be subject to any multiplicity adjustment. 


 
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Figure 2 
Graphical presentation of the Multiple Testing Procedure 
 
Note: The number in the circles refer to the initial weighting of alpha. The number along 
the arrows refer to the weighting of alpha which is passed along to the next test. 


 
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5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
14.3 
Appendix 3: Assessment Windows 
14.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
14.5 
Appendix 5: Data Display Standards & Handling Conventions 
14.5 
Appendix 6: Derived and Transformed Data 
14.7 
Appendix 7: Reporting Standards for Missing Data 
14.8 
Appendix 8: Laboratory Parameters of Interest 
14.9 
Appendix 9: List of Preferred Terms 
14.10 
Appendix 10: Missing Data Imputation Strategies 
 


 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the “Screened”, “Randomised”, 
“Enrolled” or “ITT” population, unless otherwise specified. 
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.   
All concomitant medications summaries will use the “while on treatment” approach, i.e. 
any concomitant medications which are taken post discontinuation of study intervention 
plus safety follow-up (+84 days), will be excluded. 
Additional study population outputs relating to the COVID-19 pandemic will be based on 
GSK Core Data Standards, including: 
• Participant status and disposition by relationship to COVID-19 pandemic 
• Treatment status and reasons for discontinuation of study treatment by relationship to 
COVID-19 pandemic 
• Participants by country and site by implementation of pandemic measures 
• Protocol deviations related to COVID-19 pandemic 
• COVID-19 Visits and Assessments Impacts 
• Recruitment relative to COVID-19 pandemic measures 
Details of the planned displays are presented in Appendix 12: List of Data Displays.   
 


 
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7. 
EFFICACY ANALYSES 
As discussed in the ICH E9 addendum (R1) [ICH HARMONISED GUIDELINE, 2019] 
the specification of treatment effects to be estimated (the estimand) should include: 
• The population of interest. 
• The treatment condition of interest. 
• The outcome variable of interest. 
• The summary measure (which may be a model-based estimate or comparison). 
• The identification and strategy for handling potential intercurrent events. 
The following sections provide clarity on each of these components for the efficacy 
treatment effects to be estimated in this study and details on how missing outcomes will 
be handled. 
7.1. 
Primary Efficacy Analyses 
7.1.1. 
Primary Estimand Strategy 
The primary estimand for this study is derived directly from the primary objective of the 
study to determine whether GSK3196165 150mg is superior to placebo in the treatment 
of participants with moderately to severely active RA despite treatment with biological 
DMARDs and/or Janus Kinase inhibitors(i.e. bDMARD-IR and/or JAKi-IR) This will be 
assessed by the odds ratio of ACR20 at Week 12 for GSK3196165 versus placebo, 
regardless of: IP discontinuation for any reason, prohibited medication use or change in 
stable dose of background therapy.  Each component of this estimand is described below. 
7.1.1.1. 
Population 
Participants with moderately to severely active RA despite bDMARD or JAKi treatment, 
which is targeted using the inclusion and exclusion criteria.  
7.1.1.2. 
Treatment 
Those who receive at least one dose at either dose of GSK3196165 150mg, compared to 
those who receive at least one dose of placebo in addition to any other medication taken 
during the study 
7.1.1.3. 
Outcome Variable 
• ACR20 response at week 12. 
7.1.1.4. 
Summary Measure 
The odds ratio comparing GSK3196165 150mg with placebo. This measure will be 
derived from model-based adjusted estimates. 


 
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7.1.1.5. 
Strategy for Intercurrent (Post-Randomization) Events 
The intercurrent (post-randomisation) event (IE) anticipated to impact on the 
interpretation of the treatment effect for the primary objective are: 
1. Discontinuation of study intervention for any reason. 
2.  Use of prohibited medication 
3.  Change in stable dose of background medication 
The handling strategy for all of these IEs will be based on a treatment policy approach; 
specifically, the effects estimated will be based on initial randomized treatment arm 
regardless of whether the participant had observed the IE. Data will continue to be 
collected after the occurrence of the occurrence of the IE, until the participant either 
completes the study or withdraws from the study before completion.  
7.1.1.6. 
Handling of missing data 
Intermittent missing data (i.e. between two non-missing assessments) for the ACR20 
response will be imputed under a missing at random (MAR) assumption. 
If a participant experiences any of the IEs but efficacy data continues to be collected, 
their data will be analysed as if they were still on the original randomised intervention.  
Study withdrawal before the completion of the study will create missing outcome data. 
This may occur concurrently or after the IE.  
Missing data for the ACR20 response resulting from study withdrawal will be imputed 
using three possible MI models depending on the availability of off-treatment data (i.e. 
data that has been collected post discontinuation of study intervention), using principles 
introduced by Roger, 2019 (Computational details are included in Section 14.10): 
1. MI using off-treatment data within randomised treatment arm:  
If there is sufficient off-treatment data within a randomised treatment arm (i.e. at 
least 3 participants per arm per visit), then missing data will be imputed 
conditional on the participant’s observed outcomes, using off-treatment data 
within randomised treatment arm. The use of this MI model assumes that missing 
outcomes resulting from participants withdrawing from the study would behave in 
a similar way to other participants who discontinued study intervention, were 
randomised to the same treatment arm, and continued providing data post-
discontinuation of study intervention. 
 
2. MI using off-treatment data across all treatment arms: 
If there is insufficient off-treatment data within a randomised treatment arm (i.e. 
failure of the imputation model in option 1) but there is sufficient off-treatment 
data across all treatment arms combined (i.e. at least 3 participants per visit), then 
missing data will be imputed conditional on the participant’s observed outcomes, 
using off-treatment data across all treatment arms. The use of this MI model 
assumes that missing outcomes resulting from participants withdrawing from the 
study would behave in a similar way to other participants who discontinued study 


 
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intervention and continued providing data post-discontinuation of study 
intervention regardless of randomised treatment arm. 
 
3. MI under MAR assumption: 
If there is insufficient off-treatment data (i.e. neither option 1 nor 2 is feasible) 
then all missing data will be imputed under a MAR assumption. This MI model 
uses all available data collected on- and off-treatment within randomised 
treatment arm, and assumes missing outcomes resulting from participants 
withdrawing from the study would behave in a similar way to participants who 
were randomised to the same treatment arm and had data collected in the study, 
with no adjustment for values before or after intercurrent events. 
 
Note: Week 1 data will not be included in any imputation models due to the 
unavailability of off-treatment data at this visit by design of the study. 
7.1.1.7. 
Sensitivity Analysis for the handling of missing data 
An additional tipping point analysis will be performed as sensitivity if the endpoint is 
statistically significant and it is plausible that the imputation strategy for missing data 
could alter the conclusions of the analysis.  This will be performed at an ACR20 
responder level assuming all possible ACR20 response rates from 0 to 100% amongst 
those with missing ACR20 response in GSK3196165 arm and pooled placebo arm, 
separately. Full details of this analysis will be included in a separate analysis plan and 
results included in a separate report. 
7.1.2. 
Supplementary Analysis  
Two additional estimands for the primary objective will be considered and are described 
in this section. Computational details on both of these strategies are included in Section 
14.10. 
7.1.2.1. 
Supplemental Estimand 1 
As an additional estimand for the primary objective, a composite strategy will be 
considered for the handling of the IE of discontinuation of study intervention for any 
reason; specifically, a composite response definition will be used. A participant will be 
considered to be a non-responder if they do not meet the ACR20 response criterion or 
they discontinue study intervention for any reason. All other IEs will be handled using 
the same strategies as for the Primary Estimand Strategy (i.e. treatment policy). 
7.1.2.2. 
Supplemental Estimand 2 
As a second additional estimand for the primary objective, a hypothetical strategy will be 
considered for the handling of the IE of discontinuation of study intervention for any 
reason; specifically, the effects estimated will be under the hypothetical scenario where 
the IE did not occur.  
Any efficacy data collected after the occurrence of this IE will be excluded from the 
analysis. All data for the treatment response after the occurrence of the IE will be 


 
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imputed conditional on the participant’s observed outcomes, using on- and off-treatment 
data within randomised treatment arm. The use of this MI model assumes that missing 
outcomes would behave in a similar way to other participants who were randomised to 
the same treatment arm and had data collected in the study, with no adjustment for values 
before or after intercurrent events. 
All other IEs will be handled using the same strategies as for the Primary Estimand 
Strategy (i.e. treatment policy). 
7.1.2.3. 
Per-protocol Analysis 
As a supportive analysis, the primary analyses will be repeated using the “Per-protocol” 
population (see Section 14.1 for the definition).  
7.1.3. 
Statistical Analyses / Methods 
The efficacy analyses will be based in the “Intent-to-Treat” population, unless otherwise 
specified. 
Details of the planned displays are provided in Appendix 12 and will be based on GSK 
data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.1.1.3 will be 
summarised using descriptive statistics and graphically presented (where appropriate). 


 
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7.1.3.1. 
Statistical Methodology Specification 
Endpoint / Variables 
• Proportion of participants with ACR20 response at week 12. 
Model Specification 
• Each estimate will be generated for each imputed data set produced by the multiple 
imputation (MI) procedure described in Section 7.1.1.6, and the corresponding results will be 
combined using Rubin’s rules. 
• The proportion of participants with ACR20 response will be statistically analysed using a 
Logistic Regression model, comparing each randomised treatment arm with control group. 
• The Logistic Regression model will be fitted including fixed effects for treatment arm 
(GSK3196165 150mg, GSK3196165 90mg, sarilumab 200mg, pooled placebo), baseline 
swollen joint count 66 and baseline tender joint count 68, and previously failed medication 
category (1 bDMARD, >1 bDMARD, ≥1 JAK inhibitor). 
Model Checking & Diagnostics 
• If the logistic model fails to converge due to a small number of responders, the primary 
endpoint will be analysed using an exact logistic regression. In case of response rates of 0% 
or 100% in any of the treatment groups, confidence intervals for risk difference and p-values 
from the t-test for the risk difference comparing to 0 will be provided. 
Model Results Presentation 
• Results will be summarised using proportions of subjects (after MI) achieving a response. 
• Differences in the proportions of subjects (after MI) achieving response between each 
randomized treatment arm and pooled placebo will be summarised. 95% CI for the 
differences will be constructed using their asymptotic standard errors (asymptotic Wald 
confidence limits) without continuity correction. 
• Estimates of the Odds Ratio (OR), corresponding 95% confidence intervals and p-values will 
be constructed using the least squares (LS) means estimates from the logistic regression 
model. 
• Plots of the proportion of subjects achieving a response and their corresponding asymptotic 
standard errors will be generated for each treatment group by time. 
Subgroup Analyses 
• See Section 5.4 for details on subgroup analyses. 
Sensitivity and Supportive Analyses 
• Sensitivity Analysis on the missing data imputation methods may be performed as described 
in Section 7.1.1.7. 
• Supportive Analysis will be performed as described in Section 7.1.2. 
7.2. 
Secondary Efficacy Analyses 
7.2.1. 
Estimand strategy 
The secondary efficacy analysis will use the same estimand as the primary efficacy 
analysis (see Section 7.1.1 for details). 


 
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7.2.1.1. 
Population 
The population of interest for the secondary efficacy analysis is the same as is stated for 
the primary efficacy analysis (see Section 7.1.1.1). 
7.2.1.2. 
Treatment 
The treatment of interest for the secondary efficacy analysis is the same as is stated for 
the primary efficacy analysis (see Section 7.1.1.2). 
7.2.1.3. 
Outcome Variables 
The key secondary outcomes of interest are: 
• ACR20 response at week 12 (superiority of GSK3196165 90mg over placebo 
comparison). 
• HAQ-DI at week 12 (superiority over placebo comparison).  
• CDAI Total Score at week 24 (superiority over sarilumab). 
• FACIT-Fatigue at week 12 (superiority over placebo comparison) and at week 24 
(superiority over sarilumab comparison). 
• Pain VAS at week 24 (superiority over sarilumab). 
The other secondary outcomes of interest (at each visit) are: 
• ACR20/50/70 response. 
• CDAI LDA (CDAI Total Score≤2.8). 
• CDAI Remission (CDAI Total Score≤2.8). 
• DAS28-CRP LDA (DAS28-CRP≤3.2). 
• DAS28-ESR LDA (DAS28-ESR≤3.2). 
• DAS28-CRP Remission (DAS28-CRP<2.6). 
• DAS28-ESR Remission (DAS28-ESR<2.6). 
• Good/moderate EULAR response. 
• ACR/EULAR Remission. 
• TJC28/68 and SJC28/66. 
• CRP (mg/L). 
• PtGA/PhGA. 
• DAS28-(CRP/ESR). 
• Arthritis pain VAS. 
• SF-36 physical and mental component scores, and individual domain scores. 
• FACIT-Fatigue score. 
7.2.1.4. 
Summary Measure 
The key secondary summary measures are: 
• The odds ratio comparing GSK3196165 90mg arm with placebo in the proportion of 
participants achieving ACR20 at week 12. 
• The difference between GSK3196165  arms and placebo in the change from baseline 
in HAQ-DI at week 12. 
• The difference between GSK3196165 arms and Sarilumab  in the change from 
baseline in CDAI Total Score at week 24. 


 
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• The difference between GSK3196165 arms and placebo in the change from baseline 
in FACIT-Fatigue Score at week 12. 
• The difference between GSK3196165 arms and Sarilumab  in the change from 
baseline in arthritis pain VAS at week 24. 
• The difference between GSK3196165 arms and Sarilumab in the change from 
baseline in FACIT-Fatigue Score at week 24. 
For all secondary endpoints (including the key secondary endpoints), the following 
summary measures will be assessed: 
• Odds ratio and/or difference from placebo at all assessment visits up to week 12.   
• Odds ratio and/or difference from Sarilumab at all assessment visits.  
All summary measures will be derived from model-based adjusted estimates for each 
treatment arm. 
7.2.1.5. 
Strategy for Intercurrent (Post-Randomization) Events 
The same strategy as the primary efficacy analysis will be implemented for all secondary 
efficacy analyses (See Section 7.1.1.5 for full details) 
7.2.1.6. 
Handling of missing data 
The same missing data handling strategy as the primary efficacy analysis will be 
implemented for all secondary efficacy analyses (See Section 7.1.1.6 for full details) 
7.2.1.7. 
Sensitivity Analysis for the handling of missing data 
A tipping point analysis will be performed as sensitivity of the key secondary efficacy 
analyses if the endpoints are statistically significant and it is plausible that the imputation 
strategy for missing data could alter the conclusions of the analysis.  For binary 
endpoints, the same tipping point strategy as for the primary endpoint will be 
implemented (see Section 7.1.1.7 for full details). For continuous endpoints, this will be 
performed by applying a shift parameter to the mean for the participants with missing 
outcomes in the GSK3196165 arms and the control arm, separately. Full details of this 
analysis will be included in a separate analysis plan and results included in a separate 
report. 
7.2.2. 
Supplementary Analysis 
The same supplemental strategies as the primary efficacy analysis may be implemented 
for the key secondary efficacy endpoint analyses as follows: 
• Supplemental estimand 1 will be applied to ACR20 (see Section 7.1.2.1 for details). 
• Supplemental estimand 2 will be applied to CDAI Total score and Pain VAS (see 
Section 7.1.2.2 for details). 


 
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7.2.3. 
Statistical Analyses / Methods 
The secondary efficacy analyses will be based in the “Intent-to-Treat” population, unless 
otherwise specified. 
Details of the planned displays are provided in Appendix 12, and will be based on GSK 
data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.2.1.3 will be 
summarised using descriptive statistics and graphically presented (where appropriate). 


 
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7.2.3.1. 
Statistical Methodology Specification 
Binary Endpoints 
Endpoint / Variables 
• Proportion of participants achieving ACR20 response. 
• Proportion of participants achieving CDAI-LDA (CDAI Total Score≤10).  
• Proportion of participants achieving ACR50/70 response. 
• Proportion of participants achieving CDAI Remission (CDAI Total Score≤2.8). 
• Proportion of participants achieving DAS28-(CRP/ESR) LDA (DAS28-CRP≤3.2 or DAS28-
ESR≤3.2). 
• Proportion of participants achieving DAS28-(CRP/ESR) remission (DAS28-CRP<2.6 or 
DAS28-ESR<2.6). 
• Proportion of participants achieving Good/moderate EULAR response. 
 
Model Specification 
• Each estimate will be generated for each imputed dataset produced by the multiple 
imputation (MI) procedure described in Section 7.1.1.6, and the corresponding results will be 
combined using Rubin’s rules. 
• Binary Endpoints will be statistically analysed using the same methods as for the primary 
endpoint (See Section 7.1.3.1 for full details) however the model will be adjusted for the 
following baseline values: 
Binary Endpoint  
Baseline adjustment 
ACR20  
TJC68, SJC66 
ACR50  
TJC68, SJC66 
ACR70  
TJC68, SJC66 
CDAI-LDA  
CDAI Total Score 
CDAI Remission  
CDAI Total Score 
DAS28-CRP LDA  
DAS28-CRP 
DAS28-CRP Remission  
DAS28-CRP 
DAS28-ESR LDA  
DAS28-ESR 
DAS28-ESR Remission  
DAS28-ESR 
Good/Moderate EULAR (CRP)  
DAS28-CRP 
• A separate logistic regression model will be fitted for each assessment time point. For time 
points up to week 12, all treatment arms will be included in the model (i.e. pooled placebo, 
GSK3196165 150mg, GSK3196165 90mg, sarilumab 200mg). For time points beyond week 
12, only GSK3196165 150mg, GSK3196165 90mg and sarilumab 200mg randomised 
treatment arms will be included in the model. 
• If at any time point the convergence criterion is not satisfied or maximum likelihood 
estimates do not exist, then the results of this model will not be reported. 
Model Checking & Diagnostics 
• The same model checking and diagnostics will be used as for the primary endpoint. See 
Section 7.1.3.1 for full details. 


 
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Model Results Presentation 
• Binary Endpoints will be presented using the same methods as the primary endpoint. See 
Section 7.1.3.1 for full details. 
• The results from each assessment time point model will be presented within the same 
output. 
• Non-inferiority over sarilumab on ACR20 will be concluded if the lower limit of the multiplicity 
corrected 95% CI in the difference in proportions (GSK3196165 minus sarilumab) is greater 
than -12% (Note: non-inferiority was calculated using the FDA fixed margin approach [FDA, 
2016]). 
Subgroup Analyses 
• See Section 5.4 for details on subgroup analyses. 
Sensitivity and Supportive Analyses 
• Sensitivity Analysis on the missing data imputation methods will be performed as described 
in Section 7.2.1.7. 
• Supportive Analysis will be performed as described in Section 7.2.2. 
 
Continuous Endpoints 
Endpoint / Variables 
• Change from baseline in HAQ-DI. 
• Change from baseline in CDAI Total Score. 
• Change from baseline in FACIT-Fatigue score. 
• Change from baseline in arthritis pain VAS. 
• Change from baseline in TJC28/68 and SJC28/66. 
• Change from baseline in CRP (mg/L) 
• Change from baseline in PtGA/PhGA. 
• Change from baseline in DAS28-(CRP/ESR). 
• Change from baseline in SF-36 physical and mental component scores. 
Model Specification 
• Each estimate will be generated for each imputed dataset produced by the multiple 
imputation (MI) procedure described in Section 7.1.1.6, and the corresponding results will be 
combined using Rubin’s rules. 
• Continuous endpoints will be statistically analysed using an analysis of covariance 
(ANCOVA) comparing each randomised treatment arm with control groups when controlling 
for treatment arm, respective baseline value and previously failed medication category (1 
bDMARD, >1 bDMARD, ≥1 JAK inhibitor). 
• A separate ANCOVA will be conducted for each assessment time point. For time points up 
to week 12, all treatment arms will be included in the model (i.e. pooled placebo, 
GSK3196165 150mg, GSK3196165 90mg, sarilumab 200mg). For time points beyond week 
12, only GSK3196165 150mg, GSK3196165 90mg and sarilumab 200mg randomised 
treatment arms will be included in the model. 


 
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Model Checking & Diagnostics 
• If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data. 
Model Results Presentation 
• The results from each assessment time point will be presented within the same output. 
• Point estimates and corresponding 95% confidence intervals will be constructed for the 
treatment differences over placebo and over sarilumab at each visit using the least squares 
(LS) means estimates.  
• Plots of LS means and corresponding standard error from the model will be generated for 
each treatment group by visit. 
• Non-inferiority over sarilumab on change from baseline in CDAI Total score will be 
concluded if the upper limit of the multiplicity corrected 95% CI in the treatment difference 
(GSK3196165 minus sarilumab) is less than 3.5 (Note: non-inferiority was calculated using 
the FDA fixed margin approach [FDA, 2016]). 
• Non-inferiority over sarilumab on change from baseline in Pain VAS will be concluded if the 
upper limit of the multiplicity corrected 95% CI in the treatment difference (GSK3196165 
minus sarilumab) is less than 5.3 (Note: non-inferiority was calculated using the FDA fixed 
margin approach [FDA, 2016]). 
Subgroup Analyses 
• See Section 5.4 for details on subgroup analyses. 
Sensitivity and Supportive Analyses 
• 
Sensitivity Analysis on the missing data imputation methods will be performed as 
described in Section 7.2.1.7. 
• 
Supportive Analysis will be performed as described in Section 7.2.2. 
• 
Non-parametric analyses may be conducted if the normality assumption does not hold. 
 


 
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8.  
S A F E T Y A N A L Y S E S  
T he safet y a nal yses will be base d o n t he “ Safet y” p o p ulati o n, u nless ot her wise s pecifie d.  
Safet y a nal ysis will be dis pla ye d i n t hree differe nt wa ys (see Secti o n  5. 1. 3  f or details). 
 
All pri mar y s afet y a nal ysis will use t he “ w hile o n treat me nt” a p pr oac h, i.e. a n y s afet y 
e ve nts w hic h occ ur p ost disc o nti n uati o n of st u d y i nter ve nti o n w hic h are n ot classifie d as 
treat me nt e mer ge nt u n der t he defi niti o n s pecifie d i n Secti o n  1 4. 4. 2 , will be e x cl u de d. A 
se nsiti vit y a nal ysis will  be perf or me d  o n ke y s afet y o ut p uts  usi n g t he “ treat me nt p olic y” 
a p pr oac h, i. e. all safet y e ve nts re p orte d i n t he st u d y will be i n cl u de d.  
Missi n g safet y d ata will n ot be i m p ute d.  T he details of t he pla n ne d dis pla ys are pr o vi de d 
i n A p pe n di x 1 2 . 
8. 1.  
A d v er s e E v e nt s A n al y s e s  
•  A d verse e ve nts a n al ys es  i ncl u di n g the a n al ysis of a d verse e ve nts ( A Es), Seri o us 
a d verse e ve nts ( S A Es) a n d ot her i m p orta nt a d verse e ve nts will be base d o n G S K 
C ore Data Sta n dar ds.  
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• All AEs will be classified using the current standard GSK Medical Dictionary for 
Regulatory Activities (i.e. MedDRA version in use at the time of reporting), and 
grouped by SOC and PT, unless otherwise stated.  MedDRA version will be detailed 
on every table that uses MedDRA. 
• Exposure adjusted incidence rates per 100 patient years by treatment group will be 
presented for all AEs and SAEs. 
• Common AEs will be defined as ≥ 5% incidence in any treatment group, unless 
otherwise specified. Relative risks, based on observed frequencies, for the proportions 
of subjects with common AEs will be calculated for the comparisons specified in 
Section 5.1.3. 
• AEs with missing intensity will be considered severe.  
• Additional safety outputs relating to COVID-19 adverse events including COVID-19 
assessments and symptom assessments will be based on GSK Core Data Standards. 
8.1.1. 
Adverse Events of Special Interest and Other Important AEs 
Analyses 
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event. Changes to the MedDRA dictionary may occur between the start of 
the study and the time of reporting and/or emerging data from on-going studies may 
highlight additional adverse events of special interest, therefore the list of terms to be 
used for each event of interest and the specific events of interest will be based on the 
safety review team (SRT) agreements in place at the time of reporting.  
The details regarding the derivations of adverse events of special interest (AESI) and 
other important AEs are provided in Section 14.6.4.   
Exposure adjusted incidence rates per 100 patient-years by treatment group will be 
calculated for each category of AESI and other important AE. 
Relative risks, based on observed frequencies, for the proportions of subjects with AESIs 
will be calculated for the comparisons specified in Section 5.1.3. 
8.2. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, fasting lipids, and liver function tests will be based on GSK 
Core Data Standards. 
All laboratory parameters will be summarised, but only laboratory parameters of interest 
with available CTCAE grades will be used in summary table by grades. 


 
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Laboratory parameters of interest are: 
• WBCs 
• Neutrophils  
• Lymphocytes 
• Hemoglobin 
• Platelets 
• ALT 
• AST 
• ALP 
• Bilirubin  
• Creatinine  
• eGFR  
• Total cholesterol  
• Low-density lipoprotein (LDL)  
• High-density lipoprotein (HDL) 
• Triglycerides  
Local laboratory parameters will not be included in any summaries and will appear in the 
listing only. 
8.3. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. 
8.3.1. 
Immunogenicity Analyses  
An immune response to GSK3196165 can lead to generation of anti-drug antibodies 
(ADA). For the immunogenicity assessment, two types of antibody assays will be 
performed, a binding antibody assay and a neutralizing antibody assay. 
For the binding antibody assay, there will be three testing steps: screening, confirmation, 
and titration. The screening assay produces a result of positive or negative relative to a 
screening cut point. Positive samples continue with the confirmation assay, which also 
produces a result of positive or negative relative to a confirmation cut point. For samples 
with a positive confirmation result, a titre value will also be obtained to quantify the 
degree of binding in a titration assay. Subjects with confirmed positive results, will also 
be tested in the neutralizing antibody assay, which also reports results as positive or 
negative. 
Subjects will be categorized as positive or negative based on confirmation step and a 
positive ADA event will further be categorized as transient positive or persistent positive 
at each visit and for anytime post baseline visit. Transient positive is defined as a single 
positive immunogenic response where the previous visit is negative, that does not occur 
at the final study assessment and persistent positive is defined as a positive immunogenic 
response where the previous visit is positive or the final study assessment is positive. 
Titers will be summarized by median, minimum, and maximum. 


 
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 A summary of treatment emergent positive confirmation binding ADA assay results in 
the subset of subjects who did not have a positive confirmation binding ADA assay result 
prior to the dosing of study treatment will also be presented. 
Neutralizing antibody assay results will be summarised by visit. For anytime post 
baseline visit, highest result will be used, i.e. according to the following hierarchy: ADA 
result will be Persistent Positive > Transient Positive > Negative, NAB result will be 
Positive > Negative and highest titer value.  
 


 
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9. 
PHARMACOKINETIC ANALYSES 
9.1. 
Primary Pharmacokinetic Analyses 
9.1.1. 
Endpoint / Variables 
GSK3196165 serum concentrations. 
9.1.1.1. 
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 14.5.3 
Reporting Standards for Pharmacokinetic) 
9.1.2. 
Summary Measure 
GSK3196165 serum concentrations at each assessment visit.  
9.1.3. 
Population of Interest  
The primary pharmacokinetic analyses will be based on the Pharmacokinetic population, 
unless otherwise specified. 
9.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
No strategy for the handling of intercurrent events will be implemented. 
9.1.5. 
Statistical Analyses / Methods 
Details of the planned displays will be based on GSK Data Standards and statistical 
principles. 
Unless otherwise specified, endpoints / variables defined in Section 9.1.1 will be 
summarised using descriptive statistics and listed. 


 
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10. 
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES 
The primary goal of this analysis is to characterize the population pharmacokinetics of 
GSK3196165 administered subcutaneously in participants with Rheumatoid Arthritis. 
The influence of subject demographics, baseline characteristics, including disease 
activity, modality of administration, and co-medication on the pharmacokinetics of 
GSK3196165 in this population will be investigated. The PK data from this study will be 
combined with PK data from other studies in GSK3196165. Details of the population PK 
analysis will be provided in a separate technical analysis plan and reported in a 
standalone report. 


 
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P H A R M A C O D Y N A MI C A N D BI O M A R K E R A N A L Y S E S  
1 1. 1.  
E x pl or at or y P h ar m a c o d y n a mi c a n d Bi o m ar k er A n al y s e s  
1 1. 1. 1.  
E n d p oi nt / V ari a bl e s  
•  P har mac o d y na mic  bi o mar kers:  
o  C he m o ki ne ( C -C M otif) Li ga n d 1 7 ( C C L 1 7) 
o  M M P De gra de d T y p e 1 C olla ge n ( C 1 M)  
o  C olla ge n III N e o -pe pti de C 3 M ( C 3 M) 
o  S ol u ble I nterl e u ki n 2 Rece pt or (I L 2 S R ) 
o  I nterle u ki n 6 (IN T L K 6 ) 
o  Macr o p ha ge -D eri ve d C h e m o ki ne ( M D C)  
o  Oste ocalci n ( O S T E O C)  
o  P 4 N P 7 S  I nt E pit o pe 7 S D o mai n T I V C oll ( P 4 N P 7 S)  
o  Citr ulli nate d M M P -De gra de d Vi me nti n  ( VI C M) 
•  He patic C Y P 3 A  bi o mar kers:  
o  4 ꞵ-h y dr o x yc h olester ol ( 4 B -O H C ) 
o  C h olester ol  
o  N or malise d 4 ꞵ-h y dr o x yc h olester ol  ( Rati o of 4 B-O H C/ C h olest er ol) 
•  Safet y bi o mar kers:  
o  G M -C S F A ut oa nti b o d y  
•  Tar get E n ga ge me nt bi o mar kers:  
o  G M -C S F C o m ple x  
o  G M -C S F Free S ol u ble  
1 1. 1. 2.  
S u m m ar y M e a s ur e  
•  C ha n ge fr o m bas eli ne  i n p har mac o d y n a mic bi o mar kers at eac h assess me nt visit : 
o  Differe nce fr o m place b o at all assess me nt visits u p t o wee k 1 2.   
o  Differe nce fr o m Saril u m a b at all assess me nt visits.  
•  O bser ve d res ult a n d rati o t o  baseli ne i n he patic C Y P 3 A  bi o mar kers  at eac h 
assess me nt visit  
1 1. 1. 3.  
P o p ul ati o n of I nt er e st  
T he e x pl orat or y p h ar mac o d y na mic a n d bi o mar ker  a nal ys es will be base d o n t he  Safet y  
p o p ulati o n, u nless ot her wise s pecifie d.  
1 1. 1. 4.  
Str at e g y f or I nt er c urr e nt ( P o st -R a n d o mi z ati o n) E v e nt s  
N o strate g y f or t h e ha n dli n g of i nterc urre nt e ve nts will be i m ple me nte d. 
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11.1.5. 
Statistical Analyses / Methods 
Details of the planned displays will be based on GSK Data Standards and statistical 
principles. 
Unless otherwise specified, endpoints / variables defined in Section 11.1.1 will be 
summarised using descriptive statistics and graphically presented (where appropriate). 
Biomarker levels below the lower limit of quantification (LLOQ) will replaced by 
0.5*LLOQ in all analyses. 
 
Endpoint/Variables 
• Change from baseline in pharmacodynamic biomarkers 
Model Specification 
• Endpoints will be statistically analysed using Mixed Model Repeated Measures (MMRM) 
model 
• Two models will be fitted: 
o Up to week 12 (placebo comparison): where all treatment arms will be included in 
the model (i.e. pooled placebo, GSK3196165 150mg, GSK3196165 90mg, 
sarilumab 200mg). 
o Week 0 to Week 24 (sarilumab comparison): where only GSK3196165 150mg, 
GSK3196165 90mg and sarilumab 200mg randomised treatment arms will be 
included in the model. 
• The models will include terms for treatment arm, visit, respective baseline value, previously 
failed medication category (1 bDMARD, >1 bDMARD, ≥1 JAK inhibitor) and treatment arm-
by-visit interaction. 
• Models will be fitted using an unstructured covariance matrix. 
• The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used. 
Model Checking and Diagnostics 
• If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data. 
Model Results Presentation 
• Point estimates and corresponding 95% confidence intervals will be constructed for the 
treatment differences over placebo and over sarilumab at each visit using the least squares 
(LS) means estimates.  
• Plots of LS means and corresponding standard error from the model will be generated for 
each treatment group by visit. 
 


 
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12. 
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES 
The primary goal of this analysis is to characterize the pharmacokinetic / 
pharmacodynamic relationship of effect of GSK3196165 on efficacy, safety and target 
engagement including downstream signalling of GM-CSF after SC administration in 
combination with a csDMARD in participants with moderately to severely active 
rheumatoid arthritis. The data from this study might be combined with data from other 
studies in GSK3196165.  Details of the PK/PD analysis will be provided in a separate 
technical analysis plan and reported in a standalone report. 


 
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13. 
REFERENCES 
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med. 2009;28(4):586-604. 
FDA (Food and Drug Administration). Guidance for Industry: Non-Inferiority Clinical 
Trials to Establish Effectiveness. 2016. https://www.fda.gov/media/78504/download  
Freynhagen R, Baron R, Gockel U, Tölle T.R, CurrMed ResOpin Vol 22, 2006, 1911-
1920 © 2006 Pfizer Pharma GmbH, Pfizerstr.1, 76139 Karlsruhe, Germany. 
ICH HARMONISED GUIDELINE. Addendum on estimands and sensitivity analysis in 
clinical trials to the guideline on statistical principles for clinical trials E9(R1). 2019. 
https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf 
NCI. National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 
NCI, NIH, DHHS. 2017. 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Q
uick_Reference_5x7.pdf 
Roger JH, Bratton DJ, Mayer B, Abellan JJ, Keene ON. Treatment policy estimands for 
recurrent event data using data collected after cessation of randomised treatment. 
Pharmaceutical Statistics. 2019;18:85–95. 


 
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14. 
APPENDICES 
14.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
14.1.1. 
Exclusions from Per Protocol Population 
A subject meeting any of the following criteria will be excluded from the Per Protocol 
population: 
Number 
Exclusion Description 
01 
Participant was randomised despite not meeting an eligibility criteria which, in the 
judgement of the clinical team, constitutes an exclusion from the Per protocol population 
(Subset of Important Protocol Deviations with GSK category 2) 
02 
Medication/Vaccine excluded by the protocol was administered, including those restricted 
prior to the study, during the study and/or during the safety follow-up of the study 
(Important Protocol Deviations with GSK categories 4A or 4B) 
03 
Participant substantially did not receive medication as planned per protocol (Important 
Protocol Deviations with GSK category 7A). 
04 
Participant received medication while in contraindication (Important Protocol Deviations 
with GSK category 7B) 
05 
Participant received wrong study treatment or assignment (Important Protocol Deviations 
with GSK category 7C) 
06 
Participant had significant non-compliance or dose modification of background treatment 
(Important Protocol Deviations with GSK category 7OT) 
07 
Participant developed withdrawal criteria specified in the protocol but were not withdrawn 
and continued dosing (Important Protocol Deviations with GSK category 3A, 3B or 3OT) 
08 
Study blind/unblind procedures: Investigator/site staff/participant/GSK Clinical team did 
not remain blinded to treatment assignment through Week 24 Exit visit efficacy 
evaluation, includes emergency unblinding for medical reasons (Important Protocol 
Deviations with GSK category 8B) 
09 
Other: a deviation that does not satisfy the above criteria, however, in the judgment of the 
clinical team, including the medical monitor, constitutes an exclusion from the Per 
Protocol population. 
 
 


 
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14.2. 
Appendix 2: Schedule of Activities 
14.2.1. 
Protocol Defined Schedule of Events 
 
 
 
 


 
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14.3. 
Appendix 3: Assessment Windows 
14.3.1. 
Definitions of Assessment Windows for Analyses 
Data will be analysed as per the planned visit assignment. 
Early withdrawal and unscheduled visits will be slotted to the appropriate planned visit.  
The assigned visit will be based on the interval in which the Study Day for the early 
withdrawal or unscheduled visit falls according to intervals provided below. 
Analysis Set / 
Domain 
Target  
Analysis Window 
Analysis Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
All 
Day-1 
Day -42 
Day -1 
Screening 
All 
Day 1 
Day 1 
Day 1 
Baseline 
All (Efficacy, lung 
auscultation and 
pulse oximetry) 
Day 8 
Day 2 
Day 11 
Week 1 
All (Safety) [1] 
Day 8 
Day 2 
Day 22 
Week 2 
All (Efficacy, lung 
auscultation and 
pulse oximetry) 
Day 15 
Day 12 
Day 22 
Week 2 
All 
Day 29 
Day 23 
Day 43 
Week 4 
All 
Day 57 
Day 44 
Day 71 
Week 8 
All  
Day 85 
Day 72 
Day 88 
Week 12 
All  
Day 92 
Day 89 
Day 95 
Week 13 
All (Safety) 
Day 113 
Day 96 
Day 135 
Week 16 
All (Efficacy) 
Day 113 
Day 96 
Day 141 
Week 16 
All (Safety) 
Day 155 
Day 136 
Day 160 
Week 22 
All (Efficacy) 
Day 169 
Day 142 
Day 231 
Week 24 
All (Safety) 
Day 169 
Day 161 
Day 231 
Week 24 
All (Safety) 
Day 239 
Day 232 
Day 232+ 
12-week Follow-up (for 
participants who don’t 
transition into LTE 
study) 
Safety 
(participants 
withdrawn early 
from treatment) 
84 days after 
last treatment 
77 days after last 
treatment 
91 days after last 
treatment 
12 Week Follow Up 
NOTES: 
• 
If there are two values within a time window, the value closest to the target day for that window will be used . 
If values are the same distance from the target, then the mean will be taken. 
• 
[1] Excluding lung auscultation and pulse oximetry 
 


 
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14.4. 
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events 
14.4.1. 
Study Phases 
Assessments and events will be classified according to the time of occurrence relative to 
study treatment start date. 
On-Treatment AEs will be reported as treatment emergent AEs (TEAE). Definition for 
TEAE can be found in Section 14.4.2. 
If an AE happened at week 12 visit, it will be assigned to Period 2. 
For Placebo: 
Study Phase 
Period 
Definition 
Pre-Treatment 
 
Date ≤ Study Treatment Start Date 
On-Treatment 
Period 1 
Study Treatment Start Date < Date ≤ Week 12 Visit Date or Early 
Withdrawal (if before Week 12) Visit Date  
Off-Treatment 
Safety Follow-Up[1] 
 
Study Treatment Stop Date < Date ≤ Study Treatment Stop Date + 84 
days 
Off-Treatment 
 
Date ≥ Study Treatment Stop Date + 84 days 
[1] The safety follow up definition for Placebo is only valid for participants who withdraw early. The participants that are 
on placebo who complete Period 1, will continue into Period 2. 
For GSK3196165: 
Study Phase 
Period 
Definition 
Pre-Treatment   
Date ≤ Study Treatment Start Date 
On-Treatment 
Period 1 
Study Treatment Start Date < Date ≤ Week 12 Visit Date or Early 
Withdrawal (if before week 12) Visit Date + 7 days 
Period 2 
Week 12 Visit Date < Date ≤ Study Treatment Stop Date + 7 days or Early 
Withdrawal (if after week 12) Visit Date + 7 days 
Off-Treatment 
Safety Follow-
Up 
 
Study Treatment Stop Date + 7 days < Date ≤ Study Treatment Stop Date + 
84 days 
Off-Treatment 
 
Date ≥ Study Treatment Stop Date + 84 days 
 


 
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For Sarilumab: 
Study Phase 
Period 
Definition 
Pre-Treatment   
Date ≤ Study Treatment Start Date 
On-Treatment 
Period 1 
Study Treatment Start Date < Date ≤ Week 12 Visit Date or Early 
Withdrawal (if before week 12) Visit Date+ 14 days 
Period 2 
Week 12 Visit Date < Date ≤ Study Treatment Stop Date + 14 days or Early 
Withdrawal (if after week 12) Visit Date + 14 days 
Off-Treatment 
Safety Follow-
Up 
 
Study Treatment Stop Date + 14 days < Date ≤ Study Treatment Stop Date 
+ 84 days 
Off-Treatment 
 
Date ≥ Study Treatment Stop Date + 84 days 
 
14.4.1.1. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
Any medication that started before first dose of study treatment 
Concomitant 
Any medication that is taken post first dose of study treatment, regardless of whether it 
was started prior to the first dose of study treatment or not 
NOTES:  
• 
Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing. 
 
14.4.2. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
• 
Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date + 84 
days. 
NOTES:  
• 
If the study treatment stop date is missing, then the AE will be considered to be On-Treatment. 
• 
Time of study treatment dosing and start/stop time of AEs should be considered, if collected. 
• 
If AE happens on the week 12 visit date, it will be assigned to period 2. 
 


 
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14.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
14.5.1. 
Reporting Process 
Software 
• 
The currently supported versions of SAS software 9.4 will be used. 
Reporting Area 
HARP Server 
: UK1SALX00175 
HARP Compound 
: GSK3196165/MID202018 
Analysis Datasets  
• 
Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.1).  
Generation of RTF Files 
• 
RTF files will be generated for the final reporting effort for tables and listings. 
14.5.2. 
Reporting Standards 
General 
• 
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
o 4.03 to 4.23: General Principles 
o 5.01 to 5.08: Principles Related to Data Listings 
o 6.01 to 6.11: Principles Related to Summary Tables 
o 7.01 to 7.13: Principles Related to Graphics  
• 
Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject 
level listings should be located in the modular appendices as ICH or non-ICH listings 
Formats 
• 
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected, unless otherwise stated. 
• 
Numeric data will be reported at the precision collected on the eCRF. 
• 
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s.  
Planned and Actual Time 
• 
Reporting for tables, figures, and formal statistical analyses: 
• 
Planned time relative to dosing will be used in figures, summaries, statistical analyses, and 
calculation of any derived parameters, unless otherwise stated. 
• 
The impact of any major deviation from the planned assessment times and/or scheduled visit 
days on the analyses and interpretation of the results will be assessed as appropriate. 
• 
Reporting for Data Listings:  
• 
Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1). 
• 
Unscheduled or unplanned readings will be presented within the subject’s listings.  
Unscheduled Visits 
• 
Unscheduled visits will be slotted as stated in Section 14.3.1 unless otherwise stated. 
• 
All unscheduled visits will be included in listings. 


 
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Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• 
Refer to IDSL Statistical Principals 7.01 to 7.13. 
14.5.3. 
Reporting Standards for Pharmacokinetic Concentration Data 
Pharmacokinetic Concentration Data 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_000722, Section 3.5.1 
“For the calculation of mean or median pharmacokinetic profiles”  
 
14.5.4. 
Reporting Standards for Log-transformed Parameters 
Reporting of Log-Transformed Parameters 
Descriptive 
Summary Statistics  
N, n, geometric mean, 95% CI of geometric mean, geometric coefficient of 
variation (CVb (%)) will be reported. 
[1] CVb (%) = √ (exp(SD2) - 1) * 100 
Figures 
Axes will be presented with actual values with an appropriate log-scale (either 
base 2 or base 10) depending on range of values 
 
 


 
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14.6. 
Appendix 6: Derived and Transformed Data 
14.6.1. 
General 
Multiple Measurements at One Analysis Time Point 
• 
Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented. 
• 
Data will be analysed as per the planned visit assignment. 
• 
Early withdrawal and unscheduled visits will be slotted to the appropriate planned visit (as per 
Section 14.3.1). If there are two slotted values within a time window the value closest to the target 
day for that window will be used except for ECGs. If values are the same distance from the target, 
then the mean will be taken. 
• 
In the instance of both local and central labs being collected at the same timepoint, only the central 
labs will be used in any analysis. 
• Triplicate ECG measures will be averaged for each subject and visit prior to generating 
summary tables. 
• 
Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance 
summary tables. 
Study Day 
• 
Calculated as the number of days from First Dose Date: 
• 
Ref Date = Missing              → Study Day = Missing  
• 
Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date 
• 
Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1     
Period 1 (Up to Week 12) 
• 
Period 1 (Up to Week 12) is defined as time from randomisation up to dosing of period 2 study 
medication (week 12) or date of study withdrawal or date of treatment withdrawal plus follow up, 
whichever is earlier. 
• 
A participant completed 12 weeks of treatment if study medication (injection) was administered at 
week 11 visit or later up to next study medication administration or study medication (capsule) was 
administered at week 11 plus 6 days or later up to next study medication administration 
• 
A participant completed week 12 if week 12 assessments were performed and study medication of 
the next period was administered. 
• 
A participant withdrew from the study if the withdrawal date is < date of study medication 
administration of period 2 (week 12) 
Period 2 (Post Week 12)  
• 
Period 2 (post week 12) is defined as time from first dose of study medication of period 2 (Week 12) 
until date of study completion or date of study withdrawal or date of treatment withdrawal plus safety 
follow up whichever is earlier. 
• 
A participant withdrew from the study if the withdrawal date > date of study medication administration 
of period 2 
Study Completion  
• 
For subjects not entering LTE study: completion of study is defined as completion of treatment plus 
follow up period. 
• 
For subjects entering LTE: completion of study is defined as completion of the week 52 visit. 
 


 
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14.6.2. 
Study Population 
Treatment Compliance 
• 
Treatment compliance will be calculated based on the formula: 
For GSK3196165:   
Treatment Compliance =  
(Number of Actual Doses / Planned Treatment Duration in Weeks) *100 
For Sarilumab: 
Treatment Compliance =  
(Number of Actual Doses / (Planned Treatment Duration in Weeks/2)) *100 
• 
Treatment compliance could be greater than 100% if there are events of overdose. Cumulative 
compliance (since Day 1) at each visit will be calculated. 
• 
Planned Treatment Duration is 24 weeks. 
• 
Compliance for early treatment discontinuation participants will only be calculated up until the date of 
early treatment discontinuation. 
Date of Birth and Age 
• Only the year of birth will be captured, and therefore the date of birth is then derived as follows: 
Year of birth = YYYY → Date of birth = 30th June YYYY 
• 
Age in years will be calculated as integer part of (latest of (randomisation date, screening date)– date 
of birth). 
• 
Birth date will be presented in listings as ‘YYYY’. 
Extent of Exposure 
• 
Number of days of exposure to study drug will be calculated based on the formula:   
For GSK3196165: 
Duration of Exposure in Days =  
[(Treatment stop date – treatment start date) + 7]-[(Number of missed injections) * 7] 
For Sarilumab:  
Duration of Exposure in Days = 
[(Treatment Stop Date – Treatment Start Date) + 14]-[(Number of missed injections) * 7] 
 
• 
Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure.  
• 
The cumulative dose will be based on the formula: 
Cumulative Dose = Sum of Total Dose at Each Visit 
Disease History/Duration 
• RA duration since diagnosis in years will be calculated based on the formula: 
RA Duration Since Diagnosis in Years =   
(Date of First Dose of Study Treatment - Start date of RA diagnosis + 1)/365.25 
• RA duration since first symptoms in years will be calculated based on the formula: 
RA Duration Since First Symptoms in Years =   
(Date of First Dose of Study Treatment - Start date of first symptoms + 1)/365.25 
 
 
Stratification Stratum (Previously Failed Medication) 
• Stratification stratum will be derived from the randomisation numbers as follows: 


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
6 4  
 
R a n d o miz ati o n N u m b er s  
Str at u m  
1 b D M A R D  
> 1 b D M A R D  
> = 1 J A K i n hi bitor  
 
C orti c o st er oi d  S cali n g Fact or  
•  T o ass ess cortic ost er oid use a nd d et er mi n e av er ag e daily c ortic ost er oi d d ose, all 
c ortic ost er oi d d osa g es will b e c o nv ert ed to a pr e dnis o n e e quiv al e nt i n milli gr a ms by 
m ulti plyi n g t he d os e of th e st er oi d ( usi ng t he c o d ed t er m fr o m G S K Dru g) by th e c o nv ersio n  
f act or to g et pr ed nis on e e quiv al e nt u nits.  
•  T h e f oll o wi ng c o nv ersi o n f act ors will b e use d:  
 
 
 
 
 
 
 
 
 
 
C orti c o st er oi d  
S c ali n g Fa ct or  
B et a m et h aso n e  
8. 3 3  
D ex a m et h as o ne  
6. 6 7  
M e pr e d nis on e  
0. 8  
M et hyl pr e dnis ol o ne  
0. 8  
Pr e d nis olo n e  
1  
Pr e d nis on e, Pr e d nis o n e Acet ate  
1  
Tri a mci n ol o n e  
0. 8  
Pr e d m et ( N O S)  
0. 8  
D efl az ac ort  
1. 2  
 
P P D


 
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Prior and Concomitant Medication 
RA Concomitant medication will be split into following categories: 
             - DMARDs 
                        - Methotrexate (all methotrexate medications combined into one category) 
                        - Other csDMARDs (not Methotrexate) 
                        - csDMARDs > 1 
                        - bsDMARDs/boDMARDs/tsDMARDs 
- Corticosteroids (the following groups will be derived by route) 
           -Oral  
           -Intra-Articular 
- Other RA medications 
 
Prior RA medications will be split into following categories: 
-DMARDs 
           - Methotrexate (all methotrexate medications combined into one category) 
           - Other csDMARDs (not Methotrexate) 
           - csDMARDs >1 
            -bsDMARDs/boDMARDs/tsDMARDs 
                       ->=1 of the above 
                       -=1 of the above 
                       ->1 of the above 
                       -Inadequate response to >=1 bs/boDMARD 
                       -Inadequate response to >=1 tsDMARD 
                       -Inadequate response to >1 bsDMARD/boDMARD/tsDMARD 
-Oral corticosteroids   
-Other RA medications 
 
RA Concomitant medication will be derived as following: 
Follow Section 14.4.1.1 for definition of “concomitant” medication. 
o DMARDs: 
Derived from “RA Medications MTX, csDMARD and bDMARD” page in eCRF, C1CAT=”DISEASE-
MODIFYING ANTIRHEUMATIC DRUG” using all “medication type” which includes 
C1SCAT=“CONVENTIONAL SYNTHETIC DMARDS”, C1SCAT=“BIOLOGICAL ORIGINATOR 
DMARDS”, C1SCAT=“BIOSIMILAR DMARDS”, and C1SCAT=“TARGETED SYNTHETIC 
DMARDS”. 
 
o Methotrexate: 
Derived from “RA Medications MTX, csDMARD and bDMARD” page in eCRF, C1CAT=”DISEASE-
MODIFYING ANTIRHEUMATIC DRUG”, using C1SCAT=“CONVENTIONAL SYNTHETIC DMARDS” 
where ingredient/CMDECOD contains “METHOTREXATE”. All methotrexate medications will be 
combined together into one category called “Methotrexate” 
 
o Other csDMARDs (not methotrexate): 
Derived from “RA Medications MTX, csDMARD and bDMARD” page in eCRF, C1CAT=”DISEASE-
MODIFYING ANTIRHEUMATIC DRUG”, using C1SCAT=“CONVENTIONAL SYNTHETIC 
DMARDS”, but excluding methotrexate (where ingredient/CMDECOD contains “METHOTREXATE”) 
 
o csDMARDs > 1: 


 
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 Derived from “RA Medications MTX, csDMARD and bDMARD” page in eCRF, C1CAT=”DISEASE-
MODIFYING ANTIRHEUMATIC DRUG” using C1SCAT=“CONVENTIONAL SYNTHETIC DMARDS” 
where a participant has taken more than 1 csDMARD (2 or more). 
 
o bsDMARDs/boDMARDs/tsDMARDs: 
Derived from “RA Medications MTX, csDMARD and bDMARD” page in eCRF, C1CAT=”DISEASE-
MODIFYING ANTIRHEUMATIC DRUG” using “medication type” which includes 
C1SCAT=“BIOLOGICAL ORIGINATOR DMARDS”, C1SCAT=“BIOSIMILAR DMARDS” and 
C1SCAT=“TARGETED SYNTHETIC DMARDS”. 
 
o Corticosteroids Oral: 
Derived from “RA other medication” page in eCRF, C1CAT=”OTHER RHEUMATOID ARTHRITIS 
MEDICATION” using C1SCAT= “CORTICOSTEROID” and C1ROUTE=”ORAL”  
 
o Corticosteroids IA: 
 Derived from “Intra-Articular Corticosteroids” page in eCRF,C1CAT=”OTHER RHEUMATOID 
ARTHRITIS MEDICATION” using C1SCAT=”CORTICOSTEROID” and C1ROUTE = “INTRA-
ARTICULAR”  
 
o Other RA medication:  
Derived from “RA other medication” page in eCRF, C1CAT=”OTHER RHEUMATOID ARTHRITIS 
MEDICATION” using all “medication type” which includes C1SCAT=“Corticosteroid” all routes except 
C1ROUTE=“ORAL” and C1ROUTE=“INTRA-ARTICULAR”, C1SCAT=“OPIOID” and 
C1SCAT=“OTHER”. 
 
 
Non-RA Concomitant medication will be derived as following: 
Follow Section 14.4.1.1 for definition of “concomitant” medication. 
 
Non RA medication is derived from “Non-RA concomitant medications” page in eCRF, C1CAT=”NON 
RHEUMATOID ARTHRITIS MEDICATION”. 
 
Uncoded concomitant medication will be combined together in one category called “Uncoded” 
 
Prior RA medication will be derived as following: 
Follow Section 14.4.1.1 for definition of “prior” medication. 
 
o DMARDs:  
Derived from “RA Medications MTX, csDMARD and bDMARD” page in eCRF, C1CAT=”DISEASE-
MODIFYING ANTIRHEUMATIC DRUG”  using all “medication type” which includes 
C1SCAT=“CONVENTIONAL SYNTHETIC DMARDS”, C1SCAT=“BIOLOGICAL ORIGINATOR 
DMARDS”, C1SCAT=“BIOSIMILAR DMARDS” and C1SCAT=“TARGETED SYNTHETIC DMARDS”. 
o Methotrexate: 
Derived from “RA Medications MTX, csDMARD and bDMARD” page in eCRF, C1CAT=”DISEASE-
MODIFYING ANTIRHEUMATIC DRUG” using C1SCAT=“CONVENTIONAL SYNTHETIC DMARDS” 
where ingredient/CMDECOD contains “METHOTREXATE”. All methotrexate medications will be 
combined together into one category called “Methotrexate” 
 
o Other csDMARDs (not methotrexate): 


 
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Derived from “RA Medications MTX, csDMARD and bDMARD” page in eCRF, C1CAT=”DISEASE-
MODIFYING ANTIRHEUMATIC DRUG” using C1SCAT=“CONVENTIONAL SYNTHETIC DMARDS” 
where ingredient/ CMDECOD contains “METHOTREXATE”. 
 
o csDMARDs > 1: 
Derived from “RA Medications MTX, csDMARD and bDMARD” page in eCRF, C1CAT=”DISEASE-
MODIFYING ANTIRHEUMATIC DRUG” using C1SCAT=“CONVENTIONAL SYNTHETIC DMARDS” 
where a participant has taken more than 1 csDMARD. 
 
 
 
o bsDMARDS/boDMARDs/tsDMARDs: 
Derived from “RA Medications MTX, csDMARD and bDMARD” page in eCRF, C1CAT=”DISEASE-
MODIFYING ANTIRHEUMATIC DRUG” using C1SCAT=“BIOSIMILAR DMARDS”, 
C1SCAT=“BIOLOGICAL ORIGINATOR DMARDS” and C1SCAT=“TARGETED SYNTHETIC 
DMARDS”. 
o >=1 of the above is derived as above for participants that have taken at least 
one of the bsDMARDS, boDMARDs or tsDMARDs  
o =1 of the above is derived as above for participants that have taken one of the 
bsDMARDS, boDMARDs or tsDMARDs  
o >1 of the above is derived as above for participants that have taken more than 
one of the bsDMARDS, boDMARDs or tsDMARDs  
 
o Inadequate response to >=1 bs/boDMARD: 
Derived from “RA Medications MTX, csDMARD and bDMARD” page in eCRF, C1CAT=”DISEASE-
MODIFYING ANTIRHEUMATIC DRUG”  where a subject had at least one of the following: 
C1SCAT=“BIOSIMILAR DMARDS” or C1SCAT=“BIOLOGICAL ORIGINATOR DMARDS”, with one 
or more of the following selected “lack of initial efficacy” or “loss of efficacy” or “adverse event”, 
QNAM=”PRSMEDEN” and QVAL contains "ADVERSE EVENT", "LACK OF INITIAL EFFICACY", or 
"LOSS OF EFFICACY".  
 
o Inadequate response to >=1 tsDMARD: 
Derived from “RA Medications MTX, csDMARD and bDMARD” page in eCRF, C1CAT=”DISEASE-
MODIFYING ANTIRHEUMATIC DRUG”  where a subject had at least one C1SCAT=“TARGETED 
SYNTHETIC DMARDS” , with one or more of the following selected “lack of initial efficacy” or “loss of 
efficacy” or “adverse event”, QNAM=”PRSMEDEN” and QVAL contains "ADVERSE EVENT", "LACK 
OF INITIAL EFFICACY", or "LOSS OF EFFICACY".  
 
o Inadequate response to >1 bsDMARD/boDMARD/tsDMARD: 
Derived from “RA Medications MTX, csDMARD and bDMARD” page in eCRF, C1CAT=”DISEASE-
MODIFYING ANTIRHEUMATIC DRUG”  where a subject had at least two of the following: C1SCAT= 
“BIOSIMILAR DMARDS” or C1SCAT=“BIOLOGICAL ORIGINATOR DMARDS” or 
“C1SCAT=TARGETED SYNTHETIC DMARDS”, with one or more of the following selected “lack of 
initial efficacy” or “loss of efficacy” or “adverse event”, QNAM=”PRSMEDEN” and QVAL contains 
"ADVERSE EVENT", "LACK OF INITIAL EFFICACY", or "LOSS OF EFFICACY".   
 
o Corticosteroids Oral: 
Derived from “RA other medication” page in eCRF, C1CAT=”OTHER RHEUMATOID ARTHRITIS 
MEDICATION” using C1SCAT= “CORTICOSTEROID” and C1ROUTE= ”ORAL”. 
 


 
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o Other RA medication: 
Derived from “RA other medication” page in eCRF, C1CAT=”OTHER RHEUMATOID ARTHRITIS 
MEDICATION”  using all “medication type” which includes C1SCAT=“corticosteroid” which includes 
all routes except C1ROUTE=“ORAL”, C1SCAT=“OPIOID” and C1SCAT=“OTHER”. 
 
The following medications will be combined into one category: 
o All Methotrexate medications will be combined into one category called “Methotrexate”  
o Hydroxychloroquine and Hydroxychloroquine Sulfate will be combined into “Hydroxychloroquine” 
o Chloroquine, Chloroquine Phosphate and Chloroquine Sulfate will be combined into 
“Chloroquine” 
o 
Filgotinib and Filgotinib Maleate will be combined into "Filgotinib" 
o 
Tofacinitib and Tofacitinib Citrate will be combined into "Tofacitinib" 
 
Concomitant COVID-19 Vaccine 
• 
COVID-19 Vaccines will be derived from the most recent list of terms provided by GSK Medical 
Dictionary at the time of reporting 
 
14.6.3. 
Efficacy 
14.6.3.1. 
ACR20/50/70 
ACR20/50/70 
Proportion of ACR20/50/70 responders 
• 
The American College of Rheumatology’s (ACR) definition for calculating improvement in RA is 
calculated as a 20% improvement (ACR20) in both tender and swollen joint counts and 20% 
improvement in 3 of the 5 remaining ACR-core set measures: patient and physician global 
assessments, patient’s assessment of arthritis pain, disability, and an acute-phase reactant (i.e. CRP 
value).  Similarly, ACR50 and ACR70 are calculated with the respective percent improvement.  This 
efficacy measurement will be made at every post-baseline study assessment time point. 
 
• 
The specific components of the ACR Assessments that will be used in this study are: 
o Tender/Painful Joint count 68 (TJC68) 
o Swollen Joint Count 66 (SJC66) 
o Patient’s Assessment of Arthritis Pain 
o Patient’s Global Assessment of Arthritis Disease Activity 
o Physician’s Global Assessment of Arthritis 
o CRP (mg/L) 
o Health Assessment Questionnaire – Disability Index (HAQ-DI) 
 
• 
Individual components collected outside of a +/- 2 day window from visit date will be considered 
missing for the purpose of the ACR calculation. 
 
• 
For all visits, if any of the component scores are missing, then those scores will be considered as not 
having met the criteria for improvement.  Therefore, if TJC68 or SJC66 or 3 or more of the 5 
remaining ACR-core set measures are missing, ACR20/ ACR50/ ACR70 will each be considered 
missing.   


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
6 9  
 
•  
F or c o m po n e nt sc ores wit h missi n g B as eli n e v al ues or a B as eli ne v al u e of 0, t h e p erc ent ag e 
i m pr ove m e nt c a n’t b e c alc ul ate d a n d t he c o m p o n ent will b e c o nsid er e d as missi n g for all visits.  If 
t h e b as eli ne v al u e is missi n g, d o n ot us e scr e e ni n g visit d at a f or i m put ati on. 
 
1 4. 6. 3. 2.  
T e n d er/ P ai nf ul a n d S w oll e n J oi nt C o u nt s  
T e n d er/ P ai nf ul J oi nt C o u nt ( T J C) a n d S w oll e n J oi nt C o u nt  ( S J C) 
T J C2 8/ 6 8 a n d S J C 28/ 6 6  
•  
F o ur diff ere nt sc or es will b e c alc ul ate d t o ev alu at e s w elli n g an d t e n d ern ess of j oi nts. TJ C 2 8 a n d 
SJ C 2 8 will tak e 28 j oints i nt o acc o u nt, SJ C 6 6 an d TJ C 6 8 will us e 6 6 a n d 68 j oints, r es p ectiv ely.  
•  
T h e ass ess m e nt f or s w elli n g is t h e t otal n u m b er of j oints with a pr ese nt s w elli ng a n d r an ges fr o m 0 
t o 2 8 f or SJ C 28 a n d 0 t o 6 6 f or SJ C 6 6. 
•  
T h e ass ess m e nt f or t e nd er n ess is th e t ot al n u m b er of j oi nts wit h a pr ese nt t en d er n ess an d r a n g es 
fr o m 0 t o 2 8 f or TJ C 2 8 a nd 0 to 6 8 f or TJ C 6 8. 
•  
T h e f ollo wi n g 28 j oints will b e tak e n int o acc o unt f or TJ C 2 8 an d SJ C 2 8: S h oul d er ( 2 j oints), K n e e ( 2), 
El b o w ( 2), Wrist ( 2), Fin g ers (I P, PI P, M C P: 2 0).  
•  
A d diti o nally t h e f oll o win g j oi nts will b e tak e n i nt o acco u nt f or SJ C 6 6/ TJ C 6 8: Te m p or o m a n dib ul ar ( 2), 
St er n ocl avic ul ar ( 2), Acr o mi oclavic ul ar ( 2), Fi n g ers ( DI P: 8), A nkl e ( 2), Tars us ( 2), T oes (I P, PI P, 
M T P: 2 0), Hi p (2, o nly f or TJ C).  
•  
Re pl ac e d or f use d j oi nts ar e co nsi d ere d n on -ev al u a ble i n the s w elli n g a nd t e n der n ess assess me nt.  
•  
If t h er e ar e missi ng o bs erv ati ons f or t en d er or s w oll en j oints th e n t h e r e m ai ni n g obs erv ati ons will be 
ass ess e d a n d w eig ht e d by dividi n g t h e n u mb er pr es e nt e d by n u m b er of n o n -missi n g a n d by 
m ulti plyin g by 2 8/ 6 6/ 6 8 f or t h e j oi nt c o u nt.  
•  
If a j oint h as u n d erg o n e i nt er-artic ul ar i njectio n  of c ortic ost eroi d d uri ng t h e c o urse of t he st udy, t his 
j oi nt is r ec or d e d i n t h e c o nc o mit a nt me dicati o n d at as et. T he joi nt will b e c o nsi d er e d t o b e ten d er a n d 
s woll e n f or 8 w e eks  p ost I A c ortic oster oi d i nj ecti on.  
 
1 4. 6. 3. 3.  
P ai n V A S  
P ati e nt’ s a s se s s m e nt of Art hriti s P ai n V A S  
P ai n V A S  
•  
S u bj ects will assess t h e s ev erity of t h eir c urre nt art hritis p ai n usi n g a c o nti n u ous vis ual a nalo g sc al e 
( V A S) wit h a nc h ors “ 0” ( 
) a n d “ 1 0 0” (
). 
1 4. 6. 3. 4.  
P ati e nt’ s/ P h y si ci a n’ s Gl o b al A s s e s s m e nt of Art hriti s Di s e a s e A cti vit y  
P ati e nt’ s/ P h y si cia n’ s Gl o b al A s s e s s m e nt of Art hriti s Di se a s e A cti vit y ( Pt G A/ P h G A)  
Pt G A  
•  
S u bj ects will c o mpl et e a glo b al assess m e nt of dis e ase activity usin g t h e p ati ent gl ob al ass ess m ent 
of dis eas e activity ( Pt G A) ite m, a c o nti n u o us V A S wit h a nc h ors “ 0” ( 
) to “ 1 0 0” ( 
).  
P h G A  
•  
P hysici a ns will c o mpl et e a glob al ass ess m ent of dis e as e activity usin g t h e p hysici a n gl o b al 
ass ess me nt of dis eas e activity it e m ( P h G A), a co nti nu o us V A S wit h a nc h ors “ 0” ( 
) t o “ 1 0 0” 
(
). 
 
C CI
C CI
C CI
C CI
C CI
C CI


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
7 0  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d 
p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
7 1  
 
1 4. 6. 3. 6.  
C D AI  
C D AI  
C D AI T ot al S c or e  
•  
T h e Cli nic al Dis e as e Activity In d ex ( C D AI) is a c o m p osit e scor e c o nsisti n g of t h e s u m of SJ C 2 8, 
TJ C 2 8, Pt G A an d P h G A.  Si nce Pt G A a n d P h G A ar e b ot h c oll ect ed o n a V A S sc al e 0 -1 00, t h e  
r es p ectiv e sc ores will b e divi de d by 10 b ef or e c o m p utin g t h e C D AI t ot al scor e. 
•  
C D AI r a n g es fr o m 0 t o 76 wit h hi g h er v al ues r e pres e nti n g hig h er dis e ase activity.  
•  
I n divid u al c o mp o n e nts coll ecte d o utsi d e of a +/- 2 d ay wi ndo w fr o m visit d at e will b e c o nsid er e d 
missi n g for t h e pur p ose of t h e C D AI c alc ulati o n.  
•  
If o n e of th e co m p o ne nts is missi n g at a n i n divi du al ass ess me nt p oi nt t h e C D AI v al u e f or t hat 
ass ess me nt will b e s et t o missi n g.  
C D AI L o w di s e a s e a cti vit y ( C D AI -L D A)  
•  
L o w Dis e ase Activity is ac hi eve d f or  a no n -missin g C D AI t otal scor e ≤1 0.  
C D AI Re mi s si o n  
•  
Re missi o n is ac hi ev e d f or a no n -missi ng C D AI t ot al sc or e ≤2. 8.  
 
1 4. 6. 3. 7.  
D A S 2 8 -C R P a n d D A S 2 8 -E S R  
D A S 2 8 -C R P  
D A S 2 8 -C R P  
•  
T h e c o m p o n e nts of t h e D A S 28 -C R P art hritis ass ess m e nt incl u d es:  
o  T e n d er Joi nt C o unt 2 8 ( TJ C 2 8) 
o  S w oll e n J oi nt C o u nt 2 8 ( SJ C 28)  
o  C -r e activ e pr ot ei n ( C R P) (i n mg/ L)  
o  P ati e nt’s Gl o b al Ass ess m e nt of Art hritis Dis e as e Activity ( Pt G A) (vis u al an al og u e sc ale with 
v al u es fr o m 0 = 
 t o 10 0 = 
) 
•  
T h e D A S 2 8 -C R P sc or e will b e c alcul at ed usi n g t he f ollo wi n g f or m ul a:  
D A S 2 8 -C R P = 0. 5 6* √T J C 2 8 + 0. 2 8* √S J C 2 8 + 0. 3 6*l n( C R P + 1) + 0. 0 1 4* Pt G A + 0. 96  
•  
I n divid u al c o mp o n e nts coll ecte d o utsi d e of a +/- 2 d ay wi ndo w fr o m visit d at e will b e c o nsid er e d 
missi n g for t h e pur p ose of t h e D A S 2 8 c alc ul atio n.  
•  
If o n e of th e co m p o ne nts is missi n g at a n i n divi du al ass ess me nt p oi nt, n o i m p utati o ns will be d o n e 
a n d t h e D A S 2 8 v al u e f or t h at ass ess me nt will b e s et t o missi n g.  
D A S 2 8 -C R P L o w di s e a s e acti vit y ( L D A)  
•  
L o w Dis e ase Activity is ac hi eve d f or a D A S 2 8 -C R P ≤3.2.  
C CI
C CI
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d 
p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
7 2  
 
D A S 2 8 -C R P R e mi s si o n  
•  
Re missi o n is ac hi ev e d f or a D A S 2 8 -C R P < 2. 6  
D A S 2 8 -E S R  
D A S 2 8 -E S R  
•  
T h e c o m p o n e nts of t h e D A S 28 -E S R art hritis assess m e nt i ncl u d es:  
o  T e n d er Joi nt C o unt 2 8 ( TJ C 2 8)  
o  S w oll e n J oi nt C o u nt 2 8 ( SJ C 28)  
o  Eryt hr ocyt e s edi me nt atio n r at e ( E S R) (i n m m/ hr)  
o  P ati e nt’s Gl o b al  Ass ess m e nt of Art hritis Dis e as e Activity ( Pt G A) (vis u al an al og u e sc ale with 
v al u es fr o m 0 = 
 t o 10 0 = 
) 
•  
T h e D A S 2 8 -E S R sc or e will b e c alcul at ed usi n g t he f ollo wi n g f or m ul a:  
D A S 2 8( E S R) = 0. 5 6* √T J C2 8 +0. 2 8* √S J C 2 8 +0. 7*l n( E S R) + 0.0 1 4* Pt G A  
•  
I n divid u al c o mp o n e nts coll ecte d o utsi d e of a +/- 2 d ay wi ndo w fr o m visit d at e will b e c o nsid er e d 
missi n g for t h e pur p ose of t h e D A S 2 8 c alc ul atio n.  
•  
If o n e of th e co m p o ne nts is missi n g at a n i n divi du al ass ess me nt p oi nt, n o i m p utati o ns will be d o n e 
a n d t h e D A S 2 8 v al u e f or t h at a ss ess me nt will b e s et t o missi n g. 
•  
A n E S R v al u e of 0 will b e su bstit ut ed wit h E S R = 1 f or th e c alc ul atio n of D A S 2 8 -E S R.  
D A S 2 8 -E S R L o w di s e a s e acti vit y ( L D A)  
•  
L o w Dis e ase Activity is ac hi eve d f or a D A S 2 8 -E S R ≤3. 2.  
D A S 2 8 -E S R R e mi s si o n  
•  
Re missi o n is ac hi ev e d f or a D A S 2 8-E S R < 2. 6  
 
C CI
C CI


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
7 3  
 
1 4. 6. 3. 8.  
E U L A R R e s p o n s e  
E U L A R R e s p o n s e  
E U L A R G o o d/ M o d er at e R e s p o n s e  
•  
D A S 2 8 -C R P a n d D A S 2 8 -E S R sc or es will e ac h b e cat e g oris e d usin g E UL A R r es p ons e criteri a.  
Res p o nse at a giv en ti me p oint is d efi n e d b as ed o n t he c o mbi n ati on of c urr e nt D A S 2 8 sc or e a n d t h e 
i m pr ove m e nt i n t he c urr ent D A S 2 8 sc ore r el ativ e to b as elin e.  T h e d efi nitio n of no r esp o ns e, 
m o d er at e r es p ons e a n d g oo d r es p o ns e is c a pt ur e d in t h e follo wi n g t a bl e:  
•  
If t h e p ost-b as eli ne D A S 2 8 v alu e is missi n g, t h e n th e corr es po n di n g E UL A R c at e g ory will be  s et t o 
missi n g.  
 
1 4. 6. 3. 9.  
A C R/ E U L A R R e mi s si o n  
A C R/ E U L A R R e mi s si o n  
B o ol e a n -b a s e d A C R/ E U L A R R e mi s si o n  
•  
B o ol e a n -b as e d re missio n is ac hi eve d if all of t h e foll o win g re q uir e me nts ar e m et at t h e s a m e ti me:  
o  TJ C 6 8 ≤ 1  
o  SJ C 6 6 ≤ 1  
o  C R P ≤ 1 m g/ dl  
o  Pt G A ≤ 10  
•  
I n divid u al c o mp o n e nts coll ecte d o utsi d e of a +/- 2 d ay wi ndo w fr o m visit d at e will b e c o nsid er e d 
missi n g for t h e pur p ose of t h e c alc ul atio n.  
•  
If o n e of th e co m p o ne nts is missi n g at a n i n divi du al ass ess me nt p oi nt, t h e B ool e a n-b as ed re missi o n 
f or t h at ass ess me nt will b e s et t o missi ng. 
I n d e x-b a s e d A C R/ E U L A R R e mi s si o n  
•  
T h e Si m pl e Dis e as e Activity Ind ex ( S D AI) is a c o m p osit e sc or e c o nsisti n g of t h e su m of SJ C 2 8, 
TJ C 2 8, Pt G A, P h G A, a n d C R P ( m g/ dl).  Si nc e Pt G A a n d P h G A ar e b oth c oll ect e d o n a V A S sc al e 0 -
1 0 0, t h e res p ective sc or es will b e divi d e d by 10 b ef or e c o m puti n g t he S D AI t ot al sc or e. 
•  
I n d ex-b as e d r e missi on is ac hiev e d if t h e f oll o wi ng r e q uir e m ent is m et:  
o  S D AI ≤ 3. 3  
•  
I n divid u al c o mp o n e nts coll ecte d o utsi d e of a +/- 2 d ay wi ndo w fr o m visit d at e will b e c o nsid er e d 
missi n g for t h e pur p ose of t h e c alc ul atio n.  
•  
If o n e of th e co m p o ne nts is missi n g at a n i n divi du al ass ess me nt p oi nt, t h e In d ex-b as ed r e missio n f or 
t h at ass ess m e nt will b e s et t o missi n g. 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e 
pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


 
CONFIDENTIAL 
 
 
 
202018 
 
74 
 
14.6.3.10. SF-36 
SF-36 
SF-36 
• 
Health-related quality of life will be assessed using the subject-completed Medical Outcomes Study 
Short-Form 36 (SF-36) which is a generic health survey that contains 36 questions covering eight 
domains of health.  The SF-36 yields an eight-scale profile of functional health and well-being scores 
as well as physical and mental component health summary scores.  The version 2, 1-week recall 
questionnaire will be used. Recoding, calculations, and standardisation will be done using Quality 
Metrics SF-36 scoring software. 
SF-36 Domain Scores 
• 
Individual question responses will be inputted into the Quality Metrics SF-36 scoring software to 
compute the eight domain scores: 
o Physical functioning (PF) 
o Role function – Physical aspect (RP) 
o Bodily Pain (BP) 
o General health perception (GH)  
o Mental Health (MH) 
o Role function – Emotional aspect (RE) 
o Social functioning (SF) 
o Vitality (VT) 
• 
Higher scores represent better health status. 
 
SF-36 Physical and Mental component scores 
• 
Individual question responses will be inputted into the Quality Metrics SF-36 scoring software to 
compute the physical and mental component scores. 
 


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
7 5  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d 
p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
7 6  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d 
p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
7 7  
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d 
p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
7 8  
 
A d v er s e E v e nt s of S p eci al I nt ere st ( A E SI)  
A E s of S p e ci al I nt er e st ( A E SI)  
•  
A dv ers e ev e nts of s p eci al i nt er est ( A E SI) a n d oth er i m p ort a nt a dv ers e eve nts will be d eriv ed usi ng 
M E D R A a n d C o m m o n T er minol o gy Criteri a for A dv ers e Ev ents v 5.0 ( N CI , 2 0 17) a n d will incl u d e: 
 
A E SI  
Pr o gra m m ati c al D eri v ati o n  
S eri o us i nf ecti o ns  a n d S eri o us i nf ecti o ns 
excl udi n g C O VI D -1 9 I nf ecti ons  
S eri o us i nf ecti o ns: Filt er o n Infecti o ns a n d 
I nf est ati o ns S O C, li mit ed t o seri o us.  
S eri o us i nf ecti o ns excl u di n g C O VI D -1 9 
i nf ecti o ns: Filter o n I nfectio ns a n d I nf est atio ns 
S O C, li mit e d t o s erio us an d excl u d e th e 
f oll o wi ng P Ts:  S us p ect e d C O VI D-1 9”, “ C O VI D -
1 9”, “ C O VI D -1 9 p ne u m o ni a” or “ Asy m pto m atic 
C O VI D -1 9”.  
O p p ort unistic inf ecti o ns  
O p p ort unistic inf ecti o ns will b e d eriv ed , usi n g 
t h e “ O p port u nistic i nf ecti ons” ( Br o a d) S M Q a n d 
a dj u dic at e d by th e S R T.  A dj udic at ed 
o p p ort u nistic i nfectio ns will b e s u m mariz ed.   
Activ e T B , l at e nt T B,  a n d T B r e activ ati on  
D eriv e d fr o m pr ef erre d t er ms of “ T u b ercul osis”. 
Us e H L T: ‘ T u berc ul o u s Inf ectio ns’.  
All t u b erc ul osis i nf ecti o ns will b e a dj udic at e d by 
S R T. T h e o utco m e of t h e adj udic atio n will b e 
Activ e T B , l at e nt T B or T B r e activ at i o n w hic h will 
b e s u m m aris e d.   
Ne utr o p e ni a  
D eriv e d usi n g P T of “ N e utr o peni a”  a n d/or 
“ n e utr o p hil c ou nt d ecr e as e d” an d/ or “ n e utro p hil 
p erc e nt ag e d ecr e ase d” . O nly A Es/ S A Es of 
n e utr o p e ni a  a nd/ or n eutr o p hil c o u nt decr e as e d  
a n d/ or n eutr o p hil p erc e nt a ge d ecr e as e d  w h er e 
t h e c orr es p o n di n g abs ol ut e n eutr o p hil c o unt 
(fr o m l a bor at ory d at a) are C T C A E gr a d e 3 or 4 
will b e r ep ort e d as A E SI.  
P ersist ent C o u g h  
C o u g h C T C A E ≥ Gr ad e 2 r ecor d e d f or 3 
c o ns ec utiv e w e eks ( ≥2 1 D ays). 
 
I d e ntifie d fr o m: 
C o u g h ‘ Y es’ e nt ere d i n t h e p ul m o n ary 
ass ess me nt e C R F wit h Gr a d e d et er mi n e d fr o m 
A E r e p orti n g with t h e foll o win g d efi niti o n:  
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s 
or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n 
e x cl u d e d.


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
7 9  
 
 
P ersist ent dys p n ea  
P ersist ent dys p n oe a gr a de ≥ 2 f or t hr e e 
c o ns ec utiv e w e eks ( ≥2 1 days).   
I d e ntifie d fr o m:Dys pn o e a r ati ng sc al e o n th e 
p ul m o nary ass ess me nt e C R F p a g e wit h th e 
f oll o wi ng gr a din g: 
P A P ( P ul m o n ary alve ol ar protei n osis)  
D eriv e d usi n g pr ef err e d t er m ( P T) “ alv e ol ar 
pr ot ei n osis’.  ( L L T of ‘ pul mo n ary alve ol ar 
pr ot ei n osis’ m aps t o  P T of ‘ alv e ol ar pr otei n osis’). 
All c as es adj u dic at ed by P ul mo n ary A dju dicati o n 
C o m mitt ee  ( P A C).  
T h e a dj udicat e d P A P o utc o m e will b e 
s u m mariz ed. 
S eri o us h y p ers e nsitivity re actio ns, 
i ncl udi n g a n a p hyl axis 
S eri o us h y p ers e nsitivity re actio ns will b e 
a dj u dic at e d usin g ‘Hyp ers ensitivity ’ ( Br o a d) 
S M Q, ‘A n ap hyl actic r e acti on ’ ( Br o a d) S M Q a n d 
‘a n a p hyl actic/a n a p hyl act oi d s hock co n diti o n ’ 
( Br o a d) S M Q bas e d o n S A E listi n gs.  
Fi n al adj u dic ati o n will b e c o n duct e d by S R T a n d 
t h e a dj udicat e d hy p erse nsitivity will be 
s u m mariz ed. 
 
I nj ecti o n sit e r eacti ons 
D eriv e d fr o m H L T t er m “i njectio n sit e r e acti o n s”, 
H L T t er m “ a d mi nistr atio n sit e re acti on N E C” a n d 
P T t er m “i nj ecti o n r elat e d r eacti o n” .  
 
  
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e 
A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, 
w hi c h ar e pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d 
t h er ef or e h a v e b e e n e x cl u d e d.
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e 
A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, 
w hi c h ar e pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d 
t h er ef or e h a v e b e e n e x cl u d e d.


 
CONFIDENTIAL 
 
 
 
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80 
 
Other Important AEs 
Protocol defined cardiovascular (CV) events and adjudicated CV events 
• 
CV Events 
CV events as reported in the database will be included in the summary table for all AEs.  
• 
Adjudicated CV Events 
Endpoints of interest: cardiovascular (CV) death, myocardial infarction (MI), hospitalisation for 
unstable angina, stroke, hospitalisation for heart failure, deep vein thrombosis (DVT) and pulmonary 
embolism (PE). These will be derived using PT terms listed in clinical events classification (CEC) 
Charter and adjudicated by Duke Clinical Research Institute (DCRI) CEC group. Adjudicated CV 
endpoints will be summarised.  
Adjudicated CV Events will also be reported as the following categories: 
o MACE: CV death, non-fatal MI, non-fatal stroke 
o Broad MACE: CV death, MI, hospitalisation for unstable angina, stroke, hospitalisation for 
heart failure, DVT and PE) 
o Broad MACE excluding DVT and PE  
o VTE (DVT and/or PE) 
o DVT only 
o PE only 
GI Perforation and Adjudicated GI perforation 
• 
GI perforation Events 
GI perforation events as reported in the database will be included in the summary table for all AEs.  
• 
Adjudicated GI perforation 
This will be adjudicated by CEC. Data reported in EDC and the adjudicated GI Perforation will be 
used in the outputs.  
Malignancy 
• 
Malignancies will be reported as the following categories:  
o Solid, excluding non-melanoma skin cancer (NMSC) – derived from Non-haematological 
malignant tumours (SMQ) and Non-haematological tumours of unspecified malignancy 
(SMQ) and excluding NMSC terms identified below 
o NMSC – PTs derived from Skin neoplasms, malignant and unspecified (SMQ): 
▪ 
Atypical fibroxanthoma 
▪ 
Basal cell carcinoma 
▪ 
Basosquamous carcinoma of skin 
▪ 
Bowen’s disease 
▪ 
Carcinoma in situ of skin 
▪ 
Keratoacanthoma 
▪ 
Marjolin’s ulcer 
▪ 
Skin squamous cell carcinoma metastatic 
▪ 
Skin squamous cell carcinoma recurrent 
▪ 
Squamous cell carcinoma of skin 
o Hematologic – derived from Haematological malignant tumours (SMQ) and Haematological 
tumours of unspecified malignancy (SMQ) 
o Lymphoma – derived from Malignant Lymphomas (broad SMQ) 
Herpes Infections 
• 
Derived from HLT term “Herpes Viral Infections” excluding the following terms: Human herpesvirus 6 
encephalitis, Human herpesvirus 6 infection, Human herpesvirus 7 infection, Human herpesvirus 8 
infection, Exanthema subitum 


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
8 1  
 
Ot h er I m p ort a nt A E s  
•  
T h ey will b e f urt h er cat e g oris ed  as H er p es Z ost er, H er p es Si m pl ex a n d N o n -S pecific usi n g pr ef err e d 
t er ms fr o m t h e m ost r ec ent v ersi o n of M e d D R A at t he ti me of r e p orti ng.  
All C a u s e M ort alit y  
•  
A ny S A E wit h a f atal o utc o me  
S eri o u s P ul m o n ar y i nf e cti o ns  
•  
A ny S A E i n  H L G T “res pirat ory tr act i nf ecti o ns”  
S eri o u s P ul m o n ar y i nf e cti o ns e x cl u di n g C O VI D -1 9 I nf e cti o n s  
•  
A ny S A E i n H L G T “res pirat ory tr act i nf ecti o ns” excl u din g t h e f oll o wi ng P Ts:  S us p ect e d C O VI D -1 9”, 
“ C O VI D-1 9”, “ C O VI D -1 9 p n eu m o ni a” or “ Asy m pt o matic C O VI D -1 9”.  
P n e u m o ni a ( s eri o u s a n d n o n -s eri o u s)  
•  
Deriv e d fr o m I nf ectiv e p n eu mo ni a ( n arr o w S M Q)  
P n e u m o ni a ( s eri o u s a n d n o n -s eri o u s) e x cl u di n g C O VI D -1 9 I nf e cti o n s 
•  
Deriv e d fr o m I nf ectiv e p n eu mo ni a ( n arr o w S M Q) exclu di ng th e f ollo wi n g P Ts:  S us pect e d C O VI D -
1 9”, “ C O VI D-1 9”, “ C O VI D -1 9 pn e u m o ni a” or “ Asy m pto m atic C O VI D -1 9”.  
He p atiti s B a n d He p atiti s B R e a cti v ati o n   
•  
A Es a n d S A Es usi n g P Ts ‘ h epatitis B’ a n d ‘ h e p atitis B r e activati o n’  
T hr o m b o e m b oli c ev e nt s  
•  
A Es a n d S A Es usi n g ‘ E m b olic a n d t hr o m b otic eve nts ( S M Q)  
C O VI D -1 9 I nf e cti o n s a n d A dj u di c at e d C O VI D -1 9 I nf e cti o ns  
•  
C O VI D -1 9 I nf ecti o ns  
C O VI D -1 9 i nf ecti o ns will b e d eriv e d fr o m t h e f ollo wi n g P Ts: “ S us p ecte d C O VI D -1 9”, “ C O VI D -1 9”, 
“ C O VI D-1 9 p n e u m o ni a” or “ Asy m pt o m atic C O VI D -1 9”.  
All ev ents will b e s plit i nto s erio us or no n -s eri o us b as ed o n ho w t h ey ar e re p ort e d i. e. all C O VI D -1 9 
S A Es will b e c at e goris ed as seri o us a n d all C O VI D -1 9 A Es will b e c at e g oris ed as n o n -s erio us.   
No n -s eri o us c as es of C O VI D-1 9 will be s plit int o co nfir m e d,  s us p ect e d or pr o b abl e c as es b as e d on 
t h e e C R F a n d c as es f or eac h c at e g ory will b e dis play e d. 
T h e s erio us adv ers e ev e nts of C O VI D -1 9 will be a dju dic at e d by P A C a n d o nly t he a dju dic at e d 
ev e nts s u m m aris e d.  
•  
A dj u dicat e d C O VI D -19 I nf ectio ns  
E ac h c as e t hat is a dj udic at e d to c o nfir m e d c as e of C O VI D -19 or pr o b a bl e cas e of C O VI D -1 9 will 
als o be assi g ne d a gr ad e b ase d o n W orld H e alt h Or g anisatio n ( W H O) ori gi n al scal e.  
All a dj udicat e d c o nfir m e d c as es of C O VI D -1 9 an d all a dj u dicat es pr ob a bl e c ases of C O VI D -1 9 will 
b e  s plit i nto 3 cat e g ori es (s e e th e c at eg oris ati o n b el o w) an d cas es for e ach c ate g ory will be 
s u m maris ed: 
•  
N o n h os pit alis e d i nclu d es t h e foll o wi n g W H O gr a des: gra d e 1 -
 a n d gr a d e 
2 -
.  
•  
H os pit alis ed i ncl u d es t h e f ollo wi n g W H O gr a des: gra d e 3 -
; gra d e 4-
 
; gr a de 5-
; gr ad e 6- 
 a n d gr a d e 7- 
 
). 
•  
De at h  
 
L a b orat ory P ara m et er s  
e G F R 
•  
T his will b e provid e d in t h e datas et by Q 2 
C CI
C CI
C CI
C CI
C CI
C CI
C CI


 
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Laboratory Parameters 
Laboratory Results 
If a laboratory value which is expected to have a numeric value for summary purposes,  
has a non-detectable level reported in the database, where the numeric value is missing,  
but typically a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or  
greater than x in the comment field) is present, the number of significant digits in the  
observed values will be used to determine how much to add or subtract in order to impute  
the corresponding numeric value.  
• Example 1: 2 Decimal Places=  ‘< x ‘ becomes x – 0.01 
• Example 2: 1 Decimal Place=  ‘> x’ becomes x + 0.1 
• 
Example 3: 0 Decimal Places= ‘< x’ becomes x – 1 
Immunogenicity 
• Positive binding antibody assay results are to be categorised as transient positive or 
persistent positive accordingly to the following definitions: 
• For all post-baseline visits, other than final study assessment 
o Transient positive = a single positive immunogenic response at a visit, where the 
previous visit was negative 
o Persistent positive = a positive immunogenic response at a visit, where the previous 
visit was also positive 
 
 


 
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14.7. 
Appendix 7: Reporting Standards for Missing Data 
14.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
Participant study completion (i.e. as specified in the protocol) was defined as 
completion of all phases of the study including the follow up.  
• 
Withdrawn participants will not be replaced in the study. 
• 
All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.  
• 
Withdrawal visits will be slotted as per Appendix 3: Assessment Windows or will be 
summarised as withdrawal visits. 
• 
If a scheduled visit and an EW visit occur within the same visit window and are both 
available, the scheduled visit will be used for any summaries/analyses. The EW visit 
will appear in listing only. 
• 
For efficacy analyses, if an EW visit is assigned to a non-standard efficacy visit, i.e., a 
visit at which efficacy assessments are not scheduled per the Time and Events Table, 
then these EW data will be ignored in the statistical analysis, but all data will be listed. 
14.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• 
Missing data occurs when any requested data is not provided, leading to blank fields 
on the collection instrument: 
o These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
Outliers 
• 
Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
Adverse 
Events 
• 
AEs with missing intensity will be considered as severe. 


 
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14.7.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in subject listing displays. 
Adverse 
Events 
• 
Although every effort will be made to prevent and eliminate partial dates, the eCRF 
allows for the possibility of partial dates (i.e., only month and year) to be recorded 
for AE start and end dates; that is, the day of the month may be missing. In such a 
case, the following conventions will be applied for calculating the time to onset and 
the duration of the event: 
o Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used 
and hence the event is considered On-treatment as per Appendix 4: Study 
Phases and Treatment Emergent Adverse Events. 
o Missing Stop Day: Last day of the month will be used, unless this is after the 
stop date of study treatment; in this case the study treatment stop date will be 
used. 
• 
Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be missing. 
Concomitant 
Medications/ 
Medical 
History 
• 
Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention: 
o If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month 
o If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month. 
• 
The recorded partial date will be displayed in listings. 
RA diagnosis 
and symptom 
onset 
• 
Missing day, but month and year present: 
o Date is set to the first day of the month (e.g., XX-Sep-2010 is considered as 
01-Sep-2010). 
• 
Missing day and month, but year present:  
o Date is set to 01 January (e.g., XX-XXX-2010 is considered as 01-Jan-2010) 
 
14.7.2.2. 
Handling of Missing Efficacy Data 
Unless otherwise stated, apply the missing data imputation strategies detailed in Section 
7.1.1.6 and Section 7.2.1.6. 
 


 
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14.8. 
Appendix 8: Laboratory Parameters of Interest 
14.8.1. 
Laboratory Value Gradings 
Laboratory value gradings will be derived using the most recent version of CTCAE at the 
time of reporting. 
 
14.8.2. 
Laboratory Values of Potential Clinical Importance 
Hematology 
Laboratory Parameter 
 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Hematocrit  
Ratio of 
1 
Male 
0.2 
0.6 
Female 
0.2 
0.6 
Change 
from 
baseline 
↓0.075 
 
Hemoglobin  
g/L 
 
Male 
80 
180 
Female 
80 
180 
Change 
from 
baseline 
↓20 
 
Lymphocytes  
x109/ L 
 
 0.75 
 
Neutrophil Count  
x109/ L 
 
1.0 
16 
Platelet Count  
x109/ L 
 
100 
550 
While Blood Cell Count 
(WBC) 
x109/ L 
 
2.0 
20 
Eosinophils 
x109/ L 
 
 
1 
 
Clinical Chemistry 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Albumin  
g/L 
 
30 
55 
Calcium 
mmol/L 
 
2 
2.75 
Creatinine 
µmol/L 
 
 
150 
µmol/L 
Change 
from 
baseline 
 
↑ 44.2 
Glucose 
mmol/L 
 
3 
11 
Potassium 
mmol/L 
 
3 
5.5 
Sodium 
mmol/L 
 
130 
160 


 
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Clinical Chemistry 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
GFR from Creatinine 
Adjusted for BSA 
mL/min/1.73 
m2 
 
60 
 
Cholesterol 
mmol/L 
 
 
 6.5 
Triglycerides 
mmol/L 
 
 
 2.3 
Urea 
mmol/L 
 
 
10.5 
 
Liver Function 
Test Analyte 
Units 
Category 
Clinical Concern Range 
ALT/SGPT  
U/L 
High 
 2x ULN 
AST/SGOT  
U/L 
High 
 2x ULN 
AlkPhos  
U/L 
High 
 2x ULN 
T Bilirubin  
µmol/L 
High 
 1.5xULN 
Creatinine Kinase 
U/L 
High 
 2x ULN 
Gamma Glutamyl Transferase 
U/L 
High 
 2x ULN 
Lactate Dehydrogenase 
U/L 
High 
 2x ULN 
 
Urinalysis 
Test Analyte 
Clinical Concern Range 
Bacteria 
Moderate 
Many 
Squamous Epithelial Cells 
Moderate (6-20)  
Many (21 or greater) 
Glucose 
1+ OR 1/4 G/DL (%)  
2+ OR 1/4 G/DL (%)  
3+ OR 1/4 G/DL (%) 
Protein 
1+  
2+  
3+  
Erythrocytes 
10-15 
12-25 
25-50 
50-100 
>100 
Leukocytes 
10-15 
12-25 
25-50 
50-100 
>100 


 
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Urinalysis 
Test Analyte 
Clinical Concern Range 
Yeast Cells 
Moderate 
Many 
 
For the listing of Laboratory Data for Subjects with any value of Potential Clinical 
Important, only include the following laboratory data: 
• Alanine Aminotransferase 
• Albumin 
• Albumin/Globulin 
• Alkaline Phosphate 
• Aspartate Aminotransferase 
• Basophils 
• Bilirubin 
• C Reactive Protein 
• Calcium 
• Cholesterol 
• Creatinine Kinase 
• Creatinine 
• Cyclic Citrullinated Peptide Antibody 
• Direct Bilirubin 
• Eosinophils 
• Erythrocyte Sedimentation Rate 
• Erythrocytes 
• GFR from Creatinine Adjusted for BSA 
• Gamma Glutamyl Transferase 
• Glucose 
• HDL Cholesterol, Direct 
• Hematocrit 
• Hemoglobin 
• Hepatitis B Core Antibody Total, Qual 
• Hepatitis B Virus DNA 
• Hepatitis B Virus DNA, copies 
• Hepatitis B Virus DNA, log 
• Hepatitis B Virus Surface Antibody, Qual 
• Hepatitis B Virus Surface Antigen, Qual 
• Hepatitis C Antibody, Qual 
• Hepatitis C Virus RNA 
• Hepatitis C Virus RNA, log 
• Interferon Gamma, Qualitative 
• LDL Cholesterol 
• Lactate Dehydrogenase 
• Leukocytes 
• Lymphocytes 


 
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• Monocytes 
• Neutrophils 
• Platelets 
• Potassium 
• Protein 
• Prothrombin Intl. Normalized Ratio 
• Reticulocytes/Erythrocytes 
• Rheumatoid Factor 
• Theophylline 
• Triglycerides 
• Urea 
14.8.3. 
ECG Values of Potential Clinical Importance 
ECG Parameter 
Units 
Clinical Concern Range 
 
 
Lower 
Upper 
Absolute 
Absolute QTc Interval 
msec 
 
>450 
Absolute PR Interval 
msec 
< 110 
> 220  
Absolute QRS Interval 
msec 
< 75  
> 110  
Change from Baseline 
Increase from Baseline QTc 
msec 
 
>30↑ 
14.8.4. 
Vital Signs Values of Potential Clinical Importance  
Vital Sign Parameter 
 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Systolic Blood Pressure 
mmHg 
< 85 
> 160 
Diastolic Blood Pressure 
mmHg 
< 45 
> 100 
Heart Rate 
bpm 
< 40 
> 110 
Change from Baseline 
Systolic Blood Pressure 
mmHg 
≥ 20↓ 
≥ 20↑ 
Diastolic Blood Pressure 
mmHg 
≥ 10↓ 
≥ 10↑ 
Heart Rate 
bpm 
≥ 15↓ 
≥ 15↑ 
 


 
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14.9. 
Appendix 9: List of Preferred Terms 
14.9.1. 
Herpes Zoster   
Adjudication by GSK SRT will identify events that are recurrent or disseminated. Herpes 
Zoster is considered disseminated if there is involvement of other organs other than the 
skin or if skin lesions (1) cross the midline of the body or (2) are in non-adjacent 
dermatomes or (3) are located in more than three adjacent dermatomes.  Herpes zoster is 
considered an opportunistic infection (OI) if it is adjudicated as recurrent or 
disseminated.  However, there may be some uncommon occurrences of a herpes zoster 
case that is adjudicated as an OI but is neither recurrent nor disseminated. 
14.9.2. 
Mycobacterium Tuberculosis 
Tuberculosis (TB) cases are reviewed by the GSK SRT to determine if a case is an OI. 
The following principles are applied: Pulmonary TB in an endemic area is not considered 
an OI. Pulmonary TB in a non-endemic area would be considered an OI unless the 
participant had close contact with a person infected with TB. Extra pulmonary TB is 
generally considered an OI unless the affected extra pulmonary area followed a wound or 
trauma. 
 


 
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14.10. 
Appendix 10: Missing Data Imputation Strategies 
14.10.1. 
Primary Estimand Strategy 
14.10.1.1. Multiple Imputation using off-treatment data within treatment arm 
1. Exclude week 1 data and participants with missing baseline values. 
2. Generate 1000 multiply imputed datasets using a monotone logistic imputation 
with augmentation (binary endpoints) or monotone regression imputation 
(continuous endpoints) including terms for baseline value, all previous visit 
values, treatment group, treatment discontinuation and treatment group-by-
treatment discontinuation interaction, i.e. a model  of the form 
𝑦𝑖= 𝛼1𝑖+ 𝛼2𝑖𝑏𝑎𝑠𝑒+ 𝛼3𝑖𝑇𝐷𝑖+ 𝛼4𝑖𝑡𝑟𝑡+ 𝛼5𝑖(𝑡𝑟𝑡∗𝑇𝐷𝑖) + 𝛽𝑖−1𝑦𝑖−1 + ⋯+ 𝛽1𝑦1 
where 𝑦𝑖 is the result at visit i and 𝑇𝐷𝑖 is the treatment discontinuation indicator at 
visit i. 
3. Perform statistical analysis as detailed in Section 7.1.3 and Section 7.2.3. 
 
14.10.1.2. Multiple Imputation using off-treatment data across all treatment arms 
1. Exclude week 1 data and participants with missing baseline values. 
2. Generate 1000 multiply imputed datasets using a monotone logistic imputation 
with augmentation (binary endpoints) or monotone regression imputation 
(continuous endpoints) including terms for baseline value, all previous visit 
values, treatment group and treatment discontinuation, i.e. a model of the form 
𝑦𝑖= 𝛼1𝑖+ 𝛼2𝑖𝑏𝑎𝑠𝑒+ 𝛼3𝑖𝑇𝐷𝑖+ 𝛼4𝑖𝑡𝑟𝑡+ 𝛽𝑖−1𝑦𝑖−1 + ⋯+ 𝛽1𝑦1 
where 𝑦𝑖 is the result at visit i and 𝑇𝐷𝑖 is the treatment discontinuation indicator at 
visit i. 
3. Perform statistical analysis as detailed in Section 7.1.3 and Section 7.2.3. 
14.10.1.3. Multiple imputation under MAR assumption  
1. Exclude week 1 data and participants with missing baseline values. 
2. Generate For each of the 1000 multiply imputed datasets using a monotone 
logistic imputation with augmentation (binary endpoints) or monotone regression 
imputation (continuous endpoints) including terms for baseline value, all previous 
visit values and treatment group, to impute any missing data post study 
withdrawal, i.e. a model of the form 
𝑦𝑖= 𝛼1𝑖+ 𝛼2𝑖𝑏𝑎𝑠𝑒+ 𝛼3𝑖𝑡𝑟𝑡+ 𝛽𝑖−1𝑦𝑖−1 + ⋯+ 𝛽1𝑦1 
where 𝑦𝑖 is the result at visit i. 
3. Perform statistical analysis as detailed in Section 7.1.3 and Section 7.2.3. 


 
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14.10.2. 
Supplemental Estimand 1 Strategy 
1. Impute all data for each visit following the intercurrent event for categorical 
variables to be non-response. 
2. Exclude week 1 data and participants with missing baseline values. 
3. In order to impute intermittent missing data, generate 1000 multiply imputed 
datasets using a monotone logistic imputation with augmentation (binary 
endpoints) or monotone regression imputation (continuous endpoints) including 
terms for baseline value, all previous visit values and treatment group, i.e. a 
model of the form 
𝑦𝑖= 𝛼1𝑖+ 𝛼2𝑖𝑏𝑎𝑠𝑒+ 𝛼3𝑖𝑡𝑟𝑡+ 𝛽𝑖−1𝑦𝑖−1 + ⋯+ 𝛽1𝑦1 
where 𝑦𝑖 is the result at visit i. 
4. Perform statistical analysis as detailed in Section 7.1.3 and Section 7.2.3. 
14.10.3. 
Supplemental Estimand 2 Strategy 
1. Set all data for each visit following the intercurrent event to missing. 
2. Exclude week 1 data and participants with missing baseline values. 
3. Generate 1000 multiply imputed datasets, using a monotone logistic imputation 
with augmentation (binary endpoints) or monotone regression imputation 
(continuous endpoints) including terms for baseline value, all previous visit 
values, and treatment group, i.e. a model of the form 
𝑦𝑖= 𝛼1𝑖+ 𝛼2𝑖𝑏𝑎𝑠𝑒+ 𝛼3𝑖𝑡𝑟𝑡+ 𝛽𝑖−1𝑦𝑖−1 + ⋯+ 𝛽1𝑦1 
where 𝑦𝑖 is the result at visit i. 
4. Perform statistical analysis as detailed in Section 7.1.3 and Section 7.2.3. 
14.10.4. 
Intermittent Missing Data Multiple Imputation 
Under the primary estimand strategy detailed in Section 14.10.1, in the absence of a 
treatment discontinuation flag at a particular visit, the models will all reduce to a model 
of the form: 
𝑦𝑖= 𝛼1𝑖+ 𝛼2𝑖𝑏𝑎𝑠𝑒+ 𝛼3𝑖𝑡𝑟𝑡+ 𝛽𝑖−1𝑦𝑖−1 + ⋯+ 𝛽1𝑦1 
where 𝑦𝑖 is the result at visit i, which will satisfy an MAR assumption for intermittent 
missing data. 
Under the supplemental estimand 1 strategy detailed in Section 14.10.2, intermittent 
missing data will be imputed separately under an MAR assumption. 
Under the supplemental estimand 2 strategy detailed in Section 14.10.3, all data, 
including intermittent missing data, is imputed under an MAR assumption. 


 
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14.11. 
Appendix 11: Abbreviations and Trademarks  
14.11.1. 
Abbreviations 
Abbreviation 
Description 
AAC 
All Analysis Complete 
ACR 
American College of Rheumatology 
ADA 
Anti-Drug Antibodies 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of Covariance 
bDMARD 
Biologic Disease-Modifying Anti-Rheumatic Drug 
BMI 
Body Mass Index 
boDMARD 
Biological Originator Disease-Modifying Antirheumatic Drug 
bsDMARD 
Biosimilar Disease-Modifying Antirheumatic Drug 
CDAI 
Clinical Disease Activity Index 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CIRT 
Cenduit Interactive Response Technology 
CRP 
C-Reactive Protein 
csDMARD 
Conventional Synthetic Disease Modifying Antirheumatic Drug 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Cardiovascular 
CVb / CVw 
Coefficient of Variation (Between) / Coefficient of Variation (Within) 
DAS 
Disease Activity Score 
DBF 
Database Freeze 
DBR 
Database Release 
DMARD 
Disease-Modifying Antirheumatic Drug 
DOB 
Date of Birth 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
EMA 
European Medicines Agency 
ESR 
Erythrocyte Sedimentation Rate 
EULAR 
European League Against Rheumatism 
EW 
Early Withdrawal 
FACIT 
Functional Assessment of Chronic Illness Therapy - Fatigue 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Clinical Results Disclosure Requirements 
GM-CSF 
Granulocyte-Macrophage Colony-Stimulating Factor 
GSK 
GlaxoSmithKline 
HAQ-DI 
Health Assessment Questionnaire Disability Index 
HDL 
Headline Results 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee  


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
9 3  
 
A b br e vi ati o n  
D e s cri pti o n  
I D S L 
I nt e gr at ed D ata Sta n dar ds Li br ary 
I E 
I nt erc urr e nt Eve nt 
I P 
I nv esti gati o nal Pr od uct 
I T T 
I nt e nt-T o -Tr e at  
I W R S 
I nt er active W e b Res p ons e Syst e m 
J A Ki 
J a n us Ki n ase I nhi bit or 
L D A 
L o w Dis e ase Activity  
L L O Q  
L o w er Li mit of Q u a ntific ati on  
L S 
L e ast S qu ar es  
M A C E  
M aj or A dv ers e Car di ov ascul ar Ev e nt  
M A R  
Missi n g at R an d o m  
M CI D  
Mi ni m u m Cli nic ally I m p ort a nt Diff er ent  
M C M C  
M ark ov C h ai n M ont e C arlo  
M C S  
M e nt al C o m po n ent Sc or e  
M e d D R A  
M e dic al Dicti o n ary for R e gul at ory Activiti es  
MI  
M ulti pl e I m p utati on  
M M R M  
Mix e d M o d el R ep eat e d M eas ur es  
M T X  
M et h otr exat e  
N Q  
N o n -q u antifi abl e  
N R S  
N u m eric al R ati n g Sc al e  
O R  
O d ds R ati o  
P A P  
P ul m o n ary Alv e ol ar Prot ei nosis  
P CI  
P ot e nti al Cli nic al I m port a nce  
P C S  
P hysic al C o m p on ent Scor e  
P D  
P h ar mac ody n a mic  
P D M P  
Pr ot oc ol Devi ati o n M a na g e m e nt Pl an  
P h G A  
P hysici a n’s Gl ob al Assess m e nt of Art hritis Dis e ase Activity  
P K  
P h ar mac oki netic  
P P  
P er Pr otoc ol  
P o p P K  
P o p ulati o n P K  
P R O  
P ati e nt R e p ort ed O utco m e  
P T  
Pr ef erre d Ter m  
Pt G A  
P ati e nt’s Gl o b al Ass ess m ent of Arthritis Dis e as e Activity  
Q C  
Q u ality C o ntr ol  
Q Tc F  
Fr e d eric a’s Q T I nt erv al C orrect e d f or H eart R ate  
Q Tc B  
B az ett’s Q T I nterv al C orr ecte d for H e art R at e  
Q W  
Ev ery W e ek  
Q 2 W  
Ev ery 2 W eeks  
R A  
R h e u m atoi d Arthritis  
R A P  
R e p orti n g & A n alysis Pl an  
R F  
R h e u m atoi d F actor  
S A C  
St atistic al An alysis C o m pl ete  
S A E  
S eri o us A dv ers e Ev ents  
C CI
C CI


 
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Abbreviation 
Description 
SC 
Subcutaneous 
SDTM 
Study Data Tabulation Model 
SF-36 
36-Item Short Form Survey 
SJC 
Swollen Joint Count 
SMQ 
Standardised MedDRA Query 
SOC 
System Organ Class 
SOP 
Standard Operation Procedure 
SRT 
Safety Review Team 
TA 
Therapeutic Area 
TB 
Mycobacterium Tuberculosis 
TEAE 
Treatment Emergent Adverse Event 
TFL 
Tables, Figures & Listings  
TJC 
Tender Joint Count 
tsDMARD 
Targeted Synthetic Disease Modifying Antirheumatic Drug 
VAS 
Visual Analog Scale 
WOCBP 
Woman of Childbearing Potential 
WPMI 
Within Patient Meaningful Improvement 
4B-OHC 
4ꞵ-hydroxycholesterol 
14.11.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
N/A 
 
PainDETECT 
 
 
PROMIS 
 
 
SAS 
 
 
SF-36 
 
 


 
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14.12. 
Appendix 12: List of Data Displays 
All data displays will use the term “subject” rather than “participant” in accordance with 
CDSIC and GSK Statistical Display Standards. 
14.12.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.30 
1.1 to 1.2 
Japan Study Population 
1.301 to 1.307 
- 
Efficacy 
2.1 to 2.88 
2.1 to 2.68 
Japan Efficacy 
2.301 to 2.308 
- 
Safety 
3.1 to 3.137 
3.1 to 3.7 
Japan Safety 
3.301 to 3.336 
- 
Pharmacokinetic 
4.1  
- 
Japan Pharmacokinetic 
4.301 to 4.302 
- 
Pharmacodynamic and / or Biomarker 
5.1 to 5.10 
5.1 to 5.4 
Section 
Listings 
ICH Listings 
1 to 14 
Other Listings 
15 to 45 
 
14.12.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in the final version of this document. 
14.12.3. 
Deliverables 
Delivery [Priority] [1] 
Description 
HDL[1] 
Headline Results Complete 
SAC[2] 
Statistical Analysis Complete 
AAC[3] 
All Analysis Complete 
NOTES:  
1. 
Indicates priority (i.e. order) in which displays will be generated for the reporting effort 
 


 
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Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1. 
Randomised 
Non-
Standard 
POP_T1 
(Based on 
ES1) 
Summary of Subject Disposition for the Subject 
Conclusion Record 
ICH E3, FDAAA, EudraCT 
 
Include Total Column 
SAC[2] 
1.2. 
Randomised 
Non-
Standard 
POP_T1 
(Based on 
ES1) 
Summary of Subject Status and Subject Disposition for 
Withdrawals due to COVID-19 Pandemic 
Only include: 
• 
Related to COVID-19 
Pandemic 
This information should be gathered 
from COVID-19 impact form in eCRF. 
Include Total Column 
SAC[2] 
1.3. 
Randomised 
Non-
Standard 
POP_T2 
(Based on 
SD1) 
Summary of Treatment Status and Reasons for 
Discontinuation of Study Treatment 
ICH E3 
 
Include Total Column 
SAC[2] 
1.4. 
Randomised 
Non-
Standard 
POP_T2 
(Based on 
SD1) 
Summary of Treatment Status and Reasons for 
Discontinuation of Study Treatment due to COVID-19 
Pandemic 
Only include: 
• 
Related to COVID-19 
Pandemic 
This information should be gathered 
from COVID-19 impact form in eCRF. 
Include Total Column 
SAC[2] 


 
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Study Population Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.5. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen 
Failure 
Journal Requirements 
 
SAC[2] 
1.6. 
Enrolled 
NS1 
Summary of Number of Subjects by Country and Site ID 
by Implementation of Pandemic Measures 
EudraCT/Clinical Operations 
Summarise by: 
• 
Overall 
• 
Before Implementation of 
Pandemic Measures 
• 
After Implementation of 
Pandemic Measures 
SAC[2] 
Protocol Deviation 
1.7. 
ITT 
DV1 
Summary of Important Protocol Deviations 
ICH E3 
Only categories are to be reported in 
the table. 
SAC[2] 
1.8. 
ITT 
DV1 
Summary of Important Protocol Deviations Related to the 
COVID-19 Pandemic 
Only include: 
• 
Important related to COVID-
19 Pandemic 
Only categories are to be reported in 
the table. 
SAC[2] 
Population Analysed 
1.9. 
Screened 
SP1  
Summary of Study Populations  
IDSL 
 
SAC[2] 


 
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Study Population Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.10. 
Enrolled 
SP2  
 
Summary of Protocol Deviations Leading to Exclusion 
from the Per Protocol Population(s) 
IDSL 
Include total column. 
Only categories are to be reported in 
the table. 
SAC[2] 
Demographic and Baseline Characteristics 
1.11. 
ITT 
DM1 
Summary of Demographic Characteristics 
ICH E3, FDAAA, EudraCT 
Add BMI to the output. 
HDL[1] 
1.12. 
Enrolled 
DM11 
Summary of Age Ranges 
EudraCT 
SAC[2] 
1.13. 
ITT 
DM6 
Summary of Race and Racial Combinations 
ICH E3, FDA, FDAAA, EudraCT 
SAC[2] 
1.14. 
ITT 
Non-
Standard 
POP_T3 
Summary of Baseline Efficacy Parameters 
Include all efficacy endpoints 
HDL[1] 
1.15. 
ITT 
Non-
Standard 
POP_T4 
Summary of Rheumatoid Arthritis Disease History 
 
HDL[1] 
1.16. 
ITT 
Non-
Standard 
POP_T5 
Summary of History of Tobacco Use and Family History of 
Cardiovascular Risk Factors 
Display by Overall, Age <50 and 
Age>=50 
SAC[2] 
Prior and Concomitant Medications 
1.17. 
ITT 
AE1 
Summary of Medical Conditions 
ICH E3  
Include Preferred Terms. 
SAC[2] 


 
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Study Population Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.18. 
ITT 
Non-
Standard 
POP_T6  
Summary of RA Concomitant Medications  
Include Total Column. 
SAC[2] 
1.19. 
ITT  
CM1 
Summary of All Concomitant Medications 
ICH E3 
Include Total Column. 
SAC[2] 
1.20. 
ITT 
Non-
Standard 
POP_T7 
Summary of RA Prior Medications  
Include Total Column. 
SAC[2] 
1.21. 
ITT 
CM1 
Summary of All Prior Medications 
Include Total Column. 
SAC[2] 
1.22. 
ITT 
Non-
Standard 
POP_T8 
Summary of RA Medications taken at Baseline (Day 1)  
Include Total Column. 
SAC[2] 
1.23. 
ITT 
Non-
Standard 
POP_T9 
Summary of Concomitant COVID-19 Vaccines 
Include Total Column. 
SAC[2] 
Exposure and Treatment Compliance 
1.24. 
Safety 
Non-
Standard 
POP_T10 
Summary of Exposure to Study Treatment 
ICH E3 
Include Total Column. 
SAC[2] 
1.25. 
Safety 
Non-
Standard 
POP_T11 
Summary of Overall Compliance Based on Exposure 
Include Total Column. 
SAC[2] 


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
1 0 0  
 
St u d y P o p ul ati o n T a ble s  
N o.  
P o p ul ati o n  
I D S L / 
E x a m ple 
S h ell  
Titl e   
Pr o gr a m mi n g N ote s  
D eli v era bl e 
[ Pri orit y] 
C O VI D -1 9  
1. 2 6.   
I T T 
P A N 4  
S u m m ary of C O VI D -1 9 Visit I m p acts  
 
S A C[ 2]  
1. 2 7.   
I T T 
D M 1  
S u m m ary of D e m ogr a phic C h ar act eristics by Pr e an d 
P ost Pa nd e mic M e as ures  
Su m m aris e by:  
•  
B ef or e I m pl e m e nt ati o n of 
P a n d e mic M e as ur es  
•  
Aft er I m pl e m e nt ati o n of 
P a n d e mic M e as ur es  
S A C[ 2]  
T a bl e s f or Dis cl os ur e  
1. 2 9.   R a n d o mis ed  
N o n -
St a nd ar d 
P O P _ T 1  
S u m m ary of Su bj ect Dis p ositi o n f or th e S u bject 
C o ncl usi o n Rec or d ( by R a nd o mis e d Tr eat m e nt Ar m)  
Dis pl ay by r a n d o mis e d tr e at m e nt ar m 
(i. e. all 6 tr e at m e nt ar ms) 
A A C[ 3]  
1. 3 0.   
I T T 
D M 1  
S u m m ary of D e m ogr a phic C h ar act eristics ( by 
R a n d o mis ed Tr e at m ent Ar m)  
Dis pl ay by r a n d o mis e d tr e at m e nt ar m 
(i. e. all 6 tr e at m e nt ar ms) 
A A C[ 3]  
J a p a n S u b gr o u p  
1. 3 01.   J a p an es e 
R a n d o mis ed  
N o n -
St a nd ar d 
P O P _ T 1  
( B as e d o n 
E S 1)  
S u m m ary of Su bj ect Dis p ositi o n f or th e S u bject 
C o ncl usi o n Rec or d f or J ap an es e S u bjects 
I ncl u d e T ot al C ol u m n. 
A A C[ 3]  
C CI


 
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Study Population Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.302
Japanese 
ITT 
DM1 
Summary of Demographic Characteristics for Japanese 
Subjects 
 
AAC[3] 
1.303
Japanese 
ITT 
Non-
Standard 
POP_T3 
Summary of Baseline Efficacy Parameters for Japanese 
Subjects 
Include Total Column. 
AAC[3] 
1.304
Japanese 
ITT 
Non-
Standard 
POP_T4 
Summary of Rheumatoid Arthritis Disease History for 
Japanese Subjects 
Include Total Column. 
AAC[3] 
1.305
Japanese 
ITT 
Non-
Standard 
POP_T8 
Summary of RA Medications taken at Baseline (Day 1) for 
Japanese Subjects 
Include Total Column. 
AAC[3] 
1.306
Japanese 
Safety 
Non-
Standard 
POP_T10 
Summary of Exposure to Study Treatment for Japanese 
Subjects 
Include Total Column. 
AAC[3] 
1.307
Japanese 
Safety 
Non-
Standard 
POP_T11 
Summary of Overall Compliance Based on Exposure for 
Japanese Subjects 
Include Total Column. 
AAC[3] 
 


 
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Study Population Figures 
 
Study Population Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1. 
Randomised 
PAN6 
Plot of Recruitment over time by Country Relative to 
COVID-19 Pandemic Measures 
 
SAC[2] 
COVID-19 
1.2. 
ITT 
PAN8 
Plot of Visits Impacted by COVID-19 Pandemic 
 
SAC[2] 


 
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Efficacy Tables 
Efficacy: Tables 
No. 
Population 
IDSL /  
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
ACR20 
2.1. 
ITT 
Non-Standard  
EFF_T1 
Summary and Analysis of ACR20 Response at Each 
Assessment Visit (Primary Estimand) 
 
HDL[1] 
2.2. 
ITT 
Non-Standard  
EFF_T1 
Summary and Analysis of ACR20 Response at Each 
Assessment Visit (Supplemental Estimand 1) 
 
SAC[2] 
2.3. 
ITT 
Non-Standard  
EFF_T1 
Summary and Analysis of ACR20 Response at Each 
Assessment Visit (Supplemental Estimand 2) 
 
AAC[3] 
2.4. 
ITT 
Non-Standard 
EFF_T2 
Summary of Observed ACR20 Response at Each 
Assessment Visit 
 
SAC[2] 
HAQ-DI 
2.5. 
ITT 
Non-Standard 
EFF_T3 
Analysis of Change from Baseline in HAQ-DI Score at 
Each Assessment Visit (Primary Estimand) 
 
HDL[1] 
2.6. 
ITT 
Non-Standard 
EFF_T4 
Summary of Observed Change from Baseline in HAQ-DI 
Score and in Functional Areas of the HAQ-DI Score at 
Each Assessment Visit 
 
SAC[2] 
CDAI Total Score 
2.7. 
ITT 
Non-Standard 
EFF_T3 
Analysis of Change from Baseline in CDAI Total score at 
Each Assessment Visit (Primary Estimand) 
 
HDL[1] 
2.8. 
ITT 
Non-Standard 
EFF_T3  
Analysis of Change from Baseline in CDAI Total score at 
Each Assessment Visit (Supplemental Estimand 2) 
 
AAC[3] 


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
1 0 4  
 
Effi c a c y: Ta bl e s  
N o.  
P o p ul ati o n  
I D S L /  
E x a m ple 
S h ell  
Titl e   
Pr o gr a m mi n g N ote s  
D eli v era bl e 
[ Pri orit y] 
2. 9.   
I T T 
N o n -St a n d ar d  
E F F _ T 4  
S u m m ary of Obs erv ed C h an g e fr o m B aseli n e i n C D AI 
T ot al Scor e at E ach Assess m e nt Visit  
 
S A C[ 2]  
Art hriti s P ai n V A S  
2. 1 2.  
 
I T T 
N o n -St a n d ar d  
E F F _ T 3  
A n alysis of C h an g e fr o m B as eli n e i n Art hritis P ai n V A S 
Sc or e at E ach Assess m e nt Visit ( Pri m ary Esti ma n d)  
 
H D L [1 ] 
2. 1 3.  
 
I T T 
N o n -St a n d ar d  
E F F _ T 3  
A n alysis of C h an g e fr o m B as eli n e i n Art hritis P ai n V A S 
Sc or e at E ach Assess m e nt Visit ( S u p ple m e ntal  Esti m an d  
2 ) 
 
A A C[ 3 ] 
2. 1 4.  
 
I T T 
N o n -St a n d ar d  
E F F _ T 4  
S u m m ary of Obs erv ed C h an g e fr o m B aseli n e i n Art hritis 
P ai n V A S Scor e at Eac h Ass ess m e nt Visit  
 
S A C[ 2]  
C D AI -L D A  
2. 1 5.  
 
I T T 
N o n -St a n d ar d  
E F F _ T 1  
S u m m ary a nd A nalysis of C D AI -L D A R es p o ns e  
( C D AI ≤1 0) at E ac h Ass ess m e nt Visit ( Pri m ary Esti ma nd)  
 
S A C[ 2]  
2. 1 6.  
 
I T T 
N o n -St a n d ar d 
E F F _ T 2  
S u m m ary of Obs erv ed C D AI -L D A R es p o ns e  ( C D AI ≤1 0) 
at E ach Assess m e nt Visit  
 
S A C[ 2]  
C CI


 
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Efficacy: Tables 
No. 
Population 
IDSL /  
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
ACR50/70  
2.17. 
ITT 
Non-Standard  
EFF_T1 
Summary and Analysis of ACR50 Response at Each 
Assessment Visit (Primary Estimand) 
 
SAC[2] 
2.18. 
ITT 
Non-Standard  
EFF_T1 
Summary and Analysis of ACR70 Response at Each 
Assessment Visit (Primary Estimand) 
 
SAC[2] 
2.19. 
ITT 
Non-Standard 
EFF_T2 
Summary of Observed ACR50/70 Response at Each 
Assessment Visit 
Page by ACR50 and ACR70 
SAC[2] 
CDAI Remission 
2.20. 
ITT 
Non-Standard  
EFF_T1 
Summary and Analysis of CDAI Remission Response 
(CDAI≤2.8) at Each Assessment Visit (Primary Estimand) 
 
SAC[2] 
2.21. 
ITT 
Non-Standard 
EFF_T2 
Summary of Observed CDAI Remission (CDAI≤2.8) at 
Each Assessment Visit 
 
SAC[2] 
DAS28-CRP LDA 
2.22. 
ITT 
Non-Standard  
EFF_T1 
Summary and Analysis of DAS28-CRP LDA Response 
(DAS28-CRP≤3.2) at Each Assessment Visit (Primary 
Estimand) 
 
SAC[2] 
2.23. 
ITT 
Non-Standard 
EFF_T2 
Summary of Observed DAS28-CRP LDA Response 
(DAS28-CRP≤3.2) at Each Assessment Visit 
 
SAC[2] 


 
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Efficacy: Tables 
No. 
Population 
IDSL /  
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
DAS28-CRP Remission 
2.24. 
ITT 
Non-Standard  
EFF_T1 
Summary and Analysis of DAS28-CRP Remission 
Response (DAS28-CRP<2.6) at Each Assessment Visit 
(Primary Estimand) 
 
SAC[2] 
2.25. 
ITT 
Non-Standard 
EFF_T2 
Summary of Observed DAS28-CRP Remission Response 
(DAS28-CRP<2.6) at Each Assessment Visit 
 
SAC[2] 
DAS28-ESR LDA 
2.26. 
ITT 
Non-Standard  
EFF_T1 
Summary and Analysis of DAS28-ESR LDA Response 
(DAS28-ESR≤3.2) at Each Assessment Visit (Primary 
Estimand) 
 
SAC[2] 
2.27. 
ITT 
Non-Standard 
EFF_T2 
Summary of Observed DAS28-ESR LDA Response 
(DAS28-ESR≤3.2) at Each Assessment Visit 
 
SAC[2] 
DAS28-ESR Remission 
2.28. 
ITT 
Non-Standard  
EFF_T1 
Summary and Analysis of DAS28-ESR Remission 
Response (DAS28-ESR<2.6) at Each Assessment Visit 
(Primary Estimand) 
 
SAC[2] 
2.29. 
ITT 
Non-Standard 
EFF_T2 
Summary of Observed DAS28-ESR Remission Response 
(DAS28-ESR<2.6) at Each Assessment Visit 
 
SAC[2] 
Good/Moderate EULAR Response 
2.30. 
ITT 
Non-Standard  
EFF_T1 
Summary and Analysis of Good/Moderate EULAR 
Response (based on DAS28-CRP) at Each Assessment 
Visit (Primary Estimand) 
  
SAC[2] 


 
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Efficacy: Tables 
No. 
Population 
IDSL /  
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.31. 
ITT 
Non-Standard 
EFF_T2 
Summary of Observed Good/Moderate EULAR Response 
(based on DAS28-CRP) at Each Assessment Visit 
 
SAC[2] 
ACR/EULAR Remission Boolean-based and Index-based 
2.32. 
ITT 
Non-Standard 
EFF_T2 
Summary of Observed Index-based ACR/EULAR 
Remission Response at Each Assessment Visit 
 
SAC[2] 
2.33. 
ITT 
Non-Standard 
EFF_T2 
Summary of Observed Boolean-based ACR/EULAR 
Remission Response at Each Assessment Visit 
 
SAC[2] 
Tender Joint Counts 
2.34. 
ITT 
Non-Standard 
EFF_T3 
Analysis of Change from Baseline in TJC28 at Each 
Assessment Visit (Primary Estimand) 
 
SAC[2] 
2.35. 
ITT 
Non-Standard 
EFF_T3 
Analysis of Change from Baseline in TJC68 at Each 
Assessment Visit (Primary Estimand) 
 
SAC[2] 
2.36. 
ITT 
Non-Standard 
EFF_T4 
Summary of Observed Change from Baseline in TJC28 
and TJC68 at Each Assessment Visit 
 
SAC[2] 
Swollen Joint Counts 
2.37. 
ITT 
Non-Standard 
EFF_T3 
Analysis of Change from Baseline in SJC28 at Each 
Assessment Visit (Primary Estimand) 
 
SAC[2] 
2.38. 
ITT 
Non-Standard 
EFF_T3 
Analysis of Change from Baseline in SJC66 at Each 
Assessment Visit (Primary Estimand) 
 
SAC[2] 
2.39. 
ITT 
Non-Standard 
EFF_T4 
Summary of Observed Change from Baseline in SJC28 
and SJC66 at Each Assessment Visit 
 
SAC[2] 


 
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Efficacy: Tables 
No. 
Population 
IDSL /  
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
CRP/ESR 
2.40. 
ITT 
Non-Standard 
EFF_T3 
Analysis of Change from Baseline in CRP (mg/L) at Each 
Assessment Visit (Primary Estimand)  
 
SAC[2] 
2.41. 
ITT 
Non-Standard 
EFF_T4 
Summary of Observed Change from Baseline in CRP 
(mg/L) and ESR (mm/h) at Each Assessment Visit 
 
SAC[2] 
2.42. 
ITT 
Non-Standard 
EFF_T5 
Summary of Ratio to Baseline in CRP (mg/L) and ESR 
(mm/h) at Each Assessment Visit (Log Transformed) 
 
SAC[2] 
Patient’s Global Assessment 
2.43. 
ITT 
Non-Standard 
EFF_T3 
Analysis of Change from Baseline in Patient’s Global 
Assessment of Arthritis at Each Assessment Visit 
(Primary Estimand) 
 
SAC[2] 
2.44. 
ITT 
Non-Standard 
EFF_T4 
Summary of Observed Change from Baseline in Patient’s 
Global Assessment of Arthritis at Each Assessment Visit 
 
SAC[2] 
Physician’s Global Assessment 
2.45. 
ITT 
Non-Standard 
EFF_T3 
Analysis of Change from Baseline in Physician’s Global 
Assessment of Arthritis at Each Assessment Visit 
(Primary Estimand) 
 
SAC[2] 
2.46. 
ITT 
Non-Standard 
EFF_T4 
Summary of Observed Change from Baseline in 
Physician’s Global Assessment of Arthritis at Each 
Assessment Visit 
 
SAC[2] 


 
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Efficacy: Tables 
No. 
Population 
IDSL /  
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
DAS28-CRP 
2.47. 
ITT 
Non-Standard 
EFF_T3 
Analysis of Change from Baseline in DAS28-CRP at Each 
Assessment Visit (Primary Estimand) 
 
SAC[2] 
2.48. 
ITT 
Non-Standard 
EFF_T4 
Summary of Observed Change from Baseline in DAS28-
CRP at Each Assessment Visit 
 
SAC[2] 
DAS28-ESR 
2.49. 
ITT 
Non-Standard 
EFF_T3 
Analysis of Change from Baseline in DAS28-ESR at Each 
Assessment Visit (Primary Estimand) 
 
SAC[2] 
2.50. 
ITT 
Non-Standard 
EFF_T4 
Summary of Observed Change from Baseline in DAS28-
ESR at Each Assessment Visit 
 
SAC[2] 
SF-36 (Physical, Mental and Individual Components) 
2.51. 
ITT 
Non-Standard 
EFF_T3 
Analysis of Change from Baseline in Physical Score of 
SF-36 at Each Assessment Visit (Primary Estimand) 
 
SAC[2] 
2.52. 
ITT 
Non-Standard 
EFF_T4 
Summary of Observed Change from Baseline in Physical 
Score of SF-36 at Each Assessment Visit 
 
SAC[2] 
2.53. 
ITT 
Non-Standard 
EFF_T3 
Analysis of Change from Baseline in Mental Score of SF-
36 at Each Assessment Visit (Primary Estimand) 
 
SAC[2] 
2.54. 
ITT 
Non-Standard 
EFF_T4 
Summary of Observed Change from Baseline in Mental 
Score of SF-36 at Each Assessment Visit 
 
SAC[2] 
2.55. 
ITT 
Non-Standard 
EFF_T4 
Summary of Observed Change from Baseline in Domain 
Scores of SF-36 at Each Assessment Visit 
 
SAC[2] 


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
1 1 0  
 
Effi c a c y: Ta bl e s  
N o.  
P o p ul ati o n  
I D S L /  
E x a m ple 
S h ell  
Titl e   
Pr o gr a m mi n g N ote s  
D eli v era bl e 
[ Pri orit y] 
C CI


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
1 1 1  
 
Effi c a c y: Ta bl e s  
N o.  
P o p ul ati o n  
I D S L /  
E x a m ple 
S h ell  
Titl e   
Pr o gr a m mi n g N ote s  
D eli v era bl e 
[ Pri orit y] 
C CI


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
1 1 2  
 
Effi c a c y: Ta bl e s  
N o.  
P o p ul ati o n  
I D S L /  
E x a m ple 
S h ell  
Titl e   
Pr o gr a m mi n g N ote s  
D eli v era bl e 
[ Pri orit y] 
C CI


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
1 1 3  
 
Effi c a c y: Ta bl e s  
N o.  
P o p ul ati o n  
I D S L /  
E x a m ple 
S h ell  
Titl e   
Pr o gr a m mi n g N ote s  
D eli v era bl e 
[ Pri orit y] 
C CI


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
1 1 4  
 
Effi c a c y: Ta bl e s  
N o.  
P o p ul ati o n  
I D S L /  
E x a m ple 
S h ell  
Titl e   
Pr o gr a m mi n g N ote s  
D eli v era bl e 
[ Pri orit y] 
S e n siti vit y A n aly s es  
2. 8 8.  
 
P er 
Pr ot oc ol  
N o n -St a n d ar d  
E F F _ T 1  
S u m m ary a nd A nalysis of A C R 2 0 R es po ns e at E ac h 
Ass ess m e nt Visit ( Pri m ary Esti ma n d) ( P er Pr ot ocol 
P o p ulati o n)  
 
A A C[ 3]  
J a p a n S u b gr o u p  
2. 3 01  
J a p an es e 
I T T 
N o n -St a n d ar d  
E F F _ T 2  
S u m m ary of Obs erv ed A C R2 0 R esp o nse at E ach 
Ass ess m e nt Visit f or Ja p anes e Su bj ects  
Dis pl ay r a w pr o p orti o ns  
A A C[ 3]  
2. 3 02  
J a p an es e 
I T T 
N o n -St a n d ar d  
E F F _ T 4  
S u m m ary of Obs erv ed C h an g e fr o m B aseli n e i n H A Q -DI 
Sc or e an d in F u ncti o nal Ar eas of t h e H A Q -DI Sc ore at 
E ac h Ass ess m e nt Visit for J a p an es e S ubj ects  
 
A A C[ 3]  
2. 3 03  
J a p an es e 
I T T 
N o n -St a n d ar d  
E F F _ T 4  
S u m m ary of Obs erv ed C h an g e fr o m B aseli n e i n C D AI 
T ot al Scor e at E ach Assess m e nt Visit for J a pa nes e 
S u bj ects  
 
A A C[ 3]  
C CI


 
CONFIDENTIAL 
 
 
 
202018 
 
115 
 
Efficacy: Tables 
No. 
Population 
IDSL /  
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.304 
Japanese 
ITT 
Non-Standard 
EFF_T4 
Summary of Observed Change from Baseline in FACIT-
Fatigue at Each Assessment Visit for Japanese Subjects 
 
AAC[3] 
2.305 
Japanese 
ITT 
Non-Standard 
EFF_T4 
Summary of Observed Change from Baseline in Arthritis 
Pain VAS Score at Each Assessment Visit for Japanese 
Subjects 
 
AAC[3] 
2.306 
Japanese 
ITT 
Non-Standard 
EFF_T2 
Summary of Observed ACR50/70 Response at Each 
Assessment Visit for Japanese Subjects 
 
AAC[3] 
2.307 
Japanese 
ITT 
Non-Standard 
EFF_T4 
Summary of Observed Change from Baseline in DAS28-
CRP at Each Assessment Visit for Japanese Subjects 
 
AAC[3] 
2.308 
Japanese 
ITT 
Non-Standard 
EFF_T4 
Summary of Observed Change from Baseline in DAS28-
ESR at Each Assessment Visit for Japanese Subjects 
 
AAC[3] 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
116 
 
Efficacy Figures 
Efficacy: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
ACR20 
2.1. 
ITT 
Non-Standard 
EFF_F1 
Proportion of Subjects Achieving ACR20 Response at 
Each Assessment Visit (Primary Estimand) 
 
HDL[1] 
2.2. 
ITT 
Non-Standard 
EFF_F1 
Proportion of Subjects Achieving ACR20 Response at 
Each Assessment Visit (Supplemental Estimand 1) 
 
SAC[2] 
2.3. 
ITT 
Non-Standard 
EFF_F1 
Proportion of Subjects Achieving ACR20 Response at 
Each Assessment Visit (Supplemental Estimand 2) 
 
AAC[3] 
HAQ-DI 
2.4. 
ITT 
Non-Standard 
EFF_F2 
Plot of Least Squares Means of Change from Baseline in 
HAQ-DI Score at Each Assessment Visit (Primary 
Estimand)  
 
HDL[1] 
CDAI Total Score 
2.5. 
ITT 
Non-Standard 
EFF_F2 
Plot of Least Squares Means of Change from Baseline in 
CDAI Total Score at Each Assessment Visit (Primary 
Estimand) 
 
HDL[1] 
2.6. 
ITT 
Non-Standard 
EFF_F2 
Plot of Least Squares Means of Change from Baseline in 
CDAI Total Score at Each Assessment Visit 
(Supplemental Estimand 2) 
 
AAC[3] 


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
1 1 7  
 
Effi c a c y: Fi g ure s  
N o.  
P o p ul ati o n  
I D S L / 
E x a m ple 
S h ell  
Titl e   
Pr o gr a m mi n g N ote s  
D eli v era bl e 
[ Pri orit y] 
Art hriti s P ai n V A S  
2. 8.   
I T T 
N o n -St a n d ar d  
E F F _ F 2  
Pl ot of L east S q uar es M e ans of C ha n ge fr o m Bas eli ne i n 
Art hritis P ai n V A S at E ac h Ass ess m e nt Visit ( Pri m ary 
Esti m a n d)  
 
H D L [1 ] 
2. 9.   
I T T 
N o n -St a n d ar d  
E F F _ F 2  
Pl ot of L east S q uar es M e ans of C ha n ge fr o m Bas eli ne i n 
Art hritis P ai n V A S at E ac h Ass ess m e nt Visit 
( S u p pl e m ent al Esti m a nd 2 ) 
 
A A C[ 3 ] 
C D AI -L D A  
2. 1 0.  
 
I T T 
N o n -St a n d ar d 
E F F _ F 1  
Pr o p orti on of S ubj ects Ac hievi n g C D AI -L D A ( C D AI ≤1 0) at 
E ac h Ass ess m e nt Visit ( Pri m ary Esti m a n d)  
 
S A C[ 2]  
A C R 5 0/ 7 0  
2. 1 1.  
 
I T T 
N o n -St a n d ar d 
E F F _ F 1  
Pr o p orti on of S ubj ects Ac hievi n g A C R 50 R esp o nse at 
E ac h Ass ess m e nt Visit ( Pri m ary Esti ma n d)  
 
S A C[ 2]  
2. 1 2.  
 
I T T 
N o n -St a n d ar d 
E F F _ F 1  
Pr o p orti on of S ubj ects Ac hievi n g A C R 70 R esp o nse at 
E ac h Ass ess m e nt Visit ( Pri m ary Esti ma n d) 
 
S A C[ 2]  
C D AI R e mi s si o n  
2. 1 3.  
 
I T T 
N o n -St a n d ar d 
E F F _ F 1  
Pr o p orti on of S ubj ects Ac hievi n g C D AI Re missi o n  
( C D AI ≤2. 8) at E ach Assess m e nt Visit ( Pri m ary Esti ma nd)  
 
S A C[ 2]  
C CI


 
CONFIDENTIAL 
 
 
 
202018 
 
118 
 
Efficacy: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
DAS28-CRP LDA 
2.14. 
ITT 
Non-Standard 
EFF_F1 
Proportion of Subjects Achieving DAS28-CRP LDA 
(DAS28-CRP≤3.2) at Each Assessment Visit (Primary 
Estimand) 
 
SAC[2] 
DAS28-CRP Remission 
2.15. 
ITT 
Non-Standard 
EFF_F1 
Proportion of Subjects Achieving DAS28-CRP Remission 
(DAS28-CRP<2.6) at Each Assessment Visit (Primary 
Estimand) 
 
SAC[2] 
DAS28-ESR LDA 
2.16. 
ITT 
Non-Standard 
EFF_F1 
Proportion of Subjects Achieving DAS28-ESR LDA 
(DAS28-ESR≤3.2) at Each Assessment Visit (Primary 
Estimand) 
 
SAC[2] 
DAS28-ESR Remission 
2.17. 
ITT 
Non-Standard 
EFF_F1 
Proportion of Subjects Achieving DAS28-ESR Remission 
(DAS28-ESR<2.6) at Each Assessment Visit (Primary 
Estimand) 
 
SAC[2] 
Good/Moderate EULAR Response 
2.18. 
ITT 
Non-Standard 
EFF_F1 
Proportion of Subjects Achieving Good/Moderate EULAR 
Response (based on DAS28-CRP) at Each Assessment 
Visit (Primary Estimand) 
 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
119 
 
Efficacy: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Tender Joint Counts 
2.19. 
ITT 
Non-Standard 
EFF_F2 
Plot of Least Squares Means of Change from Baseline in 
TJC28 at Each Assessment Visit (Primary Estimand) 
 
SAC[2] 
2.20. 
ITT 
Non-Standard 
EFF_F2 
Plot of Least Squares Means of Change from Baseline in 
TJC68 at Each Assessment Visit (Primary Estimand) 
 
SAC[2] 
Swollen Joint Counts 
2.21. 
ITT 
Non-Standard 
EFF_F2 
Plot of Least Squares Means of Change from Baseline in 
SJC28 at Each Assessment Visit (Primary Estimand) 
 
SAC[2] 
2.22. 
ITT 
Non-Standard 
EFF_F2 
Plot of Least Squares Means of Change from Baseline in 
SJC66 at Each Assessment Visit (Primary Estimand) 
 
SAC[2] 
CRP 
2.23. 
ITT 
Non-Standard 
EFF_F2 
Plot of Least Squares Means of Change from Baseline in 
CRP (mg/L) at Each Assessment Visit (Primary Estimand)   
SAC[2] 
Patient’s Global Assessment 
2.24. 
ITT 
Non-Standard 
EFF_F2 
Plot of Least Squares Means of Change from Baseline in 
Patient’s Global Assessment at Each Assessment Visit 
(Primary Estimand) 
 
SAC[2] 
Physician’s Global Assessment 
2.25. 
ITT 
Non-Standard 
EFF_F2 
Plot of Least Squares Means of Change from Baseline in 
Physician’s Global Assessment at Each Assessment Visit 
(Primary Estimand) 
 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
120 
 
Efficacy: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
DAS28-CRP 
2.26. 
ITT 
Non-Standard 
EFF_F2 
Plot of Least Squares Means of Change from Baseline in 
DAS28-CRP at Each Assessment Visit (Primary 
Estimand) 
 
SAC[2] 
DAS28-ESR 
2.27. 
ITT 
Non-Standard 
EFF_F2 
Plot of Least Squares Means of Change from Baseline in 
DAS28-ESR at Each Assessment Visit (Primary 
Estimand) 
 
SAC[2] 
SF-36 (Physical, Mental and Individual Components) 
2.28. 
ITT 
Non-Standard 
EFF_F2 
Plot of Least Squares Means of Change from Baseline in 
Physical Score of SF-36 at Each Assessment Visit 
(Primary Estimand) 
 
SAC[2] 
2.29. 
ITT 
Non-Standard 
EFF_F2 
Plot of Least Squares Means Change from Baseline in 
Mental Score of SF-36 at Each Assessment Visit (Primary 
Estimand) 
 
SAC[2] 
2.30. 
ITT 
Non-Standard 
EFF_F3 
Spydergram of Individual Domain Scores of SF-36 at 
Each Assessment Visit  
 
SAC[2] 
Subgroup: ACR20 
2.31. 
ITT 
Non-Standard 
EFF_F4 
Forest Plot of Demographic Subgroup Results for ACR20 
– Comparison to Placebo at Week 12 
 
SAC[2] 
2.32. 
ITT 
Non-Standard 
EFF_F4 
Forest Plot of Demographic Subgroup Results for ACR20 
– Comparison to Sarilumab at Week 24 
 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
121 
 
Efficacy: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.33. 
ITT 
Non-Standard 
EFF_F4 
Forest Plot of Disease Characteristic Subgroup Results 
for ACR20 – Comparison to Placebo at Week 12 
 
SAC[2] 
2.34. 
ITT 
Non-Standard 
EFF_F4 
Forest Plot of Disease Characteristic Subgroup Results 
for ACR20 – Comparison to Sarilumab at Week 24 
 
SAC[2] 
Subgroup: HAQ-DI 
2.35. 
ITT 
Non-Standard 
EFF_F5 
Forest Plot of Demographic Subgroup Results for HAQ-DI 
– Comparison to Placebo at Week 12 
 
SAC[2] 
2.36. 
ITT 
Non-Standard 
EFF_F5 
Forest Plot of Demographic Subgroup Results for HAQ-DI 
– Comparison to Sarilumab at Week 24 
 
SAC[2] 
2.37. 
ITT 
Non-Standard 
EFF_F5 
Forest Plot of Disease Characteristic Subgroup Results 
for HAQ-DI – Comparison to Placebo at Week 12 
 
SAC[2] 
2.38. 
ITT 
Non-Standard 
EFF_F5 
Forest Plot of Disease Characteristic Subgroup Results 
for HAQ-DI – Comparison to Sarilumab at Week 24 
 
SAC[2] 
Subgroup: CDAI Total 
2.39. 
ITT 
Non-Standard 
EFF_F5 
Forest Plot of Demographic Subgroup Results for CDAI 
Total Score – Comparison to Placebo at Week 12 
 
SAC[2] 
2.40. 
ITT 
Non-Standard 
EFF_F5 
Forest Plot of Demographic Subgroup Results for CDAI 
Total Score – Comparison to Sarilumab at Week 24 
 
SAC[2] 
2.41. 
ITT 
Non-Standard 
EFF_F5 
Forest Plot of Disease Characteristic Subgroup Results 
for CDAI Total Score – Comparison to Placebo at Week 
12 
 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
122 
 
Efficacy: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.42. 
ITT 
Non-Standard 
EFF_F5 
Forest Plot of Disease Characteristic Subgroup Results 
for CDAI Total Score – Comparison to Sarilumab at Week 
24 
 
SAC[2] 
Subgroup: Arthritis Pain VAS 
2.43. 
ITT 
Non-Standard 
EFF_F5 
Forest Plot of Demographic Subgroup Results for Arthritis 
Pain VAS – Comparison to Placebo at Week 12 
 
SAC[2] 
2.44. 
ITT 
Non-Standard 
EFF_F5 
Forest Plot of Demographic Subgroup Results for Arthritis 
Pain VAS – Comparison to Sarilumab at Week 24 
 
SAC[2] 
2.45. 
ITT 
Non-Standard 
EFF_F5 
Forest Plot of Disease Characteristic Subgroup Results 
for Arthritis Pain VAS – Comparison to Placebo at Week 
12 
 
SAC[2] 
2.46. 
ITT 
Non-Standard 
EFF_F5 
Forest Plot of Disease Characteristic Subgroup Results 
for Arthritis Pain VAS – Comparison to Sarilumab at Week 
24 
 
SAC[2] 
Additional Figures Splitting out Pooled Placebo Post Week 12 
2.47. 
ITT 
Non-Standard 
EFF_F1 
Proportion of Subjects Achieving ACR20 Response at 
Each Assessment Visit (Primary Estimand) Splitting out 
Pooled Placebo Post Week 12 
Display pooled placebo arm split out 
after week 12 
AAC[3] 
2.48. 
ITT 
Non-Standard 
EFF_F2 
Plot of Least Squares Means of Change from Baseline in 
HAQ-DI Score at Each Assessment Visit (Primary 
Estimand) Splitting out Pooled Placebo Post Week 12 
Display pooled placebo arm split out 
after week 12 
AAC[3] 


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
1 2 3  
 
Effi c a c y: Fi g ure s  
N o.  
P o p ul ati o n  
I D S L / 
E x a m ple 
S h ell  
Titl e   
Pr o gr a m mi n g N ote s  
D eli v era bl e 
[ Pri orit y] 
2. 4 9.  
 
I T T 
N o n -St a n d ar d 
E F F _ F 2  
Pl ot of L east S q uar es M e ans of C ha n ge fr o m Bas eli ne i n 
C D AI T ot al Scor e at Eac h Ass ess m e nt Visit ( Pri m ary 
Esti m a n d)  Splitti n g o ut P ool e d Pl ace bo Post W e ek 1 2  
Dis pl ay p o ol e d pl ac e b o ar m s plit o ut 
aft er w e ek 1 2  
A A C[ 3]  
2. 5 0.  
 
I T T 
N o n -St a n d ar d 
E F F _ F 2  
Pl ot of  L east S q uar es M e ans of C ha n ge fr o m Bas eli ne i n 
Art hritis P ai n V A S at E ac h Ass ess m e nt Visit ( Pri m ary 
Esti m a n d)  Splitti n g o ut P ool e d Pl ace bo Post W e ek 1 2  
Dis pl ay p o ol e d pl ac e b o ar m s plit o ut 
aft er w e ek 1 2  
A A C[ 3]  
2. 5 1.  
 
I T T 
N o n -St a n d ar d 
E F F _ F 1  
Pr o p orti on of S ubj ects Ac hievi n g A C R 50 R esp o nse at 
E ac h Ass ess m e nt Visit ( Pri m ary Esti ma n d)  S plittin g o ut 
P o ol ed Pl ace b o P ost W e ek 1 2  
Dis pl ay p o ol e d pl ac e b o ar m s plit o ut 
aft er w e ek 1 2  
A A C[ 3]  
C CI


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
1 2 4  
 
Effi c a c y: Fi g ure s  
N o.  
P o p ul ati o n  
I D S L / 
E x a m ple 
S h ell  
Titl e   
Pr o gr a m mi n g N ote s  
D eli v era bl e 
[ Pri orit y] 
C CI


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
1 2 5  
 
Effi c a c y: Fi g ure s  
N o.  
P o p ul ati o n  
I D S L / 
E x a m ple 
S h ell  
Titl e   
Pr o gr a m mi n g N ote s  
D eli v era bl e 
[ Pri orit y] 
 
C CI


 
CONFIDENTIAL 
 
 
 
202018 
 
126 
 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events (AEs) 
3.1. 
Safety 
AE13 
(modified) 
Overall Summary of Adverse Events (Period 1) 
 
SAC[2] 
3.2. 
Safety - 
Subjects 
who 
Entered 
Period 2 
AE13 
(modified) 
Overall Summary of Adverse Events (Period 2) 
 
SAC[2] 
3.3. 
Safety 
AE13 
(modified) 
Overall Summary of Adverse Events (Period 1+2) 
 
SAC[2] 
3.4. 
Safety 
AE1 
Summary of All Adverse Events by System Organ Class 
and Preferred Term (Period 1) 
ICH E3 
 
SAC[2] 
3.5. 
Safety - 
Subjects 
who 
Entered 
Period 2 
AE1 
Summary of All Adverse Events by System Organ Class 
and Preferred Term (Period 2) 
ICH E3 
 
SAC[2] 
3.6. 
Safety 
AE1 
Summary of All Adverse Events by System Organ Class 
and Preferred Term (Period 1+2) 
ICH E3 
 
SAC[2] 
3.7. 
Safety 
AE1 
Summary of All Drug-Related Adverse Events by System 
Organ Class and Preferred Term (Period 1) 
ICH E3 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
127 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.8. 
Safety - 
Subjects 
who 
Entered 
Period 2 
AE1 
Summary of All Drug-Related Adverse Events by System 
Organ Class and Preferred Term (Period 2) 
ICH E3 
SAC[2] 
3.9. 
Safety 
AE1 
Summary of All Drug-Related Adverse Events by System 
Organ Class and Preferred Term (Period 1+2) 
ICH E3 
SAC[2] 
3.10. 
Safety 
AE1 
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Period 1) 
ICH E3 
HDL[1] 
3.11. 
Safety - 
Subjects 
who 
Entered 
Period 2 
AE1 
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Period 2) 
ICH E3 
SAC[2] 
3.12. 
Safety 
AE1 
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Period 1+2) 
ICH E3 
HDL[1] 
3.13. 
Safety 
AE1  
 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment by System Organ 
Class and Preferred Term (Period 1) 
IDSL 
 
SAC[2] 
3.14. 
Safety - 
Subjects 
who 
Entered 
Period 2 
AE1  
 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment by System Organ 
Class and Preferred Term (Period 2) 
IDSL 
 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
128 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.15. 
Safety 
AE1  
 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment by System Organ 
Class and Preferred Term (Period 1+2) 
IDSL 
 
SAC[2] 
3.16. 
Safety 
AE3 
Summary of Common (>=5%) Adverse Events by Overall 
Frequency (Period 1) 
ICH E3 
 
SAC[2] 
3.17. 
Safety - 
Subjects 
who 
Entered 
Period 2 
AE3 
Summary of Common (>=5%) Adverse Events by Overall 
Frequency (Period 2) 
ICH E3 
 
SAC[2] 
3.18. 
Safety 
AE3 
Summary of Common (>=5%) Adverse Events by Overall 
Frequency (Period 1+2) 
ICH E3 
 
SAC[2] 
3.19. 
Safety 
AE15 
Summary of Common (>=5%) Non-Serious Adverse 
Events by System Organ Class and Preferred Term 
(Number of Subject and Occurrences) (Period 1) 
FDAAA, EudraCT 
 
SAC[2] 
3.20. 
Safety - 
Subjects 
who 
Entered 
Period 2 
AE15 
Summary of Common (>=5%) Non-Serious Adverse 
Events by System Organ Class and Preferred Term 
(Number of Subject and Occurrences) (Period 2) 
FDAAA, EudraCT 
 
SAC[2] 
3.21. 
Safety 
AE15 
Summary of Common (>=5%) Non-Serious Adverse 
Events by System Organ Class and Preferred Term 
(Number of Subject and Occurrences) (Period 1+2) 
FDAAA, EudraCT 
 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
129 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.22. 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences) (Period 1) 
FDAAA, EudraCT 
 
SAC[2] 
3.23. 
Safety - 
Subjects 
who 
Entered 
Period 2 
AE16 
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences) (Period 2) 
FDAAA, EudraCT 
 
SAC[2] 
3.24. 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences) (Period 1+2) 
FDAAA, EudraCT 
 
SAC[2] 
3.25. 
Safety 
AE5A 
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term (Period 1) 
ICH E3 
SAC[2] 
3.26. 
Safety - 
Subjects 
who 
Entered 
Period 2 
AE5A 
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term (Period 2) 
ICH E3 
SAC[2] 
3.27. 
Safety 
AE5A 
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term (Period 1+2) 
ICH E3 
SAC[2] 
3.28. 
Safety 
AE5A 
Summary of All Drug-Related Adverse Events by Maximum 
Intensity by System Organ Class and Preferred Term 
(Period 1) 
ICH E3 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
130 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.29. 
Safety - 
Subjects 
who 
Entered 
Period 2 
AE5A 
Summary of All Drug-Related Adverse Events by Maximum 
Intensity by System Organ Class and Preferred Term 
(Period 2) 
ICH E3 
SAC[2] 
3.30. 
Safety 
AE5A 
Summary of All Drug-Related Adverse Events by Maximum 
Intensity by System Organ Class and Preferred Term 
(Period 1+2) 
ICH E3 
SAC[2] 
3.31. 
Safety 
AE3 
Summary of Non-Serious Drug-Related Adverse Events by 
Overall Frequency (Period 1) 
PLS Requirements 
SAC[2] 
3.32. 
Safety - 
Subjects 
who 
Entered 
Period 2 
AE3 
Summary of Non-Serious Drug-Related Adverse Events by 
Overall Frequency (Period 2) 
PLS Requirements 
SAC[2] 
3.33. 
Safety 
AE3 
Summary of Non-Serious Drug-Related Adverse Events by 
Overall Frequency (Period 1+2) 
PLS Requirements 
SAC[2] 
3.34. 
Safety 
AE20 
Summary of Serious Fatal and Non-Fatal Drug-Related 
Adverse Events by Overall Frequency (Period 1) 
PLS Requirements 
SAC[2] 
3.35. 
Safety - 
Subjects 
who 
Entered 
Period 2 
AE20 
Summary of Serious Fatal and Non-Fatal Drug-Related 
Adverse Events by Overall Frequency (Period 2) 
PLS Requirements 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
131 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.36. 
Safety 
AE20 
Summary of Serious Fatal and Non-Fatal Drug-Related 
Adverse Events by Overall Frequency (Period 1+2) 
PLS Requirements 
SAC[2] 
3.37. 
Safety 
Non-Standard 
SAFE_T1 
Summary of Exposure Adjusted Incidence Rates per 100 
Person Years for All Adverse Events (Period 1) 
 
SAC[2] 
3.38. 
Safety - 
Subjects 
who 
Entered 
Period 2 
Non-Standard 
SAFE_T1 
Summary of Exposure Adjusted Incidence Rates per 100 
Person Years for All Adverse Events (Period 2) 
 
SAC[2] 
3.39. 
Safety 
Non-Standard 
SAFE_T1 
Summary of Exposure Adjusted Incidence Rates per 100 
Person Years for All Adverse Events (Period 1+2) 
 
SAC[2] 
Adverse Events of Special Interest (AESI) and Other Important AEs 
3.40. 
Safety 
Non-Standard 
SAFE_T2 
Summary of Adverse Events of Special Interest (AESI) 
(Period 1) 
 
HDL[1] 
3.41. 
Safety - 
Subjects 
who 
Entered 
Period 2 
Non-Standard 
SAFE_T2 
Summary of Adverse Events of Special Interest (AESI) 
(Period 2) 
 
SAC[2] 
3.42. 
Safety 
Non-Standard 
SAFE_T2 
Summary of Adverse Events of Special Interest (AESI) 
(Period 1+2) 
 
HDL[1] 


 
CONFIDENTIAL 
 
 
 
202018 
 
132 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.43. 
Safety 
Non-Standard 
SAFE_T1 
Summary of Exposure Adjusted Incidence Rates per 100 
Person Years for Adverse Events of Special Interest 
(Period 1) 
 
SAC[2] 
3.44. 
Safety - 
Subjects 
who 
Entered 
Period 2 
Non-Standard 
SAFE_T1 
Summary of Exposure Adjusted Incidence Rates per 100 
Person Years for Adverse Events of Special Interest 
(Period 2) 
 
SAC[2] 
3.45. 
Safety 
Non-Standard 
SAFE_T1 
Summary of Exposure Adjusted Incidence Rates per 100 
Person Years for Adverse Events of Special Interest 
(Period 1+2) 
 
SAC[2] 
3.46. 
Safety 
Non-Standard 
SAFE_T3 
Summary of Other Important Adverse Events (Period 1) 
 
SAC[2] 
3.47. 
Safety - 
Subjects 
who 
Entered 
Period 2 
Non-Standard 
SAFE_T3 
Summary of Other Important Adverse Events (Period 2) 
 
SAC[2] 
3.48. 
Safety  
Non-Standard 
SAFE_T3 
Summary of Other Important Adverse Events (Period 1+2) 
 
SAC[2] 
3.49. 
Safety 
Non-Standard 
SAFE_T1 
Summary of Exposure Adjusted Incidence Rates per 100 
Person Years for Other Important Adverse Events (Period 
1) 
 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
133 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.50. 
Safety - 
Subjects 
who 
Entered 
Period 2 
Non-Standard 
SAFE_T1 
Summary of Exposure Adjusted Incidence Rates per 100 
Person Years for Other Important Adverse Events (Period 
2) 
 
SAC[2] 
3.51. 
Safety 
Non-Standard 
SAFE_T1 
Summary of Exposure Adjusted Incidence Rates per 100 
Person Years for Other Important Adverse Events (Period 
1+2) 
 
SAC[2] 
3.52. 
Safety 
Non-Standard 
SAFE_T4 
Summary of Adjudicated Cardiovascular Event Categories 
(Period 1) 
 
SAC[2] 
3.53. 
Safety - 
Subjects 
who 
Entered 
Period 2 
Non-Standard 
SAFE_T4 
Summary of Adjudicated Cardiovascular Event Categories 
(Period 2) 
 
SAC[2] 
3.54. 
Safety 
Non-Standard 
SAFE_T4 
Summary of Adjudicated Cardiovascular Event Categories 
(Period 1+2) 
 
SAC[2] 
3.55. 
Safety 
ESI1 
(modified) 
Summary of Characteristics of Injection Site Reactions 
(Period 1)  
 
SAC[2] 
3.56. 
Safety - 
Subjects 
who 
Entered 
Period 2 
ESI1 
(modified) 
Summary of Characteristics of Injection Site Reactions 
(Period 2)  
 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
134 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.57. 
Safety 
ESI1 
(modified) 
Summary of Characteristics of Injection Site Reactions 
(Period 1+2)  
 
SAC[2] 
3.58. 
Safety 
Non-Standard 
SAFE_T5 
Summary of Injection Site Reactions (Period 1) 
 
SAC[2] 
3.59. 
Safety - 
Subjects 
who 
Entered 
Period 2 
Non-Standard 
SAFE_T5 
Summary of Injection Site Reactions (Period 2) 
 
SAC[2] 
3.60. 
Safety 
Non-Standard 
SAFE_T5 
Summary of Injection Site Reactions (Period 1+2) 
 
SAC[2] 
3.61. 
Safety 
Non-Standard 
SAFE_T6 
Summary of Serious or Adjudicated Opportunistic 
Infections (Period 1) 
Display only the rows with counts for 
Type of Infection and Origin of 
Infection. 
SAC[2] 
3.62. 
Safety - 
Subjects 
who 
Entered 
Period 2 
Non-Standard 
SAFE_T6 
Summary of Serious or Adjudicated Opportunistic 
Infections (Period 2) 
Display only the rows with counts for 
Type of Infection and Origin of 
Infection. 
SAC[2] 
3.63. 
Safety 
Non-Standard 
SAFE_T6 
Summary of Serious or Adjudicated Opportunistic 
Infections (Period 1+2) 
Display only the rows with counts for 
Type of Infection and Origin of 
Infection. 
SAC[2] 
3.64. 
Safety 
Non-Standard 
SAFE_T7 
Summary of Adjudicated Serious Hypersensitivity 
Reactions (Period 1) 
 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
135 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.65. 
Safety - 
Subjects 
who 
Entered 
Period 2 
Non-Standard 
SAFE_T7 
Summary of Adjudicated Serious Hypersensitivity 
Reactions (Period 2) 
 
SAC[2] 
3.66. 
Safety 
Non-Standard 
SAFE_T7 
Summary of Adjudicated Serious Hypersensitivity 
Reactions (Period 1+2) 
 
SAC[2] 
Pulmonary Findings 
3.67. 
Safety 
Non-Standard 
SAFE_T8 
Summary of Pulmonary Findings (Period 1) 
 
SAC[2] 
3.68. 
Safety - 
Subjects 
who 
Entered 
Period 2 
Non-Standard 
SAFE_T8 
Summary of Pulmonary Findings (Period 2) 
 
SAC[2] 
3.69. 
Safety 
Non-Standard 
SAFE_T8 
Summary of Pulmonary Findings (Period 1+2) 
 
SAC[2] 
3.70. 
Safety 
Non-Standard  
SAFE_T9 
Summary of Pulse Oximetry Results (Period 1) 
 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
136 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.71. 
Safety - 
Subjects 
who 
Entered 
Period 2 
Non-Standard  
SAFE_T9 
Summary of Pulse Oximetry Results (Period 2) 
 
SAC[2] 
3.72. 
Safety 
Non-Standard  
SAFE_T9 
Summary of Pulse Oximetry Results (Period 1+2) 
 
SAC[2] 
Laboratory: Chemistry, Hematology & Fasting Lipids  
3.73. 
Safety 
LB1 
Summary of Chemistry Changes from Baseline (Period 1) 
ICH E3 
Exclude CRP 
 
SAC[2] 
3.74. 
Safety - 
Subjects 
who 
Entered 
Period 2 
LB1 
Summary of Chemistry Changes from Baseline (Period 2) 
ICH E3 
Exclude CRP 
 
SAC[2] 
3.75. 
Safety 
LB1 
Summary of Chemistry Changes from Baseline (Period 
1+2) 
ICH E3 
Exclude CRP 
 
SAC[2] 
3.76. 
Safety 
LB16A 
(modified) 
Summary of Worst Case Chemistry Results by Maximum 
Grade Shift Post-Baseline Relative to Baseline (Period 1) 
ICH E3 
 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
137 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.77. 
Safety - 
Subjects 
who 
Entered 
Period 2 
LB16A 
(modified) 
Summary of Worst Case Chemistry Results by Maximum 
Grade Shift Post-Baseline Relative to Baseline (Period 2) 
ICH E3 
 
SAC[2] 
3.78. 
Safety 
LB16A 
(modified) 
Summary of Worst Case Chemistry Results by Maximum 
Grade Shift Post-Baseline Relative to Baseline (Period 
1+2) 
ICH E3 
 
SAC[2] 
3.79. 
 Safety 
LB1 
Summary of Hematology Changes from Baseline (Period 
1) 
ICH E3 
Exclude ESR 
SAC[2] 
3.80. 
Safety - 
Subjects 
who 
Entered 
Period 2 
LB1 
Summary of Hematology Changes from Baseline (Period 
2) 
ICH E3 
Exclude ESR 
 
SAC[2] 
3.81. 
 Safety 
LB1 
Summary of Hematology Changes from Baseline (Period 
1+2) 
ICH E3 
Exclude ESR 
 
SAC[2] 
3.82. 
Safety 
LB16A 
(modified) 
Summary of Worst Case Hematology Results by Maximum 
Grade Shift Post-Baseline Relative to Baseline (Period 1) 
ICH E3 
 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
138 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.83. 
Safety - 
Subjects 
who 
Entered 
Period 2 
LB16A 
(modified) 
Summary of Worst Case Hematology Results by Maximum 
Grade Shift Post-Baseline Relative to Baseline (Period 2) 
ICH E3 
 
SAC[2] 
3.84. 
Safety 
LB16A 
(modified) 
Summary of Worst Case Hematology Results by Maximum 
Grade Shift Post-Baseline Relative to Baseline (Period 
1+2) 
ICH E3 
 
SAC[2] 
3.85. 
Safety 
LB1 
Summary of Fasting Lipids Changes from Baseline (Period 
1) 
 
SAC[2] 
3.86. 
Safety - 
Subjects 
who 
Entered 
Period 2 
LB1 
Summary of Fasting Lipids Changes from Baseline (Period 
2) 
 
SAC[2] 
3.87. 
Safety 
LB1 
Summary of Fasting Lipids Changes from Baseline (Period 
1+2) 
 
SAC[2] 
3.88. 
Safety 
LB18 
Summary of Laboratory Parameters of Interest CTCAE 
Worst Grade Shift from Baseline Grade (Period 1) 
 
SAC[2] 
3.89. 
Safety – 
Subjects 
who 
Entered 
Period 2 
LB18 
Summary of Laboratory Parameters of Interest CTCAE 
Worst Grade Shift from Baseline Grade (Period 2) 
 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
139 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.90. 
Safety  
LB18 
Summary of Laboratory Parameters of Interest CTCAE 
Worst Grade Shift from Baseline Grade (Period 1+2) 
 
SAC[2] 
3.91. 
Safety 
UR1 
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline 
(Period 1) 
ICH E3 
 
SAC[2] 
3.92. 
Safety – 
Subjects 
who 
Entered 
Period 2 
UR1 
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline 
(Period 2) 
ICH E3 
 
SAC[2] 
3.93. 
Safety  
UR1 
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline 
(Period 1+2) 
ICH E3 
 
SAC[2] 
Laboratory: Hepatobiliary (Liver) 
3.94. 
 Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting 
(Period 1) 
IDSL 
SAC[2] 
3.95. 
Safety - 
Subjects 
who 
Entered 
Period 2 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting 
(Period 2) 
IDSL 
SAC[2] 
3.96. 
 Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting 
(Period 1+2) 
IDSL 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
140 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.97. 
 Safety 
LIVER10 
Summary of Hepatobiliary Laboratory Abnormalities 
(Period 1) 
IDSL 
 
SAC[2] 
3.98. 
Safety - 
Subjects 
who 
Entered 
Period 2 
LIVER10 
Summary of Hepatobiliary Laboratory Abnormalities 
(Period 2) 
IDSL 
 
SAC[2] 
3.99. 
Safety 
LIVER10 
Summary of Hepatobiliary Laboratory Abnormalities 
(Period 1+2) 
IDSL 
 
SAC[2] 
ECG 
3.100. 
 Safety 
EG1 
Summary of ECG Findings  
IDSL 
 
SAC[2] 
3.101. 
Safety 
EG2 
Summary of Change from Baseline in ECG Values by Visit 
(Period 1) 
IDSL 
 
SAC[2] 
3.102. 
Safety - 
Subjects 
who 
Entered 
Period 2 
EG2 
Summary of Change from Baseline in ECG Values by Visit 
(Period 2) 
IDSL 
 
SAC[2] 
3.103. 
Safety 
EG2 
Summary of Change from Baseline in ECG Values by Visit 
(Period 1+2) 
IDSL 
 
SAC[2] 
3.104. 
Safety 
EG10 
Summary of Maximum QTc Values Post-Baseline Relative 
to Baseline by Category (Period 1) 
IDSL 
  
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
141 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.105. 
Safety – 
Subjects 
who 
Entered 
Period 2 
EG10 
Summary of Maximum QTc Values Post-Baseline Relative 
to Baseline by Category (Period 2) 
IDSL 
 
SAC[2] 
3.106. 
Safety 
EG10 
Summary of Maximum QTc Values Post-Baseline Relative 
to Baseline by Category (Period 1+2) 
IDSL 
 
SAC[2] 
3.107. 
Safety 
EG11 
Summary of Maximum Increase in QTc Values Post-
Baseline Relative to Baseline by Category (Period 1) 
IDSL 
  
SAC[2] 
3.108. 
Safety – 
Subjects 
who 
Entered 
Period 2 
EG11 
Summary of Maximum Increase in QTc Values Post-
Baseline Relative to Baseline by Category (Period 2) 
IDSL 
 
SAC[2] 
3.109. 
Safety 
EG11 
Summary of Maximum Increase in QTc Values Post-
Baseline Relative to Baseline by Category (Period 1+2) 
IDSL 
 
SAC[2] 
Vital Signs 
3.110. 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs (Period 
1) 
ICH E3 
 
SAC[2] 
3.111. 
Safety - 
Subjects 
who 
Entered 
Period 2 
VS1 
Summary of Change from Baseline in Vital Signs (Period 
2) 
ICH E3 
 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
142 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.112. 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs (Period 
1+2) 
ICH E3 
 
SAC[2] 
3.113. 
Safety 
VS3 
 
Summary of Worst Case Vital Signs Results Relative to 
Normal Range Post-Baseline Relative to Baseline (Period 
1) 
IDSL 
 
SAC[2] 
3.114. 
Safety – 
Subjects 
who 
Entered 
Period 2 
VS3 
 
Summary of Worst Case Vital Signs Results Relative to 
Normal Range Post-Baseline Relative to Baseline (Period 
2) 
IDSL 
 
SAC[2] 
3.115. 
Safety  
VS3 
 
Summary of Worst Case Vital Signs Results Relative to 
Normal Range Post-Baseline Relative to Baseline (Period 
1+2) 
IDSL 
 
SAC[2] 
Safety Biomarkers (Immunogenicity) 
3.116. 
Safety 
Non-Standard 
SAFE_T10 
Summary of Anti-GSK3196165 Antibodies (ADA) 
 
AAC[3] 
3.117. 
Safety 
Non-Standard 
SAFE_T11 
Summary of Binding Antibody at Each Assessment Visit 
 
AAC[3] 
3.118. 
Safety 
Non-Standard 
SAFE_T12 
Summary of Neutralising Antibody at Each Assessment 
Visit 
 
AAC[3] 


 
CONFIDENTIAL 
 
 
 
202018 
 
143 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
COVID-19 
3.119. 
Safety 
PAN1 
Summary of COVID-19 Assessments for Subjects with 
COVID-19 Adverse Events (Period 1) 
 
SAC[2] 
3.120. 
Safety - 
Subjects 
who 
Entered 
Period 2 
PAN1 
Summary of COVID-19 Assessments for Subjects with 
COVID-19 Adverse Events (Period 2) 
 
SAC[2] 
3.121. 
Safety 
PAN1 
Summary of COVID-19 Assessments for Subjects with 
COVID-19 Adverse Events (Period 1+2) 
 
SAC[2] 
3.122. 
Safety 
PAN2 
Summary of COVID-19 Additional Assessments for 
Subjects with COVID-19 Adverse Events (Period 1) 
 
SAC[2] 
3.123. 
Safety - 
Subjects 
who 
Entered 
Period 2 
PAN2 
Summary of COVID-19 Additional Assessments for 
Subjects with COVID-19 Adverse Events (Period 2) 
 
SAC[2] 
3.124. 
Safety 
PAN2 
Summary of COVID-19 Additional Assessments for 
Subjects with COVID-19 Adverse Events (Period 1+2) 
 
SAC[2] 
3.125. 
Safety 
PAN3 
Summary of COVID-19 Symptoms for Subjects with 
COVID-19 Adverse Events (Period 1) 
Remove “no” and “unknown” rows 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
144 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.126. 
Safety - 
Subjects 
who 
Entered 
Period 2 
PAN3 
Summary of COVID-19 Symptoms for Subjects with 
COVID-19 Adverse Events (Period 2) 
 
 
Remove “no” and “unknown” rows 
SAC[2] 
3.127. 
Safety 
PAN3 
Summary of COVID-19 Symptoms for Subjects with 
COVID-19 Adverse Events (Period 1+2) 
Remove “no” and “unknown” rows 
SAC[2] 
3.128. 
Safety 
Non-Standard 
SAFE_T13 
Summary of Adjudicated Serious Cases of COVID-19 
Infections (Period 1) 
 
SAC[2] 
3.129. 
Safety - 
Subjects 
who 
Entered 
Period 2 
Non-Standard 
SAFE_T13 
Summary of Adjudicated Serious Cases of COVID-19 
Infections (Period 2) 
 
SAC[2] 
3.130. 
Safety 
Non-Standard 
SAFE_T13 
Summary of Adjudicated Serious Cases of COVID-19 
Infections (Period 1+2) 
 
SAC[2] 
3.131. 
Safety 
Non-Standard 
SAFE_T15 
Summary of COVID-19 Infections (Period 1) 
 
SAC[2] 
3.132. 
Safety - 
Subjects 
who 
Entered 
Period 2 
Non-Standard 
SAFE_T15 
Summary of COVID-19 Infections (Period 2) 
 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
145 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.133. 
Safety 
Non-Standard 
SAFE_T15 
Summary of COVID-19 Infections (Period 1+2) 
 
SAC[2] 
Additional Adverse Events 
3.134. 
Safety 
Non-Standard 
SAFE_T14 
Summary of Common (>=2%) Adverse Events by Time 
from Randomisation 
 
AAC[3] 
Exposure Adjusted SAEs 
3.135. 
Safety 
Non-Standard 
SAFE_T1 
Summary of Exposure Adjusted Incidence Rates per 100 
Person Years for Serious Adverse Events (Period 1) 
 
SAC[2] 
3.136. 
Safety - 
Subjects 
who 
Entered 
Period 2 
Non-Standard 
SAFE_T1 
Summary of Exposure Adjusted Incidence Rates per 100 
Person Years for Serious Adverse Events (Period 2) 
 
SAC[2] 
3.137. 
Safety 
Non-Standard 
SAFE_T1 
Summary of Exposure Adjusted Incidence Rates per 100 
Person Years for Serious Adverse Events (Period 1+2) 
 
SAC[2] 
Japan subgroup 
3.301. 
Japanese 
Safety 
AE1 
Summary of All Adverse Events by System Organ Class 
and Preferred Term (Period 1) for Japanese Subjects 
 
AAC[3] 


 
CONFIDENTIAL 
 
 
 
202018 
 
146 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.302. 
Japanese 
Safety – 
Subjects 
who 
Entered 
Period 2 
AE1 
Summary of All Adverse Events by System Organ Class 
and Preferred Term (Period 2) for Japanese Subjects 
 
AAC[3] 
3.303. 
Japanese 
Safety 
AE1 
Summary of All Adverse Events by System Organ Class 
and Preferred Term (Period 1+2) for Japanese Subjects 
 
AAC[3] 
3.304. 
Japanese 
Safety 
AE1 
Summary of All Drug-Related Adverse Events by System 
Organ Class and Preferred Term (Period 1) for Japanese 
Subjects 
 
AAC[3] 
3.305. 
Japanese 
Safety – 
Subjects 
who 
Entered 
Period 2 
AE1 
Summary of All Drug-Related Adverse Events by System 
Organ Class and Preferred Term (Period 2) for Japanese 
Subjects 
 
AAC[3] 
3.306. 
Japanese 
Safety 
AE1 
Summary of All Drug-Related Adverse Events by System 
Organ Class and Preferred Term (Period 1+2) for 
Japanese Subjects 
 
AAC[3] 
3.307. 
Japanese 
Safety 
AE1 
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Period 1) for Japanese 
Subjects 
 
AAC[3] 


 
CONFIDENTIAL 
 
 
 
202018 
 
147 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.308. 
Japanese 
Safety – 
Subjects 
who 
Entered 
Period 2 
AE1 
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Period 2) for Japanese 
Subjects 
 
AAC[3] 
3.309. 
Japanese 
Safety 
AE1 
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Period 1+2) for Japanese 
Subjects 
 
AAC[3] 
3.310. 
Japanese 
Safety 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from 
Study by System Organ Class and Preferred Term (Period 
1) for Japanese Subjects 
 
AAC[3] 
3.311. 
Japanese 
Safety – 
Subjects 
who 
Entered 
Period 2 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from 
Study by System Organ Class and Preferred Term (Period 
2) for Japanese Subjects 
 
AAC[3] 
3.312. 
Japanese 
Safety 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from 
Study by System Organ Class and Preferred Term (Period 
1+2) for Japanese Subjects 
 
AAC[3] 


 
CONFIDENTIAL 
 
 
 
202018 
 
148 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.313. 
Japanese 
Safety 
Non-Standard 
SAFE_T2 
Summary of Adverse Events of Special Interest (AESI) 
(Period 1) for Japanese Subjects 
 
AAC[3] 
3.314. 
Japanese 
Safety – 
Subjects 
who 
Entered 
Period 2 
Non-Standard 
SAFE_T2 
Summary of Adverse Events of Special Interest (AESI) 
(Period 2) for Japanese Subjects 
 
AAC[3] 
3.315. 
Japanese 
Safety 
Non-Standard 
SAFE_T2 
Summary of Adverse Events of Special Interest (AESI) 
(Period 1+2) for Japanese Subjects 
 
AAC[3] 
3.316. 
Japanese 
Safety 
LB1 
Summary of Chemistry Changes from Baseline (Period 1) 
for Japanese Subjects 
 
AAC[3] 
3.317. 
Japanese 
Safety - 
Subjects 
who 
Entered 
Period 2 
LB1 
Summary of Chemistry Changes from Baseline (Period 2) 
for Japanese Subjects 
 
AAC[3] 
3.318. 
Japanese 
Safety 
LB1 
Summary of Chemistry Changes from Baseline (Period 
1+2) for Japanese Subjects 
 
AAC[3] 
3.319. 
Japanese 
Safety 
LB16 
Summary of Worst Case Chemistry Results by Maximum 
Grade Shift Post-Baseline Relative to Baseline (Period 1) 
for Japanese Subjects 
 
AAC[3] 


 
CONFIDENTIAL 
 
 
 
202018 
 
149 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.320. 
Japanese 
Safety - 
Subjects 
who 
Entered 
Period 2 
LB16 
Summary of Worst Case Chemistry Results by Maximum 
Grade Shift Post-Baseline Relative to Baseline (Period 2) 
for Japanese Subjects 
 
AAC[3] 
3.321. 
Japanese 
Safety 
LB16 
Summary of Worst Case Chemistry Results by Maximum 
Grade Shift Post-Baseline Relative to Baseline (Period 
1+2) for Japanese Subjects 
 
AAC[3] 
3.322. 
Japanese 
Safety 
LB1 
Summary of Hematology Changes from Baseline (Period 
1) for Japanese Subjects 
 
AAC[3] 
3.323. 
Japanese 
Safety - 
Subjects 
who 
Entered 
Period 2 
LB1 
Summary of Hematology Changes from Baseline (Period 
2) for Japanese Subjects 
 
AAC[3] 
3.324. 
Japanese 
Safety 
LB1 
Summary of Hematology Changes from Baseline (Period 
1+2) for Japanese Subjects 
 
AAC[3] 
3.325. 
Japanese 
Safety 
LB16 
Summary of Worst Case Hematology Results by Maximum 
Grade Shift Post-Baseline Relative to Baseline (Period 1) 
for Japanese Subjects 
 
AAC[3] 


 
CONFIDENTIAL 
 
 
 
202018 
 
150 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.326. 
Japanese 
Safety - 
Subjects 
who 
Entered 
Period 2 
LB16 
Summary of Worst Case Hematology Results by Maximum 
Grade Shift Post-Baseline Relative to Baseline (Period 2) 
for Japanese Subjects 
 
AAC[3] 
3.327. 
Japanese 
Safety 
LB16 
Summary of Worst Case Hematology Results by Maximum 
Grade Shift Post-Baseline Relative to Baseline (Period 
1+2) for Japanese Subjects 
 
AAC[3] 
3.328. 
Japanese 
Safety 
LB1 
Summary of Fasting Lipids Changes from Baseline (Period 
1) for Japanese Subjects 
 
AAC[3] 
3.329. 
Japanese 
Safety - 
Subjects 
who 
Entered 
Period 2 
LB1 
Summary of Fasting Lipids Changes from Baseline (Period 
2) for Japanese Subjects 
 
AAC[3] 
3.330. 
Japanese 
Safety 
LB1 
Summary of Fasting Lipids Changes from Baseline (Period 
1+2) for Japanese Subjects 
 
AAC[3] 
3.331. 
Japanese 
Safety 
UR1 
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline 
(Period 1) for Japanese Subjects 
 
AAC[3] 


 
CONFIDENTIAL 
 
 
 
202018 
 
151 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.332. 
Japanese 
Safety - 
Subjects 
who 
Entered 
Period 2 
UR1 
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline 
(Period 2) for Japanese Subjects 
 
AAC[3] 
3.333. 
Japanese 
Safety 
UR1 
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline 
(Period 1+2) for Japanese Subjects 
 
AAC[3] 
3.334. 
Japanese 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs (Period 
1) for Japanese Subjects 
 
AAC[3] 
3.335. 
Japanese 
Safety - 
Subjects 
who 
Entered 
Period 2 
VS1 
Summary of Change from Baseline in Vital Signs (Period 
2) for Japanese Subjects 
 
AAC[3] 
3.336. 
Japanese 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs (Period 
1+2) for Japanese Subjects 
 
AAC[3] 
 


 
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152 
 
Safety Figures 
Safety: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events 
3.1. 
Safety 
AE10 
Plot of Relative Risks for Common (>= 5%) Adverse 
Events  
 
SAC[2] 
3.2. 
Safety 
AE10 
Plot of Relative Risks for Adverse Events of Special 
Interest 
 
SAC[2] 
Laboratory: Chemistry, Hematology & Fasting Lipids 
3.3. 
Safety 
LB9 
Distribution of Laboratory Parameters of Interest by Time 
and Treatment with Maximum over Time 
 
SAC[2] 
Laboratory: Hepatobiliary (Liver) 
3.4. 
Safety 
LIVER14 
Scatter Plot of Maximum vs Baseline for ALT 
 
SAC[2] 
3.5. 
Safety 
LIVER9 
Scatter Plot of Maximum Total Bilirubin vs Maximum ALT 
 
SAC[2] 
Adverse Events (Treatment Policy Handling Strategy) 
3.6. 
Safety 
AE10 
Plot of Relative Risks for Common (>= 5%) Adverse 
Events (Treatment Policy Handling Strategy) 
 
AAC[3] 
3.7. 
Safety 
AE10 
Plot of Relative Risks for Adverse Events of Special 
Interest (Treatment Policy Handling Strategy) 
 
AAC[3] 
 
 
 


 
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202018 
 
153 
 
Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK Concentration 
4.1. 
PK 
PK01 
Summary of GSK3196165 Serum Concentrations (ng/mL) 
by Visit 
 
SAC[2] 
Japan Subgroup 
4.301. 
Japanese 
PK 
PK01 
Summary of GSK3196165 Serum Concentrations (ng/mL) 
by Visit for Japanese Subjects 
 
AAC[3] 
4.302. 
Non-
Japanese 
PK 
PK01 
Summary of GSK3196165 Serum Concentrations (ng/mL) 
by Visit for Non-Japanese Subjects 
 
AAC[3] 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
154 
 
Biomarker Tables 
 Biomarker: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Exploratory: Pharmacodynamic Biomarkers 
5.1 
Safety 
Non-Standard 
BIOM_T1 
Summary of Observed Change from Baseline in 
Pharmacodynamic Biomarkers at Each Assessment Visit 
 
AAC[3] 
5.2 
Safety 
Non-Standard 
BIOM_T1 
Summary of Observed Percentage Change from Baseline 
in Pharmacodynamic Biomarkers at Each Assessment 
Visit 
 
AAC[3] 
5.3 
Safety 
Non-Standard 
BIOM_T2 
Repeated Measures Analysis of Change from Baseline in 
Pharmacodynamic Biomarkers at Each Assessment Visit 
(Placebo Comparison) 
 
AAC[3] 
5.4 
Safety 
Non-Standard 
BIOM_T2 
Repeated Measures Analysis of Change from Baseline in 
Pharmacodynamic Biomarkers at Each Assessment Visit 
(Sarilumab Comparison) 
 
AAC[3] 
5.5 
Safety 
Non-Standard 
BIOM_T3 
Repeated Measures Analysis of Ratio to Baseline in 
Pharmacodynamic Biomarkers at Each Assessment Visit 
(Placebo Comparison) (Log Transformed) 
 
AAC[3] 
5.6 
Safety 
Non-Standard 
BIOM_T3 
Repeated Measures Analysis of Ratio to Baseline in 
Pharmacodynamic Biomarkers at Each Assessment Visit 
(Sarilumab Comparison) (Log Transformed) 
 
AAC[3] 


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
1 5 5  
 
 Bi o m ar k er : T a bl es 
N o.  
P o p ul ati o n  
I D S L / 
E x a m ple 
S h ell  
Titl e   
Pr o gr a m mi n g N ote s  
D eli v era bl e 
[ Pri orit y] 
E x pl or at or y: S af et y Bi o mar k ers  
5. 9  
S af ety  
N o n -St a n d ar d  
BI O M _ T 1  
S u m m ary of Obs erv ed R esult of G M -C S F A ut o a ntib o dy 
( u g/ L) at B aseli n e 
 
A A C[ 3]  
 
C CI
C CI


 
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156 
 
Biomarker Figures 
 Biomarker: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Exploratory: Pharmacodynamic Biomarkers 
5.1 
Safety 
Non-Standard 
EFF_F2 
Plot of Observed Change from Baseline in 
Pharmacodynamic Biomarkers at Each Assessment Visit 
 
AAC[3] 
5.2 
Safety 
Non-Standard 
EFF_F2 
Plot of Observed Percentage Change from Baseline in 
Pharmacodynamic Biomarkers at Each Assessment Visit 
 
AAC[3] 
5.3 
Safety 
Non-Standard 
EFF_F2 
Plot of Least Squares Means from Repeated Measures 
Analysis of Change from Baseline in Pharmacodynamic 
Biomarkers at Each Assessment Visit (Placebo 
Comparison) 
 
AAC[3] 
5.4 
Safety 
Non-Standard 
EFF_F2 
Plot of Least Squares Means from Repeated Measures 
Analysis of Change from Baseline in Pharmacodynamic 
Biomarkers at Each Assessment Visit (Sarilumab 
Comparison) 
 
AAC[3] 
5.5 
Safety 
Non-Standard 
EFF_F2 
Plot of Least Squares Means from Repeated Measures 
Analysis of Ratio to Baseline in Pharmacodynamic 
Biomarkers at Each Assessment Visit (Placebo 
Comparison) (Log Transformed) 
 
AAC[3] 
5.6 
Safety 
Non-Standard 
EFF_F2 
Plot of Least Squares Means from Repeated Measures 
Analysis of Ratio to Baseline in Pharmacodynamic 
Biomarkers at Each Assessment Visit (Sarilumab 
Comparison) (Log Transformed) 
 
AAC[3] 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
157 
 
ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.  
Randomised 
ES2  
Listing of Reasons for Study Withdrawal 
ICH E3 
SAC[2] 
2.  
Randomised 
SD2 
Listing of Reasons for Study Treatment Discontinuation 
ICH E3 
 
SAC[2] 
3.  
ITT 
BL1 
Listing of Subjects for Whom the Treatment Blind was 
Broken 
ICH E3 
 
SAC[2] 
Protocol Deviations 
4.  
ITT 
DV2 
Listing of Important Protocol Deviations  
ICH E3 
 
SAC[2] 
5.  
ITT 
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations 
ICH E3 
SAC[2] 
Populations Analysed 
6.  
Enrolled 
SP3 
Listing of Subjects Excluded from Per Protocol Population 
ICH E3 
 
SAC[2] 
Demographic and Baseline Characteristics 
7.  
ITT 
DM2 
Listing of Demographic Characteristics 
ICH E3 
Include BMI in output. 
SAC[2] 
8.  
ITT 
DM9  
Listing of Race 
ICH E3 
SAC[2] 
Exposure and Treatment Compliance 
9.  
Safety 
EX3  
Listing of Exposure Data 
ICH E3 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
158 
 
ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events 
10.  
Safety 
AE8  
Listing of All Adverse Events 
ICH E3 
SAC[2] 
11.  
Safety 
AE14 
Listing of Reasons for Considering as a Serious Adverse 
Event 
ICH E3 
SAC[2] 
12.  
Safety 
DD3 
Death Subject Profile 
ICH E3 
SAC[2] 
All Laboratory 
13.  
Safety 
 
LB5A 
Listing of All Laboratory Data for Subjects with Any Value 
of Potential Clinical Importance 
ICH E3 
 
SAC[2] 
14.  
Safety 
UR2 
Listing of Urinalysis Data for Subjects with Any Value of 
Potential Clinical Importance 
ICH E3 
SAC[2] 


 
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159 
 
Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
15.  
Screened 
ES7 
Listing of Reasons for Screen Failure 
BIMO Requirements 
SAC[2] 
Protocol Deviations 
16.  
ITT 
DV2 
Listing of Non-Important COVID-19 related Protocol 
Deviations 
COVID Requirements 
SAC[2] 
Prior and Concomitant Medications 
17.  
ITT 
CM3  
Listing of Prior and Concomitant Medications 
BIMO Requirements 
Include “medication taken for pain” 
SAC[2] 
18.  
ITT 
CM3 
Listing of Intra-Articular Corticosteroids 
Add columns for: 
• 
“medication taken for pain” 
• 
“Location of dose 
administration” 
• 
“Laterality” 
SAC[2] 
Adverse Events 
19.  
Safety 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
Non-ICH Required 
SAC[2] 
20.  
Safety 
AE8XO  
Listing of Non-Fatal Serious Adverse Events 
Non-ICH Required 
Include “Action Taken with 
Background Therapy” 
SAC[2] 
21.  
Safety 
AE8XO  
Listing of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from 
Study  
Non-ICH Required 
Include “Action Taken with 
Background Therapy” 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
160 
 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
22.  
Safety 
AE8XO  
Listing of Other Significant Adverse Events 
Non-ICH Required 
Include “Action Taken with 
Background Therapy” 
SAC[2] 
23.  
Safety 
AE8XO 
Listing of Adverse Events of Special Interest (AESI) 
Include “Action Taken with 
Background Therapy” 
SAC[2] 
24.  
Safety 
AE2 
Listing of Relationship Between Adverse Event System 
Organ Classes, Preferred Terms, and Verbatim Text 
BIMO Requirements 
SAC[2] 
25.  
Safety 
Non-Standard 
SAFE_L1 
Listing of Neutrophils and Associated Infections 
Select the following subgroup and add 
under the title: 
“Subset of Subjects who experienced 
grade 3 or 4 Neutropenia” 
SAC[2] 
26.  
Safety 
Non-Standard 
SAFE_L1 
Listing of Lymphocytes and Associated Infections 
Select the following subgroup and add 
under the title: 
“Subset of Subjects who experienced 
grade 3 or 4 Lymphopenia” 
SAC[2] 
Hepatobiliary (Liver) 
27.  
Safety 
LIVER15 
Listing of Liver Event Stopping Profile 
Non-ICH Required 
SAC[2] 
All Laboratory 
28.  
Safety 
LB5A 
Listing of All Local Laboratory Data 
COVID Requirements 
SAC[2] 
ECG 
29.  
Safety 
EG5 
Listing of All ECG Findings for Subjects with an Abnormal 
ECG Finding 
BIMO Requirements 
SAC[2] 
30.  
Safety 
EG3 
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance 
BIMO Requirements 
SAC[2] 


 
CONFIDENTIAL 
 
 
 
202018 
 
161 
 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Vital Signs 
31.  
Safety 
VS4 
Listing of All Vital Signs for Subjects with any Value of 
Potential Clinical Importance 
BIMO Requirements 
SAC[2] 
32.  
Safety 
PREG1 
Listing of Subjects Who Became Pregnant During the 
Study 
Non-ICH Required 
SAC[2] 
PK Concentrations 
33.  
Safety 
PK07 
Listing of GSK3196165 Serum Concentrations 
Non-ICH Required 
Include “Time Since Last Dose (days)” 
SAC[2] 
COVID-19 
34.  
ITT 
PAN7 
Listing of All Subjects with Visits and Assessments 
Impacted by COVID-19 Pandemic 
COVID Requirements 
SAC[2] 
35.  
Safety 
PAN12 
Listing of COVID-19 Assessments and Symptom 
Assessments for Subjects with COVID-19 Adverse 
Events 
COVID Requirements 
Include “Serious Event” 
SAC[2] 
36.  
Screened 
PAN5 
Listing of Start Dates of COVID-19 Pandemic Measures 
by Country  
COVID Requirements 
SAC[2] 
Cardiovascular Event Listings (Conditionally required) 
37.  
Safety 
ARR1 
Arrhythmia Subject Profile 
Non-ICH Required 
AAC[3] 
38.  
Safety 
CHF1 
Congestive Heart Failure Subject Profile 
Non-ICH Required 
AAC[3] 
39.  
Safety 
CVATIA1 
Cerebrovascular Events/Stroke Subject Profile 
Non-ICH Required 
AAC[3] 
40.  
Safety 
DVT1 
Deep venous Thrombosis/ Pulmonary Embolism Subject 
Profile 
Non-ICH Required 
AAC[3] 


 
CONFIDENTIAL 
 
 
 
202018 
 
162 
 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
41.  
Safety 
MI1 
Myocardial Infarction /Unstable Angina Subject Profile 
Non-ICH Required 
AAC[3] 
42.  
Safety 
PATE1 
Peripheral Arterial Thrombosis Embolism Subject Profile 
Non-ICH Required 
AAC[3] 
43.  
Safety 
PUL1 
Pulmonary Hypertension Subject Profile 
Non-ICH Required 
AAC[3] 
44.  
Safety 
REV1 
Revascularization Subject Profile 
Non-ICH Required 
AAC[3] 
45.  
Safety 
VAL1 
Valvulopathy Subject Profile 
Non-ICH Required 
AAC[3] 
 


 
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163 
 
14.13. 
Appendix 13: Example Mock Shells for Data Displays 
Example: POP_T1 
Protocol: 202018                                                                                            Page 1 of n 
Population: Safety 
Table 1.1 
Summary of Subject Status and Subject Disposition for the Study Conclusion Record 
 
___________________________________________________________________________________________________________________________ 
                                       
Treatment 1   Treatment 2   Treatment 3   Treatment 4   Treatment 5  Treatment 6 
                                         
(N=xx)        (N=xx)        (N=xx)        (N=xx)        (N=xx)         (N=xx) 
Subject Status 
  Completed                               xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%) 
    Completed Safety Follow up            xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
    Entered Long Term Extension           xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
     
  Withdrawn                               xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%) 
    Withdrawn in Period 1 [1]      
  xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%) 
    Withdrawn in Period 2 [2]      
xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%) 
 
Primary Reason [3] for Study  
Withdrawal in Period 1 [1]      
  ADVERSE EVENT                           xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  LACK OF EFFICACY                        xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%) 
  PROTOCOL DEVIATION                      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  PROTOCOL-SPECIFIED WITHDRAWAL           xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%) 
  CRITERION MET 
  STUDY TERMINATED BY SPONSOR             xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  LOST TO FOLLOW-UP                       xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  PHYSICIAN DECISION                      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  INFORMED CONSENT WITHDRAWN              xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)  
  INVESTIGATOR SITE CLOSED                xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
   
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
164 
 
Example: POP_T1 (cntd.) 
Protocol: 202018                                                                                                Page 1 of n 
Population: Safety 
Table 1.1 
Summary of Subject Status and Subject Disposition for the Study Conclusion Record 
 
___________________________________________________________________________________________________________________________ 
                                         Treatment 1   Treatment 2   Treatment 3   Treatment 4   Treatment 5   Treatment 6 
                                           (N=xx)        (N=xx)        (N=xx)        (N=xx)        (N=xx)         (N=xx) 
 
Primary Reason [3] for Study  
Withdrawal in Period 2 [2]      
  ADVERSE EVENT                           xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  LACK OF EFFICACY                        xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%) 
  PROTOCOL DEVIATION                      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  PROTOCOL-SPECIFIED WITHDRAWAL           xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%) 
  CRITERION MET 
  STUDY TERMINATED BY SPONSOR             xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  LOST TO FOLLOW-UP                       xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  PHYSICIAN DECISION                      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  INFORMED CONSENT WITHDRAWN              xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)  
  INVESTIGATOR SITE CLOSED                xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
 
Outcome of Adverse Events Which 
Led to Study Withdrawal in Period 1 [1]  
  NON-FATAL                               xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  FATAL                                   xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%) 
Outcome of Adverse Events Which 
Led to Study Withdrawal in Period 2 [2]  
  NON-FATAL                               xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  FATAL                                   xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%) 
 
[1] Period 1 - up to 12 weeks, defined as time from randomisation and first dose of treatment up to dosing of Period 2 
treatment (Week 12) or date of study withdrawal or date of treatment withdrawal plus safety follow up whichever is earlier.  
[2] Period 2 – post week 12,  defined as time from first dose of treatment of period 2 (week 12) until date of study 
completion or date of study withdrawal or date of treatment withdrawal plus safety follow up whichever is earlier. 
[3] Subjects may have only one primary reason. 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
165 
 
Example: POP_T2 
Protocol: 202018                                                                                                Page 1 of n 
Population: Safety 
Table 1.x 
Summary of Treatment Status and Reasons for Discontinuation of Study Treatment 
 
___________________________________________________________________________________________________________________________ 
                                         Treatment 1   Treatment 2   Treatment 3   Treatment 4   Treatment 5   Treatment 6 
                                           (N=xx)        (N=xx)        (N=xx)        (N=xx)        (N=xx)         (N=xx) 
Treatment Status 
  Prematurely Discontinued Treatment      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%) 
      Prematurely Discontinued Treatment  xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%) 
      in Period 1 [1]         
      Prematurely Discontinued Treatment  xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%) 
      in Period 2 [2]         
 
Primary Reason [3] for Treatment  
Discontinuation in Period 1 [1]      
  ADVERSE EVENT                           xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  LACK OF EFFICACY                        xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%) 
  PROTOCOL DEVIATION                      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  PROTOCOL-SPECIFIED WITHDRAWAL           xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%) 
  CRITERION MET 
  STUDY TERMINATED BY SPONSOR             xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  LOST TO FOLLOW-UP                       xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  PHYSICIAN DECISION                      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  WITHDRAWAL BY SUBJECT                   xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  SPONSOR TERMINATED STUDY                xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  TREATMENT 
  INVESTIGATOR SITE CLOSED                xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
166 
 
Example: POP_T2 (cntd.) 
Protocol: 202018                                                                                                Page 1 of n 
Population: Safety 
Table 1.x 
Summary of Treatment Status and Reasons for Discontinuation of Study Treatment 
 
___________________________________________________________________________________________________________________________ 
                                         Treatment 1   Treatment 2   Treatment 3   Treatment 4   Treatment 5   Treatment 6 
                                           (N=xx)        (N=xx)        (N=xx)        (N=xx)        (N=xx)         (N=xx) 
 
Primary Reason [3] for Treatment  
Discontinuation in Period 2 [2]      
  ADVERSE EVENT                           xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  LACK OF EFFICACY                        xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%) 
  PROTOCOL DEVIATION                      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  PROTOCOL-SPECIFIED WITHDRAWAL           xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%) 
  CRITERION MET 
  STUDY TERMINATED BY SPONSOR             xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  LOST TO FOLLOW-UP                       xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  PHYSICIAN DECISION                      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  WITHDRAWAL BY SUBJECT                   xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  SPONSOR TERMINATED STUDY                xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
  TREATMENT 
  INVESTIGATOR SITE CLOSED                xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)      xx (xx%)       xx (xx%)    
 
 
[1] Treatment Discontinuation in Period 1- defined as time from first dose of treatment up to date of 
treatment withdrawal prior to week 12 dosing. 
[2] Treatment Discontinuation in Period 2- defined as time from first dose of treatment period 2 (week 12) 
until date of treatment withdrawal post week 12. 
[3] Subjects may have only one primary reason for treatment discontinuation. 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
167 
 
Example: POP_T3 
Protocol: 202018                                                                                              Page 1 of n 
Population: Intent-to-Treat 
Table 1.x    
Baseline Efficacy Parameters 
 
 
 
Statistic 
Treatment 1 
(N=xx) 
Treatment 2  
(N=xx) 
Treatment 3 
(N=xx) 
Treatment 4 
(N=xx) 
 
 
 
 
 
 
Swollen Joint Count 28 
n 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
Minimum 
xx 
xx 
xx 
xx 
 
Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Swollen Joint Count 66 
n 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
Minimum 
xx 
xx 
xx 
xx 
 
Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Tender Joint Count 28 
n 
xx 
xx 
xx 
xx 
 
… 
… 
… 
… 
… 
Tender Joint Count 68 
n 
xx 
xx 
xx 
xx 
 
… 
… 
… 
… 
… 
… 
n 
xx 
xx 
xx 
xx 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
168 
 
Example: POP_T4 
Protocol: 202018 Confidential                                                                                  Page 1 of n 
Population: Intent-to-Treat  
Table 1.x 
Summary of Rheumatoid Arthritis Disease History 
 
 
Treatment 1 
N=xx 
Treatment 2 
N=xx 
Treatment 3 
N=xx 
Treatment 4 
N=xx 
Treatment 5 
N=xx 
Treatment 6 
N=xx 
Time since RA diagnosis (years) 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
  SD 
 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
  Median  
 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
  Min. 
 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
  Max. 
 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
Time since RA diagnosis 
  n 
 
xx 
xx 
xx 
xx 
xx 
xx 
  <= 2 years 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  >2-5 years 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  >5-10 years 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  >10 years 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  Missing 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
 
RA functional class 
  n 
 
xx 
xx 
xx 
xx 
xx 
xx 
  I 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  II 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  III 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
 
Time since start of RA symptoms (years) 
  n 
 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean 
 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
  SD 
 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
  Median  
 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
  Min. 
 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
  Max. 
 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Note: Time since RA diagnosis and start of RA symptoms is calculated up to date of first study medication administration. 
[1] Stratum information is obtained from IWRS. 
 
Example: POP_T4 (continued) 


 
CONFIDENTIAL 
 
 
 
202018 
 
169 
 
Protocol: 202018 Confidential                                                                                  Page 2 of n 
Population: Intent-to-Treat  
Table 1.x 
Summary of Rheumatoid Arthritis Disease History 
 
 
 
Treatment 1 
N=xx 
Treatment 2 
N=xx 
Treatment 3 
N=xx 
Treatment 4 
N=xx 
Treatment 5 
N=xx 
Treatment 6 
N=xx 
Stratum (Previously failed medication) [1] 
  n 
 
xx 
xx 
xx 
xx 
xx 
xx 
  1 bDMARD 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  >1 bDMARD 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  >=1 JAK inhibitor 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
 
Baseline Anti-CCP Status 
  n 
 
xx 
xx 
xx 
xx 
xx 
xx 
  Positive  
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  Negative 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  Missing 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
 
Baseline RF Status 
  n 
 
xx 
xx 
xx 
xx 
xx 
xx 
  Positive  
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  Negative 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  Missing 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
 
Baseline Anti-CCP and RF Status 
  n 
 
xx 
xx 
xx 
xx 
xx 
xx 
  At Least one Positive  
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  Both Negative 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
 
Note: Time since RA diagnosis and start of RA symptoms is calculated up to date of first study medication administration. 
[1] Stratum information is obtained from IWRS. 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
170 
 
Example: POP_T5 
Protocol: 202018                                                                                              Page 1 of n 
Population: Intent-to-Treat 
Table 1.x 
Summary of Cardiovascular Risk Factors 
 
Age group: xxxxxx 
 
 
Treatment 1 
N=xx 
Treatment 2 
N=xx 
Treatment 3 
N=xx 
Treatment 4 
N=xx 
Treatment 5 
N=xx 
Treatment 6 
N=xx 
 
 
 
 
 
 
 
 
History of Tobacco Use  
 
 
 
 
 
 
 
  n 
 
 xx 
 xx 
 xx 
 xx 
 xx 
 xx 
  Never smoked 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
  Current Smoker 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
  Former Smoker 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
  Unknown 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 
 
 
 
 
 
 
 
If former smoker: Time between last  
smoking and assessment date (years) 
  n 
 
 xx 
 xx 
 xx 
 xx 
 xx 
 xx 
  Mean 
 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
  SD 
 
  x.xx 
  x.xx 
  x.xx 
  x.xx 
  x.xx 
  x.xx 
  Median  
 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
  Min. 
 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
  Max. 
 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
Family history of cardiovascular  
risk factors [1] 
  n 
 
 xx 
 xx 
 xx 
 xx 
 xx 
 xx 
  Yes 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
  No 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
  Unknown 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 
 
 
 
 
 
 
 
Angina Pectoris 
  n 
 
 xx 
 xx 
 xx 
 xx 
 xx 
 xx 
  Current 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
  Past 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
  No Medical History 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: [1] Family history of premature coronary artery disease in women <65 years or men < 55 years in first degree relatives 
only. 


 
CONFIDENTIAL 
 
 
 
202018 
 
171 
 
Example: POP_T5 (continued) 
Protocol: 202018                                                                                              Page 2 of n 
Population: Intent-to-Treat 
Table 1.x 
Summary of Cardiovascular Risk Factors 
Age group: xxxxxx 
 
 
Treatment 1 
N=xx 
Treatment 2 
N=xx 
Treatment 3 
N=xx 
Treatment 4 
N=xx 
Treatment 5 
N=xx 
Treatment 6 
N=xx 
Diabetes mellitus 
  n 
 
 xx 
 xx 
 xx 
 xx 
 xx 
 xx 
  Current 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
  Past 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
  No Medical History 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 
 
 
 
 
 
 
 
Hyperlipidemia 
 
 
 
 
 
 
 
  n 
 
 xx 
 xx 
 xx 
 xx 
 xx 
 xx 
  Current 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
  Past 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
  No Medical History 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 
 
 
 
 
 
 
 
Hypertension 
  n 
 
 xx 
 xx 
 xx 
 xx 
 xx 
 xx 
  Current 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
  Past 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
  No Medical History 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 
 
 
 
 
 
 
 
Myocardial Infarction 
 
 
 
 
 
 
 
  n 
 
 xx 
 xx 
 xx 
 xx 
 xx 
 xx 
  Current 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
  Past 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
  No Medical History 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 
 
 
 
 
 
 
 
Stroke 
  n 
 
 xx 
 xx 
 xx 
 xx 
 xx 
 xx 
  Current 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
  Past 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
  No Medical History 
 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
 xx (xx%) 
Note: [1] Family history of premature coronary artery disease in women < 65 years or men < 55 years in 
first degree relatives only. 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
172 
 
Example: POP_T6  
Protocol: 202018                                                                                               Page 1 of n 
Population: Intent-to-Treat 
Table 1.x 
Summary of RA Concomitant Medications  
 
 
Treatment 1 
N=xx 
Treatment 2 
N=xx 
Treatment 3 
N=xx 
Treatment 4 
N=xx 
Treatment 5 
N=xx 
Treatment 6 
N=xx 
ANY MEDICATION 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
DMARDs 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  Methotrexate 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  Other csDMARDs (not methotrexate) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  csDMARDs >1 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  bsDMARDs/boDMARDs/tsDMARDs 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
Corticosteroids  
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  Oral 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  Intra-Articular 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
Other RA medications 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
Note: Concomitant medication is defined as any medication taken after the first dose of study treatment, regardless of whether 
it was started  prior to the first dose of study treatment or not.  
Note: For subjects that discontinued treatment, medications taken after the date of treatment discontinuation up to the end 
of safety follow up are also presented in this table.  
 


 
CONFIDENTIAL 
 
 
 
202018 
 
173 
 
Example: POP_T7  
Protocol: 202018                                                                                               Page 1 of n 
Population: Intent-to-Treat 
Table 1.x 
Summary of RA Prior Medications 
 
 
Treatment 1 
N=xx 
Treatment 2 
N=xx 
Treatment 3 
N=xx 
Treatment 4 
N=xx 
ANY MEDICATION 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
DMARDs 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  Methotrexate 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  Other csDMARDs (not methotrexate) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  csDMARDs >1 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  bsDMARDs/boDMARDs/tsDMARDs 
 
 
 
 
    >=1 of bs/bo/tsDMARDs 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    =1 of bs/bo/tsDMARDs 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    >1 of bs/bo/tsDMARDs 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    Inadequate response to >=1 bs/boDMARD  
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    Inadequate response to >=1 tsDMARD  
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    Inadequate response to >1 bs/bo/tsDMARD 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
Oral corticosteroids  
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
Other RA medications 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Note: Prior medication is defined as any medication that started before first dose of study treatment. 


 
CONFIDENTIAL 
 
 
 
202018 
 
174 
 
Example: POP_T8  
Protocol: 202018                                                                                               Page 1 of n 
Population: Intent-to-Treat 
Table 1.x 
Summary of RA Medications taken at Baseline (Day 1) 
 
 
Treatment 1 
N=xx 
Treatment 2 
N=xx 
Treatment 3 
N=xx 
Treatment 4 
N=xx 
Treatment 5 
N=xx 
Treatment 6 
N=xx 
  Methotrexate 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  Other csDMARDs (not methotrexate) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
  csDMARDs >1 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
Methotrexate dose at baseline 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
  No Methotrexate 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  <10mg/week 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
  >=10mg/week 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
Corticosteroids [1] 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
Corticosteroid dose at baseline 
(mg/day) [1] 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
  SD 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
  Median  
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
  Min. 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
  Max. 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
[1] Only includes subjects who have taken oral corticosteroids for at least 4 weeks prior to baseline 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
175 
 
Example: POP_T9  
Protocol: 202018                                                                                               Page 1 of n 
Population: Intent-to-Treat 
Table 1.x 
Summary of Concomitant COVID-19 Vaccines 
 
 
Treatment 1 
N=xx 
Treatment 2 
N=xx 
Treatment 3 
N=xx 
Treatment 4 
N=xx 
Treatment 5 
N=xx 
Treatment 6 
N=xx 
 Any Medication 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
 PFIZER BIONTECH COVID-19 VACCINE 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 MODERNA COVID-19 VACCINE 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
176 
 
Example: POP_T10 
Protocol: 202018                                                                                                Page 1 of n 
Population: Safety 
Table 1.x 
Summary of Exposure to Study Treatment 
 
 
Treatment 1 
N=xx 
Treatment 2 
N=xx 
Treatment 3 
N=xx 
Treatment 4 
N=xx 
Treatment 5 
N=xx 
Treatment 6 
N=xx 
 
 
 
 
 
 
 
Duration of drug exposure [injections] (days) 
 
 
  Period 1 
 
 
    n 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
    Mean 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    SD 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    Median 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    Min. 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
    Max. 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
 
 
 
  Period 2 
 
 
    n 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
    Mean 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    SD 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    Median 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    Min. 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
    Max. 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
 
 
 
 
 
 
 
 Period 1+2 
 
 
 
 
 
 
    n 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
    Mean 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    SD 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    Median 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    Min. 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
    Max. 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
177 
 
Example: POP_T10 (cntd.) 
Protocol: 202018                                                                                                Page 2 of n 
Population: Safety 
Table 1.x 
Summary of Exposure to Study Treatment 
 
 
Treatment 1 
N=xx 
Treatment 2 
N=xx 
Treatment 3 
N=xx 
Treatment 4 
N=xx 
Treatment 5 
N=xx 
Treatment 6 
N=xx 
 
 
 
 
 
 
 
Number of injections 
 
 
  Period 1 
 
 
    n 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
    Mean 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    SD 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    Median 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    Min. 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
    Max. 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
 
 
 
  Period 2 
 
 
    n 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
    Mean 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    SD 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    Median 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    Min. 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
    Max. 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
 
 
 
 
 
 
 
  Period 1+2 
 
 
 
 
 
 
    n 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
    Mean 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    SD 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    Median 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    Min. 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
    Max. 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
178 
 
Example: POP_T10 (cntd.) 
Protocol: 202018                                                                                                Page 3 of n 
Population: Safety 
Table 1.x 
Summary of Exposure to Study Treatment 
 
 
Treatment 1 
N=xx 
Treatment 2 
N=xx 
Treatment 3 
N=xx 
Treatment 4 
N=xx 
Treatment 5 
N=xx 
Treatment 6 
N=xx 
 
Number of injections 
  Period 1+2 
    1 - 12 
    xx (xx%) 
    xx (xx%) 
    xx (xx%) 
   xx (xx%) 
    xx (xx%)   xx (xx%) 
    13 - 24 
    xx (xx%) 
    xx (xx%) 
    xx (xx%) 
   xx (xx%) 
    xx (xx%)   xx (xx%) 
    25 - 40 
    xx (xx%) 
    xx (xx%) 
    xx (xx%) 
   xx (xx%) 
    xx (xx%)   xx (xx%) 
    > 40 
    xx (xx%) 
    xx (xx%) 
    xx (xx%) 
   xx (xx%) 
    xx (xx%)   xx (xx%) 
 
Number of missed injections 
  Period 1 
 
 
    0 missed injections 
    xx (xx%) 
    xx (xx%) 
    xx (xx%) 
   xx (xx%) 
    xx (xx%)   xx (xx%) 
    1 missed injection 
    xx (xx%) 
    xx (xx%) 
    xx (xx%) 
   xx (xx%) 
    xx (xx%)   xx (xx%) 
    >1 missed injection 
    xx (xx% 
    xx (xx%) 
    xx (xx%) 
   xx (xx%) 
    xx (xx%)   xx (xx%) 
 
  Period 2 
    0 missed injections 
    xx (xx%) 
    xx (xx%) 
    xx (xx%) 
   xx (xx%) 
    xx (xx%)   xx (xx%) 
    1 missed injection 
    xx (xx%) 
    xx (xx%) 
    xx (xx%) 
   xx (xx%) 
    xx (xx%)   xx (xx%) 
    >1 missed injection 
    xx (xx%) 
    xx (xx%) 
    xx (xx%) 
   xx (xx%) 
    xx (xx%)   xx (xx%) 
 
 
 
 
 
 
 
  Period 1+2 
 
 
 
 
 
 
    0 missed injections 
    xx (xx%) 
    xx (xx%) 
    xx (xx%) 
   xx (xx%) 
    xx (xx%)   xx (xx%) 
    1 missed injection 
    xx (xx%) 
    xx (xx%) 
    xx (xx%) 
   xx (xx%) 
    xx (xx%)   xx (xx%) 
    >1 missed injection 
    xx (xx%) 
    xx (xx%) 
    xx (xx%) 
   xx (xx%) 
    xx (xx%)   xx (xx%) 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
179 
 
Example: POP_T11 
Protocol: 202018                                                                                                Page 1 of n 
Population: Safety 
Table 1.x 
Summary of Overall Compliance Based on Exposure 
 
 
Treatment 1 
N=xx 
Treatment 2 
N=xx 
Treatment 3 
N=xx 
Treatment 4 
N=xx 
Treatment 5 
N=xx 
Treatment 6 
N=xx 
Percent Overall Compliance [injections]  
 
 
  Period 1 
 
 
    n 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
    Mean 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    SD 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    Median 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    Min. 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
    Max. 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
  Period 2 
 
 
    n 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
    Mean 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    SD 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    Median 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    Min. 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
    Max. 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
  Period 1+2 
 
 
 
 
 
 
    n 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
    Mean 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    SD 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    xx.xx 
    Median 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    xx.x 
    Min. 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
    Max. 
    xx 
    xx 
    xx 
    xx 
    xx 
    xx 
 
 
 
 
 
 
 
 
Percent Overall Compliance [injections]=(Number of Actual Doses/Planned Treatment Duration in Weeks)*100. 
Planned Treatment Duration is 24 weeks, adjusted for early treatment discontinuation subjects. 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
180 
 
Example: POP_T11 (cntd.) 
Protocol: 202018                                                                                                Page 2 of n 
Population: Safety 
Table 1.x 
Summary of Overall Compliance Based on Exposure 
 
 
Treatment 1 
N=xx 
Treatment 2 
N=xx 
Treatment 3 
N=xx 
Treatment 4 
N=xx 
Treatment 5 
N=xx 
Treatment 6 
N=xx 
 
Overall Compliance Categories [injections] 
  Period 1 
    <80% 
    xx (xx%) 
    xx (xx%) 
    xx (xx%) 
   xx (xx%) 
    xx (xx%)   xx (xx%) 
    80-105% 
    xx (xx%) 
    xx (xx%) 
    xx (xx%) 
   xx (xx%) 
    xx (xx%)   xx (xx%) 
    >105% 
    xx (xx%) 
    xx (xx%) 
    xx (xx%) 
   xx (xx%) 
    xx (xx%)   xx (xx%) 
  Period 2 
 
 
    <80% 
    xx(xx%) 
    xx(xx%) 
    xx(xx%) 
    xx(xx%) 
    xx(xx%) 
  xx(xx%) 
    80-105% 
    xx(xx%) 
    xx(xx%) 
    xx(xx%) 
    xx(xx%) 
    xx(xx%) 
  xx(xx%) 
    >105% 
    xx(xx%) 
    xx(xx%) 
    xx(xx%) 
    xx(xx%) 
    xx(xx%) 
  xx(xx%) 
  Period 1+2 
    <80% 
    xx(xx%) 
    xx(xx%) 
    xx(xx%) 
    xx(xx%) 
    xx(xx%) 
  xx(xx%) 
    80-105% 
    xx(xx%) 
    xx(xx%) 
    xx(xx%) 
    xx(xx%) 
    xx(xx%) 
  xx(xx%) 
    >105% 
    xx(xx%) 
    xx(xx%) 
    xx(xx%) 
    xx(xx%) 
    xx(xx%) 
  xx(xx%) 
 
 
 
 
 
 
 
 
Percent Overall Compliance [injections]=(Number of Actual Doses/Planned Treatment Duration in Weeks)*100. 
Planned Treatment Duration is 24 weeks, adjusted for early treatment discontinuation subjects. 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
181 
 
Example: POP_T12 
Protocol: 202018                                                                                                Page 1 of n 
Population: Intent-to-Treat 
Table 1.x 
Summary of Neuropathic Pain Component as Identified by the Pain DETECT Questionnaire 
 
 
Treatment 1 
N=xx 
Treatment 2 
N=xx 
Treatment 3 
N=xx 
Treatment 4 
N=xx 
Treatment 5 
N=xx 
Treatment 6 
N=xx 
Total 
N=xx 
 
 
Screening Result 
 
 
 
 
 
 
 
   n 
   xx 
   xx 
   xx 
   xx 
   xx 
   xx 
   xx 
   Neuropathic 
   xx (xx%) 
   xx (xx%) 
   xx (xx%) 
   xx (xx%) 
   xx (xx%) 
   xx (xx%)    xx (xx%) 
   Nociceptive 
   xx (xx%) 
   xx (xx%) 
   xx (xx%) 
   xx (xx%) 
   xx (xx%) 
   xx (xx%)    xx (xx%) 
   Unclear 
   xx (xx%) 
   xx (xx%) 
   xx (xx%) 
   xx (xx%) 
   xx (xx%) 
   xx (xx%)    xx (xx%) 
 
 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
182 
 
Example: EFF_T1 
Protocol: 202018 Confidential                                                                   Page 1 of n 
Population: Intent-To-Treat                                     
Table 2.x  
Summary and Analysis of the Proportion of Subjects Achieving [ACR20/CDAI-LDA/…] at Each Assessment Visit 
Visit: Week X 
Statistic 
Pooled PBO 
(N=xx) 
OTI 90mg QW 
(N=xx) 
OTI 150mg QW 
(N=xx) 
SARI 200mg 
Q2W 
(N=xx) 
PBO to OTI 
90mg QW 
(N=xx) 
PBO to OTI 
150mg QW 
(N=xx) 
PBO to SARI 
200mg Q2W 
(N=xx) 
 
 
 
 
 
 
 
 
%Responders  
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
SE %Responders 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
 
 
 
 
 
 
 
 
 
Difference vs. 
Pooled PBO (%) 
 
xx.x 
xx.x 
xx.x 
 
 
 
  95% CI (%) 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
 
 
 
 
 
 
 
 
 
 
Difference vs. 
SARI(%) 
xx.x 
xx.x 
xx.x 
 
 
 
 
  95% CI (%) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
Odds Ratio vs. 
Pooled PBO 
 
xx.x 
xx.x 
xx.x 
 
 
 
  95% CI (%) 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
 
 
  p-value 
 
0.xxxx 
0.xxxx 
0.xxxx 
 
 
 
 
 
 
 
 
 
 
 
Odds Ratio vs. 
SARI 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
   95% CI (%) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
 
 
   p-value 
0.xxxx 
0.xxxx 
0.xxxx 
0.xxxx 
 
 
 
 
 
 
 
 
 
 
 
Note: All estimates are produced following multiple imputation specified for the [primary estimand/supplemental estimand 
1/supplemental estimand 2]. 
Note: Positive differences and Odds Ratios >1 indicate an improvement of treatment over placebo or sarilumab. 
Note: 95% confidence intervals for the difference to placebo and sarilumab are constructed using asymptotic Wald confidence 
limits without correction. 
Note: Odds Ratios and corresponding 95% confidence intervals for odds ratios are generated from the logistic regression 
model  adjusted for [Baseline Value], Treatment Group and Previously Failed Medication Category. 
Note: Placebo switch treatment arms will only be displayed after Week 12. 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
183 
 
Example: EFF_T2 
Protocol: 202018 Confidential                                                                    Page 1 of n 
Population: Intent-To-Treat                                     
Table 2.x  
Summary of Observed [ACR20] Response at Each Assessment Visit 
Parameter: XXX [optional] 
 
Note: N is the number of subjects with non-missing data at that visit 
 
Pooled PBO 
(N=xx) 
OTI 90mg QW 
(N=xx) 
OTI 150mg QW 
(N=xx) 
SARI 200mg 
Q2W 
(N=xx) 
PBO to OTI 
90mg QW 
(N=xx) 
PBO to OTI 
150mg QW 
(N=xx) 
PBO to SARI 
200mg Q2W 
(N=xx) 
 
 
 
 
 
 
 
 
Week 1 
 
 
 
 
 
 
 
   N 
xx 
xx 
xx 
xx 
 
 
 
   n(%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
 
 
 
 
Week 2 
 
 
 
 
 
 
 
   N 
xx 
xx 
xx 
xx 
 
 
 
   n(%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
 
 
 
 
Week 3 
 
 
 
 
 
 
 
   N 
xx 
xx 
xx 
xx 
 
 
 
   n(%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 13 
 
 
 
 
 
 
 
   N 
 
xx 
xx 
xx 
xx 
xx 
xx 
n(%) 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
184 
 
Example: EFF_T3 
Protocol: 202018 Confidential                                                                    Page 1 of n 
Population: Intent-To-Treat                                     
Table 2.x  
Analysis of Change from Baseline in [HAQ-DI/CDAI Total/…] at Each Assessment Visit [(Primary Estimand)] 
Visit: Week 1 
Statistic 
Pooled PBO 
(N=xx) 
OTI 90mg QW 
(N=xx) 
OTI 150mg QW 
(N=xx) 
SARI 200mg 
2QW 
(N=xx) 
PBO to OTI 
90mg QW 
(N=xx) 
PBO to OTI 
150mg QW 
(N=xx) 
PBO to SARI 
200mg Q2W 
(N=xx) 
 
 
 
 
 
 
 
 
LS Mean Change 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
Standard Error 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
 
 
 
 
 
 
 
 
 
LS Mean Difference 
from Pooled PBO 
 
xx.x 
xx.x 
xx.x 
 
 
 
  95% CI (%) 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
 
 
  p-value 
 
0.xxxx 
0.xxxx 
0.xxxx 
 
 
 
 
 
 
 
 
 
 
 
LS Mean Difference 
from SARI 
xx.x 
xx.x 
xx.x 
 
 
 
 
   95% CI (%) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
 
 
 
   p-value 
0.xxxx 
0.xxxx 
0.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
Note: All estimates are produced following multiple imputation specified for the [primary estimand/supplemental estimand 
1/supplemental estimand 2] 
Note: All estimates are obtained from an ANCOVA analysis adjusted for Baseline Value, Treatment Group and Previously Failed 
Medication Category. 
Note: Placebo switch treatment arms will only be displayed after Week 12. 


 
CONFIDENTIAL 
 
 
 
202018 
 
185 
 
Example: EFF_T4 
Protocol: 202018 Confidential                                                                   Page 1 of n 
Population: Intent-To-Treat                                     
Table 2.x  
Summary of Observed [Result/Change from Baseline] in [HAQ-DI/CDAI Total/…] at Each Assessment Visit 
 
Parameter: XXXX [optional] 
 
Treatment 
Visit 
n 
Mean 
SD 
95% CI 
Median 
Min. 
Max. 
Pooled PBO (N=xx) 
Baseline 
xx 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
Week 1 
xx 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
OTI 90mg QW 
(N=xx) 
Baseline 
xx 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
Week 1 
xx 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
… 
… 
… 
… 
… 
… 
… 
… 
 
Week 13 
xx 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
Week 16 
xx 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
PBO to OTI 90mg QW 
(N=xx) 
Baseline 
xx 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
Week 13 
xx 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
Week 16 
xx 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
186 
 
Example: EFF_T5 
Protocol: 202018 Confidential                                                                    Page 1 of n 
Population: Intent-To-Treat                                     
Table 2.x  
Summary of Ratio to Baseline in [CRP] at Each Assessment Visit (Log Transformed) 
 
Parameter: XXXX 
 
 
 
Treatment 
Visit 
n 
Geometric Mean 
%CVb 
95% CI 
Median 
Min. 
Max. 
Pooled PBO (N=xx) 
Baseline 
xx 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
Week 1 
xx 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
 
 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
OTI 90mg QW 
(N=xx) 
Baseline 
xx 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
Week 1 
xx 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
 
 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
… 
… 
… 
… 
… 
… 
… 
… 
 
Week 13 
xx 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
 
 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
Week 16 
xx 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
 
 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
PBO to OTI 90mg 
QW (N=xx) 
Baseline 
xx 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
Week 13 
xx 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
 
 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
Week 16 
xx 
xx.x 
xx.xx 
(xx.x,xx.x) 
xx.x 
xx 
xx 
 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
187 
 
Example: EFF_T6 
Protocol: 202018 Confidential                                                                    Page 1 of n 
Population: Intent-To-Treat                                     
Table 2.x  
Summary of Observed [ACR20] Response Within 4/8/12/16/24 Weeks Post Baseline 
 
 
Achieved Response 
Pooled PBO 
(N=xx) 
OTI 90mg QW 
(N=xx) 
OTI 150mg QW 
(N=xx) 
SARI 200mg Q2W 
(N=xx) 
 
 
 
 
 
Within 4 weeks 
 
 
 
 
   n(%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
Within 8 weeks 
 
 
 
 
   n(%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
Within 12 weeks 
 
 
 
 
   n(%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
Within 16 weeks 
 
 
 
 
n(%) 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
Within 24 weeks 
 
 
 
 
   n(%) 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
188 
 
Example: EFF_T7 
Protocol: 202018 Confidential                                                                    Page 1 of n 
Population: Intent-To-Treat                                     
Table 2.x  
Summary of Observed Maintained [ACR20] Response for 12 Weeks After the First Occurrence 
 
 
 
 
 
 
 
 
Note: If a subject has at most two non-consecutive visits with missing response data within the 12 week window after first 
occurrence of response and the subject was in response for all other visits, then the subject will be considered to have 
maintenance of response. 
 
Maintained Response 
OTI 90mg QW 
(N=xx) 
OTI 150mg QW 
(N=xx) 
SARI 200mg Q2W 
(N=xx) 
 
 
 
 
For 12 weeks 
 
 
 
   n(%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
189 
 
Example: EFF_T8 
Protocol: 202018 Confidential                                                                    Page 1 of n 
Population: Intent-To-Treat                                     
Table 2.x  
 Analysis of Time to Onset of [ACR20] Response 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Statistics will be missing when the number of events is too low to estimate the values from the 
survival function. 
[2] A hazard ratio <1 indicates a lower risk with this treatment compared with Sarilumab. Hazard Ratio is 
adjusted for Baseline TJC68, Baseline SJC66 and Previously Failed Medication Category. 
[3] Among subjects achieving response. 
 
 
 
 
OTI 90mg QW 
(N=xx) 
OTI 150mg QW 
(N=xx) 
SARI 200mg Q2W 
(N=xx) 
 
 
 
 
Number of Subjects 
 
 
 
   n 
xx  
xx  
xx  
   Endpoint (ACR20) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
   Censored 
xx (xx%) 
xx (xx%) 
xx (xx%) 
      Early Study Withdrawal 
xx (xx%) 
xx (xx%) 
xx (xx%) 
      Study Completion 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
Estimate for Time to ACR20 (Weeks) [1] 
 
 
 
   1st Quartile 
xx.x 
xx.x 
xx.x 
   Median 
xx.x 
xx.x 
xx.x 
   3rd Quartile 
xx.x 
xx.x 
xx.x 
 
 
 
 
Adjusted Hazard Ratio [2] 
 
 
 
   Estimate 
x.xx 
x.xx 
x.xx 
   95% CI 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
   p-value 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
Estimate for Time to ACR20 (Weeks) [3] 
 
 
 
   1st Quartile 
xx.x 
xx.x 
xx.x 
   Median 
xx.x 
xx.x 
xx.x 
   3rd Quartile 
xx.x 
xx.x 
xx.x 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
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190 
 
Example: EFF_F1 
Protocol: 202018 Confidential                                                                       Page 1 of n 
Population: Intent-to-Treat                                     
Figure 2.x  
Proportion of Subjects Achieving [ACR20/50/70 Response] at Each Assessment Visit [(Primary Estimand)] 
 
Note: All estimates are produced following multiple imputation specified for the [primary estimand/supplemental estimand 
1/supplemental estimand 2] 
 


 
CONFIDENTIAL 
 
 
 
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191 
 
Example: EFF_F2 
Protocol: 202018 Confidential                                                                       Page 1 of n 
Population: Intent-to-Treat                                     
Figure 2.x  
Plot of Least Squares Means of Change from Baseline in [HAQ-DI/CDAI Total Score/…] at Each Assessment Visit 
[(Primary Estimand)] 
 
Note: All estimates are produced following multiple imputation specified for the [primary estimand/supplemental estimand 
1/supplemental estimand 2] 
Note: All estimates are obtained from an ANCOVA analysis adjusted for Baseline Value, Treatment Group and Previously Failed 
Medication Category. 


 
CONFIDENTIAL 
 
 
 
202018 
 
192 
 
Example: EFF_F3 
Protocol: 202018 Confidential                                                                       Page 1 of n 
Population: Intent-to-Treat                                     
Figure 2.x  
Spydergram of Individual Domain Scores of SF-36 at Each Assessment Visit 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
193 
 
Example: EFF_F4 
Protocol: 202018 Confidential                                                                       Page 1 of n 
Population: Intent-to-Treat                                     
Figure 2.x  
Forest Plot of [Demographic] Subgroup Results for [ACR20] – Comparison to [Placebo at Week 12] 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
194 
 
Example: EFF_F5 
Protocol: 202018 Confidential                                                                       Page 1 of n 
Population: Intent-to-Treat                                     
Figure 2.x  
Forest Plot of [Demographic] Subgroup Results for [HAQ-DI] – Comparison to [Placebo at Week 12] 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
195 
 
Example: EFF_F6 
Protocol: 202018 Confidential                                                                       Page 1 of n 
Population: Intent-to-Treat                                     
Figure 2.x  
Proportion of Subjects Achieving Maintained [ACR50 Response] for At Least 12 Weeks After the First Occurrence 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
196 
 
Example: BIOM_T1 
Protocol: 202018 Confidential                                                                       Page 1 of n 
Population: Intent-to-Treat                                     
Table 5.x  
Summary of Observed [Result/Change from Baseline] in [Pharmacodynamic Biomarkers/…] at Each Assessment Visit 
 
Parameter: XXXX 
Note: Values reported below lower limit of quantification were replaced by one-half the limit of quantification. 
 
 
Treatment 
Visit 
n 
Mean 
SD 
Median 
(Q1, Q3) 
Min 
Max 
Pooled PBO (N=xx) 
Baseline 
xx 
xx.x 
xx.xx 
xx.x 
(xx.x,xx.x) 
xx 
xx 
 
Week 1 
xx 
xx.x 
xx.xx 
xx.x 
(xx.x,xx.x) 
xx 
xx 
 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
OTI 90mg QW 
(N=xx) 
Baseline 
xx 
xx.x 
xx.xx 
xx.x 
(xx.x,xx.x) 
xx 
xx 
 
Week 1 
xx 
xx.x 
xx.xx 
xx.x 
(xx.x,xx.x) 
xx 
xx 
 
… 
… 
… 
… 
… 
… 
… 
… 
 
Week 13 
xx 
xx.x 
xx.xx 
xx.x 
(xx.x,xx.x) 
xx 
xx 
 
Week 16 
xx 
xx.x 
xx.xx 
xx.x 
(xx.x,xx.x) 
xx 
xx 
 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
PBO to OTI 90mg QW 
(N=xx) 
Baseline 
xx 
xx.x 
xx.xx 
xx.x 
(xx.x,xx.x) 
xx 
xx 
 
Week 13 
xx 
xx.x 
xx.xx 
xx.x 
(xx.x,xx.x) 
xx 
xx 
 
Week 16 
xx 
xx.x 
xx.xx 
xx.x 
(xx.x,xx.x) 
xx 
xx 
 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
197 
 
Example: BIOM_T2 
Protocol: 202018 Confidential                                                                       Page 1 of n 
Population: Intent-to-Treat                                     
Table 5.x  
Repeated Measures Analysis of Change from Baseline in Pharmacodynamic Biomarkers at Each Assessment Visit 
([Placebo/Sarilumab] Comparison) 
 
 
 
 
 
 
 
 
[1] Number of subjects with analysable data at the given timepoint. 
Note: All estimates are obtained from an MMRM analysis adjusted for Baseline Value, Treatment Group, Previously Failed 
Medication Category, Visit and Treatment Group by Visit. 
 
Biomarker: [Chemokine (C-C Motif) Ligand 17] 
Visit: Week 1 
Statistic 
Pooled PBO 
N=xx 
OTI 90mg QW 
N=xx 
OTI 150mg QW 
N=xx 
SARI 200mg Q2W 
N=xx 
 
 
 
 
 
n [1] 
      xx 
      xx 
      xx 
     xx 
 
 
 
 
 
LS Mean Change 
xx.x 
xx.x 
xx.x 
xx.x 
Standard Error 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
 
 
 
LS Mean Difference from 
Pooled PBO 
 
xx.x 
xx.x 
xx.x 
  95% CI (%) 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
  p-value 
 
0.xxxx 
0.xxxx 
0.xxxx 
 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
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198 
 
Example: BIOM_T3 
Protocol: 202018 Confidential                                                                       Page 1 of n 
Population: Intent-to-Treat                                     
Table 5.x  
Repeated Measures Analysis of Change from Baseline in Pharmacodynamic Biomarkers at Each Assessment Visit 
([Placebo/Sarilumab] Comparison) (Log Transformed) 
 
 
 
 
 
 
 
 
[1] Number of subjects with analysable data at the given timepoint. 
Note: All estimates are obtained from an MMRM analysis adjusted for Baseline Value, Treatment Group, Previously Failed 
Medication Category, Visit and Treatment Group by Visit. 
 
Biomarker: [Chemokine (C-C Motif) Ligand 17] 
Visit: Week 1 
Statistic 
Pooled PBO 
N=xx 
OTI 90mg QW 
N=xx 
OTI 150mg QW 
N=xx 
SARI 200mg Q2W 
N=xx 
 
 
 
 
 
n [1] 
      xx 
      xx 
      xx 
     xx 
 
 
 
 
 
LS Geometric Mean 
xx.x 
xx.x 
xx.x 
xx.x 
%CVb 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
 
 
 
Ratio to Pooled PBO 
 
xx.x 
xx.x 
xx.x 
  95% CI (%) 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
  p-value 
 
0.xxxx 
0.xxxx 
0.xxxx 
 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
199 
 
Example: AE13 (modified) 
Protocol: 202018                                                                                                Page 1 of n 
Population: Safety 
                                                              
Table 3.x 
Overall Summary of Adverse Events (Period X) 
 
 
 
Treatment 1 
N=xx 
Treatment 2 
N=xx 
Treatment 3 
N=xx 
Treatment 4 
N=xx 
 
 
 
 
 
Any AE 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
AEs related to study treatment 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    AEs leading to discontinuation of 
study treatment only 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
AEs leading to discontinuation of 
background therapy only 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
AEs leading to discontinuation of 
both study treatment and background 
therapy  
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
AEs leading to dose 
interruption/delay of study treatment 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
AEs leading to dose 
interruption/delay of background 
therapy 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
AEs leading to dose reduction of 
background therapy 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
Any SAE 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
SAEs related to study treatment 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Fatal SAEs 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Fatal SAEs related to study treatment 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
Any SAE excluding COVID-19 Infections 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
SAEs excluding COVID-19 Infections 
related to study treatment 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Fatal SAEs excluding COVID-19 
Infections 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Fatal SAEs excluding COVID-19 
Infections related to study treatment 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
200 
 
Example: SAFE_T1 
Protocol: 202018                                                                                                Page 1 of n 
Population: Safety 
                                                              
Table 3.x 
Summary of Exposure Adjusted Incidence Rates per 100 years for All Adverse Events (Period X) 
 
 
System Organ Class 
  Preferred Term 
Treatment 1 
N=xx 
Treatment 2 
N=xx 
Treatment 3 
N=xx 
Treatment 4 
N=xx 
 
 
 
 
 
Total Treatment Exposure (person-years) 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
 
 
 
Any Adverse Event 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
 
 
 
 
 
Infections and Infestations 
  Any Adverse Event 
  Nasopharyngitis 
  Upper Respiratory Tract 
  Infection 
  Bronchitis 
  Pharyngitis 
  Rhinitis 
  Oral Herpes 
  Viral Infection 
 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
 
 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
xx.x [xx] 
 
Note: The rate and number of events "Rate [#]" are reported in this table. #= Number of events. 
Note: Rate is event rate per 100 person-years, calculated as the number of events multiplied by 100, divided by the total 
treatment exposure in years. 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
201 
 
Example: SAFE_T2 
Protocol: 202018                                                                                                Page 1 of n 
Population: Safety 
                                                              
Table 3.x 
Summary of Adverse Events of Special Interest (AESI) (Period X)  
 
 
Treatment 1 
N=xx 
 n (%) [#] 
Treatment 2 
N=xx 
 n (%) [#] 
Treatment 3 
N=xx 
 n (%) [#] 
Treatment 4 
N=xx 
 n (%) [#] 
Treatment 5 
N=xx 
 n (%) [#] 
Treatment 6 
N=xx 
 n (%) [#] 
 
Any AESI 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
x (x) [x] 
x (x) [x] 
 
Serious infections 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
x (x) [x] 
x (x) [x] 
Serious infections excluding 
COVID-19 Infections 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
x (x) [x] 
x (x) [x] 
Opportunistic infections 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
x (x) [x] 
x (x) [x] 
  Active TB   
  Latent TB 
TB reactivation 
  x (x) [x]   
  x (x) [x] 
  x (x) [x]    
  x (x) [x]   
  x (x) [x] 
  x (x) [x] 
  x (x) [x]   
  x (x) [x] 
  x (x) [x] 
  x (x) [x]   
  x (x) [x] 
  x (x) [x] 
x (x) [x] 
x (x) [x] 
x (x) [x] 
x (x) [x] 
x (x) [x] 
x (x) [x] 
Neutropenia 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
x (x) [x] 
x (x) [x] 
Persistent cough 
Persistent dyspnoea  
Pulmonary alveolar proteinosis 
Serious Hypersensitivity 
reactions 
Injection site reaction 
  x (x) [x] 
  x (x) [x] 
  x (x) [x]   
  x (x) [x] 
 
  x (x) [x] 
  x (x) [x] 
  x (x) [x]    
  x (x) [x] 
  x (x) [x] 
 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x]   
  x (x) [x] 
 
  x (x) [x] 
x (x) [x] 
x (x) [x] 
x (x) [x] 
x (x) [x] 
 
x (x) [x] 
x (x) [x] 
x (x) [x] 
x (x) [x] 
x (x) [x] 
 
x (x) [x] 
 
Note: n=number of subjects with at least one event. #=number of individual occurrences.  
Note: Persistent cough or persistent dyspnoea defined as a cough (CTACE Grade >= 2) or a dyspnoea (dyspnoea scale Grade >= 
2) for three consecutive weeks (>=21 days). 
Note: Neutropenia is defined as AEs/SAEs of neutropenia where the corresponding absolute neutrophil counts are grade 3 or 4 
(<1.0 X 10^9/L). 
Note: Opportunistic infections, Active TB, Latent TB, TB reactivation events, serious hypersensitivity reactions and 
pulmonary alveolar proteinosis have been adjudicated and only adjudicated events displayed in the summary table. 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
202 
 
Example: SAFE_T3 
Protocol: 202018                                                                                                Page 1 of n 
Population: Safety 
Table 3.x 
Summary of Other Important Adverse Events (Period X) 
 
 
Treatment 1 
N=xx 
 n (%) [#] 
Treatment 2 
N=xx 
 n (%) [#] 
Treatment 3 
N=xx 
 n (%) [#] 
Treatment 4 
N=xx 
 n (%) [#] 
 
 
Any Other Important AEs 
 
Adjudicated GI Perforation 
 
Adjudicated CV Events 
 
  CV Death             
 
  Myocardial Infarction 
 
  Hospitalisation for Unstable Angina 
 
  Stroke 
 
  Hospitalisation for Heart Failure   
 
  Deep Vein Thrombosis 
 
  Pulmonary Embolism 
 
Any Malignancy 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
  
 
   Solid, Excluding Non-melanoma Skin Cancer   x (x) [x]     x (x) [x] 
x (x) [x] 
x (x) [x] 
 
    Non-melanoma Skin Cancer 
x (x) [x] 
x (x) [x] 
x (x) [x] 
 x (x) [x] 
 
 
Hematologic                                 x (x) [x]     x (x) [x]       x (x) [x]      x (x) [x] 
 
    Lymphoma 
x (x) [x]     x (x) [x]       x (x) [x] 
x (x) [x] 
 
Note: n=number of subjects with at least one event. #=number of individual occurrences. 
Note: Some Pneumonia SAEs may also be captured in category of Serious Pulmonary Infection. 


 
CONFIDENTIAL 
 
 
 
202018 
 
203 
 
Example: SAFE_T3 (continued) 
Protocol: 202018                                                                                                Page 2 of n 
Population: Safety 
Table 3.x 
Summary of Other Important Adverse Events (Period X)  
 
 
Treatment 1 
N=xx 
 n (%) [#] 
Treatment 2 
N=xx 
 n (%) [#] 
Treatment 3 
N=xx 
 n (%) [#] 
Treatment 4 
N=xx 
 n (%) [#] 
 
 
 
  Any Herpes Infection 
 
  Herpes Zoster 
 
  Herpes Simplex 
 
  Non-Specific Herpes Infection             
 
All-Cause Mortality 
 
Serious Pulmonary Infections 
 
Serious Pulmonary Infections excluding 
COVID-19 Infections 
 
Pneumonia (Serious and Non-Serious) 
 
Pneumonia (Serious and Non-Serious) 
excluding COVID-19 Infections 
 
Hepatitis B and Hepatitis B Reactivation   
 
  Thromboembolic Events 
 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
 
x (x) [x] 
 
  x (x) [x] 
 
 
x (x) [x] 
 
  x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
 
x (x) [x] 
 
x (x) [x] 
 
 
x (x) [x] 
 
   x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
 
x (x) [x] 
 
x (x) [x] 
 
 
x (x) [x] 
 
   x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
 
x (x) [x] 
 
x (x) [x] 
 
 
x (x) [x] 
 
   x (x) [x] 
 
  
 
Note: n=number of subjects with at least one event. #=number of individual occurrences. 
Note: Some Pneumonia SAEs may also be captured in category of Serious Pulmonary Infection. 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
204 
 
Example: SAFE_T4 
Protocol: 202018                                                                                                Page 1 of n 
Population: Safety 
Table 3.x 
Summary of Adjudicated Cardiovascular Event Categories (Period X) 
 
 
Treatment 1 
N=xx 
 n (%) [#] 
Treatment 2 
N=xx 
 n (%) [#] 
Treatment 3 
N=xx 
 n (%) [#] 
Treatment 4 
N=xx 
 n (%) [#] 
 
 
 
Any Adjudicated CV Event 
 
MACE 
 
Broad MACE 
 
Broad MACE, Excluding DVT and PE            
 
VTE (DVT and/or PE) 
 
DVT only 
 
  PE only 
 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
x (x) [x] 
 
 
  
 
 
Note: n=number of subjects with at least one event. #=number of individual occurrences. 


 
CONFIDENTIAL 
 
 
 
202018 
 
205 
 
Example ESI1 (modified) 
Protocol: 202018                                                                                             Page 1 of n 
Population: Safety 
Table 3.x 
Summary of Characteristics of Injection Site Reaction 
Period: Period X 
 
Treatment 1 
(N=100)  
Treatment 2 
(N=100) 
Treatment 3 
(N=100) 
 
 
 
 
Number of Subjects with the Event 
   50     (50%) 
   40     (40%) 
   40     (40%) 
Number of Events 
   60 
   65 
   55 
 
 
 
 
Event Characteristics (% based on all subjects)[1] 
 
 
 
Serious 
   10/100 (10%) 
   16/100 (16%) 
    8/100  (8%) 
Study treatment related 
 
   25/100 (25%) 
     
   10/100 (10%) 
     
   20/100 (20%) 
     
Led to study withdrawal 
    5/100  (5%) 
    4/100  (4%) 
    2/100  (2%) 
 
 
 
 
Event Characteristics (% based on subjects with the 
Event)[1] 
 
 
 
Serious 
   10/50  (20%) 
   16/40  (40%) 
    8/40  (20%) 
Study treatment related 
 
   25/50  (50%) 
     
   10/40  (25%) 
 
   20/40  (50%) 
 
Led to study withdrawal 
    5/50  (10%) 
    4/40  (10%) 
    2/40   (5%) 
 
 
 
 
 
 
Note: [1] Subjects may be included in more than one category for ‘Event Characteristics’. 
Note: [2] Outcome worst case hierarchy: Fatal > Not Recovered/Not Resolved > Recovered/Resolved with sequelae > 
Recovering/Resolving > Recovered/Resolved 
Note: [3] Subjects are counted once under each action that was taken. 
Note: [4] Background therapy is any csDMARD. 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
206 
 
Example ESI1 (modified) 
Protocol: 202018                                                                                             Page 2 of n 
Population: Safety 
Table 3.x 
Summary of Characteristics of Injection Site Reaction  
Study: Period X 
 
Treatment 1  
(N=100) 
Treatment 2 
(N=100) 
Treatment 3 
(N=100) 
 
 
 
 
Number of occurrences (% based on all subjects) 
 
 
 
One 
   30/100 (30%) 
   20/100 (20%) 
    8/100  (8%) 
Two 
   15/100 (15%) 
   10/100 (10%) 
   30/100 (30%) 
Three or more 
    5/100  (5%) 
   10/100 (10%) 
    2/100  (2%) 
 
 
 
 
Number of occurrences (% based on subjects with the Event) 
 
 
 
One 
   30/50  (60%) 
   20/40  (50%) 
    8/40  (20%) 
Two 
   15/50  (30%) 
   10/40  (25%) 
   30/40  (75%) 
Three or more 
    5/50  (10%) 
   10/40  (25%) 
    2/40   (5%) 
 
 
 
 
Outcome (% based on all subjects)[2] 
 
 
 
Recovered/Resolved 
   20/100 (20%) 
   10/100 (10%) 
    8/100  (8%) 
Recovering/Resolving 
   10/100 (10%) 
   20/100 (20%) 
   30/100 (30%) 
Not Recovered/Not Resolved 
   10/100 (10%) 
    5/100  (5%) 
    0/100   
Recovered/Resolved with sequelae 
    5/100  (5%) 
    0/100 
    0/100 
Fatal 
    5/100  (5%) 
    5/100  (5%) 
    2/100  (2%) 
 
 
 
 
Outcome (% based on subjects with the Event)[2] 
 
 
 
Recovered/Resolved 
   20/50  (40%) 
   10/40 (25%) 
    8/40 (20%) 
Recovering/Resolving 
   10/50  (20%) 
   20/40 (50%) 
   30/40 (75%) 
Not Recovered/Not Resolved 
   10/50  (20%) 
    5/40 (13%) 
    0/40   
Recovered/Resolved with sequelae 
    5/50  (10%) 
    0/40 
    0/40 
Fatal 
    5/50  (10%) 
    5/40 (13%) 
    2/40  (5%) 
 
Note: [1] Subjects may be included in more than one category for ‘Event Characteristics’. 
Note: [2] Outcome worst case hierarchy: Fatal > Not Recovered/Not Resolved > Recovered/Resolved with sequelae > 
Recovering/Resolving > Recovered/Resolved 
Note: [3] Subjects are counted once under each action that was taken. 
Note: [4] Background therapy is any csDMARD. 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
207 
 
Example ESI1 (modified) 
Protocol: 202018                                                                                             Page 3 of n 
Population: Safety 
Table 3.x 
Summary of Characteristics of Injection Site Reaction  
Period: Period X 
 
Treatment 1  
(N=100) 
Treatment 2 
(N=100) 
Treatment 3 
(N=100) 
 
 
 
 
Maximum Intensity (% based on all subjects) 
 
 
 
Mild 
   30/100 (30%) 
   20/100 (20%) 
    8/100  (8%) 
Moderate 
   15/100 (15%) 
   10/100 (10%) 
   30/100 (30%) 
Severe 
    5/100  (5%) 
   10/100 (10%) 
    2/100  (2%) 
 
 
 
 
Maximum Intensity (% based on subjects with the Event) 
 
 
 
Mild 
   30/50  (60%) 
   20/40  (50%) 
    8/40  (20%) 
Moderate 
   15/50  (30%) 
   10/40  (25%) 
   30/40  (75%) 
Severe 
    5/50  (10%) 
   10/40  (25%) 
    2/40   (5%) 
 
 
 
 
 
Note: [1] Subjects may be included in more than one category for ‘Event Characteristics’. 
Note: [2] Outcome worst case hierarchy: Fatal > Not Recovered/Not Resolved > Recovered/Resolved with sequelae > 
Recovering/Resolving > Recovered/Resolved 
Note: [3] Subjects are counted once under each action that was taken. 
Note: [4] Background therapy is any csDMARD. 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
208 
 
Example ESI1 (modified) 
Protocol: 202018                                                                                             Page 4 of n 
Population: Safety 
Table 3.x 
Summary of Characteristics of Injection Site Reaction  
Period: Period X 
 
Treatment 1 
(N=100)   
Treatment 2 
(N=100) 
Treatment 3 
(N=100) 
 
 
 
 
Action Taken (% based on all subjects)[3] 
 
 
 
Study treatment withdrawn 
   20/100 (20%) 
   10/100 (10%) 
    8/100  (8%) 
Dose not changed 
    5/100  (5%) 
    0/100 
    0/100 
Dose interrupted/delayed 
    0/100 
    5/100  (5%) 
    2/100  (2%) 
Not applicable 
    5/100 (10%) 
    0/100 
    0/100 
 
 
 
 
Action Taken (% based on subjects with the Event)[3] 
 
 
 
Study treatment withdrawn 
   20/50  (40%) 
   10/40 (25%) 
    8/40 (20%) 
Dose not changed 
    5/50  (10%) 
    0/40 
    0/40 
Dose interrupted/delayed 
    0/50   
    5/40 (13%) 
    2/40  (5%) 
Not applicable 
    5/50  (10%) 
    0/40 
    0/40 
 
 
 
 
Action 
Taken 
with 
Background 
Therapy(% 
based 
on 
all 
subjects)[3] [4] 
 
 
 
Drug withdrawn 
   20/100 (20%) 
   10/100 (10%) 
    8/100  (8%) 
Dose reduced 
   10/100 (10%) 
   20/100 (20%) 
   30/100 (30%) 
Dose not changed 
    5/100  (5%) 
    0/100 
    0/100 
Dose interrupted/delayed 
    0/100 
    5/100  (5%) 
    2/100  (2%) 
Not applicable 
    5/100 (10%) 
    0/100 
    0/100 
 
 
 
 
Action Taken (% based on subjects with the Event)[3] 
 
 
 
Background Therapy [4] withdrawn 
   20/50  (40%) 
   10/40 (25%) 
    8/40 (20%) 
Dose reduced 
   10/50  (20%) 
   20/40 (50%) 
   30/40 (75%) 
Dose not changed 
    5/50  (10%) 
    0/40 
    0/40 
Dose interrupted/delayed 
    0/50   
    5/40 (13%) 
    2/40  (5%) 
Not applicable 
    5/50  (10%) 
    0/40 
    0/40 
 
 
 
 
Note: [1] Subjects may be included in more than one category for ‘Event Characteristics’. 
Note: [2] Outcome worst case hierarchy: Fatal > Not Recovered/Not Resolved > Recovered/Resolved with sequelae > 
Recovering/Resolving > Recovered/Resolved 
Note: [3] Subjects are counted once under each action that was taken. 
Note: [4] Background therapy is any csDMARD. 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
209 
 
Example: SAFE_T5 
Protocol: 202018                                                                                                Page 1 of n 
Population: Safety 
Table 3.x 
Summary of Injection Site Reaction (Period X) 
 
 
Treatment 1 
N=xx 
 n (%) [#] 
Treatment 2 
N=xx 
 n (%) [#] 
Treatment 3 
N=xx 
 n (%) [#] 
Treatment 4 
N=xx 
 n (%) [#] 
Any injection site reactions 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
 
 
 
 
 
<= 1 Day post injection 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
> 1 Day post injection $ 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
 
 
 
 
 
Reported as a non-serious AE 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
Reported as an SAE 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
 
 
 
 
 
Type of Reactions 
 
 
 
 
  Itching/Pruritus 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Redness/Erythema 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Pain 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Bruising 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Swelling/Edema 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Warm to Touch 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
 
 
 
 
 
Note: n=number of subjects with at least one event. #=number of individual occurrences. ($) until 1 day before next injection.  
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
210 
 
Example: SAFE_T6 
Protocol: 202018                                                                                                Page 1 of n 
Population: Safety  
Table 3.x 
Summary of Serious or Adjudicated Opportunistic Infections (Period X)  
 
 
Treatment 1 
N=xx 
 n (%) [#] 
Treatment 2 
N=xx 
 n (%) [#] 
Treatment 3 
N=xx 
 n (%) [#] 
Treatment 4 
N=xx 
 n (%) [#] 
Any serious or opportunistic infections 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
 
 
 
 
 
 
 
 
 
 
Reported as a non-serious AE 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
Reported as an SAE 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
 
 
 
 
 
Type of Infection 
 
 
 
 
  Bacterial – Gram Positive 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Bacterial – Gram Negative 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Bacterial - Atypical  
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Bacterial - Unknown 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Bacterial – Other 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Viral - Zoster/shingles 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Viral - Simplex, orogenital 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Viral - EBV 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Viral - HCV 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Viral - HBV 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Viral - HBV Reactivation 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Viral - Unknown 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Viral - Other 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
 
 
 
 
 
Note: n=number of subjects with at least one event. #=number of individual occurrences. 
Note: $ until 1 day before next injection. 
Note: Adjudication of serious hypersensitivity reactions was done internally.  
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
211 
 
Example: SAFE_T6 (continued) 
Protocol: 202018                                                                                                Page 2 of n 
Population: Safety  
Table 3.x 
Summary of Serious or Adjudicated Opportunistic Infections (Period X) 
 
 
Treatment 1 
N=xx 
 n (%) [#] 
Treatment 2 
N=xx 
 n (%) [#] 
Treatment 3 
N=xx 
 n (%) [#] 
Treatment 4 
N=xx 
 n (%) [#] 
Type of Infection 
 
 
 
 
  Opportunistic - Esophageal candidiasis 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Opportunistic - CMV viremia 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Opportunistic - CMV invasive 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Opportunistic - Pneumocystis Jiroveci 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Opportunistic - Cryptococcus 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Opportunistic - Disseminated herpes zoster 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Opportunistic - BK virus encephalitis 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Opportunistic - Fungal 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Opportunistic - Protozoal/helminthic 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Opportunistic - Latent tuberculosis 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Opportunistic - Active tuberculosis 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Opportunistic - Atypical mycobacterial 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Opportunistic - Aspergillus 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Opportunistic - Fungal non aspergillus 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Opportunistic - Fungal non cryptococcal 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Opportunistic - Unknown 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Opportunistic - Other 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
 
 
 
 
 
Note: n=number of subjects with at least one event. #=number of individual occurrences. 
Note: $ until 1 day before next injection. 
Note: Adjudication of serious hypersensitivity reactions was done internally.  
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
212 
 
Example: SAFE_T6 (continued) 
Protocol: 202018                                                                                                Page 3 of n 
Population: Safety 
Table 3.x 
Summary of Serious or Adjudicated Opportunistic Infections (Period X) 
 
 
Treatment 1 
N=xx 
 n (%) [#] 
Treatment 2 
N=xx 
 n (%) [#] 
Treatment 3 
N=xx 
 n (%) [#] 
Treatment 4 
N=xx 
 n (%) [#] 
Origin of Infection 
 
 
 
 
  Community 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Hospital 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  ICU  
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Unknown 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
 
 
 
 
 
Parenteral antibiotics or antimicrobial medication administered   x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
 
 
 
 
 
Culture/swab taken 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
 
 
 
 
 
Diagnostic imaging or other diagnostic tests performed 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
 
 
 
 
 
Had grade 3 neutropenia or worse at the time of infection 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
 
 
 
 
 
Note: n=number of subjects with at least one event. #=number of individual occurrences.  
Note: $ until 1 day before next injection. 
Note: Adjudication of serious hypersensitivity reactions was done internally. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
213 
 
Example: SAFE_T7 
Protocol: 202018                                                                                                Page 1 of n 
Population: Safety 
Table 3.x 
Summary of Adjudicated Serious Hypersensitivity Reactions (Period X) 
 
 
Treatment 1 
N=xx 
 n (%) [#] 
Treatment 2 
N=xx 
 n (%) [#] 
Treatment 3 
N=xx 
 n (%) [#] 
Treatment 4 
N=xx 
 n (%) [#] 
Any serious hypersensitivity reactions 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
 
 
 
 
 
<= 1 Day post injection 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
> 1 Day post injection $ 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
 
 
 
 
 
Reported as a non-serious AE 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
Reported as an SAE 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
 
 
 
 
 
Type of Systemic Reactions 
 
 
 
 
  Headache 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Pruritus 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Urticaria 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Rash 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Angioedema 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Fatigue 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Myalgia 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Arthralgia 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Bronchospasm 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Hypotension requiring vasopressors 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Hypotension not requiring vasopressors 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Dizziness 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Syncope 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Crampy abdominal pain 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Respiratory failure requiring intubation 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  ICU Management required 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Other 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
 
 
 
 
 
Note: n=number of subjects with at least one event. #=number of individual occurrences. ($) until 1 day before next injection.  
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
214 
 
Example: SAFE_T7 (continued) 
Protocol: 202018                                                                                                Page 2 of n 
Population: Safety 
 
Table 3.x 
Summary of Adjudicated Serious Hypersensitivity Reactions (Period X) 
 
 
Treatment 1 
N=xx 
 n (%) [#] 
Treatment 2 
N=xx 
 n (%) [#] 
Treatment 3 
N=xx 
 n (%) [#] 
Treatment 4 
N=xx 
 n (%) [#] 
Met anaphylaxis criteria 
 
 
 
 
  Criterion 1 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Criterion 2 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  Criterion 3 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
  x (x) [x] 
 
 
 
 
 
Note: n=number of subjects with at least one event. #=number of individual occurrences. ($) until 1 day before next injection. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
215 
 
Example: SAFE_T8 
Protocol: 202018                                                                                   Page 1 of n 
Population: Safety 
Table 3.x 
Summary of Pulmonary Findings (Period X) 
 
 
Note: Cough includes subjects who reported cough of any grade. 
Note: Abnormal lung auscultation includes subjects with any abnormality recorded. 
Note: Dyspnoea includes subjects who reported dyspnoea of any grade. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects with at least one 
event of 
Treatment 1 
N=xx 
 
Treatment 2 
N=xx 
 
Treatment 3 
N=xx 
 
Treatment 4 
N=xx 
 
 
 
 
 
 
Cough 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
 
 
 
 
 
Abnormal lung auscultation 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
 
 
 
 
 
Dyspnoea 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
216 
 
Example: SAFE_T9 
Protocol: 202018                                                                                   Page 1 of n 
Population: Safety 
Table 3.x 
Summary of Pulse Oximetry Results (Period X) 
 
 
 
Visit 
  Blood Oxygen 
Treatment 1 
N=xx 
 
Treatment 2 
N=xx 
 
Treatment 3 
N=xx 
 
Treatment 4 
N=xx 
 
 
 
 
 
 
Baseline 
 
 
 
 
   n 
   xx 
      xx 
    xx 
  xx 
   <80% 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
   80% to <90% 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
   >=90% 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
 
 
 
 
 
Worst Post-Baseline Result 
 
 
 
 
   n 
      xx 
      xx 
       xx 
     xx 
   <80% 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
   80% to 90% 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
   >=90%    
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
217 
 
Example: LB16A (modified) 
Protocol: 202018  
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of n 
Population: Safety 
Table 3.76 
Summary of Worst Case Chemistry Results by Maximum Grade Shift Post-Baseline Relative to Baseline 
(Period 1) 
Test (units): Alanine Aminotransferase (IU/L) 
Term: Alanine aminotransferase increased 
 
Treatment  
 
 
 
Planned Time   
 
Change Categories [2] 
------------------------------------------------------------------------------------------------------------ 
Pooled PBO (N=78)   
Baseline  
 
 
 
n  
 
 
 
 
xx 
Grade 1  
 
 
 
xx (xx%) 
Grade 2  
 
 
 
xx (xx%)  
Grade 3  
 
 
 
xx (xx%) 
Grade 4  
 
 
 
xx (xx%) 
 
Maximum Grade Shift Post  n  
 
 
 
 
xx 
Baseline 
Worsen to Grade 1   
xx (xx%) 
Worsen to Grade 2   
xx (xx%) 
Worsen to Grade 3   
xx (xx%) 
Worsen to Grade 4   
xx (xx%) 
Worsen to Grades 1 to 4  
xx (xx%) 
Worsen to Grades 2 to 4  
xx (xx%) 
Worsen to Grades 3 to 4  
xx (xx%) 
 
 
OTI 90mg QW (N=157)  
Baseline  
 
 
 
n  
 
 
 
 
xx 
Grade 1  
 
 
 
xx (xx%) 
Grade 2  
 
 
 
xx (xx%) 
Grade 3  
 
 
 
xx (xx%) 
Grade 4  
 
 
 
xx (xx%) 
--------------------------------------------------------------------------------------------------------------- 
Note: A worsening is defined as a worsening in grade relative to baseline grade. Subjects with missing 
baseline values are assumed to have baseline value of grade 0. 
[1] Grades were derived based on numeric criteria as defined in CTCAEv5.0 and did not take into 
consideration of clinical signs or symptoms, concomitant medication usage which is needed for the final 
grade associated with the adverse event. 
[2] n = number of subjects with values at the specified planned time. 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
218 
 
Example: SAFE_T10 
Protocol: 202018                                                                                   Page 1 of n 
Population: Safety 
Table 3.x 
Summary of Anti-GSK3196165 Antibodies (ADA) 
 
 
Note: A subject is considered to have a positive ADA result if they have a positive screening assay, a positive 
confirmation assay and a titre value. A baseline ADA result is the closest ADA sample prior to the subject receiving the 
first dose of GSK3196165. Only confirmed ADA positive samples were tested in the Neutralizing Antibody assay. 
 
 
 
 
 
 
 
Treatment 1 
N=xx 
Treatment 2 
N=xx 
Treatment 3 
N=xx 
Baseline ADA results 
 
 
 
   n 
xx 
xx 
xx 
   Negative  ADA 
xx (xx) 
xx (xx) 
xx (xx) 
   Confirmed positive ADA 
xx (xx) 
xx (xx) 
xx (xx) 
At least one confirmed positive ADA that 
subsequently tested positive for 
Neutralising Antibodies 
xx (xx) 
xx (xx) 
xx (xx) 
At least one confirmed positive ADA that 
subsequently tested negative for 
Neutralising Antibodies 
xx (xx) 
xx (xx) 
xx (xx) 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
219 
 
Example: SAFE_T10 (continued) 
Protocol: 202018                                                                                   Page 2 of n 
Population: Safety 
Table 3.x 
Summary of Anti-GSK3196165 Antibodies (ADA) 
 
 
Note: A subject is considered to have a positive ADA result if they have a positive screening assay, a positive 
confirmation assay and a titre value. A baseline ADA result is the closest ADA sample prior to the subject receiving the 
first dose of GSK3196165. Only confirmed ADA positive samples were tested in the Neutralizing Antibody assay. 
 
 
 
 
 
 
 
Treatment 1 
N=xx 
Treatment 2 
N=xx 
Treatment 3 
N=xx 
Post-baseline ADA results 
 
 
 
    n 
xx 
xx 
xx 
At least one confirmed positive ADA 
result 
xx (xx) 
xx (xx) 
xx (xx) 
All negative ADA results  
xx (xx) 
xx (xx) 
xx (xx) 
Confirmed positive ADA result that are 
positive for Neutralising Antibodies 
xx (xx) 
xx (xx) 
xx (xx) 
Confirmed positive ADA result that are 
negative for Neutralising Antibodies 
xx (xx) 
xx (xx) 
xx (xx) 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
220 
 
Example: SAFE_T11 
Protocol: 202018                                                                                   Page 1 of n 
Population: Safety 
Table 3.x 
Summary of Binding Antibody at Each Assessment Visit 
 
Note: The values shown at the anytime post baseline visit are based on each subject’s highest post baseline titre. 
Note: Any Time Post Baseline would be positive for a subject who had negative and positive baseline results. 
Note: Transient positive is defined as a single positive immunogenic response where the previous visit is negative, that does 
not occur at the final study assessment and persistent positive is defined as a positive immunogenic response where the 
previous visit is positive of the final study assessment is positive. 
Note: The titre value includes the method sample dilution of 1/10. 
 
Visit 
Assay Result 
 
Treatment 1 
N=xx 
Treatment 2 
N=xx 
Treatment 3 
N=xx 
Baseline 
n 
 
xx 
xx 
xx 
 
Negative 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Positive 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Titre Value 
Median 
xx.x 
xx.x 
xx.x 
 
 
Min. 
xx 
xx 
xx 
 
 
Max. 
xx 
xx 
xx 
 
 
 
 
 
 
Week 2 
n 
 
xx 
xx 
xx 
 
Negative 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Positive 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Titre Value 
Median 
xx.x 
xx.x 
xx.x 
 
 
Min. 
xx 
xx 
xx 
 
 
Max. 
xx 
xx 
xx 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
ANY TIME POST 
BASELINE 
n 
 
xx 
xx 
xx 
 
Negative 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Positive 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
  Persistent positive 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
  Transient positive 
 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Titre Value 
Median 
xx.x 
xx.x 
xx.x 
 
 
Min. 
xx 
xx 
xx 
 
 
Max. 
xx 
xx 
xx 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
221 
 
Example: SAFE_T12 
Protocol: 202018                                                                                               Page 1 of n 
Population: Safety 
Table 3.x 
Summary of Neutralising Antibody at Each Assessment Visit 
 
Note: NAb assay result is only presented for subjects with a positive ADA assay. 
Note: Any Time Post Baseline would be positive for a subject who had negative and positive baseline results. 
 
 
 
 
Visit 
Assay Result 
Treatment 1 
N=xx 
Treatment 2 
N=xx 
Treatment 3 
N=xx 
Baseline 
n 
xx 
xx 
xx 
 
Negative 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Positive 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
Week 2 
n 
xx 
xx 
xx 
 
Negative 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Positive 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
ANY TIME POST 
BASELINE 
n 
xx 
xx 
xx 
 
Negative 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
Positive 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 


 
C O N FI D E N TI A L  
 
 
 
2 0 2 0 1 8  
 
2 2 2  
 
E x a m p l e :  S A F E _ T 1 3  
P r o t o c o l :  2 0 2 0 1 8                                                                                            P a g e  1  o f  n  
P o p u l a t i o n :  S a f e t y  
T a b l e  3 . x  
S u m m a r y  o f  A d j u d i c a t e d  S e r i o u s  C a s e s  o f  C O V I D - 1 9  I n f e c t i o n s  ( P e r i o d  X )  
 
 
T r e a t m e n t  1  
N = x x  
 n  ( % )   
T r e a t m e n t  2  
N = x x  
 n  ( % )   
T r e a t m e n t  3  
N = x x  
 n  ( % )  
T r e a t m e n t  4  
N = x x  
 n  ( % )  
 
C o n f i r m e d  C a s e s  o f  C O V I D - 1 9  
 
   N o n  H o s p i t a l i s e d  ( W H O  g r a d e  1  a n d  2 )  
   H o s p i t a l i s e d  ( W H O  g r a d e  3 ,  4  a n d  5 )  
   H o s p i t a l i s e d  ( W H O  g r a d e  6  a n d  7 )  
   D e a t h  
 
P r o b a b l e  C a s e s  o f  C O V I D - 1 9  
   N o n  H o s p i t a l i s e d  ( W H O  g r a d e  1  a n d  2 )  
   H o s p i t a l i s e d  ( W H O  g r a d e  3 ,  4  a n d  5 )  
   H o s p i t a l i s e d  ( W H O  g r a d e  6  a n d  7 )  
   D e a t h  
 
     x  ( x )  
     x  ( x )    
     x  ( x )  
     x  ( x )  
     x  ( x )    
      
     x  ( x )  
     x  ( x )  
     x  ( x )  
     x  ( x )  
     x  ( x )  
 
           
     x  ( x )  
      
     x  ( x )  
 
     x  ( x )  
 
     x  ( x )  
 
     x  ( x )  
 
 
 
     x  ( x )  
 
     x  ( x )  
 
     x  ( x )  
 
     x  ( x )  
 
     x  ( x )  
     x  ( x )  
     
     x  ( x )  
 
     x  ( x )  
 
     x  ( x )  
 
     x  ( x )  
 
      
      
     x  ( x )  
 
     x  ( x )  
 
     x  ( x )  
 
     x  ( x )  
 
     x  ( x )  
     x  ( x )  
     
     x  ( x )  
 
     x  ( x )  
 
     x  ( x )  
 
     x  ( x )  
 
 
     
     x  ( x )  
 
     x  ( x )  
 
     x  ( x )  
 
     x  ( x )  
 
     x  ( x )  
 
N o t e :  W H O  o r i g i n a l  s c a l e  -  n o n  h o s p i t a l i s e d  ( g r a d e  1
;  g r a d e  2 -
( g r a d e  3 -
 g r a d e  4 -
;  g r a d e  5 -
 
;  g r a d e  6 -  
;  g r a d e  7 -  
 
 
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


 
CONFIDENTIAL 
 
 
 
202018 
 
223 
 
Example: SAFE_T14  
Protocol: 202018                                                                                               Page 1 of n 
Population: Safety 
Table 1.x 
Summary of Common (>=2%) Adverse Events by Time from Randomisation  
 
Time From Randomisation : [<=12 weeks / >12 weeks and <=24 weeks / >24 weeks and <=36 weeks / >36 weeks and <=52 
weeks ] 
 
Treatment 1 
N=xx 
Treatment 
2 
N=xx 
Treatment 
3 
N=xx 
Treatment 4 
N=xx 
Treatment 5 
N=xx 
Treatment 6 
N=xx 
Any Adverse Event 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
    XXXXX 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
224 
 
Example: SAFE_T15 
Protocol: 202018                                                                                           Page 1 of x 
Population: Safety 
Table 3.x 
Summary of COVID-19 Infections (Period X) 
 
 
 
Treatment 1 
(N=xx) 
Treatment 2 
(N=xx) 
Treatment 3 
(N=xx) 
Treatment 4 
(N=xx) 
 
 
 
 
 
Any COVID-19 Infection 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
Any Non-Serious COVID-19 
Infection 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
   Confirmed COVID-19 Infection 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
   Suspected COVID-19 Infection 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
   Probable COVID-19 Infection 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
Any Serious COVID-19 Infection 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
   Confirmed COVID-19 Infection 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
   Suspected COVID-19 Infection 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
   Probable COVID-19 Infection 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
 
 
202018 
 
225 
 
Example: SAFE_L1 
Protocol: 202018                                                                                   Page 1 of n 
Population: Safety 
Listing x 
Listing of Neutrophils and Associated Infections 
Subset of Subjects who experienced grade 3 or 4 Neutropenia 
 
Site=xxx; Subject=xxxxxx.xxxxxx; Arm=xxxxxxxxxxx; 
Sex=x; Age(YEARS)=xx; Race Details=xxxxxxxx; Weight(kg)=xx.xx 
 
 
 
Neutrophils (unit)  
 Associated Infections  
Treatment/ 
Period 
Visit 
Analysis 
Visit 
Date 
Study 
Day 
Result
Out of 
Normal 
Toxicity 
Grade 
 
Preferred Term/ 
VERBATIM TEXT 
Placebo/ 
1 
SCREENING 
SCREENING xxxx-xx-xx 
x
x.xx 
 
 
BASELINE 
BASELINE 
xxxx-xx-xx 
xx
x.xx 
xxx 
x 
WEEK 1 
WEEK 1 
xxxx-xx-xx 
xx
x.xx 
xxx 
x 
WEEK 2 
WEEK 2 
xxxx-xx-xx 
xx
x.xx 
 
 
UNSCHEDULED WEEK 2 
xxxx-xx-xx 
xx
x.xx 
xxx 
x 
WEEK 4 
WEEK 4 
xxxx-xx-xx 
xx
x.xx 
 
 
 
 
 
 
Note: Lower Limit of Normal: xx, Upper Limit of Normal: xx 
 


Si g nat ure Pa ge f or  2 0 2 0 1 8 T M F- 1 4 4 3 3 7 0 1 v 1. 0
Si g nat ure Pa ge f or T M F- 1 4 4 3 3 7 0 1 v 1. 0
Reas o n f or si g ni n g: A p pr o ve d
Na me:
R ole: A p pr o ver
Date of si g nat ure: 0 4- Fe b- 2 0 2 2 1 3: 2 9: 1 0 G M T + 0 0 0 0
Reas o n f or si g ni n g: A p pr o ve d
Na me: 
R ole: A p pr o ver
Date of si g nat ure: 0 4- Fe b- 2 0 2 2 1 4: 0 5: 1 7 G M T + 0 0 0 0
P P D
P P D