Conditions: Colitis, Ulcerative
Keywords: GSK2831781 Ulcerative colitis Anti-LAG3 cell Depleting monoclonal antibody Dose-response
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 104
Healthy volunteers: no

Brief summary:
This is a Phase 2, multicenter, randomized, double-blind, parallel group, placebo-controlled study to investigate the safety, tolerability, efficacy and dose-response of GSK2831781 in participants with moderate to severe active ulcerative colitis. The study consists of a 5-week screening window, 10-week Induction Phase, 30-week double-blind Extended Treatment Phase (ETP) with 42-week Follow-Up Phase. Non-Responders identified following the Week 10 assessment will be allocated to open label treatment, consisting of Induction (Weeks 12 to 22), an Open label ETP (Weeks 22 to 42) and a follow-Up to Week 54.

Detailed description:

Arms:
arm 1: Eligible participants will receive GSK2831781 intravenously in the double blind induction phase at different dose levels. Participants identified as Responders at Week 10 will then receive GSK2831781 subcutaneously during the double-blind ETP from Week 14 until Week 26 arm 2: Eligible participants will receive GSK2831781 intravenously in the open label induction phase. Participants identified as Non-Responders at Week 10 will receive GSK2831781 from Week 12 until Week 22. Participants identified as Responders at Week 22 will enter open label ETP to receive GSK2831781 from Week 26 until Week 38. Participants identified as Non- Responders at Week 22 will discontinue treatment. arm 3: Eligible participants will receive Placebo in the double blind induction phase Participants identified as Responders at Week 10 will continue to receive Placebo subcutaneously during the double-blind ETP from Week 14 until Week 26.

Interventions: intervention 1: GSK2831781 - Double Blind Phase intervention 2: Placebo intervention 3: GSK2831781 - Open Label phase
Intervention descriptions: intervention 1: GSK2831781 will be administered intravenously in the double blind induction phase and subcutaneously in the double blind ETP (both according to randomization). intervention 2: Placebo (commercial saline solution) will be administered intravenously in the double blind induction phase and subcutaneously in the double blind ETP (both according to randomization). intervention 3: GSK2831781 will be administered intravenously in the open label induction phase and subcutaneously in the open label ETP.

Protocol document:
Prot_000.pdf: 
TMF-2197350 
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TITLE PAGE 
Protocol Title: A multicentre randomized, double-blind, placebo-controlled Phase 2 study 
to evaluate the safety, tolerability, efficacy, dose-response, pharmacokinetics and 
pharmacodynamics of repeat dosing of an anti-LAG3 cell depleting monoclonal antibody 
(GSK2831781) in patients with active ulcerative colitis. 
Protocol Number: 204869/04 
 Compound Number: 
GSK2831781 
Study Phase: Phase 2 
Short Title: Safety, tolerability, efficacy and dose-response of GSK2831781 in 
ulcerative colitis.  
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Regulatory Agency Identifying Number(s):  
IND: 139126 
EudraCT: 2018-003278-28 
Approval Date: 12-NOV-2020 
 
 
 
 
 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited. 
 


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SPONSOR SIGNATORY: 
 
 
 
 
 
 
 
Ruth Tarzi, BM BCh PhD FRCP 
Clinical Development Leader 
 
 
 
Date 
 
 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Document Date 
DNG Number 
Amendment 4 
12-NOV-2020 
TMF-2197350 
Amendment 3 
03-SEP-2020 
2017N337668_03 
Amendment 2 
10-SEP-2019 
2017N337668_02 
Amendment 1 
17-JAN-2019 
2017N337668_01 
Original Protocol 
15-OCT-2018 
2017N337668_00 
 
Amendment 4: 12-NOV-2020 
Overall Rationale for the Amendment: 
The rationale for the amendment includes: 
• Main changes: Response to Health Authority feedback following review of 
Protocol Amendment 3, regarding the first SC dose administration and post dose 
monitoring. 
• Minor changes: clarification for investigators and administrative corrections. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 
Synopsis - Number of 
participants 
Updated ‘a complete week 10 Complete 
4-domain Mayo score assessment’ to ‘an 
incomplete week 10 Complete 4-domain 
Mayo score assessment’. 
Correction to align 
mismatched text with Section 
4.1.3. 
Section 1.2 
Schema 
Removed the ambiguity for non-
responders at Week 22: for these 
participants there are no remaining 
scheduled visits other than the Follow-up 
Visit. 
Clarification for Investigators. 
Section 1.3 
Schedule of Activities 
(SoA): Double Blind 
Treatment 
Repositioned/added table footnote 
superscripts (number 22) and updated 
text for footnotes 15, 20, 21, 22 and 28. 
Clarification for Investigators.   
Section 1.3 
Schedule of Activities 
(SoA): Open Label 
Treatment 
Repositioned/added table footnote 
superscripts (number 13) and updated 
text for footnotes 7, 8 and 13. 
Clarification for Investigators.  
Section 3 
Objectives, Endpoints and 
Estimands 
Updated the secondary endpoint 
‘Histological severity as determined by 
the Geboes Score at Week 10’ to 
‘Histological severity as determined by 
the Geboes Histological Index at Week 
10’. 
Correction to align 
mismatched text with Section 
1.1 (Synopsis). 
Section 4.1.2  
Open Label Treatment for 
Added ‘clinical response is calculated 
centrally in eCRF’ and removed the 
Clarification for Investigators. 


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Section # and Name 
Description of Change 
Brief Rationale 
Non-Responders 
ambiguity for non-responders at Week 
22: for these participants there are no 
remaining scheduled visits other than the 
Follow-up Visit. 
Section 4.3.3. 
Open Label Treatment 
Deleted a redundant sentence, as not 
relevant to the ‘Dose Justification’ 
section. 
Clarification for Investigators. 
Section 4.4 
End of Study Definition  
“Participants who withdraw from the study 
early should be encouraged to complete 
all visits for that specific phase as set 
out in the SoA (Section 1.3); however, if 
this is not possible at a minimum 
participants will be asked to complete all 
assessments at both the Early 
Withdrawal visit and a Follow-Up visit 
approximately 16 weeks after the last 
dose (Section 7.2) to ensure participant 
monitoring following drug wash out.” 
 
• 
Added ‘for that specific phase’. 
• 
Changed ‘until drug washout is 
achieved’ to ‘following drug 
washout’. 
Clarification for Investigators. 
Section 6.2 
Intervention Administration 
Updated Table 1 and Table 2 to Increase 
the post dose monitoring period, for the 
first SC dose, from 30 mins to 2 hours. 
Response to a request from a 
Health Authority, following 
Protocol Amendment 3 
review. 
Updated Table 1 and Table 2 to include 
the flush time for the 3rd and 4th IV 
doses. 
Clarification for Investigators: 
to be consistent with the 1st 
and 2nd IV dosing duration, 
which includes the flush time. 
Section 6.3 
Preparation/Handling/ 
Storage/Accountability 
Deleted ‘from GSK’ to clarify that a 
Material Safety Data Sheet (MSDS)/ 
equivalent is ‘available upon request.’ 
Clarification for Investigators. 
Section 7.1  
Discontinuation of Study 
Intervention 
Updated to reflect that participants 
discontinuing study treatment will be 
requested to attend the remaining visits 
for the treatment phase they are in, and 
that an Early Withdrawal visit is only 
needed for participants that do not wish to 
attend these remaining visits. 
Clarification for Investigators. 
Section 7.2  
Participant 
Discontinuation/Withdrawal 
from the Study 
Updated to reflect that participants 
discontinuing study treatment will be 
requested to attend the remaining visits 
for the treatment phase they are in, and 
that an Early Withdrawal visit is only 
needed for participants that do not wish to 
attend these remaining visits 
Clarification for Investigators. 
Section 8.7.1 
Time Period and 
Removed a redundant sentence and 
clarified that all SAEs are to be collected 
Clarification for Investigators. 


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Section # and Name 
Description of Change 
Brief Rationale 
Frequency for Collecting 
AE and SAE Information. 
from the signing of the informed consent 
form. 
Section 10.10 
Appendix 10 
Home Healthcare 
Removed ‘Week 14’ from ‘Double-blind 
Responders’ and ‘Week 26’ from ‘Open 
Label Responders’ as visits where home 
health care may be permitted. 
Added ‘first SC dosing’ to the first bullet 
under ‘exceptions to the option for home 
healthcare include:’. 
Response to a request from a 
Health Authority, following 
review of Protocol 
Amendment 3. 
Section 10.12  
Appendix 12 
Abbreviations and 
Trademarks 
Removed duplicate listing of 
abbreviations: ‘ETP’ and ‘ECG’ 
Correction of errors. 
 


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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): ....................................................................... 15 
2. 
INTRODUCTION .................................................................................................... 21 
2.1. 
Study Rationale .......................................................................................... 21 
2.2. 
Background ................................................................................................ 21 
2.3. 
Benefit/Risk Assessment ............................................................................ 22 
2.3.1. 
Risk Assessment ......................................................................... 23 
2.3.2. 
Benefit Assessment ..................................................................... 31 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 31 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS .................................................... 31 
4. 
STUDY DESIGN .................................................................................................... 38 
4.1. 
Overall Design ............................................................................................ 38 
4.1.1. 
Double-Blind Treatment ............................................................... 39 
4.1.2. 
Open Label Treatment for Non-Responders ................................ 40 
4.1.3. 
Type and number of participants .................................................. 41 
4.2. 
Scientific Rationale for Study Design .......................................................... 42 
4.3. 
Justification for Dose .................................................................................. 43 
4.3.1. 
Double-Blind Induction Phase ...................................................... 43 
4.3.2. 
Double-Blind Extended Treatment Phase (ETP) .......................... 44 
4.3.3. 
Open Label Treatment ................................................................. 44 
4.4. 
End of Study Definition ............................................................................... 44 
5. 
STUDY POPULATION ........................................................................................... 45 
5.1. 
Inclusion Criteria ......................................................................................... 45 
5.2. 
Exclusion Criteria ........................................................................................ 46 
5.3. 
Lifestyle Considerations .............................................................................. 49 
5.3.1. 
Tobacco and Caffeine .................................................................. 49 
5.4. 
Screen Failures........................................................................................... 49 
6. 
STUDY INTERVENTION ........................................................................................ 50 
6.1. 
Study Intervention(s) Administered ............................................................. 50 
6.2. 
Intervention Administration ......................................................................... 51 
6.3. 
Preparation/Handling/Storage/Accountability .............................................. 52 
6.4. 
Measures to Minimize Bias: Randomization and Blinding ........................... 52 
6.4.1. 
Method of Treatment Assignment ................................................ 52 
6.4.2. 
Blinding ........................................................................................ 54 
6.5. 
Study Intervention Compliance ................................................................... 54 
6.6. 
Concomitant Therapy.................................................................................. 55 
6.6.1. 
Permitted Concomitant Medications ............................................. 55 
6.6.1.1. 
Corticosteroids ........................................................... 55 
6.6.1.2. 
Other therapies ........................................................... 56 
6.6.2. 
Prohibited Concomitant Medications ............................................ 56 


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6.6.3. 
Rescue Therapy .......................................................................... 57 
6.6.4. 
Potential for drug-drug interactions .............................................. 58 
6.7. 
Dose Modification ....................................................................................... 58 
6.8. 
Intervention after the End of the Study ........................................................ 58 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 58 
7.1. 
Discontinuation of Study Intervention .......................................................... 58 
7.1.1. 
Individual Safety Stopping Criteria ............................................... 59 
7.1.2. 
Haematologic Temporary Withholding and Stopping 
Criteria ......................................................................................... 59 
7.1.2.1. 
Temporary withholding ............................................... 59 
7.1.2.2. 
Permanent discontinuation ......................................... 60 
7.1.3. 
Liver Chemistry Stopping Criteria ................................................ 60 
7.1.4. 
QTc Stopping Criteria .................................................................. 61 
7.1.5. 
Group and Study Safety Stopping Criteria ................................... 61 
7.1.6. 
Temporary withholding of IP ........................................................ 61 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 62 
7.3. 
Lost to Follow-Up ........................................................................................ 62 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 63 
8.1. 
Baseline Assessments ................................................................................ 63 
8.2. 
Efficacy Assessments ................................................................................. 64 
8.2.1. 
Clinical Disease Assessments ..................................................... 64 
8.2.1.1. 
Mayo Score ................................................................ 64 
8.2.1.2. 
Ulcerative Colitis Endoscopic Index of Severity .......... 65 
8.2.2. 
Histological Disease Assessments............................................... 65 
8.2.3. 
Extraintestinal Manifestations ...................................................... 65 
8.2.4. 
Patient Reported Outcomes ......................................................... 65 
8.2.4.1. 
Participant Bowel Symptom Diary ............................... 66 
8.2.4.2. 
Patient Reported Outcomes (PRO) for Health 
Outcomes Assessment ............................................... 66 
8.2.4.2.1. 
Inflammatory Bowel Disease 
Questionnaire (IBDQ) ............................. 66 
8.2.4.2.2. 
Short Form-36, version 2 (SF-36) ........... 67 
8.2.4.2.3. 
Patients Global Impression of 
Change (PGIC) and Severity 
(PGIS) .................................................... 67 
8.2.4.2.4. 
FACIT Fatigue ........................................ 67 
8.2.5. 
Exit Interviews ............................................................................. 68 
8.3. 
Pharmacokinetics ....................................................................................... 68 
8.3.1. 
Soluble LAG3 (sLAG3) ................................................................ 69 
8.4. 
Pharmacodynamics .................................................................................... 69 
8.4.1. 
Biomarkers .................................................................................. 69 
8.4.1.1. 
Exploratory biomarkers in Blood ................................. 70 
8.4.1.2. 
Biomarkers in faeces .................................................. 70 
8.4.1.3. 
Tissue Biopsy ............................................................. 70 
8.5. 
Pharmacogenetics ...................................................................................... 70 
8.6. 
Safety Assessments ................................................................................... 71 
8.6.1. 
Physical Examinations ................................................................. 71 
8.6.2. 
Vital Signs .................................................................................... 71 
8.6.3. 
Electrocardiograms ...................................................................... 71 


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8.6.4. 
Clinical Safety Laboratory Assessments ...................................... 72 
8.6.5. 
Immunogenicity Assessments ...................................................... 72 
8.6.6. 
Infusion-related Reactions, Hypersensitivity Reactions and 
Cytokine Release Syndrome. ....................................................... 73 
8.6.7. 
Immunosuppression and Infections.............................................. 73 
8.6.8. 
Autoimmunity ............................................................................... 73 
8.7. 
Adverse Events and Serious Adverse Events ............................................. 74 
8.7.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 74 
8.7.2. 
Method of Detecting AEs and SAEs ............................................. 74 
8.7.3. 
Follow-up of AEs and SAEs ......................................................... 74 
8.7.4. 
Regulatory Reporting Requirements for SAEs ............................. 75 
8.7.5. 
Pregnancy ................................................................................... 75 
8.7.6. 
Cardiovascular and Death Events ................................................ 75 
8.8. 
Treatment of Overdose ............................................................................... 76 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 76 
9.1. 
Statistical Hypotheses................................................................................. 76 
9.2. 
Sample Size Determination ........................................................................ 77 
9.2.1. 
Sample Size Assumptions ........................................................... 77 
9.2.2. 
Sample Size Re-estimation .......................................................... 79 
9.3. 
Populations for Analyses ............................................................................ 79 
9.4. 
Statistical Analyses ..................................................................................... 80 
9.4.1. 
Efficacy Analyses ......................................................................... 80 
9.4.2. 
Safety Analyses ........................................................................... 82 
9.4.3. 
Pharmacokinetic (PK) and 
Pharmacokinetic/Pharmacodynamic (PK/PD) analyses ............... 82 
9.4.4. 
Other Analyses ............................................................................ 82 
9.5. 
Interim Analyses ......................................................................................... 82 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 85 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 85 
10.1.1. 
Regulatory and Ethical Considerations ........................................ 85 
10.1.2. 
Financial Disclosure ..................................................................... 85 
10.1.3. 
Informed Consent Process .......................................................... 86 
10.1.4. 
Data Protection ............................................................................ 86 
10.1.5. 
Committees Structure .................................................................. 87 
10.1.6. 
Dissemination of Clinical Study Data ........................................... 87 
10.1.7. 
Data Quality Assurance ............................................................... 88 
10.1.8. 
Source Documents ...................................................................... 88 
10.1.9. 
Study and Site Closure ................................................................ 89 
10.1.10. Publication Policy ......................................................................... 89 
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................... 90 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 92 
10.3.1. 
Definition of AE ............................................................................ 92 
10.3.2. 
Definition of SAE .......................................................................... 93 
10.3.3. 
Definition of Cardiovascular Events ............................................. 94 
10.3.4. 
Recording and Follow-Up of AE and SAE .................................... 95 
10.3.5. 
Reporting of SAE to GSK ............................................................. 96 


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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................. 98 
10.4.1. 
Definitions: ................................................................................... 98 
10.4.2. 
Contraception Guidance .............................................................. 99 
10.4.3. 
Collection of Pregnancy Information: ......................................... 100 
10.5. 
Appendix 5: Genetics ................................................................................ 101 
10.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments Guidelines ........................................................................... 102 
10.7. 
Appendix 7: Mayo Clinic Score Definitions ................................................ 105 
10.8. 
Appendix 8: Country-specific requirements ............................................... 107 
10.8.1. 
The Netherlands ........................................................................ 107 
10.9. 
Appendix 9: COVID-19 ............................................................................. 108 
10.9.1. 
Overall Rationale for this Appendix ............................................ 108 
10.9.2. 
Study Procedures During COVID-19 Pandemic ......................... 108 
10.9.3. 
Protocol Defined Procedures/Visits: ........................................... 108 
10.9.4. 
Study Intervention(s) .................................................................. 109 
10.9.5. 
Data Management/Monitoring: ................................................... 109 
10.10. Appendix 10: Home Healthcare ................................................................ 110 
10.10.1. Home nursing ............................................................................ 111 
10.10.2. Telemedicine ............................................................................. 111 
10.11. Appendix 11: References .......................................................................... 112 
10.12. Appendix 12: Abbreviations and Trademarks ............................................ 114 
10.13. Appendix 13: Protocol Amendment History ............................................... 117 
10.13.1. Amendment 1: 17-JAN-2019...................................................... 117 
10.13.2. Amendment 2: 10-SEP-2019 ..................................................... 118 
10.13.3. Amendment 3: 03-SEP-2020 ..................................................... 125 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A multicentre randomized, double-blind, placebo-controlled Phase 2 study 
to evaluate the safety, tolerability, efficacy, dose-response, pharmacokinetics and 
pharmacodynamics of repeat dosing of an anti-LAG3 cell depleting monoclonal antibody 
(GSK2831781) in patients with active ulcerative colitis. 
Short Title: Safety, tolerability, efficacy and dose-response of GSK2831781 in ulcerative 
colitis. 
Rationale: 
T cells are integral to the pathogenesis of ulcerative colitis (UC), and clinical experience 
with anti-integrin monoclonal antibodies has established the principle of T cell-targeted 
therapies in the disease. Lymphocyte Activation Gene-3 (LAG3) is expressed on recently 
activated T cells, and LAG3+ T cells are present in only low numbers in the circulation and 
healthy tissues. They are, however, increased in the colon in active UC, where their 
numbers correlate with disease activity [Slevin, 2018]. GSK2831781 causes targeted 
depletion of LAG3+ T cells and has shown preliminary evidence of clinical efficacy in 
plaque psoriasis (another T cell-mediated disease). It is therefore hypothesized that 
GSK2831781 will selectively deplete activated mucosal T cells in UC, but with relative 
sparing of resting T cells. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
• To evaluate the safety and 
tolerability of repeat doses of 
GSK2831781 during the Double-
Blind Induction Phase. 
 
 
 
 
 
 
 
 
• To characterise the efficacy dose-
response of GSK2831781 during 
the Double-Blind Induction Phase. 
• Incidence of adverse events and serious 
adverse events during the Double-Blind 
Induction Phase. 
• Incidence of findings of potential clinical 
importance1 during the Double-Blind 
Induction Phase for: 
o Vital signs 
o Clinical laboratory values 
(haematology, clinical chemistry 
and urinalysis).  
o QTc. 
 
• Change from baseline in Complete 4-
domain Mayo score2 at Week 10. 


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Objectives 
Endpoints 
Secondary 
• To evaluate the safety and 
tolerability of repeat doses of 
GSK2831781 during the Double-
Blind Extended Treatment Phase. 
 
• Incidence of adverse events and serious 
adverse events in the Double-Blind 
Extended Treatment Phase. 
• Incidence of findings of potential clinical 
importance during the Double-Blind 
Extended Treatment Phase for: 
o Vital signs 
o Clinical laboratory values 
(haematology, clinical 
chemistry and urinalysis).  
o QTc. 
• To investigate the effect of repeat 
doses of GSK2831781 on clinical 
efficacy including endoscopic 
mucosal healing during the 
Double-Blind Induction Phase. 
 
• Adapted Mayo endoscopic score of 0 or 1 
at Week 10. 
• Adapted Mayo clinical remission3 at 
Week 10. 
• Adapted Mayo clinical response3 at 
Week 10. 
• Symptomatic remission4 over time. 
• Change from baseline in Partial Mayo 
score over time. 
• Change from baseline in Adapted Mayo 
endoscopic score and Ulcerative Colitis 
Endoscopic Index of Severity (UCEIS) at 
Week 10. 
• To investigate the effect of repeat 
doses of GSK2831781 on UC 
histologic disease activity during 
the Double-Blind Induction Phase. 
• Histological severity as determined by the 
Robarts Histopathology Index at Week 10. 
• Histological severity as determined by the 
Nancy Histological Index at Week 10. 
• Histological severity as determined by the 
Geboes Histological Index at Week 10. 
• To investigate the effect of repeat 
doses of GSK2831781 on 
biomarkers of UC disease activity 
during the Double-Blind Induction 
Phase. 
• Change from baseline in serum C-reactive 
protein over time. 
• Change from baseline in faecal calprotectin 
over time. 
• To investigate the 
pharmacokinetics of GSK2831781 
following subcutaneous dosing. 
• GSK2831781 PK parameters: AUC(0-tau), 
Cmax, tmax. 


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Objectives 
Endpoints 
• To investigate the immunogenicity 
of repeat doses of GSK2831781 
during the Double-Blind Induction 
Phase. 
• Incidence of anti-drug antibodies at each 
visit. 
Safety 
• To evaluate the safety and 
tolerability of repeat doses of 
GSK2831781 in all trial phases. 
• Adverse events, vital signs, clinical 
laboratory values (haematology, clinical 
chemistry, and urinalysis), 12-lead ECG. 
• To investigate the immunogenicity 
of repeat doses of GSK2831781 in 
all trial phases. 
• Incidence of anti-drug antibodies at each 
visit. 
Footnotes: 
1 
Potential clinical importance is defined in the RAP for each relevant safety endpoint. 
2 
The Complete 4-domain Mayo score is used for the primary endpoint due to its wider dynamic 
range for assessment of dose-response compared to the Adapted Mayo score used for secondary 
and exploratory endpoints. 
3 
Clinical response and remission for the various iterations of the Mayo score are defined in 
Appendix 7, Section 10.7. 
4 
Symptomatic remission is defined as a rectal bleeding subscore of 0, and a stool frequency subscore 
of ≤1, with no worsening from baseline. 
 
Overall Design: 
This is a Phase 2, multicentre, randomized, double-blind, parallel group, placebo-
controlled study to investigate safety, tolerability, efficacy and dose-response of 
GSK2831781 in participants with moderate to severe active UC as defined by a 4-domain 
(Complete) Mayo score of 6-12. The study will consist of five arms: GSK2831781 at 
450 mg, 300 mg, 150 mg and 45 mg and a placebo group and will investigate the Induction 
(up to Week 10), and maintenance with an Extended Treatment Phase (Weeks 10-30), of 
the achievement and maintenance of clinical response, remission and mucosal healing. 
In addition, Non-Responders identified following the Week 10 assessment will be moved 
to open label treatment consisting of Induction (Weeks 12 to 22), an Extended Treatment 
Phase (Weeks 22 to 52), and a Follow-Up to Week 54. 
Disclosure Statement: This is a parallel group treatment study with five arms that is 
participant, Investigator and sponsor blinded.  
Number of Participants: 
Approximately 242 participants will be randomly assigned to study intervention under the 
assumption that a proportion will not receive all planned doses up to Week 10 and/or have 
an incomplete Week 10 Complete 4-domain Mayo score assessment. If the attrition rate is 
higher than planned for (e.g., 15% or more) then additional participants, up to a maximum 
of 320, may be recruited. 


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Intervention Groups and Duration: 
Total duration for participants who respond to GSK2831781 will be approximately 47 
weeks (see Section 1.2). The study consists of a 5-week screening window, 10-week 
Induction Phase (IP), 20-week Extended Treatment Phase (ETP), and a 12-week Follow-
Up Phase. Non-Responders allocated to Open Label Treatment (GSK2831781 450 mg) 
who subsequently respond to treatment may spend up to 59 weeks in total on study. 
Intervention groups are shown in the schema below, Section 1.2. 
Data Review Committee (DRC):  
A DRC will be utilised in this study to review the interim analyses data in an unblinded 
manner. The DRC will be comprised of a predefined subset of project team members, 
senior GSK stakeholders and experts external to the project team to ensure that persons 
with the appropriate expertise and knowledge conduct and interpret interim reviews of 
data. No study personnel with direct contact with sites or site staff will be involved in the 
DRC (see Appendix 1, Section 10.1.5). 
 
1.2. 
Schema 
 
 
*Randomisation will initially be 2:1 to GSK2831781 450 mg or Placebo. When an 
appropriate number of participants have been randomised in these two arms for the interim 
analysis (Interim Analysis 3, see Section 9.5), randomisation to all dose regimens 
(GSK2831781 450 mg, 300 mg 150 mg, 45 mg or placebo) will be opened at a ratio of 
2:3:3:3:2.. Dosing during the Double-Blind Induction Phase will be undertaken at Weeks 
0 (Day 1), 2, 6 and 10. Responders at Week 10 (where Responder status is determined by 
a pre-specified algorithm in the eCRF) will continue into the Double-Blind ETP. 


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Participants originally randomised to GSK2831781 IV treatment arms (Induction) will 
receive subcutaneous doses of 300 mg GSK2831781 every 4 weeks at Weeks 14, 18, 22, 
and 26. Participants originally on placebo treatment arm, who attained response, will 
continue to receive blinded placebo through SC dosing at Weeks 14, 18, 22 and 26. The 
Double-Blind ETP ends at Week 30, with Follow-Up until Week 42 (16 weeks after the 
last dose). 
†The open label patient journey is described fully in Section 4.1.2 and Figure 3. The Open 
Label ETP, for Non-Responders at Week 10, will constitute a full 10 weeks of induction 
dosing according to the same dosing schedule as GSK2831781 450 mg (IV doses at 
Weeks 12, 14, 18 and 22). The Open Label Induction Phase (OLIP) will start at Week 12 
to allow turnaround of centrally determined responder status. Response following OLIP 
will be assessed at Week 22 in the Open Label ETP, and Responders will continue with 
doses of 300 mg GSK2831781 subcutaneously every 4 weeks from Week 26 to 38. 
Participants will then undertake a Follow-Up period of 12 weeks from Week 42 to Week 
54. Participants in the Open Label ETP who are Non-Responders at Week 22 will 
discontinue study treatment and be managed according to physician standard of care but 
are still required to attend a Follow-Up visit approximately 16 weeks from the last dose 
event. 
 


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1.3. 
Schedule of Activities (SoA): 
Double-Blind Treatment SoA 
Screening 
Induction Phase 
Extended Treatment Phase 
Follow-Up20 
Early 
Withdrawal 
Visit21, 26 
WEEK  
 
Pre- 
dose 
Post-
dose 
2 
426 
6 
10 
1219 
14 
1826 
2226 
2626 
30 
4226 
DAY 
-35 to -
723 
-14 to -
714 
Day 1 
15 
29 
43 
71 
85 
99 
127 
155 
183 
211 
295 
 
Window (days) 
 
 
 
±2 
±3 
±3 
±3 
±5 
±3 
±3 
±3 
±3 
±3 
±7 
 
Study Population 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
X 
X 
History1 (Medical/Disease/ 
IBD Therapy) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Extra-Intestinal 
Manifestations History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking status 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Efficacy 
Determination of 'Normal' 
stool count for Mayo Score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endoscopy with Biopsy2 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X22 
Mayo (Complete or Partial) 
P 
C 
P 
 
P 
P 
P 
C 
 
P 
 
P 
 
C 
P 
C22/P 
Steroid Taper 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Extra-Intestinal 
Manifestations Activity 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Safety Assessments 
Vital Signs 
X 
 
X 
X16 
X16 
X 
X 
X 
 
X16 
X16 
X 
X 
X 
X 
X 
12-lead ECG3 
X 
 
X 
X16 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
Full/Brief Physical 
F 
 
B 
 
B 
B 
B 
B 
 
B 
B 
B 
B 
B 
F 
F 
Concomitant Medications 
X 
 
<-----------------------------------------------------------------------------------------------------------------------> 
AEs / SAEs4 
<---------------------------------------------------------------------------------------------------------------------------------------------------> 
Haematology5 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry (incl. CRP)5 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test (WOCBP)5, 6 
X 
 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 


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Screening 
Induction Phase 
Extended Treatment Phase 
Follow-Up20 
Early 
Withdrawal 
Visit21, 26 
WEEK  
 
Pre- 
dose 
Post-
dose 
2 
426 
6 
10 
1219 
14 
1826 
2226 
2626 
30 
4226 
DAY 
-35 to -
723 
-14 to -
714 
Day 1 
15 
29 
43 
71 
85 
99 
127 
155 
183 
211 
295 
 
Window (days) 
 
 
 
±2 
±3 
±3 
±3 
±5 
±3 
±3 
±3 
±3 
±3 
±7 
 
Urinalysis5 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
TB – QuantiFERON ± PPD7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (HIV, HBV, HCV, 
CMV, EBV and VZV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clostridium difficile toxin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH & oestradiol (if 
appropriate)8  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing and PK/PD 
Randomization 
 
 
X27 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administration9 
 
 
IV 
 
IV 
 
IV 
IV 
 
SC 
SC 
SC 
SC 
 
 
 
PK10, 11 
 
 
X 
X17 
X 
 
X18 
X 
 
X 
X 
X 
X 
X 
X 
X 
sLAG310, 11 
 
 
X 
X17  
X 
 
X18 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood proteomic signature5 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Blood transcriptomic 
signature5 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
LAG3 Cell Depletion (by Flow 
Cytometry)5,12 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
X 
X28 
X28 
Immunogenicity  
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
4β-hydroxycholesterol 
(4βHC)5 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Faecal Calprotectin24 
 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
X 
X 
X 
Serum Tryptase5 
 
 
X 
 
 
 
X 
X 
 
 
 
X 
 
X 
X 
X 
Patient Reported Outcomes 
IBDQ, FACIT-Fatigue and SF-
3613 
 
 
X 
 
 
 
X 
X 
 
 
 
X 
 
X 
X 
X 
Bowel symptom eDiary 
<---------------------------------------------------------------------------------------------------------------------------------------------------------> 
PGIC & PGIS13  
 
 
X15 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Exit Interview 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X25 
X25 
Other 
PGx Sample 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Footnotes: 
1 
See SRM for requirements for data collection. 
2 
Endoscopy should be flexible sigmoidoscopy. However, colonoscopy can be performed at screening if required for assessment of dysplasia risk (see Section 
5.1), and at any timepoint if clinically indicated. 
3 
ECG in triplicate at screening and single at all other time points. See Section 8.6.3, Electrocardiograms for further detail. 
4 
Collection of SAEs starts from screening whilst collection of AEs will commence from Day 1. 
5 
Unless specified otherwise, all samples will be taken prior to administration of study treatment. 
6 
Negative test required during screening and immediately prior to the first dose of study treatment. A serum pregnancy test is required at screening, after 
which a highly sensitive urine pregnancy test is adequate. If a urine test cannot be confirmed as negative, a serum pregnancy test is required. 
7 
A PPD test maybe performed following two indeterminate Quantiferon tests to determine TB status, see Section 5.2. 
8 
To confirm postmenopausal status, serum FSH and oestradiol testing will be performed for all postmenopausal females at the screening visit. 
9 
See Section 6.2 for details of dosing duration and monitoring period. 
10 
Unless stated, samples taken on a day of dosing must be pre-dose sample (up to 2 hr before the next dose). 
11 
Additional sampling will be required in a subset of participants to characterise SC pharmacokinetics. See Section 8.3, for schedule. 
12 
LAG3 depletion will only be undertaken in sites where shipping to central lab can be achieved in the required timeframe, see Section 8.4, and SRM. 
13 
IBDQ, FACIT-Fatigue, SF-36, PGIC and PGIS are to be performed before any other assessments on visit days. 
14 
A 7-day window enables turnaround of centrally read endoscopy score for inclusion to arrange Day 1 visit; however, endoscopy can be performed up to Day -
3 if all other criteria for study eligibility have been met by this time and Robarts have agreed rapid turnaround of central endoscopy read. 
15 
PGIC not to be done on Day 1. 
16 
Vital signs to be taken every 30 minutes (±5 minutes) until completion of post dose monitoring period. A single ECG be taken within 4 hours of completion 
of dose administration. For participants who have discontinued treatment but remain on study, post-dose monitoring does not apply. 
17 
Samples to be taken immediately after end of IV infusion (preferably within 15 minutes). 
18 
Samples to be taken up to 2 hr before the next dose, and one sample immediately after end of IV infusion (within 15 minutes). 
19 
Week 12 visit scheduled to enable recall of Non-Responders to move to Open Label dosing at Week 12, see Open Label Treatment SoA below. Telephone 
call can be used to ensure Responders initiate steroid taper and cancel scheduled visit for Responders next due to undertake dosing at Week 14. 
20 
In case of Early treatment discontinuation, or study withdrawal, the investigator should undertake a Follow-Up visit approximately 16 weeks after the last 
dose event to allow safety monitoring following drug washout. 
21 
Participants who discontinue study treatment are encouraged to complete remaining scheduled visits for the treatment phase they are in.  However, an Early 
withdrawal visit is only required for participants who prematurely discontinue study treatment and do not agree to complete the remaining scheduled visits 
for that phase. 
22 
Complete 4-domain Mayo Score (including Endoscopy) to be performed if withdrawal from study treatment occurs after Week 4 but prior to Week 10 (all 
participants) or between Week 18 and Week 30 for Responders. The endoscopy is to be performed either at the Early Withdrawal Visit (for participants who 
do not wish to complete remaining scheduled visits), or at Week 10 or Week 30 (for participants that agree to complete remaining scheduled visits after 
withdrawing from treatment). 
23 
The window for Screening Visit 1 can be extended to Day -45 where indeterminate test results are returned for assays requiring long central laboratory 
turnaround times (e.g., QuantiFERON and C. difficile). However, if haematology, clinical chemistry and (if applicable) serum pregnancy tests have been 


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performed outside of the Day -35 window they must be repeated and recorded as an unscheduled visit in the eCRF to confirm eligibility, even if performed 
at Screening Visit 2. 
24 
Faecal Calprotectin sample may be taken up to 48 hours prior to scheduled visit. 
25 
Exit interview, if applicable, to be undertaken either at Early Withdrawal or Follow-Up. 
26 
Home health care / telemedicine visits may be permitted where applicable country and local regulations and infrastructure allow. 
27 
Randomisation may be performed on Day -1. Randomisation may only proceed when all information pertaining to patient eligibility has been confirmed, 
including eCRF Mayo score eligibility calculation. 
28 
Samples only to be taken for participants that achieved a responder status at Week 10 and subsequently withdraw from treatment. 
 
• Safety, pharmacokinetic, pharmacodynamic/biomarker or other assessments may be altered during the study based on newly 
available data (e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring. 
• Any changes in the timing or addition of time points for any planned study assessments as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study must be documented and approved by the relevant study team member and 
then archived in the sponsor and site study files, but will not constitute a protocol amendment. The Competent Authority (CA) and 
ethics committee (EC) will be informed of any safety issues that constitute a substantial amendment and require alteration of the 
safety monitoring scheme or amendment of the informed consent form (ICF). The changes will be approved by the CA and the EC 
before implementation. 
• For details on home healthcare and telemedicine approaches, please refer to Appendix 10. 
 
 


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Open Label Treatment SoA 
Open Label Induction Phase 
Open Label Extended Treatment Phase 
Open Label 
Follow up7 
Open Label 
Early 
Withdrawal 
Visit8, 12 
WEEK  
12 
14 
18 
22 
24 
26 
3012 
3412 
3812 
4212 
5412 
DAY 
85 
99 
127 
155 
169 
183 
211 
239 
267 
295 
379 
 
Window (days) 
±5 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
  
Endoscopy with Biopsy 
 
 
 
X 
 
 
 
 
 
 
 
X 
Mayo (Complete or Partial) 
P 
P 
P 
C 
 
 
P 
 
P 
P 
P 
C13/P 
Extra-Intestinal 
Manifestations Activity  
 
 
 
X 
 
 
 
 
 
X 
X 
X13 
Steroid Taper 
 
 
 
 
X 
 
 
 
 
 
 
 
Weight 
 
 
 
X 
 
 
 
 
 
X 
 
 
Safety Assessments 
Vital Signs 
X5 
X5 
X 
X 
 
X5 
X5 
X 
X 
X 
X 
X 
12-lead ECG 
X9 
 
 
X 
 
 
 
 
 
 
X 
X 
Full/Brief Physical 
B 
B 
B 
B 
 
B 
B 
B 
B 
B 
F 
F 
Concomitant Medications 
<----------------------------------------------------------------------------------------------------------------------------------------------------> 
AEs / SAEs 
<----------------------------------------------------------------------------------------------------------------------------------------------------> 
Haematology1 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry (incl. 
CRP)1 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test (WOCBP)1, 2 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Urinalysis1 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Dosing and PK/PD 
IMP administration3 
IV 
IV 
IV 
IV 
 
SC 
SC 
SC 
SC 
 
 
 
PK1 
X6 
 
 
X6 
 
 
 
 
 
X 
X 
X 
sLAG31  
X6 
 
 
X6 
 
 
 
 
 
X 
X 
X 
Immunogenicity1 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Faecal Calprotectin10 
X 
 
X 
X 
 
 
 
 
X 
X 
X 
X 
Patient Reported Outcomes 
IBDQ, FACIT-Fatigue and 
SF-364 
 
 
X 
X 
 
 
 
 
X 
X 
X 
X 
Bowel symptom eDiary 
<------------------------------------------------------------------------------------------------------------------------------------> 
PGIC & PGIS4  
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Exit Interview 
 
 
 
 
 
 
 
 
 
 
X11 
X11 


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Footnotes: 
1 
Unless specified otherwise, all samples will be taken prior to administration of study treatment. 
2 
A highly sensitive urine pregnancy test is adequate. If a urine test cannot be confirmed as negative, a serum pregnancy test is required. 
3 
See Section 6.2, for details of dosing durations and monitoring periods. 
4 
IBDQ, FACIT-Fatigue, SF-36, PGIC and PGIS are to be performed before any other assessments on visit days. 
5 
Vital signs to be taken every 30 minutes (±5 minutes) until completion of post dose monitoring period. For participants who have discontinued treatment but 
remain on study, post-dose monitoring does not apply. 
6 
Additional PK sample immediately after end of IV infusion (preferably within 15 minutes of end of IV infusion). 
7 
In case of Early treatment discontinuation, or study withdrawal, the investigator should undertake a Follow-Up visit approximately16 weeks after the last dose 
event to allow safety monitoring following drug washout. 
8 
Participants who discontinue study treatment are encouraged to complete remaining scheduled visits for the treatment phase they are in.  However, an Early 
withdrawal visit is only required for participants who prematurely discontinue study treatment and do not agree to complete the remaining scheduled visits for 
that phase. 
9 
A single ECG to be taken any time within post-dose monitoring period 
10 Faecal Calprotectin sample may be taken up to 48 hours prior to scheduled visit. 
11 Exit interview, if applicable, to be undertaken either at Early Withdrawal or Follow-Up. 
12 Home health care / telemedicine visits may be permitted where applicable country and local regulations and infrastructure allow. 
13 Complete 4-domain Mayo Score (including Endoscopy) to be performed if withdrawal from study treatment occurs after Week 16 but prior to Week 22 (all 
participants). The endoscopy is to be performed either at the Early Withdrawal Visit (for participants who do not wish to complete remaining scheduled visits), 
or at Week 22 (for participants that agree to complete remaining scheduled visits after withdrawing from treatment).  
 
 
• Safety, pharmacokinetic, pharmacodynamic/biomarker and/or other assessments may be altered during the study based on newly 
available data (e.g. to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring.  
• Any changes in the timing or addition of time points for any planned study assessments as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study must be documented and approved by the relevant study team member and 
then archived in the sponsor and site study files, but will not constitute a protocol amendment. The Competent Authority (CA) and 
ethics committee (EC) will be informed of any safety issues that constitute a substantial amendment and require alteration of the 
safety monitoring scheme or amendment of the informed consent form (ICF). The changes will be approved by the CA and the EC 
before implementation.  
• For details on home healthcare and telemedicine approaches, please refer to Appendix 10. 
 


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2. 
INTRODUCTION 
2.1. 
Study Rationale 
Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD) characterized by 
chronic relapsing and remitting inflammation of the colon and rectum. There remains a 
high unmet need for novel treatments that achieve a higher rate of efficacy in resolving 
disease symptoms, and inducing and maintaining mucosal healing to achieve long-term 
corticosteroid-free remission. 
This study is the first experience in patients with active moderate to severe UC with 
GSK2831781, a humanised Antibody-Dependent Cell Cytotoxicity (ADCC)-enhanced 
monoclonal antibody that is specific to the Lymphocyte Activation Gene-3 (LAG3) 
protein. LAG3 is not expressed by resting T cells, but is upregulated after T cell activation 
[Workman, 2002]. Furthermore, as only 0.5 to 5% of T cells in blood and secondary 
lymphoid organs express LAG3, GSK2831781 should spare LAG3- resting memory and 
naïve T cells, as well as the majority of natural regulatory T cells that are responsible for 
normal immune homeostasis. Therefore, the key attribute of LAG3 is its relatively 
selective expression profile for activated T cells. 
T cells are integral to the pathogenesis of UC, and clinical experience with anti-integrin 
monoclonal antibodies such as Vedolizumab establishes the principle of T cell modulation 
in treatment. LAG3+ cell numbers are increased in the colon in active UC, correlate with 
disease activity, and reduce after successful treatment with established biologic therapies 
but not in non-responders [Slevin, 2018]. By rapid and potent depletion of LAG3+ T cells 
in diseased tissues, there is the potential to achieve fast and long-term disease remission. 
Given the highly selective nature of depletion, there may be improved safety and 
tolerability compared to current standard of care, and by targeting both intestinal and extra-
intestinal activated T cells, GSK2831781 may have additional positive impacts on extra-
intestinal manifestations of disease, such as arthropathy. 
The primary objectives of this Phase 2 study are to assess the safety and tolerability of 
repeat doses of GSK2831781, and characterise the dose-response of GSK2831781 in 
change from baseline in Mayo score at Week 10. Key secondary endpoints include 
endoscopic mucosal healing and Mayo remission at Week 10, following which there will 
be an Extended Treatment Phase until Week 30 to gain insights into maintenance of 
remission. 
2.2. 
Background 
Ulcerative colitis is a chronic, relapsing-remitting inflammatory disorder with a prevalence 
estimated to be 70-500 cases per 100,000 [Ng, 2018]. Symptoms vary depending on the 
severity of inflammation and extent of disease, but patients typically experience recurrent 
episodes of rectal bleeding and diarrhoea, often associated with crampy abdominal pain 
and tenesmus. Severe or refractory colitis can necessitate surgical colectomy, and patients 
with longstanding UC are at increased risk of colorectal cancer. There are currently no 
medical therapies that are curative, and surgery is associated with significant morbidity 
(including recurrent pouchitis in up to 25% of patients, faecal incontinence, and female 


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infertility). With existing pharmacological treatments, many patients either fail to respond 
or respond incompletely (i.e. have residual symptoms or ongoing mucosal inflammation), 
lose response over time, or experience treatment-limiting side-effects. Only a minority 
attain and maintain steroid-free remission in the long-term, and consequently other 
treatments are required to fulfil these unmet needs. 
Clinical experience with GSK2831781 to date comes from a single IV ascending dose 
study (NCT02195349, GSK Study 200630) in healthy volunteers (up to 0.15 mg/kg) and 
patients with mild to moderate plaque psoriasis (0.5-5 mg/kg). No safety or tolerability 
concerns were identified. Proof of mechanism was achieved, with dose-dependent 
depletion of LAG3+ cells in blood and skin, positive effects on psoriatic skin disease 
activity markers such as CD3 and pro-inflammatory messenger ribonucleic acid (mRNA) 
transcripts, and preliminary evidence of clinical efficacy in ameliorating psoriasis plaques 
[see GSK2831781 Investigator Brochure (IB)].  
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks of 
GSK2831781 may be found in the Investigator’s Brochure. 
 


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2.3.1. 
Risk Assessment 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Refer to GSK2831781 IB for details  
Mitigation Strategy 
Investigational Product (IP) [GSK 2831781] 
Neutropaenia 
Non-clinical: 
In the 1-month GLP toxicology study, clinically 
significant decreases in neutrophil count, which were 
considered adverse, were observed in 2/12 monkeys 
which 
were 
administered 
100 
mg/kg/week 
subcutaneously (SC) or intravenously (IV). 
 
Including 
separate 
single 
and 
repeat 
dose 
pharmacology studies, decreases in neutrophil count of 
a similar magnitude occurred in 2/15 animals at 30 
mg/kg, but not in 7 animals administered at 3 mg/kg. 
 
In the 26-week GLP toxicology study a transient 
decrease in neutrophil counts was observed at 
≥30 mg/kg/week from Day 14 in females and Day 
21/29 in males. The neutrophil count increased to or 
close to pre-study levels by the end of treatment (except 
in 1 male, which had immune complex disease). These 
changes were not considered adverse. 
 
Clinical: 
No neutropaenia, or trends towards reduced neutrophil 
counts, were observed in the FTIH study (200630) in 
healthy volunteers or patients with plaque psoriasis, up 
Exclusion criteria for low neutrophil counts 
(<1.5x109/L) at baseline. 
Neutrophil count and adverse events (AE)/serious 
adverse events (SAEs) related to neutropaenia will 
be monitored. 
Haematological 
temporary 
withholding 
and 
stopping criteria.  
 
Investigators should manage participants as 
clinically indicated if neutropaenia is seen. 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Refer to GSK2831781 IB for details  
Mitigation Strategy 
to a maximum single dose of 5 mg/kg, or in the Phase 
1 study (207823), at single doses of 150 mg or 450 mg. 
Infection 
Non-clinical: 
No specific studies have been conducted in nonclinical 
species to investigate the effect of GSK2831781 on 
response to viral or bacterial infection. 
 
In the 26-week study, natural killer cells were lower 
(down to 0.3 or 0.1X pre-study) in 4 of the 8 monkeys 
dosed at 100 mg/kg/week from Day 29, although levels 
were at or near the normal range.  
 
A significant proportion of newly activated T cells 
express LAG3, and therefore T cell proliferation upon 
encounter with an infectious agent may be inhibited by 
GSK2831781 if exposure is at the same time. However, 
it has been demonstrated that in healthy volunteers only 
a small proportion of central memory T cells express 
LAG3, so there is low risk of eliminating central 
memory of anti-infectious immune response against 
future encounter. 
 
Clinical: 
No clinical concerns regarding infections were 
identified in the Phase 1 studies (200630 and 207823). 
Appropriate exclusion criteria for history of e.g. 
tuberculosis 
(screening 
for 
latent 
infection 
included) or other relevant chronic infectious 
disease (e.g. Hepatitis B and C, HIV). In addition, 
participants with a recent infection or evidence of 
significant active infection will be excluded from 
the study. 
 
Participants will not be allowed to receive live 
vaccines within the 4 weeks prior to Day 1 or 
during the study until the end of Follow-Up. 
Investigators are expected to follow local and/or 
national guidelines with respect to vaccinations, 
including against influenza and pneumococcus. If 
indicated, non-live vaccines may be administered 
while receiving GSK2831781 based on a treating 
physician assessment of the benefit:risk (e.g., risk 
of theoretical decreased responsiveness). 
 
Close monitoring of participants for infections will 
be continued up to the Follow-Up visit, and 
supportive therapy (including anti-infectives) 
provided as clinically indicated. 
Infusion 
reaction/hypersensitivity 
 
Non-clinical: 
No evidence to date. 
 
IV investigational medicinal product (IMP) will be 
administered by clinical staff at clinical sites with 
appropriate staff training and facilities for the 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Refer to GSK2831781 IB for details  
Mitigation Strategy 
Clinical: 
No infusion reactions or hypersensitivity were 
observed in the Phase 1 studies (200630 and 207823). 
emergency 
management 
of 
hypersensitivity, 
angioedema and anaphylaxis. Participants with be 
monitored as per the monitoring schedules outlined 
in Section 6.2. 
SC dosing may be undertaken, either at clinical 
sites, or where applicable country and local 
regulations 
and 
infrastructure 
allow, 
at 
participants’ homes. For home administration, this 
will only be conducted by clinical staff with 
advanced cardiovascular life support (ACLS) 
training. Participants will not be eligible for home 
drug administration if they have previously 
experienced an infusion or hypersensitivity 
reaction during IV dosing of study treatment, if the 
participant’s home is more than 30 minutes away 
from an emergency medical facility with capability 
to manage a severe hypersensitivity reaction, or in 
any other situation where the Investigator considers 
dosing at the clinical site to be in the participant’s 
best interests for safety. 
Individual safety stopping criteria and appropriate 
treatment for hypersensitivity reactions. 
Local 
injection 
site 
reaction 
Non-clinical: 
Mononuclear 
cell 
perivascular 
infiltration 
was 
observed at SC injection sites of monkeys given 
30 mg/kg/week in the 26-week study. Partial recovery 
Injection sites will be monitored visually following 
SC administrations as per the monitoring schedules 
outlined in Section 6.2, and any adverse reactions 
managed appropriately and monitored until 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Refer to GSK2831781 IB for details  
Mitigation Strategy 
in females and full recovery in males at 30 mg/kg/week 
was observed after 17 weeks off-dose. Not seen with 
IV administration. 
 
Clinical: 
No 
reactions 
were 
observed 
following 
IV 
administration in the FTIH study (200630). No 
reactions were observed following SC dosing in the 
Phase 1 study 207823. 
resolution. If a reaction is observed, Investigators 
and home nurses are advised to rotate sites in the 
affected individual to help mitigate further risk. 
Participants in whom no reaction is observed 
following the first two SC administrations will be 
advised to report any reactions that subsequently 
occur to the clinical Investigators, who will arrange 
management as appropriate and monitor until 
resolution. 
Immunogenicity  
Non-clinical: 
A single dose of 3 mg/kg GSK2831781 in a 
cynomolgus monkey PK study led to a significant anti-
drug antibody (ADA) response in all monkeys. 
 
In the 4-week and 26-week GLP toxicology studies 
ADAs were also seen in four monkeys at 30 mg/kg and 
in one at 100 mg/kg post dose. These findings were not 
associated with adverse effects. In one male neutrophil 
counts remained low for the duration of treatment. This 
animal also had a number of nonspecific changes 
including reduced body weight, increased heart rate, 
decreased serum albumin, increased serum protein, 
alkaline phosphatase, total bilirubin and cholesterol, 
proteinuria, increased reticulocytes and decreased 
platelet count. These changes, considered to be 
immune complex mediated, were transient and of 
minimal magnitude. In general, the relevance of such 
Safety and tolerability is being assessed in 
participants 
(including 
clinical 
chemistry, 
haematology, adverse events, hypersensitivity 
reactions).  
 
Immunogenicity and the impact, if any, on 
pharmacokinetic and safety parameters will be 
monitored. 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Refer to GSK2831781 IB for details  
Mitigation Strategy 
preclinical findings is not thought to predict ADA 
formation in man. 
 
Clinical: 
Pre-existing ADAs and post-dosing ADA have been 
identified in humans. No adverse reactions or 
alterations in PK associated with immunogenicity were 
observed 
in 
the 
FTIH 
study 
200630. 
No 
immunogenicity was observed in the Phase 1 study 
207823. 
Cytokine 
release 
syndrome (CRS) 
Non-clinical: 
Hyper-immune activation leading to activation of the 
innate immune system is only a theoretical safety 
concern, as there is no in vitro and in vivo evidence of 
cytokine release associated with LAG3+ and the T cell 
depletion mechanism.  
 
As GSK2831781 is expected to induce ADCC, this 
may lead to cytokine release due to cell lysis. However, 
a low proportion of T cells express LAG3, therefore the 
risk of this is expected to be lower than less targeted 
depleting monoclonal antibodies (mAbs). 
 
Clinical: 
No cytokine release syndrome was observed in the 
Phase 1 studies 200630 and 207823. In study 200630 
there were minor transient increases in serum TNF-α 
concentrations between 6-48 hours after dosing at all 
Appropriate monitoring for clinical symptoms 
associated with cytokine release such as fever, 
nausea, chills, hypotension, tachycardia, asthenia, 
headache, rash, tongue and throat swelling, and 
dyspnoea, during and for an appropriate period 
after dosing. Participants will be informed in the 
ICF to seek prompt medical advice should any of 
these symptoms occur, particularly within 72 hours 
of dosing. 
 
 
Staff 
administering 
and 
monitoring 
IMP 
administration will be trained in emergency care 
and resuscitation. All IV doses will be administered 
at clinical sites. SC administration may take place 
at clinical sites, or where applicable country and 
local regulations and infrastructure allow, at the 
participant’s home; for home administration, staff 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Refer to GSK2831781 IB for details  
Mitigation Strategy 
dose levels, but no dose-response relationship, and the 
magnitude of these rises was not clinically relevant. 
There were no meaningful changes to serum IL-6, IL-
8, IFN-γ or G-CSF. 
must be ACLS trained, with access to an 
emergency medical facility no more than 30 
minutes away. 
Autoimmune-like 
reactions 
A small percentage of regulatory T cells express 
LAG3. The clinical relevance of this minority subset of 
T cells in the pathogenesis of autoimmune reactions is 
unknown. 
 
In the 4-week study minimally increased percentages 
of subpopulations of regulatory T cells were noted on 
Day 29 at 100 mg/kg/week IV, which was not observed 
in monkeys administered 100 mg/kg/week SC. No 
changes in regulatory T cells were observed in the 26-
week study, from Day 25 to Week 29. 
 
Increases in anti-KLH IgM and IgG responses were 
noted after each KLH injection (administered during 
Weeks 16 and 19) in monkeys given 30 or 100 
mg/kg/week for 26-weeks, which persisted in the 30 
mg/kg/week group at 12-weeks off-dose. 
 
Clinical: 
No autoimmune phenomena were observed in the 
FTIH study 200630. In patients who received 
GSK2831781, clinical activity scores for psoriasis (a T 
cell-mediated disease) tended to improve over the time 
course of exposure to IMP. In the Phase 1 study 
Appropriate exclusion criteria for participants (e.g. 
exclusions for acute severe colitis), to exclude 
patients most at risk in the event of disease 
worsening. 
Participants 
will 
undergo 
regular 
clinical 
examination and AEs that could be related to 
autoimmunity, including worsening of underlying 
disease, will be monitored. 
 
Given the increases in anti-KLH IgM and IgG 
responses observed in cynomolgus monkeys, there 
is a theoretical potential for an enhanced response 
to vaccination, which has not yet been evaluated in 
clinical studies. The implications of this are not 
known but are not considered high risk. 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Refer to GSK2831781 IB for details  
Mitigation Strategy 
207823, GSK2831781 did not reduce the numbers of 
circulating regulatory T cells in peripheral blood 
compared to placebo. 
Drug-drug interactions 
Formal drug interaction studies have not been 
performed with GSK2831781; however, during 
inflammation, enzymes such as cytochrome P450 
(CYP) can be down-regulated leading to instances of 
reduced clearance and increased plasma concentrations 
of administered drugs. As GSK2831781 depletes 
activated T cells, this could result in a reduction in 
proinflammatory cytokines systemically, which might 
exert an indirect effect on drug metabolizing enzyme 
(DME) expression and activity. Reports of clinical 
effects with other drugs suggest that the magnitude and 
impact of such drug interactions are generally small 
(<2-fold) and clinically significant only for drugs that 
have a narrow therapeutic range. 
Participants who are co-administered drugs with a 
narrow therapeutic index should be monitored for 
clinical evidence of changes in exposure, and 
therapeutic 
drug 
monitoring 
performed 
as 
clinically indicated. 
Reproductive Toxicity 
Non-clinical: 
Whereas there are no data for the drug class or mode of 
action pointing to a known pregnancy hazard, no 
animal reproduction testing has been conducted. 
Therefore, there is the potential for unidentified risks to 
the embryo-foetus or pregnancy.  
 
Doses up to 100 mg/kg/week for 26-weeks did not 
result in pathology in the reproductive organs of mature 
monkeys or effects on spermatogenesis staging. 
 
Women who are pregnant, lactating or are planning 
on becoming pregnant during the study are not 
eligible to participate. 
 
WOCBP will be required to have established, 
proper use of a highly effective method for 
avoiding pregnancy (see Appendix 4, Section 
10.4.2) at screening to ensure there is a minimum 
of 1 month of effective contraception prior to first 
dose, and to utilize one form of highly effective 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
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Mitigation Strategy 
Clinical: 
WOCBP were included in the psoriasis cohorts of 
study 200630, with appropriate pregnancy testing and 
contraceptive requirements. No pregnancies have been 
observed.  
The IMP level of mAb in human semen is expected to 
be too low to be of concern. 
 
contraception throughout the study until after the 
Follow-Up visit.  
 
Pregnancy testing will be performed at screening 
and prior to the first dose, at least monthly during 
the dosing period, and at regular intervals until 
Follow-Up, as documented in the clinical protocol. 
 
WOCBP who are partners of male subjects in the 
study will not be required to be protected from 
seminal fluid exposure or need to use a condom 
plus highly effective method of contraception.  
Study Procedures 
Endoscopy with biopsy 
 
Whilst endoscopic examination of the gut is generally 
well tolerated, potential risks of the procedure include 
discomfort, bleeding or perforation (1/5000 for 
sigmoidoscopy and 1/3000 for colonoscopy). 
Sigmoidoscopy rather than colonoscopy (unless a 
colonoscopy is clinically indicated, for example for 
malignancy/dysplasia screening at baseline) will be 
used 
to 
reduce 
risk 
of 
endoscopy-related 
complications. Endoscopy will be performed by 
experienced and trained staff only. 
 
Participants will be informed of expected post-
procedure bleeding and will be instructed to contact 
the clinical site should they experience any adverse 
events after the procedure. 
 


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2.3.2. 
Benefit Assessment 
There are additional, but limited, treatment options available for participants who have an 
inadequate response to current therapies for UC. It is hypothesised that GSK2831781 will 
deplete potentially pathogenic, recently activated LAG3+ T cells, which are enriched at the 
disease site in T cell-driven immunoinflammatory disorders such as inflammatory bowel 
disease (IBD), leading to a reduction of disease activity. There will be some direct benefit 
to the participant through their contribution to the process of developing new therapies in 
an area of unmet need, including more frequent contact and assessment by clinicians expert 
in managing UC. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Taking into account the measures to minimise risks, the potential risks of participation in 
this study of GSK2831781 are justified by the anticipated benefits that may be afforded to 
participants with UC. 
 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
Objectives 
Endpoints 
Primary 
• To evaluate the safety and 
tolerability of repeat doses of 
GSK2831781 during the Double-
Blind Induction Phase. 
 
 
 
 
 
 
 
 
• To characterise the efficacy dose-
response of GSK2831781 during 
the Double-Blind Induction Phase. 
• Incidence of adverse events and serious 
adverse events during the Double-Blind 
Induction Phase. 
• Incidence of findings of potential clinical 
importance1 during the Double-Blind 
Induction Phase for: 
o Vital signs. 
o Clinical laboratory values 
(haematology, clinical chemistry 
and urinalysis).  
o QTc. 
 
• Change from baseline in Complete 4-
domain Mayo score2 at Week 10. 
Secondary 
• To evaluate the safety and 
tolerability of repeat doses of 
GSK2831781 during the Double-
Blind Extended Treatment Phase. 
 
• Incidence of adverse events and serious 
adverse events in the Double-Blind 
Extended Treatment Phase. 
• Incidence of findings of potential clinical 
importance5 during the Double-Blind 
Extended Treatment Phase for: 
o Vital signs. 


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Objectives 
Endpoints 
o Clinical laboratory values 
(haematology, clinical 
chemistry and urinalysis).  
o QTc. 
• To investigate the effect of repeat 
doses of GSK2831781 on clinical 
efficacy including endoscopic 
mucosal healing during the Double-
Blind Induction Phase. 
 
• Adapted Mayo endoscopic score of 0 or 1 
at Week 10. 
• Adapted Mayo clinical remission3 at 
Week 10. 
• Adapted Mayo clinical response3 at 
Week 10. 
• Symptomatic remission4 over time.  
• Change from baseline in partial Mayo 
score over time. 
• Change from baseline in Adapted Mayo 
endoscopic score and Ulcerative Colitis 
Endoscopic Index of Severity (UCEIS) at 
Week 10. 
• To investigate the effect of repeat 
doses of GSK2831781 on UC 
histologic disease activity during 
the Double-Blind Induction Phase. 
• Histological severity as determined by the 
Robarts Histopathology Index at Week 10. 
• Histological severity as determined by the 
Nancy Histological Index at Week 10. 
• Histological severity as determined by the 
Geboes Histological Index at Week 10. 
• To investigate the effect of repeat 
doses of GSK2831781 on 
biomarkers of UC disease activity 
during the Double-Blind Induction 
Phase. 
• Change from baseline in serum C-reactive 
protein over time. 
• Change from baseline in faecal 
calprotectin over time. 
• To investigate the pharmacokinetics 
of GSK2831781 following 
subcutaneous dosing. 
• GSK2831781 PK parameters: AUC(0-tau), 
Cmax, tmax. 
• To investigate the immunogenicity 
of repeat doses of GSK2831781 
during the Double-Blind Induction 
Phase. 
• Incidence of anti-drug antibodies at each 
visit. 
Safety 
• To evaluate the safety and 
tolerability of repeat doses of 
GSK2831781 in all trial phases. 
• Adverse events, vital signs, clinical 
laboratory values (haematology, clinical 
chemistry, and urinalysis), 12-lead ECG. 


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Objectives 
Endpoints 
• To investigate the immunogenicity 
of repeat doses of GSK2831781 in 
all trial phases. 
• Incidence of anti-drug antibodies at each 
visit. 
Exploratory  
• To investigate the effect of repeat 
doses of GSK2831781 on patient-
reported outcomes in all trial 
phases. 
• Change from baseline in daily e-Symptom 
Diary, FACIT-Fatigue, Inflammatory 
Bowel Disease Questionnaire (IBDQ), SF-
36, and PGIS. 
• PGIC at Week 10 and Week 30. 
• To investigate the effect of repeat 
doses of GSK2831781 on clinical 
efficacy during the Double-Blind 
Extended Treatment Phase. 
• Change from baseline in Adapted Mayo 
score between Week 10, and Week 30. 
• Adapted Mayo endoscopic score of 0 or 1 
at Week 30. 
• Adapted Mayo clinical remission3 at 
Week 30. 
• Adapted Mayo clinical response3 at 
Week 30. 
• Change from baseline in Adapted Mayo 
endoscopic score and Ulcerative Colitis 
Endoscopic Index of Severity (UCEIS) at 
Week 30. 
• Symptomatic remission4 over time. 
• Change from baseline in Partial Mayo 
score over time. 
• Change from baseline in histological 
severity as determined by the Robarts 
Histopathology Index, Nancy Histological 
Index and Geboes Score at Week 30. 
• Clinical response3 at Week 10, maintained 
at Week 30. 
• Clinical remission3 at Week 10, 
maintained at Week 30. 
• To investigate the effect of repeat 
doses of GSK2831781 on oral 
corticosteroid use for participants 
using corticosteroids at baseline. 
• Corticosteroid-free Adapted Mayo clinical 
remission at Week 30 (with at least 28 
consecutive days corticosteroid-free, 
including Weeks 26 to 30). 


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Objectives 
Endpoints 
• Change from baseline daily corticosteroid 
dose to average daily corticosteroid dose 
during the taper period5. 
• To investigate the effect of repeat 
doses of GSK2831781 on 
biomarkers of disease activity in 
patients moderate to severe active 
UC during the Double-Blind 
Extended Treatment Phase and 
Open Label Treatment Phases. 
• Change from baseline in serum C-reactive 
protein over time. 
• Change from baseline in faecal 
calprotectin over time. 
• To investigate the effect of repeat 
doses of GSK2831781 on colon 
biopsy tissue and blood biomarkers 
in patients with moderate to severe 
active UC in all Treatment Phases. 
• Change from baseline in colon biopsy 
tissue biomarkers at Week 10 and 
Week 30, which may include but not be 
limited to: 
o Number of LAG3+ and CD3+ cells by 
IHC. 
o Composition of immune cell 
populations, including but not limited 
to CD3+ cells by epigenetic counting 
or T cell receptor sequencing. 
o Transcriptomic profiles, including but 
not limited to LAG3. 
• Change from baseline in blood 
biomarkers, which may include but not be 
limited to:  
o Number of LAG3+ cells at Week 10 
and Week 30. 
o 4β-hydroxycholesterol:cholesterol 
ratio. 
o Serum tryptase. 
o Proteomic profiles. 
• To investigate the effect of repeat 
doses of GSK2831781 on plasma 
sLAG3 in patients with moderate to 
severe active UC in all Treatment 
Phases.  
• Soluble LAG3 (sLAG3) concentrations. 
• To evaluate the concentration-time 
profiles of GSK2831781 after 
repeat intravenous and 
• GSK2831781 PK concentrations. 


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Objectives 
Endpoints 
subcutaneous dosing in all 
Treatment Phases. 
• To investigate the effect of repeat 
doses of GSK2831781 on clinical 
efficacy in Non-Responder patients 
during Open Label Induction and 
Extended Treatment Phases. 
• Change from baseline in Adapted Mayo 
score between Week 10, and Week 22. 
• Adapted Mayo endoscopic score of 0 or 1 
at Week 22. 
• Adapted Mayo clinical remission3 at 
Week 22. 
• Adapted Mayo clinical response3 at 
Week 22. 
• Change from baseline in Adapted Mayo 
endoscopic score and Ulcerative Colitis 
Endoscopic Index of Severity (UCEIS) at 
Week 22. 
• Change from baseline in histological 
severity as determined by the Robarts 
Histopathology Index, Nancy Histological 
Index and Geboes Score at Week 22. 
• Clinical response based on partial Mayo 
score3 at Week 22, maintained at Week 42. 
• Clinical remission based on partial Mayo 
score3 at Week 22, maintained at Week 42. 
• Symptomatic remission4 over time.  
• Change from baseline in partial Mayo 
score over time. 
• To investigate the effect of repeat 
doses of GSK2831781 on 
extraintestinal manifestations in all 
Treatment Phases. 
• Incidence of extraintestinal manifestations 
over time. 
Footnotes: 
1 
Potential clinical importance is defined in the research analysis plan (RAP) for each relevant safety 
endpoint. 
2 
The Complete 4-domain Mayo score is used for the primary endpoint due to its wider dynamic 
range for assessment of dose-response compared to the Adapted Mayo score used for secondary 
and exploratory endpoints. 
3 
Clinical response and remission for the various iterations of Mayo score are defined in Appendix 
7, Section 10.7. 
4 
Symptomatic remission is defined as a rectal bleeding subscore of 0, and a stool frequency subscore 
of ≤1, with no worsening from baseline. 
5 
Taper period is defined from the start of the taper (Weeks 12 or 24, respectively, for the Double-
Blind and Open Label Extended Treatment Phases) to completion of the respective Extended 
Treatment Phases. 


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Primary estimand for dose-response: “Treatment policy” 
Objective: To characterise the efficacy dose-response of GSK2831781 during the 
Double-Blind Induction Phase. 
Estimand: 
Primary efficacy estimand 
Description 
Mean change from baseline to Week 10 in Complete 4-domain Mayo 
score for each dose level and placebo in patients with moderate to severe, 
active Ulcerative Colitis and in the absence of IP discontinuation due to 
the COVID-19 pandemic. 
Attributes 
• Treatment: Placebo and four doses of GSK2831781 IV: 450 mg, 300 
mg, 150 mg and 45 mg in addition to background therapy and stable 
dose of corticosteroid where relevant.  
• Population: Patients with moderate to severe, active Ulcerative 
Colitis as per inclusion/exclusion criteria.  
• Outcome measure: Change from baseline to Week 10 in Complete 4-
domain Mayo score.  
• Intercurrent events and strategy:  
o Intercurrent event (ICE): Discontinuations due to the COVID-19 
pandemic 
• Strategy: handled as though discontinuation had not occurred 
(hypothetical strategy, setting assessments to missing with missing at 
Random [MAR] assumption). 
o ICE: Discontinuations not due to the COVID-19 pandemic 
• Strategy: treatment policy. 
• Population-level summary: Mean change from baseline.  
 
Additional estimand for dose-response: “Hypothetical” 
Objective: To characterise the efficacy dose-response of GSK2831781 during the 
Double-Blind Induction Phase. 
Estimand: 
Additional estimand for primary efficacy objective and endpoint 
Description 
Mean change from baseline to Week 10 in Complete 4-domain Mayo 
score for each dose level and placebo in patients with moderate to severe, 
active Ulcerative Colitis and in the absence of the listed inter-current 


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events which include IP discontinuation and specified important protocol 
deviations. 
Attributes 
• Treatment: Placebo and four doses of GSK2831781 IV: 450 mg, 300 
mg, 150 mg and 45 mg in addition to background therapy and stable 
dose of corticosteroid where relevant.  
• Population: Patients with moderate to severe, active Ulcerative 
Colitis as per inclusion/exclusion criteria.  
• Outcome measure: Change from baseline to Week 10 in Complete 4-
domain Mayo score.  
• Intercurrent events and strategy:  
o Discontinuation from IP (for any reason). 
o Excluded medication administered.  
o Wrong study treatment dosed (including protocol deviation 
subcategory of “study treatment not administered per protocol” 
which covers missed doses). 
o Unblinding of participant’s treatment allocation for site and/or 
participant. 
o For all of these ICEs a ‘hypothetical’ strategy will be used that 
assumes that the specified intercurrent event did not occur. The 
assessments will be set to missing with MAR assumption. 
• Population-level summary: Mean change from baseline.  
 
Key secondary estimand for decision making: “Composite” 
Objective: To investigate the effect of repeat doses of GSK2831781 on clinical 
efficacy including endoscopic mucosal healing during the Double-Blind 
Induction Phase. 
Estimand: Description 
Difference in response rates between active doses of GSK2831781 and 
Placebo when added to background therapy in patients with moderate to 
severe, active, Ulcerative Colitis.  
Attributes 
• Treatment: Placebo and active doses of GSK2831781 in addition to 
background therapy and stable dose of corticosteroid where relevant.  
• Population: Patients with moderate to severe, active Ulcerative Colitis 
as per inclusion/exclusion criteria.  
• Outcome measure: Endoscopic Mucosal Healing at Week 10 
assessment, where success is defined as: 
o Achieving a score on the endoscopic component of the Adapted 
Mayo score of 0 or 1, and 


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o Not discontinuing IP due to reasons unrelated to the COVID-19 
pandemic, and 
o Not taking medications excluded by the protocol or increasing 
dose of corticosteroid. 
 
• Intercurrent events and strategy:  
o ICE: discontinuation from IP, unrelated to COVID-19 pandemic. 
▪ Strategy: included in outcome via composite strategy 
(setting response status as non-responder). 
 
o ICE: discontinuation from IP due to COVID-19 pandemic.  
▪ Strategy: handled as though discontinuation had not 
occurred (hypothetical strategy, setting response status to 
missing with MAR assumption). 
 
o ICE: valid endoscopy result not available due to COVID-19 
pandemic. 
▪ Strategy: handled as though missing assessment had not 
occurred (hypothetical strategy, setting response status to 
missing with MAR assumption). 
 
o ICE: valid endoscopy result not available for technical reasons. 
▪ Strategy: handled as though missing assessment had not 
occurred (hypothetical strategy, setting response status to 
missing with MAR assumption). 
 
• Population-level summary: Difference in proportion of participants 
who achieve response between placebo and relevant active doses. 
 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 2, multicentre, randomized, double-blind, parallel group, placebo-
controlled study of GSK2831781 in participants with moderate to severe active UC. This 
study will investigate the safety and tolerability, efficacy, dose-response, PK and PD of 
GSK2831781. In addition, the study will investigate SC dosing during the Extended 
Treatment Phase. 
Following the Induction Phase (up to Week 10), participants who respond will enter a 
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Responders identified following the Week 10 assessment will move to Open Label 
Treatment, consisting of Induction (Weeks 12 to 22) an Open Label Extended Treatment 
Phase (Weeks 22 to 42) and a Follow-Up to Week 54 (see Section 4.1.2). 
At the start of the study, participants will be randomised to GSK2831781 450 mg or 
placebo in a 2:1 ratio. When an appropriate number of participants have been randomised 
in these two arms for the futility interim analysis (Interim Analysis 3, See Section 9.5), 
randomisation to all dose regimens (GSK2831781 450 mg, 300 mg 150 mg, 45 mg or 
placebo) will be opened in a 2:3:3:3:2 ratio. No pause in recruitment is planned, although 
study recruitment may be paused for internal decision making at the Sponsor’s discretion.  
A number of interim analyses will be performed during the study, where the DRC will 
review unblinded data for decision-making purposes (see Section 9.5 for further details).  
In line with routine pharmacovigilance, an internal GSK Safety Review Team (SRT) 
(which will include a subset of the 204869 study team) will review blinded safety data, 
including clinical laboratory parameters and adverse events, at appropriate intervals during 
the period of study conduct. 
An overview of the patient journey for the study is shown in Figure 1 and described below. 
Figure 1 
Participant journey 
 
 
 
4.1.1. 
Double-Blind Treatment 
Following informed consent, the screening period for participants is 35 days. Eligible 
participants, determined by entry criteria including the baseline centrally read endoscopy 
(endoscopy to be completed no earlier than Day -14), will be randomised on either Day 1 
or Day -1, and commence 10 weeks of blinded treatment in the Double Blind Induction 
Phase (IP). 


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At Week 10, all participants will undergo an Induction Assessment, including centrally 
read endoscopy. Following the endoscopy, the Responder status (see Appendix 7, Section 
10.7), as identified by the results of the central assessment of clinical response and 
implemented in the eCRF, will be communicated to sites prior to the Week 12 visit. 
Participants identified as Responders who received GSK2831781 during Induction will 
then receive 300 mg GSK2831781 subcutaneously (SC) every four weeks during the 
double-blind Extended Treatment Phase (ETP), from Week 14 until Week 26. Responders 
in the placebo group during Induction will continue to receive placebo SC every four weeks 
in the double-blind ETP (Figure 2). A mandatory corticosteroid taper (if applicable) will 
begin at Week 12, described in Section 6.6.1.1. 
At Week 30, all participants in the Double-Blind ETP will undergo an Assessment, 
including centrally read endoscopy. Subsequently, all participants will remain in study, but 
off treatment, to Week 42 in the 12-week Follow-Up phase. 
 
Figure 2 
Double-blind ETP dosing regimen (for Responders only) 
 
 
4.1.2. 
Open Label Treatment for Non-Responders 
Participants who have not attained clinical response, determined following a centrally read 
endoscopy at Week 10 (calculated centrally through the eCRF), will be assigned to Open 
Label Treatment. This offers the opportunity to characterise participants who may respond 
slower to treatment, as well as providing participants who have not responded on their 
randomized dose regimen the opportunity to receive GSK2831781 at the highest dose. The 
total duration of open label treatment will be up to an additional 30 weeks of treatment 


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(Week 12 to Week 42) and a 12-week Follow-Up (Figure 3).  
Participants who have not attained clinical response, determined following a centrally read 
endoscopy at Week 22 (calculated centrally through the eCRF), will discontinue study 
treatment and are still required to attend a Follow-Up visit approximately 16 weeks from 
the last dose event. 
Participants identified as Responders will then receive 300 mg GSK2831781 SC every 
four weeks during the Open Label Extended Treatment Phase from Week 22 until Week 
42. A mandatory corticosteroid taper (if applicable) will begin at Week 24, described in 
Section 6.6.1.1. 
Subsequent to Week 42, all Open Label Extended Treatment Phase participants will remain 
in study, but off treatment, to Week 54 in a 12-week Follow-Up phase. 
 
Figure 3 
Open Label Treatment for Non-Responders at Week 10 
 
 
4.1.3. 
Type and number of participants 
Participants with moderate to severe active UC as defined by a 4-domain (Complete) Mayo 
score of 6-12 at screening, including a centrally read Mayo endoscopic score of ≥2 within 
14 days of randomization (Day 1), will be randomised into the study (see Section 5, for 
full list of inclusion/exclusion criteria). Participants will be stratified first by ethnicity 
(Japanese or non-Japanese). Non-Japanese participants will then be further stratified 
according to prior treatment (advanced therapy naïve, experienced a single class of 
advanced therapy, or experienced multiple classes of advanced therapies [advanced 


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therapies include anti-TNF therapies, anti-integrin therapies, anti-IL-12/23 monoclonal 
antibodies, and JAK inhibitors]). 
Approximately 242 participants will be randomly assigned to study intervention under the 
assumption that a proportion will not receive all planned doses up to Week 10 and/or have 
an incomplete Week 10 Complete 4-domain Mayo score assessment. If the attrition rate is 
higher than planned for (e.g., 15% or more) then additional participants, up to a maximum 
of 320, may be recruited. At the start of the study, participants will be randomised to 
GSK2831781 450 mg and Placebo in a 2:1 ratio. When an appropriate number of 
participants have been randomised in these two arms for the interim analysis (Interim 
Analysis 3, See Section 9.5), randomisation to all dose regimens (GSK2831781 450 mg, 
300 mg, 150 mg, 45 mg or Placebo) will be opened. See Section 6.4 for the randomisation 
ratios. 
No pause in recruitment to the study is planned whilst interim analyses are conducted, 
although recruitment into the study may be paused for internal decision making at the 
Sponsor’s discretion. At appropriate interim analyses a sample size re-estimation may be 
conducted, to ensure that sufficient participants are recruited. The randomisation will be 
stratified to ensure participants will be appropriately represented across the dose regimens 
and placebo. The maximum number of randomized participants will be 320 (see Section 
9.2.2 for further details). 
The proposed SoA for the study, including the Open Label Treatment, can be seen in 
Section 1.3. 
4.2. 
Scientific Rationale for Study Design 
This is the first study of GSK2831781 in participants with moderate to severe active UC, 
and the first repeat dose study. There are two primary objectives, the first of which is to 
evaluate the safety and tolerability of repeat doses GSK2831781. The second primary 
objective is to characterise the efficacy dose-response in the Induction Phase of 
GSK2831781 in patients with moderate to severe active UC. 
The placebo group is required for a valid evaluation of adverse events attributable to 
GSK2831781 treatment versus those independent of GSK2831781 treatment. The placebo 
participants will also serve as controls for the biomarker and efficacy assessments. 
Participants randomised to receive placebo during the Induction Phase who have not 
responded by the Induction Assessment (Week 10) will have opportunity to access Open 
Label treatment with GSK2831781 450 mg IV. 
The endpoint chosen for primary characterisation of the dose-response is the change from 
baseline in Mayo score (See Appendix 7, Section 10.7) at Week 10. This will be evaluated 
alongside the key secondary endpoint of endoscopic mucosal healing. Longitudinal data 
demonstrate that patients who attain mucosal healing have a superior long-term prognosis, 
including lower risk of future surgery and hospitalisation, need for systemic steroids, and 
development of colorectal cancer [Rutter, 2004]. Patient-reported outcomes are also 
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In addition to endoscopic and symptomatic assessments, other key endpoints contributing 
to an understanding of whether GSK2831781 successfully ameliorates mucosal 
inflammation are being undertaken, including: histological, immunohistochemical and 
transcriptomic assessment of gut biopsies; levels of faecal calprotectin; and C-reactive 
protein (CRP) concentrations in blood. Further exploratory endpoints include 
characterisation of PK and efficacy with a single dose level of subcutaneous GSK2831781 
in the Extended Treatment Phase, to determine applicability of this dosing route in future 
studies. 
Participants will be followed for 16 weeks after the last administration of GSK2831781. 
Due to the non-linear nature of the PK and limited number of observations in the final 
phase, the terminal half-life could not be determined in the FTIH study 200630. However, 
the data from this study show that after dosing at 5 mg/kg IV (470 mg on average), the 
mean plasma concentration of GSK2831781 at Day 85 (i.e. 12 weeks after dosing) had 
dropped to 0.5 µg/mL, from a mean Cmax of 162 µg/mL, and in 2 out of 6 participants the 
concentration had dropped below the limit of quantification (10 ng/mL). At Day 121 (i.e. 
17 weeks after dosing; next time point for PK), the concentrations in all participants who 
had received 5 mg/kg had dropped below the limit of quantification. Since only very 
limited accumulation is expected for monoclonal antibodies in general and, based on 
population PK modelling of the data from study 200630, a wash out period of 16 weeks 
after the last administration has been selected as a sufficient time for washout and 
determination of repletion of LAG3+ cells.  
A key feature of the study is that there will be a number of interim analyses that may be 
performed, which will include the assessment of PK and an assessment of futility (see 
Section 9.5 for further details).  
4.3. 
Justification for Dose 
4.3.1. 
Double-Blind Induction Phase 
The top dose will be 450 mg IV at Day 1 (Week 0), Day 15 (Week 2), Day 43 (Week 6) 
and Day 71 (Week 10). Simulations using a PK/PD model that was developed using PK 
and cell depletion data in blood from the FTIH study (Study 200630), and LAG3+ cell 
numbers from colon [Slevin, 2018] show that at a dosing interval of 4 weeks, this dose is 
predicted to reduce LAG3+ T cells (memory compartment) in blood to ~5%, and in colon 
to 5-20%, of baseline levels as measured in patients with active UC. 
The dosing interval is 4-weekly, except for the first 2 doses, which will be 2 weeks apart. 
This is predicted to achieve the maximum reduction in LAG3+ T cells faster, particularly 
in colon. 
The maximum dose in the FTIH study was 5 mg/kg. Since the average weight of the 
participants was 94.38 kg in that treatment group (range of 85.3-108, N=6), on average the 
administered dose was 470 mg, which is similar to the proposed top dose of 450 mg IV. 
The population PK model predicts an average Cmax of 204 g/mL and AUC(0-4wks) of 
37 mg.hr/mL at Week 10. In the FTIH study, Cmax ranged between 120-230 g/mL and 
AUC(0-t) ranged between 33-59 mg.hr/mL. Therefore, it is expected that the exposure at 


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the top dose in the current study will be similar to the observed exposure in FTIH study at 
5 mg/kg single dose IV. Additionally, the proposed starting dose of 450 mg (~6.4 mg/kg 
for 70 kg participant) is 15.6x lower than the NOAEL (100 mg/kg/week, highest dose 
tested) from the 26-week GLP toxicity study in monkey, and the predicted mean Cmax 
and AUC are 15.2x and 12.1x lower, respectively. 
For characterising the dose-response relationship, three further dose levels are included: 
300 mg, 150 mg and 45 mg, all administered at the same time points as 450 mg. At the 
lowest dose of 45 mg, PK/PD modelling predicts only limited depletion of LAG3+ T cells 
in colon, and in blood to about 25-50%. 
4.3.2. 
Double-Blind Extended Treatment Phase (ETP) 
All participants who responded during the double-blind Induction Phase (see Section 4.1) 
will be dosed during the ETP via the subcutaneous route. It is anticipated in the longer 
term that SC administration will be preferable, and lower doses may be required to 
maintain target depletion. This is based on clinical experience with other mAbs in UC (for 
example, Infliximab and Vedolizumab), and the biology of the disease (after successful 
induction treatment, the elevated levels of LAG3+ cells in the colon are expected to be 
reduced). Therefore, the dose during the double-blind ETP will be 300 mg SC every 4 
weeks. For participants in the 45 mg or 150 mg cohorts who respond in the Induction 
Phase, this may represent a dose escalation; however, this is still considered justified to 
explore the potential to achieve even more clinically meaningful responses and deep 
remission. 
4.3.3. 
Open Label Treatment 
All participants who did not respond during the double-blind Induction Phase will receive 
450 mg IV at Weeks 12, 14, 18 and 22 (Open Label Induction Phase), followed by 300 mg 
SC every 4 weeks from Week 26-38 (Open Label Extended Treatment Phase). Since only 
minimal (further) accumulation of GSK2831781 is expected, continuing treatment at 
450 mg IV for Non-Responders who might have received this dose during the double-blind 
Induction Phase as well will result in only limited, if any, increases in exposure. 
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 scheduled assessment shown in the SoA (Section 1.3). 
Participants who withdraw from the study early should be encouraged to complete all visits 
for that specific phase as set out in the SoA (Section 1.3); however, if this is not possible 
at a minimum participants will be asked to complete all assessments at both the Early 
Withdrawal visit and a Follow-Up visit approximately 16 weeks after the last dose (Section 
7.2) to ensure participant monitoring following drug wash out. 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 


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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
AGE and WEIGHT 
1. Participant must be 18 years of age or older and >40kg at the time of signing the 
informed consent. 
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS  
Participants who have a: 
2. Diagnosis of ulcerative colitis, established at least 3 months prior to screening, as 
documented by diagnostic sigmoidoscopy or colonoscopy, and biopsy. 
3. Complete 4-domain Mayo Score of 6 to 12, with disease extending ≥15cm from the 
anal verge, with a centrally read endoscopic subscore of ≥2 at screening endoscopy, 
and a rectal bleeding subscore ≥1.  
4. A history of at least one of the following: 
• Inadequate response to, loss of response to, or intolerance to azathioprine or 
mercaptopurine (including thiopurine methyltransferase (TPMT) and NUDT15 
genetic mutations precluding use), ciclosporin, tacrolimus or methotrexate. 
• Inadequate response to, loss of response to, intolerance to, or demonstrated 
dependence on oral corticosteroids. 
• Inadequate response to, loss of response to, or intolerance to at least one approved 
advanced therapy for UC, including anti-TNF therapies, anti-integrin therapies, 
anti-IL-12/23 monoclonal antibodies or JAK inhibitors. 
5. Surveillance colonoscopy (performed according to local standards) within 12 
months of screening (or during screening, if required) for participants with:  
• Pancolitis of >8 years duration; or 
• Patients with left-sided colitis of >12 years duration; or 
• For patients for whom this criterion does not apply, colorectal cancer surveillance 
should be undertaken according to local or national guidelines for patients with 
age ≥50, or with other known risk factors for colorectal cancer.  


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SEX 
6. Male and Female participants:  
Both male and female participants are eligible to participate. 
A female participant is eligible to participate if she is not pregnant, not breastfeeding, 
and at least one of the following conditions applies: 
• Not a woman of childbearing potential (WOCBP), see Section 10.4.1. 
OR 
• A WOCBP who agrees to use a highly effective contraceptive method for at 
least 4 weeks prior to dosing, until the Follow-Up visit. See Section 10.4.2. 
 
INFORMED CONSENT 
7. Capable of giving signed informed consent as described in Section 10.1.3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
MEDICAL CONDITIONS 
1. Participants with a current diagnosis of indeterminate colitis, inflammatory bowel 
disease-unclassified, Crohn’s disease, infectious colitis, or ischaemic colitis. 
2. Participants with fulminant ulcerative colitis (as defined by 6 bloody stools daily 
AND 1 or more of: i) body temperature ≥100.4°F (or 38°C) or ii) heart rate >90 
beats per minute), or toxic megacolon. 
3. 
Prior extensive colonic resection, subtotal or total colectomy, or proctocolectomy, 
or planned surgery for UC. 
4. Participants with any uncontrolled medical conditions, other than active UC, that in 
the opinion of the Investigator put the participant at unacceptable risk or interfere 
with study assessments or integrity of the data. Other medical conditions should be 
stable at the time of screening and be expected to remain stable for the duration of 
the study. 
5. Unstable lifestyle factors, such as alcohol use to excess or recreational drug use, to 
the extent that in the opinion of the Investigator they would interfere with the ability 
of a participant to complete the study. 
6. An active infection or a history of serious infections as follows: 


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- Use of antimicrobials (antibacterials, antivirals, antifungals or antiparasitic 
agents) for an infection within 30 days before first dose (topical treatments may 
be allowed at the Medical Monitor’s discretion). 
- A history of opportunistic infections within 1 year of screening (e.g. 
Pneumocystis jirovecii, aspergillosis or CMV colitis). This does not include 
infections that may occur in immunocompetent individuals, such as fungal nail 
infections or vaginal candidiasis, unless it is of an unusual severity or recurrent 
nature. 
- Recurrent or chronic infection or other active infection that, in the opinion of the 
Investigator, might cause this study to be detrimental to the patient. 
- Symptomatic herpes zoster within 3 months prior to screening. 
- History of tuberculosis (active or latent), irrespective of treatment status. 
- A positive diagnostic TB test at screening (defined as a positive QuantiFERON 
test). In cases where the QuantiFERON test is indeterminate, the participant may 
have the test repeated once and if their second test is negative they will be 
eligible. In the event a second test is also indeterminate, the Investigator has the 
option to undertake PPD testing. If the PPD reaction is <5 mm, then the 
participant is eligible. If the reaction is ≥5 mm, or PPD testing is not undertaken, 
the participant is not eligible. 
- Positive Clostridium difficile toxin test during screening. However, rescreening 
can be undertaken following successful treatment. 
7. Current or history of chronic liver or biliary disease (with the exception of Gilbert’s 
syndrome, asymptomatic gallstones or uncomplicated fatty liver disease). 
8. Hereditary or acquired immunodeficiency disorder, including immunoglobulin 
deficiency (unless the participant has a documented history of selective IgA 
deficiency). 
9. A major organ transplant (e.g. heart, lung, kidney, liver, pancreas) or haematopoietic 
stem cell/marrow transplant. 
10. Any planned major surgical procedure during the study. 
11. A history of malignant neoplasm within the last 5 years, except for adequately 
treated non-metastatic basal or squamous cell cancers of the skin (within 1 year) or 
carcinoma in situ of the uterine cervix (within 3 years) that has been fully treated 
and shows no evidence of recurrence. 
 
PRIOR/CONCOMITANT THERAPY 
12. A change in dose of oral sulfasalazine or aminosalicylate within 2 weeks prior to 
baseline endoscopy. 
13. Greater than 20 mg/day oral prednisolone (or equivalent, see SRM), or a change in 
dose of corticosteroid within 2 weeks prior to baseline endoscopy, or anticipated 


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inability to maintain a stable dose of corticosteroids (≤20 mg oral prednisolone or 
equivalent, see SRM) until Week 12. 
14. Topical (rectal) corticosteroids or topical (rectal) aminosalicylate within 2 weeks 
prior to baseline endoscopy. 
15. Initiation or a change in dose of mercaptopurine or azathioprine (including initiation 
or discontinuation of allopurinol) or methotrexate within 8 weeks prior to baseline 
endoscopy. 
16. Treatment with ciclosporin, tacrolimus or thalidomide within 4 weeks prior to 
baseline endoscopy. 
17. Treatment with an anti-TNF biologic within 8 weeks prior to baseline endoscopy, 
anti-integrin or anti-IL-12/23 biologics within 12 weeks prior to baseline endoscopy, 
or a JAK inhibitor within 4 weeks prior to baseline endoscopy. 
18. A history of inadequate response, loss of response, or intolerance to more than three 
classes of approved advanced therapies for UC (including anti-TNF therapies, anti-
integrin therapies, anti-IL-12/23 monoclonal antibodies, or JAK inhibitors; but 
excluding exposure within a clinical trial setting), of which participants must not 
have had inadequate response (primary non-response) to more than two classes. 
19. Received faecal microbiota transplantation within 4 weeks prior to baseline 
endoscopy. 
20. Received live vaccination within 4 weeks of Day 1 or plan to receive during the study 
until Follow-Up. 
 
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE 
21. The participant has participated in a clinical trial and has received an investigational 
product within the following time period prior to the screening endoscopy day in the 
current study: 
a. Biologics: 3 months, 5 half-lives, or twice the duration of the biological effect 
of the investigational product (whichever is longer); 
b. New Chemical Entities (NCEs): 30 days, 5 half-lives or twice the duration of 
the biological effect (whichever is longer). 
 
DIAGNOSTIC ASSESSMENTS* 
22. Absolute neutrophil count <1.5x109/L or a haemoglobin <80 g/L or lymphocyte 
count <0.8x109/L. 
23. Estimated glomerular filtration rate (GFR) by Chronic Kidney Disease 
Epidemiology Collaboration equation (CKD-EPI) calculation <60 ml/min/1.73m2 at 
screening. 
24. ALT >2x ULN and bilirubin >1.5x ULN (isolated bilirubin >1.5xULN is acceptable 
if bilirubin is fractionated and direct bilirubin <35%) at screening. 


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25. Other clinically significant abnormalities of laboratory assessments, as judged by the 
Investigator and/or GSK Medical Monitor, that could affect the safety of the 
participant, or the interpretation of the data from the study. 
26. Presence of hepatitis B surface antigen (HBsAg) or Hepatitis B core antibody 
(HBcAb), or positive hepatitis C antibody result at screening (NB. 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). 
27. Positive serology for HIV at screening. 
28. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 3 months. 
29. QTc >450 msec or QTc >480 msec for participants with bundle branch block at 
screening and Day 1. The QTc is the QT interval corrected for heart rate according 
to either Bazett’s formula (QTcB), Fridericia’s formula (QTcF), or another method, 
machine or over read.** 
* Retesting, in the case of potentially spurious results or sample handling errors, is allowed 
during the screening period. 
** Same correction to be used throughout the study. 
OTHER EXCLUSION CRITERIA 
30. Participants with hypersensitivity to GSK2831781 or any excipients in the clinical 
formulation of GSK2831781 (See GSK2831781 Investigator Brochure). 
 
5.3. 
Lifestyle Considerations 
5.3.1. 
Tobacco and Caffeine 
Smoking and caffeine can have an influence on the severity of ulcerative colitis disease 
symptoms. For that reason, participants should keep their smoking habits and caffeine 
intake broadly constant throughout the study. Use of nicotine replacement therapy should 
be recorded as concomitant medication. 
 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse events (SAEs). 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened twice in future at the discretion of the Investigator, in discussion with the 


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Medical Monitor as needed. Rescreened individuals will be assigned a new participant 
number. 
Screening assessments that yield aberrant results (e.g., safety laboratory samples) may be 
repeated once within the screening window by the Investigator based upon judgement. 
Retested participants should be assigned the same participant number as for the initial 
screening. 
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 
Intervention Name 
GSK2831781 
Placebo 
Type  
Biologic 
N/A 
Dose Formulation 
Commercial saline 
solution (0.9% (w/v) 
Sodium Chloride) 
Unit Dose Strength(s) 
150 mg/mL 
N/A 
Dosage Level(s) 
IV: 45 mg, 150 mg, 300 mg and 
450 mg  
SC: 300 mg 
N/A 
Route(s) of 
Administration 
IV infusion and SC injection 
IV infusion & SC injection 
IMP and NIMP 
IMP 
NIMP 
Sourcing 
 
Provided centrally by the Sponsor or 
designee 
Supplied by site 
Packaging and 
Labelling 
 
Study intervention will be provided in 
vial. Each vial will be labelled as 
required per country requirement. 
N/A 
[Current/Former 
Name(s) or Alias(es)] 
aLAG3, anti-LAG3 
N/A 
 
CCI


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6.2. 
Intervention Administration 
GSK2831781 is a fully humanized monoclonal antibody and all formulation ingredients 
have been previously used in the clinic. The intervention administration timings and 
monitoring periods as shown in Table 1 (Responders) and Table 2 (Open Label) must be 
undertaken for each participant. 
Table 1 
Intervention Duration and Monitoring Schedule (Double-Blind 
Induction and Double-Blind Extended Treatment Phase) 
Dose 
Dosing Duration* 
Monitoring period 
IV (Week 0, Day 1) 
2 hr 
2 hr 
IV (Week 2) 
2 hr 
2 hr 
IV (Week 6) 
32 min 
1 hr 
IV (Week 10) 
32 min 
30 min 
SC (Week 14) 
n/a 
2 hr 
SC (Week 18) 
n/a 
30 min 
SC (Week 22) 
n/a 
n/a 
SC (Week 26) 
n/a 
n/a 
* Including flush, see Study Reference Manual for details. 
 
Table 2 
Intervention Duration and Monitoring Schedule (Open Label 
Induction and Open Label Extended Treatment Phase) 
Dose 
Dosing Duration* 
Monitoring period 
IV (Week 12) 
2 hr 
2 hr 
IV (Week 14) 
2 hr 
2 hr 
IV (Week 18) 
32 min 
1 hr 
IV (Week 22) 
32 min 
30 min 
SC (Week 26) 
n/a 
2 hr 
SC (Week 30) 
n/a 
30 min 
SC (Week 34) 
n/a 
n/a 
SC (Week 38) 
n/a 
n/a 
* Including flush, see Study Reference Manual for details. 
 


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6.3. 
Preparation/Handling/Storage/Accountability 
1. The Investigator or designee 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. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized 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 authorized site staff. 
3. 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). 
4. Further guidance and information for the final disposition of unused study intervention 
are provided in the SRM.  
Under normal conditions of handling and administration, study intervention is not expected 
to pose significant safety risks to site staff. Take adequate precautions to avoid direct eye 
or skin contact and the generation of aerosols or mists. In the case of unintentional 
occupational exposure notify the monitor, Medical Monitor and/or GSK study contact. 
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. 
 
6.4. 
Measures to Minimize Bias: Randomization and Blinding 
6.4.1. 
Method of Treatment Assignment 
At Screening a unique Participant Number (case report form (CRF) number) will be 
assigned to any participant who has at least one Screening procedure performed, other than 
informed consent. The unique Participant Number will be used to identify individual 
participants during the study. 
Participants who meet the screening eligibility criteria will be randomised to a treatment 
group through RAMOS NG. RAMOS NG will confirm the participant’s CRF number 
(Participant number) and provide the randomisation number, where a randomisation 
number will be assigned from a randomisation schedule generated by Clinical Statistics, 
prior to the start of the study, using validated internal software. Once assigned, this number 
must not be reassigned to any other participant in the study. 
Therefore, the randomisation is centrally controlled by RAMOS NG. 
Randomisation of participants must be undertaken prior to dosing, preferably on Day 1, 
but may be conducted on Day -1 if required to allow the site pharmacist to prepare the 
dose. Randomisation may only occur if all information pertaining to patient eligibility has 
been confirmed, including eCRF Mayo score eligibility calculation. 


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The total number of participants recruited to the study will be up to a maximum of 320. At 
the start of the study, participants will be randomised in a 2:1 ratio to GSK2831781 450 mg 
and Placebo. When an appropriate number of participants have been randomised in these 
two arms for the interim analysis (Interim Analysis 3, see Section 9.5), randomisation to 
all dose regimens (GSK2831781 450 mg, 300 mg 150 mg, 45 mg or Placebo) will be 
opened in the ratio 2:3:3:3:2.  
Randomisation will first be stratified by ethnicity (Japanese or non-Japanese participant). 
For the purposes of stratification, a Japanese participant must be living in Japan at the time 
of randomisation. Non-Japanese participants will be further stratified according to prior 
treatment (advanced therapy naïve, experienced a single class of advanced therapy, or 
experienced multiple classes of advanced therapies). 
To ensure balance across the doses within Japanese participants, recruitment to 
GSK2831781 450 mg or placebo in a 2:1 ratio may continue after all dose regimens have 
been opened. When an appropriate number of Japanese participants have been dosed to 
GSK2831781 450 mg or placebo in a 2:1 ratio, recruitment to the remaining doses will 
continue using the same ratio as the rest of the participants. Due to number of expected 
Japanese participants, randomisation within this group will not be stratified according to 
prior treatment. 
The treatment codes are as follows: 
Treatment Code 
Treatment Description 
A 
GSK2831781 450 mg 
B 
GSK2831781 300 mg 
C 
GSK2831781 150 mg 
D 
GSK2831781 45 mg 
P 
Placebo 
 
Following the double-blind Induction Phase of the study, participants will be allocated to 
the next treatment phase according to their Responder status: 
Responder status at Week 10 
 Treatment Phase 
GSK2831781 Responder 
Double-blind Extended Treatment Phase 
• 
GSK2831781 300 mg SC every four weeks 
Placebo Responder 
Double-blind Extended Treatment Phase 
• 
Placebo SC every four weeks 
Non-Responder 
Initiate Open Label Induction Phase followed by Open 
Label Extended Treatment Phase 


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6.4.2. 
Blinding 
This will be a double-blind study with respect to allocation of GSK2831781 or placebo to 
participants (excluding Open Label Treatment). All site staff will be blinded with the 
exception of unblinded pharmacists or delegates. The following will apply: 
• RAMOS NG will be programmed with blind-breaking instructions. The 
Investigator or treating physician may unblind a participant’s treatment assignment 
only in the case of an emergency OR in the event of a serious medical 
condition when knowledge of the study treatment is essential for the appropriate 
clinical management or welfare of the participant as judged by the Investigator. 
• It is preferred (but not required) that the Investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the participant’s treatment assignment. 
• If GSK personnel are not contacted before the unblinding, the Investigator must 
notify GSK within 24 hours of breaking the blind, but without revealing the 
treatment assignment of the unblinded participant, unless that information is 
important for the safety of participants currently in the study. 
• The date and reason for the unblinding must be fully documented in the CRF. 
• A participant may continue in the study if the participant’s treatment code is 
unblinded by the Investigator or treating physician. If the participant discontinues 
the date and primary reason for discontinuation (the event or condition which led 
to the unblinding) will be recorded in the CRF. 
• GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind 
the treatment assignment for any 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 treatment assignment, may be sent to 
Investigators in accordance with local regulations and/or GSK policy. 
• The DRC committee, consisting of a restricted set of key project team personnel 
with no contact with sites, senior stakeholders and external experts will review 
unblinded study data. No one external to the DRC committee will see unblinded 
study data. Further details of how the blind will be protected in the committee are 
included in the DRC charter. 
 
6.5. 
Study Intervention Compliance 
• 
When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff.  
• 
GSK2831781 will be intravenously and subcutaneously (if Responders) administered 
to participants at the site. Administration will be documented in the source documents 
and reported in the CRF. 
• 
All efforts should be made to administer GSK2831781 according to the SoA (Section 
1.3), but if a dose is missed, it should be administered as soon as possible. However, 
two consecutive doses, whether IV or SC, should never be given less than 7 days apart. 
The Medical Monitor should be contacted if there are any questions regarding missed 
doses. 


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6.6. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, herbal supplements and/or probiotics) that the participant is receiving at the time 
of enrolment or receives during the study must be recorded 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. Participants will be questioned about concomitant medication at each 
study visit. 
6.6.1. 
Permitted Concomitant Medications 
Investigators are expected to comply with all local standard of care practices and product 
labelling for listed permitted concomitant medications including prophylactic therapies, 
contraception requirements, laboratory testing, follow-up care and other precautions and 
contraindications should continue to be followed throughout the study. 
6.6.1.1. 
Corticosteroids 
Oral corticosteroids are allowed up to a maximum dose of 20 mg/day prednisolone (or 
equivalent, as detailed in the SRM) on entry to the study, providing they have not been 
commenced, or the dose altered, within two weeks prior to the baseline endoscopy. The 
dose of corticosteroids should not change between the baseline endoscopy and Week 12. 
A dose increase as rescue therapy for UC constitutes an individual stopping criterion (see 
Section 7.1.1). If the dose of corticosteroid needs to be reduced due to a safety concern, 
this should be documented appropriately. 
A corticosteroid taper is mandatory from Week 12 for participants who are Responders at 
the Induction Assessment. Non-Responders at Induction who commence Open Label 
treatment and subsequently attain response (determined following a centrally read 
endoscopy at Week 22) will undergo corticosteroid taper from Week 24. For Responders, 
corticosteroids should be tapered according to the following regimen: 
• For prednisolone doses >10 mg/day (or equivalent), the dose should be reduced from 
Week 12 at a rate of 5 mg/week (or equivalent) until a 10 mg/day dose is reached.  
• For prednisolone doses ≤10 mg/day (or equivalent), or once a 10 mg/day dose (or 
equivalent) is achieved by tapering, the dose should be reduced at a rate of 2.5 mg/week 
(or equivalent) until discontinuation. 
• Where the initial steroid dose is such that tapering by the above regimen would be 
challenging because of medicine formulation, it is acceptable for the first step of the 
taper to be down to a dose that subsequently allows a taper by the above parameters. 
However, this initial reduction should be by no more than 5 mg prednisolone 


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equivalent (if initial prednisolone equivalent dose is >10mg/day) or by 2.5 mg (if initial 
prednisolone equivalent dose is ≤10 mg/day). 
• For participants who cannot tolerate the corticosteroid taper without recurrence or 
exacerbation of clinical symptoms, corticosteroids may be increased up to a maximum 
of the original dose at the start of the Induction Phase (but should not exceed the 
baseline dose). In such cases, the tapering regimen above must be reinitiated within 2 
weeks of the dose increase. Following two unsuccessful attempts at corticosteroid 
taper, the patient may re-escalate doses of corticosteroid up to the baseline level. 
6.6.1.2. 
Other therapies 
The therapies for UC specified in Table 3 are allowed providing the dosages are stable for 
the specified period of time prior to baseline endoscopy and throughout the study until 
Follow-Up. Decreases in dosing for safety reasons are allowed if required, but the reasons 
for the change, date and time of the change, as well as the name and dosage regimen 
adopted must be recorded. The dose should not be subsequently increased: 
Table 3 
Permitted concomitant medications 
Medication 
Stable Dose Period Requirement 
Oral 5-ASA or sulfasalazine. 
For 2 weeks prior to baseline endoscopy 
until after the Follow-Up visit. 
Azathioprine or mercaptopurine. 
For 8 weeks prior to baseline endoscopy 
until after the Follow-Up visit (including 
initiation or discontinuation of 
allopurinol). 
Oral methotrexate. 
For 8 weeks prior to baseline endoscopy 
until after the Follow-Up visit. 
Oral corticosteroids. 
See Section 6.6.1.1. 
 
6.6.2. 
Prohibited Concomitant Medications 
The following medications are prohibited for the time period prior to baseline endoscopy 
until after the last endoscopy or Follow-Up visit (as detailed in Table 4). Participants who 
initiate prohibited medications must be discussed with the Medical Monitor and may be 
asked to discontinue study treatment if there is a safety concern. Details of any medication 
received must be recorded as described above (Section 6.6.1). Table 4 below lists the 
prohibited medications. 


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Table 4 
Prohibited Medications 
Medication 
Time period of Prohibition 
Topical (rectal) or intravenous 
corticosteroids, or topical (rectal) 5-ASA. 
Within 2 weeks prior to baseline 
endoscopy until after the last endoscopy. 
Ciclosporin, tacrolimus, mycophenolate 
mofetil or thalidomide. 
Within 4 weeks prior to baseline 
endoscopy until after the Follow-Up visit. 
Anti-TNF therapy (e.g. infliximab, 
adalimumab, golimumab, or biosimilars). 
8 weeks prior to baseline endoscopy until 
after the Follow-Up visit. 
Anti-integrin or anti-IL-12/23 biologics 
12 weeks prior to baseline endoscopy 
until after the Follow-Up visit. 
Tofacitinib. 
Within 4 weeks prior to baseline 
endoscopy until after the Follow-Up visit. 
Rituximab. 
Within 1 year prior to baseline endoscopy 
until after the Follow-Up visit. 
Any other biologic therapy for the 
treatment of UC not listed above.  
Within 3 months, 5 half-lives or twice the 
duration of the biological effect 
(whichever is longer) prior to baseline 
endoscopy until after the Follow-Up visit. 
Any other small molecule agent for the 
treatment of UC not listed above. 
Within 30 days, 5 half-lives or twice the 
duration of the biological effect 
(whichever is longer) prior to baseline 
endoscopy until after the Follow-Up visit.  
Treatment with any other form of 
systemic immunosuppressive medication 
not mentioned elsewhere in this table or in 
Section 6.6.1. 
Prohibited during the study and until after 
the Follow-Up visit. 
Leukocyte apheresis. 
Within 4 weeks prior to baseline 
endoscopy until after the Follow-Up visit. 
Faecal microbiota transplantation. 
Within 4 weeks prior to baseline 
endoscopy until after the Follow-Up visit. 
Live vaccination. 
Within 4 weeks of Day 1 until after the 
Follow-Up visit. 
 
6.6.3. 
Rescue Therapy 
If a participant requires rescue therapy for UC (including treatments specified in Section 
6.6.2, and/or surgical intervention), or a dose increase of background UC medication is 
required, he/she should discontinue study Intervention, and the appropriate treatment 
should be given at the discretion of the Investigator. Doses of permitted concomitant 
medication for UC should not otherwise be increased for the duration of the study, although 
if a corticosteroid taper has occurred, prescribed corticosteroid doses may be increased up 
to, but not beyond, the dose prescribed at baseline (see Section 6.6.1.1). The date and time 
of rescue intervention, as well as the name and dosage regimen of the rescue medication, 
must be recorded. Following intervention discontinuation participants should undertake an 
Early Withdrawal visit and a Follow-Up visit approximately 16 weeks after the last dose 


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at a minimum. However, it is encouraged that participants undertake all remaining 
scheduled visits set out in the SoA, Section 1.3. 
6.6.4. 
Potential for drug-drug interactions 
No formal drug-drug interaction studies have been performed with GSK2831781. 
However, during inflammation, enzymes such as cytochrome P450 can sometimes be 
down-regulated, leading to reported instances of reduced clearance and increased plasma 
concentrations of administered drugs. If inflammation related to ulcerative colitis changes 
over the course of the study, this might have an indirect effect on drug metabolising 
enzyme expression and activity, although the magnitude and impact of such interactions 
are generally small.  
Participants who are co-administered drugs that are metabolised by cytochrome P450 and 
have a narrow therapeutic index should be monitored for clinical evidence of changes in 
exposure (e.g. evidence of reductions in drug efficacy, or of increased effect or toxicity). 
Therapeutic drug monitoring should be performed as clinically indicated. 
6.7. 
Dose Modification 
Dose regimens (levels and/or frequencies) of GSK2831781 as described in Section 4.3 
may be modified up or down based on ongoing review of the unblinded safety, 
pharmacokinetic, pharmacodynamic, biomarker and efficacy data by the DRC. However, 
exposure levels will not exceed those of the GSK2831781 450 mg dose regimen. 
6.8. 
Intervention after the End of the Study 
Study intervention will cease at the end of a participant’s Follow-Up period. GSK2831781 
will not be made available to participants after the end of the study due to the early stage 
of development, and because other treatments are available. The Investigator is responsible 
for ensuring that consideration has been given to the post-study care of the participant’s 
medical condition. 
 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
An SRT will oversee the safety of participants in this study. The SRT will review blinded 
safety data at regular intervals during the study and ad hoc as required, and have oversight 
of any emerging safety data related to GSK2831781, as described in the SRT charter. The 
DRC will review unblinded safety and efficacy data at defined intervals. Full details are 
included in the DRC Charter. 
7.1. 
Discontinuation of Study Intervention 
If study intervention is permanently discontinued, the participant should be encouraged to 
remain in the study and complete the planned visits and assessments for the treatment 
phase they are in at the time of treatment discontinuation, with a final Follow-Up visit 


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approximately 16 weeks from the last dose received, if possible. In the event of an early 
withdrawal from the study (See Section 7.2), participants should be encouraged to 
complete the early withdrawal visit and a Follow-Up visit approximately 16 weeks after 
the last dose event. 
In addition, the Investigator should determine the primary reason for study intervention 
discontinuation. Withdrawal from study intervention due to an AE should be distinguished 
from withdrawal from study intervention due to insufficient response according to the 
definition of an adverse event.  
7.1.1. 
Individual Safety Stopping Criteria 
Study medication will be discontinued in the event of any of the following:  
• The participant develops a serious or severe opportunistic or atypical infection.  
• The participant experiences a serious or severe clinically significant 
hypersensitivity reaction following study investigational product administration, 
meeting the CTCAE criteria: 
o 
Anaphylaxis Grade 3 or 4. 
o 
Allergic reaction Grade 3 or 4. 
o 
Serum Sickness Grade 2-4. 
• The participant experiences a serious clinically significant Cytokine Release 
Syndrome, defined as CTCAE Grade 2-4. 
• The participant experiences an SAE where in the clinical judgement of the 
Investigator there is a reasonable possibility that the SAE may be caused by the 
investigational product.  
• 
The participant becomes pregnant. 
• The participant requires prohibited medications or an escalation of background 
medications above baseline for the treatment of ulcerative colitis (Section 6.6.2), 
including surgery. 
• If the predetermined haematologic stopping criteria; liver chemistry stopping 
criteria; or QTc stopping criteria are met.  
 
Full CTCAE descriptions and grades can be found in the accompanying SRM or the U.S 
Department of Health and Human Services, Common Terminology Criteria for Adverse 
Events (CTCAE), Version 5.0 (2017). 
7.1.2. 
Haematologic Temporary Withholding and Stopping Criteria 
7.1.2.1. 
Temporary withholding 
Study treatment will be temporarily withheld for a participant if the absolute neutrophil 
count falls below 1.0x109/L. Confirmatory re-testing should be undertaken within 3-5 
days, and should be re-tested every 3-5 days until values have returned to above the 
haematological exclusion criteria threshold (1.5x109/L), at which point dosing can be 
resumed (however, two consecutive doses of GSK2831781, whether IV or SC, should 
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within a period of time judged reasonable by the Investigator, the aetiology should be 
identified, and the sponsor notified. 
7.1.2.2. 
Permanent discontinuation 
Study treatment will be discontinued for a participant if the following haematological 
stopping criteria are met:  
• Absolute neutrophil count <0.5x109/L on any occasion (confirmed on repeat 
testing within 3-5 days).  
• Absolute neutrophil count <1.0x109/L for 2 weeks. 
• Grade 3 febrile neutropaenia (neutrophil count <1.0x109/L and fever ≥38.5 °C). 
Treatment restart or re-challenge for these participants is not allowed. The Investigator 
must immediately inform the Medical Monitor of the event, and repeat testing must be 
conducted at an appropriate frequency until haematological laboratory values have 
returned to above the lower limit of normal.  
7.1.3. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed (see 
algorithm below) to assure participant safety and evaluate liver event aetiology.  
 
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse 
event; ULN = upper limit of normal. 
Symptoms of liver injury or hypersensitivity include: fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash, and/or eosinophilia. 
 
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6, Section 10.6. 
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
➢If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
➢Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
➢Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5*


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7.1.4. 
QTc Stopping Criteria 
A participant who meets the bulleted criteria based on the average of triplicate ECG 
readings will discontinue study treatment:  
• QTc >500 msec OR uncorrected QT >600 msec. 
• Change from baseline of QTc >60 msec. 
 
7.1.5. 
Group and Study Safety Stopping Criteria 
In addition to the individual stopping criteria specified above, blinded data of AEs, SAEs, 
laboratory abnormalities, ECG abnormalities, and changes in vital signs occurring across 
all randomised participants will be regularly reviewed by the SRT to ensure appropriate 
participant safety.  
Study stopping criteria have been set with respect to numbers of individual permanent 
discontinuations due to neutropaenia attributable to GSK2831781 (see Section 7.1.2.2): 
• ≥2 participants, in up to 9 participants dosed in the study. 
• ≥5 participants, in up to 60 participants dosed in the study. 
• ˃10% of participants for the remainder of the study. 
Rates meeting these thresholds will trigger an ad hoc DRC review, to determine whether 
neutropaenia is likely to be attributable to GSK2831781. Furthermore, the study may be 
terminated prematurely if there are new toxicological findings, SAEs or frequent AEs that 
invalidate the positive benefit-risk assessment. Any changes to the study due to safety 
reasons will be promptly communicated to the appropriate Regulatory Authorities. 
7.1.6. 
Temporary withholding of IP 
Temporary withholding of IP may occur in the event of: 
• Meeting treatment withholding criteria for neutropaenia (see Section 7.1.2.1) 
• In the event of a clinically significant infection that the Investigator believes may 
be related to, or exacerbated by, ongoing treatment with the study drug, and none 
of the permanent stopping rules have been met. 
• In the event that the participant has a close household contact with a highly 
transmissible infection, the Investigator has discretion to delay dosing. 
 
If the scheduled dose window is missed, re-initiation of study treatment intervention should 
be restarted as soon as possible but should not result in two consecutive doses, whether IV 
or SC, being given less than 7 days apart (see Section 6.5). 
 


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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. 
At the time of discontinuing study treatment, participants should be encouraged to stay on 
schedule and attend all remaining visits set out in the SoA (Section 1.3) until the end of the 
current study phase. An Early withdrawal visit is only required for participants who 
prematurely discontinue study treatment and do not agree to complete the remaining 
scheduled visits for that phase. In both cases, all participants should undertake a Follow-
Up visit approximately 16 weeks from the last dose received, where the participant will be 
permanently discontinued from the study at that time. 
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled 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, Section 10.1.9. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
A signed, written informed consent form must be obtained from the participant prior 
to any study-specific procedures or assessments being performed. 
• 
Study procedures and their timing are summarized in Section 1.3.  
• 
Protocol waivers or exemptions are not allowed.  
• 
Immediate safety concerns should be discussed with the Sponsor 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. 
• 
The maximum amount of blood collected from each participant over the duration of 
the study is not expected to exceed 600 mL; however, repeat or unscheduled samples 
may be taken for safety reasons or for technical issues with the samples. 
For details on home healthcare and telemedicine approaches, please refer to Appendix 10. 
 
8.1. 
Baseline Assessments 
Baseline assessments will be captured to ensure characterisation of participants at baseline. 
The information to be captured is described fully in the SRM; however, in summary it 
includes but is not limited to: 
• Extent of disease (proctosigmoiditis, left-sided or extensive/pancolitis). 
• Duration of disease (date of diagnosis). 
• Activity of disease. 
• Previous treatment(s) for UC and reasons for discontinuation (if discontinued) – 
for each treatment. 
• Smoking status. 
• Extra-intestinal manifestations. 
• Past medical history. 
• Medication history. 


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8.2. 
Efficacy Assessments 
8.2.1. 
Clinical Disease Assessments 
8.2.1.1. 
Mayo Score 
Clinical disease assessments will be undertaken using the Mayo Score. Multiple 
derivations will be calculated (described below) to enable characterisation of disease 
status, whilst also enabling comparison of disease remission and response with previous 
clinical studies in UC. 
• The Complete 4-domain Mayo Score is a 12-point scoring system where disease is 
evaluated based on stool frequency, rectal bleeding, physician global assessment 
(PGA) and endoscopic appearance (with 
associated with an 
endoscopic score of ).  
• The Adapted Mayo Score is a 9-point scoring system where disease is evaluated 
based on stool frequency, rectal bleeding and endoscopic appearance (with any 
associated with an endoscopic score of
or ). 
• The Partial Mayo Score is a 9-point scoring system where disease is evaluated 
based on stool frequency, rectal bleeding and PGA, but no endoscopy component, 
and will be used to follow changes in these parameters over the course of the study. 
The patient reported outcomes of Stool Frequency and Rectal Bleeding for Mayo scores 
will be calculated from participant eDiary data. To provide a participant’s Mayo score 
status during study conduct, eDiary data will be transcribed into the eCRF for calculation 
of the Stool Frequency and Rectal Bleeding subscores. Identification of data to be used for 
calculation of the Mayo score will be based on:  
• 3 consecutive days. 
o Where 3 consecutive days are not available, non-consecutive days may be used.  
o For determining eligibility in Screening, 3 days are mandatory. Exceptionally, 
for determining Responder status at Week 10 double blind and Week 22 Open 
Label, 2 days may be sufficient, the RAP details how these participants will be 
handled in the study analysis. 
• Within 7 days prior to the endoscopy. 
• As close to the date of endoscopy as possible. 
• Excluding any days in which bowel preparations are administered. 
 
For further guidance on which days to select in case of missed eDiary entries in any of the 
targeted days, see SRM for full details. Note that calculations must be made within eCRF 
to determine Eligibility (prior to Randomisation) and Responder status. 
Complete and Adapted Mayo Scores will be calculated from eDiary data, site reported 
PGA scores and centrally read endoscopy scores at all time points indicated in the SoA 
(Section 1.3). Definitions of each of the Mayo Score systems, and associated response and 
remission definitions for each score, can be found in Appendix 7, Section 10.7. 
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To enable Mayo scoring of stool frequency it is necessary to determine baseline ‘normal’ 
number of stools per day through discussion between the patient and the Investigator. 
‘Normal’ will be defined to the participant as “the number of stools in a 24 hour period 
when you are not experiencing a UC flare, or when you were in remission”. If the patient 
reports that they have not attained remission, then the patient will be asked to identify the 
number of stools he or she had per day before the initial onset of signs and symptoms of 
UC. This will be used to inform subsequent Mayo scoring of stool frequency. 
8.2.1.2. 
Ulcerative Colitis Endoscopic Index of Severity 
The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) will be used as an additional 
tool to assess disease activity based on endoscopic vascular pattern, bleeding, erosions and 
ulcerations (see SRM for detail). It has been shown to accurately reflect overall assessment 
of endoscopic severity of UC and predict outcomes in severe disease [Xie, 2018]. Its 
broader range than the Mayo endoscopic score facilitates assessment of the dose-response 
relationship [Travis, 2012]. The UCEIS will be collected and scored centrally at all time 
points indicated in the SoA (see Section 1.3). 
8.2.2. 
Histological Disease Assessments 
Definitions of histological remission for histological disease assessments are included in 
the RAP. During the study, the Robarts Histopathology Index, Nancy Histological Index 
and Geboes Score will be assessed by central reading of gut pinch biopsies. Key domains 
for scoring of the indices include: chronic inflammatory infiltrate; neutrophils in the 
epithelium; lamina propria neutrophils (and eosinophils – Geboes Score); erosion and 
ulceration; and crypt destruction (Geboes Score). 
8.2.3. 
Extraintestinal Manifestations 
Extraintestinal manifestation (EIM) assessments are key clinical manifestations related to 
UC, and will be evaluated at screening and during the study (see SoA, Section 1.3). A 
number of EIMs will be assessed including but not limited to: 
• Peripheral arthritis. 
• Axial arthropathy. 
• Dermatological manifestations. 
• Uveitis. 
• Primary sclerosing cholangitis. 
• Oral aphthous ulceration. 
If present, EIMs will be scored by the Investigator as detailed in the SRM. 
8.2.4. 
Patient Reported Outcomes 
All patient reported outcome (PRO) questionnaires will be completed on an electronic 
device. A Bowel Symptom Diary will be completed by participants daily at home, 
throughout the study. PRO measures for health outcomes assessment will be completed at 


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study visits, before any other study assessments, also on an electronic device. Sites will 
receive notification from the ePRO vendor when patients fail to complete the ePRO diary 
or other measures, and should follow-up with the patient to ensure completeness for all 
PRO questionnaires. 
8.2.4.1. 
Participant Bowel Symptom Diary 
Participants will be provided with a hand-held electronic device on which to record their 
bowel symptom data on a daily basis. The instructions will be provided to participants, to 
record the following information during the study: 
Concepts covered: 
• Absolute number of toilet visits for bowel movement.  
• Frequency and description of blood in stools. 
• Night time awakenings to go to the toilet for a stool.  
• Bowel urgency. 
• Tenesmus. 
8.2.4.2. 
Patient Reported Outcomes (PRO) for Health Outcomes Assessment 
The electronic device will be used to record various patient-reported outcomes (PRO) 
assessments on the specified study visit days before any other clinic assessments (refer to 
Section 1.3). The PROs used within this study will include but not be limited to: 
• Inflammatory Bowel Disease Questionnaire (IBDQ).  
• Short Form-36, version 2 (SF-36).  
• FACIT-Fatigue. 
• Patients’ Global Impression of Change (PGIC) and Severity (PGIS). 
 
8.2.4.2.1. Inflammatory Bowel Disease Questionnaire (IBDQ) 
The IBDQ questionnaire is a psychometrically validated patient-reported outcome (PRO) 
instrument for measuring the disease-specific quality of life in participants with 
Inflammatory Bowel Disease, including UC. The IBDQ comprises 32 items, which are 
grouped into four dimensions: bowel function (10 items), systemic symptoms (5 items), 
social function (5 items), and emotional status (12 items). The four domains are scored as 
follows:  
• Bowel symptoms: 10 to 70. 
• Systemic symptoms: 5 to 35. 
• Emotional function: 12 to 84. 
• Social function 5 to 35. 


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The total IBDQ score ranges from 32 to 224. For the total score and each domain, a higher 
score indicates better quality of life. A score of at least 170 corresponds to clinical 
remission and an increase of at least 16 points is considered to indicate a clinically 
meaningful improvement. See SRM for the complete IBDQ. 
8.2.4.2.2. Short Form-36, version 2 (SF-36) 
The SF-36 is a widely used general health status questionnaire that assesses 8 domains of 
functional health and well-being: Physical Functioning, Role Limitations due to Physical 
Health Problems, Bodily Pain, Social Functioning, Mental Health, Role Limitations due to 
Emotional Problems, Vitality, and General Health Perceptions. A Physical health 
component summary score and Mental health component summary score are calculated 
from the 8 domain scores. The measure uses a recall period of one week. All questions are 
scored on a scale from 0 to 100, with 100 representing the highest level of functioning 
possible. The SF-36 is a psychometrically valid and reliable instrument that has been 
translated into many languages, and the scores have been shown to be responsive to 
change. Higher scores indicate better health-related quality of life. 
On the specified study visit days, participants should complete the SF-36 on the electronic 
hand-held device, before other clinic assessments (refer to Section 1.3). The SF-36 should 
be checked for completeness by the study site staff. See SRM for the complete SF-36. 
8.2.4.2.3. Patients Global Impression of Change (PGIC) and Severity (PGIS) 
Patient Global Impression of Change is a subjective instrument commonly used to measure 
the perceived degree of change experienced by the patient. Patients will be asked to choose 
the response option that best describes the overall change in their UC symptoms since they 
started taking the study medication, on a 5-point Likert scale, at specific timepoints 
throughout the study (See Section 1.3). Response options range from “Much Better” to 
“Much Worse”. See SRM for the full PGIC. 
Patient Global Impression of Severity is a subjective instrument commonly used to 
measure the degree of disease severity experienced by the patient. Patients will be asked 
to choose the response option that best describes the severity of their UC symptoms in the 
last 7 days, on a 5-point Likert scale, at specific timepoints throughout the study (see 
Section 1.3). Response options range from “None” to “Very Severe”. See SRM for the full 
PGIS. 
8.2.4.2.4. FACIT Fatigue  
The Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-Fatigue) is a 13-
item tool that measures an individual’s level of fatigue during their usual daily activities 
over the past week. Each question is rated on a scale of 0 (“
”) to 4 (“
”), 
with total scores ranging from 0 to 52, and lower scores representing greater fatigue.  
On the specified study visit days, participants should complete the FACIT-Fatigue scale 
on the electronic hand-held device, before other clinic assessments (refer to Section 1.3). 
The FACIT-Fatigue should be checked for completeness by the study site staff. See SRM 
for the full FACIT-Fatigue. 
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8.2.5. 
Exit Interviews 
A sub-group of participants will be invited to take part in qualitative, one-to-one interviews 
at the end of the study (see Section 1.3, and the SRM). Exit interviews will cover the 
following scope: 
• Patient feedback on the daily Bowel Symptom Diary, including patient burden, 
comprehensiveness of symptoms covered, completion time, recall period, clarity 
of instructions, clarity of questions and supporting definitions and appropriateness 
of response options. 
• Patient feedback on PRO measures for Health Outcomes Assessment (including 
IBDQ, SF-36, FACIT-Fatigue, PGIS and PGIC), including patient burden, ease of 
completion, comprehensiveness of symptoms and impacts covered by these 
instruments. 
• Patient feedback on trial experience. 
8.3. 
Pharmacokinetics 
Blood samples for pharmacokinetic analysis of GSK2831781 will be collected at the time 
points indicated in Section 1.3, for all participants. 
In order to properly characterise subcutaneous bioavailability and PK, additional 
subcutaneous PK and sLAG3 sampling will be performed on a subset of participants. The 
additional samples will be taken according to one of two schedules (Table 5 and Table 6), 
determined in discussion with the Sponsor or their representative and the study site. Once 
samples have been collected for a sufficient number of participants, this sampling may be 
discontinued, at the discretion of the Sponsor. The actual date and time of each blood 
sample collection will be recorded. The timing of PK samples may be altered and/or PK 
samples may be obtained at additional time points to ensure thorough PK monitoring. 
Collection, sample handling, processing, storage and shipping procedures are provided in 
the SRM or equivalent. 
For details on home healthcare approaches, please refer to Appendix 10. 
 


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Table 5 
SC PK and sLAG3 characterisation schedules for selected 
participants – Schedule 1 
Week 
14 
 
15 
Days since first SC dose  
1 
3 
7 
PK 
X 
X 
X 
sLAG3 
X 
X 
X 
Footnote: Samples can be taken at any time on the day 
 
Table 6 
SC PK and sLAG3 characterisation schedules for selected 
participants – Schedule 2 
Week 
14 
 
15 
Days since first SC dose  
2 
5 
10 
PK 
X 
X 
X 
sLAG3 
X 
X 
X 
Footnote: Samples can be taken at any time on the day 
8.3.1. 
Soluble LAG3 (sLAG3) 
Venous blood samples will be collected for measurement of soluble LAG3 (sLAG3) as 
specified in the Section 1.3, and in Table 5 and Table 6. 
8.4. 
Pharmacodynamics 
The pharmacodynamic (PD) effect of GSK2831781 on LAG3+ cell depletion will be 
determined through analysis of blood, and gut pinch biopsies. Blood PD analysis will be 
undertaken in a subset of the patient population, at selected sites able to meet shipping 
requirements (within 48 hrs of testing labs) through flow cytometry. In addition, the PD of 
GSK2831781 will be determined in gut pinch biopsies through immunohistochemistry. 
Further detail on gut biopsy can be found in Section 8.4.1.3.  
8.4.1. 
Biomarkers 
Collection of samples for other biomarker research to explore UC disease processes and 
the impact of GSK2831781 is also part of this study. The following samples for biomarker 
research are required and will be collected from all participants in this study as specified 
in the SRM or equivalent: 
• Blood. 
• Faeces. 


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• Intestinal pinch biopsy. 
8.4.1.1. 
Exploratory biomarkers in Blood 
Serum samples for blood biomarkers will be collected at the time points indicated in the 
SoA (Section 1.3) to characterise systemic markers of UC and the impact of GSK2831781. 
Changes from baseline of markers of inflammation including but not limited to C-reactive 
protein (CRP) and cytokines will be explored. Proteomic and transcriptomic analysis may 
also be conducted on blood samples to investigate markers of disease activity, pathogenesis 
and potential stratifying markers of responsiveness. 
8.4.1.2. 
Biomarkers in faeces 
To further characterise biomarkers of UC and the impact of GSK2831781 on intestinal 
inflammation, faecal samples will be taken to enable measurement of markers including 
but not limited to faecal calprotectin, at the time points indicated in the SoA (Section 1.3). 
Information on sample processing is provided in the SRM or equivalent. 
8.4.1.3. 
Tissue Biopsy 
Tissue biopsies will be taken to assess the impact of GSK2831781 on mucosal healing, 
inflammation and target cell depletion. A target of nine ‘adequate’ biopsies for trial 
purposes (see SRM for detail) will be taken throughout the inflamed colon 15-25 cm from 
the anal verge during the endoscopy at baseline screening, Week 10 (all participants), and 
at Week 30 for Responders and Week 22 for Non-Responders on Open Label Treatment.  
Details of biopsy sample collection processing, storage and shipping procedures are 
provided in the SRM or equivalent. Tissue samples will be divided accordingly for: 
• Histology and immunohistochemistry assessments (approximately 3 biopsies). 
including but not restricted to numbers of CD3+ LAG3+ T cells. 
• Gene expression analyses (approximately 3 biopsies) of markers of inflammation 
and tissue healing, including not limited to LAG3, IL-1β, IL-6 and IL-8. 
• With the remaining biopsies (approximately 2, up to 3 biopsies), additional 
techniques including and not limited to epigenetic counting and T cell receptor 
(TCR) sequencing may be used to determine the effect of GSK2831781 on 
pathophysiological pathways in IBD.  
8.5. 
Pharmacogenetics 
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 
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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, Section 10.5 for Information regarding genetic research. Details on 
processes for collection and shipment and destruction of these samples can be found in 
SRM or equivalent. 
8.6. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3).  
8.6.1. 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the Skin, 
Cardiovascular, Respiratory, Gastrointestinal, Endocrine and Neurological systems. 
Height (at baseline only) and weight will also be measured and recorded. 
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (including liver and spleen). 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
For telemedicine visits, an evaluation of the participant will be performed by a physician 
through a video telemedicine format. If the Investigator feels an adequate clinical 
assessment has not been achieved, a clinic visit must be performed. 
8.6.2. 
Vital Signs 
Pre-dose vital signs are to be taken before blood collection for laboratory tests. 
Vital signs to be measured in a seated or semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure and pulse rate. 
Blood pressure and pulse measurements will be with a completely automated device. 
Manual techniques will be used only if an automated device is not available. 
8.6.3. 
Electrocardiograms 
• Triplicate (at screening) or single 12-lead ECG will be obtained as outlined in 
Section 1.3 using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTc intervals. The same QT correction formula must 
be used for each individual participant to determine eligibility for and 
discontinuation from the study, and this formula may not be changed or substituted 
once the participant has been screened. 
• Where single ECG measurements are obtained, if the QTc measurement fulfils a 
QTc withdrawal criterion an additional two QTc readings will be obtained and the 


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average of these three measurements will be used. Refer to Section 7.1.4 for QTc 
withdrawal criteria and additional QTc readings that may be necessary. 
At each time point at which triplicate ECG are required, 3 individual ECG tracings should 
be obtained as closely as possible in succession, but no more than 2 minutes apart. The full 
set of triplicates should be completed in less than 4 minutes. 
8.6.4. 
Clinical Safety Laboratory Assessments 
Refer to Appendix 2, Section 10.2 for the list of clinical laboratory tests to be performed 
and to Section 1.3 for the timing and frequency. 
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 16 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 laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the Investigator (e.g. SAE or AE or dose modification), this must 
be documented in the eCRF. 
If such values do not return to normal/baseline within a period of time judged reasonable 
by the Investigator, the aetiology should be identified and the sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 2, Section 10.2, must 
be conducted in accordance with the SRM or equivalent and Section 1.3. 
8.6.5. 
Immunogenicity Assessments 
Antibodies to GSK2831781 will be evaluated in serum samples collected from all 
participants according to Section 1.3. Additionally, serum samples will also be collected 
at the Withdrawal visit from participants who discontinued study intervention or were 
withdrawn from the study. The detection and characterization of antibodies to 
GSK2831781 will be performed using a validated assay method by or under the 
supervision of the Sponsor. 
Serum samples will be assessed for the presence of ADA using a tiered approach. Samples 
will first be screened for antibodies binding to GSK2831781. Samples with screening 
result above the screening cut point will be further assayed in an assay to confirm the 
specificity of the ADA. Samples testing positive in the confirmation assay will be further 
assayed through sequential dilution in order to report a titre value. The titre is the reciprocal 
of the last dilution at which the sample tests positive in the screening assay. Additional 
analysis may be performed on samples collected to monitor immunogenicity to assess the 


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presence of neutralizing antibodies to GSK2831781 and/or to further characterize the 
immunogenicity of GSK2831781. 
8.6.6. 
Infusion-related Reactions, Hypersensitivity Reactions and 
Cytokine Release Syndrome. 
As GSK2831781 is a fully humanized monoclonal antibody, it is considered unlikely that 
acute allergic reactions will occur in response to GSK2831781 exposure; however, all 
participants should be monitored carefully for evidence of allergic response. In the event 
of a suspected acute hypersensitivity reaction two blood samples should be taken for serum 
tryptase analysis: 
• As soon as possible after the onset of symptoms, and 
• Within 1-2 hours (but no later than 4 hours) from the onset of symptoms. 
Participants should be instructed to report the development of rash, hives, pruritus, 
flushing, urticaria, vomiting, or other symptoms that may represent a hypersensitivity 
reaction to study intervention. In the case of a mild reaction, study intervention 
administration may be reinitiated (with appropriate pre-medication) at the discretion of the 
Investigator. Participants with a serious or severe clinically significant hypersensitivity 
reaction following study investigational product administration meeting the CTCAE 
criteria set out in Section 7.1.1 should discontinue study treatment. 
If cytokine release syndrome (CRS) is suspected, in addition to assessment for infection, 
cytokine levels (including IL-6, IL-8, IFN-γ and TNF-α) and CRP should be measured 
approximately every other day until symptoms show improvement or an alternative 
diagnosis is confirmed. 
8.6.7. 
Immunosuppression and Infections 
Patients with signs and symptoms suggestive of infection should be treated as clinically 
indicated according to medical best practice. Blood, sputum, urine, and/or stool cultures 
will be obtained as appropriate for detection and diagnosis of infection. Blood samples for 
determination of viral serology ± measurement of viral load (CMV, EBV, VZV), as well 
as measurement of immunoglobulins, will be taken if the participant demonstrates clinical 
symptoms consistent with viral reactivation; serology samples for these viruses will also 
be tested at baseline. 
If the infection fulfils the Individual Safety Stopping Criteria specified in Section 7.1.1, 
study treatment should be discontinued. 
8.6.8. 
Autoimmunity 
There are a small percentage of regulatory T cells that are LAG3+ [Chung, 2013 Gagliani, 
2013; Bornkamp, 2014; Camisaschi, 2010; and GSK internal data], and therefore 
Investigators should be alert for the development of autoimmunity. Any participant who 
reports symptoms suspicious for autoimmunity should be investigated and managed as 
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8.7. 
Adverse Events and Serious Adverse Events 
The definitions of an AE and SAE can be found in Appendix 3, Section 10.3. 
The Investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the study, 
or that caused the participant to discontinue GSK2831781 treatment (see Section 7). 
8.7.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
All SAEs will be collected from the signing of the informed consent form until the Follow-
Up visit at the time point specified in the SoA (Section 1.3). 
All AEs will be collected from the start of intervention until the Follow-Up visit 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, Section 10.3. 
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. 
8.7.2. 
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, 
Section 10.3. 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
8.7.3. 
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 AE/SAEs will be followed until the event is 
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in Section 7.3). Further information on follow-up procedures is given in Appendix 3, 
Section 10.3 
8.7.4. 
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 SAEs) 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. 
 
8.7.5. 
Pregnancy 
Details of all pregnancies in female participants will be collected after the start of study 
intervention and until the end of Follow-Up.  
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, Section 10.4.3. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.7.6. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Appendix 3, Section 10.3.3 (Definition of 
Cardiovascular Events) and all deaths, whether or not they are considered SAEs, specific 
Cardiovascular (CV) and Death sections of the CRF will be required to be 
completed. These sections include questions regarding cardiovascular (including sudden 
cardiac death) and non-cardiovascular death.  
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities Terminology (MedDRA) terms. The CV information 
should be recorded in the specific cardiovascular section of the CRF within one week of 
receipt of a CV Event data query prompting its completion. 


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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. 
8.8. 
Treatment of Overdose 
For this study, any dose of GSK2831781 greater than the agreed dose level and frequency 
for a particular cohort will be considered an overdose. 
GSK does not recommend specific treatment for an overdose.  
In the event that an overdose is identified by unblinded staff, but is less than 450 mg in a 
7 day period, this should be documented by the unblinded monitor (including the quantity 
and duration of the overdosing), but no additional action need be taken. 
If the total dose administered has exceeded 450 mg in a 7 day period, the unblinded 
monitor should:  
1. Contact the Medical Monitor immediately. 
2. Ask the Medical Monitor to request that the Investigator closely monitors the 
participant for AE/SAE and laboratory abnormalities for at least 4 weeks from the 
date the overdose occurred, and thereafter as advised by the Medical Monitor. 
3. If the overdose is identified within 21 days of its occurrence, request that the 
Medical Monitor advises the Investigator to obtain a plasma sample for PK analysis 
as soon as possible, and thereafter as advised by the Medical Monitor.  
4. Document the quantity of the excess dose as well as the duration of the overdosing 
 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The first primary objective of this study is to assess the safety and tolerability of 
GSK2831781 in participants with moderate to severe UC. No formal hypotheses will be 
tested for this objective. 
The second primary objective of this study is to evaluate the dose-response relationship in 
the change from baseline in the Complete 4-domain Mayo score, following 10 weeks of 
treatment with GSK2831781 or placebo. The dose response relationship will be 
characterised using the posterior probabilities of the parameters of an Emax model and by 
estimating the response at each dose level, using Bayesian methodologies, this will be the 
primary efficacy analysis. The primary efficacy analysis will therefore not use frequentist 
hypothesis testing, a characteristic of a well fitted model will be that the half width of the 
95% credible interval for the change from baseline in Complete 4-domain Mayo response 
at ED90 is ≤1. The dose-response relationship will also be assessed for selected categorical 
secondary endpoints (Endoscopic Improvement, Clinical Response and Clinical 
Remission). 


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9.2. 
Sample Size Determination 
9.2.1. 
Sample Size Assumptions 
Approximately 242 participants will be randomly assigned to study intervention under the 
assumption that a proportion will not be able to provide a Week 10 Complete 4-domain 
Mayo score assessment under the additional (hypothetical) estimand. If the attrition rate is 
higher than planned for (e.g., 15% or more) then additional participants, up to a maximum 
of 320, may be recruited. 
Primary Analysis: Dose-response change from baseline in Mayo score 
At Week 10 the expected distribution of the change from baseline in the continuous Mayo 
score in the placebo group is a mean of -1 and a standard deviation of 1.5 (based on 
tofacitinib Phase II data [Sandborn, 2012]). Based on these assumptions the proposed 
sample size of 68 participants on the GSK2831781 450mg dose level, 42 participants on 
each of the GSK2831781 lower dose levels, and 48 participants on placebo are sufficient 
to characterise the dose-response curve. This is based on 5000 simulated trials where the 
following Emax model was fitted to simulated data: 
Y = E0 + Emax * (Di) /{ED50 + (Di)  } 
Where E0 is the minimum dose effect, Emax is the maximum achievable effect above 
placebo, ED50 is the dose at half Emax, Di are doses = 0, 45, 150, 300, 450 and  is the 
slope parameter (shape of the potential dose response curve). Y is the change from baseline 
in the continuous Mayo score. E0 is the assumed effect with Dose=0 (placebo) which is -
1, the Emax is taken as -3, is assumed to be 1 and ED50 is assumed to be 100. 
For the E0 and Emax parameters a normal prior with mean 0 and standard deviation of 100 
was used. For ED50 a beta(0.5, 5.2) was used scaled between 0 and 675 (1.5*top dose, as 
suggested by Bornkamp, 2014 as an approximation to the functional uniform prior). For 
the standard deviation a gamma (shape=2, rate=0.1) was used (Chung, 2013). 
Figure 4 below illustrates a sample of fitted model curves. In these simulations the half 
width of the 95% credible interval for the Complete Mayo response at ED90 is ≤1 97% of 
the time: 


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Figure 4 
Dose-response precision based on outlined assumptions 
 
Note: True means from simulation marked in blue 
To illustrate the properties of this sample size if it were to be analysed within a 
frequentist framework, the following sample size assessment is also provided: 
Assuming normal distributions with a standard deviation of 1.5, there would be greater 
than 90% power for a pairwise comparison to detect a difference from placebo of 2 points 
on the change from baseline at Week 10 in Complete 4-domain Mayo score between 42 
participants randomised to GSK2831781 at one of the three lower dose levels and 48 
participants randomised to placebo at a 5% significance level. 
Interim Analysis 3 (See Section 9.5) 
The sample size for the Interim Analysis 3 is based on the change from baseline in the 
Complete 4-domain Mayo score. With 40 participants randomised to GSK2831781 
450 mg and 20 randomised to placebo, assuming a placebo change from baseline of -1 and 
standard deviation of 1.5, there would be 90% power to detect a clinically meaningful 
difference of 2 points on the Complete 4-domain Mayo score between GSK2831781 and 
placebo at a 5% significance level. 
Decision rules at Interim Analysis 3 and at primary completion are based on the proportion 
of participants who achieve endoscopic healing. At Interim Analysis 3, the predictive 
probability of success at the end of the study will be also calculated based on the 
endoscopic healing data observed at this interim analysis and the sample size was also 
evaluated through the assessment of operating characteristics of decision rules based on 


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this endpoint. The study would be stopped for futility if the probability of success was low. 
With this number of participants, assuming a placebo response of 20%, if there was no 
effect of GSK2831781 then there would be a >80% probability that the study would stop 
at this point.  
The Bayesian decision criteria including the definition of end-of-study success are outlined 
in the DRC charter. Supportive frequentist analyses for pairwise treatment differences in 
change from baseline in the Complete 4-domain Mayo score will be provided. 
 
9.2.2. 
Sample Size Re-estimation 
At interim analyses 2, 3 and 4 (see Section 9.5) the sample size may be re-estimated based 
on emerging data. This will be based on the change from baseline in the continuous Mayo 
score. The sample size may need to be re-estimated if higher variability or differing 
placebo means are observed compared to those the study has been designed on. Therefore, 
any significant deviation from the assumptions used to power the study may result in 
changes to the study population including the number of participants to be randomized.  
As part of this re-estimation if the distribution of the advanced therapy experience status 
(naïve or experienced) is unbalanced across the treatment groups then the recruitment 
strategy may be altered to establish a balance. A maximum of 320 participants could be 
randomized into the study following this sample size re-estimation.  
9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Enrolled 
All participants who sign the ICF and were screened for 
eligibility. 
Randomized 
All participants who were randomly assigned to treatment in 
the study. 
Safety 
All randomized participants who receive at least 1 dose of 
study treatment.  
PK 
All participants in the Safety population who had at least 1 
non-missing PK assessment (non-quantifiable values will be 
considered as non-missing values). 
Intent to Treat 
Exposed (ITTE) 
The ITTE population is defined as all participants who were 
randomised to treatment, who received at least one dose of 
study medication and who have at least one valid post dose 
assessment. 


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Population 
Description 
Per Protocol (PP) 
The PP Population is defined as all participants who are 
included in the ITTE population and are not major protocol 
violators with regards to inclusion/exclusion criteria, 
investigational 
product 
compliance 
and 
concomitant 
medication instructions, as defined in the RAP. 
Participants to be excluded from the PP population will be 
identified prior to randomisation being unblinded or any data 
evaluation being performed. 
 
9.4. 
Statistical Analyses 
The Induction Phase and Extended Treatment Phase will be reported separately, where 
the primary and secondary analyses are based on the Weeks 0-10 of the Induction Phase. 
9.4.1. 
Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
(efficacy) 
• Bayesian dose-response analyses will be conducted for change from 
baseline in the Complete 4-domain Mayo score at Week 10. 
• The data will be initially analysed using an Emax model of the form: 
Y = E0 + Emax * (Di) /{ ED50 + (Di)  }; where E0 is the minimum 
dose effect, Emax is the maximum achievable effect above placebo, 
ED50 is the dose at half Emax, Di are doses =0, 45, 150, 300, 450mg 
and  is the slope parameter (shape of the potential sigmoid dose-
response curve). Y is a measure of change from baseline in Mayo 
continuous score. 
• Initially, normal vague priors will be used for E0,  and Emax: 
Normal(0, sd=100). A functional uniform prior will be used for ED50 
and h (Bornkamp, 2014), where the prior density for the functional 
uniform prior is based on all the parameters in the model. The 
parameterisation of the priors used in the analysis will be reported in 
the clinical study report. 
• The primary dose-response model is the 4-parameter Emax model. 
Additional models will also be investigated: 3-parameter Emax 
model, power model, linear, quadratic, log-transformed dose. Each 
of the models will be fitted to the data and their fit compared using 
the Deviance Information Criterion (DIC). The model with the lowest 
DIC will be the primary model for inference if it shows a DIC 
difference from the 4-parameter Emax of at least 5. 
• A four parameter Emax dose-response model, once fitted, will be 
used to estimate the minimally effective dose and 95% credible 
interval of each dose level relative to placebo. 


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Endpoint 
Statistical Analysis Methods 
• If the four parameter Emax model is not applicable then additional 
models will be investigated: three parameter Emax model, power 
model, linear, quadratic, log-transformed dose. Each of the models 
will be fitted to the data and their fit compared using the Deviance 
Information Criterion (DIC), where the model with the lowest DIC 
will be the primary model for inference. 
• Prior medication will be included as a stratification factor: advanced 
therapy naïve, experienced a single class of advanced therapy, or 
experienced multiple classes of advanced therapies. 
• Further details of the Emax model will be defined in the RAP. 
• The primary analysis will use the ITTE analysis population. 
• The primary estimand will use a treatment policy strategy for 
intercurrent events, with the exception of discontinuations due to 
COVID-19 pandemic which will use a hypothetical strategy. 
• Under the hypothetical strategy, data set to missing would be 
assumed to be missing at random (MAR). 
Secondary 
• Analyses of the secondary endpoints will be conducted using similar 
methodology as for the primary endpoint (with an appropriate link-
function for binary endpoints). 
• The decision criteria at the interim analyses 3 and following 
completion of the primary analysis will primarily be based on the 
proportion of participants who achieve endoscopic healing. These are 
based on predictive probabilities based on the data available. Details 
are outlined in Section 9.5, and in the interim analysis charter and 
RAP. 
Exploratory 
• Will be described in the RAP. 
 
 


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9.4.2. 
Safety Analyses 
All safety analyses will be performed on the Safety Population.  
Endpoint 
Statistical Analysis Methods 
Primary 
(safety) 
• No formal statistical testing will be performed on safety data. 
• All safety evaluations will be based on the safety population. 
Clinical interpretation will be based upon review and displays of 
adverse events, laboratory values and vital signs. The principle 
consideration in this evaluation will be the Investigator-reported 
relationships of either adverse events or laboratory abnormalities to 
investigational product.  
• Safety data will be presented in tabular and/or graphical format and 
summarized descriptively according to GSK’s Integrated Data 
Standards Library (IDSL) standards. 
 
9.4.3. 
Pharmacokinetic (PK) and Pharmacokinetic/Pharmacodynamic 
(PK/PD) analyses 
All PK analyses (non-compartmental analysis and population PK analysis) will be 
performed on the PK population. All PK/PD analyses will be performed on the ITTE 
population. 
Using standard non-compartmental analysis methods, the following PK parameters will be 
determined, as data permit, for each participant after SC dosing: Cmax, tmax and AUC(0-
tau). 
The population PK analysis and PK/PD analyses may be presented separately from the 
main clinical study report (CSR). The RAP will describe the planned analyses in greater 
detail. 
9.4.4. 
Other Analyses 
Pharmacodynamic and biomarker exploratory analyses will be described in the RAP.  
9.5. 
Interim Analyses 
In line with routine pharmacovigilance, an internal GSK SRT, which will include a subset 
of the 204869 study team, will review blinded safety data, including clinical laboratory 
parameters and adverse events, at appropriate intervals during the period of study conduct. 
At the interim analyses the data will be reviewed by the DRC. Further details of the DRC 
remit are provided in the DRC charter, and in Section 10.1.5. This charter outlines how the 
DRC will ensure data integrity and appropriate quality control of data prior to making 
decisions, as well as outlining membership of the DRC. 


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Up to four interim analyses may be conducted to assess the safety, pharmacokinetics and 
efficacy of GSK2831781 in this study. Recruitment will continue while the interim 
analyses are being conducted, except in the case of a safety concern. Interim analysis 3 
incorporates a decision for futility. 
 
Interim Analysis 
When 
Objective 
1 (PK) 
Approximately 
fifteen participants 
(across the highest 
dose and placebo) 
have completed 
their 
pharmacokinetic 
assessment at 
Week 2. 
PK will be assessed to determine if the 
exposures 
in 
ulcerative 
colitis 
participants 
are 
similar 
to 
those 
predicted based on data observed in 
healthy volunteers and psoriasis patients. 
2 (Early Efficacy) 
Optional 
Up to a maximum 
of thirty-six 
participants 
(across the highest 
dose and placebo) 
have completed 
Week 10 
assessments. 
Assessment of the endoscopic mucosal 
healing response. 
Data will be reviewed by the DRC for 
internal decision making, where decision 
criteria are outlined in the DRC charter. 
An assessment of futility will not be 
made at this point. 
Additional data may be reviewed, 
including stool frequency and rectal 
bleeding. 
3 (Efficacy futility) 
 
Up to a maximum 
of sixty 
participants 
(across the highest 
dose and placebo) 
have completed 
Week 10 
assessments. 
Assess futility based on the proportion of 
participants who achieve endoscopic 
healing, based on the Mayo score. 
The predictive probability of success at 
the end of the study will be calculated 
based on the data observed at this interim 
analysis.  
The futility rule is outlined in the DRC 
charter and characteristics of which are 
included in the RAP. 
Additional data may be reviewed. 


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Interim Analysis 
When 
Objective 
4 (Pharmacodynamic) 
 
Approximately 
twenty 
participants per 
GSK2831781 
dose level have 
completed 
Week 10 
assessments. 
Assessment of pharmacodynamic dose-
response at Week 10. 
Data will be reviewed by the DRC for 
internal decision making, where decision 
criteria are outlined in the DRC charter. 
An assessment of futility will not be 
made at this point. 
 
The DRC Charter and RAP will describe the planned interim analyses in greater detail. 


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


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10.1.3. 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study. 
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
Participants who are rescreened are required to sign a new ICF. 
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The 
Investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate and 
may withdraw their consent at any time and for any reason during the storage period. A 
separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate will not provide this separate signature. 
10.1.4. 
Data Protection 
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.  
The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant.  
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
 


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10.1.5. 
Committees Structure 
Safety Review Team (SRT) 
In line with routine pharmacovigilance, an internal GSK SRT, which will include a limited 
number of 204869 study team members, will review blinded safety data, including clinical 
laboratory parameters and adverse events, at appropriate intervals during the period of 
study conduct. The SRT charter will outline the roles and responsibilities in more detail. 
Data Review Committee (DRC) 
A DRC will be utilised in this study to ensure objective medical and statistical review of 
safety and efficacy issues in order to protect the ethical and safety interests of participants 
and to protect the scientific validity of the study via review of unblinded study data at 
interim analyses. 
At the planned Interim Analyses unblinded study data will be reviewed by the DRC, and 
decisions made based on the criteria included in the DRC charter, which could include 
stopping the study for futility or altering the sample size based on sample size re-
estimation, increasing up to the maximum of 320 participants.  
The DRC will be composed of a limited number of people, who may be members of the 
204869 study team, including the statistician, a senior safety representative, lead physician 
and where appropriate the pharmacokineticist. Detailed membership is outlined in the 
DRC charter. No members of the study team involved in the direct day to day conduct of 
the study or in the acquisition of data will take part in the DRC. 
10.1.6. 
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 randomization 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 anonymized patient-level data from this trial available to external 
researchers for scientific analyses or to conduct further research that can help advance 
medical science or improve patient care. This helps ensure the data provided by trial 
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A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge. 
10.1.7. 
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.  
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 or contract. 
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 Organizations). 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized 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 15 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. 
10.1.8. 
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 


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explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
10.1.9. 
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. 
10.1.10. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.  
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 7, will be performed by the central laboratory (Q2).  
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 response evaluation. If a local sample is 
required, it is important that the sample for central analysis is obtained at the same 
time.  
• If an emergent result, condition or event warrants further investigation requiring 
tests not performed by the central laboratory (Q2).  
 
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  
• Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria. 
• Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at intervals specified in the SoA (Section 1.3) during intervention. In the 
event of early study withdrawal, pregnancy testing (urine or serum) should be 
conducted at the end of the relevant systemic exposure plus an additional 30 days. 
 
Table 7 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry1 
BUN 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total and direct 
bilirubin 


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Laboratory 
Assessments 
Parameters 
 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein 
Albumin 
 
Glucose 
(nonfasting) 
Calcium 
Alkaline 
phosphatase 
C-Reactive 
Protein 
Routine 
Urinalysis 
• Specific gravity. 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick. 
• Microscopic examination (if blood or protein is abnormal). 
Other 
Screening 
Tests 
• Follicle-stimulating hormone and oestradiol (as needed in women of non-
childbearing potential only). 
• Highly sensitive serum or urine human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of childbearing potential)2. 
• Serology HIV antibody, hepatitis B surface antigen [HBsAg], hepatitis B 
core antibody, and hepatitis C virus antibody. 
• Serology CMV, EBV and VZV at baseline and in the event of possible viral 
reactivation. 
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 7. All events of ALT 3 × upper limit of normal (ULN) 
and bilirubin 2 × ULN (>35% direct bilirubin), or ALT 3 × ULN and international normalized 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. 
Serum testing will be conducted for inclusion criteria. Local urine testing will be standard for the protocol unless 
serum testing is required by local regulation or IRB/IEC. A positive urine test will be confirmed by a serum test. 
 
Laboratory results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded. 


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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
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. hospitalization 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 hospitalization or prolongation of existing hospitalization 
In general, hospitalization 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 hospitalization are AE. If a 
complication prolongs hospitalization or fulfils any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 


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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, diarrhoea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
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 hospitalization but may jeopardize 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 hospitalization, 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. 
• 
Revascularization. 
 


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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 (e.g. 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 utilized 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. 


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• 
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, 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 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. 
 
10.3.5. 
Reporting of SAE to GSK 
SAE Reporting to GSK via eCRF Tool 
• 
The primary mechanism for reporting SAE to GSK will be the eCRF. 
• 
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. 


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• 
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 relationship of each SAE to GSK2831781/study participation (causality) 
within 72 hours of SAE entry into the eCRF. 
• 
After the study is completed at a given site, the eCRF 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 eCRF 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 
• 
In rare circumstances and in the absence of email or facsimile equipment, 
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. 
 


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10.4. 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information 
10.4.1. 
Definitions: 
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. 
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 blood sample with simultaneous follicle stimulating hormone and oestradiol 
falling into the central laboratory’s postmenopausal reference range is 
confirmatory. In questionable cases for women <60 years of age. 
• Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-oestrogen 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 
HIGHLY EFFECTIVE CONTRACEPTIVE METHODSa 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 
• 
Vasectomized partner 
Note: Vasectomized 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 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. 
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. 


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10.4.3. 
Collection of Pregnancy Information: 
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 for medical reasons 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 or be withdrawn from the study. 


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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 
aetiology; 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 GSK2831781 or IBD and related 
diseases. They may also be used to develop tests/assays (including diagnostic tests) 
related to GSK2831781, and/or IBD. Genetic research may consist of the analysis of 
one or more candidate genes or the analysis of genetic markers throughout the genome 
(as appropriate). 
• 
DNA samples will be analysed for epigenetic and T cell repertoire analysis. Additional 
analyses may be conducted if it is hypothesized 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 GSK2831781 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 GSK2831781 (or study interventions 
of this class) or IBD 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 Safety: Required Actions and Follow-up 
Assessments Guidelines 
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event aetiology  
Phase II liver chemistry stopping criteria and required follow up assessments  
Liver Chemistry Stopping Criteria  
ALT-absolute 
ALT 5xULN 
ALT Increase 
ALT 3xULN persists for 4 weeks 
Bilirubin1, 2 
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2 
ALT 3xULN and INR >1.5 
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  
Actions 
Follow Up Assessments 
• Immediately discontinue study intervention.  
• Report the event to GSK within 24 hours. 
• Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2. 
• Perform liver chemistry event follow-up 
assessments. 
• Monitor the participant until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below). 
• Do not restart/rechallenge participant with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 
granted (see below). 
• If restart/rechallenge not allowed per 
protocol or not granted, permanently 
discontinue study treatment and continue 
• Viral hepatitis serology4. 
• Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show downward 
trend. 
• Obtain blood sample for 
pharmacokinetic (PK) analysis, as 
soon as possible, and at least within 7 
days5. 
• 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 


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participant in the study for any protocol 
specified follow up assessments. 
 
MONITORING: 
For bilirubin or INR criteria:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and INR) and 
perform liver event follow up assessments 
within 24 hrs. 
• Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline.  
• A specialist or hepatology consultation is 
recommended. 
For all other criteria:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and INR) and 
perform liver event follow up assessments 
within 24-72 hrs.  
• Monitor participants weekly until liver 
chemistries resolve, stabilize or return to within 
baseline. 
hypersensitivity, on the AE report 
form. 
• Record use of concomitant 
medications on the concomitant 
medications report form including 
acetaminophen, herbal remedies, 
other over the counter medications. 
• Record alcohol use on the liver event 
alcohol intake case report form (CRF) 
page.  
 
 
For bilirubin or INR criteria: 
• Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG) or gamma globulins. 
• Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite or 
likely acetaminophen use in the 
preceding week). 
• Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and/or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
pages. 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
2. All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin), or ALT 3xULN and INR>1.5, which may 
indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the threshold value stated will not apply to participants receiving anticoagulants. 
3. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia). 
4. Includes: Hepatitis A immunoglobulin M (IgM) antibody; HBsAg and HBcAb; Hepatitis C RNA; Cytomegalovirus 
IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 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-GSK comparator 
interventions. Record the date/time of the PK blood sample draw and the date/time of the last dose of study 


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intervention prior to 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 SRM. Not required for single-dose studies or equivalent. 
 
Phase II liver chemistry increased monitoring criteria with continued therapy 
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
ALT 3xULN and <5xULN and 
bilirubin <2xULN, without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks 
• Notify the GSK Medical Monitor within 24 hours 
of learning of the abnormality to discuss 
participant safety.  
• Participant can continue study intervention.  
• Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline.  
• If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above. 
• If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice 
monthly until liver chemistries normalize or return 
to within baseline. 
 
 


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10.7. 
Appendix 7: Mayo Clinic Score Definitions 
Complete 4-domain Mayo Clinic Score (MCS)* 
Clinical remission: 
Complete MCS ≤2, with no individual subscore >1. 
Clinical response: 
 Reduction in Complete MCS ≥3 points from baseline AND ≥30% 
from baseline AND decrease in the rectal bleeding subscore of ≥1 
point from baseline (or a score of 0 or 1). 
Partial MCS* 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third 
party copyright laws and therefore have been excluded.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third 
party copyright laws and therefore have been excluded.


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Clinical remission: 
Partial MCS ≤2, with no individual subscore >1. 
Clinical response: 
Reduction in partial MCS ≥2 points from baseline AND ≥30% 
from baseline, AND a decrease in the rectal bleeding score of ≥ 1 
point from baseline or a score of 0 or 1. 
Adapted 3-domain MCS* 
Clinical remission: 
Adapted MCS of ≤2 with no individual subscore >1, a rectal 
bleeding subscore of 0, and stool frequency subscore ≤1 and not 
greater than baseline. 
Clinical response: 
Reduction in adapted MCS ≥2 points from baseline AND ≥30% 
from baseline, AND a decrease in the rectal bleeding score of ≥ 1 
point from baseline or a score of 0 or 1. 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third 
party copyright laws and therefore have been excluded.
CCI


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10.8. 
Appendix 8: Country-specific requirements 
10.8.1. 
The Netherlands 
Participants recruited from the Netherlands must fulfil the following inclusion criterion: 
• Inadequate response to, loss of response to, or intolerance to at least one approved 
advanced therapy for UC, including anti-TNF therapies, anti-integrin therapies, 
anti-IL-12/23 monoclonal antibodies or JAK inhibitors. 
 
 
 


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10.9. 
Appendix 9: COVID-19 
10.9.1. 
Overall Rationale for this Appendix  
The COVID-19 pandemic may impact the conduct of clinical studies. Challenges may arise 
from quarantines, site closures, travel limitations, interruptions to the supply chain for the 
investigational product or ancillary supplies, or other considerations if site personnel or 
study participants become infected with COVID-19. These challenges may lead to 
difficulties in meeting protocol-specified procedures, including administering or using the 
investigational product or adhering to protocol-mandated visits and laboratory/diagnostic 
testing. 
 
This protocol appendix outlines measures that may be applicable for any site impacted by 
the COVID-19 pandemic. The purpose of the appendix is to provide information on the 
measures to be taken to protect participants’ safety, welfare and rights, and promote data 
integrity. 
10.9.2. 
Study Procedures During COVID-19 Pandemic 
During the special circumstances caused by the current COVID-19 pandemic, you should 
consider specific public health guidance, the impact of any travel restrictions implemented 
by local/regional health authorities and local institutions, and individual benefit/risk when 
making enrollment and treatment decisions for trial participants. 
Every effort should be made to adhere to protocol-specified assessments for participants 
on study intervention, including follow-up. However, where this is not possible, the 
following measures may be implemented for enrolled participants. Clinical Investigators 
should document in site files and in participant notes/Electronic Heath Records, as 
appropriate, how restrictions related to COVID-19 led to the changes in study conduct, the 
duration of those changes, and indicate which trial participants were impacted and how 
those trial participants were impacted (as per current local COVID-19 related regulatory 
guidance). 
Missing protocol required data/visits due to COVID-19 should be noted in participant notes 
and recorded as a COVID-19 protocol deviation. 
10.9.3. 
Protocol Defined Procedures/Visits: 
Where applicable country and local regulations and infrastructure for home healthcare 
allow, home nursing and telemedicine may take place at a location other than the clinical 
trial site to perform study assessments, which may include collection of blood, faeces and 
urine samples, measurement of vital signs and weight, and subcutaneous administration of 
study drug (at the discretion of the Investigator). It is the responsibility of the Investigator 
to inform GSK when this occurs and to document in source notes. For details on home 
healthcare approaches, please refer to Appendix 10. 


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The study Investigator is responsible for ensuring that the identification, management, and 
reporting of AEs and SAEs are completed in accordance with the protocol and applicable 
regulations. In addition, home nurses may identify AEs as well and report them to the 
Investigator for evaluation. 
 
10.9.4. 
Study Intervention(s) 
• Staff at each clinical study center will be responsible for preparation of SC study 
intervention, according to procedures detailed in the Pharmacy Manual.  
• The Principal Investigator assumes GCP responsibilities for IMP handling and the 
medical control for dispensing to patients. Site Staff should document the 
dispensing in the Dispensing/Accountability Logs adding a comment that this was 
a direct to patient (DTP) dispensing.  
• For home healthcare, the home healthcare nurse assumes Good Clinical Practice 
(GCP) responsibilities for IMP handling from the point of dispensing to 
administration to patients.  
 
10.9.5. 
Data Management/Monitoring: 
If the eDiary device was provided to the participant, it must be returned to the site after the 
end of the relevant data collection period. 
If on-site monitoring is no longer permitted, GSK will consider remote Source Data 
Verification/Source Document Review (SDV/SDR), where permitted by the clinical 
site/institution. Remote SDV/SDR will be proposed to study sites to meet a patient and/or 
critical quality need (e.g., to assess participant safety or to ensure data integrity). In case of 
remote SDV/SDR, GSK will work with the site to ensure participant privacy.  
Essential Document Sign-Off Process: If an Investigator is unable to print and sign 
essential documents such as a Protocol Amendment signature page then email approval 
can be accepted by replying to the relevant email that is sent by GSK or its delegate. 
 
 
 


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10.10. 
Appendix 10: Home Healthcare 
The option for home healthcare, where applicable country and local regulations and 
infrastructure allow, may be permitted for the following visits (as per the SoA): 
• All participants: Week 4. 
• Additional SC PK analysis: All visits. 
• Double-blind Responders: Weeks 18, 22 and 26. 
• Open Label Responders: Weeks 30, 34, 38 and 42. 
• All participants: Early Withdrawal, where endoscopy is not mandated or is refused. 
• All participants: Follow-up. 
 
Exceptions to the option for home healthcare include: 
• All participants: Scheduled screening, IV dosing, first SC dosing and endoscopy 
visits. 
• Anyone with any reaction (infusion reaction, hypersensitivity or CRS) following 
IV dosing of study treatment, irrespective of grade, during the Induction Phase 
(Double-Blind and Open Label). 
• Anyone who, in the judgement of the Investigator, might have an issue accessing 
rapid emergency care should it be needed (including an anticipated time greater 
than 30 minutes transit to an emergency medical facility capable of managing a 
clinically significant hypersensitivity or anaphylactic reaction). 
• Any other situation where the Investigator considers that dosing should be 
performed at the clinical site for participant safety. 
• Any situation where the home nurse or participant may be put at risk of potential 
infection that cannot be adequately mitigated with available infection control 
precautions. 
• The participant does not consent to home healthcare. 
 
Home healthcare is defined as a remote visit that is performed at the participant’s home by 
a nurse and an Investigator-led telemedicine call. The home nurse must have active 
certification for advanced cardiovascular life support as per local requirements, and at 
minimum within the preceding 4 years.  
The participant must be informed of any potential risks associated with home healthcare 
and sign a revised Informed Consent Form, if required. IRB/Ethics committee should be 
informed and approve of this change in approach and the process documented in study 
files. 
 


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10.10.1. 
Home nursing 
Activities that may be done as part of a home nurse visit must follow the schedule provided 
in the SoA (Section 1.3) and may include:  
• Ensuring completion of PROs (IBDQ, FACIT-F, SF-36). 
• Measurement of vital signs (BP, heart rate, body temperature) and weight. 
• Facilitation of telemedicine call by PI or appropriately medically qualified designee. 
• 12-lead ECG, using site-specific QT correction formula. 
• Collection of all SoA mandated samples. 
• Administration of study drug (subcutaneous delivery only, no infusions). 
• Post-dose monitoring. 
• Sending all collected samples to central labs. 
 
10.10.2. 
Telemedicine 
Telemedicine is defined as online (virtual) visits which will use a secure, video-enabled 
conference, web portal, or mobile application, as a way of communicating with and 
monitoring the participant’s progress. Telemedicine visits are conducted by an Investigator 
or appropriately medically qualified designee, and should be undertaken in combination 
with visits from home nurses (see above). 
Activities to be performed as part of a telemedicine visit must follow the schedule provided 
in the SoA (Section 1.3), and may include: 
• Participant medical evaluation, and review of symptoms.  
• Identification and reporting of concomitant medications. 
• Daily eDiary review of compliance. 
• Physician Global Assessment (PGA). 
• EIM assessment. 
• Identification, management, and reporting of AEs and SAEs. 
 
Note: The Investigator or designee must ensure reporting of AEs and SAEs is completed 
in accordance with the protocol and applicable regulations, and that the appropriate medical 
intervention, therapeutic intervention, and/or support measures are instituted, as necessary.  
 
 


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10.11. 
Appendix 11: References 
Bornkamp, B. (2014). Practical considerations for using functional uniform prior 
distributions for dose‐response estimation in clinical trials. Biometrical Journal, 56(6), 
947–962. 
Camisaschi C, Casati C, Rini F, Perego M, De Filippo A, Triebel F, Parmiani G, Belli F, 
Rivoltini L, Castelli C (2010). LAG-3 expression defines a subset of CD4(+) CD25(high) 
Foxp3(+) regulatory T cells that are expanded at tumor sites. J. Immunol; 184: 6545-51. 
Chung, Y., Rabe-Hesketh, S., Dorie, V., Gelman, A., Liu, J. (2013). A nondegenerate 
penalized likelihood estimator for variance parameters in multilevel models. 
Psychometrika, 78, 685–709. 
Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, Guo B, 
Herbert DR, Bulfone A, Trentini F, Di Serio C, Bacchetta R, Andreani M, Brockmann L, 
Gregori S, Flavell RA, Roncarolo MG (2013). Coexpression of CD49b and LAG-3 
identifies human and mouse T regulatory type 1 cells. Nat Med;19(6):739-46. 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM (2009). Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos; 37: 1779-1784. 
Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, Panaccione R, Ghosh 
S, Wu JCY, Chan FKL, Sung JJY, Kaplan GG (2018). Worldwide incidence and 
prevalence of inflammatory bowel disease in the 21st century: a systematic review of 
population-based studies. Lancet. Dec 23; 390(10114): 2769-2778. 
Rutter MD, Saunders BP, Wilkinson KH, Rumbles S, Schofield G, Kamm MA, Williams 
CB, Price AB, Talbot IC, Forbes A. (2004). Cancer surveillance in longstanding ulcerative 
colitis: endoscopic appearances help predict cancer risk. Gut; 53: 1813–1816. 
Sandborn WJ. Ghosh S. Panes J. Vranic I. Su C. Rousell S. Niezychowski W. (2012). 
Tofacitinib, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis. N Engl J Med; 
367:616-624. 
Slevin S, Tan M, Lahiff C, Williamson K, Geremia A, Hughes S, Leavens K, Nevin K, 
Marks DJB, Tarzi R, Srinivasan N, Arancibia C, Keshav S. (2018). Intestinal expression 
of LAG-3 correlates with inflammatory activity and response to biological therapy in 
ulcerative colitis. Journal of Crohn's and Colitis, Volume 12, Issue supplement_1; S125. 
Travis SP, Schnell D, Krzeski P, et al (2012). Developing an instrument to assess the 
endoscopic severity of ulcerative colitis: the Ulcerative Colitis Endoscopic Index of 
Severity (UCEIS) Gut; 61:535–42. 
Workman CJ1, Dugger KJ, Vignali DA. (2002). Cutting edge: molecular analysis of the 
negative regulatory function of lymphocyte activation gene-3. J Immunol; 169(10): 5392-
5. 


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Xie T, Zhang T, Ding C, Dai X, Li Y, Guo Z, Wei Y, Gong J, Zhu W, and Li J (2018). 
Ulcerative Colitis Endoscopic Index of Severity (UCEIS) versus Mayo Endoscopic Score 
(MES) in guiding the need for colectomy in patients with acute severe colitis. 
Gastroenterology Report; 6 (1): 38–44. 


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10.12. 
Appendix 12: Abbreviations and Trademarks 
List of Abbreviations 
ACLS 
ADA 
ADCC 
AE 
AIC 
ALT 
AUC 
Advanced Cardiovascular Life Support 
Anti-drug antibody 
Antibody-dependent cell-mediated cytotoxicity 
Adverse event 
Akaike’s Information Criterion 
Alanine transaminase  
Area under the curve 
BUN 
CMV 
CRP 
CYP 
DIC 
DoR 
DME 
DRC 
DTH 
DTP 
EBV 
ECG 
eCRF 
EIM 
ePRO 
ETP 
FACIT-Fatigue 
Blood urea nitrogen 
Cytomegalovirus 
C-reactive protein 
Cytochrome P450 
Deviance Information Criterion 
Delegation of Responsibilities 
Drug metabolizing enzyme  
Data Review Committee  
Delayed type hypersensitivity 
Direct to Pharmacy 
Epstein Barr virus 
Electrocardiogram 
Electronic case report form 
Extra-intestinal manifestation 
Electronic Patient Reported Outcome 
Extended treatment phase 
Functional Assessment of Chronic Illness Therapy-Fatigue 
FSH 
FTIH 
Follicle stimulating hormone 
First Time in Human 
GCP 
GLP 
GSK 
HBV 
HCV 
HIV 
HRQoL 
IB 
IBD 
IBDQ 
IEC 
ICE 
ICF 
ICH 
 
IDSL 
IND 
INR 
IMP 
Good Clinical Practice 
Good Laboratory Practice 
GlaxoSmithKline 
Hepatitis B virus 
Hepatitis C virus 
Human Immunodeficiency Virus 
Health-related quality of life 
Investigator’s Brochure 
Inflammatory bowel disease 
Inflammatory bowel disease questionnaire 
Independent Ethics Committee 
Intercurrent Event 
Informed consent form 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
Integrated Data Standards Library 
Investigational new drug 
International normalized ratio 
Investigational medicinal product 


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IP 
IRB 
ITTE 
IV 
KLH 
LAG3 
mAb 
MAR 
MCH 
MCV 
MedRA 
MHC 
mRNA 
NCE 
NIMP 
NOAEL 
OL 
OLETP 
OLIP 
PBMC 
PBPK 
PD 
PGA 
PGIC 
PGIS 
PGx 
PK 
PRO 
PROMIS 
RAP 
RB 
SAE 
SC 
SDR 
SDV 
SE 
SF 
SF-36 
sLAG3 
SoA 
SRT 
VZV 
WOCBP 
UC 
UCEIS 
ULN 
Induction phase 
Institutional Review Boards 
Intent to Treat Exposed 
Intravenous 
Keyhole limpet hemocyanin 
Lymphocyte activation gene-3 
Monoclonal antibody 
Missing at Random 
Mean Corpuscular Haemoglobin 
Mean corpuscular volume 
Medical Dictionary for Regulatory Activities Terminology 
Major histocompatibility complex 
Messenger ribonucleic acid 
New Chemical Entity 
Non-investigational medicinal product 
No-observed-adverse-effect-level 
Open Label 
Open label extended treatment phase 
Open label induction phase 
Peripheral blood mononuclear cell 
Physiologically based pharmacokinetic 
Pharmacodynamic 
Physician Global Assessment 
Patient Global Impression of Change 
Patient Global Impression of Severity 
Pharmacogenetic 
Pharmacokinetic 
Patient-Reported Outcome 
Patient-Reported Outcomes Measurement Information System 
Research Analysis Plan 
Rectal bleeding 
Serious adverse event 
Subcutaneous 
Source document review 
Source data verification 
Standard error 
Stool frequency 
Short form health survey -36 
Soluble lymphocyte activation gene-3 
Schedule of activities 
Safety Review Team 
Varicella zoster virus 
Women of child bearing potential 
Ulcerative colitis 
Ulcerative colitis endoscopic index of severity 
Upper limit of normal 


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Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
 
Chiron RIBA 
 
 
SAS 
 
 
WinNonlin 
 
 


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10.13. 
Appendix 13: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
10.13.1. 
Amendment 1: 17-JAN-2019 
Overall Rationale for the Amendment: 
• Changes requested by MHRA 
 
Section # 
and Name 
Description of Change 
Brief Rationale 
Section 1.3, 
Schedule of 
Activities 
Footnote 6 of Double Blind 
Treatment SoA updated to include 
requirement for serum pregnancy 
test at screening. 
Serum pregnancy testing to definitively 
exclude pregnancy at screening.  
5.2 Exclusion 
Criteria 
Added exclusion criteria regarding 
participants with hypersensitivity 
to GSK2831781 or any excipients 
in the clinical formulation of 
GSK2831781. 
Hypersensitivity excluded as per the 
Investigator brochure. 
  
5.2 Exclusion 
Criteria 
Exclusion criteria renumbered. 
Enable alignment of eCRF with amended 
protocol. 
6.6 
Concomitant 
medications 
Additional section added to 
concomitant medications section 
to include potential for drug-drug 
interactions and clinical monitoring 
of co-administered narrow 
therapeutic index drugs 
metabolised by cytochrome P450. 
Potential impact from removal of down-
regulation of metabolising enzymes 
because of reduction in pro-inflammatory 
cytokines. 
10.4.2 
Appendix 4: 
Contraceptive 
Guidance 
Removed reference to ‘Acceptable 
Methods’ of contraception from 
the table and updated footnotes. 
Ensure alignment with need for highly 
effective contraception as set out in 
protocol and Investigator Brochure. 
Footnotes updated to reflect changes 
made to table and align no need for male 
contraception as highlighted in protocol 
Section 2.3.1. 
 


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10.13.2. 
Amendment 2: 10-SEP-2019 
Overall Rationale for amendment: 
• Exclusion criteria adapted to allow participants following inadequate response, 
loss of response, or intolerance to up to three classes of approved advanced 
therapies for ulcerative colitis 
• Amalgamation of comments from regulatory authorities 
• Incorporation of stratification for Japanese ethnicity, and  
• Protocol clarifications and corrections. 
 
Section # 
and Name 
Description of Change 
Brief Rationale 
Title and 
Section 6.4.2, 
Blinding 
Protocol updated to remove mention 
of ‘Sponsor Open’ (repeated 
throughout the protocol). 
Amended for clarity. Although the Data 
Review Committee can view limited 
data for decision making, the study 
team and wider organisation are 
blinded to study data. 
Section 1.1, 
Number of 
Participants 
Evaluable subjects changed from 280 
to 242 (repeated throughout the 
protocol). 
 
 
 
Alignment of Secondary Objectives in 
Synopsis with main protocol. 
Modelling demonstrates that the 
overall participant number can be 
reduced without impacting study 
robustness. However, the maximum 
number remains unchanged to enable 
sample size re-estimation if required. 
 
Correction of typographical errors to 
ensure consistency. 
Section 1.3, 
Schedule of 
Activities 
Corrected Days in Open Label 
Treatment SoA to align with the 
weeks from: 
85, 99, 113, 127, 141, 155, 169, 183, 
197 and 379 
To: 
85, 99, 127, 155, 183, 211, 239, 267, 
295 and 379 
Days (but not study weeks) were 
incorrect in previous versions of 
protocol 
Section 1.3, 
Schedule of 
Activities 
EIM activity assessment moved from 
Screening Visit 1 to Day 1 pre-dose 
Day 1 considered more appropriate 
baseline for the study 
Section 1.3, 
Schedule of 
Footnote added to allow extension of 
screening window up to 6 weeks 
(although key safety and efficacy 
Provides sites time to undertake 
retesting where indeterminate test 
results are returned for assays 


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Section # 
and Name 
Description of Change 
Brief Rationale 
Activities 
assessments must still be conducted 
within the previously specified time 
windows).  
requiring long central laboratory 
turnaround times. 
Section 1.3, 
Schedule of 
Activities 
Steroid Taper included in Double-
Blind Treatment and Open Label 
Treatment SoA at Week 12. 
Provide greater clarity on mandatory 
steroid taper start date. 
Section 2.3.1, 
Risk 
Assessment: 
Drug-drug 
interactions 
Potential for indirect drug-drug 
interactions through releasing 
suppression of CYPs by ameliorating 
systemic cytokine response 
highlighted 
Highlight theoretical risk to 
Investigators and advice to monitor 
patients receiving medicines with 
narrow therapeutic indices for evidence 
of changes in exposure. 
Section 2.3.1, 
Risk 
Assessment: 
Reproductive 
toxicity 
WOCBP who are partners of male 
subjects in the study will not be 
required to be protected from seminal 
fluid exposure or need to use a 
condom plus highly effective method 
of contraception. Any pregnancy 
data however will be collected 
Changed to: 
WOCBP who are partners of male 
subjects in the study will not be 
required to be protected from seminal 
fluid exposure or need to use a 
condom plus highly effective method 
of contraception. 
Preclinical studies show no impact on 
testes and spermatogenesis and drug 
levels in semen will be at such low 
concentrations to be biologically 
meaningless. 
Section 3, 
Objectives 
and 
Endpoints: 
Primary 
Endpoint 
(safety) 
Primary endpoint limited to findings 
up to Week 10  
Safety and tolerability with Sub 
Cutaneous administration during the 
Double-Blind Extended Treatment 
Phase moved to key secondary 
endpoint.  
Remaining safety findings including 
from open label treatment moved to 
separate safety objective 
Align primary safety endpoint with 
timing of primary efficacy endpoint, to 
enable full reporting of safety findings 
at the time of primary analysis 
Enable reporting of safety findings by 
study phase. 


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Section # 
and Name 
Description of Change 
Brief Rationale 
Section 3, 
Objectives 
and 
Endpoints: 
Primary 
Endpoint 
(efficacy) 
Clarified that dose-response will be 
conducted on the Complete Mayo 
score 
Complete (12-point) Mayo score has 
wider dynamic range for the 
assessment of dose-response than the 
Adapted (9-point) Mayo score. 
Section 3, 
Objectives 
and 
Endpoints: 
Secondary 
Endpoints 
Clarified analyses of key efficacy 
endpoints will be performed on the 
Adapted Mayo Score. 
Added endpoint of symptomatic 
remission (RB subscore=0, SF 
subscore ≤1, with no worsening from 
baseline). 
Use of Adapted Mayo Score inline with 
FDA and EMA guidance on exclusion 
of PGA and presence of friability on 
endoscopy inconsistent with remission 
and mucosal healing.  
Symptomatic remission now 
recognised as important endpoint in 
recent trials. 
Section 5.1, 
Inclusion 
criteria 
Inclusion criteria for corticosteroids 
extended to also include patients who 
have loss of response to steroid 
therapy 
Represents a subpopulation of patients 
with limited options for disease 
management of exacerbations of UC. 
Section 5.1 
and 5.2, 
Inclusion and 
Exclusion 
criteria 
Inclusion criteria changed from: 
Inadequate response to, loss of 
response to, or intolerance to one 
biologic class ONLY for the treatment 
of UC: either one or more anti-TNF 
therapies (e.g. infliximab, 
adalimumab, golimumab, or 
biosimilar) OR vedolizumab 
To: 
• Inadequate response to, loss of 
response to, or intolerance to at least 
one approved advanced therapy for 
UC, including anti-TNF therapies 
(e.g. infliximab, adalimumab, 
golimumab, or biosimilar), anti-
integrin therapies, anti-IL-12/23 
monoclonal antibodies or JAK 
inhibitors. 
 
Exclusion criteria changed from: 
A history of treatment with 
Inclusion/exclusion criteria changed to 
allow inclusion of participants having 
primary non response to two advanced 
therapies for treatment of UC.  
Clarified exclusion windows for anti-
integrin therapies, anti-IL-12/23 and 
JAK inhibitor therapies. 
Exclusion window provide for faecal 
microbiota transplantation based on 
timing to microbial homeostasis in 
scientific investigations in humans. 
Clarified exclusion windows for clinical 
study experience for biologics and 
NCEs to reflect the different half-lives 
of these classes of therapies, but with 
provision for longer extensions in those 
with protracted pharmacodynamic 
effect. Timing of restriction also moved 
from Day 1 to screening endoscopy, as 
latter provides key baseline efficacy 
assessments. 


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Section # 
and Name 
Description of Change 
Brief Rationale 
vedolizumab AND an anti-TNF 
biologic, regardless of treatment 
response (unless exposure to one or 
both drugs was only within a clinical 
trial setting). 
To: 
18. A history of inadequate response, 
loss of response, or intolerance to 
more than three classes of approved 
advanced therapies for UC 
(including; anti-TNF therapies, anti-
integrin therapies, anti-IL-12/23 
monoclonal antibodies, or JAK 
inhibitors; but excluding exposure 
within a clinical trial setting), but with 
primary non-response to more than 
two classes 
 
Updated exclusion criteria regarding 
biologics and JAK inhibitors to: 
17. Treatment with an anti-TNF 
biologic within 8 weeks prior to 
baseline endoscopy, or anti-integrin 
or anti-IL-12/23 biologics within 12 
weeks prior to baseline endoscopy, 
or a JAK inhibitor within 4 weeks 
prior to baseline endoscopy. 
19. Received faecal microbiota 
transplantation within 4 weeks prior 
to baseline endoscopy. 
 
Clarified exclusion criterion 21 for 
prior/concurrent clinical trial 
experience to: 
a) Biologics: 3 months, 5 half-lives, or 
twice the duration of the biological 
effect of the investigational product 
(whichever is longer); 
b) New Chemical Entities (NCEs): 30 
days, 5 half-lives or twice the 
duration of the biological effect 
Changes also reflected in the 
concomitant medication tables. 


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Section # 
and Name 
Description of Change 
Brief Rationale 
(whichever is longer). 
Section 6.1 
Study 
Intervention(s) 
Administration 
Dose formulation concentration of 
Methionine changed from 80 to 8 
mM. 
Incorrect Methionine concentration in 
previous protocol version. 
Section 6.4.1 
Method of 
Treatment 
Assignment 
Stratification criteria changed to 
include Japanese ethnicity as first 
strata followed by advanced 
treatment experience status. 
Align stratification with inclusion of 
Japan in global study and updated 
exclusion criteria (biological experience 
status). 
Section 6.6.2, 
Prohibited 
Concomitant 
Medications 
Added the following concomitant 
medications: 
Intravenous corticosteroids 
Rituximab 
Leukocyte apheresis 
Faecal microbiota transplantation 
 
Amended Tofacitinib wash out period 
from 2 to 4 weeks 
 
Clarified prohibition windows for other 
biologic or small molecule therapies 
for UC. 
IV steroids are prohibited within 2 
weeks prior to baseline endoscopy, 
and requirement for IV steroid for 
treatment of UC following 
randomisation would be a 
rescue/salvage therapy. 
Leukocyte apheresis is prohibited 
within 4 weeks prior to baseline 
endoscopy.  
Faecal microbiota transplantation is 
prohibited within 4 weeks prior to 
baseline endoscopy. 
Extended washout period ensures no 
lasting PD effects from Tofacitinib for 
participants joining the study. 
Aligned exclusion windows for other 
biologic or small molecule therapies 
with exclusion criterion 21. 
Section 
8.2.1.1, Mayo 
Score 
Definitions of the Complete, Adapted 
and Partial Mayo scores updated. 
 
Information regarding scoring of 
rectal bleeding and stool frequency 
domains changed from: 
The patient reported outcomes of 
Stool Frequency and Rectal Bleeding 
for Mayo scores will be calculated by 
the physician based on three 
consecutive days within the last 
week, but which should not include 
Typographical errors fixed 
 
 
Scores are determined centrally in the 
eCRF following site input of 
participants daily scores from their 
eDiary. 


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Section # 
and Name 
Description of Change 
Brief Rationale 
days in which bowel preparations are 
administered. 
To: 
The patient reported outcomes of 
Stool Frequency and Rectal Bleeding 
for Mayo scores will be calculated 
from participant eDiary data, ideally 
based on three consecutive days 
within the last week (see SRM for full 
details). These should not include 
days in which bowel preparations are 
administered.  
 
Section 
8.2.4.2.2, 
Short Form-
36 
Changed text: 
The measure uses a recall period of 
four weeks. 
To: 
The measure uses a recall period of 
one week. 
 
Recall period incorrect. 
Section 9.2.1, 
Sample Size 
Assumptions 
AND 
Section 9.5, 
Interim 
Analyses  
Interim Analysis 5 removed and 
primary endpoint added. 
 
Assumptions changed to support the 
new 242 evaluable subjects target for 
recruitment. 
 
Deleted Interim Analysis 5 from the 
Interim Analysis Table. 
Interim Analysis 5 now correctly named 
primary analysis. 
 
Assumptions aligned to reduced 
evaluable participant requirements of 
the study. 
 
 
Interim Analyses aligned with change 
of IA5 to primary endpoint. 
Appendix 7, 
Mayo Clinical 
Score 
Definitions 
Corrected language for rectal 
bleeding subscore to align with 
original MCS. 
Also changed Adapted MCS clinical 
response definition from: 
Adapted MCS ≤2, with no individual 
Correction of language to align with 
eDiaries, which are primary source for 
this variable. 
 
Adapted MCS response definition 
updated to align with published clinical 


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Section # 
and Name 
Description of Change 
Brief Rationale 
subscore >1. 
To: 
Adapted MCS of ≤2 with no 
individual subscore > 1 and a rectal 
bleeding sub score of 0, and stool 
frequency subscore ≤1 and not 
greater than baseline  
studies. 
 
 
Appendix 8 
Addition of country-specific 
requirement for the Netherlands. 
Clarification based on current 
treatment pathways in the Netherlands. 
 


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10.13.3. 
Amendment 3: 03-SEP-2020 
Overall Rationale for the Amendment: 
• Provision for home healthcare (home nursing and telemedicine) approaches for 
selected study visits where applicable country and local regulations and 
infrastructure allow. 
• Clarification of COVID-19 specific measures. 
• Correction of protocol inconsistencies and clarification of study procedures and 
objectives, including the time frame of the collection of safety data in the induction 
period (primary endpoint). 
• Estimands have been introduced following best practice and the term ‘evaluable’ 
has been removed for consistency. The study retains the principle that if more 
participants (of those required for the hypothetical estimand) drop out than has 
been planned for, then additional participants may be recruited. 
• The primary analysis will now fit the originally planned dose-response model 
using a Bayesian framework with non-informative priors. This allows consistency 
in estimation across endpoints, including when data are missing, but does not 
change the sample size required. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 
Synopsis 
Objectives and endpoints table 
and overall design updated. 
Remove the term ‘evaluable’ 
instead link attrition rate to 
participants not reaching and 
completing an adequate Week 10 
assessment). 
Clarification of study phases 
and endpoints. 
Remove the term ‘evaluable’ 
for consistency with 
estimands but retain principle 
that if more participants drop 
out than planned for, then 
additional participants may be 
recruited. 
Section 1.2 Schema 
Clarify that responder status is 
determined by a pre-specified 
algorithm in the electronic case 
report form (ECRF). 
Clarify mechanism of defining 
responder status. 
Section 1. 3 
SoA 
Added text related to home 
healthcare and clarified timing of 
events. 
Allow home healthcare 
approaches during study 
conduct, and clarification of 
timings of activities. 
Section 2.3.1 Risk 
Assessment 
Amended cytokine release 
syndrome, neutropaenia, 
infection, hypersensitivity, 
infusion, local site reactions, 
immunogenicity and autoimmune-
like reactions text based upon 
additional clinical study data. Also 
added mitigation strategies for 
home healthcare SC dosing. 
Updated risks and mitigations 
based upon completed Phase 
I studies experience and 
implementation of home 
healthcare during study 
conduct. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 3. 
Objectives and endpoints table 
updated with respect to study 
phases and to extend time frame 
for collection of safety data in 
double blind induction. Addition of 
exploratory endpoint of 
extraintestinal manifestations. 
Addition of estimands for primary 
and key secondary efficacy 
endpoints. 
Clarification of Objectives and 
Endpoints. Safety data will be 
reported against double blind 
induction until the first dose of 
the next study phase. Addition 
of extraintestinal 
manifestation endpoints. 
Addition of estimands to 
protocol following best 
practice. 
Section 4.1.1 
Double-Blind Treatment 
Treatment phase and timing of 
randomisation updated. 
Clarification for Investigators. 
Section 4.1.2 
Open Label Treatment for 
Non Responders 
Additional text added to clarify 
eCRF calculation of responder 
status and Responder patient 
journey. 
Clarification for Investigators. 
Section 4.3.3 
Open Label Treatment 
Text updated to ensure non-
responders proceed to Follow-Up 
visit 16 weeks post last dose.  
Clarification for Investigators. 
Section 5.1 Inclusion 
Criteria 
NUDT15 mutation added to 
precluding genetic mutations for 
thiopurines. 
Mutation prevalence in Japan. 
Section 6.2 Intervention 
administration 
Reduced post SC dose 
monitoring period for first SC dose 
only. 
Updated to reflect latest 
clinical experience and safety 
information. 
Section 6.4 
Method of Treatment 
Assignment 
Timing of randomisation updated, 
including pre-requisites. 
Clarification for Investigators. 
Section 7.1.6 
Temporary withholding of 
IP 
Reasons for temporary 
withholding IP updated. 
Clarification for Investigators. 
Section 7.2 Participant 
discontinuation/Withdrawal 
from the study 
Section updated to clarify that all 
participants withdrawn from study 
will complete the current study 
phase and follow-up visit 
approximately 16 weeks after last 
dose, and not the entire study. 
Clarification for Investigators. 
Section 8 
Study Assessments & 
Procedures 
Added text to highlight signed 
consent required and reference 
home healthcare and 
telemedicine approaches. 
Implementation of healthcare 
approaches during study 
conduct. 
Section 8.2.1.1 
Mayo Score 
Added text relating to capture of 
stool frequency and rectal 
bleeding for eCRF calculation 
during the study. 
Clarification for Investigators 
to ensure correct days are 
chosen from diary for 
calculation of Mayo scores. 
Section 8.3 
Added text related to PK being 
Clarification and 


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Section # and Name 
Description of Change 
Brief Rationale 
Pharmacokinetics 
undertaken on subset of 
participants and home healthcare 
and telemedicine approaches. 
implementation of healthcare 
approaches during study 
conduct. 
Section 8.6.1 Physical 
Examinations 
Added text related to home 
healthcare and telemedicine 
approaches. 
Implementation of healthcare 
approaches during study 
conduct. 
Section 8.6.2 
 Vital signs 
Added text indicating vital signs to 
be performed prior to blood 
collection. 
Clarification for Investigators. 
Section 9.1 Statistical 
Hypotheses 
Specify that the primary dose-
response analysis will be 
Bayesian. 
A Bayesian implementation of 
the original planned Emax 
model will provide consistency 
of estimation and handling of 
missing data across endpoints 
in the study. 
9.2.1 Sample size 
assumptions 
Sample size section adjusted to 
reflect the Bayesian sample size 
assessment and assumptions. 
Section re-ordered to add clarity.  
 
Remove the term ‘evaluable’. 
Instead, link attrition rate to 
participants not reaching and 
completing an adequate Week 10 
assessment). 
See justification for Section 
9.1. No change has been 
made to the sample size of 
this study. 
 
Remove the term ‘evaluable’ 
for consistency with 
estimands but retain principle 
that if more participants drop 
out than planned for, then 
additional participants may be 
recruited. 
9.3 Populations for 
Analyses 
Intention to Treat population 
renamed to Intention to Treat 
Exposed (ITTE). Consolidation of 
‘Enrolled’ and ‘Screened’ 
populations. 
Renaming of Intention to 
Treat Exposed more precisely 
reflects the analysis 
population. Consolidation of 
populations removes effective 
duplication. 
9.4.1 Efficacy analyses 
Adjust specification of the primary 
dose-response analysis and 
details of model fitting to reflect 
the change to Bayesian. Added 
summary of estimation for inter 
current events for primary 
estimand. 
See justification for Section 
9.1. 
Appendix 9 
COVID-19 
Added Appendix, including text to 
clarify: 
• Procedures including 
reporting COVID impact. 
• Home healthcare availability. 
• Data management. 
Clarification of measures that 
may be applicable for any site 
impacted by the COVID-19 
pandemic. 


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Section # and Name 
Description of Change 
Brief Rationale 
Appendix 10 
Home Healthcare & 
Telemedicine 
Added Appendix to allow home 
healthcare and telemedicine, 
including exceptions and 
exclusions. 
Implementation of healthcare 
approaches during study 
conduct. 
 

SAP_001.pdf: 
0 
 
 
 
Reporting and Analysis Plan 
Study ID: 204869 
Official Title of Study:  Reporting and Analysis Plan for: A multicentre randomized, double-blind, 
placebo-controlled Phase 2 study to evaluate the safety, tolerability, efficacy, dose-response, 
pharmacokinetics and pharmacodynamics of repeat dosing of an anti-LAG3 cell depleting monoclonal 
antibody (GSK2831781) in patients with active ulcerative colitis 
 
Date of Document: 02-JUN-2021 


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
204869 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP)  
 
Title 
: Reporting and Analysis Plan for: 
A multicentre randomized, double-blind, placebo-controlled 
Phase 2 study to evaluate the safety, tolerability, efficacy, 
dose-response, pharmacokinetics and pharmacodynamics of 
repeat dosing of an anti-LAG3 cell depleting monoclonal 
antibody (GSK2831781) in patients with active ulcerative 
colitis 
Short Title: Safety, tolerability, efficacy and dose-response 
of GSK2831781 in ulcerative colitis  
Compound Number  : GSK2831781 
Effective Date  
: Refer to Document Date 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 204869. 
 
RAP Author(s): 
Author 
Date 
Lead:
27-MAY-2021 
Statistician (Biostatistics) 
Co-Author:
 
26-MAY-2021 
Lead Programmer (Biostatistics) 
Co-Author:
Clinical Pharmacology (CPMS) 
26-MAY-2021 
Co-Author:
26-MAY-2021 
Manager Quantitative Clinical Pharmacology (CPMS) 
 
 
 
Copyright 2021 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
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CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
204869 
 
2 
 
RAP Team Review Confirmations 
(Method: E-mail) 
Reviewer 
Date 
Clinical Development Lead (Clinical Sciences) 
25-MAY-2021 
26-MAY-2021 
SERM
(SMG Pharma Safety) 
27-MAY-2021 
Clinical Science Lead (Clinical Sciences) 
25-MAY-2021 
Clinical Development
(Clinical Sciences IBD) 
Clinical Biomarker Lead (CPEM) 
21-MAY-2021 
Manager, Clinical Data Management (GCDO DM) 
26-MAY-2021 
 
Clinical Statistics and Clinical Programming Approvals: 
(Method: approval in the TMF system) 
Approver 
 (Biostatistics) 
Hep/GI Clinical Programming
(Biostatistics) 
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CONFIDENTIAL 
 
 
 
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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 
2.1.1. 
Changes to Analysis Populations ................................................... 7 
2.1.2. 
Changes to Interim and Final Analyses .......................................... 7 
2.1.3. 
Changes to Endpoints and Definitions ........................................... 7 
2.1.3.1. 
Efficacy ......................................................................... 7 
2.1.3.2. 
Biomarkers ................................................................... 7 
2.1.3.3. 
Patient Reported Outcomes ......................................... 8 
2.1.4. 
Changes to Efficacy Estimands and Statistical Analyses ............... 8 
2.2. 
Study Objectives and Endpoints ................................................................... 9 
2.3. 
Study Design .............................................................................................. 14 
2.4. 
Statistical Hypotheses / Statistical Analyses ............................................... 19 
3. 
PLANNED ANALYSES .......................................................................................... 20 
3.1. 
Interim Analyses ......................................................................................... 20 
3.2. 
Final Analyses ............................................................................................ 21 
4. 
ANALYSIS POPULATIONS ................................................................................... 22 
4.1. 
Populations for the Induction Phase ............................................................ 22 
4.2. 
Populations for the Extended Treatment Phase .......................................... 22 
4.3. 
Populations for the Open Label Induction Phase ........................................ 23 
4.4. 
Populations for the Open Label Extended Treatment Phase ....................... 23 
4.5. 
Protocol Deviations ..................................................................................... 24 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 24 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 24 
5.1.1. 
Randomised, Double Blind Treatments ........................................ 24 
5.1.2. 
Partial doses ................................................................................ 26 
5.2. 
Baseline Definitions .................................................................................... 26 
5.3. 
Multicentre Studies ..................................................................................... 26 
5.4. 
Examination of Covariates, Other Strata and Subgroups ............................ 27 
5.4.1. 
Covariates and Other Strata ........................................................ 27 
5.4.2. 
Examination of Subgroups ........................................................... 28 
5.5. 
Multiple Comparisons and Multiplicity ......................................................... 28 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 28 
6. 
STUDY POPULATION ANALYSES ....................................................................... 29 
6.1. 
Overview of Planned Study Population Analyses ........................................ 29 
7. 
SAFETY ANALYSES ............................................................................................. 30 
7.1. 
Adverse Events Analyses ........................................................................... 30 
7.2. 
Clinical Laboratory Analyses ....................................................................... 30 
8. 
EFFICACY ANALYSES .......................................................................................... 31 
8.1. 
Primary Efficacy Analyses .......................................................................... 31 


 
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8.1.1. 
Primary Endpoint ......................................................................... 31 
8.1.1.1. 
Primary Estimand – Treatment Policy ......................... 31 
8.1.1.2. 
Statistical Analysis ...................................................... 32 
Bayesian analysis for continuous endpoint ........................................ 32 
8.1.1.3. 
Additional analyses for the Primary Endpoint.............. 33 
8.2. 
Secondary Efficacy Analyses ...................................................................... 34 
8.2.1. 
Key Secondary Endpoint ............................................................. 34 
8.2.1.1. 
Estimand .................................................................... 34 
8.2.1.2. 
Statistical Analysis ...................................................... 36 
8.2.2. 
Other Secondary Endpoints - Categorical .................................... 38 
8.2.3. 
Other Secondary Endpoints - Continuous .................................... 39 
8.2.3.1. 
Statistical Analysis ...................................................... 39 
8.3. 
Exploratory Efficacy Analyses ..................................................................... 40 
9. 
PATIENT REPORTED OUTCOMES ANALYSES .................................................. 41 
10. PHARMACODYNAMIC AND BIOMARKER ANALYSES ........................................ 42 
10.1. 
Pharmacodynamic and Biomarker Analyses ............................................... 42 
10.1.1. 
Endpoint / Variables ..................................................................... 42 
11. PHARMACOKINETIC ANALYSES ......................................................................... 44 
11.1. 
Pharmacokinetic Analyses .......................................................................... 44 
11.1.1. 
Endpoint / Variables ..................................................................... 44 
11.1.1.1. Drug Concentration Measures .................................... 44 
11.1.1.2. Derived Pharmacokinetic Parameters......................... 44 
11.1.2. 
Summary Measure ...................................................................... 44 
11.1.3. 
Population of Interest ................................................................... 44 
11.1.4. 
Statistical Analyses / Methods ..................................................... 45 
12. POPULATION PHARMACOKINETIC (POPPK) ANALYSES .................................. 46 
12.1. 
Statistical Analyses / Methods .................................................................... 46 
13. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES ................................. 47 
13.1. 
Statistical Analyses / Methods .................................................................... 47 
14. REFERENCES ....................................................................................................... 48 
15. APPENDICES ........................................................................................................ 49 
15.1. 
Appendix 1: Protocol Deviation Management and Definitions for 
Analysis Population Exclusions ................................................................... 49 
15.2. 
Appendix 2: Schedule of Activities (SoA): ................................................... 50 
15.3. 
Appendix 3: Assessment Windows ............................................................. 56 
15.3.1. 
Definitions of Assessment Windows for Analyses ........................ 56 
15.4. 
Appendix 4: Treatment Phases and Study Phases ..................................... 59 
15.4.1. 
Treatment Phases ....................................................................... 59 
15.4.2. 
Study Phases .............................................................................. 59 
15.4.2.1. Study Phases for Adverse Events .............................. 59 
15.4.2.2. Study Phases for Concomitant Medication ................. 60 
15.4.3. 
Treatment Emergent Flag for Adverse Events ............................. 60 
15.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 61 
15.5.1. 
Reporting Process ....................................................................... 61 
15.5.2. 
Reporting Standards .................................................................... 62 
15.5.3. 
Reporting Standards for Pharmacokinetic .................................... 63 


 
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15.6. 
Appendix 6: Derived and Transformed Data ............................................... 64 
15.6.1. 
General ........................................................................................ 64 
15.6.2. 
Study Population .......................................................................... 64 
15.6.3. 
Efficacy ........................................................................................ 65 
15.6.3.1. Mayo score versions ................................................... 65 
15.6.3.2. Mayo sub scores ........................................................ 68 
15.6.3.3. Endoscopy scores ...................................................... 71 
15.6.3.4. Histology scores ......................................................... 72 
15.6.3.5. Intercurrent Events Selection ...................................... 76 
15.6.4. 
Safety .......................................................................................... 76 
15.6.5. 
Immunogenicity............................................................................ 78 
15.6.6. 
Pharmacodynamic and Biomarker ............................................... 79 
15.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 80 
15.7.1. 
Premature Withdrawals ................................................................ 80 
15.7.2. 
Handling of Missing Data ............................................................. 80 
15.7.2.1. Handling of Missing and Partial Dates ........................ 81 
15.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 82 
15.8.1. 
Laboratory Values ........................................................................ 82 
15.8.2. 
Urinalysis ..................................................................................... 83 
15.8.3. 
ECG ............................................................................................. 83 
15.8.4. 
Vital Signs .................................................................................... 84 
15.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ...................... 85 
15.9.1. 
Population Pharmacokinetic (PopPK) Dataset 
Specification ................................................................................ 85 
15.9.2. 
Population Pharmacokinetic (PopPK) Methodology ..................... 85 
15.10. Appendix 10: Pharmacokinetic / Pharmacodynamic Analyses .................... 86 
15.10.1. Pharmacokinetic / Pharmacodynamic Dataset 
Specification ................................................................................ 86 
15.10.2. Pharmacokinetic / Pharmacodynamic Methodology ..................... 86 
15.11. Appendix 11: Abbreviations & Trademarks ................................................. 88 
15.11.1. Abbreviations ............................................................................... 88 
15.11.2. Trademarks ................................................................................. 89 
15.12. Appendix 12: List of Data Displays.............................................................. 90 
15.12.1. Data Display Numbering .............................................................. 90 
15.12.2. Mock Example Shell Referencing ................................................ 90 
15.12.3. Deliverables ................................................................................. 90 
15.12.4. Study Population Tables .............................................................. 92 
15.12.5. Efficacy Tables ............................................................................ 98 
15.12.6. Efficacy Figures ......................................................................... 106 
15.12.7. Safety Tables ............................................................................. 109 
15.12.8. Safety Figures ........................................................................... 119 
15.12.9. Pharmacokinetic Tables ............................................................. 121 
15.12.10. Pharmacokinetic Figures ........................................................... 122 
15.12.11. Pharmacokinetic Population (PopPK) Tables ............................. 124 
15.12.12. Pharmacokinetic Population (PopPK) Figures ........................... 125 
15.12.13. Pharmacodynamic / Biomarker Tables ...................................... 126 
15.12.14. Pharmacodynamic / Biomarker Figures ..................................... 129 
15.12.15. Pharmacokinetic / Pharmacodynamic Tables ............................ 132 
15.12.16. Pharmacokinetic / Pharmacodynamic Figures ........................... 133 
15.12.17. Patient Reported Outcome Tables ............................................. 134 
15.12.18. Patient Reported Outcome Figures ............................................ 137 
15.12.19. ICH Listings ............................................................................... 140 


 
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15.12.20. Non-ICH Listings ........................................................................ 145 
15.13. Appendix 13: Example Mock Shells for Data Displays .............................. 148 
15.14. Appendix 14: Selection criteria for the Informative Placebo Priors ............ 149 
15.14.1. Examples of robustified prior for endoscopic mucosal 
healing (key secondary endpoint) .............................................. 150 
 


 
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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 of protocol 204869: 
2017N337668_00 
15-OCT-2018 
Original 
2017N337668_01 
17-JAN-2019 
Amendment 1 
2017N337668_02 
10-SEP-2019 
Amendment 2 
2017N337668_03 
03-SEP-2020 
Amendment 3 
TMF-2197350 
12-NOV-2020 
Amendment 4 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
The following changes have been made to the originally planned statistical analysis 
specified in the 204869 protocol (amendment 4, dated 12-NOV-2020). The majority of 
the changes are due to GSK’s decision to terminate study 204869 on 14-JAN-2021. 
2.1.1. 
Changes to Analysis Populations 
The analysis populations defined in the protocol relate to the induction phase and 
additional analysis populations have been introduced to account for reporting in the other 
phases of the trial. 
Per Protocol populations in Double Blind Induction and Double Blind Extended 
Treatment phases have been removed to simplify the reporting of efficacy. 
2.1.2. 
Changes to Interim and Final Analyses 
Interim Analysis 2 (IA2), Interim Analysis 4 (IA4) and Primary Completion (PC) are 
documented in the protocol, but no outputs or reporting are planned due to the study 
team’s decisions not to conduct IA2 and the termination of the study prior to IA4 and PC. 
2.1.3. 
Changes to Endpoints and Definitions 
2.1.3.1. 
Efficacy 
Exploratory efficacy endpoints (excluding Serum C-Reactive Protein and Faecal 
Calprotectin) are documented in the protocol, but their analysis is not covered in this 
RAP due to the termination of the study. 
2.1.3.2. 
Biomarkers 
The following biomarker endpoints are documented in the protocol, but their analysis is 
not covered in this RAP and may be conducted using other analysis plans: 
• Proteomic profiles 


 
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• Transcriptomic profiles, including but not limited to LAG3 
• Composition of immune cell populations, including but not limited to CD3+ cells by 
epigenetic counting or T cell receptor sequencing 
The following biomarker endpoints are documented in the protocol, but their analysis is 
not covered in this RAP due to the termination of the study: 
• 4β-hydroxycholesterol:cholesterol ratio 
• Serum tryptase 
Additionally, this RAP covers LAG3+ T Cells in Blood and Cell Counts in Colon 
reporting only in the Double Blind Induction phase because of projected lack of patients 
randomised to other treatment arms following study termination. 
2.1.3.3. 
Patient Reported Outcomes 
Exploratory Patient Reported Outcome (PRO) endpoints are documented in the protocol, 
but their analysis is not covered in this RAP due to the termination of the study. 
2.1.4. 
Changes to Efficacy Estimands and Statistical Analyses 
The “Hypothetical” additional estimand for Complete Mayo Score has been removed to 
simplify the reporting of efficacy. 
The primary estimand (Complete Mayo Score) and key secondary estimand (Endoscopic 
Improvement) have been modified to account for “discontinuation due to sponsor’s 
decision to terminate the study” intercurrent event. 
New estimands are defined for secondary continuous and categorical efficacy endpoints. 
The populations and intercurrent event strategies for these estimand are the same as the 
Primary estimand for Complete Mayo Score (in the case of secondary continuous 
endpoints) or Key secondary estimand for Endoscopic Improvement (in the case of 
secondary categorical endpoints). 
The primary dose response model for Complete Mayo Score has been modified to only 
analyse the 450mg IV and Placebo IV arms due to projected lack of patients randomised 
to other treatment arms following study termination. 


 
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2.2. 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• To evaluate the safety and 
tolerability of repeat doses of 
GSK2831781 during the Double-
Blind Induction Phase. 
 
 
 
 
 
 
 
 
• To characterise the efficacy dose-
response of GSK2831781 during 
the Double-Blind Induction Phase. 
• Incidence of adverse events and serious 
adverse events during the Double-Blind 
Induction Phase. 
• Incidence of findings of potential clinical 
importance1 during the Double-Blind 
Induction Phase for: 
o Vital signs. 
o Clinical laboratory values 
(haematology, clinical chemistry 
and urinalysis).  
o QTc. 
 
• Change from baseline in Complete 4-
domain Mayo score2 at Week 10. 
Secondary 
• To evaluate the safety and 
tolerability of repeat doses of 
GSK2831781 during the Double-
Blind Extended Treatment Phase. 
 
• Incidence of adverse events and serious 
adverse events in the Double-Blind 
Extended Treatment Phase. 
• Incidence of findings of potential clinical 
importance5 during the Double-Blind 
Extended Treatment Phase for: 
o Vital signs. 
o Clinical laboratory values 
(haematology, clinical 
chemistry and urinalysis).  
o QTc. 
• To investigate the effect of repeat 
doses of GSK2831781 on clinical 
efficacy including endoscopic 
mucosal healing during the Double-
Blind Induction Phase. 
 
• Adapted Mayo endoscopic score of 0 or 1 
at Week 10. 
• Adapted Mayo clinical remission3 at 
Week 10. 
• Adapted Mayo clinical response3 at 
Week 10. 
• Symptomatic remission4 over time.  
• Change from baseline in partial Mayo 
score over time. 
• Change from baseline in Adapted Mayo 
endoscopic score and Ulcerative Colitis 


 
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Objectives 
Endpoints 
Endoscopic Index of Severity (UCEIS) at 
Week 10. 
• To investigate the effect of repeat 
doses of GSK2831781 on UC 
histologic disease activity during 
the Double-Blind Induction Phase. 
• Histological severity as determined by the 
Robarts Histopathology Index at Week 10. 
• Histological severity as determined by the 
Nancy Histological Index at Week 10. 
• Histological severity as determined by the 
Geboes Score at Week 10. 
• To investigate the effect of repeat 
doses of GSK2831781 on 
biomarkers of UC disease activity 
during the Double-Blind Induction 
Phase. 
• Change from baseline in serum C-reactive 
protein over time. 
• Change from baseline in faecal 
calprotectin over time. 
• To investigate the pharmacokinetics 
of GSK2831781 following 
subcutaneous dosing. 
• GSK2831781 PK parameters: AUC(0-tau), 
Cmax, tmax. 
• To investigate the immunogenicity 
of repeat doses of GSK2831781 
during the Double-Blind Induction 
Phase. 
• Incidence of anti-drug antibodies at each 
visit. 
Safety 
• To evaluate the safety and 
tolerability of repeat doses of 
GSK2831781 in all trial phases. 
• Adverse events, vital signs, clinical 
laboratory values (haematology, clinical 
chemistry, and urinalysis), 12-lead ECG. 
• To investigate the immunogenicity 
of repeat doses of GSK2831781 in 
all trial phases. 
• Incidence of anti-drug antibodies at each 
visit. 
Exploratory  
• To investigate the effect of repeat 
doses of GSK2831781 on patient-
reported outcomes in all trial 
phases. 
• Change from baseline in daily e-Symptom 
Diary, FACIT-Fatigue, Inflammatory 
Bowel Disease Questionnaire (IBDQ), SF-
36, and PGIS. 
• PGIC at Week 10 and Week 30. 
• To investigate the effect of repeat 
doses of GSK2831781 on clinical 
efficacy during the Double-Blind 
Extended Treatment Phase. 
• Change from baseline in Adapted Mayo 
score between Week 10, and Week 30. 
• Adapted Mayo endoscopic score of 0 or 1 
at Week 30. 


 
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Objectives 
Endpoints 
• Adapted Mayo clinical remission3 at 
Week 30. 
• Adapted Mayo clinical response3 at 
Week 30. 
• Change from baseline in Adapted Mayo 
endoscopic score and Ulcerative Colitis 
Endoscopic Index of Severity (UCEIS) at 
Week 30. 
• Symptomatic remission4 over time. 
• Change from baseline in Partial Mayo 
score over time. 
• Change from baseline in histological 
severity as determined by the Robarts 
Histopathology Index, Nancy Histological 
Index and Geboes Score at Week 30. 
• Clinical response3 at Week 10, maintained 
at Week 30. 
• Clinical remission3 at Week 10, 
maintained at Week 30. 
• To investigate the effect of repeat 
doses of GSK2831781 on oral 
corticosteroid use for participants 
using corticosteroids at baseline. 
• Corticosteroid-free Adapted Mayo clinical 
remission at Week 30 (with at least 28 
consecutive days corticosteroid-free, 
including Weeks 26 to 30). 
• Change from baseline daily corticosteroid 
dose to average daily corticosteroid dose 
during the taper period5. 
• To investigate the effect of repeat 
doses of GSK2831781 on 
biomarkers of disease activity in 
patients moderate to severe active 
UC during the Double-Blind 
Extended Treatment Phase and 
Open Label Treatment Phases. 
• Change from baseline in serum C-reactive 
protein over time. 
• Change from baseline in faecal 
calprotectin over time. 
• To investigate the effect of repeat 
doses of GSK2831781 on colon 
biopsy tissue and blood biomarkers 
in patients with moderate to severe 
active UC in all Treatment Phases. 
• Change from baseline in colon biopsy 
tissue biomarkers at Week 10 and 
Week 30, which may include but not be 
limited to: 
o Number of LAG3+ and CD3+ cells by 
IHC. 


 
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Objectives 
Endpoints 
o Composition of immune cell 
populations, including but not limited 
to CD3+ cells by epigenetic counting 
or T cell receptor sequencing. 
o Transcriptomic profiles, including but 
not limited to LAG3. 
• Change from baseline in blood 
biomarkers, which may include but not be 
limited to:  
o Number of LAG3+ cells at Week 10 
and Week 30. 
o 4β-hydroxycholesterol:cholesterol 
ratio. 
o Serum tryptase. 
o Proteomic profiles. 
• To investigate the effect of repeat 
doses of GSK2831781 on plasma 
sLAG3 in patients with moderate to 
severe active UC in all Treatment 
Phases.  
• Soluble LAG3 (sLAG3) concentrations. 
• To evaluate the concentration-time 
profiles of GSK2831781 after 
repeat intravenous and 
subcutaneous dosing in all 
Treatment Phases. 
• GSK2831781 PK concentrations. 
• To investigate the effect of repeat 
doses of GSK2831781 on clinical 
efficacy in Non-Responder patients 
during Open Label Induction and 
Extended Treatment Phases. 
• Change from baseline in Adapted Mayo 
score between Week 10, and Week 22. 
• Adapted Mayo endoscopic score of 0 or 1 
at Week 22. 
• Adapted Mayo clinical remission3 at 
Week 22. 
• Adapted Mayo clinical response3 at 
Week 22. 
• Change from baseline in Adapted Mayo 
endoscopic score and Ulcerative Colitis 
Endoscopic Index of Severity (UCEIS) at 
Week 22. 
• Change from baseline in histological 
severity as determined by the Robarts 


 
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Objectives 
Endpoints 
Histopathology Index, Nancy Histological 
Index and Geboes Score at Week 22. 
• Clinical response based on partial Mayo 
score3 at Week 22, maintained at Week 42. 
• Clinical remission based on partial Mayo 
score3 at Week 22, maintained at Week 42. 
• Symptomatic remission4 over time.  
• Change from baseline in partial Mayo 
score over time. 
• To investigate the effect of repeat 
doses of GSK2831781 on 
extraintestinal manifestations in all 
Treatment Phases. 
• Incidence of extraintestinal manifestations 
over time. 
Footnotes: 
1 
Potential clinical importance is defined in Section 15.8 for each relevant safety endpoint. 
2 
The Complete 4-domain Mayo score is used for the primary endpoint due to its wider dynamic 
range for assessment of dose-response compared to the Adapted Mayo score used for secondary 
and exploratory endpoints. 
3 
Clinical response and remission for the various iterations of Mayo score are defined in Appendix 
7, Section 15.7. 
4 
Symptomatic remission is defined as a rectal bleeding subscore of 0, and a stool frequency subscore 
of ≤1, with no worsening from baseline. 
5 
Taper period is defined from the start of the taper (Weeks 12 or 24, respectively, for the Double-
Blind and Open Label Extended Treatment Phases) to completion of the respective Extended 
Treatment Phases. 
 


 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
• 
Phase 2, multicentre, randomized, double-blind parallel, placebo-controlled 
• 
Double-blind Induction Phase up to 10 Weeks for all participants  
• 
At Week 10, all participants undergo an Induction Assessment, including 
centrally read endoscopy. Responder status is identified by the results of the 
assessment of clinical response calculated by the eCRF and determines the 
participant’s subsequent path through the study. 
 
Week 10 Responders 
• Participants identified as Responders who received GSK2831781 during the 
Induction phase will then receive 300mg GSK2831781 subcutaneously (SC) 
every four weeks during the double-blind Extended Treatment Phase (ETP), 
from Week 14 until Week 26.  
 
• Week 10 Responders in the placebo group during the Induction phase will 
continue to receive placebo SC every four weeks in the double-blind ETP.  
 
• At Week 30, all participants in the Responder ETP will undergo an 
Assessment, including a centrally read endoscopy. Subsequently, all 
participants will remain in study, but off treatment, to Week 42 in the 12-week 
Follow-Up phase. 
 
 
 
 
 
 
 
 
 


 
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Overview of Study Design and Key Features 
Extended Treatment Phase – Dosing regimen for Responders only 
 
 
 
 
Open Label Treatment – Dosing Regimen for Non-Responders 
 
 
Week 10 Non-Responders 
• Participants identified as Non-Responders at Week 10 will be assigned to 
open label treatment in the Open Label Induction Phase. The total duration of 
open label treatment will be up to an additional 30 weeks of treatment (Week 
12 to Week 42) and a 12-week Follow-Up. Participants who have not attained 
clinical response, determined following a centrally read endoscopy at Week 
22 (calculated centrally through the eCRF), will discontinue study treatment 
and are still required to attend a Follow-Up visit approximately 16 weeks from 
the last dose event. 
• Participants in the Open Label part who respond at Week 22 will then receive 
300mg GSK2831781 subcutaneously (SC) every four weeks during the Open 
Label Extended Treatment Phase (ETP), from Week 26 until Week 38.  
• Subsequently, all Open Label participants will remain in study, but off 
treatment, to Week 54 in the 12-week Open Label Follow-Up phase. 
 
 


 
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Overview of Study Design and Key Features 
Dosing 
INDUCTION Phase:                                  
• 
GSK2831781 450 mg IV                               
• 
GSK2831781 300 mg IV          
• 
GSK2831781 150mg IV 
• 
GSK2831781 45mg IV 
• 
Placebo IV 
EXTENDED Treatment Phase for RESPONDERS  
• 
GSK2831781 300 mg SC 
• 
Placebo SC 
OPEN LABEL Treatment Phase for NON-RESPONDERS 
• 
GSK2831781 450 mg IV – weeks 12, 14, 18 and 22 
• 
GSK2831781 300 mg SC for Open Label Responders (assessed at week 22) 
• 
Treatment discontinuation for Open Label Non-Responders (assessed at week 22)  
 
Time & 
Events 
• 
Refer to Appendix 2: Schedule of Activities (SoA) 
Treatment 
Assignment 
• 
At Screening a unique Participant Number (case report form (CRF) number) 
will be assigned to any participant who has at least one Screening procedure 
performed, other than informed consent. The unique Participant Number will 
be used to identify individual participants during the study. 
• Participants who meet the screening eligibility criteria will be randomised to a 
treatment group through RAMOS NG. RAMOS NG will confirm the 
participants CRF number (Participant number) and provide the 
randomisation number. The randomization is centrally controlled by RAMOS 
NG. Once the randomization number is assigned, it cannot be reassigned to 
another participant in the study. 
• 
At the start of the study, participants will be randomised in a 2:1 ratio to 
GSK2831781 450mg and Placebo. 
• 
When an appropriate number of participants have been randomised in these 
two arms for the interim analysis (Interim Analysis 3, see below), 
randomisation to all dose regimens (GSK2831781 450mg, 300mg 150mg, 
45mg or placebo) will be opened in the ratio 2:3:3:3:2.  
• 
The randomisation will be stratified according to: 
1. Country (Japan or not Japan); if not Japan further stratification 
by: 
2. Prior advanced therapy experience (advanced therapy naïve, 
experienced a single class of advanced therapy, or experienced 
multiple classes of advanced therapies).  
• 
There is no re-randomisation for the ETP – if the participant is a placebo 
responder then the participant will stay on blinded placebo 
• 
At least 242 evaluable participants who complete all Week 10 assessments 
or withdraw will be recruited. The study size will not exceed 320 participants.   
Interim 
Analysis 
Up to 4 interim analysis will be conducted to assess the safety, pharmacokinetics, 
pharmacodynamics and efficacy of GSK2831781. Recruitment will continue while the 
interim analyses are being conducted, except in the case of a safety concern.  
• 
Interim Analysis 1 – PK 
• 
Interim Analysis 2 – Early Efficacy 
• 
Interim Analysis 3 – Efficacy futility 


 
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Overview of Study Design and Key Features 
• 
Interim Analysis 4 – Pharmacodynamic 
Blinded safety data, including clinical laboratory parameters and adverse events will be 
reviewed at appropriate intervals during the study conduct by an internal GSK SRT team 
according to routine pharmacovigilance practice.  
At the interim analyses, the data will be reviewed by the Data Review Committee (DRC) 
to ensure objective medical and statistical review of safety and efficacy issues to protect 
the ethical and safety interests of participants and to protect the scientific validity of the 
study via review of unblinded study data. 
 
Figure 1 below shows the paths that a participant can take through the study.  White 
rectangles are double blinded phases, grey rectangles are unblinded (open label or off 
drug phases). Note that at any point participants can discontinue from study drug but 
continue in the study until the end of the study phase. 
• Group A: Induction Phase  
• Group B: Extended Treatment Phase (Week 10 Responders) 
• Group C: Open Label Induction (Week 10 Non-Responders) 
• Group D: Open Label ETP (Week 22 Responders) 
• Week 22 Non-responders will complete a follow-up visit and withdraw from the 
study. 
The strategy for reporting study phases is to use analysis populations to define the 
participants for each phase. Post-Week 22 data for Week 22 Non-responders will be 
listed, not summarised. 
  


 
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Figure 1 
Participant Flow 
 


 
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2.4. 
Statistical Hypotheses / Statistical Analyses 
The study has two primary objectives.  
No formal hypothesis will be tested for the first, primary objective that assesses the safety 
and tolerability of GSK2831781 in participants.  
The second primary study objective is to evaluate the dose-response relationship in the 
change from baseline in Complete Mayo score, following 10 weeks of treatment with 
GSK2831781 or placebo. 
Due to the low number of participants in the 3 middle doses, this will be done by 
estimating the posterior probabilities of the difference between GSK2831781 450 mg IV 
and placebo, using Bayesian methodologies (Section 8.1.1 Primary Endpoint). 


 
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3. 
PLANNED ANALYSES 
In line with routine pharmacovigilance, an internal GSK SRT, which will include a 
subset of the 204869 study team, will review blinded safety data, including clinical 
laboratory parameters and adverse events, at appropriate intervals during the period of 
study conduct. See the SRT charter for further details, including the team members of the 
SRT. 
3.1. 
Interim Analyses 
At the interim analyses, the data will be reviewed by the DRC (Data Review 
Committee). Further details of the DRC remit are provided in the DRC charter which 
outlines how the DRC will ensure data integrity and appropriate quality control of data 
prior to making decisions, as well as documenting membership of the DRC. 
The following interim analyses are planned to assess the safety, pharmacokinetics and 
efficacy of GSK2831781 in this study. Recruitment will continue while the interim 
analyses are being conducted, except in the case of a safety concern. Interim analysis 3 
incorporates a decision for futility. Note: not all interim analyses may be conducted. 
Interim Analysis 
When 
Objective 
1 (PK) 
Approximately fifteen 
participants (across 
the highest dose and 
placebo) have 
completed their 
pharmacokinetic 
assessment at Week 2. 
PK will be assessed to determine if 
the exposures in ulcerative colitis 
participants are similar to those 
predicted based on data observed in 
healthy volunteers and psoriasis 
patients.    
2 (Early Efficacy) 
Approximately thirty-
six participants 
(across the highest 
dose and placebo) 
have completed Week 
10 assessments. 
Assessment of the endoscopic 
mucosal healing response. 
Data will be reviewed by the DRC 
for internal decision making, where 
decision criteria are outlined in the 
DRC charter. 
An assessment of futility will not be 
made at this point. 
Additional data may be reviewed, 
including stool frequency and rectal 
bleeding. 
3 (Efficacy futility) 
Approximately sixty 
participants (across 
the highest dose and 
placebo) have 
Assess futility based on the 
proportion of participants who 


 
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Interim Analysis 
When 
Objective 
completed Week 10 
assessments. 
achieve endoscopic mucosal 
healing, based on the Mayo score. 
The predictive probability of 
success at the end of the study will 
be calculated based on the data 
observed at this interim analysis.  
The futility rule is outlined in the 
DRC charter and characteristics of 
which are included in the RAP. 
Unblinded safety data will be 
reviewed. 
Additional data may be reviewed. 
4 (Pharmacodynamic) 
A minimum of 
approximately twenty 
participants per 
GSK2831781 dose 
level have completed 
Week 10 assessments 
Assessment of pharmacodynamic 
dose-response at Week 10. 
Data may be reviewed by the DRC 
for internal decision making, where 
decision criteria are outlined in the 
DRC charter. 
An assessment of futility will not be 
made at this point. 
Unblinded safety data will be 
reviewed. 
 
3.2. 
Final Analyses 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
• All participants have completed the study as defined in the protocol  
• All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data 
Management. 
• All criteria for unblinding the randomization codes have been met.  
• Randomization codes have been distributed according to RandAll NG procedures. 


 
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4. 
ANALYSIS POPULATIONS 
The strategy for reporting study phases is to use analysis populations to define the 
participants for each study phase. 
4.1. 
Populations for the Induction Phase 
The following analysis populations apply to the double-blind induction phase of the 
study. 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened  
• 
All participants who were screened for eligibility this 
includes screening failures (who never passed 
screening even if rescreened) and participants 
screened but never enrolled into the study as well as 
enrolled participants. 
• 
Study Population 
Enrolled 
• 
All participants who were randomly assigned to 
treatment in the study. 
• 
This population will be based on the treatment the 
participant was randomised to. 
• 
Any participants who receive a treatment 
randomisation number will be considered to have 
been randomised 
• 
Study Population 
Safety 
• 
All participants who received at least one dose of 
study treatment. 
• 
Participants who were not randomized but received at 
least one dose of study treatment will be listed. 
• 
This population will be based on the treatment the 
participant actually received. 
• 
 
• 
Safety 
 
Intent-To-Treat-
Exposed (ITTE) 
• 
All enrolled participants who received at least one 
dose of study treatment, and who have at least one 
valid post dose assessment. 
• 
This population will be based on the treatment the 
participant was randomised to. 
 
• 
Efficacy 
• 
PD 
• 
Biomarker 
• 
PRO 
 
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 
4.2. 
Populations for the Extended Treatment Phase 
Population 
Definition / Criteria 
Analyses Evaluated 
Intent-To-Treat-
Exposed ETP 
(ITTE_ETP) 
• 
All participants who received at least one dose of 
study treatment in the ETP (e.g. placebo or 300mg 
SC). 
• 
This population will be based on the treatment that 
the participant was randomised to. 
• 
Study Population 
• 
Efficacy 
• 
PD 
• 
Biomarker 
• 
PRO 


 
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Population 
Definition / Criteria 
Analyses Evaluated 
Safety ETP 
• 
All participants who received at least one dose of 
study treatment in the ETP (e.g. placebo or 300mg 
SC). 
• 
This population will be based on the treatment the 
participant actually received. 
 
• 
Safety 
Pharmacokinetic 
ETP (PK_ETP) 
All participants in the Safety ETP population who had 
at least 1 non-missing PK assessment in the ETP 
phase (Non-quantifiable [NQ] values will be 
considered as non-missing values). 
• 
PK 
4.3. 
Populations for the Open Label Induction Phase 
Population 
Definition / Criteria 
Analyses Evaluated 
Intent-To-Treat-
Exposed OL_I 
(ITTE_OL_I) 
• 
All participants who received at least one dose of 
study treatment in the Open Label Induction Phase. 
• 
This population will be based on the treatment that 
the participant was allocated to. 
• 
Study Population 
• 
Efficacy 
• 
PD 
• 
Biomarker 
• 
PRO 
Safety OL_I 
• 
All participants who received at least one dose of 
study treatment in the Open Label Induction phase. 
• 
This population will be based on the treatment the 
participant actually received. 
 
• 
Safety 
Pharmacokinetic 
(PK_OL) 
• 
All participants in the Safety_OL_I population who 
had at least 1 non-missing PK assessment in Open 
Label Induction phase (Non-quantifiable [NQ] values 
will be considered as non-missing values). 
• 
PK 
4.4. 
Populations for the Open Label Extended Treatment Phase 
Population 
Definition / Criteria 
Analyses Evaluated 
Intent-To-Treat-
Exposed OL_ETP 
(ITTE_OL_ETP) 
• 
All participants who received at least one dose of 
study treatment in the OL ETP 
• 
This population will be based on the treatment that 
the participant was allocated to. 
• 
Study Population 
• 
Efficacy 
• 
PD 
• 
Biomarker 
• 
PRO 
Safety OL_ETP 
• 
All participants who received at least one dose of 
study treatment in the OL_ETP. 
• 
This population will be based on the treatment the 
participant actually received. 
 
• 
Safety 
Pharmacokinetic 
ETP 
(PK_OL_ETP) 
• 
All participants in the Safety OL_ ETP population who 
had at least 1 non-missing PK assessment in OL ETP 
(Non-quantifiable [NQ] values will be considered as 
non-missing values). 
• 
PK 
Refer to Section 15.5.2: Reporting Standards for rules used to define ‘treatment actually 
received’. 
 


 
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Refer to Appendix 12: List of Data Displays which details the population used for each 
display. 
4.5. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed. 
Protocol deviations may define Intercurrent Events (ICEs) that affect Efficacy analyses, 
as described in Section 8.1.1.1 and Section 8.2.1.1. ICEs will be listed as described in 
Appendix 12: List of Data Displays. 
Protocol deviations will be tracked by Robarts and monitored by the GSK study team 
throughout the conduct of the study in accordance with the Protocol Deviation 
Management Plan which will be updated throughout the study 
o The protocol deviations for those participants included in each interim analysis, 
up to the point of the data cut-off will be reviewed prior to unblinding.  
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the 
analysis are captured and categorised consistently on the protocol deviations 
datasets.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF. 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
5.1.1. 
Randomised, Double Blind Treatments 
For within-study phase reporting the following descriptions will be used. 
Treatment Group Descriptions 
RandAll NG Randomization System 
Data Displays for Reporting where characters are 
limited 
Code 
Description 
Description 
Order in TLF  
A 
GSK2831781 450 mg IV 
GSK2831781 450 mg IV 
2 
B 
GSK2831781 300 mg IV 
GSK2831781 300 mg IV 
3 
C 
GSK2831781 150 mg IV 
GSK2831781 150 mg IV 
4 
D 
GSK2831781 45 mg IV 
GSK2831781 45 mg IV 
5 


 
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Treatment Group Descriptions 
RandAll NG Randomization System 
Data Displays for Reporting where characters are 
limited 
Code 
Description 
Description 
Order in TLF  
P 
Placebo IV 
Placebo IV 
1 
X 
GSK2831781 300mg SC 
GSK2831781 300mg SC 
7 
Y 
Placebo SC 
Placebo SC 
6 
 
Treatment comparisons in induction will be displayed as follows using the descriptors as 
specified: 
1. 
GSK2831781 450 mg IV vs Placebo IV 
2. 
GSK2831781 300 mg IV vs Placebo IV 
3. 
GSK2831781 150 mg IV vs Placebo IV 
4. 
GSK2831781 45 mg IV vs Placebo IV 
5.  
6. For reporting within the extended treatment phase the following treatment 
descriptions will be used. 
7. 
Treatment Group Descriptions – Extended Treatment Phase for week 10 responders 
RandALL NG Randomization System 
Data Displays for Reporting where characters 
are limited 
Code  
Description 
Description 
Order in TLF 
8. AX 
9. 
GSK2831781 450 mg IV 
induction, 300 mg 
subcutaneous from week 
14 
10.  
11.  
12.  
13.  
14. GSK2831781 300mg 
SC  
15. 2 
16. BX 
17. GSK2831781 300 mg IV 
induction, 300 mg 
subcutaneous from week 
14 
18. 2 
19. CX 
20. GSK2831781 150 mg IV 
induction, 300 mg 
subcutaneous from week 
14 
21. 2 
22. DX 
23. GSK2831781 45 mg IV 
induction, 300 mg 
subcutaneous from week 
14 
24. 2 
25. PY 
26. Placebo IV induction, 
Placebo subcutaneous 
from week 14 
27. Placebo SC 
28. 1 
Treatment comparisons in the extended treatment phase will be displayed as follows 
using the following descriptor as specified: 


 
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GSK2831781 300 mg SC vs Placebo SC 
5.1.2. 
Partial doses  
If an incomplete IV dose is given then the dose received will be calculated as a 
proportion of the planned dosing duration (see below), this makes the simplifying 
assumption that the IP will be dosed at a constant rate.  If an incomplete SC dose is given, 
the number of injections will be used to derive the received dose.  For details of these 
calculations see Section 15.6 Appendix 6: Derived and Transformed Data. 
Planned dose duration for IV doses 
Phase 
Visit 
Planned duration of IV dose 
Induction 
Day 1 
2 hr 
Induction 
Week 2 
2 hr 
Induction 
Week 6 
32 min 
Induction 
Week 10 
32 min 
Open label induction 
Week 12 
2 hr 
Open label induction 
Week 14 
2 hr 
Open label induction 
Week 18 
32 min 
Open label induction 
Week 22 
32 min 
See protocol Table 1 and Table 2 for further context 
 
5.2. 
Baseline Definitions 
The baseline value will be the latest pre-dose assessment with a non-missing value, 
including those from screening and unscheduled visits 
If baseline data is missing no derivation will be performed and baseline will be set to 
missing. 
5.3. 
Multicentre Studies 
In this multicentre global study, enrolment will be presented by the investigative site.  
Participants will be enrolled from approximately 100 centres.  There are no planned 
adjustments made for multiple centres in this study.  


 
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5.4. 
Examination of Covariates, Other Strata and Subgroups 
5.4.1. 
Covariates and Other Strata 
The following list of covariates and other strata will be used in descriptive summaries and 
statistical analyses of primary and key secondary efficacy endpoints, some of which will 
also be used for subgroup analyses. Additional covariates and other strata of clinical 
interest may also be considered.  For change from baseline endpoints, the baseline will 
also be included as a covariate. 
Category 
Details 
Notes 
Advanced therapy 
experience 
(Stratification factor) 
Categorical variable with three levels: 
• 
Advanced therapy naïve,  
• 
Single class of advanced therapy 
experience 
• 
Multiple classes of advanced 
therapy experience 
Derived from ‘previous UC 
medications’ in medical history. 
 
This is the stratification factor 
used in RAMOS, recorded at 
baseline in the eCRF for each 
participant; in case of conflict 
between the stratification in 
RAMOS and medical history, 
medical history will be used. 
TNF failure (Covariate) 
Categorical variable with three levels: 
• 
No TNF failure 
• 
Single TNF failure 
• 
Multiple TNF failures 
Derived from medical history, 
covariate will be used as 
secondary analysis at primary 
completion 
biologic experience 
type (Covariate) 
 
Categorical variable with three levels: 
• 
Biologic naïve 
• 
TNF experience (no Vedolizumab) 
• 
Vedolizumab (including participants 
who have both TNF and 
Vedolizumab experience) 
Note: if participant has experience of other 
biologics, they will be assigned based on 
experience of TNF and Vedolizumab. 
 
Derived from medical history. 
Comparison made as 
secondary analysis.  
Baseline mucosal 
CD3+LAG3+ cell count 
(Covariate) 
Continuous variable derived from biopsy.  
 
CD3 positive and Lag3 positive cells per 
mm2  of Lamina Propria tissue taken at 
screening biopsy. 
 
Duration of disease 
(Covariate) 
Duration of disease, years 
If day and month of diagnosis 
are missing, duration of 
disease will be calculated by 
using day=1 and month=July 
Baseline Complete 
Mayo Score 
Where the endpoint is derived from a 
version of the Mayo score, that version’s 
baseline will be used. 
 


 
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Category 
Details 
Notes 
Baseline Adapted 
Mayo Score 
Where the endpoint is derived from a 
version of the Mayo score, that version’s 
baseline will be used.   
 
5.4.2. 
Examination of Subgroups 
The list of subgroups may be used in descriptive summaries and statistical analyses. 
Additional subgroups of clinical interest may also be considered. The following subgroup 
analyses will only be performed at final analysis unless otherwise specified. 
• 
If the percentage of subjects is small 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  
Timing 
Motivation 
Any advanced therapy 
experience 
Advanced therapy naïve vs.  
Advanced therapy experienced 
Interims, SAC 
Prior expectation of 
clinical importance  
5.5. 
Multiple Comparisons and Multiplicity 
In general, no multiplicity adjustments will be made however for relevant data types 
standard analysis methods that correct for multiplicity may be employed, for example in 
the analysis of exploratory transcriptomic data. 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
following appendices: 
Section 
Component 
15.3 
Appendix 3: Assessment Windows 
15.4 
Appendix 4: Treatment Phases and Study Phases Study Phases and Treatment 
Emergent Adverse Events 
15.5 
Appendix 5: Data Display Standards & Handling Conventions 
15.6 
Appendix 6: Derived and Transformed Data 
15.7 
Appendix 7: Reporting Standards for Missing Data 
15.8 
Appendix 8: Values of Potential Clinical Importance 
 


 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The induction study population analyses will be based on the “Screened” and “Enrolled” 
populations, unless otherwise specified. 
Population outputs will be generated for the participants in the four study phases 
illustrated in Figure 1 Participant Flow: 
• Group A: Induction Phase  
• Group B: Extended Treatment Phase (Week 10 Responders) 
• Group C: Open Label Induction (Week 10 Non-Responders) 
• Group D: Open Label ETP (Week 22 Responders) 
This pattern will continue for all reported domains in this study. 
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 12: List of Data Displays. 


 
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7. 
SAFETY ANALYSES 
All safety evaluations will be based on the safety population. Displays of adverse events, 
laboratory values, ECG and vital signs will be generated. These data will be clinically 
interpreted based on a number of factors, including taking account the investigator-
reported relationships of either adverse events or laboratory abnormalities to 
investigational product.  
Safety endpoints of all types will be reported by study phase (Induction phase, Extended 
Treatment Phase, Open Label Induction Phase, Open Label Extended Treatment Phase).  
All study phases will use the same pre-dose baseline. The details of planned displays are 
provided in Appendix 12: List of Data Displays. 
No formal statistical testing will be performed on safety data. 
7.1. 
Adverse Events Analyses 
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards.  
7.2. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests, Urinalysis, and liver function tests will be based on GSK 
Core Data Standards. Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified.  
The immunogenicity of GSK2831781 will be characterized with summary statistics of 
incidence, i.e. the count of participants with positive confirmed anti-drug antibodies by 
treatment over time.  Immunogenicity testing involves a screening assay and a 
confirmation assay that together produce three results: 
• Screening assay result (binary (yes/no)) 
• Confirmatory assay result (binary (yes/no)) 
• Titre result (numeric) 
 


 
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8. 
EFFICACY ANALYSES 
Unless otherwise specified, endpoints / variables defined in this section will be 
summarised by treatment using descriptive statistics, graphically presented (where 
appropriate) and listed. 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
8.1. 
Primary Efficacy Analyses  
The primary efficacy endpoint is change from baseline over the induction phase. 
8.1.1. 
Primary Endpoint 
The Complete Mayo Score will be analysed with a Bayesian ANCOVA model, using the 
following estimands. 
8.1.1.1. 
Primary Estimand – Treatment Policy 
Primary estimand: “Treatment policy” 
Objective: To characterise the efficacy of GSK2831781 during the Induction Phase. 
Estimand: 
Primary efficacy estimand 
Description 
Mean change from baseline to Week 10 in Complete Mayo score for each 
dose level and placebo in patients with moderate to severe, active 
Ulcerative Colitis and in the absence of IP discontinuation due to the 
COVID-19 pandemic. 
Attributes 
• Treatment: Placebo and four doses of GSK2831781 IV: 450mg, 
300mg, 150mg and 45mg in addition to background therapy and stable 
dose of corticosteroid where relevant.  
• Population: Patients with moderate to severe, active, Ulcerative 
Colitis as per inclusion/exclusion criteria.  
• Outcome measure: Change from baseline to Week 10 in Complete 
Mayo score.  
• Intercurrent events and strategy:  
• Intercurrent event (ICE): Discontinuations due to the COVID-19 
pandemic 
o Strategy: hypothetical, setting assessments to missing with 
missing at Random [MAR] assumption. 
• ICE: Discontinuations due to sponsor’s decision to terminate the 
study 


 
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Primary estimand: “Treatment policy” 
o Strategy: hypothetical, setting assessments to missing with 
missing at Random [MAR] assumption. 
• ICE: Discontinuations not due to the COVID-19 pandemic or to 
sponsor’s decision to terminate the study 
o Strategy: treatment policy (no imputation). 
 
• Population-level summary: Mean change from baseline.  
 
Estimation and missing data details for the primary estimand (“Treatment 
Policy”) 
Discontinuations due to reasons related to the COVID-19 pandemic or to sponsor’s 
decision to terminate the study will be handled with a hypothetical strategy; the 
subsequent assessments will be set to missing in the analysis dataset (even if post 
discontinuation data is collected). 
Assessments following IP discontinuations for other reasons will be used in analysis. 
In all cases, the missing endpoint will be assumed to be MAR in the statistical analysis.  
The MAR assumption is implicit in the planned Bayesian analysis. 
 
8.1.1.2. 
Statistical Analysis 
 Bayesian analysis for continuous endpoint 
Endpoints 
Change from baseline in Complete Mayo Score at Week 10 
Statistical analysis 
Linear regression  
Predictors 
• 
TRT = study treatment(categorical) 
• 
Advanced 
Therapy 
Experience 
(categorical) 
(includes 
interaction with study treatment) 
• 
Baseline Complete Mayo (continuous) 
• 
Duration of disease, years (continuous) 
Model 
yi ~ Normal(mean=μ, SD=σ) 
μ = (TRT=Placebo)×(Experienced=Y)×β1 + 
(TRT=450mg)×(Experienced=Y)×β2 + 
(TRT=Placebo)×(Naive=Y)×β3 + (TRT=450mg)×(Naive=Y)×β4 
+ (Duration*)×β5 + (Baseline*)×β6 


 
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 Bayesian analysis for continuous endpoint 
Population-level 
coefficients (β) 
•  β = fixed effects, parameters associated to predictors 
βk: non-informative prior distributions, 
βk ~ Normal(mean=0, SD=100) 
• Standard deviation σ: 
Non-informative prior Gamma distribution (shape=2, 
rate=0.1) (Chung, 2013) 
* Unless otherwise specified the predictors (not including study treatment) will be 
centred around their estimated mean in the model 
 
Further details of primary analysis 
Model diagnostics and checking 
• Each chain will initially have length 0f 1,000,000, thin of 10 and burn-in length of 50,000. 
• Chain convergence diagnostics will be saved in HARP (refdata folder) and inspected.   
• The MCSE will be compared with the standard deviation of the posterior distribution (SD) to 
ensure that only a fraction of the posterior variability is due to simulation error, i.e., the ratio 
MCSE/SD should be close to 0.01   
 
Model results presentation 
• The posterior distribution of each arm and the treatment difference (overall and by Advanced 
Therapy Experience) will be summarized using median and equal-tailed 95% credible region 
and the probability of being above specific thresholds specified in the programming notes for 
this output. 
• Posterior density plots will be available in model output but will not be presented 
 
8.1.1.3. 
Additional analyses for the Primary Endpoint 
Frequentist analysis of change from baseline in Complete Mayo score at Week 10 
A fixed-effect normal linear model will be used to compare the primary endpoint 
(change from baseline in Complete Mayo score at Week 10 Double-Blind Induction) 
between 450mg GSK2831781 IV and Placebo IV. 
The following variables will be used as covariates: Duration of disease (continuous), 
Advanced Therapy Experience (Categorical), Baseline Complete Mayo (continuous) 
and treatment. 
The estimated difference in change from baseline in Complete Mayo score at Week 10 
will be displayed with 95% confidence interval (and associated p-value). 


 
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8.2. 
Secondary Efficacy Analyses 
8.2.1. 
Key Secondary Endpoint 
8.2.1.1. 
Estimand 
Key secondary estimand for decision making: “Composite” 
Objective: To investigate the effect of repeat doses of GSK2831781 on clinical 
efficacy including endoscopic mucosal healing during the Double-Blind 
Induction Phase. 
Estimand: Description 
Difference in response rates between active doses of GSK2831781 and 
Placebo when added to background therapy in patients with moderate to 
severe, active Ulcerative Colitis.  
 
Attributes 
• Treatment: Placebo and active doses of GSK2831781 in addition to 
background therapy and stable dose of corticosteroid where relevant.  
• Population: Patients with moderate to severe, active, Ulcerative 
Colitis as per inclusion/exclusion criteria.  
• Outcome measure: Endoscopic Mucosal Healing at Week 10 
assessment, where success is defined as: 
o Achieving a score on the endoscopic component of the Adapted 
Mayo score of 0 or 1, and 
o Not discontinuing IP due to reasons unrelated to the COVID-19 
pandemic or to sponsor’s decision to terminate the study, and 
o Not taking medications excluded by the protocol or increasing dose 
of corticosteroid. 
 
• Intercurrent events and strategy:  
o ICE: discontinuation from IP, unrelated to COVID-19 pandemic or 
to sponsor’s decision to terminate the study.   
o Strategy: included in outcome via composite strategy (i.e. post-ICE 
result set to non-response). 
 
o ICE: discontinuation from IP, due to COVID-19 pandemic.  
o Strategy: hypothetical, setting response status to missing. 
 
o ICE: discontinuation from IP, due to sponsor’s decision to 
terminate the study.  
o Strategy: hypothetical, setting response status to missing. 
 
o ICE:  valid endoscopy result not available, due to COVID-19 
pandemic 


 
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Key secondary estimand for decision making: “Composite” 
o Strategy: hypothetical, setting response status to missing. 
 
o ICE:  valid endoscopy result not available, for technical reasons 
o Strategy: hypothetical, setting response status to missing. 
 
o ICE:  prohibited medication taken 
o Strategy: included in outcome via composite strategy (i.e. post-ICE 
result set to non-response). 
 
o ICE:  increase in dose of permitted medications 
o Strategy: included in outcome via composite strategy (i.e. post-ICE 
result set to non-response). 
 
• Population-level summary: Difference in proportion of participants 
who achieve response between placebo and relevant active doses 
 
 
Estimation and missing data details for the key secondary estimand for decision 
making (“Composite”) 
Participants who have a missing assessment at Week 10 for reasons unrelated to the 
COVID-19 pandemic will be counted as non-responders in the analysis.  
The ICEs that will be dealt with using a hypothetical strategy will have response status 
set to missing  
In all cases, the missing response status will be assumed to be MAR in the statistical 
analysis.  
The MAR assumption is implicit in the planned Bayesian analysis. 
 


 
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8.2.1.2. 
Statistical Analysis 
 Bayesian analysis for binary endpoint 
Endpoints 
Endoscopic Mucosal Healing (Endoscopic Improvement) 
Statistical analysis 
Logistic regression  
Predictors 
• 
TRT = study treatment(categorical) 
• 
Advanced Therapy Experience (categorical) 
• 
Baseline Adapted Mayo (continuous) 
• 
Duration of disease, years (continuous) 
Model 
yi ~ Ber(pi) 
logit(pi) = (TRT=Placebo)×β1 + (TRT=450mg)×β2 + 
(Duration*)×β3 + (Baseline*)×β4 + (Experience*)×β5 
Outcome 
yi = response (0/1) for participant i 
Population-level 
coefficients (β) 
•  β = fixed effects, parameters associated to predictors 
β1 : informative prior distribution, 
logit-1(β1) ~ mixture of Betas** 
β2 : non-informative prior distribution, 
logit-1(β2) ~ Beta(1/3, 1/3) 
βk for other predictors: non-informative prior 
distributions, 
βk ~ Normal(mean=0, SD=100) 
* Unless otherwise specified the predictors (not including study treatment) will be 
centred around their estimated mean in the model 
** The parameterisation of the priors used in the analysis will be described in Appendix 
14: Details of the Informative Placebo Prior and reported in the clinical study report 
 
Further details of key secondary analysis 
Overview of approach 
 
For interim 2 and 3 the predictive probability of meeting the end of study success criteria will 
be assessed after the Week 10 endoscopy (or withdrawal) has been observed on the 
number of participants specified for that data cut.   
 
A sample from the posterior distribution of the difference in response rates between each 
treatment arm and placebo will be obtained using Markov chain Monte Carlo (MCMC). This 
analysis will account for historical placebo data by using an informative prior distribution for 
the placebo arm and a vague Beta (1/3,1/3) distribution for the active arm (Kerman, 2011). 


 
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Informative Placebo Prior 
• The prior distribution is a robust mixture prior based on historical data following the 
approach of (Schmidli, 2014). A meta analytic predictive (MAP) prior of relevant historical 
data is created, with a covariate for the proportion of Advanced Therapy Experienced in 
each historical trial. 
• The MAP prior is obtained via an MCMC model with the following specifications: 
o For each historical trial s with r responders in N placebo patients and percentage of 
Advanced Therapy Experienced %Exp: 
 
o Prior for between-trial heterogeneity τ: half-normal with μ=0, σ=z/2 where z is 
derived via the n-∞ method (Neuenschwander., 2010): 
▪ p = mean of r/N of historical trials 
▪ z = [sqrt(p*(1-p))]-1 
o Priors for coefficients α, β: normal with μ=0, σ=100 
• The  MCMC samples of the placebo response are approximated using appropriate 
parametric distributions, typically a mixture of two to three Beta distributions. Unless stated 
otherwise, the number of Beta distributions in the mixture is decided via AIC. 
• The prior used for analysis will use the proportion of Advanced Therapy Experienced 
participants observed in this trial at the relevant interim or final analysis.   
• The rules for including historical data used for this analysis will be documented in Appendix 
14: Details of the Informative Placebo Prior.   
• The MAP prior distribution is ‘robustified’ by further mixing with a non-informative 
Beta(1/2,1/2) distribution with 40% weight for the non-informative prior.   
• The final prior distribution and supporting information will be documented in the trial master 
file before the study is unblinded for interim analysis 3. 
• Examples of the parametric distributions used at different levels of the covariate are 
documented in Appendix 14: Details of the Informative Placebo Prior. 
Model Checking & Diagnostics 
• Each chain will initially have length 0f 1,000,000, thin of 10 and burn-in length of 50,000. 
• Chain convergence diagnostics will be saved in HARP (refdata folder) and inspected.   
• The MCSE will be compared with the standard deviation of the posterior distribution (SD) to 
ensure that only a fraction of the posterior variability is due to simulation error, i.e., the ratio 
MCSE/SD should be close to 0.01   
 


 
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Model Results Presentation 
• At IA3, the predictive probability that the end of study success will be achieved according to 
specific thresholds will be displayed (thresholds will be specified in the programming notes 
for this output). 
o The predictive probability of end of study success is obtained by simulating 
10,000 trials 
o In each simulated trial, post-IA3 Endoscopic Improvement results for Placebo 
and 450mg are simulated using the posterior samples for the response rates 
obtained in the MCMC model at IA3. The IA3 Endoscopic Improvement counts 
for Placebo and 450mg are summed to the simulated post-IA3 data to obtain 
simulated results for the full study. 
o In each simulated trial, end of study success is calculated using the posterior 
distributions for 450mg and Placebo (without covariates): 
▪ In the Active arm, a non-informative Beta(1/3,1/3) is used as prior. 
▪ In the Placebo arm, the MAP prior described above (an informative 
mixture of Betas) is used as prior. 
▪ The mixture Placebo prior will take the following form: 
 
▪ When computing the Placebo posterior using simulated results (r1 
responders out of n1 participant) each of the k mixture components 
takes the following form (Röver, 2020): 
 
 
 
• The posterior distribution of each arm and the treatment difference will be summarized using 
mean and equal-tailed 95% credible region and the probability of being above specific 
thresholds specified in the programming notes for this output. 
• Posterior density plots will be available in model output but will not be presented. 
 
8.2.2. 
Other Secondary Endpoints - Categorical 
The ICE strategy for the Key Secondary Estimand described in Section 8.2.1.1 above will 
be replicated in the following secondary Efficacy endpoints: 
Endpoint 
Endpoint name to be displayed for 
Estimand Analysis 
Adapted Mayo Clinical Remission at Week 10 
Secondary – Adapted Mayo Clinical Remission 
Adapted Mayo Clinical Response at Week 10 
Secondary – Adapted Mayo Clinical Response 
Symptomatic Remission at Week 10 
Secondary – Symptomatic Remission 
 
The “Secondary Estimand – Clinical Remission” will be analysed by replicating the 
statistical model described in Section 8.2.1.2 above. The other two estimands in the table 
above will be summarised only. 


 
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8.2.3. 
Other Secondary Endpoints - Continuous 
The ICE strategy for the Primary Estimand described in Section 8.1.1.1 above will be 
replicated in the following secondary Efficacy endpoints: 
Endpoint 
Endpoint name to be displayed for 
Estimand Analysis 
Change from Baseline in Partial Mayo Score at 
Weeks 2, 4, 6, 10 
Secondary – Partial Mayo Score 
Change from Baseline in Adapted Mayo Score 
at Week 10 
Secondary – Adapted Mayo Score 
Change from Baseline in Adapted Mayo 
endoscopic score at Week 10 
Secondary – Endoscopic Score 
Change from Baseline in UCEIS at Week 10 
Secondary – UCEIS Total Score 
 
The four estimands in the table above will be summarised in tables. 
In addition, a Bayesian repeated measures analysis will be conducted for the Partial Mayo 
score, the estimand is described below and the analysis details below that. 
8.2.3.1. 
Statistical Analysis 
Bayesian Repeated Measures Analysis for Continuous Endpoint 
Endpoint 
Change from baseline in Partial Mayo Score 
Statistical 
analysis 
GLMM with natural link (equivalent to MMRM) 
Model 
 
Outcome 
vector of change from baseline values for participant i 
Prior for  
σ = between-participant SD, 
 
with A reasonably large e.g. A=10 (Chung, 2013) 
Population-
level 
coefficients 
(β) 
• 
= fixed effects, parameters associated to predictors 
 = intercept, two possible prior distributions*: 
Vague: 
 
Weakly informative: see Appendix 14: Details of the 
Informative Placebo Prior 
 ~ 
 


 
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Bayesian Repeated Measures Analysis for Continuous Endpoint 
Predictors (X) • 
TRT = study treatment(categorical) 
• 
visit = visit (categorical) 
• 
TRT*visit = study treatment by-visit interactions (categorical) 
• 
BASE = baseline value of dependent variable (continuous) 
• 
Partial Mayo Score 
• 
BASE*visit =baseline value by-visit interactions (continuous) 
• 
Advanced therapy experience (categorical stratification variable) 
Random 
effects (b) 
• 
 = known design matrix for the random effects 
• 
 = unknown subject-level random effects, ~ Normal(0, Σb ), 
where Σb within-subject covariance matrix  
• 
Σb ~ Inverse Wishart (J, S), with J = number of visits (degree of 
freedom), S = covariance matrix (identity matrix) 
* The parameterisation of the priors used in the analysis will be reported in the clinical 
study report. 
 
The details of the scores and indexes including the Complete, Partial and Adapted Mayo 
scores, and the corresponding definition of response and remission are described in 
Section 15.6 Appendix 6: Derived and Transformed Data. 
Note that the absolute values for each endpoint listed as change from baseline will also be 
reported for each timepoint. 
8.3. 
Exploratory Efficacy Analyses 
Exploratory efficacy endpoints include the primary and secondary endpoints in the post-
induction study phases (ETP, OL, OL ETP). Unless stated otherwise, exploratory 
efficacy endpoints will be listed but not summarised. 
 


 
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9. 
PATIENT REPORTED OUTCOMES ANALYSES 
Exploratory Patient reported outcomes (PROs) are not covered by this RAP. 


 
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10. 
PHARMACODYNAMIC AND BIOMARKER ANALYSES 
10.1. 
Pharmacodynamic and Biomarker Analyses  
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Biomarker endpoints will be summarised in Double Blind Induction by treatment using 
descriptive statistics, graphically presented and listed. Figures summarising these 
endpoints will show Geometric Mean with 95% CI.  
10.1.1. 
Endpoint / Variables 
• Serum C-reactive protein over time in participants with elevated CRP at baseline (e.g. 
CRP ≥ 5 mg/L) 
• Faecal calprotectin over time  
• Absolute and ratio to baseline in number of CD3 and LAG3 cells by 
Immunofluorescence (IF) in colon biopsies taken in two tissue types (Lamina Propria 
or Crypt/Epithelium) for the following derived parameters: 
Description 
Name in outputs 
(superscript not 
available) 
Units for derived 
variables 
% CD3 negative and Lag3 positive 
from total Lag3 positive cell 
population (% Lag3 positive non-T 
cells) 
CD3-LAG3+ as % of 
Total LAG3+ 
% 
% CD3 positive and Lag3 positive 
from total Lag3 positive cell 
population (% Lag3 positive T cells) 
CD3+LAG3+ as % of 
Total LAG3+ 
% 
CD3 positive cells per mm2 tissue 
CD3+ 
cells/mm2 
Lag3 positive cells per mm2 tissue 
LAG3+ 
cells/mm2 
CD3 positive and Lag3 negative 
cells per mm2 tissue 
CD3+LAG3- 
cells/mm2 
CD3 negative and Lag3 positive 
cells per mm2 tissue 
CD3-LAG3+ 
cells/mm2 
CD3 positive and Lag3 positive cells 
per mm2 tissue 
CD3+LAG3+ 
cells/mm2 
CD3+LAG3+ cells/mm2 in Lamina Propria are the primary biopsy endpoint (also 
referred to as mucosal CD3+LAG3+ cell count) and will also be a potential covariate 
for efficacy and biomarker analysis. 
 
• Ratio to baseline in the following cell types from flow cytometry. The table below 
shows the cell description and the endpoint name shown in outputs for flow 
cytometry data.   


 
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Description 
Name in outputs (superscript not 
available) 
J11L1+ memory T helper cells 
CD3+CD4+CD45RA-J11L1+ 
REA351+ memory T helper cells 
CD3+CD4+CD45RA-REA351+ 
J11L1+ memory CD4- T cells 
CD3+CD4-CD45RA-J11L1+ 
REA351+ memory CD4- T cells 
CD3+CD4-CD45RA- REA351+ 
Note: REA351+ represents cell depletion, J11L1+ represents receptor occupancy. 
 
 


 
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11. 
PHARMACOKINETIC ANALYSES 
The purpose of the pharmacokinetic analysis is to characterize the PK after repeat IV and 
subcutaneous dosing of GSK2831781. 
11.1. 
Pharmacokinetic Analyses 
11.1.1. 
Endpoint / Variables 
• AUC(0-tau) 
• Cmax 
• tmax 
• PK concentration 
• Soluble LAG3 (sLAG3) concentration 
11.1.1.1. 
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 15.5.3 
Reporting Standards for Pharmacokinetic) 
11.1.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
of PK concentration according to current working practices and using the currently 
supported version of WinNonlin (version 6.3 or higher). All calculations of non-
compartmental parameters will be based on actual sampling times. Pharmacokinetic 
parameters listed will be determined from the plasma concentration-time data, as data 
permits. 
Parameter 
Parameter Description 
AUC(0-
tau) 
Area under the concentration curve to the end of the dosing period 
Cmax 
Maximum concentration observed 
tmax 
Time at which the maximum concentration Cmax is observed 
NOTES: 
• 
Additional parameters may be included as required. 
11.1.2. 
Summary Measure 
• All endpoints/variables defined in Section 11.1.1 will be summarized by treatment 
over time using descriptive statistics, graphically presented (PK and sLAG3 
concentrations) and listed. 
11.1.3. 
Population of Interest  
The pharmacokinetic analyses will be based on the “Pharmacokinetic” population, unless 
otherwise specified. 


 
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11.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Descriptive statistics (e.g., n, arithmetic mean and corresponding 95% confidence 
interval, standard deviation, minimum, median, maximum, CVb%) will be calculated for 
all pharmacokinetic endpoints by treatment. For tmax, CVb% will be calculated for each 
treatment as: CVb%=100 x (SD/mean), where SD and mean are the standard deviation 
and mean of the untransformed data. For AUC(0-tau) and Cmax, geometric means and 
between subject CVs will be calculated for each treatment as: 
Geometric mean=exp(mean on loge scale) 
CVb(%)=sqrt(exp(SD2)-1)x100, 
where SD is the standard deviation of the loge transformed data. 
 


 
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12. 
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES 
The primary goal of this analysis is to characterize the population pharmacokinetics of 
GSK2831781 following repeat intravenous and subcutaneous dosing in participants with 
active ulcerative colitis. The influence of participant demographics, baseline 
characteristics, including disease activity, and impact of anti-drug antibodies on the 
pharmacokinetics of GSK2831781 in this population will be investigated. The individual 
participant PK parameters will be estimated and documented for the purposes of any 
subsequent exposure-response (PK/PD) analyses. 
12.1. 
Statistical Analyses / Methods 
A summary of the planned population pharmacokinetic analyses is outlined below: 
o Drug GSK2831781 concentration-time data will be subjected to nonlinear mixed 
effects modelling using the program NONMEM to develop a population PK model.   
o To support this analysis a PopPK dataset will be generated. The details for the dataset 
specifications are provided in a separate document. 
 
Detailed PopPK methodology is presented in Appendix 9: Population Pharmacokinetic 
(PopPK) Analyses.  
 
A population PK report will be produced by CPMS and presented separately from the 
main clinical study report (e.g. as an appendix). 
 
 


 
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13. 
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES 
The primary goal of this analysis is to characterize the pharmacokinetic / 
pharmacodynamic relationship of GSK2831781 following repeat intravenous and 
subcutaneous dosing in participants with active ulcerative colitis. The influence of subject 
demographics and baseline characteristics, including disease activity in this population 
will be investigated. 
13.1. 
Statistical Analyses / Methods 
A summary of the planned population pharmacokinetic / pharmacodynamic analyses is 
outlined below: 
• Drug GSK2831781 concentration (or pharmacokinetic parameter) and 
pharmacodynamic data will be subjected to nonlinear mixed effects modelling using 
the program NONMEM to develop a population PK/PD model. 
• To support this analysis, a PK/PD dataset will be generated. The details for the 
dataset specifications are provided in a separate document. 
• Detailed PK/PD methodology is presented in Appendix 10: Pharmacokinetic / 
Pharmacodynamic Analyses. 
 
A PK/PD report will be produced by CPMS and presented separately from the main 
clinical study report (e.g. as an appendix). 
 


 
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14. 
REFERENCES 
Bornkamp, B. (2014). Practical considerations for using functional uniform prior 
distributions for dose‐response estimation in clinical trials. Biometrical Journal, 56(6), 
947–962. 
Chung, Y., Rabe-Hesketh, S., Dorie, V., Gelman, A., Liu, J. (2013). A nondegenerate 
penalized likelihood estimator for variance parameters in multilevel models. 
Psychometrika, 78, 685–709. 
Clinical Study Report 2017N352860_00 A randomised, double blind (sponsor 
unblinded), placebo controlled, single ascending dose study to investigate the safety, 
tolerability, pharmacokinetics, and pharmacodynamics of a IV dose of GSK2831781 in 
healthy volunteers and patients with plaque psoriasis 
Hanauer S, Panaccione R, Danese S, et al. (2019) Tofacitinib induction therapy reduces 
symptoms within 3 days for patients with ulcerative colitis. Clin Gastroenterol Hepatol 
2019;17:139–146. 
Kerman, J. (2011). Neutral noninformative and informative conjugate beta and gamma 
prior distributions. Electronic Journal of Statistics 5, 1450–1470 
Marchal-Bressenot A, et al. (2017) Development and validation of the Nancy histological 
index for UC. Gut 2017; 66:43–49. 
Neuenschwander, B., Capkun-Niggli, G., Branson, M. and Spiegelhalter, D.J. (2010) 
Summarizing historical information on controls in clinical trials. Clinical Trials, 7(1): 5-
18. 
Röver, C. and Friede, T. (2020) Dynamically borrowing strength from another study 
through shrinkage estimation. Statistical Methods in Medical Research, 29(1): 293-308 
Schmidli H, Gsteiger S, Roychoudhury S, O'Hagan A, Spiegelhalter D, Neuenschwander 
B. (2014). Robust meta-analytic-predictive priors in clinical trials with historical control 
information. Biometrics, 70(4), 1023-32. 
Spiegelhalter, DJ; Best, N; Carlin, BP; van der Linde, A. (2002). "Bayesian measures of 
model complexity and fit (with discussion)". Journal of the Royal Statistical Society, 
Series B. 64 (4): 583–639. doi:10.1111/1467-9868.00353 
Study Protocol 2017N337668_02 – A multicentre randomized, double-blind (sponsor 
open), placebo-controlled Phase 2 study to evaluate the safety, tolerability, efficacy, 
dose-response, pharmacokinetics and pharmacodynamics of repeat dosing of an anti-
LAG3 cell depleting monoclonal antibody (GSK2831781) in patients with active 
ulcerative colitis.  
 


 
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15. 
APPENDICES 
15.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Analysis Population Exclusions 
As Per-Protocol populations will not be used, participants will not be excluded from 
analyses due to protocol deviations. 


 
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15.2. 
Appendix 2: Schedule of Activities (SoA): 
Double Blind Treatment 
Screening 
Induction Phase 
Extended Treatment Phase 
Follow-Up20 
Early 
Withdrawal 
Visit21, 26 
WEEK  
 
Pre- 
dose 
Post-
dose 
2 
426 
6 
10 
1219 
14 
1826 
2226 
2626 
30 
4226 
DAY 
-35 to -
723 
-14 to -
714 
Day 1 
15 
29 
43 
71 
85 
99 
127 
155 
183 
211 
295 
 
Window (days) 
 
 
 
±2 
±3 
±3 
±3 
±5 
±3 
±3 
±3 
±3 
±3 
±7 
 
Study Population 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
X 
X 
History1 (Medical/Disease/ 
IBD Therapy) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Extra-Intestinal 
Manifestations History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking status 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Efficacy 
Determination of 'Normal' 
stool count for Mayo Score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endoscopy with Biopsy2 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X22 
Mayo (Complete or Partial) 
P 
C 
P 
 
P 
P 
P 
C 
 
P 
 
P 
 
C 
P 
C22/P 
Steroid Taper 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Extra-Intestinal 
Manifestations Activity 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Safety Assessments 
Vital Signs 
X 
 
X 
X16 
X16 
X 
X 
X 
 
X16 
X16 
X 
X 
X 
X 
X 
12-lead ECG3 
X 
 
X 
X16 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
Full/Brief Physical 
F 
 
B 
 
B 
B 
B 
B 
 
B 
B 
B 
B 
B 
F 
F 
Concomitant Medications 
X 
 
<-----------------------------------------------------------------------------------------------------------------------> 
AEs / SAEs4 
<---------------------------------------------------------------------------------------------------------------------------------------------------> 
Haematology5 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry (incl. CRP)5 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test (WOCBP)5, 6 
X 
 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 


 
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Screening 
Induction Phase 
Extended Treatment Phase 
Follow-Up20 
Early 
Withdrawal 
Visit21, 26 
WEEK  
 
Pre- 
dose 
Post-
dose 
2 
426 
6 
10 
1219 
14 
1826 
2226 
2626 
30 
4226 
DAY 
-35 to -
723 
-14 to -
714 
Day 1 
15 
29 
43 
71 
85 
99 
127 
155 
183 
211 
295 
 
Window (days) 
 
 
 
±2 
±3 
±3 
±3 
±5 
±3 
±3 
±3 
±3 
±3 
±7 
 
Urinalysis5 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
TB – QuantiFERON ± PPD7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (HIV, HBV, HCV, 
CMV, EBV and VZV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clostridium difficile toxin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH & oestradiol (if 
appropriate)8  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing and PK/PD 
Randomization 
 
 
X27 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administration9 
 
 
IV 
 
IV 
 
IV 
IV 
 
SC 
SC 
SC 
SC 
 
 
 
PK10, 11 
 
 
X 
X17 
X 
 
X18 
X 
 
X 
X 
X 
X 
X 
X 
X 
sLAG310, 11 
 
 
X 
X17  
X 
 
X18 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood proteomic signature5 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Blood transcriptomic 
signature5 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
LAG3 Cell Depletion (by Flow 
Cytometry)5,12 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
X 
X28 
X28 
Immunogenicity  
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
4β-hydroxycholesterol 
(4βHC)5 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Faecal Calprotectin24 
 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
X 
X 
X 
Serum Tryptase5 
 
 
X 
 
 
 
X 
X 
 
 
 
X 
 
X 
X 
X 
Patient Reported Outcomes 
IBDQ, FACIT-Fatigue and SF-
3613 
 
 
X 
 
 
 
X 
X 
 
 
 
X 
 
X 
X 
X 
Bowel symptom eDiary 
<---------------------------------------------------------------------------------------------------------------------------------------------------------> 
PGIC & PGIS13  
 
 
X15 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Exit Interview 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X25 
X25 
Other 
PGx Sample 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Footnotes: 
1 
See SRM for requirements for data collection. 
2 
Endoscopy should be flexible sigmoidoscopy. However, colonoscopy can be performed at screening if required for assessment of dysplasia risk (see Protocol 
Section 5.1), and at any timepoint if clinically indicated. 
3 
ECG in triplicate at screening and single at all other time points. See Protocol Section 8.6.3, Electrocardiograms for further detail. 
4 
Collection of SAEs starts from screening whilst collection of AEs will commence from Day 1. 
5 
Unless specified otherwise, all samples will be taken prior to administration of study treatment. 
6 
Negative test required during screening and immediately prior to the first dose of study treatment. A serum pregnancy test is required at screening, after 
which a highly sensitive urine pregnancy test is adequate. If a urine test cannot be confirmed as negative, a serum pregnancy test is required. 
7 
A PPD test maybe performed following two indeterminate Quantiferon tests to determine TB status, see Protocol Section 5.2. 
8 
To confirm postmenopausal status, serum FSH and oestradiol testing will be performed for all postmenopausal females at the screening visit. 
9 
See Protocol Section 6.2 for details of dosing duration and monitoring period. 
10 
Unless stated, samples taken on a day of dosing must be pre-dose sample (up to 2 hr before the next dose). 
11 
Additional sampling will be required in a subset of participants to characterise SC pharmacokinetics. See Protocol Section 8.3, for schedule. 
12 
LAG3 depletion will only be undertaken in sites where shipping to central lab can be achieved in the required timeframe, see Protocol Section 8.4, and SRM. 
13 
IBDQ, FACIT-Fatigue, SF-36, PGIC and PGIS are to be performed before any other assessments on visit days. 
14 
A 7-day window enables turnaround of centrally read endoscopy score for inclusion to arrange Day 1 visit; however, endoscopy can be performed up to Day -
3 if all other criteria for study eligibility have been met by this time and Robarts have agreed rapid turnaround of central endoscopy read. 
15 
PGIC not to be done on Day 1. 
16 
Vital signs to be taken every 30 minutes (±5 minutes) until completion of post dose monitoring period. A single ECG be taken within 4 hours of completion 
of dose administration. For participants who have discontinued treatment but remain on study, post-dose monitoring does not apply. 
17 
Samples to be taken immediately after end of IV infusion (preferably within 15 minutes). 
18 
Samples to be taken up to 2 hr before the next dose, and one sample immediately after end of IV infusion (within 15 minutes). 
19 
Week 12 visit scheduled to enable recall of Non-Responders to move to Open Label dosing at Week 12, see Open Label Treatment SoA below. Telephone 
call can be used to ensure Responders initiate steroid taper and cancel scheduled visit for Responders next due to undertake dosing at Week 14. 
20 
In case of Early treatment discontinuation, or study withdrawal, the investigator should undertake a Follow-Up visit approximately 16 weeks after the last 
dose event to allow safety monitoring following drug washout. 
21 
Participants who discontinue study treatment are encouraged to complete remaining scheduled visits for the treatment phase they are in.  However, an Early 
withdrawal visit is only required for participants who prematurely discontinue study treatment and do not agree to complete the remaining scheduled visits 
for that phase. 
22 
Complete 4-domain Mayo Score (including Endoscopy) to be performed if withdrawal from study treatment occurs after Week 4 but prior to Week 10 (all 
participants) or between Week 18 and Week 30 for Responders. The endoscopy is to be performed either at the Early Withdrawal Visit (for participants who 
do not wish to complete remaining scheduled visits), or at Week 10 or Week 30 (for participants that agree to complete remaining scheduled visits after 
withdrawing from treatment). 
23 
The window for Screening Visit 1 can be extended to Day -45 where indeterminate test results are returned for assays requiring long central laboratory 
turnaround times (e.g., QuantiFERON and C. difficile). However, if haematology, clinical chemistry and (if applicable) serum pregnancy tests have been 


 
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performed outside of the Day -35 window they must be repeated and recorded as an unscheduled visit in the eCRF to confirm eligibility, even if performed 
at Screening Visit 2. 
24 
Faecal Calprotectin sample may be taken up to 48 hours prior to scheduled visit. 
25 
Exit interview, if applicable, to be undertaken either at Early Withdrawal or Follow-Up. 
26 
Home health care / telemedicine visits may be permitted where applicable country and local regulations and infrastructure allow. 
27 
Randomisation may be performed on Day -1. Randomisation may only proceed when all information pertaining to patient eligibility has been confirmed, 
including eCRF Mayo score eligibility calculation. 
28 
Samples only to be taken for participants that achieved a responder status at Week 10 and subsequently withdraw from treatment. 
 
 


 
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Open Label Treatment 
Open Label Induction Phase 
Open Label Extended Treatment Phase 
Open Label 
Follow up7 
Open Label 
Early 
Withdrawal 
Visit8, 12 
WEEK  
12 
14 
18 
22 
24 
26 
3012 
3412 
3812 
4212 
5412 
DAY 
85 
99 
127 
155 
169 
183 
211 
239 
267 
295 
379 
 
Window (days) 
±5 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
  
Endoscopy with Biopsy 
 
 
 
X 
 
 
 
 
 
 
 
X 
Mayo (Complete or Partial) 
P 
P 
P 
C 
 
 
P 
 
P 
P 
P 
C13/P 
Extra-Intestinal 
Manifestations Activity  
 
 
 
X 
 
 
 
 
 
X 
X 
X13 
Steroid Taper 
 
 
 
 
X 
 
 
 
 
 
 
 
Weight 
 
 
 
X 
 
 
 
 
 
X 
 
 
Safety Assessments 
Vital Signs 
X5 
X5 
X 
X 
 
X5 
X5 
X 
X 
X 
X 
X 
12-lead ECG 
X9 
 
 
X 
 
 
 
 
 
 
X 
X 
Full/Brief Physical 
B 
B 
B 
B 
 
B 
B 
B 
B 
B 
F 
F 
Concomitant Medications 
<----------------------------------------------------------------------------------------------------------------------------------------------------> 
AEs / SAEs 
<----------------------------------------------------------------------------------------------------------------------------------------------------> 
Haematology1 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry (incl. 
CRP)1 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test (WOCBP)1, 2 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Urinalysis1 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Dosing and PK/PD 
IMP administration3 
IV 
IV 
IV 
IV 
 
SC 
SC 
SC 
SC 
 
 
 
PK1 
X6 
 
 
X6 
 
 
 
 
 
X 
X 
X 
sLAG31  
X6 
 
 
X6 
 
 
 
 
 
X 
X 
X 
Immunogenicity1 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Faecal Calprotectin10 
X 
 
X 
X 
 
 
 
 
X 
X 
X 
X 
Patient Reported Outcomes 
IBDQ, FACIT-Fatigue and 
SF-364 
 
 
X 
X 
 
 
 
 
X 
X 
X 
X 
Bowel symptom eDiary 
<------------------------------------------------------------------------------------------------------------------------------------> 
PGIC & PGIS4  
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Exit Interview 
 
 
 
 
 
 
 
 
 
 
X11 
X11 


 
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Footnotes: 
1 
Unless specified otherwise, all samples will be taken prior to administration of study treatment. 
2 
A highly sensitive urine pregnancy test is adequate. If a urine test cannot be confirmed as negative, a serum pregnancy test is required. 
3 
See Protocol Section 6.2, for details of dosing durations and monitoring periods. 
4 
IBDQ, FACIT-Fatigue, SF-36, PGIC and PGIS are to be performed before any other assessments on visit days. 
5 
Vital signs to be taken every 30 minutes (±5 minutes) until completion of post dose monitoring period. For participants who have discontinued treatment but 
remain on study, post-dose monitoring does not apply. 
6 
Additional PK sample immediately after end of IV infusion (preferably within 15 minutes of end of IV infusion). 
7 
In case of Early treatment discontinuation, or study withdrawal, the investigator should undertake a Follow-Up visit approximately16 weeks after the last dose 
event to allow safety monitoring following drug washout. 
8 
Participants who discontinue study treatment are encouraged to complete remaining scheduled visits for the treatment phase they are in.  However, an Early 
withdrawal visit is only required for participants who prematurely discontinue study treatment and do not agree to complete the remaining scheduled visits for 
that phase. 
9 
A single ECG to be taken any time within post-dose monitoring period 
10 Faecal Calprotectin sample may be taken up to 48 hours prior to scheduled visit. 
11 Exit interview, if applicable, to be undertaken either at Early Withdrawal or Follow-Up. 
12 Home health care / telemedicine visits may be permitted where applicable country and local regulations and infrastructure allow. 
13 Complete 4-domain Mayo Score (including Endoscopy) to be performed if withdrawal from study treatment occurs after Week 16 but prior to Week 22 (all 
participants). The endoscopy is to be performed either at the Early Withdrawal Visit (for participants who do not wish to complete remaining scheduled visits), 
or at Week 22 (for participants that agree to complete remaining scheduled visits after withdrawing from treatment).  
 
 


 
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15.3. 
Appendix 3: Assessment Windows 
15.3.1. 
Definitions of Assessment Windows for Analyses 
Note that assessment windows will be applied on an endpoint by endpoint basis. 
Early Withdrawal and Unscheduled visits will be assigned to assessment windows 
according to actual dates rather than the nominal visit labels recorded against the 
observation. 
A window around a target Study Day will typically include all days from the midpoints 
between it and the target Study Days of the previous and the proceeding visits.  In 
general, the nominal target Study Day for week w is (7 * w) +1.  The window around the 
last visit prior to follow up will be symmetrical so that it will be determined by the 
midpoint between it and the previous visit. 
If using assessment windows leads to more than one observation being allocated to a visit 
then the closest observation to the target date will be taken.  If the difference between the 
two observations is the same, the latest will be used. 
If an Early Withdrawal or Unscheduled assessment for any given parameter is allocated 
to a visit that contains multiple planned time assessments for said parameter, then it will 
be labelled as “Unscheduled/EW” in summary tables. 
Note that all observations will be listed and used for calculation of ‘worst case’ outputs 
for safety (for example “Summary of Worst-Case Chemistry Results by PCI Criteria Post 
Baseline Relative to Baseline”). 
Assessment windows do not cross study phases 
An exception to the general rule of allocating observations to the nearest visit concerns 
the transition between study phases.  Assessment windows should not allocate a visit to a 
study phase until the study phase begins for that participant (i.e. the Study Day that they 
receive their first dose for that study phase). 
For example, even if an Unscheduled visit on Week 13 for a responding participant is 
closest to the first visit for the Extended Treatment Phase, the observations from the 
Unscheduled visit would be allocated to the Induction Phase because the Extended 
Treatment Phase has not started. 
Screening and Post dose records: 
The post-dose records will be summarized under the last study phase in which 
participants received a dose. The visit windowing algorithm will be based on the 
following: 
1. CRF assessments/events collected after ‘Last Dose Date + 16 Weeks (+ 7 days)’ 
(i.e. post-treatment study phase) will not be analysed/summarised. These records 
will only be listed. 


 
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2. For CRF assessments/events collected after Last Dose Date but before ‘Last Dose 
Date + 16 Weeks (+ 7 days)’: 
a) All records collected in event datasets will be summarized as well as listed 
(e.g. AE, CM). 
b) All records collected for any other assessments will be included for ‘Worst-
Case’ summaries (e.g. LABs, Mayo score/endpoints etc). 
c) Unless stated otherwise, all records for any other assessments will be included 
in visit-based summaries as described in two scenarios below – 
i. 
The visits collected in the same study phase will be summarized 
against the visit in CRF or using windowing RAP algorithm for 
‘Unscheduled’.  
ii. 
The visits collected in subsequent study phases will be windowed as 
‘Follow-up IND/ETP’ visit (even CRF collected scheduled visits will 
be mapped). For summaries, the latest assessment among  ‘Follow-up 
IND/ETP’ will be used. 
 
Note that after the final visit (Week 30 / OL Week 42) the next visit would be the Follow-
Up and it is not expected that a participant would have an Early Withdrawal visit after 
these visits.   
Target Day 
Analysis Window (Days) 
Analysis Timepoint 
Beginning Timepoint 
Ending Timepoint 
Note:  Windowing applies to all domains except Extra Intestinal Manifestations of UC. 
1 
 1 
2 DAY 1 
15 
3 
22 WEEK 2 
29 
23 
36 WEEK 4 
43 
37 
57 WEEK 6 
71 
58 
A day prior to participant’s first 
dose of next phase. 
For participants who do not take 
a subsequent dose, maximum of 
‘Week 10 dosing date +3’ and 
day 85 WEEK 10 
 
99*  
(First Dose of 
Period + 1) 
Participant’s first dose of 
ETP 
102*  
(First dose of Period + 4) 
WEEK 14 
127*  
(First dose of 
Period + 29) 
103*  
(First dose of Period + 5) 
141*  
(First dose of Period + 43) 
WEEK 18 
155*  
(First dose of 
Period + 57) 
142*  
(First dose of Period + 44) 
169*  
(First dose of Period + 71) 
WEEK 22 


 
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Target Day 
Analysis Window (Days) 
Analysis Timepoint 
Beginning Timepoint 
Ending Timepoint 
183*  
(First dose of 
Period + 85) 
170*  
(First dose of Period + 72) 
197*  
(First dose of Period + 99) 
WEEK 26 
211*  
(First dose of 
Period + 113) 
198*  
(First dose of Period + 100) 
225*  
(First dose of Period + 127) 
WEEK 30 
 
85*  
(First Dose of 
Period + 1) 
Participant’s first dose of 
OL 
92*  
(First dose of Period + 8) 
OL WEEK 12 
99*  
(First dose of 
Period + 15) 
93*  
(First dose of Period + 9) 
113*  
(First dose of Period + 29) 
OL WEEK 14 
127*  
(First dose of 
Period + 43) 
114*  
(First dose of Period + 30) 
141*  
(First dose of Period + 57) 
OL WEEK 18 
155*  
(First dose of 
Period + 71) 
142*  
(First dose of Period + 58) 
A day prior to participant’s first 
dose of OL ETP. For participants 
who do not take a subsequent 
dose, maximum of ‘OL Week 22 
dosing date +3’ and day 197 OL WEEK 22 
 
183*  
(First Dose of 
Period + 1) 
Participant’s first dose of 
OL ETP 
186*  
(First dose of Period + 4) 
OL WEEK 26 
211*  
(First dose of 
Period + 29) 
187*  
(First dose of Period + 5) 
225*  
(First dose of Period + 43) 
OL WEEK 30 
239*  
(First dose of 
Period + 57) 
226*  
(First dose of Period + 44) 
253*  
(First dose of Period + 71) 
OL WEEK 34 
267*  
(First dose of 
Period + 85) 
254*  
(First dose of Period + 72) 
281*  
(First dose of Period + 99) 
OL WEEK 38 
295*  
(First dose of 
Period + 113) 
282*  
(First dose of Period + 100) 
309*  
(First dose of Period + 127) 
OL WEEK 42 
 
* For delayed first dose in the study phase : 
- If the first dose of a study phase is within the first visit window of that study phase, then use the number 
outside brackets in each subsequent window. 
- If the first dose of a study phase is post-ending timepoint of the first visit window of that study phase, 
then use the bracketed derivation in each subsequent window. 
 


 
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15.4. 
Appendix 4: Treatment Phases and Study Phases 
15.4.1. 
Treatment Phases 
The table below defines treatment phases. Note that if a participant receives study drug at 
all visits and completes the study, all visits will be categorised as ‘on-treatment’ 
including the follow-up visit. Note: follow-up visits for participants who early withdraw 
in Double Blind Induction and for participants who early withdraw in other study phases 
without completing all protocol-defined visits in that phase will not be summarised (they 
will be listed). 
Where treatment is discontinued during the study (i.e. the ‘study treatment 
discontinuation’ form has been completed in the eCRF), the Study Treatment Stop Date 
will be defined as the date that the last treatment was given. 
Treatment 
Phase 
Definition 
Pre-Treatment  
Date < Study Treatment Start Date 
On-Treatment 
Study Treatment Start Date ≤ Date ≤ Study Treatment Stop Date + 16 weeks (+ 7 
days, the visit window) 
Post-Treatment 
Date > Study Treatment Stop Date + 16 weeks  
 
15.4.2. 
Study Phases 
A study phase will start when the first dose for that phase is taken.  The phase will end at 
either: 
• The day before the subsequent phase starts 
• The end of the follow up visit (note, this is 16 weeks after the last dose) 
 
15.4.2.1. 
Study Phases for Adverse Events 
If a participant discontinues treatment (i.e. the ‘study treatment discontinuation’ form has 
been completed) but continues to attend visits AEs will be associated with the study 
phase until 16 weeks (+7 days) after the last dose. If an AE onset date is during the post-
treatment period the AE will not be summarised against a study phase. 
 
If an AE onset date is in one phase and resolution date is in a subsequent phase, the AE 
will be associated with the phase in which the AE starts.  AEs that cross phases where the 
maximum severity is greater than the severity at onset will be listed separately. 
 
Following the standard rules for summarising AEs, if an AE of a category repeats in the 
same study phase this will be counted once in that phase, however if the same AE repeats 
in a subsequent phase, it will be counted in both the first phase and the subsequent phase 
because AEs in each study phase are summarised in separate tables.   
 
 


 
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15.4.2.2. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
If medication end date is not missing and is before first dose of study treatment. 
Concomitant 
Any medication that is not a prior and that has start date before or during the on-
treatment phase. 
Post-Treatment 
Any medication that has a start date after the end of the on-treatment phase. 
 
15.4.3. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
• 
If AE onset date (and time) is after treatment start date (and time) and during 
the On-treatment period, the AE will be considered Treatment Emergent.  
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. 
 


 
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15.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
15.5.1. 
Reporting Process 
Software 
• 
The currently supported versions of SAS software will be used. 
Reporting Area 
HARP Server 
: uk1salx00175 
HARP Compound 
: \arenv\arprod\gsk2831781\ 
Reporting effort type 
HARP path 
N30 Dry Run 
: \arenv\arprod\gsk2831781\mid204869\data_look_01 
N30 
: \arenv\arprod\gsk2831781\mid204869\safety_01 
IA3 Dry Run 1 
: \arenv\arprod\gsk2831781\mid204869\data_look_02  
IA3 Dry Run 2 
: \arenv\arprod\gsk2831781\mid204869\data_look_04 
IA3 Headline 
: \arenv\arprod\gsk2831781\mid204869\ internal_02 
Final CSR Dry Run 
: \arenv\arprod\gsk2831781\mid204869\data_look_05 
Final CSR 
: arenv\arprod\gsk2831781\mid204869\final_01 
Analysis Datasets 
• 
Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.1. If the Study Data Standardization Plan (SDSP) exists for a study, ensure the CDISC 
versions are consistent. 
Generation of RTF Files 
• 
RTF files will be generated for the primary completion and final SAC described in the RAP. 


 
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15.5.2. 
Reporting Standards 
General 
• 
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
• 
4.03 to 4.23: General Principles 
• 
5.01 to 5.08: Principles Related to Data Listings 
• 
6.01 to 6.11: Principles Related to Summary Tables 
• 
7.01 to 7.13: Principles Related to Graphics  
• 
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: 
• 
Assessment windows will allocate actual visit time to planned visits which will be used in 
summary 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.  
Treatment Actually Received 
• 
If a participant has been dosed at more than one dose level within a phase (i.e. they have been 
incorrectly dosed) then their 'actual' treatment allocation will be defined as the highest dose 
received.   
Treatment 
• 
In listings where results are reported per visit, the treatment received in each phase will be 
associated with the visits in that phase.  Where order is ‘by treatment’ the order will be based on 
treatment received in the induction phase. 
• 
Note that summaries are, in general, reported separately for each study phase whereas, in 
general, there will be a single listing across all phases. 
Unscheduled Visits 
• 
Observations from Unscheduled visits will follow the rules for assessment windows but will not be 
separately summarised as ‘Unscheduled’ in summary tables or figures. 
• 
All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 


 
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Graphical Displays 
• 
Refer to IDSL Statistical Principles 7.01 to 7.13. 
15.5.3. 
Reporting Standards for Pharmacokinetic 
Pharmacokinetic Concentration Data 
PC Windows Non-
Linear (WNL) File 
PC WNL file (CSV format) for the non-compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
GUI_51487. 
Note: Concentration values will be imputed as per GUI_51487. 
Descriptive 
Summary Statistics, 
Graphical Displays 
and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only.  
NONMEM/Pop PK 
File 
Pop-PK file (CSV format) for the POP-PK analysis by Clinical Pharmacology 
Modelling and Simulation function will be created according to the data 
specification (separate document). 
NONMEM/PK/PD 
File 
PK/PD file (CSV format) for the PK/PD analysis by Clinical Pharmacology 
Modelling and Simulation function will be created according to the data 
specification (separate document). 
Pharmacokinetic Parameter Derivation 
PK Parameter to be 
Derived by 
Programmer 
No PK parameters will be derived by the Programmer  
Pharmacokinetic Parameter Data 
Is NQ impacted PK 
Parameters Rule 
Being Followed 
Yes, refer to SOP_314000 [Standards for Handling NQ Impacted PK 
Parameters]. 
Descriptive 
Summary Statistics, 
Graphical Displays 
and Listings 
Refer to IDSL PK Display Standards. 
Refer to GUI_51487. 
 
 


 
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15.6. 
Appendix 6: Derived and Transformed Data 
This appendix describes how data are derived for further reporting.  In general, these 
instructions apply at the participant level prior to any summaries being created. 
15.6.1. 
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. 
• 
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     
 
15.6.2. 
Study Population 
Exposure 
Partial Doses 
• 
For partial IV doses, the quantity of IP given to the participant will be calculated using the simplifying 
assumption that IP is dosed at a constant rate using the following formula:   
IP dose received = IP dose expected * ((dose stop time – dose start time) / expected duration 
of dosing) 
• 
Section 5.1.2 shows the expected duration of dosing which is dependent on visit. 
• 
For partial SC doses, the quantity of IP given to the participant will be calculated based on the 
number of injections received.  The expected SC dose is always two injections (2 x 150mg) so a 
single injection will dose 150mg. 
Number of Doses 
Summarise the number of doses received by participants within each study phase. 
Cumulative Dose 
The cumulative received dose in mg will be calculated across all phases and within each study phase for 
each participant. 
Duration of Exposure 
The number of days of exposure will be calculated for each participant within study phase and 
across all study phases.   
1. The following algorithm will be used for calculating days exposed across all study 
phases:  
Duration of Exposure = Last dose date - first dose date + 1 


 
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2. The following algorithm will be used for calculating days exposed in a study phase:  
Duration of Exposure = Last dose date of phase - first dose date of phase + 1 
Note: subjects with multiple missed doses in a phase are not expected to start the next phase. 
    
Smoking History: Pack years 
• 
Pack years = (number of daily cigarettes / 20) x number of years smoked 
o If frequency reported is weekly; number of daily cigarettes = weekly cigarettes x 7 days 
o If frequency reported is monthly; number of daily cigarettes = monthly cigarettes x 30.44 days 
 
15.6.3. 
Efficacy 
15.6.3.1. 
Mayo score versions 
All Mayo scores are the sum of the components.  The number of components and their 
definition vary as described below and will be derived programmatically. Stool 
Frequency and Rectal Bleeding will be derived from eDiary data. 
 Complete 4-Domain Mayo Clinic Score (MCS) 
Sign/Symptom 
Score 
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 Complete 4-Domain Mayo Clinic Score (MCS) 
The Complete Mayo score (sum of four components, range 0-12) includes a physician global 
assessment, and 
at endoscopy contributes to an endoscopic score of 
  The 
following categorical endpoints are derived from this score: 
• Clinical remission (Complete Mayo) is defined as: Complete MCS ≤2, with no individual 
sub-score >1 
• Clinical response (Complete Mayo) is defined as: Reduction in complete MCS ≥3 points 
from baseline AND ≥30% from baseline AND decrease in the rectal bleeding sub-score of ≥1 
point from baseline (or a score of 0 or 1) 
• Symptom Control for rectal bleeding is defined as a sub-score of 0 
• Symptom Control for stool frequency is defined as a sub-score of 0 or 1 with no worsening 
from baseline 
• Symptomatic Remission is defined as Symptom Control for both rectal bleeding and stool 
frequency 
 
 
Partial Mayo Clinical Score 
Sign/Symptom 
Score 
The Partial Mayo Clinical Score (sum of three components, range 0-9) is based on the complete 
4-domain MCS, but without the endoscopy sub-score 
• The definitions of Clinical Remission (Partial Mayo) and Clinical Response (Partial 
Mayo) are the same as described for complete Mayo with the baseline being the partial 
Mayo score instead of the complete Mayo score.  Note that the baseline visit for the Partial 
Mayo score differs from Complete and Adapted. 
 
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Adapted 3-domain Mayo Clinical Score 
Sign/Symptom 
Score 
The Adapted 3-domain Mayo Clinical Score (sum of three components, range 0-9) is based on 
the complete 4-domain MCS, but without the physician global assessment and with an 
alternative definition of the endoscopy scores.  The following categorical endpoints are derived 
from this score: 
• Clinical Remission (Adapted Mayo) is defined as adapted MCS of <=2 with no individual 
sub-score > 1 and a rectal bleeding sub score of 0 with stool frequency sub score not 
greater than baseline. 
• The definition of Clinical Response (Adapted Mayo) is the same as described for complete 
Mayo with the baseline being the adapted Mayo score instead of the complete Mayo score 
• The definition of Clinical Remission (FDA) requires an absolute stool number of 3 or fewer 
(average daily stool number during 3 days before a visit), a Mayo rectal bleeding sub-score of 
0, and an adapted Mayo endoscopic sub-score of 0 or 1. 
• Endoscopic Remission is defined as: Adapted Mayo endoscopic score = 0 
• Endoscopic Improvement is defined as: Adapted Mayo endoscopic score = 0 or 1, this 
endpoint is also referred to as ‘Endoscopic Mucosal Healing’ in the project. 
 
Extended Treatment Phase endpoints: 
• Steroid Free Clinical Remission will be reported at Week 30 only.  It is defined as Clinical 
Remission (Adapted Mayo) at Week 30 AND participant has not received a steroid dose in 
the 28 days prior to the day of the efficacy assessment. 
• Maintained Steroid Free Clinical Remission will be reported at Week 42 only.  It is defined 
as participants who were in Steroid Free Clinical Remission at Week 30 AND who are in 
Clinical Remission (partial Mayo) at Week 42 (follow up) AND that did not receive any dose 
of steroid between Week 30 and Week 42. 
• Maintained Clinical Response (Week 10 to 30 Adapted Mayo) will be reported at Week 30 
only. It is defined as Clinical Response (Adapted Mayo) at Week 10 AND Clinical 
Response (Adapted Mayo) at Week 30. 
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Adapted 3-domain Mayo Clinical Score 
• Maintained Clinical Remission (Week 10 to 30 Adapted Mayo) will be reported at Week 
30 only. It is defined as Clinical Remission (Adapted Mayo) at Week 10 AND Clinical 
Remission (Adapted Mayo) at Week 30. 
 
15.6.3.2. 
Mayo sub scores 
Mayo sub scores will be derived from the daily eDiary.  For each calculated Mayo score 
the following steps are required: 
• Select days to be used as source data from the previous seven. 
• Calculate Stool Frequency sub-score (derived from relevant daily stool counts) 
• Calculate Rectal Bleeding sub-score (simple average of relevant daily entries) 
• Calculate Absolute Stool Number (simple average of relevant daily stool counts) 
Day selection algorithm 
The eDiary should be used daily and should not allow a participant to save partial data 
(i.e. if an entry for stool count is available, then an entry for rectal bleeding should also 
be available), it is therefore assumed that both Stool Frequency and Rectal Bleeding will 
be present on a specific day, or both will be missing. 
The scores reflect a patient’s experience over an entire day and so can only be calculated 
once the day is complete.  The previous day’s score is therefore used at a study visit (i.e. 
entered into the eCRF by the site) but by contrast, the eDiary will be analysed after all 
data has been collected and so the daily sub-score will be reported against the latest study 
day in the window of possible days (the ‘named day’).  When daily sub-scores are 
presented they use the named day, for example daily sub-scores reported at study Day 1 
will include the day of the first dose of IP (Day 1) but the (Partial) Mayo score reported at 
the Day 1 visit will use the value from Day -1 for consistency with the value recorded by 
the site and general practice in using the Mayo score.  This reporting of daily sub-scores 
is consistent with practice in the literature (Hanauer, 2019). 
Considering the last 7 days (including the named day) exclude any days where a 
participant: 
• Received bowel preparation medication for an endoscopy 
• Had an endoscopy 
• Is the day after an endoscopy 
From the remaining days, working backwards from the most recent available day, use the 
following hierarchy to select the most appropriate days: 


 
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1. Three consecutive days of data, as close to the endoscopy visit as possible. 
2. If three consecutive days are not available, three non-consecutive days of data, as 
close to the endoscopy visit as possible.  
3.  If fewer than three days’ data are available in the prior seven days, set both SF 
and RB sub-scores to missing. 
 
See the table at the end of the ‘Rectal Bleeding’ section for examples of day choice in 
different circumstances. 
 
Note that the following alternative algorithm will also be calculated for sensitivity 
analyses: 
 
1. Three consecutive days of data, as close to the endoscopy visit as possible. 
2. If three consecutive days are not available, three non-consecutive days of data, as 
close to the endoscopy visit as possible.  
3. If fewer than three days’ data are available in the prior seven days, use data from 
the two most recent days. 
4. If fewer than two days’ data are available in the prior seven days, set both SF and 
RB sub-scores to missing. 
 
If there is a greater than 5% difference between the number of participants in the main 
algorithm and in the sensitivity algorithm (i.e. participants with only two days at Day 1 or 
Week 10), then a sensitivity analysis will be run. 
Stool Frequency 
The following formula should be used for calculating the Mayo stool frequency sub 
score: 
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Rectal Bleeding 
The rectal bleeding sub score will be the average of the daily scores, rounded. 
The following table illustrates day selection and RB calculation under different scenarios.  
The daily score calculated in the example would be reported day -1 for daily scores but 
used for the calculation of the Partial Mayo score on the Day 1 visit.   
Example Diary Day 
Valid days 
for 
calculation 
of scores 
Notes 
Average 
sub-
score 
RB 
-7 -
6 
-5 -4 -3 
-2 
-1 
 
 
 
 
A 
3 
1 2 
2 
3 
M 
3 
-3,-4,-5 
Consecutive 
> recent 
2.33 
2 
B 
3 
1 2 
2 
M 
2 
3 
-4,-5,-6  
Consecutive 
> recent 
1.67 
2 
C 
3 
1 2 
M 3 
2 
3 
-1,-2,-3 
 
2.67 
3 
D 
3 
1 2 
X 
E0 E1 3 
-5,-6,-7  
 
2.00 
2 
E 
3 
1 M M X 
E0 E1 Missing 
(primary 
analysis); 
-7,-6 
(sensitivity 
analysis) 
 
2.00 (in 
the 
sensiti- 
vity 
analysis) 
2 
F 
3 
1 M M 2 
M 
2 
-1,-3,-6 
3 days 
recent 
1.67 
2 
G 
3 
1 2 
M 2 
X 
E0 -5,-6,-7  
Consecutive 
> recent 
2.00 
2 
H 
3 
1 2 
M 2 
2 
M 
-5,-6,-7 
Consecutive 
> recent 
2.00 
2 
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Example Diary Day 
Valid days 
for 
calculation 
of scores 
Notes 
Average 
sub-
score 
RB 
-7 -
6 
-5 -4 -3 
-2 
-1 
 
 
 
 
I 
M 1 M M X 
E0 E1 Missing 
 
. 
. 
M = Missing, X = Bowel prep, E0=Endoscopy, E1=Day after endoscopy 
Absolute Stool Number 
The calculation of absolute stool number will follow the same methodology as the 
calculation of the rectal bleeding sub score. 
Note that the categorisation of Mayo sub scores is defined above along with full Mayo 
score definitions. 
15.6.3.3. 
Endoscopy scores 
Clinical Efficacy  
UCEIS 
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Clinical Efficacy  
 
The following endpoint for the UCEIS is to be considered at each visit:  
  
• 
UCEIS Total Score:  Sum of all likert scale anchor points scores (this will range from 0 – 8). 
15.6.3.4. 
Histology scores 
Geboes 
CCI - This section contained Clinical Outcome Assessment data collection 
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therefore have been excluded.
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Robarts Histology Index (RHI) 
 
The RHI will be derived by GSK as an additional tool to measure histologic disease activity using the 
following two tables to derive the RHI from the Geboes sub-scores. 
 
Mapping of Geboes score to Robarts Criteria 
Geboes 
Score 
Robarts 
Criteria 
Robarts 
Multiplier 
 
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Robarts Histology Index Conversion from Geboes 
 
The RHI Score is a continuous score, ranging from 0-33 with higher scores indicating more severe 
disease.  The following categorical endpoints are derived from this score:   
• 
“RHI Remission” will be defined as an RHI score <= 6  
• 
“RHI Deep Remission” will be defined as an RHI score <= 3 
Nancy Index 
The Nancy Index will be provided by Robarts as an additional tool to measure histological disease 
activity. 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, 
which are protected by third party copyright laws and therefore have been excluded.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
protected by third party copyright laws and therefore have been excluded.


 
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CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third 
party copyright laws and therefore have been excluded.


 
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15.6.3.5. 
Intercurrent Events Selection 
If more than one intercurrent event occurs for a subject, then the earliest event will be 
considered for reporting. If two events occur at the same timepoint, then (for the 
respective Estimand) the event listed first in the list below will be prioritized: 
• Secondary Efficacy Estimand: 
• Discontinuation from IP 
• Valid endoscopy result not available 
• Excluded medication 
 
Note that no distinction is made in the above list between COVID-related 
discontinuations, discontinuations due to sponsor’s decision to terminate the study and 
other discontinuations, as they are mutually exclusive and a participant can only 
experience one of these three ICEs. For the same reason, a list for the Primary Efficacy 
Estimand is not needed. 
 
15.6.4. 
Safety 
Adverse Events 
Exposure Adjusted Incidence Rates 
o For selected Preferred Terms, the exposure adjusted incidence rate of AEs will be 
reported within a study phase. Derive the exposure adjusted incidence rate as : 
 
Subject months (Person months) = sum of subject total exposure duration in days for a 
study phase (across all subjects)/30.4375, where subject total exposure duration in days 
is calculated as below – 
 
o if they DO experience the AE, then start date of first AE – treatment start date of 
the study phase + 1. 
o if they DO NOT experience the AE, then treatment stop date of the study phase – 
treatment start date of the study phase + dose specific days (Refer to Section 
15.6.2 : Study Population/Duration of Exposure) 
 
Number of subjects with event per 100 subject-months = 100*number of subjects with 
event in the study phase/subject months.   
Note that an event is only counted once per subject. 
 
 
ECG Parameters 
RR Interval 
• If RR interval (msec) is not provided directly, then RR can be derived as: 
                (1/HR)/1000(i.e. 1 / heart rate where the heart rate is taken as part of the ECG) 
• If ECGs are manually read, the RR value preceding the measurement QT interval should be 
a collected value THEN do not derive. 


 
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ECG Parameters 
Corrected QT Intervals 
• When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of 
other measurements.  QTcF or QTcB values entered by the site will always be presented in 
output.  
• IF RR interval (msec) is provided (or can be derived from HR) then missing QTcB and/or 
QTcF will be derived as:  
 
 
Handling of Multiple Measurements 
• If multiple ECG findings (interpretations/clinical significance) are collected at the same 
timepoint and categorised as Normal or Abnormal (Clinically Significant or not), the worst 
classification for each participant at the timepoint will be used in summary tables. 


 
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ECG Parameters 
Laboratory Parameters 
• If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but 
typically a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than 
x in the comment field) is present, the number of decimal places in the observed values will 
be used to determine how much to add or subtract in order to impute the corresponding 
numeric value. Similarly, if a character value starting with ‘<=x’ or ‘>=x’ is present, x will be 
used as the corresponding numeric value. 
o Example 1: 2 decimal places: ‘< x’ becomes x – 0.01 
o Example 2: 1 decimal places: ‘> x’ becomes x + 0.1 
o Example 3: 0 decimal places: ‘< x’ becomes x – 1 
o Example 4: 2 decimal places: ‘<= x’ becomes x 
o Example 5: 1 decimal places: ‘>= x’ becomes x 
o Example 6: 0 decimal places: ‘<= x’ becomes x 
• Corrected calcium will be calculated, by GSK Biostatistics as: 
 
Corrected Calcium [mmol/L] = Serum Calcium [mmol/L] + 0.02 * (40[g/L] – Serum Albumin[g/L]) 
Where Normal Serum Albumin = 40 [g/L] 
 
• eGFR (estimated Glomerular Filtration Rate) will be calculated by GSK Biostatistics at all 
timepoints, this will also be provided directly by the vendor at screening.  The GSK calculated 
value at screening will be used as primary for reporting (e.g. will be used as baseline if 
appropriate).   
• The calculation will be as follows: 
 
SI Results MDRD (GFR) (ml/min/1.73m2) = 175 * (PD9S3/88.4) 
power -1.154 * Age power - 0.203 * Race * Sex  
Where PD9S3 = Serum Creatinine (UMOL/L), 
Race = 1.212 for Black & 1.000 for other, Sex = 1.00 for males and 0.742 for females. 
  
 
15.6.5. 
Immunogenicity 
 
Immunogenicity 
• A participant will be classed as having persistently positive immunogenicity results within a 
study phase if they have a positive result for two or more sequential post baseline samples 
when pre-existing antibodies were not detected, or alternatively two or more sequential post 
baseline samples where the titre shows a 4 x increase in titre from pre-dose samples. 
• A participant will be classed as having transient immunogenicity results within a study phase 
if: 
o They are not classified as having persistent immunogenicity; and 


 
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Immunogenicity 
o They have a positive result for one or more post baseline samples when pre-
existing antibodies were not detected, or alternatively one or more post baseline 
samples where the titre shows a 4 x increase in titre from pre-dose samples. 
 
15.6.6. 
Pharmacodynamic and Biomarker 
Colon Biopsy Cell Counts by Immunofluorescence  
The following parameters will be derived for each tissue type.   
Derived parameter name 
Derivation 
Unit 
CD3-LAG3+ as % of Total LAG3+ 
(CD3-LAG3+/ LAG3+) * 100 
% 
CD3+LAG3+ as % of Total LAG3+ 
(CD3+LAG3+/ LAG3+) * 100 
% 
CD3+  
CD3+ / tissue area 
cells / mm2 
LAG3+  
LAG3+ / tissue area 
cells / mm2 
CD3+LAG3+ 
CD3+LAG3+ / tissue area 
cells / mm2 
CD3-LAG3+ 
CD3-LAG3+ / tissue area 
cells / mm2 
CD3+LAG3- 
CD3+LAG3- / tissue area 
cells / mm2 
Raw data from colon biopsies using CD3/LAG3 co-stain 
 
 
 
 
 


 
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15.7. 
Appendix 7: Reporting Standards for Missing Data 
15.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
Participant study completion (i.e. as specified in the protocol) was defined as a 
participant who has completed all phases of the study including the last scheduled 
assessment. 
• 
A Week 10 completer will be defined as a participant that has a Week 10 
assessment of the Complete 4-domain Mayo score.  
• 
For the purposes of describing the disposition of participants, the participant will be 
defined as having ‘completed’ the study phase when they take the first dose of the 
next phase or, for the final phase, have an assessment on the last visit.  These 
events are summarised below: 
 
Phase 
Event used in definition of completion 
Induction phase 
completion 
First SC dose for Extended Treatment Phase or  
first IV dose for Open Label Induction Phase 
Extended treatment phase 
completion 
Any assessment at Week 30 visit 
Open Label Induction 
phase 
First SC dose for Open Label Extended Treatment 
Phase  
Open Label Extended 
Treatment phase 
Any assessment at OL Week 42 visit 
 
• 
If a participant does not continue into the next phase by receiving treatment, they will 
be considered as ‘withdrawn’ from the previous phase. 
• 
All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be considered for inclusion in summary tables and 
figures according to the same rules as non-withdrawn participants, unless otherwise 
specified.  
• 
Early Withdrawal visits will be mapped as specified in Appendix 3: Assessment 
Windows. 
o Note that estimands and analysis population definitions may exclude these 
participants from some outputs. 
15.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• 
Missing data occurs when any requested data are not provided, leading to blank 
fields on the collection instrument: 
o These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.  


 
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Element 
Reporting Detail 
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. 
15.7.2.1. 
Handling of Missing and Partial Dates 
 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in subject listing displays. 
Adverse Events 
• 
The eCRF allows for the possibility of partial dates (i.e., only month and year) 
to be recorded for AE start and end dates; that is, the day of the month may 
be missing. In such a case, the following conventions will be applied for 
calculating the time to onset and the duration of the event: 
o Missing Start Day: First of the month will be used unless this is before 
the start date of study treatment; in this case the study treatment start 
date will be used and hence the event is considered On-treatment as per 
Appendix 4: Treatment Phases and Study Phases. 
o Missing Stop Day: Last day of the month will be used, unless this is after 
the end date of On-Treatment period in which case the On-Treatment 
Period end date will be used. 
o Note that AEs with completely missing dates will not be allowed. 
 
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. 
 


 
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15.8. 
Appendix 8: Values of Potential Clinical Importance 
15.8.1. 
Laboratory Values 
Haematology 
Laboratory Parameter 
 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Hematocrit  
Ratio of 1 
Male 
0.201 
0.599 
Female 
0.201 
0.599 
Hemoglobin  
g/L 
 
Male 
80 
180 
Female 
80 
180 
∆ from BL 
↓25 
 
Lymphocytes  
GI/L 
 
0.8 
 
Neutrophils Absolute 
GI/L 
 
1.5 
 
Platelet Count  
GI/L 
 
100 
550 
White Blood Cell Count 
(WBC) 
GI/L 
 
3 
20 
Eosinophil 
GI/L 
 
 
>=1 
 
Clinical Chemistry 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Albumin  
mmol/L 
 
30 
55 
Calcium 
mmol/L 
 
2 
2.75 
Creatinine 
mmol/L 
∆ from BL 
 
↑ 26 
Glucose 
mmol/L 
 
3.5 
7.9 
eGFR 
Ml/min/1.73m2 
 
60 
 
Potassium 
mmol/L 
 
3 
5.5 
Sodium 
mmol/L 
 
130 
150 
Total protein 
g/L 
 
50 
85 
Urea nitrogen 
mmol/L 
 
 
10.5 
CRP 
Mg/L 
 
 
30 
 
Liver Function 
Test Analyte 
Units 
Category 
Clinical Concern Range 
ALT/SGPT  
U/L 
High 
 2x ULN 
AST/SGOT  
U/L 
High 
 2x ULN 
AlkPhos  
U/L 
High 
 2x ULN 
T Bilirubin  
µmol/L 
High 
 1.5xULN 
T. Bilirubin + ALT 
µmol/L 
High 
1.5xULN T. Bilirubin 
 
+ 
U/L 
 2x ULN ALT 
 
 


 
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15.8.2. 
Urinalysis 
Urinalysis 
Test Analyte 
Units 
Category 
Clinical Concern Range 
Bilirubin 
 
High 
>1+ 
Glucose 
 
High 
>1+ 
Ketone 
 
High 
>2+ 
Leukocytes (dipstick) 
 
High 
>1+ 
Nitrite 
 
High 
Positive 
Occult blood (dipstick) 
 
High 
>1+ 
pH 
 
Low 
<4.6 
High 
>8 
Protein 
 
High 
>1+ 
RBC (microscopy) 
cells/hpf 
High 
>3 
Specific gravity 
 
Low 
<1.001 
High 
>1.035 
Urobilinogen 
mg/dL 
High 
>1 
WBC (microscopy) 
cells/hpf 
High 
>5 
 
15.8.3. 
ECG 
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Absolute QTc Interval 
msec 
 
> 450 
Absolute PR Interval 
msec 
< 110 
> 220 
Absolute QRS Interval 
msec 
< 75 
> 110 
Change from Baseline 
Increase from Baseline QTc 
msec 
> 30 
≤ 59 
msec 
≥ 60 
 
 
Categories for QTc summaries 
ECG Parameter 
Units 
Range for each category 
Lower 
Upper 
Absolute 
Absolute QTcB and QTcF 
Interval 
msec 
< 450 
 
≥ 450 
≤ 479 
≥ 480 
≤ 499 
≥ 500 
 
Change from Baseline 
Change from Baseline in 
QTcB and QTcF 
msec 
< 30 
 
≥ 30 
≤ 59 


 
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Categories for QTc summaries 
ECG Parameter 
Units 
Range for each category 
Lower 
Upper 
≥ 60 
 
Note that < 450 msec in Absolute and <30 msec in Change from Baseline QTcB/QTcF are not of clinical 
concern 
 
15.8.4. 
Vital Signs 
 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
< 85 
> 160 
Diastolic Blood Pressure 
mmHg 
< 45 
> 100 
Heart Rate 
bpm 
< 40 
> 110 
Temperature 
C 
< 35 
> 38 
 
Vital Sign Parameter 
(Change from Baseline) 
Units 
Clinical Concern Range 
Decrease 
Increase 
Lower 
Upper 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
 
≥ 40 
 
≥ 40 
Diastolic Blood Pressure 
mmHg 
 
≥ 20 
 
≥ 20 
Heart Rate 
bpm 
 
≥ 30 
 
≥ 30 


 
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15.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
15.9.1. 
Population Pharmacokinetic (PopPK) Dataset Specification 
The dataset specification for the PopPK analysis will be described in a separate 
document. 
15.9.2. 
Population Pharmacokinetic (PopPK) Methodology 
An exploratory graphical analysis of the drug plasma and sLAG3 concentration-time data 
will be performed by generating the plots as presented in Appendix 12. 
A previous PopPK model developed from the first-time in human study 200630 (GSK 
Document Number 2017N352860_00), incorporating linear and non-linear (target 
mediated drug disposition (TMDD), Michaelis-Menten) elimination pathways, will be 
used to fit the drug plasma concentration-time data. The model will be updated to 
describe the absorption profiles after SC doses of GSK2831781. For this update it will be 
assumed that the distribution and elimination of GSK2831781 will be the same regardless 
of the route of administration (IV or SC). 
The appropriateness of the updated model will be assessed by the objective function 
value (OFV), successful convergence, covariance estimation, shrinkage, parameter 
uncertainty, and standard Goodness-of-Fit (GoF). 
The GoF plots may include, but are not limited to: 
• Population and individual predictions versus observations 
• Conditional weighted residuals versus population predictions and time 
If a Visual Predictive Check (VPC) is done, this will be based on 1000 simulations with 
the model and the design structure of the observed data (i.e. dose level and time, route of 
administration, time of PK sampling and individual values of model covariates, if any). 
The median and the 10th and 90th will be compared to the observed data. Stratification 
by dose level, treatment group and model covariates, if any, will be used. VPC’s may 
also be presented stratified by geographic ancestry. 
The individual PK parameters will be computed from the PopPK model for further 
PK/PD analysis. 


 
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15.10. 
Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses 
15.10.1. 
Pharmacokinetic / Pharmacodynamic Dataset Specification 
The dataset specification for the PK/PD analysis will be described in a separate 
document. 
15.10.2. 
Pharmacokinetic / Pharmacodynamic Methodology 
An exploratory graphical analysis of the drug effect on LAG3+ T cell depletion in blood 
and colon biopsies, and clinical effect (partial Mayo Score) will be performed by 
generating the plots as presented in Appendix 12. 
PK/PD Analysis of LAG3+ T Cell Depletion in Blood 
A previous indirect response model developed from all available cell depletion data in 
blood from the first-time in human study 200630 (GSK Document Number 
2017N352860_00) will be fitted to the current LAG3+ T cell data in blood using the 
nonlinear mixed effects modelling software NONMEM. Data relative to CD4+CD45RA-
REA351+ cell count will be used to model T cell depletion. 
The appropriateness of the PopPK/PD model will be assessed by the OFV, successful 
convergence, covariance estimation, shrinkage, parameter uncertainty, and standard GoF. 
The GoF plots may include, but are not limited to: 
• 
Population and individual predictions versus observations 
• 
Conditional weighted residuals versus population predictions and time 
If a Visual Predictive Check (VPC) is done, this will be based on 1000 simulations with 
the model and the design structure of the observed data (i.e. dose level and time, route of 
administration, time of PD sampling and individual values of model covariates, if any). 
The median and the 10th and 90th will be compared to the observed data. Stratification 
by dose level, treatment group and model covariates, if any, will be used. VPC’s may 
also be presented stratified by geographic ancestry. 
PK/PD Analysis of LAG3+ Cell Depletion in Colon Biopsies 
Data relative to CD3+LAG3+ cell count will be used to model T cell depletion in colon 
using the nonlinear mixed effects modelling software NONMEM 
The initial PK/PD model of choice for the effect of GSK2831781 on T cell depletion in 
colon will be an Emax model. Further model development will be data driven. 
The appropriateness of the PopPK/PD model will be assessed by the OFV, successful 
convergence, covariance estimation, shrinkage, parameter uncertainty, and standard GoF. 
The GoF plots may include, but are not limited to: 


 
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• 
Population and individual predictions versus observations 
• 
Conditional weighted residuals versus population predictions and time 
If a Visual Predictive Check (VPC) is done, this will be based on 1000 simulations with 
the model and the design structure of the observed data (i.e. dose level and time, route of 
administration, time of PD sampling and individual values of model covariates, if any). 
The median and the 10th and 90th will be compared to the observed data. Stratification 
by dose level, treatment group and model covariates, if any, will be used. VPC’s may 
also be presented stratified by geographic ancestry. 
Exposure/Response Analysis of Complete Mayo Score 
Data relative to Complete Mayo Score will be used to model the relationship between 
exposure (PK) and clinical efficacy using the nonlinear mixed effects modelling software 
NONMEM. 
The initial PK/PD model of choice for this model will be an Emax model. Further model 
development will be data driven. 
The appropriateness of the exposure/response model will be assessed by the OFV, 
successful convergence, covariance estimation, shrinkage, parameter uncertainty, and 
standard GoF. 
The GoF plots may include, but are not limited to: 
• 
Population and individual predictions versus observations 
• 
Conditional weighted residuals versus population predictions and time 
If a Visual Predictive Check (VPC) is done, this will be based on 1000 simulations with 
the model and the design structure of the observed data (i.e. dose level and time, route of 
administration, time of Complete Mayo Score observations and individual values of 
model covariates, if any). The median and the 10th and 90th will be compared to the 
observed data. Stratification by dose level, treatment group and model covariates, if any, 
will be used. VPC’s may also be presented stratified by geographic ancestry. 


 
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15.11. 
Appendix 11: Abbreviations & Trademarks 
15.11.1. 
Abbreviations  
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AIC 
Akaike's Information Criteria 
A&R 
Analysis and Reporting  
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CRP 
C-Reactive Protein 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
CTR 
Clinical Trial Register 
CVb / CVw 
Coefficient of Variation (Between) / Coefficient of Variation (Within) 
DB 
Double Blind 
DBF 
Database Freeze 
DBR 
Database Release 
DOB 
Date of Birth 
DRC 
Data Review Committee 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
EMA 
European Medicines Agency 
ETP 
Extended Treatment Phase 
FACIT-F 
Functional Assessment of Chronic Illness Therapy - Fatigue 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Clinical Results Disclosure Requirements 
GSK 
GlaxoSmithKline 
H0 
Null hypothesis 
HA 
Alternative hypothesis 
IA 
Interim Analysis 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
ICE 
Intercurrent Event 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
IMMS 
International Modules Management System 
IP 
Investigational Product 
ITTE 
Intent-To-Treat (Exposed) 
IV 
Intravenous 
LAG3 
Lymphocyte activation gene-3 
MMRM 
Mixed Model Repeated Measures 
OL 
Open Label 
OL ETP 
Open Label Extended Treatment Phase 


 
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Abbreviation 
Description 
OLIP 
Open Label Induction Phase 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PGA 
Physician’s Global Assessment 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PPI 
Per Protocol Induction 
PPE 
Per Protocol Extended Treatment Phase 
PopPK 
Population PK 
PRO 
Patient Reported Outcome 
RB 
Rectal Bleeding 
SC 
Subcutaneous 
SF 
Stool frequency 
SF36 
Short Form Health Survey 36 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
RAMOS 
Randomization & Medication Ordering System  
RHI 
Robarts Histology Index 
sLAG3 
Soluble lymphocyte activation gene-3 
SAC 
Statistical Analysis Complete 
SDSP 
Study Data Standardization Plan 
SDTM 
Study Data Tabulation Model 
SOP 
Standard Operation Procedure 
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  
UCEIS 
Ulcerative Colitis Endoscopic Index of Severity 
ULN 
Upper Limit of Normal 
WBC 
White blood cells 
15.11.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
NONMEM 
 
 
SAS 
 
 
WinNonlin 
 
 


 
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15.12. 
Appendix 12: List of Data Displays 
15.12.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.n 
1.1 to 1.n 
Efficacy 
2.1 to 2.n 
2.1 to 2.n 
Safety 
3.1 to 3.n 
3.1 to 3.n 
Pharmacokinetic 
4.1 to 4.n 
4.1 to 4.n 
Population Pharmacokinetic (PopPK) 
5.1 to 5.n 
5.1 to 5.n 
Pharmacodynamic and / or Biomarker 
6.1 to 6.n 
6.1 to 6.n 
Pharmacokinetic / Pharmacodynamic 
7.1 to 7.n 
7.1 to 7.n 
Patient Reported Outcomes 
8.1 to 8.n 
8.1 to 8.n 
Section 
Listings 
ICH Listings 
1 to x 
Other Listings 
y to z 
 
15.12.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 13: Example Mock Shells for Data Displays. 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Efficacy 
EFF_Fn 
EFF_Tn 
EFF_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
Population Pharmacokinetic (PopPK) 
POPPK_Fn 
POPPK_Tn 
POPPK_Ln 
Pharmacodynamic and / or Biomarker 
PD_Fn 
PD_Tn 
PD_Ln 
Pharmacokinetic / Pharmacodynamic 
PKPD_Fn 
PKPD_Tn 
PK/PD_Ln 
Patient Reported Outcomes (PRO) 
PRO_Fn 
PRO_Tn 
PRO_Ln 
NOTES:  
• 
Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 
15.12.3. 
Deliverables 
Delivery [Priority] 
Description 
Additional 
details 
N30 
N=30 at 2 weeks, blinded safety summary  
For Hungarian 
ethics/regulatory 
committee 
IA2 
Interim Analysis 2 Statistical Analysis Complete 
Note that for 
interim analyses 
IA3 H 
Interim Analysis 3 Headline 


 
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Delivery [Priority] 
Description 
Additional 
details 
IA3 
Interim Analysis 3 Statistical Analysis Complete 
reporting efficacy, 
outputs in the 
efficacy domain 
produced by 
Biostatistics will 
only be reported 
for participants 
who have 
completed the 
induction phase 
(i.e. completed 
Week 10 visit)  
IA4  
Interim Analysis 4 Statistical Analysis Complete 
PC 
Primary Completion Statistical Analysis Complete 
 
PC [2] 
Primary Completion Statistical Analysis Complete if 
development will continue 
 
SAC 
Final Statistical Analysis Complete 
 
None 
Displays planned in previous versions of the RAP and 
removed after study termination decision 
 
  
 


 
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15.12.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1. 
Enrolled 
ES1 
 
Summary of Subject Disposition for the Subject Conclusion 
Record 
 
ICH E3, FDAAA, EudraCT 
Programming note: this is a summary of 
all subjects across all study phases.  
Use dose level and method to record 
last dose subject was taking at 
withdrawal/conclusion. 
Footnote “Withdrawal recorded against 
dose allocated at randomization” 
SAC 
1.2. 
Enrolled 
ES4 
Summary of Subject Disposition at Induction Phase 
ICH E3 
Five induction doses as columns 
Footnote “A subject completes the 
induction phase when they receive the 
first dose of the subsequent phase” 
 
SAC  
1.3. 
Enrolled 
ES4 
Summary of Subject Disposition in Post-Induction Phases 
ICH E3 
Programming note: Four doses in 
columns.  OL IV and OL SC will be 
associated with those phases so there 
will be blank cells off the diagonal. 
Footnote “A subject completes the 
phase when they receive the first dose 
of the subsequent phase or the final 
visit in the ETP / OL ETP” 
 
SAC 


 
CONFIDENTIAL 
 
 
 
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93 
 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.4. 
Enrolled 
ES5 
Summary of Reasons for Study Withdrawal in Induction 
Phase 
Five induction doses as columns 
 
SAC 
1.5. 
Enrolled 
ES5 
Summary of Reasons for Study Withdrawal in Post-
Induction Phases 
Programming note: Four doses in 
columns.  OL IV and OL SC will be 
associated with those phases so there 
will be blank cells off the diagonal. 
SAC 
1.6. 
Enrolled 
SD1  
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment in Induction Phase 
ICH E3 
Reviewer’s note: This table summarises 
reasons for treatment discontinuation.  
Reasons for withdrawal are 
summarised in the table above 
 
IA3H, SAC 
1.7. 
Enrolled 
SD1  
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment in Post-Induction Phases 
ICH E3 
Reviewer’s note: This table summarises 
reasons for treatment discontinuation.  
Reasons for withdrawal are 
summarised in the table above 
 
SAC 
1.8. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failure 
Journal Requirements 
 
SAC 
1.9. 
Enrolled 
NS1 
Summary of Number of Subjects by Country and Site ID 
EudraCT/Clinical Operations 
SAC 
Protocol Deviation 
1.10. 
Screened 
DV1 
Summary of Important Protocol Deviations in Induction Phase 
ICH E3 
 
SAC 
1.11. 
ITTE_ETP 
DV1 
Summary of Important Protocol Deviations in Extended 
Treatment Phase 
ICH E3 
 
SAC 


 
CONFIDENTIAL 
 
 
 
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94 
 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.12. 
ITTE_OL 
DV1 
Summary of Important Protocol Deviations in Open Label 
Induction Phase 
ICH E3 
 
SAC 
1.13. 
ITTE_OL_ETP 
DV1 
Summary of Important Protocol Deviations in Open Label 
Extended Treatment Phase 
ICH E3 
 
SAC 
Population Analysed 
1.14. 
Screened 
SP1 
Summary of Study Populations in Induction Phase 
IDSL 
 
SAC 
1.15. 
Safety_ETP 
SP1 
Summary of Study Populations in Extended Treatment Phase 
IDSL 
 
SAC 
1.16. 
Safety_OL 
SP1 
Summary of Study Populations in Open Label Induction Phase 
IDSL 
 
SAC 
1.17. 
Safety_OL_ETP 
SP1 
Summary of Study Populations in Open Label Extended 
Treatment Phase 
IDSL 
 
SAC 
1.18. 
ITTE 
SP2  
 
Summary of Protocol Deviations Leading to Exclusion from the 
Per Protocol Population 
IDSL 
 
None 
1.19. 
ITTE_ETP 
SP2  
 
Summary of Protocol Deviations Leading to Exclusion from the 
Per Protocol ETP Population 
IDSL 
 
None 
Demographic and Baseline Characteristics 
1.20. 
Safety 
DM1 
Blinded Summary of Demographic Characteristics 
 
N30 
1.21. 
ITTE 
DM1 
Summary of Demographic Characteristics in Induction Phase 
ICH E3, FDAAA, EudraCT 
Add smoker status (“Currently Smoke” 
from SU1) 
IA3H, SAC 


 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.22. 
ITTE_ETP 
DM1 
Summary of Demographic Characteristics in Extended 
Treatment Phase 
ICH E3, Consort 
SAC 
1.23. 
ITTE_OL 
DM1 
Summary of Demographic Characteristics in Open Label 
Induction Phase 
ICH E3, Consort 
SAC 
1.24. 
ITTE_OL_ETP 
DM1 
Summary of Demographic Characteristics in Open Label 
Extended Treatment Phase 
ICH E3, Consort 
SAC 
1.25. 
Enrolled 
DM11 
Summary of Age Ranges by Induction Phase Treatment 
Rationale: EudraCT (requires enrolled 
population) 
SAC 
1.26. 
Safety 
DM5 
Summary of Race and Racial Combinations by Induction Phase 
Treatment 
ICH E3, FDA, FDAAA, EudraCT 
SAC 
Medical History 
1.27. 
ITTE 
MH1 
 
Summary of Current and Past Medical Conditions by Induction 
Phase Treatment 
ICH E3  
 
SAC 
1.28. 
ITTE 
POP_T1 
Summary of Ulcerative Colitis Disease Characteristics at 
Baseline in Induction Phase 
Include Complete and Adapted Mayo 
IA3H, SAC 
Prior and Concomitant Medications 
1.29. 
ITTE 
CM1 
Summary of Concomitant Medications taken in Induction Phase 
ICH E3 
Note that prior medications should only 
be UC medical history and are reported 
in a separate table below 
 
SAC 
1.30. 
ITTE_ETP 
CM1 
Summary of Concomitant Medications taken in Extended 
Treatment Phase 
 
SAC 


 
CONFIDENTIAL 
 
 
 
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96 
 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.31. 
ITTE_OL 
CM1 
Summary of Concomitant Medications taken in Open Label 
Induction Phase 
 
SAC 
1.32. 
ITTE_OL_ETP 
CM1 
Summary of Concomitant Medications taken in Open Label 
Extended Treatment Phase 
 
SAC 
1.33. 
ITTE 
POP_T2 
Summary of Ulcerative Colitis Therapeutic History for Induction 
Treatment Phase Subjects 
 
IA3H, SAC 
1.34. 
ITTE_ETP 
POP_T2 
Summary of Ulcerative Colitis Therapeutic History for Extended 
Treatment Phase Subjects  
 
SAC 
Exposure and Treatment Compliance 
1.35. 
Safety 
EX5 
Blinded Summary of Exposure to Study Treatment in Induction 
Phase 
Programmers: Summarise number of 
doses received in the study phase. 
N30 
1.36. 
ITTE 
Take elements 
from EX1 and 
EX5 
Summary of Exposure to Study Treatment in Induction Phase 
ICH E3 
Length of exposure (days) within 
study phase and in the study 
Cumulative dose (mg) [in shell EX1] 
report cumulative dose only for current 
study phase 
Summarise number of doses 
received as categorical [replaces 
cycles, shell EX5] (use levels 1, 2, 3, 4 
doses). 
Footnotes:  
““Dose” is planned dosing events, not 
number of injections, and includes 
partial doses.” 
SAC 


 
CONFIDENTIAL 
 
 
 
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97 
 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.37. 
ITTE_ETP 
EX1 and EX5 
Summary of Exposure to Study Treatment in Extended 
Treatment Phase 
ICH E3 
Items as for induction phase, except for 
length of exposure in the study. 
Footnote:  
“Exposure is summarised within the 
current study phase except where 
specified.   
“Dose” is planned dosing events, not 
number of injections, and includes 
partial doses.” 
SAC 
1.38. 
ITTE_OL_I 
EX1 and EX5 
Summary of Exposure to Study Treatment in Open Label 
Induction Phase 
ICH E3 
Items as for induction phase, except for 
length of exposure in the study. 
 
Footnote:  
“Exposure is summarised within the 
current study phase. 
“Dose” is planned dosing events, not 
number of injections, and includes 
partial doses.” 
SAC 


 
CONFIDENTIAL 
 
 
 
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98 
 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.39. 
ITTE_OL_ETP 
EX1 and EX5 
Summary of Exposure to Study Treatment in Open Label 
Extended Treatment Phase 
ICH E3 
Items as for induction phase, except for 
length of exposure in the study. 
 
Footnote:  
“Exposure is summarised within the 
current study phase.  
“Dose” is planned dosing events, not 
number of injections, and includes 
partial doses.” 
SAC 
 
15.12.5. 
Efficacy Tables 
Efficacy: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Clinical Efficacy – Continuous endpoints 
2.1.  
PPI 
PD1 
Summary of Mayo Score by Endpoint – Induction Phase Per 
Protocol Analysis 
Produce table by absolute and change 
from baseline for the following 
endpoints: 
Complete Mayo score, Adapted Mayo 
Score and Partial Mayo Score for each 
relevant timepoint (partial Mayo 
reported more frequently) 
 
Change from shell: replace SD with SE 
on shell 
None 


 
CONFIDENTIAL 
 
 
 
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99 
 
Efficacy: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.2.  
ITTE 
PD1 
Summary of Mayo Score by Endpoint in Induction Phase - 
Observed 
Produce table by absolute and change 
from baseline for the following 
endpoints: 
Complete Mayo score, Adapted Mayo 
Score, Adapted Mayo Endoscopic 
Score and Partial Mayo Score for each 
relevant timepoint (partial Mayo 
reported more frequently) 
 
Change from shell: replace SD with SE 
on shell 
SAC 
2.3.  
ITTE ETP 
PD1 
Summary of Mayo Score by Endpoint – Extended Treatment 
Phase 
Endpoints as above. 
Change from shell: replace SD with SE 
on shell 
None 
2.4.  
ITTE ETP 
PD1 
Summary of Mayo Score by Endpoint – Extended Treatment 
Phase (by Induction Dose) 
Condition ETP efficacy summaries on 
induction treatment dose. 
Endpoints as above. 
Change from shell: replace SD with SE 
on shell 
None 
2.5.  
ITTE_OL_I 
PD1 
Summary of Mayo Score by Endpoint – Open Label Induction 
Endpoints as above. 
Change from shell: replace SD with SE 
on shell 
None 
2.6.  
ITTE_OL_ETP 
PD1 
Summary of Mayo Score by Endpoint – Open Label Extended 
Treatment Phase 
. 
Change from shell: replace SD with SE 
on shell 
None 


 
CONFIDENTIAL 
 
 
 
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100 
 
Efficacy: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.7.  
ITTE 
PD1 
Summary of Daily Diary Scores at Selected Timepoints in 
Induction Phase 
By endpoint 
Every third day from Study Day 3 until 
Study Day 21, then every week i.e. Day 
28, 35, 42, 56, 63, 70) 
Endpoints: 
Stool Frequency sub-score 
Rectal Bleeding sub-score 
SAC 
2.8.  
ITTE 
PD1 
Summary of UCEIS Total Score in Induction Phase - Observed 
 
SAC 
2.9.  
ITTE ETP 
PD1 
Summary of UCEIS Total Score – Extended Treatment Phase 
 
None 
2.10. 
ITTE_OL_I 
PD1 
Summary of UCEIS Total Score – Open Label Induction 
 
None 
2.11. 
PPI 
EFF_T1 
Statistical Analysis of Dose Response Relationship for Complete 
Mayo Score – Per Protocol Population 
 
None 
2.12. 
ITTE 
EFF_T1 
Statistical Analysis of Complete Mayo Score in Induction Phase 
SAC: Change from Baseline in 
Complete Mayo Score at Week 10 
SAC 
2.13. 
ITTE 
EFF_T1 
Statistical Analysis of Dose Response Relationship for Mayo 
Score by subgroup in Induction Phase 
Complete Mayo Score only Subgroups: 
• 
Advanced therapy experience 
• 
 
• 
Race  
• 
Race2  
• 
 
None 


 
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101 
 
Efficacy: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.14. 
ITTE 
PRO_T02 
Statistical Analysis of Absolute and Change from Baseline in 
Partial Mayo Score in Induction Phase 
By Endpoint then visit 
Note: Repeated measures, 
Bayesian 
SAC 
Corticosteroid use 
2.15. 
ITTE_ETP 
EFF_T06 
Summary of Corticosteroid Use After Mandatory Taper in 
Extended Treatment Phase 
Add footnote: 
“Note: Average Daily Prednisolone 
Equivalent Dose is calculated from the 
start of the taper to the end of the study 
phase.  Note that the taper starts at 
Week 12 and the Extended Treatment 
Phase (ETP) starts at Week 14.  
subjects that start the taper but don’t 
start the ETP are not included in this 
summary and are listed separately” 
None 
2.16. 
ITTE_OL_ET
P 
EFF_T6 
Summary of Corticosteroid Use After Mandatory Taper in Open 
Label Extended Treatment Phase 
Add footnote: 
“Note: Average Daily Prednisolone 
Equivalent Dose is calculated from the 
start of the taper to the end of the study 
phase.  Note that the taper starts at 
Week 24 and the Open Label Extended 
Treatment Phase (OL ETP) starts at 
Week 26.  Subjects that start the taper 
but don’t start the OL ETP are not 
included in this summary and are listed 
separately” 
None 


 
CONFIDENTIAL 
 
 
 
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102 
 
Efficacy: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Clinical Efficacy – Categorical Endpoints 
2.17. 
ITTE 
EFF_T2 
Summary of Categorical Efficacy by Endpoint in Induction Phase 
- Observed 
Report by endpoint, visit. Report the 
endpoints below at different interims. 
 
Additionally, report summaries by each 
level of advanced therapy experience’ 
and ‘all’ 
 
Endoscopic Improvement, Clinical 
Remission (Adapted Mayo), 
Symptomatic Remission, Endoscopic 
Remission 
 
IA3H, SAC 
2.18. 
ITTE ETP 
EFF_T2 
Summary of Categorical Efficacy by Endpoint in Extended 
Treatment Phase 
Report by endpoint, visit.   
Include the following ETP only 
endpoints: 
• Maintained Clinical Response 
(Week 10 to 30 Adapted Mayo) 
• Maintained Clinical Remission 
(Week 10 to 30 Adapted Mayo 
• Steroid Free Clinical Remission 
• Maintained Steroid Free Clinical 
Remission 
 
None 
2.19. 
ITTE_OL_I 
EFF_T2 
Summary of Categorical Efficacy by Endpoint in Open Label 
Phase 
Report by endpoint, visit.   
 
None 
2.20. 
ITTE_OL_ET
P 
EFF_T2 
Summary of Categorical Efficacy by Endpoint in Open Label 
Extended Treatment Phase 
Report by endpoint, visit.   
• 
 
None 


 
CONFIDENTIAL 
 
 
 
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103 
 
Efficacy: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.21. 
ITTE 
EFF_T7 
Statistical Analysis of Categorical Efficacy in Induction Phase 
Report the endpoints below, Induction 
phase only: 
 
Endoscopic Improvement, Clinical 
Remission 
 
Also report estimate for each level of 
‘Advanced Therapy experience’ (i.e. 
subgroup) 
IA3H, SAC 
2.22. 
ITTE 
EFF_T7 
Statistical Analysis of Categorical Efficacy in Induction Phase – 
Sub Group 
Endoscopic Improvement and Clinical 
Remission only. 
Subgroup for each level of stratification 
factor (advanced therapy experience) 
Full population: 
• 
Subgroup Race and Race2  
Sub-population of biologic experience: 
• 
Biologic experience type 
Sub-population of TNF failure 
• 
TNF failure mechanisms 
• 
 
None 


 
CONFIDENTIAL 
 
 
 
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104 
 
Efficacy: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.23. 
ITTE 
EFF_T3 
Statistical Analysis of Dose Response Relationship for 
Categorical Endpoints 
By Endpoint then estimand. 
• 
Endoscopic Improvement 
(IA4 and PC) 
• 
Endoscopic Improvement, 
Clinical Response, Clinical 
Remission, ( PC only) 
• 
 
Present analysis results for both 
‘Treatment Policy’ and ‘Hypothetical’ 
estimands if conducted 
None 
Histological assessments 
2.24. 
ITTE 
EFF_T2 
Summary of Categorical Histology at each Dose Level by 
Endpoint in Induction Phase 
Report by endpoint, visit.   
Geboes Histological Remission 
RHI Remission 
RHI Deep Remission 
Nancy Index Remission 
 
 
SAC 
2.25. 
ITTE ETP 
EFF_T2 
Summary of Categorical Histology by Endpoint in Extended 
Treatment Phase 
Report by endpoint, visit.   
 
None 


 
CONFIDENTIAL 
 
 
 
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105 
 
Efficacy: Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Extra Intestinal Manifestations 
2.26. 
ITTE 
EFF_T4 
Summary of Extra Intestinal Manifestations (EIMs) - Incidents by 
Severity, across Study Phases. 
For EIMs without severity (Peripheral 
Arthritis and Axial Arthropathy) set 
levels of severity to missing 
 
Slot early withdrawal visits to next EIM 
visit (there is one EIM visit at the end of 
each study phase) 
 
Summary is cross-phase: Report by 
treatment sequence, not by treatment in 
an individual study phase 
None 
Continuous Efficacy – Pairwise Statistical Analysis 
2.27. 
ITTE 
EFF_T5 
Statistical Analysis of Change from Baseline in Complete Mayo 
Score in Induction Phase 
 
IA3H 
Summaries of Efficacy after Estimand Imputations 
2.28. 
ITTE 
EFF_T2 
Summary of Categorical Efficacy by Endpoint in Induction Phase 
- Estimands 
 
IA3H, SAC 
2.29. 
ITTE 
PD1 
Summary of Mayo Score by Endpoint in Induction Phase - 
Estimands 
 
SAC 
2.30. 
ITTE 
PD1 
Summary of UCEIS Total Score in Induction Phase - Estimands 
 
SAC 
 
 
 


 
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15.12.6. 
Efficacy Figures 
Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Continuous Efficacy 
2.1.
ITTE 
EFF_F01 
Forest plot of Observed Mayo Score Change from Baseline 
By “Overall” then Advanced Therapy 
Experience level then by endpoint: 
Complete, Adapted, Partial (at 
matching timepoint only).  Note: 
categorical axis shows dose level. 
SAC 
2.2.  
ITTE 
EFF_F02 
Forest plot of Estimated Difference from Placebo in Mayo Score 
Change from Baseline 
By “Overall” then Advanced Therapy 
Experience level then by endpoint: 
Complete, Adapted, Partial (Partial at 
matching timepoint only).   
Note: categorical axis shows dose level 
SAC 
2.3.  
IIT_ETP 
EFF_F01 
Forest plot of Observed Mayo Score Change from Baseline – 
Extended Treatment Phase 
By “Overall” then Advanced Therapy 
level then panelled by endpoint: 
Complete, Adapted, Partial (Partial at 
matching timepoint only).   
Note: categorical axis shows (both) 
dose levels 
None 
2.4.  
ITTE 
Study 200630, 
Figure 2.5 
Mean (SE) Plot of Partial Mayo Score over time in induction 
phase 
By dose 
Page by Absolute and Change from 
Baseline 
SAC 
2.5.  
IIT_ETP 
EFF_F01 
Forest plot of Observed UCEIS Total Score – Induction Phase 
By “Overall” then Advanced Therapy 
Experience level 
Note: categorical axis shows dose level 
 
None 


 
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107 
 
Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Categorical Efficacy 
2.6.  
ITTE 
EFF_F03 
Forest plot of Proportions for Categorical Endpoints in Induction 
Phase - Observed 
Panel by Endpoint, then Visit, then 
Dose. 
Subgroup (within panel) Advanced 
Therapy Experience level 
(Note that proportions / odds ratios are 
on the same scale across endpoints). 
IA3H, SAC 
2.7.  
ITTE 
EFF_F04 
Forest Plot for Estimated Response Rates for Categorical 
Endpoints in Induction Phase 
Panel by Endpoint, then Visit, then 
Dose, then rate/delta. 
Subgroup (within panel) Advanced 
Therapy Experience level 
(Note that proportions / odds ratios are 
on the same scale across endpoints). 
 
Endoscopic Improvement and 
Clinical Remission 
IA3H, SAC 
2.8.  
ITTE_ETP 
EFF_F03 
Forest plot of Observed Proportions for Categorical Endpoints in 
Extended Treatment Phase 
Panel by Endpoint, then Visit, then 
Dose. 
Subgroup (within panel) Advanced 
Therapy Experience level 
(Note that proportions / odds ratios are 
on the same scale across endpoints).   
 
Some reporting efforts will not report 
all endpoints. 
Footnote: 
Median and equal tailed credible 
intervals using non-informative priors in 
a beta-binomial model. 
None 


 
CONFIDENTIAL 
 
 
 
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Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.9.  
ITTE 
EFF_F03 
Forest plot of Proportions for Categorical Endpoints in Induction 
Phase - Estimands 
 
IA3H, SAC 
Daily Diary Scores 
2.10. 
ITTE 
EFF_F05 
Mean (+/-SE) Plot of Daily Diary Scores in Induction Phase 
Intervals of 3 days in the x-axis 
SAC 
2.11. 
ITTE 
EFF_F06 
Plot of Daily Diary Scores for Individual Subjects in Induction 
Phase - Subgroups 
Use the non-rounded versions of 
derived Rectal Bleeding and Absolute 
Stool Number 
 
Show patients with Discontinuation and 
Ulcerative Colitis AEs in induction as a 
separate groups; 
 
Intervals of 3 days in the x-axis 
SAC 
 
 


 
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15.12.7. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events (AEs) 
3.1.  
Safety 
AE5A 
Summary of All Adverse Events by Intensity, System Organ 
Class and Preferred Term in Induction Phase 
N30: blinded output, do not report 
treatment group. 
N30, SAC 
3.2.  
Safety 
AE1 
Summary of All Adverse Events by System Organ Class and 
Preferred Term in Induction Phase 
ICH E3 
Add footnote:   
Note: Onset date of Adverse Event is 
used to associate AE to study phase. 
On request by 
DRC and SAC 
3.3.  
Safety ETP 
AE5A 
Summary of All Adverse Events by Intensity, System Organ 
Class and Preferred Term in Extended Treatment Phase 
Add footnote:   
Note: Onset date of Adverse Event is 
used to associate AE to study phase. 
On request by 
DRC and SAC 
3.4.  
Safety OL I 
AE5A 
Summary of All Adverse Events by Intensity, System Organ 
Class and Preferred Term for Open Label Induction Phase 
Add footnote:   
Note: Onset date of Adverse Event is 
used to associate AE to study phase. 
On request by 
DRC and SAC 
3.5.  
Safety OL 
ETP 
AE5A 
Summary of All Adverse Events by Intensity, System Organ 
Class and Preferred Term for Open Label Extended Treatment 
Phase 
Add footnote:   
Note: Onset date of Adverse Event is 
used to associate AE to study phase. 
On request by 
DRC and SAC 
3.6.  
Safety 
AE3 
Summary of Common (>=5%) Adverse Events by Overall 
Frequency for Induction Phase 
Rationale: ICH E3 
Add footnote:   
Note: Onset date of Adverse Event is 
used to associate AE to study phase. 
SAC 
3.7.  
Safety ETP 
AE3 
As above for Extended Treatment Phase 
 
None 
3.8.  
Safety OL I 
AE3 
As above for Open Label Induction Phase 
 
None 
3.9.  
Safety OL 
ETP 
AE3 
As above for Open Label Extended Treatment Phase 
 
None 


 
CONFIDENTIAL 
 
 
 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.10. 
Safety 
AE1  
 
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term for Induction Phase 
 
Rationale: ICH E3 
Add footnote:   
Note: Onset date of Adverse Event is 
used to associate AE to study phase. 
SAC 
3.11. 
Safety ETP 
AE1 
As above for Extended Treatment Phase 
 
SAC 
3.12. 
Safety OL I 
AE1 
As above for Open Label Induction Phase 
 
SAC 
3.13. 
Safety OL 
ETP 
AE1 
As above for Open Label Extended Treatment Phase 
 
SAC 
3.14. 
Safety 
AE15 
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences) for Induction Phase 
Rationale: disclosure for FDAAA, 
EudraCT 
Add footnote:   
Note: Onset date of Adverse Event is 
used to associate AE to study phase. 
SAC 
3.15. 
Safety ETP 
AE15 
Summary of Non-serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences) for Extended Treatment Phase 
 
SAC 
3.16. 
Safety OL I 
AE15 
As above for Open Label Induction Phase 
 
SAC 
3.17. 
Safety OL 
ETP 
AE15 
As above for Open Label Extended Treatment Phase 
 
SAC 
Serious and Other Significant Adverse Events 
3.18. 
Safety 
AE16 
Blinded summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences) for Induction Phase 
This is a blinded output, do not report 
treatment group. 
 
N30 


 
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111 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.19. 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences) for 
Induction Phase 
Rationale: disclosure for FDAAA, 
EudraCT 
Add footnote:   
Note: Onset date of Adverse Event is 
used to associate AE to study phase. 
SAC 
3.20. 
Safety ETP 
AE16 
As above for Extended Treatment Phase 
 
SAC 
3.21. 
Safety OL I 
AE16 
As above for Open Label Induction Phase 
 
SAC 
3.22. 
Safety OL 
ETP 
AE16 
As above for Open Label Extended Treatment Phase 
 
SAC 
3.23. 
Safety 
AE3 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
Overall Frequency for Induction Phase 
IDSL 
Add footnote:   
Note: Onset date of Adverse Event is 
used to associate AE to study phase. 
SAC 
3.24. 
Safety ETP 
AE3 
As above for Extended Treatment Phase 
 
None 
3.25. 
Safety OL I 
AE3 
As above for Open Label Induction Phase 
 
None 
3.26. 
Safety OL 
ETP 
AE3 
As above for Open Label Extended Treatment Phase 
 
None 
Laboratory: Chemistry  
3.27. 
Safety 
LB1 
Summary of Chemistry Changes from Baseline for Induction 
Phase 
Rationale: ICH E3 
 
SAC 
3.28. 
Safety ETP 
LB1 
As above for Extended Treatment Phase 
Rationale: ICH E3 
 
SAC 
3.29. 
Safety OL I 
LB1 
As above for Open Label Induction Phase 
Rationale: ICH E3 
 
SAC 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.30. 
Safety OL 
ETP 
LB1 
As above for Open Label Extended Treatment Phase 
Rationale: ICH E3 
 
SAC 
3.31. 
Safety 
LB17 
Summary of Worst-Case Chemistry Results by PCI Criteria 
Post-Baseline Relative to Baseline for Induction Phase 
Rationale: ICH E3 and disclosure 
 
SAC 
3.32. 
Safety ETP 
LB17 
Summary of Worst-Case Chemistry Results by PCI Criteria 
Post-Baseline Relative to Baseline for Extended Treatment 
Phase 
Rationale: ICH E3 
Footnote: “Note: Induction phase 
baseline used” 
 
SAC 
3.33. 
Safety OL I 
LB17 
Summary of Worst-Case Chemistry Results by PCI Criteria 
Post-Baseline Relative to Baseline for Open Label Induction 
Phase 
Rationale: ICH E3 
Footnote: “Note: Induction phase 
baseline used” 
 
SAC 
3.34. 
Safety OL 
ETP 
LB17 
Summary of Worst-Case Chemistry Results by PCI Criteria 
Post-Baseline Relative to Baseline for Open Label Extended 
Treatment Phase 
Rationale: ICH E3 
Footnote: “Note: Induction phase 
baseline used” 
 
SAC 
Laboratory: Haematology 
3.35. 
Safety 
LB1 
Summary of Haematology Changes from Baseline for Induction 
Phase  
Rationale: ICH E3 
 
SAC 
3.36. 
Safety ETP 
LB1 
As above for Extended Treatment Phase 
Rationale: ICH E3 
 
SAC 
3.37. 
Safety OL I 
LB1 
As above for Open Label Induction Phase 
Rationale: ICH E3 
 
SAC 
3.38. 
Safety OL 
ETP 
LB1 
As above for Open Label Extended Treatment Phase 
Rationale: ICH E3 
 
SAC 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.39. 
Safety 
LB17 
Summary of Worst-Case Haematology Results by PCI Criteria 
Post-Baseline Relative to Baseline for Induction Phase 
Rationale: ICH E3 and disclosure 
 
SAC 
3.40. 
Safety ETP 
LB17 
Summary of Worst-Case Haematology Results by PCI Criteria 
Post-Baseline Relative to Baseline for Extended Treatment 
Phase 
Rationale: ICH E3 
Footnote: “Note: Induction phase 
baseline used” 
 
SAC 
3.41. 
Safety OL I 
LB17 
Summary of Worst-Case Haematology Results by PCI Criteria 
Post-Baseline Relative to Baseline for Open Label Induction 
Phase 
Rationale: ICH E3 
Footnote: “Note: Induction phase 
baseline used” 
 
SAC 
3.42. 
Safety OL 
ETP 
LB17 
Summary of Worst-Case Haematology Results by PCI Criteria 
Post-Baseline Relative to Baseline for Open Label Extended 
Treatment Phase 
Rationale: ICH E3 
Footnote: “Note: Induction phase 
baseline used” 
 
SAC 
Laboratory: Urinalysis 
3.43. 
Safety 
UR1 
Summary of Worst-Case Urinalysis Results by PCI Criteria Post-
Baseline Relative to Baseline for Induction Phase 
ICH E3 
 
SAC 
3.44. 
Safety ETP 
UR1 
Summary of Worst-Case Urinalysis Results by PCI Criteria Post-
Baseline Relative to Baseline for Extended Treatment Phase 
ICH E3 
 
SAC 
3.45. 
Safety OL I 
UR1 
Summary of Worst-Case Urinalysis Results by PCI Criteria Post-
Baseline Relative to Baseline for Open Label Induction Phase 
ICH E3 
 
SAC 
3.46. 
Safety OL 
ETP 
UR1 
Summary of Worst-Case Urinalysis Results by PCI Criteria Post-
Baseline Relative to Baseline for Open Label Extended 
Treatment Phase 
ICH E3 
 
SAC 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
ECG 
3.47. 
Safety 
EG1 
Summary of ECG Findings for Induction Phase  
IDSL 
 
SAC 
3.48. 
Safety ETP 
EG1 
As above for Extended Treatment Phase 
 
SAC 
3.49. 
Safety OL I 
EG1 
As above for Open Label Induction Phase 
 
SAC 
3.50. 
Safety OL 
ETP 
EG1 
As above for Open Label Extended Treatment Phase 
 
SAC 
3.51. 
Safety 
EG2 
Summary of Change from Baseline in ECG Values by Visit for 
Induction Phase 
 
None 
3.52. 
Safety ETP 
EG2 
As above for Extended Treatment Phase 
 
None 
3.53. 
Safety OL I 
EG2 
As above for Open Label Induction Phase 
 
None 
3.54. 
Safety OL 
ETP 
EG2 
As above for Open Label Extended Treatment Phase 
 
None 
3.55. 
Safety 
EG10 
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category for Induction Phase 
IDSL 
 
SAC 
3.56. 
Safety ETP 
EG10 
As above for Extended Treatment Phase 
Footnote: “Note: Induction phase 
baseline used” 
SAC 
3.57. 
Safety OL I 
EG10 
As above for Open Label Induction Phase 
Footnote: “Note: Induction phase 
baseline used” 
SAC 
3.58. 
Safety OL 
ETP 
EG10 
As above for Open Label Extended Treatment Phase 
Footnote: “Note: Induction phase 
baseline used” 
SAC 
3.59. 
Safety 
EG11 
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category for Induction Phase 
Rationale: disclosure 
IDSL 
 
SAC 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.60. 
Safety ETP 
EG11 
As above for Extended Treatment Phase 
Footnote: “Note: Induction phase 
baseline used” 
SAC 
3.61. 
Safety OL I 
EG11 
As above for Open Label Induction Phase 
Footnote: “Note: Induction phase 
baseline used” 
SAC 
3.62. 
Safety OL 
ETP 
EG11 
As above for Open Label Extended Treatment Phase 
Footnote: “Note: Induction phase 
baseline used” 
SAC 
Vital Signs 
3.63. 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs for Induction 
Phase 
ICH E3 
 
SAC 
3.64. 
Safety ETP 
VS1 
As above for Extended Treatment Phase 
 
SAC 
3.65. 
Safety OL I 
VS1 
As above for Open Label Induction Phase 
 
SAC 
3.66. 
Safety OL 
ETP 
VS1 
As above for Open Label Extended Treatment Phase 
 
SAC 
3.67. 
Safety 
VS7 
Summary of Worst-Case Vital Signs Results by PCI Criteria 
Post-Baseline Relative to Baseline for Induction Phase 
IDSL 
Note: Adjust shell to include 
temperature (required for disclosure).  
Use footnote and title of middle 
category from VS7 (i.e. change ‘normal’ 
to ‘within range’) 
Include change from baseline for 
Systolic Blood Pressure, Diastolic 
Blood Pressure and Heart Rate 
 
SAC 
3.68. 
Safety ETP 
VS7 
As above for Extended Treatment Phase 
 
SAC 
3.69. 
Safety OL I 
VS7 
As above for Open Label Induction Phase 
 
SAC 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.70. 
Safety OL 
ETP 
VS7 
As above for Open Label Extended Treatment Phase 
 
SAC 
Immunogenicity 
3.71. 
Safety 
sb240563/mid20
5050/final_02/ 
Table 3.38 
Summary of Confirmed Positive Binding Antibody by Visit for 
Induction Phase 
 
SAC 
3.72. 
Safety ETP 
sb240563/mid20
5050/final_02/ 
Table 3.38 
As above for Extended Treatment Phase 
 
SAC 
3.73. 
Safety OL I 
sb240563/mid20
5050/final_02/ 
Table 3.38 
As above for Open Label Induction Phase 
 
SAC 
3.74. 
Safety OL 
ETP 
sb240563/mid20
5050/final_02/ 
Table 3.38 
As above for Open Label Extended Treatment Phase 
 
SAC 
3.75. 
Safety 
sb240563/mid20
5050/final_02/ 
Table 3.39 
Summary of Confirmed Positive Neutralising Antibody by Visit 
for Induction Phase 
 
None 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.76. 
Safety ETP 
sb240563/mid20
5050/final_02/ 
Table 3.39 
As above for Extended Treatment Phase 
 
None 
3.77. 
Safety OL I 
sb240563/mid20
5050/final_02/ 
Table 3.39 
As above for Open Label Induction Phase 
 
None 
3.78. 
Safety OL 
ETP 
sb240563/mid20
5050/final_02/ 
Table 3.39 
As above for Open Label Extended Treatment Phase 
 
None 
Adverse Events – Additional Summaries 
3.79. 
Safety 
AE17 
Summary of Exposure Adjusted Incidence Rates for Adverse 
Events in Induction Phase 
For selected Preferred Terms –  
1) All Preferred terms in System Organ 
class of Infections and Infestations   
2) Preferred Term – Colitis Ulcerative  
SAC 
3.80. 
Safety 
TTE1 
Summary of Time to Ulcerative Colitis Adverse Event in 
Induction Phase 
For selected Preferred Terms – 
1) Preferred Term – Colitis Ulcerative 
SAC 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
COVID-19 Pandemic Impact 
3.81. 
Safety 
PAN4 
Summary of COVID-19 Pandemic Visit Impacts 
 
SAC 
 
 


 
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15.12.8. 
Safety Figures 
Safety: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events 
3.1.  
Safety 
AE10 
Plot of Common (>=5%) Adverse Events for Induction 
Phase 
Incidence ≥5% on either active or 
placebo  
Separate page for each treatment 
compared to placebo; plus combined 
treatment compared to placebo 
 
Add following footnote and use in 
programming rules: 
“Note: All displayed Adverse Events 
(AEs) have occurrence >= 5% in an 
active treatment group and the AE has to 
have at least 1 occurrence in the placebo 
group for relative risk to be calculated. 
Only AEs with calculated relative risk are 
displayed.” 
SAC 
Hepatobiliary (Liver) 
3.2.  
Safety 
LIVER14 
Scatter Plot of Maximum vs. Baseline for ALT for 
Induction Phase 
 
SAC 
3.3.  
Safety_ETP 
LIVER14 
Scatter Plot of Maximum vs. Baseline for ALT for 
Extended Treatment Phase 
Footnote: “Note: Induction phase baseline 
used” 
None 
3.4.  
Safety_OL_I 
LIVER14 
Scatter Plot of Maximum vs. Baseline for ALT for Open 
Label Induction Phase 
Footnote: “Note: Induction phase baseline 
used” 
None 
3.5.  
Safety_OL_ETP 
LIVER14 
Scatter Plot of Maximum vs. Baseline for ALT for Open 
Label Extended Treatment Phase 
Footnote: “Note: Induction phase baseline 
used” 
None 


 
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Safety: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.6.  
Safety 
LIVER9 
Scatter Plot of Maximum ALT vs. Maximum Total 
Bilirubin for Induction Phase 
 
SAC 
3.7.  
Safety_ETP 
LIVER9 
Scatter Plot of Maximum ALT vs. Maximum Total 
Bilirubin for Extended Treatment Phase 
 
None 
3.8.  
Safety_OL_I 
LIVER9 
Scatter Plot of Maximum ALT vs. Maximum Total 
Bilirubin for Open Label Induction Phase 
 
None 
3.9.  
Safety_OL_ETP 
LIVER9 
Scatter Plot of Maximum ALT vs. Maximum Total 
Bilirubin for Open Label Extended Treatment Phase 
 
None 
 


 
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15.12.9. 
Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK concentration 
4.1.  
PK 
PKCT1 
Summary of Plasma GSK2831781 Concentration-Time Data 
(ng/mL) for Induction Phase  
Note: LLQ=10 ng/mL. 
SE and 95% CI (Lower, Upper) are set 
to missing if No. Imputed/n > 0.3. 
 
SAC 
4.2.  
PK_ETP 
PKCT1 
Summary of Plasma GSK2831781 Concentration-Time Data 
(ng/mL) in Extended Treatment Phase 
Note: LLQ=10 ng/mL. 
SE and 95% CI (Lower, Upper) are set 
to missing if No. Imputed/n > 0.3. 
Programming note: data should be 
summarised by dose group of 
Induction Phase 
SAC 
4.3.  
PK_OL 
PKCT1 
Summary of Plasma GSK2831781 Concentration-Time Data 
(ng/mL) in Open Label Induction Phase by Double Blind 
Induction Treatment 
Note: LLQ=10 ng/mL. 
SE and 95% CI (Lower, Upper) are set 
to missing if No. Imputed/n > 0.3. 
Please add a note: “Note that subjects 
had different doses during the 
Induction Phase” 
SAC 
4.4.  
PK_OL_ETP 
PKCT1 
Summary of Plasma GSK2831781 Concentration-Time Data 
(ng/mL) in Open Label Extended Treatment Phase by Double 
Blind Induction Treatment 
Note: LLQ=10 ng/mL. 
SE and 95% CI (Lower, Upper) are set 
to missing if No. Imputed/n > 0.3. 
SAC 
PK derived parameters 
4.5.  
PK_ETP 
PK03 
Summary of derived plasma GSK2831781 pharmacokinetic 
parameters in Extended Treatment Phase (SC dosing) 
 
SAC 


 
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Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.6.  
PK_ETP 
PK05 
Summary of log-transformed derived plasma GSK2831781 
pharmacokinetic parameters in Extended Treatment Phase (SC 
dosing) 
 
SAC 
 
15.12.10. Pharmacokinetic Figures 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.1.  
PK_ETP 
PKCF1P 
Individual GSK2831781 Plasma Concentration-Time Plot by 
Subject (Linear and Semi-Log) at Week 14 and Week 15 in 
Extended Treatment Phase 
Note for programmers: Please use 
only the data from Week 14 and Week 
15 – ie from pre-dose at Week 14, until 
the very last sample at Week 15. 
Footnote for all PK and PK/PD figures: 
‘Note: LLQ=10 ng/mL. Values below 
LLQ have been imputed to 0.’ 
Use actual time (days) as x axis 
(where days is a continuous variable) 
None 
4.2.  
PK 
PKCF4 
Mean (+SD) Plasma GSK2831781 Concentration-Time Plots 
by Treatment (Linear and Semi-log) in Induction Phase (pre-
dose samples only) 
Use planned time (days) as x axis 
(where days is a continuous variable) 
Plot data from all dose groups on 1 
graph, colour coded by dose group 
None 


 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.3.  
PK_ETP 
PKCF4 
Mean (+SD) Plasma GSK2831781 Concentration-Time Plots 
(Linear and Semi-Log) in Extended Treatment Phase (pre-dose 
samples only) 
Use planned time (days) as x axis 
(where days is a continuous variable) 
Add footnote “Note: samples are taken 
pre-dose, and do not include Week 
14 and 15 samples” 
Plot all data on 1 graph, colour coded 
by dose group of Induction Phase 
None 
4.4.  
PK_ETP 
PKCF4 
Mean (+SD) Plasma GSK2831781 Concentration-Time Plots 
(Linear and Semi-Log) in Extended Treatment Phase (Week 14 
and Week 15 only) 
Use planned time (days) as x axis 
(Weeks 14 and 15 only) (where days is 
a continuous variable) 
Add footnote “Sub-set of subjects with 
post-dose samples taken according to 
one of two protocol defined schedules 
are plotted.” 
None 
4.5.  
PK_OL 
PKCF4 
Mean (+SD) Plasma GSK2831781 Concentration-Time Plots 
(Linear and Semi-Log) in Open Label Induction Phase (pre-
dose samples only) 
Use planned time (days) as x axis 
(where days is a continuous variable) 
tick marks for Week 12 and Week 22 
only. 
Add x-axis jitter if necessary to 
separate points 
None 
4.6.  
PK 
201246/final/ 
Figure 4.9 
Mean (+SD) Plasma GSK2831781 Concentration-Time Plots 
grouped by Treatment (Linear and Semi-log) in Induction 
Phase  
As Figure 4.3 but on a single page, 
grouped by treatment.  See Figure 4.9 
and Figure 4.10 in ad-hoc reporting 
effort. 
Add footnote “Note: samples are taken 
pre-dose except for post-dose samples 
on Day 1 and Week 6.” 
None 
 


 
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15.12.11. Pharmacokinetic Population (PopPK) Tables 
Pharmacokinetic Population (POPPK): Tables 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
5.1.  
PK 
 
Summary of final PK model tested 
To be generated by CPMS 
IA3, SAC 
5.2.  
PK  
 
Parameter estimates of final PK model 
To be generated by CPMS 
IA3, SAC 
Note: dependent on the results of the analysis, additional tables may be generated by CPMS 
 


 
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15.12.12. Pharmacokinetic Population (PopPK) Figures 
Pharmacokinetic Population (POPPK): Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
5.1.  
PK 
 
Mean (SD) PK and sLAG3 data versus time 
To be generated by CPMS 
PK and sLAG3 will be in the same graph to 
show how the concentration-time profiles 
compare to each other 
IA3, SAC 
5.2.  
PK 
 
Individual fits of final PK model 
To be generated by CPMS 
IA3, SAC 
5.3.  
PK 
 
Standard diagnostics of final PK model 
To be generated by CPMS 
IA3, SAC 
5.4.  
PK 
 
NPDEs of final PK model 
To be generated by CPMS 
IA3, SAC 
5.5.  
PK 
 
PK versus time overlaid with population mean 
predictions from final PK model 
To be generated by CPMS 
 
IA3, SAC 
5.6.  
PK 
 
sLAG3 versus time overlaid with population mean 
predictions from final PK model 
To be generated by CPMS 
Note: this graph may show individual data, or 
median & range for each time point 
IA3, SAC 
Note: dependent on the results of the analysis, additional figures may be generated by CPMS. 
 


 
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15.12.13. Pharmacodynamic / Biomarker Tables 
Biomarker: Tables 
No. 
Population 
IDSL / 
Example Shell Title  
Programming Notes 
Deliverable 
[Priority] 
sLAG3 
6.1.  
ITTE 
PKCT1 
Summary of Plasma sLAG3 Concentration-Time Data (ng/mL) 
in Induction Phase  
 
SAC 
6.2.  
ITTE _ETP 
PKCT1 
Summary of Plasma sLAG3 Concentration-Time Data (ng/mL) 
in Extended Treatment Phase 
 
None 
6.3.  
ITTE _OL_I 
PKCT1 
Summary of Plasma sLAG3 Concentration-Time Data (ng/mL) 
in Open Label Induction Phase 
 
None 
6.4.  
ITTE_OL_ETP 
PKCT1 
Summary of Plasma sLAG3 Concentration-Time Data (ng/mL) 
in Open Label Extended Treatment Phase 
 
None 
Flow cytometry 
6.5.  
ITTE 
PD1 
Summary of Flow Cytometry by Visit in Induction Phase 
Programming note: By Analyte and 
then by Summary (absolute(raw),and 
change from baseline).  This will 
require non-standard programming as 
in shell. Note: use ABSCOUNT rather 
than COUNT for all Flow Cytometry 
outputs. 
SAC 
6.6.  
ITTE_ETP 
PD1 
Summary of Flow Cytometry by Visit in Extended Treatment 
Phase 
Programming note: By Analyte and 
then by Summary (absolute and 
change from baseline).  This will 
require non-standard programming as 
in shell. 
None 


 
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Biomarker: Tables 
No. 
Population 
IDSL / 
Example Shell Title  
Programming Notes 
Deliverable 
[Priority] 
Immunohistochemistry (IFC) in Colon Biopsies 
6.7.  
ITTE 
PD1 
Summary of Colon Biopsy Cell Counts in Induction Phase 
Produce table by: 
1) absolute and change from baseline 
2) tissue type 
For: 
All derived parameters. 
 
Geometric mean with 95% Confidence 
Interval 
IA3, SAC 
6.8.  
ITTE ETP 
PD1 
Summary of Colon Biopsy Cell Counts – Extended Treatment 
Phase 
as above. 
Change from shell: replace SD with 
SE on shell 
None 
6.9.  
ITTE 
BIO_T01 
Statistical Analysis of CD3 positive and Lag3 positive cell count 
in Colon 
Estimated difference in change from 
baseline for CD3+LAG3+ cells/mm2 in 
Lamina Propria 
None 
6.10. 
ITTE ETP 
BIO_T01 
Statistical Analysis of Colon Biopsy Cell Counts in Extended 
Treatment Phase 
Precision estimate for change from 
baseline for cell counts for 
CD3+LAG3+ cells/mm2 in Lamina 
Propria. 
None 
Disease Biomarkers  
6.11. 
ITTE 
PD1 
Summary of Disease Biomarkers in Induction Phase  
For following endpoints: 
• 
Faecal Calprotectin 
• 
CRP where elevated at 
baseline. Footnote: 
“Note that CRP for all subjects is 
reported in “Chemistry” summaries”. 
SAC 


 
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Biomarker: Tables 
No. 
Population 
IDSL / 
Example Shell Title  
Programming Notes 
Deliverable 
[Priority] 
6.12. 
ITTE ETP 
PD1 
Summary of Disease Biomarkers in Extended Treatment 
Phase 
For following endpoints: 
• 
Faecal Calprotectin 
• 
Serum Tryptase 
 
None 
6.13. 
ITTE_OL_I 
PD1 
Summary of Disease Biomarkers in Open Label Phase 
For following endpoints: 
• 
Faecal Calprotectin 
• 
Serum Tryptase 
 
None 
6.14. 
ITTE_OL_ETP 
PD1 
Summary of Disease Biomarkers in Open Label Extended 
Treatment Phase 
For following endpoints: 
• 
Faecal Calprotectin 
• 
Serum Tryptase 
 
None 
6.15. 
ITTE 
BIO_T01 
Statistical Analysis of Disease Biomarkers in Induction Phase 
Estimated difference in change from 
baseline for: 
• 
FCP 
• 
CRP 
None 
 
 


 
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15.12.14. Pharmacodynamic / Biomarker Figures 
Biomarker: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
sLAG3 
6.1.  
ITTE 
PKCF4 
Mean (+SD) Plasma sLAG3 Concentration-Time Plots by 
Treatment (Linear and Semi-log) in Induction Phase (Pre-Dose 
samples only 
Use planned time (days) as x axis 
(where days is a continuous variable) 
 
None 
6.2.  
ITTE_ETP 
PKCF4 
Mean (+SD) Plasma sLAG3 Concentration-Time Plots by 
Treatment (Linear and Semi-Log) in Extended Treatment 
Phase (Week 14 and Week 15 only) 
Use planned time (days) as x axis 
(where days is a continuous variable) 
Add footnote “Note: samples are taken 
pre-dose, week 14 and 15 samples 
were only taken in a sub-set of 
subjects” 
None 
6.3.  
ITTE_OL_I  
PKCF4 
Mean (+SD) Plasma sLAG3 Concentration-Time Plots (Linear 
and Semi-Log) in Open Label Induction Phase 
Use planned time (days) as x axis 
(where days is a continuous variable) 
tick marks for Week 12 and Week 22 
only. 
Add x-axis jitter if necessary to 
separate points 
None 
6.4.  
ITTE 
201246/final/ 
Figure 4.9 
Mean (+SD) Plasma sLAG3 Concentration-Time Plots 
grouped by Treatment (Linear and Semi-log) in Induction 
Phase  
As Figure 4.3 but on a single page, 
grouped by treatment.  See Figure 4.9 
and Figure 4.10 in ad-hoc reporting 
effort. 
Add footnote “Note: samples are taken 
pre-dose except for post-dose 
samples on Day 1 and Week 6.” 
None 


 
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Biomarker: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Flow cytometry 
6.5.  
ITTE 
207823/ 
Figure 5.1 
LAG3+ T Cells in Blood for Individual Subjects in Induction 
Phase 
As shell, combine flow marker and 
summary type in ‘by’ title. 
Use week on x axis. 
Add footnote: 
“Flow cytometry performed at a sub-
set of sites”. 
Note: plot for induction phase only 
SAC 
6.6.  
ITTE 
207823/ 
Figure 5.2 
Geometric Mean ( 95% CI) Plot of LAG3+ T Cells in Blood by 
Treatment in Induction Phase 
As shell, combine flow marker and 
summary type in ‘by’ title. 
Use week on x axis. 
Add footnote: 
“Flow cytometry performed at a sub-
set of sites”. 
Note: plot for induction phase only 
SAC 
Immunohistochemistry (IFC) in colon 
6.7.  
ITTE 
200630/ 
postcsr_2019_01/ 
Figure 1 
Cell Count in Colon Biopsies for Individual Subjects in 
Induction Phase 
Copy shell but don’t use panel 
By parameter, by induction dose. 
 
IA3, SAC 
6.8.  
ITTE 
200630/ 
postcsr_2019_01/ 
Figure 2 
Geometric Mean ( 95% CI) Plot of Cell Counts in Colon 
Biopsies by Treatment in Induction Phase 
By parameter, 
Copy shell, include all treatments in a 
plot 
Footnote for interims: “Note that the 
longer lead time for this assay means 
that fewer subjects are analysed than 
for efficacy endpoints” 
Induction phase only. 
IA3, SAC 


 
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Biomarker: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
6.9.  
ITTE 
200630/ 
postcsr_2019_01/ 
Figure 3 for panel 
structure but use 
2 x 2 
Mean (SE) Plot of Change from baseline in Cell Counts in 
Colon Biopsies by Treatment in Induction Phase 
By parameter, 
Copy shell, include all treatments in a 
plot 
Induction phase only. 
None 
6.10. 
ITTE_ETP 
200630/ 
postcsr_2019_01/ 
Figure 2 
Mean (SE) Plot of Cell Counts in Colon Biopsies by Induction 
Treatment across Phase in Extended Treatment Phase 
By parameter, 
Copy shell, include all treatments in a 
plot 
Only use ETP population and ETP 
timepoints. 
Footnote: “Summaries are by 
induction treatment, responders on 
any active dose received 300mg SC in 
ETP” 
None 
6.11. 
ITTE 
200630/ 
postcsr_2019_01/ 
Figure 3 for panel 
structure but use 
2 x 2 
Mean (SE) Plot of Change from baseline in Cell Counts in 
Colon Biopsies by Treatment in Extended Treatment Phase 
By parameter,  
Copy shell, include all treatments in a 
plot 
Induction phase only. 
None 
 


 
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15.12.15. Pharmacokinetic / Pharmacodynamic Tables 
Pharmacokinetic / Pharmacodynamic Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
7.1.  
ITTE 
 
Summary of final PK/PD model tested 
To be generated by CPMS 
IA3, IA4, PC, SAC 
7.2.  
ITTE 
 
Parameter estimates of final PK/PD model 
To be generated by CPMS 
IA3, IA4, PC, SAC 
Note: dependent on the results of the analysis, additional tables may be generated (by CPMS). 
 


 
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15.12.16. Pharmacokinetic / Pharmacodynamic Figures 
Pharmacokinetic / Pharmacodynamic Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
7.1.
ITTE 
 
PK, receptor occupancy and cell depletion data versus time 
To be generated by CPMS 
(as Figure 7.01 from FTIH 
study 200630)). Cell 
depletion data in blood and 
colon will be presented. 
IA3, SAC 
7.2.  
ITTE 
 
PK and cell depletion data versus time 
To be generated by CPMS 
(as Figure 7.06 from FTIH 
study 200630)). Cell 
depletion data in blood and 
colon will be presented. 
IA3, SAC 
7.3.  
ITTE 
 
Individual fits of final PK/PD model 
To be generated by CPMS 
IA3, SAC 
7.4.  
ITTE 
 
Standard diagnostics of final PK/PD model 
To be generated by CPMS 
IA3, SAC 
7.5.  
ITTE 
 
NPDEs of final PK/PD model 
To be generated by CPMS 
IA3, SAC 
7.6.  
ITTE 
 
Cell depletion versus time overlaid with individual predictions from 
final PK/PD model 
To be generated by CPMS 
IA3, SAC 
Note: dependent on the results of the analysis, additional figures may be generated (by CPMS). 
 
 


 
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15.12.17. Patient Reported Outcome Tables 
Patient Reported Outcome: Tables 
No. 
Population 
IDSL / 
Example Shell Title  
Programming Notes 
Deliverable 
[Priority] 
Patient Reported Outcomes 
8.1
ITTE 
PRO_T01 
Observed Proportion of Subjects with Reported Symptom 
Control by Day in Induction Phase 
By study day. 
Endpoints:  
 • Symptomatic Remission  
 • Symptom Control for rectal bleeding 
 • Symptom Control for stool frequency 
Footnote: All eDiary entries are 
summarised over three observed days 
in the last seven following rules 
specified in the RAP. 
None 
8.2.  
ITTE_ETP 
PRO_T01 
Observed Proportion of Subjects with Reported Symptom 
Control by Day in Extended Treatment Phase 
By study day. 
Footnote: All eDiary entries are 
summarised over three observed days 
in the last seven following rules 
specified in the RAP. 
None 
8.3.  
ITTE_OLI 
PRO_T01 
Observed Proportion of Subjects with Reported Symptom 
Control by Day in Open Label Induction Phase 
By study day. 
Footnote: All eDiary entries are 
summarised over three observed days 
in the last seven following rules 
specified in the RAP. 
None 
8.4.  
ITTE_OL_ETP 
PRO_T01 
Observed Proportion of Subjects with Reported Symptom 
Control by Day in Open Label Extended Treatment Phase 
By study day. 
Footnote: All eDiary entries are 
summarised over three observed days 
in the last seven following rules 
specified in the RAP. 
None 


 
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Patient Reported Outcome: Tables 
No. 
Population 
IDSL / 
Example Shell Title  
Programming Notes 
Deliverable 
[Priority] 
8.5.  
ITTE 
PD1 
SF-36 Summary, Induction Phase 
By study part and visit 
For each component summary score 
and each domain score: PCS, MCS, 
GH, PF, RP, RE, SF, BP, VT, MH 
None 
8.6.  
ITTE_ETP 
PD1 
As above for ETP 
 
None 
8.7.  
ITTE_OLI 
PD1 
As above for OL_I 
 
None 
8.8.  
ITTE_OL_ETP 
PD1 
As above for OL_ETP 
 
None 
8.9.  
ITTE 
PRO_T02 
SF-36 Estimated Difference from Placebo, Induction Phase 
For each component summary score 
and each domain score: PCS, MCS, 
GH, PF, RP, RE, SF, BP, VT, MH 
None 
8.10. 
ITTE_ETP 
PRO_T02 
SF-36 Estimated Difference from Placebo, Extended 
Treatment Phase 
For each component summary score 
and each domain score: PCS, MCS, 
GH, PF, RP, RE, SF, BP, VT, MH 
None 
8.11. 
ITTE 
PD1 
IDBQ Summary by study part 
For each Domain score and Total 
score: Total and Bowel Symptoms, 
Systemic Symptoms, Functional 
Emotion and Social Emotion 
None 
8.12. 
ITTE_ETP 
PD1 
As above for ETP 
 
None 
8.13. 
ITTE_OLI 
PD1 
As above for OL_I 
 
None 
8.14. 
ITTE_OL_ETP 
PD1 
As above for OL_ETP 
 
None 
8.15. 
ITTE 
PRO_T02 
IDBQ Estimated Difference from Placebo, Induction Phase 
For each Domain score and Total 
score: Total and Bowel Symptoms, 
Systemic Symptoms, Functional 
Emotion and Social Emotion 
None 


 
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Patient Reported Outcome: Tables 
No. 
Population 
IDSL / 
Example Shell Title  
Programming Notes 
Deliverable 
[Priority] 
8.16. 
ITTE_ETP 
PRO_T02 
IDBQ Estimated Difference from Placebo, Extended Treatment 
Phase 
For each Domain score and Total 
score: Total and Bowel Symptoms, 
Systemic Symptoms, Functional 
Emotion and Social Emotion 
None 
8.17. 
ITTE 
PD1 
Facit-Fatigue Summary, Induction Phase 
 
None 
8.18. 
ITTE_ETP 
PD1 
As above for ETP 
 
None 
8.19. 
ITTE_OLI 
PD1 
As above for OL_I 
 
None 
8.20. 
ITTE_OL_ETP 
PD1 
As above for OL_ETP 
 
None 
8.21. 
ITTE 
PRO_T02 
Facit-Fatigue. Estimated Difference from Placebo, Induction 
Phase 
 
None 
8.22. 
ITTE_ETP 
PRO_T02 
Facit-Fatigue. Estimated Difference from Placebo, Extended 
Treatment Phase 
 
None 
8.23. 
ITTE 
PRO_T03 
Patient Global Assessments Summary, Induction Phase 
By endpoint: 
PGIS 
PGIC 
None 
8.24. 
ITTE_ETP 
PRO_T03 
As above for ETP 
 
None 
8.25. 
ITTE_OLI 
PRO_T03 
As above for OL_I 
 
None 
8.26. 
ITTE_OL_ETP 
PRO_T03 
As above for OL_ETP 
 
None 
 
 


 
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15.12.18. Patient Reported Outcome Figures 
Patient Reported Outcomes: Figures 
No. 
Population 
IDSL / 
Example Shell Title  
Programming Notes 
Deliverable 
[Priority] 
8.1
ITTE 
PRO_F01 
SF-36 Component Scores Difference from Placebo for Paired 
Weeks by Study Part 
By study part (Induction and ETP) 
Each SF-36 score is recorded in week 
pairs eg.6 and 10, 22 and 30 align 
them in facets to minimize number of 
plots and time order. These need to 
cover every visit. 
None 
8.2.  
ITTE 
PRO_F02 
SF-36 Domain Scores Estimated Difference from Placebo  
By Visit for Induction and ETP study 
parts.  
Keep facet headings as small as 
possible whilst still being readable  
None 
8.3.  
ITTE 
PRO_F03 
IDBQ Total and Domain Scores Estimated Difference from 
Placebo 
By Visit for Induction and ETP study 
parts. 
Keep facet headings as small as 
possible whilst still being readable 
None 
8.4.  
ITTE 
PRO_F04 
Facit-F Score Estimated Difference from Placebo 
By Visit for Induction and ETP study 
parts. 
Keep facet headings as small as 
possible whilst still being readable 
None 
8.5.  
ITTE 
PRO_F05 
PGIC Count Stacked Bar Chart  
By Visit for Induction and ETP study 
parts. 
Stacked bar chart, please check 
colours with statistician during 
development (before stage 1 QC). 
None 
8.6.  
      ITTE 
PRO_F05 
PGIS Count Stacked Bar Chart 
By Visit for Induction and ETP study 
parts. 
Stacked bar chart, colour scheme 
consistent with figure above. 
None 


 
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Patient Reported Outcomes: Figures 
No. 
Population 
IDSL / 
Example Shell Title  
Programming Notes 
Deliverable 
[Priority] 
8.7.  
ITTE 
PRO_F06 
Observed Proportion of Subjects with Reported Symptom 
Control by Day, Induction Phase 
Line plot with points and ASE,  
Page by Categorical endpoint: 
• Symptomatic Remission,  
• Symptom control for: 
o 
Rectal Bleeding 
o 
Stool Frequency 
 
Group by treatment group. 
Start from Day 1, include 28 days per 
page  
None 
8.8.  
ITTE_ETP 
PRO_F06 
Observed Proportion of Subjects with Reported Symptom 
Control by Day, Extended Treatment Phase 
Line plot with points,  
Page by Categorical endpoint: 
• Symptomatic Remission 
• Symptom control for: 
o 
Rectal Bleeding 
o 
Stool Frequency 
o 
Bowel Urgency 
o 
Tenesmus 
o 
Night Time Awakenings to go 
to the Toilet 
Group by treatment group. 
28 days per page 
None 


 
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Patient Reported Outcomes: Figures 
No. 
Population 
IDSL / 
Example Shell Title  
Programming Notes 
Deliverable 
[Priority] 
8.9.  
ITTE_OL_I 
PRO_F06 
Observed Proportion of Subjects with Reported Symptom 
Control by Day, Open Label Induction 
Line plot with points,  
Page by Categorical endpoint: 
• Symptomatic Remission,  
• Symptom control for: 
o 
Rectal Bleeding 
o 
Stool Frequency 
o 
Bowel Urgency 
o 
Tenesmus 
o 
Night Time Awakenings to go 
to the Toilet 
Group by treatment group. 
28 days per page 
None 
8.10. 
ITTE_OL_ETP 
PRO_F06 
Observed Proportion of Subjects with Reported Symptom 
Control by Day, Open Label Extended Treatment Phase 
Line plot with points,  
Page by Categorical endpoint: 
• Symptomatic Remission,  
• Symptom control for: 
o 
Rectal Bleeding 
o 
Stool Frequency 
o 
Bowel Urgency 
o 
Tenesmus 
o 
Night Time Awakenings to go 
to the Toilet 
Group by treatment group. 
28 days per page 
None 
 
 
 
 


 
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15.12.19. ICH Listings 
Reviewer’s note: Listings will be produced at interims but, following the DRC charter, will not be shared unless requested. 
 
ICH: Listings 
No
. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.  
Screened 
ES7 
Listing of Reasons for Screen Failure 
All listings: follow a single subject 
through study phases; order by 
induction treatment. 
SAC 
2.  
Enrolled 
ES2xo 
Listing of Reasons for Study Withdrawal 
All listings with “xo” shell: replace 
“Period” column with “Phase”; 
change column title from 
‘Randomised Treatment’ to 
‘Randomised/Planned Treatment’; 
as per shell report by country then 
site. 
SAC 
3.  
Enrolled 
SD2xo 
Listing of Reasons for Study Treatment Discontinuation 
 
IA3H, SAC 
4.  
Enrolled 
BL1xo 
Listing of Subjects for Whom the Treatment Blind was 
Broken 
 
SAC 
5.  
Enrolled 
TA1xo 
Listing of Planned and Actual Treatments 
Page by centreid 
SAC 
6.  
Screened 
ES9 
Listing of Subjects Who Were Rescreened 
 
SAC 
7.  
Enrolled 
POP_L5 
Listing of Study Phases 
 
SAC 
Protocol Deviations 
8.  
Enrolled 
DV2 
Listing of Important Protocol Deviations  
 
SAC 
9.  
Enrolled 
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations 
 
SAC 


 
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ICH: Listings 
No
. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Populations Analysed 
10.  
Screened 
SP3xo 
Listing of Subjects Excluded from Any Population 
 
None 
Demographic and Baseline Characteristics 
11.  
Enrolled 
DM2xo 
Listing of Demographic Characteristics 
 
SAC 
12.  
Enrolled 
DM9xo 
Listing of Race 
 
SAC 
Prior and Concomitant Medications 
13.  
Enrolled 
CM10xo 
Listing of Concomitant Medications 
 
SAC 
Exposure and Treatment Compliance 
14.  
Enrolled 
EX3xo 
Listing of Exposure Data 
 
SAC 
Adverse Events 
15.  
Safety 
AE8xo 
Blinded Listing of All Serious and Non-Serious Adverse 
Events 
Change row order so that ‘Serious’ 
is above ‘Maximum Intensity’ in 
stack. 
Add footnote:   
Note: Onset date of Adverse Event 
is used to associate AE to study 
phase. 
N30 
16.  
Safety 
AE8xo 
Listing of All Adverse Events 
Reviewer’s note: Listings will be 
produced at interims but, following 
the DRC charter, will not be shared 
unless requested.  
Add footnote:   
Note: Onset date of Adverse Event 
is used to associate AE to study 
phase. 
On request by 
DRC, SAC 


 
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ICH: Listings 
No
. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
17.  
Safety 
AE8xo 
Listing of Adverse Events with Increasing Severity that 
Cross Study Phases 
Study specific selection of AEs:  
Select AEs where AE onset date is 
in a different study phase to AE 
resolution date and maximum 
severity is greater than severity at 
onset. 
Footnotes: “Note: Severity at onset 
and maximum severity are 
recorded, the date of increase in 
severity is not recorded” 
“Note: Onset date of Adverse 
Event is used to associate AE to 
study phase.” 
SAC 
18.  
Safety 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
Add footnote:   
Note: Onset date of Adverse Event 
is used to associate AE to study 
phase. 
SAC 
19.  
Safety 
AE2 
Listing of Relationship Between Adverse Event System 
Organ Classes, Preferred Terms, and Verbatim Text 
 
SAC 


 
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ICH: Listings 
No
. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Serious and Other Significant Adverse Events 
20.  
Safety 
AE8xo 
Listing of Fatal Serious Adverse Events 
Add footnote:   
Note: Onset date of Adverse Event 
is used to associate AE to study 
phase. 
None 
21.  
Safety 
AE8xo 
Listing of Serious Adverse Events 
Add footnote:   
Note: Onset date of Adverse Event 
is used to associate AE to study 
phase. 
On request by 
DRC, SAC 
22.  
Safety 
AE14 
Listing of Reasons for Considering as a Serious Adverse 
Event 
Add footnote:   
Note: Onset date of Adverse Event 
is used to associate AE to study 
phase. 
SAC 
23.  
Safety 
AE8xo 
Listing of Adverse Events Leading to Withdrawal from Study 
/ Permanent Discontinuation of Study Treatment 
Add footnote:   
Note: Onset date of Adverse Event 
is used to associate AE to study 
phase. 
SAC 
All Laboratory 
24.  
Safety 
LB5xo 
Listing of All Laboratory Data for Subjects with Any Value of 
Potential Clinical Importance 
 
SAC 
25.  
Safety 
LB5xo 
Listing of Laboratory Values of Potential Clinical Importance 
 
SAC 
26.  
Safety 
LB14 
Listing of Laboratory Data with Character Results 
 
None 
27.  
Safety 
UR2xo 
Listing of Urinalysis Data for Subjects with Any Value of 
Potential Clinical Importance 
 
SAC 


 
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ICH: Listings 
No
. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
ECG 
28.  
Safety 
EG3xo 
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance 
 
SAC 
29.  
Safety 
EG3xo 
Listing of ECG Values of Potential Clinical Importance 
 
SAC 
30.  
Safety 
EG5xo 
Listing of All ECG Findings for Subjects with an Abnormal 
ECG Finding 
 
None 
31.  
Safety 
EG5xo 
Listing of Abnormal ECG Findings 
 
SAC 
Vital Signs 
32.  
Safety 
VS4xo 
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance 
 
None 
33.  
Safety 
VS4xo 
Listing of Vital Signs of Potential Clinical Importance 
 
SAC 
Hepatobiliary (Liver) 
34.  
Safety 
MH2 
Listing of Medical Conditions for Subjects with Liver 
Stopping Events 
No data to display unless a subject 
experiences a liver stopping event 
None 
35.  
Safety 
SU2 
Listing of Substance Use for Subjects with Liver Stopping 
Events 
No data to display unless a subject 
experiences a liver stopping event 
None 
36.  
Safety 
LB14 
Listing of Viral Results for Subjects with Liver Stopping 
Events 
No data to display unless a subject 
experiences a liver stopping event 
None 
37.  
Safety 
LIVER5 
Listing of Liver Biopsy Details 
No data to display unless a subject 
experiences a liver stopping event 
None 
38.  
Safety 
LIVER5 
Listing of Liver Imaging Details 
No data to display unless a subject 
experiences a liver stopping event 
None 
Note for RAP authors:  listing numbers continue in the follow section.  Any additional listings must follow highest listing number. 
 


 
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15.12.20. Non-ICH Listings 
Reviewer’s note: Listings will be produced at interims but, following the DRC charter, will not be shared unless requested. 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example Shell Title  
Programming Notes 
Deliverable 
[Priority] 
Immunogenicity 
39.  
Safety 
IMM2 
Listing of Immunogenicity Results 
Produce for all phases, order by 
induction treatment, subject ID, visit.  
Display treatment at each visit in 
separate column. 
SAC 
40.  
Safety 
Custom (from 
OSM) 
Listing of Anti-GSK2831781 Neutralising and Binding Antibody 
(ADA) Positive Subjects 
 
None 
Study conduct 
41.  
ITTE 
POP_L1 
Listing of Subject Responder Status In eCRF and on Clinical 
Database 
Reports the recorded responder status 
and the decision that was made by 
eCRF for subjects (week 10 and week 
22) 
None 
42.  
Safety 
POP_L2 
Listing of Subjects Who Remained in Study after Withdrawing 
from Study Medication 
Include last dosing visit (date) last 
actual visit (date). 
None 
43.  
ITTE 
EFF_L2 
Listing of Subjects who Started Corticosteroid Taper but did 
not Start Subsequent Study Phase  
By Study Phase (i.e. Induction, OL 
Induction) then subject 
None 
Substance Use 
44.  
Safety 
SU_L01 
Listing of Substance Use 
Based on SU1, include variables from 
smoking status at screening and those 
from ‘change in substance use’ at 
W10,30,FU42 
Addition to shell: Include ‘Pack years’ 
None 


 
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Non-ICH: Listings 
No. 
Population 
IDSL / 
Example Shell Title  
Programming Notes 
Deliverable 
[Priority] 
Medical History / Concomitant Medications 
45.  
ITTE 
POP_L3 
Listing of Ulcerative Colitis Disease Characteristics at Baseline 
 
IA3H, SAC 
46.  
ITTE 
POP_L4 
Listing of Ulcerative Colitis Therapeutic History  
 
IA3H, SAC 
Efficacy 
47.  
ITTE 
EFF_L1 
Listing of Mayo Score 
 
None 
48.  
ITTE 
EFF_L1 
Listing of UCEIS Total Score 
 
None 
49.  
ITTE 
EFF_L2 
Listing of Corticosteroid Use During Mandatory Taper in 
Extended Treatment Phase and Open Label Extended 
Treatment Phase 
 
None 
50.  
ITTE 
EFF_L3 
Listing of Categorical Efficacy 
 
None 
51.  
ITTE 
EFF_L3 
Listing of Categorical Histology 
 
None 
52.  
ITTE 
EFF_L4 
Listing of Extra Intestinal Manifestations (EIMs) 
 
None 
Pharmacokinetic 
53.  
PK 
PK07xo 
Listing of Plasma GSK2831781 Concentration-Time Data 
 
SAC 
54.  
PK 
PK13xo 
Listing of Derived Plasma GSK2831781 Pharmacokinetic 
Parameters 
 
SAC 
Biomarker 
55.  
ITTE 
PK07xo 
Listing of Plasma sLAG3 Concentration-Time Data 
 
None 
56.  
ITTE 
BIO_L1 
Listing of Flow Cytometry 
 
None 
57.  
ITTE 
BIO_L1 
Listing of Colon Biopsy Cell Counts 
 
IA3, SAC 
58.  
ITTE 
BIO_L1 
Listing of Disease Biomarkers 
 
None 
Patient Reported Outcome 
59.  
ITTE 
PRO_L1 
Listing of Reported Symptom Control 
 
None 


 
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Non-ICH: Listings 
No. 
Population 
IDSL / 
Example Shell Title  
Programming Notes 
Deliverable 
[Priority] 
60.  
ITTE 
PRO_L2 
Listing of SF-36 
 
None 
61.  
ITTE 
PRO_L2 
Listing of IDBQ 
 
None 
62.  
ITTE 
PRO_L2 
Listing of Facit-Fatigue 
 
None 
63.  
ITTE 
PRO_L3 
Listing of PGIS 
 
None 
Population PK 
64.  
PK 
 
PK and sLAG3 data excluded from population PK modelling 
To be generated by CPMS 
SAC 
65.  
PK 
 
Text output of final PK model (lst-file) 
To be generated by CPMS 
SAC 
PK / PD 
66.  
ITTE 
 
PD data excluded from population PK/PD modelling 
To be generated by CPMS 
SAC 
67.  
ITTE 
 
Text output of final PK/PD model (lst-file) 
To be generated by CPMS 
SAC 
Estimands and Intercurrent Events 
68.  
ITTE 
EFF_L5 
Listing of Intercurrent Events 
 
IA3H, SAC 
69.  
ITTE 
EFF_L6 
Listing of Estimand Imputations for Efficacy 
 
IA3H 
COVID-19 Pandemic 
70.  
Safety 
PAN12 
Listing of COVID-19 Assessments and Symptom Assessments 
 
SAC 


 
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15.13. 
Appendix 13: Example Mock Shells for Data Displays 
Note: Mock shells are in a separate document. 
 


 
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15.14. 
Appendix 14: Selection criteria for the Informative Placebo 
Priors 
Placebo data from studies using the following selection criteria will be used 
Criteria 
Rationale 
Age: Publication after 2012.   
 
This marks the start of the post-TNF era when 
anti-TNF medications for Ulcerative Colitis 
were widely available and late-phase studies 
with molecules with other targets were 
recruiting.  The clinical team believe that the 
environment prior to this was quite dissimilar to 
the current study. 
Trial type and disease inclusion 
criteria: All randomised double-
blind trials will be included with 
inclusion criteria that includes 
Mayo score 6-12 at baseline or 
equivalent 
This ‘moderate to severe’ population is similar 
to key phase 2 and 3 pharmaceutical industry 
sponsored trials and matches the inclusion 
criteria of this study (204869).   
Number of sites: Single site 
studies are excluded 
 
The current study, and most competitor studies 
of interest, are multi-site studies. 
Size:  Studies with fewer than 40 
participants on the placebo arm are 
excluded 
To ensure that trials with very uncertain 
estimates are excluded. 
Assessments:  Exclude trials with 
locally read endoscopies 
Include induction studies where 
endpoint in range 6 – 12 weeks, 
where multiple timepoints existing 
for the same endpoint, chose 
primary where available and latest 
if not. 
Centrally read endoscopies are used in this trial 
(204869) and most recent and future trials. 
Induction timepoint range is consistent with this 
study and most competitors 
Endpoint:  
Clinical Remission 
Use Clinical Remission definitions 
that include RB=0, where 
documented. 
Clinical remission  
This endpoint has changed between trials with a 
recent shift to using a modified/adapted Mayo 
score which excludes the Physician Global 
Assessment and some studies report multiple 
versions of the score.  Where multiple versions 
of the scores are available for a study, the 


 
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Criteria 
Rationale 
Do include Complete Mayo clinical 
remission. 
Endoscopic Improvement 
Use endoscopic score of 0 or 1.  
Where available, use ‘adapted 
Mayo’ endoscopic score (where any 
 is a score of ) 
 
 
modified/adapted Mayo definition will be used 
as will a definition that includes RB=0 which is 
consistent with the criterion used in 204869. 
Endoscopic Improvement  
This definition has changed over the period in 
scope, with historical trials using a slightly 
different definition of endoscopic score, this data 
will still be used, where multiple scores are 
available for a study the modified/adapted Mayo 
definition will be used. 
Note that the data used for the placebo priors will be extracted from the Certara clinical outcomes 
database for Ulcerative Colitis which includes data from abstracts and scientific posters as well as 
published scientific articles. 
Note that only studies where the placebo response rate can be calculated from the number of placebo 
responders and the total number of participants in the placebo arm will be used.  No strata are used, to 
resolve duplicates where appropriate the results from the primary statistical analysis is used.  
 
15.14.1. 
Examples of robustified prior for endoscopic mucosal healing 
(key secondary endpoint) 
Examples of priors derived as best-fitting mixture of Beta distributions are provided below 
for four different levels of Advanced Therapy stratification (% Naïve) in endoscopic 
mucosal healing. Each prior is the weighted sum of the three components, including the 
non-informative prior (component 1) used for robustification.   
 
Component 1: 
weight, 
distribution 
Component 2: 
weight, 
distribution 
Component 3: 
weight, 
distribution 
Prior 1: 20% naive 
40%, Beta(1/2,1/2) 
46%, Beta(3,20) 
14%, Beta(1,4) 
Prior 2: 40% naive 
40%, Beta(1/2,1/2) 
46%, Beta(3,17) 
14%, Beta(1,4) 
Prior 3: 60% naive 
40%, Beta(1/2,1/2) 
44%, Beta(4,16) 
16%, Beta(1,4) 
Prior 4: 80% naive 
40%, Beta(1/2,1/2) 
41%, Beta(4,13) 
19%, Beta(1,3) 
40% robustification applied to each prior 
CCI
CCI


Signature Page for  204869 TMF-13801863 v1.0
Signature Page for TMF-13801863 v1.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 02-Jun-2021 09:18:46 GMT+0000
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 02-Jun-2021 10:40:10 GMT+0000
PPD
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