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
Phase: PHASE2
Conditions: Colitis, Ulcerative
Sponsor: GlaxoSmithKline

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GlaxoSmithKline group of companies 
 
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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 

TMF-2197350 
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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 
Refer to GSK2831781 IB for details  
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 
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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 
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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 
included in the secondary and exploratory analyses. 

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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 
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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 
clinically appropriate. 

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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 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as defined 

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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 # 
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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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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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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 
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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.