Clinical trial NCT05131971
Conditions: Multiple Sclerosis Colitis, Ulcerative
Keywords: Anti-Drug Antibodies Double-blind GSK3888130B Pharmacodynamics Pharmacokinetics Single Dose Escalation
Sponsor: GlaxoSmithKline
Start date: 2021-11-01; Completion date: 2023-10-12
Enrollment: 54 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a first time in human study designed to assess the safety, tolerability, pharmacokinetics and PD of GSK3888130B over a range of dose levels in healthy participants.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None arm 8: None arm 9: None arm 10: None arm 11: None arm 12: None arm 13: None arm 14: None
Interventions: intervention 1: GSK3888130B intervention 2: Placebo
Intervention descriptions: intervention 1: GSK3888130B will be administered. intervention 2: Placebo will be administered.

Protocol documents:
Prot_000.pdf: 
TMF- 15719887 
CONFIDENTIAL 
GSK group of companies 
 
213960 
 
 
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TITLE PAGE 
Protocol Title: A Randomized, Double-Blind, Placebo Controlled, Single Dose 
Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of GSK3888130B in Healthy Participants aged 18-55 inclusive. 
Protocol Number: 213960 / Amendment 06 
Compound Number 
or Name: 
GSK3888130B 
 
Brief Title: A FTIH study to Evaluate Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of GSK3888130B in Healthy Participants aged 18-55 inclusive. 
Study Phase: Phase 1 
Sponsor Name and Legal Registered Address:  
GSK Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Regulatory Agency Identifying Number(s):  
EudraCT: 2021-002063-22 
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual. 
Sponsor Signatory: 
Dr Nicolas Wisniacki MD PhD 
Head of Discovery Medicine 
Clinical Pharmacology and Experimental Medicine 
Approval Date: 21 Mar 2023 
 
 
© 2023 GSK group of companies or its licensor. All rights reserved. Unauthorized 
copying or use of this information is prohibited. 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date of Issue 
Document Identifier 
Amendment 6 
21 Mar 2023 
TMF-15719887 
Amendment 5 
25 January 2023 
TMF-15650507 
Amendment 4 
03 Nov 2022 
TMF-15099564 
Amendment 3 
05 August 2022 
TMF-14605174 
Amendment 2 
10 February 2022 
TMF-14432742 
Amendment 1 
27 September 2021 
TMF-14006150 
Original Protocol (00) 
19 August 2021 
TMF-12912890 
 
Amendment 06; 21 Mar 2023 
Identified in the Table below are substantial changes made to the Study Protocol since the 
previous submitted version.  
Section # and title 
Description of change 
Brief rationale 
Section 1.1 Synopsis  
An additional Follow-up phone 
call added 
 days after the 
last study visit.  
In line with MHRA condition for 
approval of Protocol Amendment 
5.  
Section 1.1 Synopsis 
Duration of study extended from 
 weeks to 
 weeks.  
In line with MHRA condition for 
approval of Protocol Amendment 
5. 
Section 1.3.1 
Screening, 
Admission and 
Follow-Up  
Extra column added for Follow 
up phone call 
 days post last 
study visit which includes 
Concomitant Medication Review, 
AE Review and SAE Review.  
In line with MHRA condition for 
approval of Protocol Amendment 
5. 
Section 4.1 Overall 
Design  
An additional Follow-up phone 
call added 
 days after the 
last study visit.  
In line with MHRA condition for 
approval of Protocol Amendment 
5. 
Section 4.1 Overall 
Design  
Duration of study extended from 
weeks to
 weeks. 
In line with MHRA condition for 
approval of Protocol Amendment 
5. 
Section 6.8 
Concomitant 
Therapy  
The following text was amended 
to include the word ‘final’ in 
bold:  
 
‘Participants must abstain from 
taking prescription or non-
prescription drugs (including 
NSAIDs, vitamins, recreational 
drugs, and dietary or herbal 
supplements) within 7 days (or 14 
days if the drug is a potential 
enzyme inducer) or 5 half-lives 
(whichever is longer) before the 
In line with MHRA condition for 
approval of Protocol Amendment 
5. 
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Section # and title 
Description of change 
Brief rationale 
start of study intervention until 
completion of the final follow-up 
visit, unless, in the opinion of the 
Investigator and Sponsor, the 
medication will not interfere with 
the study.’  
Section 8.3.1 Time 
Period and 
Frequency for 
Collecting AE and 
SAE Information 
The following text was amended 
to include the word ‘final’ (below 
in bold). 
 
• 
All SAEs will be collected 
from the signing the inform 
consent form until the final 
follow-up visit at the time 
points specified in the SoA 
(Section 1.3).  
• 
All SARs to study 
procedure/GSK products will 
be reported from the signing 
of the informed consent form 
(ICF) until the final follow-
up visit at time points 
specified in the SoA (Section 
1.3).  
• 
All AEs will be collected 
from the start of intervention 
until the final follow-up visit 
at the time points specified in 
the SoA (Section 1.3). 
  
In line with MHRA condition for 
approval for Protocol Amendment 
5. 
 


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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ................................................................................................................... 1 
1. 
PROTOCOL SUMMARY .......................................................................................... 7 
1.1. 
Synopsis ....................................................................................................... 7 
1.2. 
Schema ...................................................................................................... 11 
1.3. 
Schedule of Activities (SoA) ........................................................................ 12 
1.3.1. 
Screening, Admission and Follow-Up .......................................... 12 
1.3.2. 
Intravenous Dosed Cohorts ......................................................... 19 
1.3.3. 
SC Dosed Cohorts ....................................................................... 22 
2. 
INTRODUCTION .................................................................................................... 26 
2.1. 
Study Rationale .......................................................................................... 26 
2.2. 
Background ................................................................................................ 26 
2.3. 
Benefit/Risk Assessment ............................................................................ 28 
2.3.1. 
Risk Assessment ......................................................................... 30 
2.3.2. 
Benefit Assessment ..................................................................... 39 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 39 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 39 
4. 
STUDY DESIGN .................................................................................................... 42 
4.1. 
Overall Design ............................................................................................ 42 
4.2. 
Scientific Rationale for Study Design .......................................................... 44 
4.2.1. 
Participant Input into Design ........................................................ 47 
4.3. 
Justification for Dose .................................................................................. 47 
4.3.1. 
Human dose prediction for GSK3888130B .................................. 47 
4.3.2. 
Dose escalation plan for GSK3888130B ...................................... 48 
4.3.3. 
Predicted plasma exposure, safety margins, target 
engagement (IL-7 reduction) and pathway pharmacology 
(Bcl-2 reduction) .......................................................................... 48 
4.4. 
End of Study Definition ............................................................................... 51 
5. 
STUDY POPULATION ........................................................................................... 51 
5.1. 
Inclusion Criteria ......................................................................................... 51 
5.2. 
Exclusion Criteria ........................................................................................ 53 
5.3. 
Lifestyle Considerations .............................................................................. 56 
5.3.1. 
Alcohol, and Tobacco .................................................................. 56 
5.3.2. 
Activity ......................................................................................... 56 
5.3.3. 
SARS-CoV-2 related restrictions .................................................. 56 
5.3.4. 
Other consideration ..................................................................... 57 
5.4. 
Screen Failures........................................................................................... 57 
5.5. 
Criteria for Temporarily Delaying 
Enrolment/Randomization/Administration of Study Intervention 
Administration ............................................................................................. 57 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 58 
6.1. 
Study Intervention(s) Administered. ............................................................ 58 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 60 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 61 
6.3.1. 
Unblinding .................................................................................... 61 
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6.4. 
Study Intervention Compliance ................................................................... 62 
6.5. 
Dose Modification ....................................................................................... 62 
6.6. 
Continued Access to Study Intervention after the End of the Study ............ 63 
6.7. 
Treatment of Overdose ............................................................................... 63 
6.8. 
Concomitant Therapy.................................................................................. 63 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 65 
7.1. 
Discontinuation of Study Intervention .......................................................... 65 
7.2. 
Study Stopping Criteria ............................................................................... 65 
7.2.1. 
Liver Chemistry Criteria ............................................................... 65 
7.2.2. 
QTc Criteria ................................................................................. 65 
7.2.3. 
SARS-CoV-2 Related Stopping Criteria ....................................... 66 
7.2.4. 
Pharmacokinetic Dose Adjustment / Stopping Criteria ................. 66 
7.2.5. 
Safety Dose Adjustment / Stopping Criteria ................................. 67 
7.3. 
Participant Discontinuation/Withdrawal from the Study ............................... 68 
7.4. 
Lost to Follow Up ........................................................................................ 68 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 69 
8.1. 
Efficacy Assessments ................................................................................. 69 
8.2. 
Safety Assessments ................................................................................... 69 
8.2.1. 
Physical Examinations ................................................................. 69 
8.2.2. 
Vital Signs .................................................................................... 69 
8.2.3. 
Electrocardiograms ...................................................................... 70 
8.2.4. 
Holter Monitoring ......................................................................... 70 
8.2.5. 
Clinical Safety Laboratory Assessments ...................................... 70 
8.2.6. 
Injection site Reactions ................................................................ 71 
8.2.7. 
Hypersensitivity Reactions ........................................................... 71 
8.2.8. 
Immunosuppression and Infections.............................................. 71 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting ......................................................................................... 71 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 72 
8.3.2. 
Method of Detecting AEs and SAEs ............................................. 72 
8.3.3. 
Follow-up of AEs and SAEs ......................................................... 72 
8.3.4. 
Regulatory Reporting Requirements for SAEs ............................. 73 
8.3.5. 
Pregnancy ................................................................................... 73 
8.4. 
Pharmacokinetics ....................................................................................... 74 
8.5. 
Genetics and Pharmacogenomics (PGx) .................................................... 74 
8.6. 
8.7. 
Biomarkers ................................................................................................. 76 
8.7.1. 
Target Engagement Biomarkers .................................................. 76 
8.7.2. 
Blood Biomarkers ........................................................................ 76 
 
 
8.7.4. 
Cellular Biomarkers ..................................................................... 77 
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8.8. 
Immunogenicity Assessments ..................................................................... 77 
8.9. 
Health Economics ....................................................................................... 78 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 78 
9.1. 
Statistical Hypotheses................................................................................. 78 
9.2. 
Sample Size Determination ........................................................................ 78 
9.3. 
Analysis Sets .............................................................................................. 80 
9.4. 
Statistical Analyses ..................................................................................... 80 
9.4.1. 
General Considerations ............................................................... 80 
9.4.2. 
Baseline Definition ....................................................................... 80 
9.4.3. 
Primary Endpoint(s) ..................................................................... 81 
9.4.4. 
Secondary Endpoint(s) ................................................................ 81 
 
 
9.5. 
Interim Analyses ......................................................................................... 82 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 83 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 83 
10.1.1. 
Regulatory and Ethical Considerations ........................................ 83 
10.1.2. 
Financial Disclosure ..................................................................... 83 
10.1.3. 
Informed Consent Process .......................................................... 84 
10.1.4. 
Data Protection ............................................................................ 84 
10.1.5. 
Committees Structure .................................................................. 85 
10.1.6. 
Dissemination of Clinical Study Data ........................................... 86 
10.1.7. 
Data Quality Assurance ............................................................... 86 
10.1.8. 
Source Documents ...................................................................... 87 
10.1.9. 
Study and Site Start and Closure ................................................. 87 
10.1.10. Publication Policy ......................................................................... 88 
10.2. Appendix 2: Clinical Laboratory Tests ......................................................... 89 
10.3. Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 91 
10.3.1. 
Definition of AE ............................................................................ 91 
10.3.2. 
Definition of SAE .......................................................................... 92 
10.3.3. 
Recording and Follow-Up of AE and SAE .................................... 93 
10.3.4. 
Reporting of SAE to GSK ............................................................. 95 
10.4. Appendix 4: Contraceptive and Barrier Guidance ....................................... 96 
10.4.1. 
Definitions .................................................................................... 96 
10.5. Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments .............................................................................................. 98 
10.6. Appendix 6: SARS-CoV-2 Risk Mitigation Participant Counselling ............ 101 
10.8. Appendix 8: Abbreviations and Trademarks .............................................. 104 
10.9. Appendix 9: Protocol Amendment History ................................................. 108 
11. REFERENCES ..................................................................................................... 122 
 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Randomized, Double-Blind, Placebo Controlled, Single Dose 
Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of GSK3888130B in Healthy Participants aged 18-55 inclusive. 
Brief Title: A FTIH study to Evaluate Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of GSK3888130B in Healthy Participants aged 18-55 inclusive. 
Rationale: 
This is a first time in human (FTIH) study designed to evaluate the safety, tolerability, 
pharmacokinetic (PK) and pharmacodynamic (PD) profile of single ascending doses 
(SAD) of GSK3888130B. 
 
 
 
 
 
 
 
  
This study aims to provide sufficient confidence in the safety and tolerability of the 
molecule and will provide preliminary information relating to the PK and PD profile of 
GSK3888130B following intravenous (IV) or subcutaneous (SC) injection routes of 
delivery, to support future clinical development. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
• To investigate the safety and 
tolerability of single IV and SC 
doses of GSK3888130B in 
healthy participants. 
• Occurrence of Adverse Events (AEs) and 
Serious Adverse Events (SAEs). 
• Occurrence of clinically significant changes 
in laboratory values (CD4+ T cell counts, 
hematology, chemistry, urinalysis and 
virology), vital signs and 12lead 
electrocardiogram (ECG) readings. 
Secondary 
 
• To characterise the serum PK 
profile of single IV or single SC 
• Serum concentrations of GSK3888130B 
and derived PK parameters as data permit, 
including: area under the concentration-time 
curve [AUC], maximum concentration 
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Objectives 
Endpoints 
doses of GSK3888130B in 
healthy participants. 
[Cmax], time to Cmax [Tmax], half-life 
[t½], clearance [CL]. 
• To evaluate the immunogenicity 
of single doses of GSK3888130B 
in healthy participants. 
• Incidence of Anti-Drug Antibodies (ADAs) 
against GSK3888130B.  
• To characterise the effects of 
GSK3888130B on target 
engagement (TE). 
• Change from baseline 
 
 
) over time. 
• To characterise the effect of 
single doses of GSK3888130B on 
PD biomarker Bcl-2. 
• Change from baseline in T cell Bcl-2, 
measured in blood over time. 
 
Overall Design: 
This is a single centre, randomised, double-blind, placebo controlled, dose escalation 
study comprising of seven planned SAD cohorts, designed to assess safety, tolerability, 
PK and PD of GSK3888130B over a range of dose levels (from mg to 
 mg) in 
healthy participants.  
Brief Summary: 
The purpose of this study is to evaluate safety, tolerability, PK and PD of GSK3888130B 
in healthy participants.  
Participants will attend a screening visit within 28 days of study intervention. In subjects 
who require an influenza vaccination and/or SARS-CoV-2 vaccination or booster, the 
screening window may be increased to 60 days. This extended screening window applies 
only to those participants, and if their initial screening assessments are conducted more 
than 28 days prior to Day 1, screening assessments will be repeated within 28 days of 
Day 1 to confirm eligibility. Holter monitoring, viral serology (HIV, hepatitis B and 
hepatitis C), Mycobacterium tuberculosis (TB) screening, 
 
 (
) 
does not need to be repeated for extended screening windows or rescreens if within 3 
months of initial screening. 
Participants will be admitted to the clinical unit on Day -1 before administration of study 
intervention on Day 1. For cohorts where treatment administration is by IV injection, 
participants will remain in the unit until completion of all assessments on Day
 For 
cohorts where treatment administration is by SC injection, participants will remain in the 
unit until completion of all assessments on Day
 This period may be amended at the 
discretion of the principal investigator (or designee) and the GSK Dose Escalation 
Committee (DEC) as PK and safety data evolves. 
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All participants will then be required to attend the clinic for up to 9 outpatient visits over 
the course of 
days after dosing for safety assessment and sample collection and will 
receive two follow-up telephone calls; the first will be 
 days post last study visit and 
the second 
 days after their last study visit. If required, additional follow-up visits 
may be scheduled. 
 
 
. 
 
 
 
 
 
Number of Participants: 
A sufficient number of participants will be screened to ensure a minimum number of 
participants are eligible to be randomised to receive either GSK3888130B or placebo in a 
3:2 ratio in cohorts 1 and 2 or 3:1 ratio in all other SAD cohorts. 
The study will aim to recruit 54 participants into seven SAD cohorts; five participants in 
cohorts 1 and 2 and eight participants in all other cohorts, 
 
. Additional participants/cohorts 
may be enrolled to allow for replacement of withdrawals and/or evaluation of additional 
dose levels or expansion of a cohort at a particular dose level. 
If participants prematurely discontinue the study, additional participants may be recruited 
as replacement and assigned to the same treatment arm and dose level at the discretion of 
the Sponsor in consultation with the Investigator. 
The total number of participants randomised into the study will be capped at 90 
participants (across all SAD cohorts). 
Note: "Enrolled" means a participant's agreement to participate in a clinical study 
following completion of the informed consent process and screening. Potential 
participants who are screened for the purpose of determining eligibility for the study, but 
do not participate in the study, are not considered enrolled, unless otherwise specified by 
the protocol.  
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Intervention Groups and Duration: 
As this is the first administration of GSK3888130B in humans, sentinel dosing will be 
utilised for each increasing dose level (if the selected dose level is below or equivalent to 
the previous dose level, sentinel dosing may still be applied). 
Sentinel dosing will be implemented in each cohort, so that one participant is dosed with 
GSK3888130B and one participant is dosed with placebo followed by review of post-
dose safety data before additional participants in each cohort are dosed. 
The duration of post-dose safety data required for IV and SC cohorts is described below.  
For cohorts where treatment administration is by IV injection, the remaining participants 
in these cohort will only be dosed after review of at least 
hours safety & tolerability 
data (i.e. AE/SAEs, laboratory values, vital signs and 12-lead ECGs) from the sentinel 
participants by the Principal Investigator (PI) or appropriately qualified delegate, in 
consultation with the Medical Monitor or delegate if unavailable, and it has been deemed 
safe to do so. 
For cohorts where treatment administration is by SC injection, the remaining participants 
in these cohorts will only be dosed after review of at least days safety & tolerability 
data (i.e. AE/SAEs, laboratory values, vital signs and 12-lead ECGs) from the sentinel 
participants by the Principal Investigator (PI) or appropriately qualified delegate, in 
consultation with the Medical Monitor or delegate if unavailable, and it has been deemed 
safe to do so. 
Doses between cohorts are planned to escalate in a sequential fashion contingent on the 
safety, tolerability (including absolute CD4+ T cell counts) and pharmacokinetic profile, 
up to and including Day
 from a minimum of 2 participants dosed with GSK3888130B 
in cohorts 1 and 2 or a minimum of 4 participants dosed with GSK3888130B in all other 
SAD cohorts. The decision to proceed to the next dose level of GSK3888130B will be 
made by the GSK Dose Escalation Committee (DEC). 
The total duration of the study for each participant will be approximately 
 weeks. 
While every effort will be made to identify participants 
 
to assess the impact of GSK3888130B on the 
 
 
 
 
 
 
 
 
 
 
Data Monitoring/ Other Committee: A GSK Dose Escalation Committee (DEC) will 
be used for this study. 
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1.2. 
Schema 
 
 
 
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1.3. 
Schedule of Activities (SoA) 
1.3.1. 
Screening, Admission and Follow-Up 
Procedure 
Screening  
(up to 28 days before 
Day 1)1 
Day -1 
E.D 
 
 
 
 
Follow-up 
(
 days post 
last study visit) 
Follow-up 
(
 days post 
last study visit) 
Notes 
E.D = early 
discontinuation/withdrawal 
1. In participants who require 
an influenza vaccination 
and/or SARS-CoV-2 booster, 
the screening window may be 
increased to 60 days. This 
extended screening window 
applies only to those 
participants, and if their initial 
screening assessments are 
conducted more than 28 days 
prior to Day 1, screening 
assessments will be repeated 
within 28 days of Day 1. 
Informed 
consent 
X 
 
 
 
 
 
Inclusion and 
exclusion 
criteria 
X 
X 
 
 
 
 
Demography 
X 
 
 
 
 
 
Full physical 
examination 
including height 
and weight 
X 
 
 
 
 
 
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Procedure 
Screening  
(up to 28 days before 
Day 1)1 
Day -1 
E.D 
 
 
 
 
Follow-up 
(
 days post 
last study visit) 
Follow-up 
(
 days post 
last study visit) 
Notes 
E.D = early 
discontinuation/withdrawal 
1. In participants who require 
an influenza vaccination 
and/or SARS-CoV-2 booster, 
the screening window may be 
increased to 60 days. This 
extended screening window 
applies only to those 
participants, and if their initial 
screening assessments are 
conducted more than 28 days 
prior to Day 1, screening 
assessments will be repeated 
within 28 days of Day 1. 
Medical history 
(includes 
substance 
usage, 
vaccination 
history and 
Family history 
of premature 
CV disease) 
X 
 
 
 
 
 
Current medical 
conditions 
X 
 
 
 
 
 
Influenza 
vaccination  
X 
 
 
 
 
If dosing is during influenza 
season (1st October to 30th 
April) participants who have 
not had a seasonal influenza 
vaccine will be given an 
MHRA-approved influenza 
vaccine at least 30 days before 
dosing 
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Procedure 
Screening  
(up to 28 days before 
Day 1)1 
Day -1 
E.D 
 
 
 
 
Follow-up 
(
 days post 
last study visit) 
Follow-up 
(
days post 
last study visit) 
Notes 
E.D = early 
discontinuation/withdrawal 
1. In participants who require 
an influenza vaccination 
and/or SARS-CoV-2 booster, 
the screening window may be 
increased to 60 days. This 
extended screening window 
applies only to those 
participants, and if their initial 
screening assessments are 
conducted more than 28 days 
prior to Day 1, screening 
assessments will be repeated 
within 28 days of Day 1. 
Viral serology 
(HIV, hepatitis 
B and C) 
X 
 
 
 
 
Hepatitis B screening to 
include surface antigen and 
core antibody test. Viral 
serology does not need to be 
repeated for rescreens if 
within 3 months of initial 
screening. 
TB screening 
(QuantiFERON 
Gold) 
X 
 
 
 
 
TB screening does not need to 
be repeated for rescreens if 
within 3 months of initial 
screening. 
12-lead ECG 
X 
 
X 
 
 
Performed in triplicate. 
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Procedure 
Screening  
(up to 28 days before 
Day 1)1 
Day -1 
E.D 
 
 
 
 
Follow-up 
(
days post 
last study visit) 
Follow-up 
(
days post 
last study visit) 
Notes 
E.D = early 
discontinuation/withdrawal 
1. In participants who require 
an influenza vaccination 
and/or SARS-CoV-2 booster, 
the screening window may be 
increased to 60 days. This 
extended screening window 
applies only to those 
participants, and if their initial 
screening assessments are 
conducted more than 28 days 
prior to Day 1, screening 
assessments will be repeated 
within 28 days of Day 1. 
Concomitant 
medication 
review 
X 
X 
X 
X 
X 
 
Admission 
 
X 
 
 
 
 
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Procedure 
Screening  
(up to 28 days before 
Day 1)1 
Day -1 
E.D 
 
 
 
 
Follow-up 
(
days post 
last study visit) 
Follow-up 
(
days post 
last study visit) 
Notes 
E.D = early 
discontinuation/withdrawal 
1. In participants who require 
an influenza vaccination 
and/or SARS-CoV-2 booster, 
the screening window may be 
increased to 60 days. This 
extended screening window 
applies only to those 
participants, and if their initial 
screening assessments are 
conducted more than 28 days 
prior to Day 1, screening 
assessments will be repeated 
within 28 days of Day 1. 
Laboratory 
assessments 
(include clinical 
chemistry and 
haematology 
panels)  
X 
X 
X 
 
 
 
CD4+ T cell 
counts 
X 
X 
 
 
 
 
Urinalysis 
(Dipstick 
±microscopy) 
X 
X 
 
 
 
If dipstick is positive or 
participant has urinary 
symptoms send for 
microscopy. 
 
. 
Vital signs 
X 
X 
X 
 
 
 
Brief Physical 
exam 
 
X 
X 
 
 
 
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Procedure 
Screening  
(up to 28 days before 
Day 1)1 
Day -1 
E.D 
 
 
 
 
Follow-up 
(
 days post 
last study visit) 
Follow-up 
(
 days post 
last study visit) 
Notes 
E.D = early 
discontinuation/withdrawal 
1. In participants who require 
an influenza vaccination 
and/or SARS-CoV-2 booster, 
the screening window may be 
increased to 60 days. This 
extended screening window 
applies only to those 
participants, and if their initial 
screening assessments are 
conducted more than 28 days 
prior to Day 1, screening 
assessments will be repeated 
within 28 days of Day 1. 
Breath alcohol 
test, smoking 
breath test and 
urine drug 
screen 
X 
X 
 
 
 
 
SARS-CoV-2 
Test 
<=================================================> 
 
 
As per local guidelines. 
Confirmation of 
postmenopausal 
status in 
females if 
required. 
X 
 
 
 
 
FSH and oestradiol test. 
AE Review 
 
 
X 
X 
X 
 
Blood 
collection for 
Immunogenicity 
testing 
 
 
X 
 
 
 
SAE Review 
X 
X 
X 
X 
X 
Collected from signing the 
informed consent form. 
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Procedure 
Screening  
(up to 28 days before 
Day 1)1 
Day -1 
E.D 
 
 
 
 
Follow-up 
(
days post 
last study visit) 
Follow-up 
(
 days post 
last study visit) 
Notes 
E.D = early 
discontinuation/withdrawal 
1. In participants who require 
an influenza vaccination 
and/or SARS-CoV-2 booster, 
the screening window may be 
increased to 60 days. This 
extended screening window 
applies only to those 
participants, and if their initial 
screening assessments are 
conducted more than 28 days 
prior to Day 1, screening 
assessments will be repeated 
within 28 days of Day 1. 
 
 
 
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1.3.2. 
Intravenous Dosed Cohorts  
Procedure 
 
Intervention Period (Days) for IV cohorts 
Notes 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (Dipstick 
±microscopy) 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
If dipstick is positive or 
participant has urinary symptoms 
send for microscopy. 
 
. 
Study Intervention 
Administration (IV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 Test 
 
<=========================================================> 
As per local guidelines. 
Brief Physical Exam 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Laboratory assessments 
(include clinical chemistry, 
and haematology panels)  
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CD4+ T cell counts 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Viral quantification and 
serology (EBV, CMV and 
VZV) 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
Day 1 collection prior to 
administration of study 
intervention.  
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Single readings to be recorded 
pre-dose and at PK timepoints. 
Performed in triplicate if 
suspected clinically significant 
findings. 
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Intervention Period (Days) for IV cohorts 
Notes 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Day 1 vitals to be taken pre-dose 
and end of IV infusion and at 
 
 from start of IV 
dosing on Day 1. 
Blood collection for 
Pharmacokinetics 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Day 1 PK samples to be collected 
prior to, midpoint and end of IV 
infusion, and at 
 
post-start of IV dosing. 
Blood collection for Target 
Engagement (TE) 
biomarkers 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Day 1 TE samples to be collected 
prior to and at 
 post-
start of IV dosing. 
Blood collection for 
Immunogenicity 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
Day 1 collection prior to 
administration of study 
intervention 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
Day 1 collection prior to 
administration of study 
intervention 
Blood collection for cellular 
biomarkers 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
Day 1 collection prior to 
administration of study 
intervention 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
Day 1 collection prior to 
administration of study 
intervention 
AE Review 
=============================================================  
 
SAE Review 
=============================================================  
 
Concomitant medication 
review 
=============================================================  
 
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Procedure 
 
Intervention Period (Days) for IV cohorts 
Notes 
 
 
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1.3.3. 
SC Dosed Cohorts  
Procedure 
Intervention Period [Days] for SC cohorts 
Notes 
 
Randomisation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (Dipstick 
±microscopy) 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
If dipstick is positive or 
participant has urinary symptoms 
send for microscopy  
 
 
Study Intervention 
Administration (SC) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
SARS-CoV-2 Test 
<=======================================================================
===========> 
As per local guidelines 
Brief Physical Exam 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Laboratory 
assessments (include 
clinical chemistry, 
and haematology 
panels)  
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
CD4+ T cell counts 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Viral quantification 
and serology (EBV, 
CMV and VZV) 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Day 1 collection prior to 
administration of study 
intervention.  
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Notes 
 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Triplicate readings to be recorded 
pre-dose and at PK timepoints 
whilst admitted 
  
Single readings to be recorded at 
PK timepoints for outpatient 
visits. These will be performed in 
triplicate if suspected clinically 
significant findings. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Day 1 vitals to be taken pre-dose 
and at 
 post 
administration of study 
intervention. 
Blood collection for 
Pharmacokinetics 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Day 1 PK samples to be collected 
prior to and at 
 post 
administration of study 
intervention 
Blood collection for 
Target Engagement 
(TE) Biomarkers 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Day 1 TE samples collected prior 
to and at 
 post-
administration of study 
intervention. 
Blood collection for 
Immunogenicity 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
Day 1 collection prior to 
administration of study 
intervention 
Blood collection for 
Cellular Biomarkers 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Day 1 collection prior to 
administration of study 
intervention 
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Intervention Period [Days] for SC cohorts 
Notes 
 
AE review 
======================================================================
=============  
 
SAE Review 
======================================================================
=============  
 
Concomitant 
medication review 
======================================================================
=============  
 
 
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Intervention Period [Days] for SC cohorts 
Notes 
 
 
• 
The timing of planned study assessments may change during the course of the study based on emerging data/in-stream data review (e.g., to 
obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring.  
• 
Additional visits may be scheduled as required, based on participants CD4+ T cell counts and other safety data.  
• 
Any changes in the timing 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.  
• 
Participants with CD4+ counts <0.2x109/L at day 
will be offered further monitoring if, in the opinion of the Investigator (in discussion with 
the Medical Monitor as necessary), the low CD4+ counts can be reasonable attributable to study participation. Monitoring will initially involve 
laboratory assessments (including clinical chemistry and haematology panels) and a repeat CD4+ count approximately 
 post day 
 
Additional monitoring or onward referral for clinical care will be made at the discretion of the Investigator. Data collected during further 
monitoring will be reported in the clinical study report. 
• 
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. 
• 
 
 
 
. 
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2. 
INTRODUCTION 
GSK3888130B is a humanised monoclonal antibody (mAb; 
) raised against 
recombinant human interleukin (IL)-7, being developed for the treatment of Multiple 
Sclerosis.  
2.1. 
Study Rationale  
This is a first time in human (FTIH) study designed to evaluate the safety, tolerability, 
pharmacokinetic (PK) and pharmacodynamic (PD) profile of single ascending doses 
(SAD) of GSK3888130B. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
. 
This study aims to provide sufficient confidence in the safety and tolerability of the 
molecule and will obtain preliminary information relating to the PK and PD profile of 
GSK3888130B following intravenous (IV) or subcutaneous (SC) injection routes of 
delivery to support future clinical development. 
2.2. 
Background 
Interleukin (IL)-7 is reported to be a non-redundant cytokine, required for early T cell 
development as well as T cell homeostasis. It is secreted by stromal cells in the thymus 
and bone marrow (BM) environment [Mazzucchelli, 2007] and produced by fibroblastic 
reticular cells (FRC) in T cell zones of lymph nodes (LN) [Link, 2007]. It signals through 
the heterodimeric IL-7 receptor (IL-7R) complex, which consists of the IL-7Rα chain 
(Cluster of Differentiation (CD)127) and the common γ-chain (CD132). Signalling of the 
receptor heterodimer is driven through proximity-mediated activation of Janus kinase 
(JAK)1 and JAK3 tyrosine kinases leading to recruitment and subsequent signal 
transducer and activator of transcription (STAT)5 phosphorylation [Kovanen, 2004]. In 
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addition, IL-7 plays a non-redundant role in upregulating Bcl-2 expression in T cells 
which enables their survival in the periphery [Karawajew, 2020]  
The IL-7R is expressed on naïve and memory CD4+ and CD8+ T cells, T follicular helper 
cells, B cell subsets and natural killer (NK) cells, but it is notably absent or has very low 
expression on T regulatory cells [Park, 2004]. Furthermore, IL-7 can support 
differentiation of human T cells into Th1 and Th17 T cell phenotypes [Lee, 2011; Wan, 
2011]. Importantly, homeostasis of regulatory T (Treg) cells appears independent of IL-7, 
as regulatory T cells characteristically express low numbers of IL-7Rα and instead 
critically depend on IL-2 for their development and homeostasis [Burchill , 2007; Liu, 
2006]. 
The IL-7 pathway has been implicated in a number of autoimmune diseases with growing 
evidence supporting a genetic association with Multiple Sclerosis (MS) [International 
Multiple Sclerosis Genetics Consortium, 2019].    
Multiple Sclerosis is characterised by relapses, episodes of acute neurological 
dysfunction (e.g., loss of vision, weakness, numbness) and disease progression 
(accumulation of neurological deficits) [Thompson, 2018]. The pathological mechanisms 
that underly relapse biology (acute inflammation and breakdown of the blood brain 
barrier leading to demyelination) are well-understood whereas those driving disease 
progression (ongoing compartmentalised chronic central nervous system (CNS) 
inflammation) that leads to neurodegeneration have not been well-characterised and have 
been notoriously difficult to treat [Hauser, 2020]. 
The pathogenic autoreactive T cells in MS are maintained by a pool of memory T cells, 
and IL-7 is key for their development, proliferation and activation. IL-7 also enhances 
effector T cell function including proinflammatory cytokine production. 
 
 
 
 
 
 
 Blockade 
of IL-7 in the periphery therefore represents an opportunity to target the pathogenic cells 
at an early point, upstream of current therapies, in addition to targeting their effector 
function. 
Additionally, IL-7 plays a role in the development of ectopic/tertiary lymphoid tissue 
(tertiary lymphoid organ [TLOs]) involved in local T and B cell activation and associated 
with accelerated disease progressing in MS patients [Mitsdoerffer, 2016]. In chronic 
autoimmune diseases, TLOs are involved in local T and B cell activation and 
 
 
 Specifically, IL-7 is critical for the 
development of innate lymphoid cells (ILCs) that lead to TLO formation and for function 
of follicular helper T (Tfh) that are directly involved in B cell activation. IL-7 blockade 
would therefore also be expected to lead to decreased B cell activation, decreased 
autoantibody production and decreased B cell antigen presentation and decreased TLO 
formation/maintenance, all associated with autoimmunity.  
Despite recent advances in the treatment of MS, particularly for Relapsing Remitting MS 
(RRMS) where relapse frequency can be effectively reduced, a large unmet need remains 
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for treatments that can further slow disease progression and delay or avoid disability 
[Kappos, 2020]. Most patients with RRMS will transition to secondary progressive MS 
(SPMS) despite available treatments [Ziemssen, 2020]. For patients with Primary 
Progressive MS (PPMS), whose disease tends to be identified later in life, treatment is 
currently limited to the anti-CD20 depleting antibody Ocrevus (ocrelizumab). It is 
expected that additional therapies will come onto the market, but the need remains to 
target other disease mechanisms and to develop treatments that offer improved efficacy. 
The blockade of IL-7 signalling has the potential to benefit patients with both relapsing 
and progressive forms of the disease by blockade of both memory T cell activation and 
development of TLOs. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
GSK3888130B is provided in the GSK Investigator’s Brochure (IB) [RPS-CLIN-
014183]. 
2.3. 
Benefit/Risk Assessment 
The risk assessment of GSK3888130B is based on the pre-clinical studies conducted to 
date. Summaries of findings from these pre-clinical studies can be found in the IB. 
Details of these risks and the proposed strategy to mitigate/monitor these risks are 
detailed in Section 2.3.1.  
 
 
 
 
 
 
 
 
 
. 
 
 
  
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. 
In this study, safety will be monitored closely both by subjective reporting and by 
objective means, i.e. serial assessments of vital signs, clinical laboratory information and 
cardiac monitoring. The study will be run in a clinical unit with immediate access to 
hospital facilities for the treatment of medical emergencies. Participants will remain 
monitored in the clinic for an appropriate period at the start of the treatment period and 
will only be discharged from the unit if the Investigator deems it safe to do so. 
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2.3.1. 
Risk Assessment 
Potential Risk 
of Clinical 
Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
Study Intervention GSK3888130B 
Dose selection 
The first dose level (Cohort 1) of GSK3888130B is anticipated to have clinically 
insignificant biological activity, with the rationale for dose selection explained in Section 
4.3. There is a risk that the first dose level may have greater pharmacological activity than 
predicted. If this is the case, then the risks outlined in this risk assessment may be increased. 
[Note: Cohort 1 has completed study participation and so this risk has been discharged. It is 
retained here as a record of benefit/risk considerations.]   
Monitoring: 
Participants undergo inpatient monitoring 
following IMP administration. 
 
Sentinel dosing is utilised for all cohorts. 
 
Dose modification: 
Dose escalation decisions are based review 
of safety, tolerability and PK data. Available 
TE data will also be explored during dose 
escalation decisions. Dosing schedule may 
be modified within defined exposure limits.  
Infection / 
lymphopenia 
GSK3888130B potently blocks IL-7 and shows the expected impact on human T cells 
(inhibiting signalling, activation, cytokine production and proliferation of both CD4+ and 
CD8+ T cells). This may impact T-cell differentiation and function, increasing the risk for 
infection. 
Lymphopenia is one of the most prominent markers of moderate/severe coronavirus disease 
(COVID-19), with lower lymphocyte counts closely correlated with disease severity 
[Jamilloux, 2020; Zheng, 2020].  
Constitutive, global IL-7 deficient mice have pan-lymphocytopenia, with arrested 
development of B and T cell subsets, thymic hypoplasia, peripheral lymph nodes 
(hypocellular or absent), Peyer’s patches (greatly diminished or absent) and splenic 
hypoplasia with greatly diminished B and T cell regions and rare or absent marginal zone 
(MZ) B cells. 
Reactivation/new infections: 
Exclusion: participants with recent or 
recurrent infections. 
Monitoring: Baseline, midpoint and end of 
study serology and viral quantification of 
EBV, CMV and VZV. 
Temporary Halt Criteria:  CD4+ T cell 
counts below 0.2×109/L sustained for at 
least 7 days in 1 participant will result in 
review by the GSK DEC before further 
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Potential Risk 
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Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
 
 
,
 
.  Pre-clinical experience with healthy 
cynomolgus monkeys, as well as internal experience with a monoclonal antibody to the IL-
7R (GSK2618960) in two Phase 1 HV studies (NCT01808482 and NCT022931610) [Ellis, 
2019], indicate that after single doses of anti-IL-7R mAb there were minimal changes on T 
cell subsets and absolute lymphocyte counts respectively, which were also transient. An 
excess of infections was not reported in these studies; only nasopharyngitis was observed in 
17% and 50% of participants on anti-IL-7R mAb for studies I7R116702 and 200902, 
respectively. Baseline serology (EBV, HIV, HepB, HepC, HSV, CMV, VZV) was stored for 
analysis and comparison if symptoms of viral infection occurred (Study I7R116702), and 
serology analysed (EBV and CMV) only if participants had alanine amino transferase (ALT) 
>3xULN (Study 200902). There were no reports of viral infection, therefore virology 
samples were not analysed. Across both studies, no deaths, SAEs or other significant AEs 
were reported. No AEs led to study withdrawal. 
In a 12-week repeat dose study (different regimens), with an anti-IL-7R mAb [Herold, 
2019], there was a significant decline over the dosing period in CD4+ and CD8+ effector and 
central memory T cells and CD4+ naive cells, but there were fewer effects on CD8+ naive T 
cells. Only a small decline in these cells was noted after the first dose of each regimen. All 
dosing regimens had receptor occupancy >90%. Serum was collected for EBV and 
cytomegalovirus (CMV) IgG antibodies and viral deoxyribonucleic acid (DNA) at baseline, 
on day 85 and at the end of follow-up. Four participants seroconverted from negative EBV 
IgG before treatment to positive IgG antibody. Two of these participants had EBV 
symptoms. One participant who was negative at baseline for CMV viral DNA but positive 
for IgG antibody, had detectable viral DNA on day 85 (asymptomatic), returning to 
negativity by day 127. 
Recombinant IL-7 cytokine was currently being trialled (InterLeukin-7 [CYT107] To 
Improve Clinical Outcomes in Lymphopenic Patients with COVID-19 Infection UK Cohort 
[ILIAD-7-UK]; NCT04379076) to improve clinical outcomes in lymphopenic patients with 
SARS-CoV-2 infection. The study was terminated in April 2022 due to poor accrual. There 
are no publicly available results from this study.   
During the ongoing SARS-CoV-2 infection 
risk: 
Inclusion:  participants must complete a 
two-dose SARS-CoV-2 vaccination 
schedule and adhere to travel restrictions. 
Exclusion: participants with recent SARS-
CoV-2 positive contacts.  
Temporary Halt Criteria:  
1. CD4+ T cell counts below 0.2×109/L 
sustained for at least 7 days in 1 
participant will result in review by the 
GSK DEC before further participants 
are dosed. 
2. SARS-CoV-2 infection risk data are 
evolving. SARS-CoV-2 infection data 
in the UK and specifically local area 
data in the vicinity of the Phase 1 unit 
where the study will be conducted will 
be monitored. In the event of an 
increase in SARS-CoV-2 infection 
rates, with resultant increase in 
moderate to severe COVID-19, that 
cannot be managed through two-dose 
vaccination regimens available at the 
time of the study (e.g. new variants), the 
study will be temporarily halted. 
 
Participant counselling: 
See Appendix 6 
 
 
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Potential Risk 
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Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
As social contact returns to pre-pandemic norms there is likely to be a resurgence in 
influenza activity in winter 2022 to 2023 to levels similar to or higher than before the 
pandemic [Gov.UK. National flu immunisation programme, 2022] and may remain elevated 
in subsequent years. It is unknown whether blockade of IL-7 pathways may increase the risk 
of contracting, or severity of, influenza infection. 
Influenza: 
All participants must have received an 
influenza vaccination at least 30 days prior 
to dosing, if dosing falls on or between 1st 
October and 30th April.  
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Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
 
 
 
 
 
 
 
 
 
 
 
.     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
  
 
 
 
 
 
 
 
 
Immunogenicity 
and / or 
hypersensitivity 
A mAb raised against the IL-7Rα (GSK2618960) experienced a high incidence of anti-drug 
antibodies (ADA), both in cynomolgus monkey studies and in humans. This is likely due to 
receptor mediated activity. 
Exclusion: Any participant with a current or 
past history of clinically significant allergic 
reactions (anaphylaxis, urticaria) will be 
excluded. 
 
Monitoring:  
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Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
 
. 
 
 
 
 
 
 
 
• 
A validated ADA assay (screening, 
confirmation, and titration methods) 
will be used in this study. 
• 
Participants will be monitored for 
occurrence of hypersensitivity reactions 
and ADA titers. 
 
Temporary halt criteria: Clinically 
significant [National Cancer Institute - 
Common Terminology Criteria for Adverse 
Events (Version 5, National cancer institute 
- common terminology criteria for adverse 
events [NCI-CTCAE]) grade 3 or greater] 
infusion reactions occurring in 1 participant. 
Malignancy 
As with other immunomodulating agents, GSK3888130B could increase the possibility of 
immunosuppression resulting in an increased risk of malignancy.  
Genetic evidence indicates an association between the IL-7R locus and basal cell carcinoma 
with evidence that an IL-7R missense variant (Thr244Ile) is driving this association. The 
direction of this mutation is in the opposite direction as that seen in MS where knowledge 
about the IL-7/IL-7R biology is consistent with activating T cells. Blockade of this biology 
by GSK3888130B and any consequential risk is unknown. 
 
The IL-7R locus is amplified in a number of epithelial solid tumours (5-10%; NSCLC, 
oesophageal, bladder, cervical) and diverse tumour types (<10%). The functional 
significance of these amplifications is uncertain as they do not appear to result in increased 
IL-7R mRNA expression levels. 
 
Exclusion: Participants with a history of 
cancer, including malignant and non-
malignant skin cancer. 
Counselling: Participants will be counselled 
to follow usual precautions to avoid 
excessive sun exposure due to a genetic 
association with basal cell carcinoma.  
Reproductive 
toxicity 
Animal reproductive toxicity studies have not yet been carried out with GSK3888130B. 
However, there is a theoretical risk that GSK3888130B could affect the development of T 
and B cells in a developing fetus. 
Inclusion:  
• 
Only male participants and female 
participants of non-childbearing 
potential. 
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Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
• 
Male participants will be required to 
refrain from intercourse or use a 
condom, avoid semen exposure to a 
women of child bearing potential 
(WOCBP), and refrain from donating 
sperm for 
 days. 
Injection site 
reactions 
Injection site reactions have been reported for other mAbs and appear to occur more 
frequently with proteins carrying foreign sequences, such as murine or chimeric mAbs. The 
reported incidence typically ranges from 1-5%. Serious hypersensitivity reactions are rare. 
Exclusion: Any participant with a current or 
past history of clinically significant allergic 
reactions (anaphylaxis, urticaria) will be 
excluded.  
Monitoring: Participants will be closely 
monitored for injection site reactions. 
 
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Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
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Mitigation Strategy 
 
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2.3.2. 
Benefit Assessment 
The proposed study will be conducted in healthy participants. There will be no medical 
benefit to the study participants.  
Participants in this study will be contributing to the process of developing a new therapy 
in areas of unmet need including the treatment of disease progression in Multiple 
Sclerosis. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimize risk to participants participating in 
this study, the potential risks identified in association with GSK3888130B at the doses to 
be administered are considered minimal and justified. 
3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
• To investigate the safety and 
tolerability of single IV and SC 
doses of GSK3888130B in healthy 
participants. 
• Occurrence of Adverse Events (AEs) and 
Serious Adverse Events (SAEs). 
• Occurrence of clinically significant 
changes in laboratory values (CD4+ T 
cell counts, haematology, chemistry, 
urinalysis and virology), vital signs and 
12-lead electrocardiogram (ECG) 
readings. 
Secondary 
 
• To characterise the serum PK 
profile of single IV or single SC 
doses of GSK3888130B in healthy 
participants. 
• Serum concentrations of GSK3888130B 
and derived PK parameters as data 
permit, including: area under the 
concentration-time curve [AUC], 
maximum concentration [Cmax], time to 
Cmax [Tmax], half-life [t½], clearance 
[CL]. 
• To evaluate the immunogenicity of 
single doses of GSK3888130B in 
healthy participants. 
• Incidence of Anti-Drug Antibodies 
(ADAs) against GSK3888130B.  
• To characterise the effects of 
GSK3888130B on target 
engagement (TE). 
• Change from baseline in 
 
) over time. 
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Objectives 
Endpoints 
• To characterise the effect of single 
doses of GSK3888130B on PD 
biomarker Bcl-2. 
• Change from baseline in T cell Bcl-2, 
measured in blood over time. 
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Objectives 
Endpoints 
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a single centre, randomised, double-blind, placebo controlled, dose escalation 
study comprised of seven planned SAD cohorts, designed to assess safety, tolerability, 
PK and PD of GSK3888130B over a range of dose levels (from mg to 
 mg) in 
healthy participants. 
 
 
 
 
.  
While every effort will be made to identify participants 
 
to assess the impact of GSK3888130B on the 
 
 
 
 
 
 
 
 
 
 
 
All participants in the study will attend a screening visit within 28 days prior to 
administration of study intervention (Day 1). In subjects who require an influenza 
vaccination and/or SARS-CoV-2 vaccination or booster, the screening window may be 
increased to 60 days. This extended screening window applies only to those participants, 
and if their initial screening assessments are conducted more than 28 days prior to Day 1, 
screening assessments will be repeated within 28 days of Day 1 to confirm eligibility. 
Holter monitoring, viral serology (HIV, hepatitis B and hepatitis C), Mycobacterium 
tuberculosis (TB) screening,
 
(
) does not need to be repeated for 
extended screening windows or rescreens if within 3 months of initial screening. 
Participants who meet the entry criteria and provide informed consent will be randomised 
to receive either GSK3888130B or placebo. Safety assessments will be conducted 
throughout the study duration and blood samples collected for PK, immunogenicity and 
biomarker evaluation (TE and pharmacodynamic markers). 
Participants will be admitted to the clinical unit on Day -1 for final eligibility checks 
before administration of study intervention on Day 1. Administration of treatment 
intervention will be by IV infusion or SC injection, investigated in separate cohorts. A 
detailed listing of the timing of assessments and study procedures can be found in Section 
1.3 (Schedule of Activities [SoA] Table). 
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As this is the first administration of GSK3888130B in humans, sentinel dosing will be 
utilised for each increasing dose level (if the selected dose level is below or equivalent to 
the previous dose level, sentinel dosing may still be applied). Participants will be 
randomised to receive either GSK3888130B or placebo in a 3:2 ratio in cohorts 1 and 2 
or in a 3:1 ratio in all other SAD cohorts. 
Sentinel dosing will be implemented in each cohort, so that one participant is dosed with 
GSK3888130B and one participant is dosed with placebo followed by review of post-
dose safety data before additional participants in each cohort are dosed.  
• The duration of post-dose safety data required for IV and SC cohorts is described 
below. 
For cohorts where treatment administration is by IV injection: 
• The remaining participants in these cohorts will only be dosed after review of at 
least 
 safety & tolerability data (i.e. AE/SAEs, laboratory values, vital 
signs and 12-lead ECGs) from the sentinel participants by the Principal 
Investigator (PI) or appropriately qualified delegate, in consultation with the 
Medical Monitor or delegate if unavailable, and it has been deemed safe to do so. 
• Participants will remain in the unit until completion of all assessments on Day  
This period may be amended at the discretion of the Principal Investigator (or 
designee) and GSK DEC as safety and PK data evolves. 
For cohorts where treatment administration is by SC injection:  
• The remaining participants in these cohorts will only be dosed after review of at 
least 
 safety & tolerability data (i.e. AE/SAEs, laboratory values, vital signs 
and 12-lead ECGs) from the sentinel participants by the Principal Investigator (PI) 
or appropriately qualified delegate, in consultation with the Medical Monitor or 
delegate if unavailable, and it has been deemed safe to do so. 
• Participants will remain in the unit until completion of all assessments on Day  
This period may be amended at the discretion of the Principal Investigator (or 
designee) and the GSK DEC as safety and PK data evolves. 
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All subjects will then be required to attend the clinic for up to outpatient visits over the 
course of 
days after dosing for safety assessment and sample collection and will 
receive two follow-up telephone calls; the first will be 
 days post last study visit and 
the second will be 
 days post last study visit. If required, additional follow-up visits 
may be scheduled. 
The total duration of the study for each participant will be approximately 
 weeks. 
Doses between cohorts are planned to escalate in a sequential fashion contingent on the 
safety, tolerability and pharmacokinetic profile from a minimum of 2 participants dosed 
with GSK3888130B in cohorts 1 and 2 or a minimum of 4 participants dosed with 
GSK3888130B in all other SAD cohorts. The decision to proceed to the next dose level 
of GSK3888130B will be made by the GSK DEC following a review of the safety, 
tolerability (including absolute CD4+ T cell counts) and PK data up to and including Day 
 for both IV and SC dosed cohorts. Available TE data (total IL-7 levels) will also be 
explored. Further details on the GSK DEC are provided in Section 10.1.5. 
4.2. 
Scientific Rationale for Study Design 
This study will be the first administration of GSK3888130B in humans and has therefore 
been designed in accordance with regulatory guidance for the conduct of First Time in 
Human (FTIH) studies, with data obtained from preclinical assessments of 
GSK3888130B contributing to the number and timing of safety assessments and 
monitoring during the study.  
This study aims to evaluate safety, tolerability, PK and PD of GSK3888130B in healthy 
participants with the inclusion of a placebo control to allow for evaluation of safety and 
tolerability attributable to treatment, versus those independent of treatment. 
Data from healthy participants will provide preliminary data following single dosing, in 
healthy participants who are not on any concomitant medications, as to the safety and 
tolerability of GSK3888130B and enable evaluation of potential lymphopenia, risk of 
infection and risk of reoccurring infections following suppression of memory T cell 
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responses prior to study in patients with autoimmune disease, who may already be 
predisposed to infection risks and/or less able to fight-off infections due to an altered 
immune response. 
The inclusion of a placebo control will also act as biological control to account for 
biological variation (not attributable to GSK3888130B) in PD assessments being taken to 
provide confidence in TE and inhibition of downstream biological signalling. 
As this is a FTIH study, a sentinel dosing approach will be employed for any dose level 
not previously administered to humans (i.e. each increasing dose level). This will permit 
immediate assessment of the safety and tolerability of GSK3888130B in a single 
participant before the remaining participants receive study treatment. Any escalation of 
doses between cohorts, including definition of the next dose, will be made by the GSK 
DEC based upon the review of all available safety, tolerability and PK data from the 
previous dose level(s). In addition, available TE data (total IL-7 levels) will be explored. 
The duration of inpatient admission and requirement for safety data is based on the 
predicted PK time course (Cmax). The duration of this period may be amended at the 
discretion of the Principal Investigator (or designee) and GSK DEC as safety and PK data 
evolves. 
The study includes both IV and SC administration in separate cohorts to evaluate 
pharmacokinetics for the two routes. For SC administration, 
 
 
. The two SC dose levels will 
provide information on GSK3888130B 
, which 
might be dose-dependent. The IV route of administration was selected for the initial 
dosed cohorts to enable monitoring of early safety signals during infusion. SC cohorts are 
interspersed with IV cohorts to minimise the number of subjects who are exposed to 
GSK3888130B. The dose escalations have been planned to ensure that exposure 
increments remain consistent between ascending dose levels/cohorts based on PK 
exposure predicted from pre-clinical data (see Section 4.3.2). 
To ensure unbiased outcomes, a double-blind approach will be used, with the 
participants, Investigator and Clinical Unit staff all blind to treatment allocation.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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As GSK3888130B potently neutralises IL-7 and is therefore anticipated to impact T cell 
development, differentiation and function (including memory T cell responses), 
GSK3888130B has the potential to increase the risk of infection.  
Previous clinical experience with an anti-IL-7R mAb antagonist GSK2618960 in two 
Phase 1 studies (NCT01808482 and NCT022931610) in 24 healthy participants, reported 
no viral infections [Ellis, 2019] and 
 
 
 
 
 
 
 
 
In a Phase 2b, 12-week repeat-dose escalation study (NCT02038764) evaluating IL-7R 
blockade with RN168 (a humanised IgG1 mAb which binds to IL-7RA (CD127)), in 37 
subjects with type 1 diabetes, four participants seroconverted from negative Epstein-Barr 
Virus (EBV) IgG before treatment to positive IgG antibody response following dosing. 
Two of these participants had symptomatic EBV infection [Herold, 2019]. In this repeat 
dose study, between 90% and 100% IL-7R occupancy and near-complete inhibition of 
pSTAT5 (IL-7R downstream signaling) was observed at all dose levels and regimens 
tested. 
Prevalence of viral infections in the community are generally considered to be of low-risk 
in the UK due to high childhood vaccination uptake (with the exception of the recent 
SARS-CoV-2 pandemic). Therefore, in the absence of viral infections in healthy 
volunteer studies with an anti-IL-7R GSK21618960, preclinical toxicity study with 
GSK3888130B and risk mitigation plans within this study (detailed in Section 2.3.1), the 
risk to healthy volunteers from a single dose of GSK3888130B is considered to be very 
low. In addition, baseline, midpoint, and end of study viral samples will be drawn and 
analysed for EBV, CMV and VZV infection in order to characterize the infection risk 
(including asymptomatic infection) and determine trends to inform future clinical 
development. 
Severe Acute Respiratory Syndrome-Coronavirus-2 (SARs-CoV-2) vaccination and UK 
Government policies have seen the risk of severe Coronavirus 19 (COVID-19) disease 
reduced in the general population in the UK. However, it is noted that the greatest impact 
of IL-7R inhibition has been shown to be on the central and effector memory T cell 
response/cell number [Herold, 2019]. While these cell populations drive the autoimmune 
response in disease, they are also important in mounting a T cell mediated memory 
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response to infections and inhibition of IL-7 may reduce this response. Evidence suggests 
that the current approved SARS-CoV-2 vaccines are protective largely due to the B-cell 
antibody response, as efficacy correlates with antibody titres and their neutralising 
capacity [Earle, 2021]. Therefore, participants will be required to have been fully 
vaccinated for SARS-CoV2 vaccines (two-dose regimen) 30 days prior to dosing, as 
efficacy of these vaccines are reported to give substantial protection against 
hospitalisation from current SARS-CoV-2 strains. 
As social contact returns to pre-pandemic norms there is likely to be a resurgence in 
influenza activity in winter 2022 to 2023 to levels similar to or higher than before the 
pandemic [Gov.UK. National flu immunisation programme, 2022]. Therefore, all 
participants recruited into the study to be dosed within the influenza season (1st October 
to the 30th April) will be required to be vaccinated with an approved seasonal influenza 
vaccine. 
 
 
 12-lead ECGs will be routinely performed in 
both IV and SC cohorts to provide contemporaneous safety analysis and data for the 
primary outcome. 
4.2.1. 
Participant Input into Design 
There has been no participant input into this trial design. 
4.3. 
Justification for Dose 
4.3.1. 
Human dose prediction for GSK3888130B 
 
 
. 
The drug concentration and total IL-7 in blood from monkey studies were fitted with a 
two-compartment PK model that is linked to a target-mediated drug-disposition PD 
model. The model was extrapolated to human, by scaling PK parameters using allometry 
and assuming
 
. The extrapolated model was 
then used to predict the dose-response relationships for human PK, the associated 
exposure safety margin in relation to the NOAEL in the monkey, 
 
 
The PK-PD data of
 in monkey were modelled using a turnover model, where 
the drug reduced production of 
 This model, combined with the PK model that was 
scaled from monkey to human by allometry, was used to predict the dose-response 
relationship of 
 reduction in human. 
These PK-PD models were further translated from blood to tissue. However, this 
translation has not been validated by any tissue data. The 
 predicted that 
monthly dosing of approximately 
 
 
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 for Copaxone® (at its therapeutic dose) and the IL-7 receptor 
antagonist RN168 at doses investigated for type-1 diabetes. In absence of any disease 
biomarker, the therapeutic meaning of the PK-PD predictions is highly uncertain. 
4.3.2. 
Dose escalation plan for GSK3888130B 
GSK3888130B is considered a low-risk molecule for several reasons. First, it belongs to 
a drug class (monoclonal antibodies; mAbs) which is acknowledged to have low risk of 
off-target toxicity. Second, inhibition of the IL-7 pathway has been previously studied. 
IL-7 receptor (IL-7R) blockade has been investigated in healthy volunteers [Ellis, 2019] 
and patients with Type 1 diabetes [Herold, 2019]. Third, the molecule has similar in vitro 
IL-7 binding affinity for monkey and human, making the pharmacology and safety 
findings in the monkey highly relevant to the human. 
PK-PD modelling was conducted using pooled data from two PK/PD studies and the 4-
week toxicity study (all in cynomolgus monkeys) to describe PK, TE (
 
 and pathway pharmacology (
) in order to support the 
planning of dose escalation in the FTIH trial. 
At the no observed adverse effect level (NOAEL) found in the 4-week toxicology study 
in monkeys (the top dose studied), 
 
 
was demonstrated in a 
Phase 2b, 12-week repeat-dose escalation study (NCT02038764) evaluating IL-7R 
blockade with RN168 (anti-IL-7R mAb) [Herold, 2019] and with the therapeutic dose for 
Copaxone® [CopaxonePrescribingInformation, 2009; Ruggieri, 2006]. Modelling and 
simulation data predict that a 
 mg dose of GSK3888130B 
will give a 
reduction 
  
It is anticipated that the mg starting dose will result in 
 in 
blood; this low biological effect is considerably below the level of 
suppression 
previously observed in humans with RN168 and Copaxone®. The starting dose of mg 
is deemed appropriate for healthy volunteers given the low risk for off-target toxicity, the 
existing knowledge of the target pathway in human, and the high pharmacology and 
safety relevance of the pre-clinical species (outlined above in this Section). The starting 
dose of mg is further supported by PK-PD modelling and simulation which suggest 
adequate safety margins in relation to the NOAEL 
 found in the 4-week toxicology study in monkeys (see Section 4.3.3).  
4.3.3. 
Predicted plasma exposure, safety margins, target engagement 
 and pathway pharmacology 
  
Planned 
Dose 
[mg] 
Dosing 
Route* 
Exposure 
Exposure Ratio 
Monkey: Human$ 
Peak reduction in 
blood (%) 
AUC 
(µg/mL*h) 
CMAX 
(µg/mL) 
AUC 
CMAX 
 
 
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Planned 
Dose 
[mg] 
Dosing 
Route* 
Exposure 
Exposure Ratio 
Monkey: Human$ 
Peak reduction in 
blood (%) 
AUC 
(µg/mL*h) 
CMAX 
(µg/mL) 
AUC 
CMAX 
$Ratios based on total exposure at NOAEL of 
 mg/kg/wk IV in 4-wk monkey study: 
AUC 
 µg/mL*h and Cmax 
 µg/mL 
AUC=AUC from time 0 extrapolated to infinity. Cmax = maximum concentration 
Dose escalation will be at up to half-log increments in exposure, accounting for the 
anticipated exposure difference between subcutaneous and intravenous administrations.  
It is not possible to determine the therapeutic dose of GSK3888130B prior to studies in 
patient populations, as the relationship between pharmacology and clinical outcomes is 
unknown. Given this uncertainty, the study is design to explore a range of doses to 
explore pharmacological response and the top dose will, within practicality of drug 
administration, maximise the safety cover for future patient trials where repeat-dosing. In 
this single-dose study, the planned top dose of 
 mg is based on NOAEL from the 4-
week toxicology study in monkeys, and provides 
 predicted safety margins 
for AUC and Cmax, respectively. Guided by emerging data, the actual top dose will 
generate the anticipated mean AUC and Cmax with at least
 safety margin in 
relation to the exposure at the NOAEL identified in the monkey. 
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4.4. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 
A participant is considered to have completed the study if he/she has completed all 
relevant parts of the study including the final follow-up telephone call. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
 
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Informed Consent 
11. Capable of giving signed informed consent as described in Section 10.1 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. Prior medical history of anaphylaxis or severe adverse reactions to vaccines. 
2. Immunodeficiency or autoimmunity assessed by medical history. 
3. A history of recurrent infections. 
4. Treatment of a chronic infection within 3 months prior to the first dose of study drug, 
including both serious local infection (e.g. cellulitis, abscess) or systemic infection 
(e.g. pneumonia, Tuberculosis, hepatitis B, Shingles). 
5. Any acute infection (including upper respiratory tract infections and urinary tract 
infections) which has not fully resolved within four weeks of dosing. 
6. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the Investigator or GSK 
Medical Monitor, poses a safety risk with regards to participation in the trial. 
7. Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones). 
8. Participants with a history of renal disease or renal abnormalities. 
9. A clinically significant abnormality in the 12-lead ECG performed at screening 
including: 
o Heart rate <45 or >100 bpm (male) or <50 or >100 bpm (female) 
o PR interval <120 or >220 msec 
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o QRS duration <70 or >120 msec 
o QTcF interval >450 msec (QT interval corrected for heart rate according to 
Fridericia’s formula) 
o Evidence of previous myocardial infarction (does not include ST segment 
changes associated with re-polarization). 
o Conduction abnormality (including but not specific to left or right complete 
bundle branch block, atrioventricular block [2nd degree or higher], Wolf-
Parkinson-Wright syndrome). 
o Sinus Pauses >3 seconds. 
o Non-sustained or sustained ventricular tachycardia (>3 consecutive ventricular 
ectopic beats). 
o Any significant arrhythmia which, in the opinion of the Investigator or the 
GSK Medical monitor, that will interfere with the safety for the individual 
participant. 
10. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11. History of malignancy, including malignant or non-malignant skin cancer.   
12. Participants with known SARS-CoV-2 positive contacts in the past 14 days. 
13. Prior moderate/severe SARS-CoV-2 infection requiring oxygen supplementation or 
admission to hospital. 
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. 
Prior/Concomitant Therapy 
20. Antibiotics or antiviral therapy within 30 days of dosing. 
21. Receipt of live vaccination within 30 days of dosing or plan to receive live 
vaccination during the study. 
22. Use of prescription drugs or non-prescription drugs, including non-steroidal anti 
inflammatory drug (NSAIDs), within 7 days prior to dosing, if in the opinion of the 
Investigator (in consultation with the GSK Medical Monitor if required) the 
medication will interfere with the study procedures or compromise participant safety. 
Participants must not currently take any of the following: oral or systemic steroids or 
any other immune modulators (the washout period will be determined on a case by 
case basis, in consultation with the GSK Medical Monitor). Paracetamol, at doses of 
≤4 grams/day, is permitted for use any time during the study. 
 
Prior/Concurrent Clinical Study Experience 
24. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day of the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer). 
25. Exposure to more than 4 new chemical entities within 12 months prior to dosing. 
Diagnostic assessments 
26. A positive diagnostic Mycobacterium tuberculosis (MTB) test at screening (defined 
as a positive QuantiFERON Gold test).  
NOTE: 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 participant is not eligible. 
27. A positive pre-study hepatitis B surface antigen, hepatitis B core antibody or positive 
hepatitis C antibody result at screening. 
NOTE: 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. 
28. Positive hepatitis C RNA test result at screening. 
NOTE: Test is optional and participants with negative hepatitis C antibody test are 
not required to also undergo hepatitis C RNA testing. 
29. A positive test for HIV antibody at screening. 
30. A positive drug/alcohol test at screening or Day -1. 
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Other Exclusions 
31. 
 
 
. 
32. Current smoker or user of tobacco- or nicotine-containing products (e.g. nicotine 
patches or vaporizing devices) during or within 30 days prior to study participation. 
33. 
. 
34. An average weekly intake of >14 units of alcohol. One unit is equivalent to 8g of 
alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) 
measure of spirits. 
35. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within a 56-day period. 
36. The participant does not agree to adhere to UK government guidance on international 
travel during the study period. Participants must ensure that any travel does not 
impair their ability to attend scheduled visits. 
 
5.3. 
Lifestyle Considerations 
5.3.1. 
Alcohol, and Tobacco 
• During dosing (Day 1) session, participants will abstain from alcohol for 24 hours 
before the start of dosing until after collection of the final PK and/or 
pharmacodynamic sample.  
• Use of tobacco products will not be allowed from screening until after the final study 
visit on Day 
 
5.3.2. 
Activity 
• Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (e.g., watching television, reading). 
5.3.3. 
SARS-CoV-2 related restrictions 
• Participants will be required to adhere to any national, local and site-specific 
guidance regarding COVID-19, including any self-isolation guidance. 
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5.3.4. 
Other consideration 
• Participants should follow usual precautions to avoid excessive sun exposure.  
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized/entered in the study due to not meeting eligibility 
requirements. Unused participants that meet eligibility criteria are not considered screen 
failures and may undergo repeated rescreening to confirm eligibility requirements if 
randomization into study planned outside of initial screening window. 
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, any protocol deviations and any serious adverse events (SAEs). 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened once. Rescreened participants should be assigned a new participant 
number for every screening/rescreening event. Individuals who failed initial screening 
but passed rescreening may be admitted into the study based upon clinical judgement and 
after consultation with the GSK Medical Monitor. 
Holter monitoring, viral serology (HIV, hepatitis B and hepatitis C) and TB screening 
does not need to be repeated for rescreens if within 3 months of initial screening. 
If a participant fails any of the laboratory criteria, the test may be repeated once within 
the screening period without this constituting a rescreen. If the participant fails the 
laboratory criteria for a second time, they will be considered a screen failure. 
5.5. 
Criteria for Temporarily Delaying 
Enrolment/Randomization/Administration of Study 
Intervention Administration 
• SARS-CoV-2 outbreak leading to a rapid rise in case numbers and hospitalisations for 
which the approved two-dose SARS-CoV-2 vaccines appear to have lower/unknown 
efficacy, based upon clinical judgement and consultation with the GSK Medical 
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6. 
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
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. 
 
Study Intervention 
ARM Name 
GSK3888130B 
Placebo 
 
 
Intervention 
Name 
GSK3888130B 
Injection 
Placebo 
 
 
 
Type  
Drug 
Drug 
 
 
 
 
 
 
 
 
 
 
Unit Dose 
Strength(s)  
mg/mL 
0.9% 
 
 
 
 
 
Dosage 
Level(s) 
IV: 
mg 
SC:
mg 
Volume to 
match 
volume of 
 
 
 
 
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Study Intervention 
 
 
 
active dose 
administered 
Route of 
Administration 
IV or SC injection 
IV or SC 
injection 
 
 
 
 
 
 
 
 
 
 
Use 
experimental 
placebo 
 
 
 
 
 
 
 
IMP and AMP 
IMP 
IMP 
 
 
 
 
 
Sourcing 
 
Provided centrally 
by the Sponsor 
Locally 
sourced by 
the site 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
. 
 
For the IV cohorts GSK3888130B is planned to be infused over an approximate duration 
of 
. GSK3888130B can be diluted in saline (0.9% sodium chloride) 
prior to administration. 
For the SC cohorts: the appropriate volume of GSK3888130B will be injected using a 
syringe at no more than 
 per injection. Up to injections per dose may be needed. 
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The same volume of saline (used as placebo) will be infused (IV) or injected (SC) in the 
same manner as the corresponding GSK3888130B administrations in that cohort. 
Infusion durations may vary by cohort due to the wide range of dose concentrations 
planned to be administered. Where possible volumes and infusion rates will be kept 
constant. Infusion durations maybe modified based on emerging safety and PK data. 
Full instructions for dilution of study intervention to dose concentrations to be 
administered will be provided in the Pharmacy Manual. 
 
 
 
6.2. 
Preparation/Handling/Storage/Accountability 
• 
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. 
• 
Only participants enrolled in the study may receive study intervention and only 
authorised site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the Investigator and authorised site staff. 
• 
The Investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
• 
Further guidance and information for the final disposition of unused study 
intervention are provided in the Pharmacy Manual.  
• 
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 will either be provided to the 
Investigator, where this is required by local laws, or is available upon request from 
GSK. 
• 
 
. 
 
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6.3. 
Measures to Minimize Bias: Randomization and Blinding 
On Day 1 of each cohort, participants will be assigned a unique randomisation number in 
ascending numerical order. The randomisation number encodes the participant’s 
assignment to either GSK3888130B or placebo, according to the randomisation schedules 
generated prior to the study by the Statistics Department at GSK, using validated internal 
software. Once assigned, randomisation numbers must not be reassigned to any other 
participant in the study. 
The unblinded pharmacist will receive a copy of the randomisation schedules from the 
GSK randomisation co-ordinator to enable dispensing of study medication. 
The PI or delegated responsible person will assign the randomisation numbers as 
described above and the randomisation number will be entered in the case report form 
(CRF). 
To prevent accidental unblinding of participants, the investigators and study site will not 
review participant-level data concerning PK and PD parameters. Participant-level 
 
 will be reviewed by the Medical Monitor. The investigators and study site will 
only be informed if the 
 
 have met or are approaching the temporary halt 
criteria, or for other reasons related to participant safety. The transmission of this 
information will be recorded in the investigator site file. 
For the purposes of producing summaries of PK data for review prior to each dose 
escalation, Clinical Pharmacology Modelling and Simulation (CPMS) will extract blood 
concentration time data, with scrambled subject IDs from the GSK SMS2000 system.  
Thus, the subject number stated in the PK dataset will not match the true subject number 
presented with the safety data. This is to ensure that the review team is blinded with 
respect to linking PK and safety data. 
For the purposes of providing summary data (
 
) to the DEC for 
review prior to each dose escalation, the study Statistics and Programming team will be 
unblinded. However, no individual subject number identifiers will be included in the data 
presented to the DEC, to ensure all other members remain blinded. 
6.3.1. 
Unblinding 
• In case of an emergency, the Investigator has the sole responsibility for determining if 
unblinding of a participant’s treatment assignment is warranted. Participant safety 
must always be the first consideration in making such a determination. If a 
participant’s treatment assignment is unblinded GSK must be notified within 24 hours 
after breaking the blind. 
• The date and reason for the unblinding must be fully documented in the investigator 
site file. 
• 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. 
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• Global Safety staff may unblind the intervention assignment for any participant with 
an SAE. If the SAE requires that an expedited regulatory report be sent to one or 
more regulatory agencies, a copy of the report, identifying the participant’s 
intervention assignment, may be sent to investigators in accordance with local 
regulations and/or GSK policy. 
• Members of the DEC may be unblinded if individual data needs to be reviewed as 
part of the interim analysis. 
• Procedures for unblinding will be documented in the SRM. 
6.4. 
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.  
• When participants are dosed at the site, they will receive study intervention directly 
from the Investigator or designee, under medical supervision. The date and time of 
each dose administered in the clinic will be recorded in the source documents. The 
dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering 
the study intervention.   
6.5. 
Dose Modification 
This protocol allows some alteration from the currently outlined dosing schedule, but 
mean exposure is not predicted to exceed AUC(0-∞) of 
µg/mL*h or Cmax of 
 µg/mL, which are 
of the exposure observed at NOAEL in the 4-week monkey 
toxicity study. The planned top dose for this study of 
mg has sufficient safety cover 
i.e., 
 predicted safety margins for AUC and Cmax respectively based on the 
corresponding values at NOAEL from the 4-week toxicology study in the monkeys [GSK 
Document number 2020N457447_00].  
The decision to proceed to the next dose level of GSK3888130B (either an increase, 
repeat at the same level [dose expansion] or a decrease) will be made by the GSK DEC 
following a review of the safety, tolerability (including absolute CD4+ T cell counts) and 
PK data, obtained in at least two GSK3888130B-treated participants in cohorts 1 and 2 
and at least four GSK3888130B-treated participants in all other SAD cohorts, up to and 
including Day
 for both IV and SC dosed cohorts at the prior dose level. Available TE 
(total IL-7 levels) data will also be explored. 
The dosing schedule may also be adjusted to expand a dosing cohort to further evaluate 
safety, PK and PD findings at a given dose level or to add cohorts to evaluate up to two 
additional dose levels below the planned top dose 
 mg. The study procedures for 
these additional participant(s)/cohort(s) will be the same as those described for other 
study participants/cohorts. 
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6.6. 
Continued Access to Study Intervention after the End of the 
Study 
There is no continued access to study intervention after the end of this study. 
6.7. 
Treatment of Overdose 
For this study, any dose of GSK3888130B greater than the dose to be administered in the 
study in each cohort (protocol planned doses or doses defined as part of dose escalation 
decisions) will be considered an overdose. 
 
 
GSK does not recommend specific treatment for an overdose. The Investigator (or 
physician in charge of the participant at the time) will use clinical judgment to treat any 
overdose. 
In the event of an overdose, the Investigator/treating physician should: 
• Contact the Medical Monitor immediately. 
• Closely monitor the participant for AE/SAE and laboratory abnormalities until 
serum concentration of study intervention falls to below that observed in the 
highest dose cohort and lymphocyte differentials are >LLN. Duration and 
frequency of monitoring will be at least that described in the SoA. 
• Obtain additional serum sample(s) for PK analysis if requested by the Medical 
Monitor (determined on a case-by-case basis). 
• Document the quantity of the excess dose as well as the duration of the 
overdosing in the CRF. 
6.8. 
Concomitant Therapy 
Any medication (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) 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 must abstain from taking prescription or non-prescription drugs (including 
NSAIDs, vitamins, recreational drugs, and dietary or herbal supplements) within 7 days 
(or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) 
before the start of study intervention until completion of the final follow-up visit, unless, 
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in the opinion of the Investigator and Sponsor, the medication will not interfere with the 
study.  
Participants must not currently take any of the following: oral or systemic steroids or any 
other immune modulators (the washout period will be determined on a case by case basis, 
in consultation with the GSK medical monitor). 
Live vaccination is not permitted within 30 days of dosing or during the study. All other 
vaccinations (including a two-dose SARS-CoV-2 vaccination and seasonal influenza 
vaccination as per eligibility requirements) will be completed at least 30 days prior to 
dosing. 
Participants who have not received a MHRA-approved seasonal influenza vaccination 
will be required to receive vaccination as part of screening if dosing in between 1st 
October and 30th April. Information on influenza vaccination will be included within the 
ICF and participants will be provided with the product’s Patient Information Sheet prior 
to vaccination. The period for which influenza vaccination is required for study 
enrolment will be kept under review and may be changed based on emerging data. Any 
changes to the vaccination period will be approved by the DEC and will not constitute a 
protocol deviation or amendment. The influenza vaccination is not considered an 
Investigational Medicinal Product within this study. 
No participants who have a medical history of severe adverse reaction to vaccines will be 
offered or advised to undergo vaccination to meet the eligibility requirements of this 
study.  
Paracetamol, at doses of ≤4 grams/day, is permitted for use any time during the study. 
Other concomitant medication may be considered on a case-by-case basis by the 
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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
This is a single-dose study. In rare instances, a participant may not be able to complete 
the IV infusion or SC injection(s). In such circumstances, if the study intervention is 
permanently discontinued, the participant will be encouraged to remain in the study for 
the planned duration, or minimally to complete safety and PK assessments up to Day
 
The duration for which a participant will be encouraged to remain in the study will be at 
the discretion of the Investigator in discussion with the Medical Monitor. See the SoA for 
data to be collected at the time of discontinuation of study intervention and follow-up and 
for any further evaluations that need to be completed. 
7.2. 
Study Stopping Criteria 
7.2.1. 
Liver Chemistry Criteria 
Liver chemistry stopping, and participant increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology. 
• Any participant meeting the liver chemistry criteria (ALT ≥3x ULN) will have 
enhanced monitoring as detailed in Section 10.5. The participant should continue in 
the study, given this is a single dose study. 
• Liver events characterized by an ALT ≥3x ULN but not meeting SAE criteria, if 
reasonably attributable to GSK3888130B, will result in review by the GSK DEC 
before further participants are dosed. 
7.2.2. 
QTc Criteria 
QTc study stopping criteria, and individual participant increased monitoring criteria, have 
been designed to assure participant safety. The same QT correction formula must be used 
for each individual participant to determine eligibility for and discontinuation from the 
study. Use of Fridericia’s formula (QTcF) is preferred in this study. The formula may not 
be changed or substituted once the participant has been enrolled; for example, if a 
participant is eligible for the protocol based on QTcF, then QTcF must be used for 
discontinuation of this individual participant as well. Safety ECGs and other non-protocol 
specified ECGs are an exception. 
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Participants that meet either of the bulleted criterion below, additional monitoring will be 
undertaken until the QTc value is no longer clinically significant. The frequency of this 
monitoring and the decision as to when the QTc value is no longer clinically significant 
will be at the discretion of the Investigator. The participant should continue in the study, 
given this is a single dose study. 
• QTcF >500 msec. 
• Change from baseline: QTc >60 msec. 
If a single ECG demonstrates a prolonged QTc interval, then a further two ECG readings 
should be obtained over a brief recording period (e.g., 5-10 minute) and the averaged 
QTc interval used to determine whether the participant meets the criteria to trigger further 
monitoring. 
If a participant meets any of the criteria above, this will result in review by the GSK DEC 
before further participants are dosed. 
7.2.3. 
SARS-CoV-2 Related Stopping Criteria 
o 
Participants who report symptoms suggestive of SARS-CoV-2 while in the research 
unit should be isolated in the unit or at home and tested for SARS-CoV-2 infection 
using an approved molecular test according to local site procedures. 
o 
Participants testing positive for SARS-CoV-2 will be actively followed up, with 
early referral as per standard of care if there is evidence of deterioration. 
o 
Withdrawal of participants from the study will be at the discretion of the Principal 
Investigator or designee but should first be discussed and agreed with the GSK 
Medical Monitor. 
o 
Further study related procedures for the participant, except those required for 
participant safety and well-being, should be paused until the discussion is complete. 
o 
Participants who test positive for SARS-CoV-2 infection during the course of the 
study may be replaced at the discretion of the Sponsor and in consultation with the 
Principal Investigator. 
7.2.4. 
Pharmacokinetic Dose Adjustment / Stopping Criteria 
All available PK data from previous dose levels will be rapidly evaluated to estimate and 
predict the systemic exposure (Cmax and AUC(0-∞)) to the next dose level.  
The PK stopping criteria will be mean exposure exceeding or predicted to exceed 
AUC(0-∞) of 
 µg/mL*h or Cmax of 
 µg/mL, which are 
of the 
exposure observed at NOAEL in the 4-week monkey toxicity study.   
If the PK stopping criteria is met, then dose escalation will be stopped or dose adjustment 
will be planned, as appropriate. 
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7.2.5. 
Safety Dose Adjustment / Stopping Criteria 
The GSK DEC will temporarily halt the study based on of the following: 
• 
CD4+ T cell counts below 0.2×109/L are considered clinically relevant (BHIVA 
Guidelines Subcommittee, National Cancer Institute - Common Terminology 
Criteria for Adverse Events (Version 5, NCI-CTCAE) grade 3 or greater) and if 
sustained for at least 7 days in one participant, this will result in review by the 
GSK DEC before further participants are dosed. 
• 
 
 
 
this will result in review by the GSK DEC before further participants are dosed.  
NOTE: 
 
 
 which, in the opinion of the 
Investigator, can be reasonably attributed to GSK3888130B. 
• 
 are 
considered clinically relevant (National Cancer Institute - Common Terminology 
Criteria for Adverse Events (Version 5, NCI-CTCAE) grade 3 or greater). If the 
 
 in the opinion of the Investigator, can be reasonably 
attributed to GSK3888130B then this will result in review by the GSK DEC 
before further participants are dosed. 
• 
Clinically significant [National Cancer Institute - Common Terminology Criteria 
for Adverse Events (Version 5, NCI-CTCAE) grade 3 or greater] infusion 
reactions occurring in one participant. 
• 
As a result of review of safety data at the end of each cohort. 
• 
If one or more participants from any dose level experiences a Serious Adverse 
Event (SAE) which has a reasonable possibility of relation to GSK3888130B, no 
further participants will be dosed until a full safety review of the data has taken 
place. 
• 
If two or more participants in the same cohort experience a ‘severe’ non-serious 
adverse reactions which has a reasonable possibility of relation to GSK3888130B, 
no further participants will be dosed until a full safety review of the data has taken 
place. ‘Severe’ non-serious adverse reactions can be either within or not within 
the same system organ class. 
In the event of reaching the stopping criteria, the dose escalation will stop, and no further 
participants will be dosed. If after consultation the Sponsor deems that dosing can resume 
at that level or higher the Sponsor will submit an application for a substantial amendment 
to the Regulatory Agency to present the data and approve a revision to the protocol. 
The above criteria will apply even if measured PK parameters are below the pre-specified 
PK stopping criteria. Every effort will be made to take a blood sample for PK analysis at 
the time of any of the above events. 
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7.3. 
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, 
or compliance reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. See SoA for data to be collected at the 
time of study discontinuation and follow-up and for any further evaluations that need 
to be completed. 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. 
7.4. 
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, three 
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 
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• 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, 
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. 
• Safety/Laboratory/analyte results that could unblind the study will not be reported 
to investigative sites or other blinded personnel until the study has been 
unblinded. 
• The maximum amount of blood collected from each participant over the duration 
of the study, including any extra assessments that may be required, will not be 
expected to exceed 500 mL. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
8.1. 
Efficacy Assessments 
Not applicable for this study. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
skin, cardiovascular, respiratory, gastrointestinal and neurological systems. Height 
and weight will also be measured and recorded. 
• A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). 
• Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
8.2.2. 
Vital Signs 
• Tympanic temperature, pulse rate, respiratory rate, and blood pressure will be 
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• Blood pressure and pulse measurements will be assessed semi-supine with a 
completely automated device. Manual techniques will be used only if an 
automated device is not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes 
of rest for the participant in a quiet setting without distractions (e.g., television, 
mobile phones). 
• Vital signs (to be taken before blood collection for laboratory tests) will consist of 
three pulse and three blood pressure measurements (3 consecutive blood pressure 
readings will be recorded at intervals of at least 1 minute).  
8.2.3. 
Electrocardiograms 
• Triplicate and single 12-lead ECGs will be obtained as outlined in the SoA (see 
Section 1.3) using an ECG machine that automatically calculates the heart rate 
and measures PR, QRS, QT, and QTc intervals.  
• If triplicate ECG are required, 3 individual ECG tracings should be obtained as 
closely as possible in succession, but no more than 2 minutes apart. 
• Use of Fridericia’s formula (QTcF) is preferred in this study. The formula may 
not be changed or substituted once the participant has been enrolled. Safety ECGs 
and other non-protocol specified ECGs are an exception. 
8.2.4. 
 
• 
  
 
 
.  
• 
 will be captured as outlined in the SoA [Section 1.3]. 
8.2.5. 
Clinical Safety Laboratory Assessments 
• See Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.  
• The Investigator must review the laboratory report, document this review, and 
record any clinically significant changes occurring during the study as an AE. The 
laboratory reports must be filed with the source documents.  
• All laboratory tests with abnormal values (above or below the normal range) 
during participation in the study should be repeated until the values return to 
normal or baseline or are not considered clinically significant by the Investigator 
or Medical Monitor.  
o If clinically significant values do not return to normal/baseline within a 
period of time judged reasonable by the Investigator, the etiology should 
be identified and the sponsor notified. 
• All protocol-required laboratory tests, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
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• If laboratory values from non-protocol specified laboratory tests 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), then the results must be recorded. 
8.2.6. 
Injection site Reactions 
Symptoms and signs of an infusion reaction include tenderness, warmth, redness at the 
site of injection or along the vein, and/or itching. More severe reactions may additionally 
include pain at the site of injection, blistering or skin damage. 
Management may consist of discontinuing the infusion (if possible), hot or cold 
compresses, and analgesia. Treatment will be at the discretion of the Investigator and 
may include referral for specialist input if there is significant skin injury or symptomatic 
extravasation. 
8.2.7. 
Hypersensitivity Reactions 
As GSK3888130B is a humanised monoclonal antibody, it is considered unlikely that 
acute allergic reactions will occur in response to exposure; however, all participants 
should be monitored carefully for evidence of allergic response. 
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. It is important to recognize early signs of a 
hypersensitivity reaction and prevent progression to a severe reaction. In the case of a 
mild reaction during dosing, study intervention administration may be reinitiated (with 
appropriate pre-medication) at the discretion of the Investigator. 
In the event of a suspected severe acute hypersensitivity reaction or anaphylaxis, sites 
should manage this at the discretion of the Investigator in accordance with relevant local 
or national guidelines. 
8.2.8. 
Immunosuppression and Infections 
Participants 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 routinely be taken at baseline, midpoint and at end of study as per SoA. 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and 
Other Safety Reporting 
The definitions of adverse events (AE) or serious adverse events (SAEs) can be found in 
Section 10.3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
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The Investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study (see Section 7.2).  
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• All SAEs will be collected from the signing the inform consent form until the final 
follow-up visit at the time points specified in the SoA (Section 1.3).  
• All SARs to study procedure/GSK products will be reported from the signing of the 
informed consent form (ICF) until the final follow-up visit at time points specified in 
the SoA (Section 1.3).  
• All AEs will be collected from the start of intervention until the final 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 as Medical History/Current Medical 
Conditions not as AEs. 
• All SAEs will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3. The 
Investigator will submit any updated SAE data to the Sponsor within 24 hours of it 
being available. 
• Investigators are not obligated to actively seek information on AEs or SAEs after the 
conclusion of the study participation. However, if the Investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, 
and he/she considers the event to be reasonably related to the study intervention or 
study participation, the Investigator must promptly notify the Sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence.  
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.4). Further information on follow-up procedures is given in 
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8.3.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to the Sponsor of an 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. 
• An investigator who receives an investigator safety report describing an 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. 
• 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. 
8.3.5. 
Pregnancy 
• 
Details of all pregnancies in female partners of male participants will be collected 
after the start of study intervention and until 
days after the single dose of study 
intervention.  
• If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the female 
partner of a male participant (after obtaining the necessary signed informed consent 
from the female partner) pregnancy. 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. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, foetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
• The pregnant female partner will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the pregnant 
female partner and the neonate and the information will be forwarded to the Sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the sponsor as described in Section 
8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participant’s pregnant female partner, he or she may learn of an SAE 
through spontaneous reporting. 
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8.4. 
Pharmacokinetics 
Whole blood samples will be collected for measurement of serum concentrations of 
GSK3888130B as specified in the SoA (Section 1.3). 
• The timing of PK samples may be altered and/or extra samples may be collected 
at additional time points during the study if warranted and agreed upon between 
the investigator and the sponsor. The timing of sampling may be altered during 
the course of the study based on newly available data (e.g., to obtain data closer to 
the time of peak serum concentrations) to ensure appropriate monitoring. 
• Instructions for the collection, processing and handling of biological samples will 
be provided in the SRM. The actual date and time (24-hour clock time) of each 
sample will be recorded. 
• Samples collected for analyses of GSK3888130B serum concentration may also 
be used to evaluate safety or efficacy aspects related to concerns arising during or 
after the study. 
• Genetic analyses will not be performed on these samples. 
• Intervention concentration information that may/would unblind the study will not 
be reported to investigative sites or blinded personnel until the study has been 
unblinded. 
8.5. 
Genetics and Pharmacogenomics (PGx) 
Genetics are not evaluated in this study. 
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8.7. 
Biomarkers 
8.7.1. 
Target Engagement Biomarkers 
Serum samples will be collected to characterise the effects of GSK3888130B on TE. 
 Samples will be collected according to the 
schedule described in the SoA and as detailed in the SRM.  
8.7.2. 
Blood Biomarkers 
Serum samples will be collected to investigate the effect of single doses of 
GSK3888130B on PD biomarkers.
 
. 
 
. Samples will be collected 
according to the schedule described in the SoA and as detailed in the SRM. 
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8.7.4. 
Cellular Biomarkers 
Blood samples will be collected to characterise the effects of GSK3888130B on blood 
immune cell numbers and phenotypes. Biomarkers may include, but are not limited to, T 
cell Bcl-2 expression, 
 
. Samples will be collected according to the 
schedule described in the SoA and as detailed in the SRM. 
8.8. 
Immunogenicity Assessments 
Antibodies to GSK3888130B will be evaluated in serum samples collected from all 
participants according to the SoA. Additionally, serum samples should also be collected 
at the final visit from participants who discontinued study intervention or were withdrawn 
from the study. These samples will be tested by the Sponsor or Sponsor's designee. 
Serum samples will be screened for antibodies binding to GSK3888130B and the titer of 
confirmed positive samples will be reported. Other analyses may be performed to verify 
the stability of antibodies to GSK3888130B and/or further characterize the 
immunogenicity of GSK3888130B. 
The detection and characterization of antibodies to GSK3888130B will be performed 
using a validated assay method by or under the supervision of the Sponsor. All samples 
collected for detection of antibodies to study intervention will also be evaluated for 
GSK3888130B serum concentration to enable interpretation of the antibody data.  
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Antibodies may be further characterized and/or evaluated for their ability to neutralize the 
activity of the study intervention. 
8.9. 
Health Economics 
Not applicable for this study. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The primary objective of this study is to assess the safety and tolerability of single IV and 
SC doses of GSK3888130B in healthy participants. No formal hypotheses are being 
tested in this study. 
9.2. 
Sample Size Determination 
Approximately 54 participants will be recruited to seven single ascending dose cohorts. 
Five participants will be randomized to either GSK3888130B or placebo in 3:2 ratio in 
cohorts 1 and 2. Eight participants will be randomized to either GSK3888130B or 
placebo in 3:1 ratio in all other cohorts, 
 
   
No formal statistical techniques were used to calculate the sample size for this study; it 
has been determined to allow preliminary assessment of safety, tolerability, PK and PD. 
However, as a key secondary endpoint, considerations has been given to the ratio to 
baseline of the PD biomarker Bcl-2. It is assumed that this endpoint is loge normally 
distributed. Based on 6 participants from the highest GSK3888130B dosed cohort and 14 
placebo participants pooled across all cohorts, the probability of different true inhibition 
(GSK3888130B vs. placebo) thresholds of interest is given in the Table below. A non-
informative prior distribution and a maximum between participant SD (loge scale) of 0.3 
is assumed for both GSK3888130B and placebo arms. 
True Inhibition thresholds 
Probability of Meeting Thresholds Given the 
Following True Inhibitions 
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. 
Note: "Enrolled" means a participant's, or their legally acceptable representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process and screening. Potential participants who are screened for the purpose of 
determining eligibility for the study, but do not participate in the study, are not 
considered enrolled, unless otherwise specified by the protocol.  
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9.3. 
Analysis Sets 
For the purpose of analysis, following analysis sets are defined: 
Analysis Set 
Description 
Screened 
All participants who signed the ICF and are screened for eligibility.  
Enrolled 
All participants in the Screened analysis set who are entered into the 
study. 
Safety 
All participants who received study intervention. 
Pharmacokinetic All participants in the Safety analysis set and who had received an 
active study intervention and had at least 1 non-missing PK 
assessment (Non-quantifiable [NQ] values will be considered as non-
missing values). 
PD 
All participants in the Safety analysis set who had at least 1 post-
baseline PD assessment. 
 
9.4. 
Statistical Analyses 
The statistical analysis plan will be finalized prior to first participant first visit (FPFV) 
and it will include a more technical and detailed description of the statistical analyses 
described in this Section. This Section is a summary of the planned statistical analyses of 
the most important endpoints including primary and key secondary endpoints. 
9.4.1. 
General Considerations 
The main statistical analyses will be carried out in the Bayesian framework. Non 
informative priors will be used for all modelling parameters.  
The following summaries of the posterior distribution will be reported: posterior median, 
95% equal tailed credible interval, posterior probabilities of the true treatment effect 
being greater/lower than pre-specified thresholds.  
9.4.2. 
Baseline Definition 
The baseline value will be the latest pre-dose assessment with a non-missing value, 
including those from unscheduled visits. If time is not collected, Day 1 (or Day -1 where 
applicable) assessments are assumed to be taken prior to dose and used as baseline. 
If baseline data is missing, no derivation will be performed, and baseline will be set to 
missing. 
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9.4.3. 
Primary Endpoint(s) 
No formal statistical testing will be performed on safety data. 
All safety data evaluations will be based on the “Safety” analysis set. 
Clinical interpretation will be based upon review of displays of adverse events, laboratory 
values, vital signs and 12-Lead ECG readings. The principal consideration in this 
evaluation will be the investigator-reported relationships of adverse events 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) standard. 
9.4.4. 
Secondary Endpoint(s) 
9.4.4.1. 
Pharmacokinetic parameters 
The pharmacokinetic (PK) analyses will be based on the “Pharmacokinetic” analysis set. 
Individual serum concentration-time data will be graphically displayed and summary 
statistics will be produced by time point. Serum GSK3888130B concentration-time data 
will be analysed by non-compartmental methods. Calculations will be based on the actual 
sampling times recorded during the study. From the serum concentration-time data, the 
following pharmacokinetic parameters will be determined, as data permit: area under the 
concentration-time curve [AUC], maximum concentration [Cmax], time to Cmax 
[Tmax], half-life [t½ ], clearance [CL] .  
Descriptive statistics (n, arithmetic mean, standard deviation (SD), 95% CI, minimum, 
median and maximum,) will be calculated for all pharmacokinetic parameters. In 
addition, for loge-transformed variables geometric mean, 95% confidence interval (CI), 
standard deviation on the loge scale and %CVb will be provided. Full details of planned 
secondary analysis will be specified in the SAP. 
. 
9.4.4.2. 
Pharmacodynamic and Target Engagement endpoint(s) 
The analyses will be based on the “PD” analysis set. 
The pharmacodynamic biomarker, T Cell Bcl-2 will be analysed using a Bayesian 
repeated measures model, including study treatment, visit, study treatment-by-visit 
interactions and baseline. Non informative priors will be used for all model parameters. 
An inverse Wishart prior will be used for the within-subject unstructured covariance 
matrix. Other options may be investigated to determine an appropriate covariance 
structure in case of issues. If data permits, then a dose response model will be fitted. Full 
details of planned analysis will be specified in the SAP.  
 
 will also be analysed as specified above.  
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9.4.4.3. 
Other Safety Analyses 
The analyses will be based on “Safety” analysis set. 
Immunogenicity data will be summarized as the number and percentage of participants 
with confirmed positive anti-GSK3888130B antibodies and where applicable the titres 
will be listed.  
9.5. 
Interim Analyses 
Prior to each dose escalation, the DEC will review data from a minimum of 2 participants 
dosed with GSK3888130B (Cohorts 1 and 2) or a minimum of 4 participants dosed with 
GSK3888130B (all other SAD cohorts). Safety, tolerability (including absolute CD4+ T 
cell counts) and PK data up to and including Day 
will be reviewed. Available TE data 
will also be explored. Further details are described in Section 4.1, Section 6.5 and Section 
10.1.5. 
In addition, interim analyses will be performed once a minimum of four participants 
dosed with GSK3888130B in cohort 4 have completed up to and including the Day 
 
visit. At this point, in addition to the Sponsor study statistics and programming team 
members, the study CPMS team (as required) will be unblinded to cohorts 1 to 4 only, in 
order to provide required outputs to the team. As for the preparation of outputs for the 
previous dose escalations, the randomisation schedules and unblinded datasets will be 
stored on internal restricted drives such that the remaining study team members will not 
be unblinded, unless there is a specific requirement to review individual participants 
(Section 6.3.1). Safety, tolerability (including absolute CD4+ T cell counts), PK, 
immunogenicity, TE (total IL-7 assay measurements) and PD (T cell Bcl-2 if feasible) 
data will be reviewed by the GSK DEC to inform on internal decision-making activities. 
Additional interim analyses may be performed during the course of the study to inform 
internal decision-making activities. No changes to the conduct of the study will be 
implemented as a result of these analyses.  
The SAP 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: 
i. Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
ii. Applicable ICH Good Clinical Practice (GCP) Guidelines 
iii. Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB 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.  
• Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The Investigator will be responsible for the following: 
iv. 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 
v. Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures 
vi. 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), ), 
European Medical Device Regulation 2017/745 for clinical device 
research (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 
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Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to 
the participant and answer all questions regarding the study.  
• Participants must be informed that their participation is voluntary. Participants 
will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and 
the IRB/IEC or study centre.  
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorised person obtaining the informed consent must 
also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.  
• A copy of the ICF(s) must be provided to the participant.  
• Participants who are rescreened are required to sign a new ICF. 
GSK (alone or working with others) may use participant’s coded study data and samples 
and other information to carry out this study; understand the results of this study; learn 
more about GSK3888130B or about the study disease; publish the results of these 
research efforts; work with government agencies or insurers to have the GSK3888130B 
approved for medical use or approved for payment coverage.  
The ICF contains a separate Section that addresses the use of participant data and 
remaining samples for optional further research. The investigator or authorised designee 
will inform each participant of the possibility of further research not related to the 
study/disease. 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 
participant data and/or remaining leftover samples to be used for further research not 
related to the study/disease. Participants who decline further research will tick the 
corresponding “No” box. 
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 
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• 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 who will be required to give consent for 
their data to be used as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.5. 
Committees Structure 
A GSK Dose Escalation Committee (DEC) will be in place for this study. 
10.1.5.1. 
Dose Escalation Committee 
• The GSK DEC will consist of, at a minimum, the Principal Investigator (or 
appropriate designee), GSK Medical Monitor, GSK Clinical Sciences representative, 
CPMS representative, GSK Statistician, GSK Data Quality representative and a GSK 
Global Safety representative. Additional internal GSK representatives may be 
consulted and included in the dose escalation decision making, as deemed necessary 
by the GSK DEC. 
• Participant safety will be continuously monitored by the GSK DEC, which includes 
safety signal detection at any time during the study. 
• The GSK DEC will make the decision to proceed to the next dose level of 
GSK3888130B following review of safety, tolerability (including absolute CD4+ T 
cell counts), and PK data up to and including Day
 for both IV and SC dosed 
cohorts as described in Section 4.1 and Section 6.5. Available TE data (total IL-7 
levels) will also be explored. 
• Safety, PK and PD stopping criteria will be strictly applied. Details of stopping and 
temporary halt criteria can be found in Section 7.2.  
• A Dose Escalation Charter will be written outlining in detail how the study team will 
ensure data integrity used in dose selection decisions by performing clinical data 
review and appropriate quality control of data prior to making dose selection 
decisions, as well as outlining the responsibilities of the investigators and site staff for 
reporting safety data, participation during dose escalation meetings, and confirmation 
that the data used for dose escalation are accurate and complete. 
• If a stopping criterion is met, dose escalation will stop, and no further participants 
will be dosed at that dose level or any higher level. If after consultation, the Sponsor 
deems that dosing can resume at that level or higher the Sponsor will submit an 
application for a substantial amendment to the Regulatory Agency to present the data 
and approve a revision to the protocol. 
• Case unblinding may be performed for above reviews if necessary. The data may be 
reviewed in an unblinded fashion by the unblinded members of the DEC should a 
safety concern arise during the blinded review. These unblinded members will be 
defined within the Dose Escalation Charter. 
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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 all investigators who participated in the study with a summary 
of the study results and will tell the investigators what treatment their patients 
received. The investigator(s) is/are encouraged to share the summary results with the 
study participants, as appropriate. 
• Under the framework of the SHARE initiative, GSK intends to make anonymized 
participant-level data from this trial available to external researchers for scientific 
analyses or to conduct further research that can help advance medical science or 
improve patient care. This helps ensure the data provided by trial participants are used 
to maximum effect in the creation of knowledge and understanding. Requests for 
access may be made through www.clinicalstudydatarequest.com. 
• 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 participants are used to maximum effect in the creation of knowledge and 
understanding 
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.  
• Guidance on completion of CRFs will be provided in the eCRF instructions. 
• Quality tolerance limits (QTLs) will be pre-defined in the QTL Plan to identify 
systematic issues that can impact participant right, safety and/or reliability of study 
results. These pre-defined parameters will be monitored during and at the end of the 
study and all deviations from the QTLs and remedial actions taken will be 
summarized in the clinical study report. 
• 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 including definition of study critical data items 
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Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance 
issues and monitoring techniques (central, remote, or on-site monitoring) are provided 
in the Monitoring Plan. 
• The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. Detailed information about study data 
collection and management process including systems used can be found in the study 
Data Management Plan. 
• The sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations). 
• Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the investigator for 25 years from the issue of the final Clinical 
Study Report (CSR)/ equivalent summary unless local regulations or institutional 
policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor.  
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 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data and its origin can be found in Source Data 
Acknowledgment. 
• The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorised site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.  
10.1.9. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
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Study/Site Termination 
GSK or 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: 
For study termination: 
• Discontinuation of further study intervention development. 
For site termination: 
• 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 or no recruitment of participants (evaluated after a reasonable amount of 
time) by the investigator. 
• If the study is prematurely terminated or suspended, the sponsor shall promptly 
inform the investigators, the IECs/IRBs, the regulatory authorities, and any contract 
research organization(s) used in the study of the reason for termination or suspension, 
as specified by the applicable regulatory requirements. The investigator shall 
promptly inform the subject and should assure appropriate participant therapy and/or 
follow-up. 
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 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 1 will be performed by the local laboratory.  
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. 
Table 1 
Protocol-Required Safety Laboratory Tests 
Laboratory 
Assessments 
Parameters 
Haematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes  
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Haemoglobin 
Haematocrit 
 
CD4+ T cell Count 
 
Clinical 
Chemistry1 
Urea/BUN 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total and 
direct bilirubin 
 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein 
 
Glucose (non-
fasting) 
Calcium 
Alkaline 
phosphatase2 
 
 
 
 
 
 
 
 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, 
nitrite, leukocyte esterase by dipstick 
• Microscopic examination (if blood or protein is abnormal, or if any 
other trace is detected) 
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Laboratory 
Assessments 
Parameters 
• 
 described in SRM 
Viral 
quantification 
and serology 
• EBV, CMV and VZV. 
• SARS-CoV-2 (serology only) 
Other 
Screening 
Tests 
i. 
Follicle-stimulating hormone and oestradiol (as needed in women 
of non-childbearing potential only) 
ii. Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines) 
iii. Serology (HIV antibody, hepatitis B surface antigen [HBsAg], 
hepatitis B core antibody and hepatitis C virus antibody and 
hepatitis C RNA) 
iv. Mycobacterium tuberculosis QuantiFERON Gold 
v. SARS-CoV-2 testing (performed as per site local procedures) 
vi. Smoking breath test 
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 Section 10.5. All events of ALT ≥3 
× upper limit of normal (ULN) and total 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 to GSK in an expedited manner (excluding 
studies of hepatic impairment or cirrhosis). 
2. If alkaline phosphatase is elevated, consider fractionating. 
 
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10.3. 
Appendix 3: AEs and SAEs: 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 intervention- intervention 
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. 
 


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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 
An SAE is defined as any serious adverse event that, at any dose: 
• Results in death 
• Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
• Requires inpatient hospitalisation or prolongation of existing hospitalisation 
o In general, hospitalisation signifies that the participant has been admitted 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalisation are AE. If a complication prolongs hospitalisation or fulfils any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalisation” occurred or was necessary, the AE should be considered 
serious. 
o Hospitalisation for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
• Results in persistent or significant disability/incapacity 
o The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. 
o This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
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interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
• Is a congenital anomaly/birth defect 
• Other situations: 
o Possible Hy’s Law case: ALT≥3xULN AND total bilirubin ≥2xULN (>35% 
direct bilirubin) or international normalized ratio (INR) >1.5 must be reported 
as SAE 
o Medical or scientific judgment should be exercised by the Investigator in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that 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. 
o Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse. 
10.3.3. 
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. 
• 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 required form. 
• 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 
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• 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. 
• 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 makes 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 
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• 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 submitted 
documents. 
• 
The Investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
 
10.3.4. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
1. The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
2. If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next Section) to report the event within 24 hours. 
3. The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
4. After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
5. If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next Section) or to the medical monitor by telephone. 
6. Contacts for SAE reporting can be found in the SRM. 
 
SAE Reporting to GSK via Paper Data Collection Tool 
a) Facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the medical monitor. 
b) In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
c) Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the SAE data collection tool within the designated reporting 
time frames. 
d) Contacts for SAE reporting can be found in the SRM. 


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10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions 
Woman of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 
• 
Premenopausal female with permanent infertility due to one of the following (for 
the purpose of this study): 
• 
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, gonadal dysgenesis), 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. 
• 
Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
a. A high follicle-stimulating hormone (FSH) level and low oestradiol in the 
postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement 
therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with more than one measurement in line with local 
thresholds is required.  
b. Females on HRT and whose menopausal status is in doubt must 
discontinue HRT to allow confirmation of postmenopausal status before 
study enrolment. 
 
• Male Participants: 
Male participants are eligible to participate if they agree to the following during the study 
intervention period and for 
 days after the single dose of study intervention:  
o Refrain from donating sperm 
Plus either:  
o Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent  
OR 
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o Must agree to use contraception as detailed below 
o Agree to use a male condom and should also be advised of the benefit for 
a female partner to use a highly effective method of contraception as a 
condom may break or leak when having sexual intercourse with a 
woman of childbearing potential who is not currently pregnant 
 
 
 


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10.5. 
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase 1 liver chemistry stopping criteria have been designed to assure subject safety and 
to evaluate liver event etiology.  
Phase 1 Liver Chemistry Stopping Criteria and Required Follow Up Assessments 
Liver Chemistry Stopping Criteria  
 
ALT-absolute 
 
ALT3xULN 
If ALT3xULN AND total bilirubin 2xULN (>35% direct bilirubin) 
or international normalized ratio (INR) >1.5, report to GSK as an 
SAE1,2. 
 
Required Actions, Monitoring and Follow up Assessments  
Actions 
Follow Up Assessments 
1. Immediately discontinue study 
intervention 
2. Report the event to GSK within 24 
hours 
3. Complete the liver event form and 
complete an SAE data collection tool if 
the event also meets the criteria for an 
SAE2 
4. Perform liver event follow up 
assessments as described in the Follow 
Up Assessment column. 
Do not restart or rechallenge participant 
with study intervention  
5. Monitor the participant until liver 
chemistries resolve, stabilise, or return 
to within baseline (see 
MONITORING) 
MONITORING: 
If ALT≥3xULN AND total bilirubin ≥ 
2xULN or INR >1.5 
6. Repeat liver chemistries (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, total bilirubin and INR) 
• Viral hepatitis serology3 
• Obtain INR and recheck with 
each liver chemistry assessment 
until the aminotransferases values 
show downward trend 
• Obtain blood sample(s) for 
pharmacokinetic (PK) analysis as 
required, after the most recent dose4  
• Obtain serum creatine phosphokinase 
(CPK), lactate dehydrogenase (LDH), 
gamma-glutamyl transferase (GGT), 
glutamate dehydrogenase (GLDH) 
and serum albumin. 
• Fractionate bilirubin, if total bilirubin 
2xULN 
• Obtain complete blood count with 
differential to assess eosinophilia 
• Record the appearance or worsening 
of clinical symptoms of liver injury, 
or hypersensitivity, on the liver event 
form 
• Record use of concomitant 
medications on the concomitant 
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Liver Chemistry Stopping Criteria  
and perform liver event follow up 
assessments within 24 hours 
7. Monitor participant twice weekly until 
liver chemistries resolve, stabilise or 
return to within baseline 
8. A specialist or hepatology consultation 
is recommended 
 
If ALT3xULN AND total bilirubin 
<2xULN and INR 1.5: 
9. Perform liver chemistries (include 
ALT, AST, alkaline phosphatase, total 
bilirubin and INR) and perform liver 
event follow up assessments within 24-
72 hours 
10. Monitor participant weekly until liver 
chemistries resolve, stabilize or return 
to within baseline 
acetaminophen, herbal remedies, 
recreational drugs, and other over the 
counter medications. 
• Record alcohol use on the liver event 
alcohol intake form 
 
If ALT3xULN AND total bilirubin  
2xULN or INR >1.5 obtain the 
following in addition to the assessments 
listed above: 
• Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG) or gamma globulins. 
• 
Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging form. 
• 
Liver biopsy may be considered and 
discussed with local specialists if 
available, for instance: 
o In patients when serology 
raises the possibility of 
autoimmune hepatitis (AIH) 
o In patients when suspected 
drug induced liver injury 
(DILI) progresses or fails to 
resolve on withdrawal of 
study intervention 
o In patients with acute or 
chronic atypical presentation. 
• If liver biopsy is conducted, then 
complete liver biopsy form 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin 
fractionation testing is unavailable, record the absence/presence of detectable urinary bilirubin 
on dipstick, which is indicative of direct bilirubin elevations suggesting liver injury.  
2. All events of ALT  3xULN and total 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 to GSK as an SAE (excluding studies of hepatic impairment or cirrhosis); the INR 
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3. Includes: hepatitis A immunoglobulin (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; 
cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
heterophile antibody or monospot testing) and hepatitis E IgM antibody  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention 
prior to PK blood sample draw. 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 
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10.6. 
Appendix 6: SARS-CoV-2 Risk Mitigation Participant 
Counselling 
The risk to participants from SARS-CoV-2 is an evolving situation and dependent on 
factors such as public health measures, vaccination rates and the effectiveness of 
vaccination against novel variants. As such, it is impossible to predict how the risk to 
participants may change over the course of this study. The approach to risk mitigation is 
informed by UK Government guidance and is broadly described below. Any changes to 
the advice given to participants will be approved by the Principal Investigator and 
Medical Monitor, with approval from Competent Authority and ethics committee as 
required.  
All study participants: 
• Given that the extent of immunosuppression caused by GSK3888130B is unknown, 
there is the potential that prior vaccination may not provide the same level of 
protection against infection. Furthermore, it is unknown to what extent 
GSK3888130B might impair the level of protection provided by vaccines (either to a 
new pathogen, SARS-CoV-2 variant or as a booster) given after exposure to 
GSK3888130B and before pharmacodynamic markers return to baseline. 
• All participants will be counselled that prior vaccination may not be as effective 
against circulating infections. The risk of infection is considered low based on prior 
experience, pre-clinical data and because immunosuppression is expected to be 
minimal in this single dose study. However, all participants should be vigilant of any 
new or prolonged symptoms which are suggestive of infection. 
• In view of the uncertainty of vaccination and potential variants to SARS-CoV-2, 
participants must agree to adhere to UK government guidance on international travel 
during the study period. 
• Participants who become eligible for booster vaccinations to SARS-CoV-2 are 
permitted to receive these during the course of the study in accordance with national 
or local policy. The sole exception to this would be where participants are offered a 
live vaccine to SARS-CoV-2 (none currently available in the UK), in view of the risk 
of activate infection. Participants will be counselled that any booster vaccination may 
provide less protection due to immunosuppression. 
• All participants will be instructed to follow the Public Health England guidance on 
how to stop the spread of SARS-CoV-2 infection (How to stop the spread of 
coronavirus (COVID-19) - GOV.UK (www.gov.uk)). 
• In the event a participant experiences any signs/symptoms of SARS-CoV-2 infection 
or other potential infectious disease from the start of study until completed follow-up, 
they will be instructed to call the phase 1 unit as a matter of urgency for further 
advice/telephone assessment in the first instance. Early referral to the hospital setting 
will be considered if a participant is experiencing mild COVID-19 symptoms which 
is progressing.  Hospital referral will be made urgently in the event a participant has 
moderate/severe disease. Participants who become symptomatic after completion of 
follow-up should seek medical care through standard pathways (e.g., Accident & 
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CD4+ T cell counts <0.2x109/L (from detection to resolution) 
• Additional study visits and blood tests may be performed at the discretion of the 
Investigator until CD4+ T cell counts return to levels >0.2x109/L 
• Advised to follow the Public Health England Guidance for people previously 
considered clinically extremely vulnerable from COVID-19 - GOV.UK 
(www.gov.uk): 
o Follow advice you may receive from your doctor 
o Take care to avoid routine coughs, colds, and other respiratory viruses 
o Follow Public Health England guidance for Living safely with respiratory 
infections, including COVID-19 - GOV.UK (www.gov.uk). 
 


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10.8. 
Appendix 8: Abbreviations and Trademarks 
Abbreviations 
ADA 
Anti-Drug Antibodies 
AE 
Adverse Event 
AIH 
Autoimmune Hepatitis 
ALT 
Alanine Amino Transferase 
AMP 
Auxiliary Medicinal Product 
AST 
Aspartate Amino Transferase 
AUC 
Area Under the Curve 
BHIVA 
British HIV Association 
BM 
Bone Marrow 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CA 
Competent Authority 
CD 
Cluster of Differentiation 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CIOMS 
Council for International Organisations of Medical Sciences 
Cl 
Clearance 
Cmax 
Maximum Concentration 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
CONSORT 
Consolidated Standards Of Reporting Trials 
COVID-19 
Coronavirus Disease 
CPMS 
Clinical Pharmacology Modelling and Simulation 
CRF 
Case Report Form 
CRLF 
Cytokine Receptor Like Factor 
CSR 
Clinical Study Report 
CV 
Cardiovascular 
DEC 
Dose Escalation Committee 
DEP 
Dose Escalation Plan 
DILI 
Drug Induced Liver Injury 
DNA 
Deoxyribonucleic Acid 
DTH 
Delayed Type Hypersensitivity 
EBV 
Epstein-Barr Virus 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
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ED 
Early Withdrawal 
FPFV 
First Participant First Visit 
FRC 
Fibroblastic Reticular Cells 
FSH 
Follicle Stimulating Hormone 
FTIH 
First Time In Huma 
GCP 
Good Clinical Practice 
GSK 
GlaxoSmithKline 
HBsAg 
Hepatitis B Surface Antigen 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
hr 
Hour 
HRT 
Hormone Replacement Therapy 
HV 
Healthy Volunteer 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IL 
Interleukin 
ILC 
Innate Lymphoid Cells 
ILH 
Immediate Local Hypersensitivity 
IMP 
Investigational Medicinal Product 
INR 
International Normalised Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
JAK 
Janus kinase 
kg 
kilogram 
LLN 
Lower Limit of Normal 
m2 
metres squared 
mAb 
Monoclonal Antibody 
MCH 
Mean Corpuscular Haemoglobin 
MCV 
Mean Cell Volume 
mL 
millilitre 
mm 
millimetre 
MMR 
Measles Mumps Rubella 
MS 
Multiple Sclerosis 
MSDS 
Material Safety data sheet 
msec 
millisecond 
MTB 
Mycobacterium Tuberculosis 
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MZ 
Marginal Zone 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for 
Adverse Events 
NK 
Natural Killer 
NOAEL 
No Observed Adverse Effect Level 
NSAID 
Non-Steroidal Anti Inflammatory Drug 
NSCLC 
Non-small cell lung carcinoma 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Pharmacodynamic 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PPMS 
Primary Progressive Multiple Sclerosis 
QTcF 
QT Interval corrected for heart rate according to Fridericia’s formula 
QTL 
Quality Tolerance Limit 
RBC 
Red Blood Cell 
RNA 
Ribonucleic Acid 
RRMS 
Relapsing Remitting Multiple Sclerosis 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-Cov-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SC 
Subcutaneous 
SD 
Standard Deviation 
SGOT 
Serum Glutamic Oxalacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SoA 
Schedule of Activities 
SPMS 
Secondary Progressive Multiple Sclerosis 
SRM 
Study Reference Manual 
STAT 
Signal Transducer and Activator of Transcription 
SUSAR 
Suspected Unexpected Serious Adverse Event 
T1/2 
Half life 
T1D 
Type 1 Diabetes 
TB 
Tuberculosis 
TE 
Target Engagement 
TLO 
Tertiary Lymphoid Organ 
Tmax 
Time to maximum concentration 
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ULN 
Upper Limit of Normal 
URTI 
Upper Respiratory Tract Infection 
UTI 
Urinary Tract Infection 
VZV 
Varicella Zoster Virus 
WBC 
White Blood Cell 
WOCBP 
Women Of Child Bearing Potential 
WONCBP 
Women Of Non Child Bearing Potential 
g 
microgram 
 
Trademark Information 
 
Trademarks of the GSK group of 
companies 
 
Trademarks not owned by the GSK 
group of companies 
None 
 
Copaxone 
 
 
ProImmune REVEAL 
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10.9. 
Appendix 9: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
Amendment 05: 25 Jan 2023  
Identified in the Table below are substantial changes made to the Study Protocol since the 
previous submitted version.  
 
Section # and title 
Description of change 
Brief rationale 
Section 2.3.1 Risk 
Assessment: 
Reproductive toxicity 
 
 
 
 
 
 
 
Section 5.1 Inclusion 
criteria: Sex and 
Contraceptive/Barrier 
Requirements 
 
 
 
 
 
 
 
Section 8.3.5 
Pregnancy 
Duration for which 
details of pregnancies 
in female partners of 
male participants will 
be collected
 
. 
Period of data collection 
 
 
Section 10.4.1: 
Appendix 4: 
Contraceptive and 
Barrier Guidance 
 
 
 
 
. 
 
 
Section 1.3.2: 
Schedule of 
Activities 
Intravenous Dosed 
Cohorts 
Included Day 1 into AE 
& SAE Review 
Corrected table formatting to include Day 1 
in AE & SAE review to correspond with 
text in Section 8.3.1.  
• 
All AEs will be collected from the start 
of intervention until the follow-up visit. 
• 
All SAEs will be collected from the 
signing the inform consent form until 
the follow-up visit. 
Section 1.3.2: 
Schedule of 
Activities 
Intravenous Dosed 
Cohorts 
Included Day 1 into 
Concomitant 
medication review 
Corrected table formatting to include Day 1 
in concomitant medication review to 
correspond with text in Section 6.8. 
• 
Any medication (including over-the-
counter or prescription medicines, 
recreational drugs, vitamins, and/or 
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Section # and title 
Description of change 
Brief rationale 
herbal supplements) that the participant 
receives during the study must be 
recorded. 
 
Amendment 4 03 Nov 2022 
Identified in the Table below are substantial changes made to the Study Protocol since the 
previous submitted version.  
 
Section # and 
title 
Description of change 
Brief rationale 
Section 1.3 
Schedule of 
Activities 
Additional 
 
 
 
.  
Updated to 
 
 
  
Section 3 
Objectives and 
Endpoints 
Additional exploratory 
objective and related 
endpoints added. 
 
 
. 
Section 2.3 
Benefit/ Risk 
Assessment: 
Renal, 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
.  
Section 2.3 
Benefit/ Risk 
Assessment: 
haemotological 
Minor change to existing 
text.  
Grammatical correction.   
Section 2.3 
Benefit/ Risk 
Assessment: 
 
 
 
 
 
 
  
  
 
 
 
 
The statement ‘there have 
been no 
 
 has been 
corrected to ‘there have 
been no 
 
 
 
 
 
 
  
Location correction of adverse event.  
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Section # and 
title 
Description of change 
Brief rationale 
Section 2.3 
Benefit/ Risk 
Assessment: 
 
 
 
 
 
was moved to the 
appropriate section 
 
 
 
). 
Location correction of adverse event. 
Section 8.7 
Biomarkers  
Addition of Section 8.7.3 
.  
 
Included to provide instruction for collection 
and storage of 
 for assessment 
of 
. 
 
 
Amendment 3 [05 August 2022] 
Identified in the Table below are substantial changes made to the Study Protocol since the 
previous submitted version.  
 
In addition, minor typographical errors and inconsistencies have been corrected and 
minor formatting changes have been made.  
 
Section # and 
title 
Description of change 
Brief rationale 
Section 1.1 
Synopsis 
 
Section 1.2 
Schema 
Section 1.3 
Schedule of 
Activities 
  
 
.  
 
Updated number of 
participants and recruitment 
cap included. Recruitment 
statement added.  
 
Description of procedures, 
samples to be taken, change in 
Schedule of Activities updated 
to include Day  activities for 
IV cohorts and to specify 
 
 
 
 
 
Section 2.1 
Study 
Rationale 
 
Section 2.2 
Background 
  
 
.  
 
 
 
 
 
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Section # and 
title 
Description of change 
Brief rationale 
Section 2.3 
Benefit/ Risk 
Assessment 
Updated GSK3888130B risks 
relating to dose selection, 
infection/lymphopenia, 
immunogenicity and 
malignancy. 
 
 
 
 
. 
 
 
. 
Section 3 
Objectives and 
Endpoints 
 
 
 
 
 
 
. 
Additional tertiary/exploratory/other 
objectives and endpoints included. 
Section 4. 
Study Design 
  
 
.  
 
Description of procedures, 
samples to be taken, change in 
Schedule of Activities updated 
to include Day  activities for 
IV cohorts and to specify 
 
. 
 
Scientific rationale and 
 
. 
 
 
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Section # and 
title 
Description of change 
Brief rationale 
Section 5. 
Study 
Population 
Additional inclusion and 
exclusion criteria added on 
 
To specify requirements for
 
 
Section 6. 
Study 
Intervention 
Inclusion of 
 
 
 
 
 
 
 
. 
Update to include details of challenge 
agents for the 
 
  
Section 8. 
Study 
Assessments 
 
 
 
 
 
 
. 
 
 
 
 
 
 
   
 
 
Section 9. 
Statistical 
Considerations 
Increased the participants and 
included a justification 
Updated to reflect 
 
 
 
Amendment 2 [10 February 2022] 
Identified in the Table below are substantial changes made to the Study Protocol since the 
previous submitted version.  
 
In addition, non-substantial clarifications have been made to Section 1.3.2 and Section 
1.3.3 to formalise the pre-dose PK sampling in the schedule of activities. In addition, 
minor typographical errors and inconsistencies have been corrected and minor formatting 
changes have been made.  
 
 
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Section  
Current text 
Proposed text 
Rationale for 
change 
Section 
2.3.1 Risk 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 against 
GSK3888130B; a 
humanized monoclonal 
antibody. 
We do not know whether 
this finding might also 
occur in humans. Risk 
mitigation will be 
implemented in this study 
to further characterize this 
risk. 
Mitigation strategy: 
Exclusion: Participants 
must be overtly healthy to 
participate in this study and 
will be excluded if they have 
abnormal blood tests or a 
medical history of 
autoimmunity.  
Monitoring:  
• 
Participants will be 
closely monitored for 
signs of 
 
including regular 
New risk added 
to Risk 
Assessment 
Table based on 
pre-clinical 
finding of 
. 
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Section  
Current text 
Proposed text 
Rationale for 
change 
 
. 
• 
A validated ADA assay 
(screening, 
confirmation, and 
titration methods) will 
be used in this study. 
 
Section 
7.2.5 Safety 
Dose 
Adjustment 
/ Stopping 
Criteria 
 
 
 
 
 are considered 
clinically relevant (National 
Cancer Institute - Common 
Terminology Criteria for 
Adverse Events (Version 5, 
NCI-CTCAE) grade 3 or 
greater). 
 
 
 
 
 
, in the opinion of the 
Investigator, can be 
reasonably attributed to 
GSK3888130B then this will 
result in review by the GSK 
DEC before further 
participants are dosed. 
New stopping 
criterion added 
based on 
 
 
Section 9.5 
Interim 
Analysis 
Safety, tolerability 
(including absolute CD4+ T 
cell counts), PK, 
 
 
 
) and 
PD (T cell Bcl-2) data will 
be reviewed by the GSK 
DEC to inform on internal 
decision-making activities. 
Safety, tolerability (including 
absolute CD4+ T cell counts), 
PK, 
, 
 
 
 
 and PD 
(T cell Bcl-2) data will be 
reviewed by the GSK DEC to 
inform on internal decision-
making activities. 
 
 
 
 
 
 
 
 
 
 
Section 
10.2 
Appendix 
2: Clinical 
Laboratory 
Tests 
 
Table 1 Protocol-Required 
Safety Laboratory Tests: 
 
 
 
 
 
 
 
added to 
laboratory 
assessment 
Table. Update 
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Section  
Current text 
Proposed text 
Rationale for 
change 
made to 
increase 
monitoring for 
 
 
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Amendment 1 [27 September 2021] 
Identified in the Table below are substantial changes made to the Study Protocol since the 
previous submitted version. Deleted text is formatted in strikethrough and added text is 
formatted in bold.  
Section  
Current text 
Proposed text 
Rationale for 
change 
Section 1.1. 
Synopsis 
To characterise the effects 
of GSK3888130B on target 
engagement. 
To characterise the effects of 
GSK3888130B on target 
engagement (TE). 
Abbreviation 
for target 
engagement 
added, 
abbreviation 
used throughout 
the protocol 
Section 1.1 
Synopsis & 
Section 1.3 
Schedule of 
Assessments 
& Section 4.1 
Overall 
design 
 
All participants will then be 
required to attend the clinic 
for up to outpatient visits 
over the course of 
 days 
after dosing for safety 
assessment and sample 
collection, and will receive 
a follow-up telephone call 
 days post last study 
visit. If required, additional 
follow-up visits may be 
scheduled. 
All participants will then be 
required to attend the clinic 
for up to  outpatient visits 
over the course of 
 days 
after dosing for safety 
assessment and sample 
collection, and will receive a 
follow-up telephone call 
days post last study visit. 
If required, additional 
follow-up visits may be 
scheduled. 
Extended the 
follow-up phone 
call to 
 
days to cover 
 
 
 
 Updates 
made 
throughout the 
protocol where 
applicable. 
1.1. Synopsis 
& 
Section 4.1 
Overall 
design 
The total duration of the 
study for each participant 
will be approximately 
 
weeks. 
The total duration of the 
study for each participant 
will be approximately 
 
weeks. 
Revised total 
duration to 
reflect the 
change in 
timing of 
follow-up 
telephone call  
Section 1.3.1 
Screening, 
admission and 
follow-up 
Applicable to IV cohorts 
hr baseline reading 
required prior to dosing. 
Applicable to IV cohorts 
hr reading during 
screening period is required 
prior to dosing. 
Revised to 
clarify that this 
will be used for 
screening 
participants, and 
not for baseline 
Section 1.3.2 
Intravenous 
dosed cohorts 
Recording to be started 
 
pre-dose. 
Recording to be started 
 
pre-dose. 
 
 
revised to 
increase 
duration of 
baseline data 
collection.  
Section 2.3.1. 
Risk 
assessment 
 
Potential risk: Dose 
selection 
New risk added 
to Risk 
Assessment 
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Section  
Current text 
Proposed text 
Rationale for 
change 
Rational for risk: The first 
dose level (Cohort 1) of 
GSK3888130B is 
anticipated to have 
clinically insignificant 
biological activity, with the 
rationale for dose selection 
explained in Section 4.3. 
There is a risk that the 
first dose level may have 
greater pharmacological 
activity than predicted. If 
this is the case, then the 
risks outlined in this risk 
assessment may be 
increased. 
Mitigation strategy:  
Monitoring: Participants 
undergo inpatient 
monitoring following IMP 
administration. 
Sentinel dosing is utilised 
for all cohorts. 
Dose modification: Dose 
escalation decisions are 
based on review of safety, 
tolerability and PK data. 
Available TE data will also 
be explored during dose 
escalation decisions. 
Dosing schedule may be 
modified within defined 
exposure limits. 
Table to clarify 
that the first 
dose of IMP 
(Cohort 1) may 
have 
pharmacological 
activity. 
Section 2.3.1. 
Risk 
assessment 
Male participants will be 
required to refrain from 
intercourse or use a 
condom, avoid semen 
exposure to a women of 
child bearing potential 
(WOCBP), and refrain 
from donating sperm for
 
days. 
Male participants will be 
required to refrain from 
intercourse or use a condom, 
avoid semen exposure to a 
women of child bearing 
potential (WOCBP), and 
refrain from donating sperm 
for 
 days. 
Contraception 
requirements 
 
 
 
 
 
 
Section 4.2 
Scientific 
rational for 
study design 
The study includes both IV 
and SC administration in 
separate cohorts to evaluate 
pharmacokinetics for the 
two routes. For SC 
administration, a lower and 
The study includes both IV 
and SC administration in 
separate cohorts to evaluate 
pharmacokinetics for the 
two routes. For SC 
administration, a lower and a 
Revised to 
clarify the 
rationale for 
interspersing SC 
dosing cohorts 
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Section  
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Proposed text 
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change 
a higher dose level is 
selected as per feasible 
drug administration within 
the proposed dose range 
with the higher SC dose 
limited by the volume of 
administration. The IV 
route of administration was 
selected for the initial 
dosed cohorts to enable 
monitoring of early safety 
signals during infusion. The 
dose escalations have been 
planned to ensure that 
exposure increments 
remain consistent between 
ascending dose 
levels/cohorts based on PK 
exposure predicted from 
pre-clinical data. 
higher dose level is selected 
as per feasible drug 
administration within the 
proposed dose range with 
the higher SC dose limited 
by the volume of 
administration. 
 
 
 
 
 
 
 
The IV route of 
administration was selected 
for the initial dosed cohorts 
to enable monitoring of early 
safety signals during 
infusion. SC cohorts are 
interspersed with IV 
cohorts to minimise the 
number of subjects who 
are exposed to 
GSK3888130B. The dose 
escalations have been 
planned to ensure that 
exposure increments remain 
consistent between 
ascending dose 
levels/cohorts based on PK 
exposure predicted from pre-
clinical data (see Section 
4.3.2). 
with IV dosing 
cohorts 
Section 4.1 
Overall 
design 
Section 4.2 
Scientific 
rational for 
study design, 
Section 6.5 
Dose 
modification 
& Section 
10.1.5 
Committees 
and structure 
Available TE data will also 
be explored. 
Available TE data (total IL-
7 levels) will also be 
explored. 
Clarity provided 
to define what 
TE data may be 
available for 
review (total IL-
7 levels).  
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Section  
Current text 
Proposed text 
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change 
Section 4.3.1 
Human dose 
prediction 
The model was 
extrapolated to human, by 
scaling PK parameters 
using allometry and 
 
 
 
 The extrapolated 
model was then used to 
predict the dose-response 
relationships for human 
PK, the associated exposure 
safety margin in relation to 
the NOAEL in the monkey, 
and the suppression of 
 
 in human blood. 
The model was extrapolated 
to human, by scaling PK 
parameters using allometry 
and 
 
 
. The 
extrapolated model was then 
used to predict the dose-
response relationships for 
human PK, the associated 
exposure safety margin in 
relation to the NOAEL in 
the monkey, and the 
suppression of 
 in 
human blood. 
Updated to 
provide 
additional 
information on 
antibody 
 
 
 used to 
support dose 
prediction 
between IV and 
SC cohorts 
Section 4.3.2 
Dose 
escalation 
plan 
It is anticipated that the  
mg starting dose will result 
in suppression of 
 
 
. This low 
biological effect is 
considerably below the 
level of Bcl-2 suppression 
previously observed in 
humans with RN168 and 
Copaxone. The starting 
dose of mg is supported 
by PK-PD modelling and 
simulation which suggest 
adequate safety margins in 
relation to the NOAEL 
 
 found in the 4-
week toxicology study in 
monkeys (see Table 
below). 
 
It is anticipated that the mg 
starting dose will result in 
 
 
 
 
 previously 
observed in humans with 
RN168 and Copaxone. The 
starting dose of mg is 
deemed appropriate for 
healthy volunteers given 
the low risk for off-target 
toxicity, the existing 
knowledge of the target 
pathway in human, and 
the high pharmacology 
and safety relevance of the 
pre-clinical species 
(outlined above in this 
Section). The starting dose 
of mg is further supported 
by PK-PD modelling and 
simulation which suggest 
adequate safety margins in 
relation to the NOAEL 
(
 
) found in the 4-
week toxicology study in 
monkeys (see Table below).  
 
Updated to 
clarify the 
rationale to 
support the 
starting dose 
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Section  
Current text 
Proposed text 
Rationale for 
change 
Section 4.3.3 
Predicted 
plasma 
exposure, 
safety 
margins, 
target 
engagement 
(IL-7 
reduction) 
and pathway 
pharmacology 
(Bcl-2 
reduction) 
$Ratios based on total 
exposure at NOAEL of 
 
mg/kg/wk IV in 4-wk 
monkey study: AUC 
 µg/mL*h 
and Cmax 
µg/mL 
$Ratios based on total 
exposure at NOAEL of 
 
mg/kg/wk IV in 4-wk 
monkey study: AUC 
 µg/mL*h 
and Cmax 
 µg/mL 
AUC=AUC from time 0 
extrapolated to infinity. 
Cmax = maximum 
concentration 
 
Definition 
added in 
footnote for 
AUC and Cmax  
Section 5.1 
Inclusion 
criteria & 
Section 10.4 
Contraceptive 
and barrier 
guidance  
Male participants are 
eligible to participate if 
they agree to the following 
during the study 
intervention period and for 
days after the single 
dose of study intervention:  
o Refrain from 
donating fresh 
unwashed semen 
Male participants are 
eligible to participate if they 
agree to the following during 
the study intervention period 
and for 
days after the 
single dose of study 
intervention:  
o Refrain from 
donating sperm 
Contraception 
requirements 
extended to 
 
 
 
 
 
 
 
Sperm donation 
not permitted to 
eliminate risks 
due to potential 
exposure of 
IMP  
Section 7.2.5 
Safety dose 
adjustment / 
stopping 
criteria 
• If one or more 
participants from any 
dose level experiences a 
Serious Adverse Event 
(SAE) which has a 
reasonable possibility of 
relation to 
GSK3888130B, no 
further participants will 
be dosed until a full 
safety review of the data 
has taken place. 
 
• If one or more participants 
from any dose level 
experiences a Serious 
Adverse Event (SAE) 
which has a reasonable 
possibility of relation to 
GSK3888130B, no further 
participants will be dosed 
until a full safety review of 
the data has taken place. 
• If two or more 
participants in the same 
cohort experience a 
‘severe’ non-serious 
adverse reactions which 
has a reasonable 
possibility of relation to 
GSK3888130B, no 
further participants will 
be dosed until a full 
Additional 
stopping criteria 
added per EMA 
guidance for 
First-in-Man 
trials. 
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safety review of the data 
has taken place. ‘Severe’ 
non-serious adverse 
reactions can be either 
within or not within the 
same system organ class. 
 


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11. 
REFERENCES 
 
 
. 
Belarif L, Mary C, Jacquemont L, Mai HL, Danger R, Hervouet J, et.al. IL-7 receptor 
blockade blunts antigen-specific memory T cell responses and chronic inflammation in 
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Black CA. Delayed Type Hypersensitivity: Current Theories with an Historic Perspective. 
Dermatology Online Journal. 1999; 5. 
Burchill MA, Yang J, Vang KB, and Farrar MA. Interleukin-2 Receptor Signaling in 
Regulatory T Cell Development and Homeostasis. Immunol Lett. 2007; 114 1-8. 
 
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CopaxonePrescribingInformation.2009;https://www.accessdata.fda.gov/drugsatfda_docs/l
abel/2009/020622s057lbl.pdf 
 
 
 
 
 
Earle KA, Ambrosino DM, Fiore-Gartland A, Goldblatt D, Gilbert PB, Siber GR,et.al.. 
Evidence for Antibody as a Protective Correlate for COVID-19 Vaccines. medRxiv 2021; 
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peer-reviewed]. 
Ellis J, van Maurik A, Fortunato L, Gisbert S, Chen K, Schwartz A, et.al. Anti-IL-7 
Receptor α Monoclonal Antibody (GSK2618960) in Healthy Subjects – a Randomized, 
Double-Blind, Placebo-Controlled Study. B J Clin Pharmacol. 2019; 85 304–315 
GSK Document Number 2020N457447_00. GSK3888130B. A 4-Week (Once Weekly) 
Intravenous (Bolus) and Subcutaneous Toxicity Study in Monkeys. Final Report. MAR-
2021. 
GSK Document Number RPS-CLIN-014183. GSK3888130 Investigators Brochure. 
Effective Date: 03 Aug 2021.* 
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Gov.UK. National flu immunisation programme 2021; National flu immunisation 
programme 2022 to 2023 letter web sites. Available at: www.gov.uk. Accessed July, 2022 
 
Hauser SL and Cree BAC. Treatment of Multiple Sclerosis: A Review. The American 
Journal of Medicine. 2020; 133 1380−1390. 
Herold KC, Bucktrout SL, Wang X, Bode BW, Gitelman SE, Gottlieb PA, et.al. 
Immunomodulatory activity of humanized anti–IL-7R monoclonal antibody RN168 in 
subjects with type 1 diabetes. JCI Insight. 2019; 4(24):e126054. 
 
 
 
 
 
 
 
 
 
 
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International Multiple Sclerosis Genetics Consortium. Multiple Sclerosis Genomic Map 
Implicates Peripheral Immune Cells and Microglia in Susceptibility. Science. 2019; 365 
1417-1427 
Jamilloux Y, Henry T, Belot A, Viel S, Fauter M, Jammal TE, et.al. Should we stimulate 
or supress immune response in COVID-19? Cytokine and anti-cytokine interventions. 
Autoimmunity Reviews. 2020;19(7):102567. 
Kappos L, Wolinsky JS, Giovannoni G, Arnold DL, Wang Q, Bernasconi C, et al.  
Contribution of Relapse-Independent Progression vs Relapse-Associated Worsening to 
Overall Confirmed Disability Accumulation in Typical Relapsing Multiple Sclerosis in a 
Pooled Analysis of 2 Randomized Clinical Trials. JAMA Neuro,l 2020;77:1132-40 
Karawajew L, Ruppert V, Wuchter C, Kö sser A, Schrappe M, Dö rken B, et.al. Inhibition 
of In Vitro Spontaneous Apoptosis by IL-7 Correlates with Bcl 2 Up-Regulation, 
Cortical/Mature Immunophenotype, and Better Early Cytoreduction of Childhood T Cell 
Acute Lymphoblastic Leukemia. Blood. 2000; 96 (1): 297–306.  
Kovanen PE, and Leonard WJ. Cytokines and Immunodeficiency Diseases: Critical Roles 
of the Gamma(c)-Dependent Cytokines Interleukins 2, 4, 7, 9, 15, and 21, and Their 
Signaling Pathways. Immunol Rev. 2004; 202 67-83. 
Lee LF, Axtell R, Tu GH, Logronio K, Dilley J, Yu J, et.al. IL-7 Promotes T(H)1 
Development and Serum IL-7 Predicts Clinical Response to Interferon-β in Multiple 
Sclerosis. Sci Transl Med. 2011; 3(93) 93ra68. 
Link A, Vogt TK, FavreS, Britschgi1MR, Acha-Orbea H, Hinz B, et.al. Fibroblastic 
Reticular Cells in Lymph Nodes Regulate the Homeostasis of Naive T Cells. Nat Immunol. 
2007; 8 (11) 1255-1265. 
Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, et.al. CD127 Expression Inversely 
Correlates with FoxP3 and Suppressive Function of Human CD4+ T Reg Cells. J Exp Med. 
2006; 203(7)1701-11. 
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Mazzucchelli R, Durum S. Interleukin-7 Receptor Expression: intelligent Design. Nat 
Reviews Immunol. 2007; 7 144-154. 
Mitsdoerffer M, Peters A. Tertiary Lymphoid Organs in Central Nervous System 
Autoimmunity. Front Immunol. 2016; 7:451:1-12. 
 
 
 
Park J-H, Yu Q, Erman B, Appelbaum JS, Montoya-Durango D, Grimes HL, et.al. 
Suppression of IL-7Ralpha Transcription by IL-7 and Other Prosurvival Cytokines: A 
Novel Mechanism for Maximizing IL-7-Dependent T cell Survival. Immunity. 2004; 21 
289-302. 
 
 
 
 
 
Ruggieri M, Avolio C, Scacco S, Pica C, Lia A, Zimatore G.B, et.al. Glatiramer acetate 
induces pro–apoptotic mechanisms involving Bcl-2, Bax and Cyt-c in peripheral 
lymphocytes from multiple sclerosis patients. J Neurol. 2006; 253 231–236 
 
 
 
 
 
 
 
Thompson AJ, Baranzini SE, Geurts J, Hemmer B, Ciccarelli O. Multiple Sclerosis.  The 
Lancet 2018; 391 1622-1636. 
 
 
. 
 
 
 
 
Wan Q, Kozhaya L, ElHed A, Ramesh R, Carlson TJ, Djuretic IM, et.al. Cytokine Signals 
Through PI-3 Kinase Pathway Modulate Th17 Cytokine Production by CCR6+ Human 
Memory T cells. J Exp Med. 2011; 208(9)1875-87. 
 
 
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Zheng HY, Zhang M, Yang CX, Zhang N, Wang XC, Yang XP, et.al. Elevated exhaustion 
levels and reduced functional diversity of T cells in peripheral blood may predict severe 
progression in COVID-19 patients. Cellular & Molecular Immunology. 2020;17:541-543. 
Ziemssen T, Tolley C, Bennett B, Kilgariff S, Jones E, Pikec J, et.al. A mixed methods 
approach towards understanding key disease characteristics associated with the 
progression from RRMS to SPMS: Physicians’ and patients’ views. Multiple Sclerosis and 
Related Disorders. 2020; 38 101861. 


Signature Page for  213960 TMF-15719887 v1.0
Signature Page for TMF-15719887 v1.0
Reason for signing: Approved
Name: 
Role: A
Date of signature: 21-Mar-2023 11:35:30 GMT+0000
PPD

SAP_001.pdf: 
Statistical Analysis Plan
Study ID:  213960
Official Title of Study: A Randomised, Double-Blind, Placebo Controlled, 
Single Dose Escalation Study to Evaluate Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of GSK3888130B in Healthy 
Participants aged 18-55 inclusive
Date of Document : 17-Aug-2023


CONFIDENTIAL 
The GlaxoSmithKline group of companies 
213960 
Statistical Analysis Plan (SAP) 
Page 1 of 39 
Information Type: 
Statistical Analysis Plan (SAP) 
TITLE PAGE  
Protocol Title: 
A Randomised, Double-Blind, Placebo Controlled, Single Dose 
Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics of GSK3888130B in Healthy Participants 
aged 18-55 inclusive. 
Study Number: 
213960 
Compound Number: 
GSK3888130B 
Abbreviated Title: 
A FTIH study to evaluate Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of GSK3888130B in Healthy Participants aged 
18-55 inclusive. 
Sponsor Name: GlaxoSmithKline Research & Development Limited 
Regulatory Agency Identifier Number(s) 
 
Registry 
 
ID 
EudraCT 
2021-002063-22 
 
Copyright 2023 the GlaxoSmithKline group of companies. All rights reserved.  Unauthorised 
copying or use of this information is prohibited. 
 


CONFIDENTIAL 
213960 
Statistical Analysis Plan (SAP) 
Page 2 of 39 
TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 5 
1.1. 
Objectives and Endpoints ............................................................................. 5 
1.2. 
Study Design ................................................................................................ 8 
2. 
STATISTICAL HYPOTHESES ................................................................................. 9 
2.1. 
Multiplicity Adjustment .................................................................................. 9 
3. 
ANALYSIS SETS ................................................................................................... 10 
4. 
STATISTICAL ANALYSES ..................................................................................... 11 
4.1. 
General Considerations .............................................................................. 11 
4.1.1. 
General Methodology .................................................................. 11 
4.1.2. 
Model Checking and Diagnostics ................................................. 12 
4.1.3. 
Baseline Definition ....................................................................... 12 
4.2. 
Safety Analyses .......................................................................................... 13 
4.2.1. 
Adverse Events............................................................................ 13 
4.2.2. 
Laboratory Data ........................................................................... 14 
4.2.3. 
Vital Signs .................................................................................... 15 
4.2.4. 
ECG ............................................................................................. 15 
4.3. 
Secondary Endpoint(s) Analyses ................................................................ 16 
4.3.1. 
Pharmacokinetic Analyses ........................................................... 16 
4.3.2. 
Immunogenicity Analyses ............................................................ 17 
4.3.3. 
Pharmacodynamic Biomarker Analyses ....................................... 17 
4.3.4. 
Target Engagement Biomarker Analyses ..................................... 20 
 
 
 
 
 
 
4.5. 
Other Analyses ........................................................................................... 26 
4.5.1. 
Subgroup analyses ...................................................................... 26 
4.5.2. 
Other variables and/or parameters............................................... 26 
4.6. 
Dose Escalation .......................................................................................... 26 
4.7. 
Interim Analyses ......................................................................................... 26 
4.8. 
Changes to Protocol Defined Analyses ....................................................... 28 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 29 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 31 
6.1. 
Appendix 1 Study Population Analyses ....................................................... 31 
6.1.1. 
Participant Disposition ................................................................. 31 
6.1.2. 
Demographic and Baseline Characteristics .................................. 31 
6.1.3. 
Protocol Deviations ...................................................................... 31 
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6.1.4. 
Prior and Concomitant Medications ............................................. 32 
6.1.5. 
Additional Analyses Due to the COVID-19 Pandemic .................. 32 
6.2. 
Appendix 2 Data Derivations Rule .............................................................. 33 
6.2.1. 
Reporting Standards .................................................................... 33 
6.2.2. 
Criteria for Potential Clinical Importance ...................................... 33 
6.2.3. 
Study Day and Reference Dates .................................................. 34 
6.2.4. 
Assessment Window ................................................................... 34 
6.2.5. 
Multiple measurements at One Analysis Time Point .................... 35 
6.2.6. 
Handling of Partial Dates ............................................................. 35 
7. 
REFERENCES ....................................................................................................... 39 
 


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Version history 
SAP Version 
Approval 
Date 
Protocol 
Version (Date) 
on which SAP 
is Based 
Change 
Rationale 
SAP 
14 Dec 2021 
Protocol 
Amendment 1 
(27-SEP-2021) 
Not Applicable 
Original version 
SAP 
Amendment 1 
 
Protocol 
Amendment 2 
(10-FEB-2022) 
Revised Section 4.6 
Dose Escalation to 
exclude S&P providing 
CD4+ T cell counts 
outputs for each DEC 
meetings. 
Revised due to 
delay in data 
transfer for each 
DEC. 
Revised Section 4.7 
Interim Analyses to 
include 
Immunogenicity, PD 
Bcl-2 and TE Total IL-
7 plots to be reviewed 
during first Interim 
Analyses. 
Also added clarity on 
the outputs provided 
for each DEC and IA. 
Revision based 
on Protocol 
Amendment 2 
Protocol 
Amendment 6 
(21-MAR-
2023) 
Updated Sections 1.1. 
Objectives and 
Endpoints, 1.2. Study 
Design, 
 
, 4.7. 
Interim Analyses and 5. 
Sample Size 
Determination 
Revised based 
on Protocol 
Amendment 6 
Added 
 
 
 
 
 
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1. 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to describe the planned analyses to 
be included in the Clinical Study Report (CSR) for Study 213960. Details of the planned 
interim analysis, as well as the final analyses, are provided. 
1.1. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To investigate the safety and 
tolerability of single IV and SC doses 
of GSK3888130B in healthy 
participants. 
• Occurrence of Adverse Events (AEs) and 
Serious Adverse Events (SAEs). 
• Occurrence of clinically significant 
changes in laboratory values (CD4+ T 
cell counts, haematology, chemistry, 
urinalysis and virology), vital signs and 
12lead electrocardiogram (ECG) 
readings. 
Secondary 
To characterise the serum PK profile of 
single IV or single SC doses of 
GSK3888130B in healthy participants. 
Serum concentrations of GSK3888130B and 
derived PK parameters as data permit, 
including area under the concentration-time 
curve [AUC], maximum concentration 
[Cmax], time to Cmax [Tmax], half-life [t½], 
clearance [CL]. 
To evaluate the immunogenicity of 
single doses of GSK3888130B in 
healthy participants. 
Incidence of Anti-Drug Antibodies (ADAs) 
against GSK3888130B.  
To characterise the effects of 
GSK3888130B on target engagement 
(TE). 
Change from baseline in derived free IL-7 
levels (calculated from total IL-7 assay 
measurements) over time. 
To characterise the effect of single 
doses of GSK3888130B on PD 
biomarker Bcl-2. 
Change from baseline in T cell Bcl-2, 
measured in blood over time. 
Tertiary/Exploratory/Other 
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Objectives 
Endpoints 
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Objectives 
Endpoints 
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1.2. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
• Phase 1, single centre, randomised, double-blind, placebo controlled, dose 
escalation study comprising of seven planned SAD cohorts of 
GSK3888130B over a range of dose levels (from 
mg to 
 mg) in 
healthy participants. 
• 
 
 
.  
• 
o Participants will attend a screening visit within 28 days of study 
intervention. In participants who require an influenza vaccination 
and/or SARS-CoV-2 vaccination or booster, the screening window 
may be increased to 60 days.  
o Participants will receive study intervention on Day 1. For the IV 
cohorts, participants will remain in the unit for  days and for the SC 
cohorts for  days. 
o All participants will then attend the clinic for up to  outpatient visits 
after dosing, over the course of 
 days, for safety assessments and 
sample collection and will receive two follow-up telephone calls; the 
first will be 
 days post last study visit and the second will be 
 days post last study visit. If required, additional follow-up 
visits may be scheduled.  
Study 
intervention 
Cohorts 
Study Intervention 
Cohort 1 – IV Dose 
GSK3888130B mg vs Placebo 
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Overview of Study Design and Key Features 
Cohort 2 – IV Dose 
GSK3888130B
 mg vs Placebo 
Cohort 3 – SC Dose 
GSK3888130B
 mg vs Placebo 
Cohort 4 – IV Dose 
GSK3888130B
 mg vs Placebo 
Cohort 5 – SC Dose 
GSK3888130B 
 mg vs Placebo 
Cohort 6 – IV Dose 
GSK3888130B
 mg vs Placebo 
Cohort 7 – IV Dose 
GSK3888130B 
 mg vs Placebo 
Study 
intervention 
Assignment 
• The study will aim to recruit 54 participants into seven SAD cohorts.  
• Cohort 1 and 2: Eligible participants will be randomised to receive either 
GSK3888130B or placebo in a 3:2 ratio comprising of five participants. 
• 
Cohort 3 to 7: Eligible participants will be randomised in a 3:1 ratio 
comprising of eight participants, except for cohort 6 which 
 
 
Interim 
Analysis 
First Interim analyses will be performed once a minimum of four participants 
dosed with GSK3888130B in cohort 4 have completed up to and including the 
Day 
 visit.  
Second Interim analyses will be performed once all participants in cohort 6 have 
completed up to and including the Day 
 visit for PK, TE (total IL7 levels), 
PD (T cell Bcl2) and 
 and up to and including 
Day
. 
Refer Section 4.7 for details. 
 
2. 
STATISTICAL HYPOTHESES  
The primary objective of this study is to assess the safety and tolerability of single IV and SC doses 
of GSK3888130B in healthy participants.  
No formal hypotheses are being tested in this study. 
2.1. 
Multiplicity Adjustment 
There will be no adjustments for multiplicity in this study. 
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3. 
ANALYSIS SETS 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Screened  
• All participants who signed the ICF and are 
screened for eligibility. 
Study Population 
Enrolled 
• All participants in the Screened analysis set who 
are entered into the study. 
• Note screening failures (who never passed 
screening even if rescreened) and ‘reserved’ or 
‘not used’ participants are excluded from the 
Enrolled analysis set as they did not enter the 
study. 
Study Population 
Randomised 
• All participants who are randomly assigned to 
study intervention in the study. 
Study Population 
Safety 
• All participants who received study intervention. 
• Participants will be analysed according to the 
study intervention administered. 
• Study 
Population 
• 
Safety 
Pharmacokinetic 
(PK) 
• All participants in the Safety analysis set who 
had received an active study intervention and 
had at least 1 non-missing post dose PK 
assessment (Non-quantifiable [NQ] values will 
be considered as non-missing values). 
• Data will be reported according to the actual 
study intervention. 
PK 
Pharmacodynamic 
(PD) 
• All participants in the Safety analysis set who 
had at least one post baseline PD result. 
• Data will be reported according to the actual 
study intervention. 
• 
PD/Biomarker 
 


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4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
4.1.1. 
General Methodology 
Participants who prematurely withdraw from study may be replaced. 
Unless otherwise specified, the Screened, Enrolled, Randomised or Safety Analysis Sets will be 
used for all Study Population analyses, the Safety Analysis Set will be used for all Safety analyses, 
the PK Analysis Set will be used for all Pharmacokinetic analyses and the PD Analysis Set will be 
used for all Pharmacodynamic/ Biomarker analyses. 
For all summaries, statistical analyses and plots, Placebo participants will be pooled across all 
cohorts in which the endpoint was collected, except for the following endpoints: 
• Cellular Biomarkers, 
 and 
 (Section 4.4.3): Placebo data will be 
pooled across Cohorts 1,2,3,4 and 7 
 
 
. 
• 
 
 Placebo data will be summarised by cohort since there are 
limited timepoints relative to the 
 which are common to these cohorts. 
 
 
  
 
 
Absolute baseline values will be included in all change from baseline or ratio to baseline 
summaries. Line plots will be produced on absolute values unless otherwise specified. 
95% equal tailed Credible Intervals (CrI) will be used for statistical analyses unless otherwise 
specified.  
Summary tables will provide the following descriptive statistics as a minimum, unless otherwise 
specified: 
• For continuous untransformed data (or where many zeros exist in the data): n, mean, 95% 
Confidence Intervals (CI), standard deviation (SD), median, minimum and maximum. 
Number of Zeros may also be added as an additional statistic, if deemed appropriate. 
• For continuous log-normally distributed data: n, geometric mean, 95% CI of the geometric 
mean, standard deviation on the log scale (SD (log)), %CVb (only for PK Parameters), 
median, minimum and maximum. 
• For categorical data: number and percentage of participants in each category. 
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4.1.2. 
Model Checking and Diagnostics 
The analyses will be conducted in the Bayesian framework. Models will be fitted by MCMC 
simulations using non-informative priors. 
A thinning sample may be used to aid convergence; where k is the thinning ratio and the number 
of samples are a minimum of 10,000*k.  For example, 100,000 MCMC samples may be generated 
with a thin of 10, providing 10,000 samples to be used for the estimate of the posterior distribution. 
A burn-in of 5,000 samples will be used by first intent. 
The following list of convergence diagnostics will be applied for each parameter (diagnostic 
checking outputs will be stored in the refdata folder in HARP in the relevant reporting effort): 
• The Monte Carlo Standard Errors (MCSE) should be compared with the standard deviation of 
the posterior distribution (SD) to ensure that only a fraction of the posterior variability is due 
to the simulation. The number of samples generated, and/or the thinning may be increased to 
reduce the ratio of the MCSE/SD as deemed necessary. 
• Trace plots of samples versus the simulation index will be visually inspected to assess some 
aspects of convergence. The centre of the chain should appear stable with very small 
fluctuations, i.e., the distribution of points should not change as the chain progresses and the 
posterior mean and variance are relatively constant.  
• Autocorrelation plots will be visually inspected to assess degree of autocorrelation (should 
decline rapidly and show no oscillation patterns). 
• 
Density plots of the posterior for the model parameters will be plotted (should be smooth and 
with a single hump). 
If the model is not deemed to have converged then increasing the number of MCMC samples 
and/or the thinning will be explored. The blocking of the parameters will also be considered. 
4.1.3. 
Baseline Definition 
For all endpoints the baseline value will be the latest pre-dose assessment (unless otherwise 
specified) with a non-missing value, including those from unscheduled visits. If time is not 
collected at Day 1: 
• If a pre-dose sample collection is the only scheduled visit (as per the schedule of activities 
table in the protocol), then Day 1 will be used as baseline. 
• 
Otherwise, if an assessment prior to Day 1 is available, this will be used as baseline.  
• 
Otherwise, baseline will be set to missing.  
4.1.3.1. 
Derivations and Handling of Missing Baseline Data 
For untransformed data, change from baseline at each time point is expressed as a difference. For 
loge transformed data, change from baseline will be expressed as a ratio. For individual gene data, 
change from baseline will be expressed as a fold change. 


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Definition 
Reporting Details 
Change from Baseline 
= Post-Baseline Visit Value – Baseline Value 
Ratio to Baseline  
= Post-Baseline Visit Value / Baseline Value  
OR 
= Exponential of (Log (Post-Baseline Visit Value) – Log (Baseline 
Value)) 
Fold Change Relative to 
Baseline  
= 2 to the power of (Post-Baseline Visit Value* – Baseline Value*) 
[*note that individual gene data is received on the log2 scale] 
Unless otherwise specified, if baseline data is missing, no derivation will be performed and 
baseline will be set to missing. 
4.2. 
Safety Analyses 
The primary objective of this study is to assess the safety and tolerability of single IV and SC doses 
of GSK3888130B.  
4.2.1. 
Adverse Events 
An adverse event (AE) is considered study intervention emergent if the AE onset date is on or after 
study intervention start date. All AE summaries will be based on study intervention emergent 
events unless otherwise specified. SAE summaries will be based on all SAEs reported regardless 
of whether they meet the definition of study intervention emergent or not. All AE and SAE 
summaries will be by System Organ Class (SOC) and Preferred Terms (PT) or only by PT, unless 
otherwise specified. 
Adverse events will be coded using the standard Medical Dictionary for Regulatory Affairs 
(MedDRA dictionary) and graded by the investigator according to the National Cancer Institute -
Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5).  
An overview summary of AEs, including counts and percentages of participants, will be 
summarized for the following categories and subcategories. 
• AE 
o Any AEs 
o AEs related to study intervention 
o AEs leading to study withdrawal 
• SAE 
o Any SAEs 
o SAEs related to study intervention 
A study intervention-related AE/SAE is defined as an AE for which the investigator classifies the 
possible relationship to study intervention as “Yes”. If relationship to study intervention is missing 
then worst-case approach will be applied (i.e. missing will be handled in the same way as ‘Yes’). 


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4.2.1.1. 
Adverse Events of Special Interest 
There are no adverse events of special interest identified for this study. 
4.2.1.2. 
COVID-19 Assessment and COVID-19 AEs 
The case report form will collect all COVID-19 AEs. 
The overall incidence of AEs and SAEs of COVID-19 and COVID-19 AEs leading to study 
withdrawal will be summarized. The incidence of these events at individual PT level can be 
obtained from the standard AE/SAE summaries. 
4.2.2. 
Laboratory Data 
Summary tables for change from baseline of CD4+ T cell counts, haematology and clinical 
chemistry laboratory tests will be produced. Worst-case post-baseline relative to baseline 
 results will be presented.  
Additionally, worst-case (i.e., the highest grade) change in the categories at post-baseline relative 
to baseline summary table will be provided for CD4+ T cell counts and 
 based on the cut-
off provided in the Table 1 below. 
Individual participant plots of the raw values of CD4+ T cell counts over time will be presented by 
study intervention. Line plots of the unadjusted geometric means and corresponding 95% CIs of 
CD4+ T cell counts will be presented over time. 
Listings of all Potential Clinical Important abnormalities will be presented for clinical chemistry 
and haematology (see Section 6.2.1).  
Listings of Potential Clinical Important Urinalysis data will be presented. Potential Clinical 
Important is referred as an increase in Protein or an increase in Occult Blood results, or if 
microscopy is performed during the study.   
Table 1 
Clinically Significant Grades Cut-Offs 
Parameter 
Grade 
Grade Cut-Off 
CD4+ T Cell 
Counts 
Grade 0 
Above 0.5×109/L 
Grade 1 
<0.5 to 0.2×109/L 
Grade 2 
<0.2 to 0.05×109/L 
Grade 3 
Below 0.05×109/L 
[1]: Include both absolute and change from baseline values. 
[2]: Only absolute values  
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4.2.2.1. 
Virology Data 
Virology data includes both quantitative and qualitative data as shown in Table 2. Appropriate 
summary tables (for quantitative data, these will be based on continuous untransformed data) will 
be provided (see Section 4.1.1).  
Table 2 
Virology Data 
Biomarker 
Result 
Classification 
Serology (Immunology as per SDTM data standards) 
CMV IgG (AU/mL) 
Quantitative Result 
<6.0 is Non-reactive  
>= 6.0 is Reactive 
CMV IgM 
Qualitative Result 
Positive/Negative 
EBNA IgG (U/mL) 
Quantitative Result 
< 5 U/mL is Negative 
VCA IgG (U/mL) 
Quantitative Result 
< 20 U/mL is Negative 
EBV VCA ab (IgM) (U/mL) 
Quantitative Result 
< 20 U/mL is Negative 
Varicella Zoster IgG (mIU/mL) 
Quantitative Result 
<150 mIU/mL is Negative 
Varicella Zoster IgM 
Qualitative Result 
Positive/Negative 
Viral quantification 
EBV (Copies/mL) 
Quantitative Result 
N/A 
CMV (Copies/mL) 
Quantitative Result 
N/A 
Varicella 
Qualitative Result 
Positive/Negative 
4.2.3. 
Vital Signs 
Summary table for change from baseline of Vital Signs will be produced. Listing of all Potential 
Clinical Important abnormalities will be presented (see Section 6.2.1). 
4.2.4. 
ECG 
Summary tables for ECG findings and change from baseline of 12-Lead ECG will be produced. 
Maximum QTcF (Friderica’s QT Interval Corrected for Heart Rate) values post-baseline relative 
to baseline will be produced and will be used to detect any clinical important changes. The 
categories are defined as: 
• Maximum QTcF values at post baseline relative to baseline: 
o To <=450 msec or No Change 
o Any Increase, To >450 to <=480 msec 
o Increase To >480 to <=500 msec 
o Increase To >500 msec 
• Maximum increase in QTcF values post baseline relative to baseline: 
o Increase <=30 msec 
o Increase of 31-60 msec  
o Increase of >60 msec 
Listing of all Potential Clinical Important abnormalities will be presented (see Section 6.2.1). 


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Full details of the planned safety displays are provided in the Output and Programming 
Specification (OPS). 
4.3. 
Secondary Endpoint(s) Analyses 
The secondary objectives of this study are to evaluate the Pharmacokinetics, Immunogenicity, 
Target Engagement (TE) and Pharmacodynamic biomarkers. 
4.3.1. 
Pharmacokinetic Analyses 
The PK analyses will be performed by, or under the direct auspices of GSK Biostatistics, as well 
as Clinical Pharmacology Modelling and Simulation (CPMS).  
4.3.1.1. 
Definition of endpoint(s) 
• Serum PK concentrations  
• PK Parameters as data permits:   
o Area under the Concentration-time curve 
 
o 
  
o Maximum Concentration [Cmax] 
o Time to Cmax [Tmax] 
o Half-life [t½ ] 
o 
 
o Clearance [CL or CL/F (SC cohorts)]  
o 
 
 
 
 
 
 
 
 
 
 
 
4.3.1.2. 
Main analytical approach 
Serum PK concentrations are assumed to be log-normally distributed and appropriate summary 
statistics will be displayed (see Section 4.1.1) by study intervention over time. Plots of individual 
concentration and median concentration data with range over time will be produced by GSK 
Biostatistics. 
PK parameters will be calculated by standard non-compartmental analysis using the current 
supported version of WinNonlin by CPMS and transferred back to GSK Biostatistics to provide 
descriptive statistics. All calculations of non-compartmental parameters will be based on actual 
sampling times.  
The untransformed and loge transformed PK Parameters will be summarized separately. 
Appropriate summary statistics will be displayed (see Section 4.1.1) as follows: 
• Untransformed PK parameter variables: Tmax, 
 
 
 
 
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• Loge transformed PK parameter variables: AUC 
 
, Cmax, Clearance [CL or CL/F (SC cohorts)], 
 and Half-life (t½) 
4.3.2. 
Immunogenicity Analyses 
The immunogenicity analyses will be based on the Safety Analysis Set. 
Immunogenicity testing involves a screening assay and a confirmation assay that together produce 
3 results: 
• Screening assay result (positive / negative) 
• 
Confirmatory assay result (positive / negative) if positive result in the screening assay 
• 
Titre result (numeric) if positive result in the confirmation assay 
The immunogenicity analyses will be summarised by incidence, i.e., the number of participants 
with anti-drug antibodies by study intervention over time and the titre of immunogenicity results 
will be listed. 
4.3.3. 
Pharmacodynamic Biomarker Analyses 
4.3.3.1. 
Definition of endpoint(s) 
• 
Peripheral blood T Cell Bcl-2 expression (Data captured as Bcl-2 expression in T cells): 
o Bcl-2 expression in T cells (%) 
o Bcl-2 expression in T cells (MdFI) 
o 
 
4.3.3.2. 
Main analytical approach 
It is assumed that endpoints defined in Section 4.3.3.1 are loge normally distributed, unless 
distributional properties suggest otherwise. 
The absolute values for the endpoints mentioned in Section 4.3.3.1 will be summarized 
descriptively. Line plots of the unadjusted geometric means and corresponding 95% CIs will be 
presented over time. Individual participant plots of the raw values over time will be presented by 
study intervention. 
A Bayesian Mixed Model Repeated Measures (MMRM) analysis for the pooled placebo data 
across all cohorts and all doses of GSK3888130B will be fitted for Bcl-2 expression in T cells 
(MdFI) endpoint. 
Non-informative priors will be used in this analysis. The prior for the regression coefficients will 
be normally distributed with mean 0 and a variance of 106.  Should there be convergence issues 
due to relatively small data values, the latter may be reduced to 104. The variance-covariance 
matrix will use an inverse-Wishart prior distribution, consisting of the identity matrix and the 
degrees of freedom set to the number of visits included in the model. Sensitivity to changes in the 
degrees of freedom will be considered. 
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Terms in the model are specified below:  
• Response: Absolute value on loge scale. 
• Category: Study intervention, Visit. 
• Interaction: Study intervention*Visit. 
• Repeated: Visit. 
Baseline values will be included in the response for this model, with visit = ‘Baseline’ and a distinct 
arbitrary code assigned for study intervention (the same for all baseline visits).  
The following will be calculated from the model: 
• For Baseline: The posterior mean for loge transformed Bcl-2, 
• For each study intervention: The posterior means for loge transformed Bcl-2 for each post-
baseline visit, 
• For each study intervention: The posterior means for the difference from baseline for loge 
transformed Bcl-2 for each post-baseline visit, 
• For each active study intervention: The posterior means for the difference from placebo for 
loge transformed Bcl-2 (GSK3888130B XX mg – Pooled placebo across cohorts) for each 
post-baseline visit. 
These values will then be back transformed and the following presented: 
• For Baseline: The posterior geometric mean, 
• For each study intervention: The posterior geometric means for each post-baseline visit,  
• For each study intervention: The posterior geometric means of the ratio to baseline for each 
post-baseline visit,  
• For each active study intervention: The posterior geometric means of the ratio of each 
active dose to placebo for each post-baseline visit. 
Equal tailed 95% credible intervals will be presented for each of the above back transformed 
values. In addition, the posterior probability that posterior ratios of each active dose to placebo are 
less than (<) 
 will be calculated. A line plot of the adjusted posterior 
geometric means and credible intervals over time will be presented. 
Dose Response Modelling 
If deemed appropriate, the following dose-response models will be fitted for maximum change 
from baseline on a loge scale (Max ∆) for Bcl-2 expression in T cells (MdFI) endpoint. In order to 
incorporate data from both SC and IV cohorts, the estimated bioavailability will be taken into 
account.  This bioavailability estimate will be provided by CPMS following instream PK analysis, 
utilising data up to and including Cohort 6 data, prior to the end of study database lock (DBL). 
• Four-parameters sigmoid Emax model is defined as, 
𝑀𝑎𝑥 ∆(𝐵𝑐𝑙−2 𝑒𝑥𝑝𝑟𝑒𝑠𝑠𝑖𝑜𝑛 𝑖𝑛 𝑇 𝑐𝑒𝑙𝑙𝑠) = (𝐸𝑜+ 𝑋𝛽1) + (𝐸𝑚𝑎𝑥+ 𝑋𝛽2) ∗ (
𝑑𝑜𝑠𝑒ℎ
𝐸𝐷50
ℎ+ 𝑑𝑜𝑠𝑒ℎ)+∈  
• Three-parameters Emax model is defined as, 
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𝑀𝑎𝑥 ∆(𝐵𝑐𝑙−2 𝑒𝑥𝑝𝑟𝑒𝑠𝑠𝑖𝑜𝑛 𝑖𝑛 𝑇 𝑐𝑒𝑙𝑙𝑠) = (𝐸𝑜+ 𝑋𝛽1) + (𝐸𝑚𝑎𝑥+ 𝑋𝛽2) ∗ (
𝑑𝑜𝑠𝑒
𝐸𝐷50 + 𝑑𝑜𝑠𝑒) + ∈  
Where - 
X is the continuous baseline value of Bcl-2 expression in T cells (loge scale), 
E0 is the minimum dose effect (placebo) (loge scale), 
Emax is maximum achievable effect above E0 (loge scale), 
ED50 is the dose which produces half of Emax, 
h is hill parameter determining the steepness of the dose response curve, 
∈ is random error assumed to be normally distributed with mean zero and constant variance (σ2) 
The final model will be selected based on the best fit to the data. 
Non-informative priors will be used in the analysis. The prior for E0, Emax, 𝛽1 and 𝛽2  will be 
normally distributed with mean 0 and a variance 106. 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. However, if a prior distribution appears not to be truly non-
informative then alternative prior distributions may be used. An inverse gamma prior with shape 
of 0.001 and scale of 0.001 will be used for the residual variance (σ2). 
Once the dose response model has been fitted, the posterior distribution of model parameter ED50 
will be summarized through mean, standard deviation and equal-tailed 95% credible intervals and 
the back transformed posterior distribution of model parameters E0 and Emax will be summarised 
through geometric means, standard deviation on loge scale and equal-tailed 95% credible intervals. 
The following will be calculated from the model: 
• For each study intervention: The posterior mean for Max ∆, 
• For each active study intervention: The posterior difference in Max ∆ for each dose vs 
placebo (GSK3888130B XX mg – Pooled placebo across cohorts), 
These values will then be back transformed to give: 
• For each study intervention: The posterior geometric mean for the ratio to baseline (for 
Max ∆),  
• For each active study intervention: The posterior geometric means of the ratio of each 
active dose to placebo.  
Equal-tailed 95% credible intervals will be presented for each of the above back transformed 
values. The dose response curve will be plotted for the geometric mean for the ratio to baseline 
(for Max ∆) with 95% credible intervals. The adjusted posterior geometric means and 95% credible 
intervals from the Bayesian MMRM analysis will also be included on this plot. 


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4.3.4. 
Target Engagement Biomarker Analyses 
4.3.4.1. 
Main analytical approach  
Free IL-7 levels will be derived from total IL-7 concentrations (named as Derived Free IL-7) over 
time using a nonlinear mixed effects modelling approach by the Clinical Pharmacology Modelling 
and Simulation (CPMS) department as described in Section 4.4.5. Summary outputs (geometric 
mean and 95% CIs) for derived free IL-7 inhibition will be reported by CPMS, separately to those 
outputs in the OPS but listed/cross-referenced in the CSR. 
 
 
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4.5. 
Other Analyses 
4.5.1. 
Subgroup analyses 
No formal subgroup analyses are planned. 
4.5.2. 
Other variables and/or parameters 
   
4.6. 
Dose Escalation 
The Dose Escalation Plan describes the responsibilities, conduct of the DEC and how the integrity 
of the study, including blinding, will be maintained.  
The site will provide safety reports (including CD4+ T cell counts) for each dose escalation. CPMS 
will provide PK outputs including PK profiles and derived PK parameters from non-
compartmental PK data analysis as permitted by data. 
Additionally, study Statistics and Programming team members will provide outputs for each DEC 
meeting.  describes the details of the analyses and outputs reviewed in the Dose Escalation 
meetings. 
4.7. 
Interim Analyses 
• Interim Analysis – 1 
The first Interim Analysis will be performed once a minimum of four participants dosed with 
GSK3888130B in cohort 4 have completed up to and including the Day 
 visit.  
During this interim analysis, safety data (including CD4+ T cells counts), immunogenicity, PD 
biomarker T cell Bcl-2, TE total IL-7 levels and PK data will be reviewed. 
Most of the outputs will be provided during the Cohort 4 DEC meeting. Additionally, study 
Statistics and Programming team members will provide Immunogenicity, Total IL-7 and PD 
biomarker T Cell Bcl-2 outputs for review.  describes the details of the analyses and outputs that 
will be provided for this interim analysis. 
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• Interim Analysis – 2 
The second Interim Analysis will be performed once all participants in cohort 6 have completed 
up to and including the Day 
visit for PK, TE total IL-7 levels, PD secondary endpoint T cell 
Bcl-2, 
, 
 
 
 and up to and including Day 
for safety endpoints. 
During this interim analysis, selected study population, safety data (including CD4+ T cells 
counts), immunogenicity, PK, TE total IL-7 levels, PD secondary endpoint T cell Bcl-2, cellular 
biomarkers, 
 
 
 
, 
 
 
 
 
 
 
 
will be reviewed.  describes the details of the analyses 
and outputs that will be provided for this interim analysis. 
• Early Data Extraction to CPMS 
CPMS will access unblinded data earlier than Interim Analysis – 2 reporting for the derivation of 
free IL-7 named as ‘Derived Free IL-7 and for PK/PD modelling to support dose selection in future 
studies as detailed in the Section 4.4.5. GSK Biostatistics will share PK concentrations and total 
IL-7 data with CPMS via the HARP system and the Randomization Office team will share 
randomization schedules upon request from GSK Biostatistics. Participants’ body weight data will 
be provided by Data management. Bcl-2 data will be accessed from External Alliance Portal (EAP) 
by CPMS.  
Table 3 
Summary of Dose Escalation and Interim Analysis 
Deliverables Domain 
Outputs 
Each DEC 
TE 
Summary plot of Total IL-7 Levels by 
dose (if data is available) 
Interim 
Analysis – 1 
1. Immunogenicity 
2. PD 
3. TE 
1. Summary of Immunogenicity Results 
2. Listing of Immunogenicity Results 
(only if positive immunogenicity 
results) 
3. Summary plot of T Cell Bcl-2 data 
4. Summary plot of Total IL-7 data 
Interim 
Analysis - 2 
1. Study Population 
2. Safety (including CD4+ cell 
counts) 
3. Immunogenicity 
Detailed list of outputs mentioned in OPS 
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Deliverables Domain 
Outputs 
4. PK 
5. PD Secondary endpoint (Bcl-2 
T Cell) 
6. TE (Total IL-7) 
7. 
 
  
8. 
 
9. 
 
10. 
 
11. 
 
12. 
 
Note: The subset of 
 endpoints 
will be descriptively summarized and plotted by GSK Biostatistics based on internal review and 
will be included in the second Interim analysis. 
4.8. 
Changes to Protocol Defined Analyses 
There were no changes or deviations to the originally planned statistical analysis specified in the 
protocol amendment 2 (Dated: 10-FEB-2022). 
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5. 
SAMPLE SIZE DETERMINATION 
Approximately 54 participants will be recruited to seven single ascending dose cohorts. Five 
participants will be randomized to either GSK3888130B or placebo in 3:2 ratio in cohorts 1 and 
2. Eight participants will be randomized to either GSK3888130B or placebo in 3:1 ratio in all other 
cohorts, 
 
 
  
No formal statistical techniques were used to calculate the sample size for this study; it has been 
determined to allow preliminary assessment of safety, tolerability, PK and PD. However, as a key 
secondary endpoint, considerations has been given to the ratio to baseline of the PD biomarker 
Bcl-2. It is assumed that this endpoint is loge normally distributed. Based on 6 participants from 
the highest GSK3888130B dosed cohort and 14 placebo participants pooled across all cohorts, the 
probability of different true inhibition (GSK3888130B vs. placebo) thresholds of interest is given 
in the table below. A non-informative prior distribution and a maximum between participant SD 
(loge scale) of 0.3 is assumed for both GSK3888130B and placebo arms. 
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6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Study Population Analyses 
A summary of the number of participants in each of the participant level analysis set will be 
provided. 
6.1.1. 
Participant Disposition 
A summary of the number and percentage of participants who completed the study as well as those 
who prematurely withdrew from the study will be provided. Reasons for study withdrawal will be 
summarized. 
6.1.2. 
Demographic and Baseline Characteristics 
The demographic characteristics including age, gender, ethnicity, height/weight at screening and 
race will be summarized with descriptive statistics. In addition, the following age categories will 
be summarized: 18-64, 65-84 and >=85 based on the Enrolled Analysis Set. 
6.1.3. 
Protocol Deviations 
Important protocol deviations will be summarized. 
Protocol deviations will be tracked by the study team throughout the conduct of the study. These 
protocol deviations will be reviewed to identify those considered as important as follows: 
o Data will be reviewed prior to unblinding and freezing the database to ensure all important 
deviations (where possible without knowing the study intervention details) are captured 
and categorised in the protocol deviations dataset.  
o The Statistics and Programming team will review any treatment deviations after unblinding 
and will notify the study team. This is also captured and categorised in the protocol 
deviations dataset. 
o This dataset will be the basis for the summaries of important protocol deviations. 
In addition to the overall summary of important protocol deviations, separate summaries will be 
produced for important protocol deviations related to COVID-19, and important protocol 
deviations not related to COVID-19 respectively. 
Visits and assessments missed due to the COVID-19 pandemic, together with visits conducted 
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6.1.4. 
Prior and Concomitant Medications 
Concomitant medications will be coded using the GSK Drug dictionary. The summary of 
concomitant medications will be provided by ingredient, i.e. multi-ingredient medications will be 
summarized for each individual ingredient rather than a combination of ingredients. The summary 
will be created using ingredient base names, i.e. ingredients with the same base name but different 
salt will appear under one base name in the summary. Anatomical Therapeutic Chemical (ATC) 
classifications will not appear in the summary.  
6.1.5. 
Additional Analyses Due to the COVID-19 Pandemic 
A participant is defined as having a suspected, probable or confirmed COVID-19 infection during 
the study if the answer is “Confirmed”, “Probable” or “Suspected” to the case diagnosis question 
from the COVID-19 coronavirus infection assessment eCRF (Electronic Case Record Form). 
Numbers of participants with a suspected, probable or confirmed COVID-19 infection, and of 
COVID-19 test results will be summarized. 


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6.2. 
Appendix 2 Data Derivations Rule 
6.2.2. 
Criteria for Potential Clinical Importance 
The following criteria will be used to flag potential clinical importance:  
Laboratory Values: 
Haematology 
Laboratory 
Parameter 
  
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Hematocrit  
Ratio of 1 
 
  
0.54 
Hemoglobin  
g/L  
 
 
180 
∆ from BL 
>25  
 
Lymphocytes  
x109/ L 
 
0.8 
 
Neutrophil Count  
x109/ L 
 
1.5 
  
Platelet Count  
x109/ L 
 
100 
550 
While Blood Cell 
Count (WBC) 
x109/ L 
 
3 
20 
Clinical Chemistry 
Laboratory 
Parameter 
Units 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Albumin  
g/L 
30 
 
Calcium 
mmol/L 
2 
2.75 
Creatinine 
umol/L 
 
>1.5xbaseline or increase from 
baseline ≥26 umol/L 
Glucose 
mmol/L 
3 
9 
Potassium 
mmol/L 
3 
5.5 
Sodium 
mmol/L 
130 
150 
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Liver Function 
Test Analyte 
Units 
Category 
Clinical Concern Range 
ALT/SGPT  
U/L 
High 
≥ 2x ULN 
AST/SGOT  
U/L 
High 
≥ 2x ULN 
AlkPhos  
U/L 
High 
≥ 2x ULN 
T Bilirubin  
µmol/L 
High 
≥ 1.5x ULN 
T. Bilirubin + ALT 
µmol/L 
 
U/L 
High 
1.5x ULN T. Bilirubin 
+ 
≥ 2x ULN ALT 
12 Lead ECG Values: 
ECG Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
PR Interval 
msec 
< 110 
> 220 
QRS Interval 
msec 
< 70 
> 120 
Absolute QTcF interval 
msec 
 
>450 
Increase from baseline 
QTcF 
msec 
 
>30 
Vital Signs Values: 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
< 85 
> 160 
Diastolic Blood Pressure 
mmHg 
< 45 
> 100 
Heart Rate 
bpm 
< 40 
> 110 
 
6.2.3. 
Study Day and Reference Dates 
The reference date is the study intervention start date and will be used to calculate study day. 
The study day is calculated as below: 
• 
Assessment Date = Missing              → Study Day = Missing  
• 
Assessment Date < Reference Date → Study Day = Assessment Date – Ref Date 
• 
Assessment Data ≥ Reference Date → Study Day = Assessment Date – Ref Date + 1 
6.2.4. 
Assessment Window  
For data summaries by visit, scheduled visits with nominal visit description as well as the worst-
case post baseline will be displayed. Unscheduled visits will not be displayed or slotted into a visit 
window but will be included in the derivation of worst-case post baseline assessment. All 
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6.2.5. 
Multiple measurements at One Analysis Time Point 
When multiple assessments are taken, the mean of the measurement will be calculated first and 
summary statistics will be based on the calculated mean. This will apply to both baseline and post 
baseline assessments. 
For lab tests on a study day, if multiple assessments are taken, the worst case will be used. 
6.2.6. 
Handling of Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in participant listing displays.   
• 
However, where necessary, display macros may impute dates as temporary 
variables for sorting data in listings only.  
• 
Imputed partial dates will not be used to derive study day, time to onset or 
duration (e.g., time to onset or duration of adverse events)  
Adverse 
Events 
• 
Partial dates for AE recorded in the CRF will be imputed using the following 
conventions: 
Missing start 
day 
If study intervention start date is missing (i.e. participant 
did not start study intervention), then set start date = 1st of 
month. 
Else if study intervention start date is not missing: 
o If month and year of start date = month and year of 
study intervention start date, then 
▪ 
If stop date contains a full date and stop date is 
earlier than study intervention start date, then 
set start date= 1st of month. 
▪ 
Else set start date = study intervention start 
date. 
Else set start date = 1st of month. 
Missing start 
day and month 
If study intervention start date is missing (i.e. participant 
did not start study intervention), then set start date = 
January 1. 
Else if study intervention start date is not missing: 
o If year of start date = year of study intervention start 
date, then 
▪ 
If stop date contains a full date and stop 
date is earlier than study intervention start 
date, then set start date = January 1. 
▪ 
Else set start date = study intervention start 
date. 
Else set start date = January 1. 


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Element 
Reporting Detail 
Missing end day  A '28/29/30/31' will be used for the day (dependent on the 
month and year). 
Missing end day 
and month 
No Imputation 
Completely 
missing 
start/end date 
No imputation 
Concomitant 
Medications 
• 
Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention: 
Missing start 
day 
If study intervention start date is missing (i.e. participant 
did not start study intervention), then set start date = 1st of 
month. 
Else if study intervention start date is not missing: 
o If month and year of start date = month and year of 
study intervention start date, then 
▪ 
If stop date contains a full date and stop date is 
earlier than study intervention start date, then 
set start date= 1st of month. 
▪ 
Else set start date = study intervention start 
date. 
Else set start date = 1st of month. 
Missing start 
day and month 
If study intervention start date is missing (i.e. participant 
did not start study intervention), then set start date = 
January 1. 
Else if study intervention start date is not missing: 
o If year of start date = year of study intervention start 
date, then 
▪ 
If stop date contains a full date and stop date is 
earlier than study intervention start date, then 
set start date = January 1. 
▪ 
Else set start date = study. intervention start 
date. 
Else set start date = January 1. 
Missing end day 
A '28/29/30/31' will be used for the day (dependent on the 
month and year).  
Missing end day 
and month 
A '31' will be used for the day and 'Dec' will be used for 
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Element 
Reporting Detail 
Completely 
missing start/end 
date 
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TRADEMARKS 
Trademarks of the GlaxoSmithKline Group 
of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
NONMEM 
 
 
SAS 
 
 
WinNonlin 
 


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7. 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GSK Document Number TMF-15650507. Study ID 213960: A Randomised, Double-Blind, 
Placebo Controlled, Single Dose Escalation Study to Evaluate Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of GSK3888130B in Healthy Participants aged 18-55 
inclusive. 21-MAR-2023. 
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